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WO2016002853A1 - Medicinal composition for treating diabetes - Google Patents

Medicinal composition for treating diabetes Download PDF

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Publication number
WO2016002853A1
WO2016002853A1 PCT/JP2015/069031 JP2015069031W WO2016002853A1 WO 2016002853 A1 WO2016002853 A1 WO 2016002853A1 JP 2015069031 W JP2015069031 W JP 2015069031W WO 2016002853 A1 WO2016002853 A1 WO 2016002853A1
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WO
WIPO (PCT)
Prior art keywords
group
methyl
amino
mmol
phenoxy
Prior art date
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PCT/JP2015/069031
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French (fr)
Japanese (ja)
Inventor
渉 宮永
瑞季 川平
佳代 松本
忠清 中川
宗孝 徳増
亘 竹下
Original Assignee
味の素株式会社
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Priority claimed from JP2014247621A external-priority patent/JP2017149647A/en
Application filed by 味の素株式会社 filed Critical 味の素株式会社
Publication of WO2016002853A1 publication Critical patent/WO2016002853A1/en

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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • 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
    • A61K31/351—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 not condensed with another ring
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    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • 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
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
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    • C07D407/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having an action of activating glycogen synthase and a pharmaceutical composition for treating diabetes containing the compound.
  • Non-Patent Documents 1 to 10 Non-Patent Documents 1 and 2.
  • the present invention has been intensively studied on the biaryloxymethylarene carboxylic acid compounds described in Patent Documents 1 to 10, and has a specific aryl group as the terminal aryl group of the biaryl ring located at one terminal, and another terminal.
  • a compound in which the aryl group located at is substituted with a specific aromatic heterocycle and the aromatic heterocycle has a specific amino group as an amino group has not only a very high ability to activate glycogen synthase but also a high glycogen accumulation action It was made based on the knowledge that the above-mentioned problems can be solved efficiently by using these compounds. That is, the present invention provides the following [1] to [10].
  • [1] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
  • These rings may be the same or different and may have one or a plurality of substituents, and the substituents include a halogen atom, a hydroxyl group, an alkyl group, an acetamido group, an aminocarbonyl group, and an alkoxy group.
  • R 1 and R 2 each independently represents a hydrogen atom, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group or an alkynyl group
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxy Represents an alkyl group, an alkoxyalkyl group or an alkynyl group
  • Ar 2 represents an aromatic heterocycle
  • L represents a bond, an alkylene group or a cycloalkylene group
  • X is a hydrogen atom, halogen atom, hydroxyl
  • the heterocyclic group of X may have a substituent, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, Thiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, imidazo [1,2-a] pyridine ring, or the following formulas (III-1) to (III-3) Represented by any of the formulas (In the formula, R 11 is represented by a hydrogen atom, an alkyl group or an alkylcarbonyl group; n 1 , n 2 and n 3 are represented by integers of 0-2.
  • substituents consist of a halogen atom, a hydroxyl group, an alkyl group, an acetamide group, an aminocarbonyl group, an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxyalkyl group, and a halogenoalkoxy group.
  • R 1 and R 2 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with one or more by deuterium;
  • R 3 and R 5 are each represented by a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,
  • R 4 and R 6 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, or a methoxymethyl group,
  • R 7 and R 8 represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • a pharmaceutical composition for treating diabetes comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
  • a glycogen synthase activator comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
  • FIG. 1 is a graph showing the evaluation results of glycogen synthase activity in mouse skeletal muscle of Test Example 4.
  • FIG. 2 is a graph showing the evaluation results of glycogen synthase activity in the mouse liver of Test Example 4.
  • FIG. 3 is a graph showing the results of Delta Fat mass in Test Example 5.
  • FIG. 4 is a graph showing the results of Delta Lean mass in Test Example 5.
  • FIG. 5 is a graph showing the relationship between time after glucose administration and blood glucose level in Test Example 5.
  • an “alkyl group” may be substituted with deuterium, and may be a linear or branched aliphatic hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. It is a monovalent group derived by removing one arbitrary hydrogen atom. Specific examples include groups such as methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl and the like.
  • alkyl group having 1 to 4 carbon atoms is an alkyl group having 1 to 4 carbon atoms.
  • the “alkylene group” is a divalent group that may be substituted with deuterium and is derived by removing two arbitrary hydrogen atoms from linear and branched aliphatic hydrocarbons having 1 to 6 carbon atoms. It is the basis of. Specific examples include groups such as methylene, ethylene, propylene, butylene. An alkylene group having 1 to 3 carbon atoms is preferable, and methylene or ethylene is more preferable.
  • the “cycloalkylene group” is a divalent group derived by removing two arbitrary hydrogen halves from a cyclic aliphatic hydrocarbon having 3 to 8 carbon atoms.
  • alkynyl group is a monovalent having at least one triple bond (two adjacent SP carbon atoms) among a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms. It is the basis of. Specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl and the like. Preferred is alkynyl having 2 to 3 carbon atoms, and more preferred is propargyl.
  • “Aromatic heterocycle” means a 5- to 7-membered monocycle composed of one or more atoms selected from the oxygen atom, sulfur atom, and nitrogen atom, or the same or different, and 1 to 6 carbon atoms.
  • Non-aromatic heterocycle or composed of 9 to 14 atoms consisting of one or more atoms selected from the same or different from oxygen, sulfur and nitrogen atoms and 1 to 13 carbon atoms A condensed polycyclic aromatic ring is meant.
  • a furan ring, a thiophene ring, a thiazole ring or a pyridine ring is preferable, and a furan ring, a thiophene ring or a thiazole ring is more preferable.
  • Halogen atom means a fluorine, chlorine, bromine, iodine atom or the like.
  • Alkoxy group means alkyl-O— having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2- Methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy , 3-hexyloxy and the like.
  • alkoxy having 1 to 3 carbon atoms Preferred is alkoxy having 1 to 3 carbon atoms.
  • the “halogenoalkyl group” means the alkyl group substituted with the halogen atom. Specific examples include groups such as monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl and trifluoroethyl. Preferred is an alkyl group having 1 to 4 carbon atoms with 1 to 3 halogen atoms, and more preferred is trifluoromethyl.
  • the “hydroxyalkyl group” means the alkyl group substituted with a hydroxyl group. Specific examples include groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypentyl, hydroxyhexyl and the like.
  • alkyl group having 1 to 3 carbon atoms with one hydroxy group and more preferred is hydroxymethyl.
  • alkoxyalkyl group means the alkyl group substituted with the alkoxy group. Specific examples include groups such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, and ethoxyethyl.
  • Preferred is an alkyl group having 1 to 3 carbon atoms with one alkoxy group having 1 or 2 carbon atoms, and more preferred is a memethoxymethyl group or a methoxyethyl group.
  • the “monoalkylamino group” is an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl group, and means alkyl-NH—.
  • the alkyl group is as described above. Preferably, it is a monoalkylamino group that is an alkyl group having 1 to 3 carbon atoms.
  • the “dialkylamino group” is an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the alkyl, and means (alkyl) 2 N—.
  • the alkyl groups may be the same or different. Specific examples include groups such as dimethylamino and diethylamino.
  • each alkyl group is a dialkylamino having 1 to 4 carbon atoms.
  • the “monoalkylaminocarbonyl group” is a carbonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—C (O) —. Specific examples include groups such as methylaminocarbonyl and ethylaminocarbonyl. Preferably, it is a monoalkylaminocarbonyl group having 1 to 3 carbon atoms in the alkyl group.
  • the “dialkylaminocarbonyl group” is a carbonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted with the alkyl, and means (alkyl) 2 NC (O) —.
  • alkyl groups may be the same or different. Specific examples include carbonyl groups with groups such as dimethylamino and diethylamino. Further, alkyls may share the same carbon atom to form a ring having 3 to 6 carbon atoms, and specific examples thereof include pyrrolidinylcarbonyl, piperidinylcarbonyl and the like.
  • the “monoalkylaminosulfonyl group” is a sulfonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—SO 2 —.
  • Specific examples include groups such as methylaminosulfonyl and ethylaminosulfonyl.
  • it is a monoalkylaminosulfonyl group having 1 to 3 carbon atoms in the alkyl group.
  • dialkylaminosulfonyl group is a sulfonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the alkyl, and means (alkyl) 2 —N—SO 2 —. .
  • the alkyl groups may be the same or different. Specific examples include sulfonyl groups with groups such as dimethylamino and diethylamino. In addition, alkyls may share the same carbon atom to form a ring having 3 to 6 carbon atoms, and specific examples include groups such as pyrrolidinylsulfonyl and piperidinylsulfonyl.
  • alkylsulfonyl group is a sulfonyl group substituted by the above alkyl and means alkyl-SO 2 —.
  • Alkyl is as described above. Preferred is alkylsulfonyl having 1 to 3 carbon atoms.
  • the “alkylsulfonylamino group” is a sulfonylamino group substituted by the above alkyl and means alkyl-SO 2 —NH—.
  • Alkyl is as described above. Preferred is alkylsulfonylamino having 1 to 3 carbon atoms.
  • alkylcarbonylamino group is a carbonylamino group substituted by the above alkyl and means alkyl-C (O) —NH—.
  • Alkyl is as described above.
  • Preferable is alkylcarbonylamino having 1 to 3 carbon atoms.
  • alkoxyalkyleneoxy group is a group in which the alkoxy group is attached to one of the alkylene groups and the oxygen atom is attached to the other, and means alkyl-O-alkylene-O—.
  • the alkyl group and the alkylene group are as described above.
  • Preferred is an alkoxyalkyleneoxy group having 1 to 3 carbon atoms in each of an alkoxy group and an alkylene group, and more preferred is methoxyethyleneoxy.
  • the “heterocyclic group” is a 5- to 7-membered non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from the same or different from an oxygen atom, a sulfur atom, and a nitrogen atom, or the aromatic heterocyclic group.
  • a group obtained by removing one hydrogen atom from a ring include groups in which one hydrogen atom has been removed from piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and the like.
  • the aromatic heterocyclic group means the aromatic heterocyclic ring.
  • R 1 and R 2 are a hydrogen atom or an alkyl group which may be substituted with deuterium.
  • the alkyl group which may be substituted with a hydrogen atom or deuterium having 1 to 3 carbon atoms is more preferable. That is, as R 1 and R 2 , a hydrogen atom, a methyl group or a CD 3 group (where D represents a deuterium atom) is particularly preferably used.
  • Ar 1 is a formula (II-3) to (II-5), it is more preferable that the following formula (II-3-1), (II-4-1) or (II-5-1) preferable.
  • R 3 and R 4 are preferably a hydrogen atom, an alkyl group, a cyano group, or a hydroxyalkyl group. More preferably, it is an alkyl group, a cyano group or a hydroxyalkyl group. As R 3 and R 4 , a hydrogen atom or a methyl group is particularly preferably used.
  • R 5 and R 6 are preferably a hydrogen atom, an alkyl group, a cyano group or an alkoxyalkyl group, and a hydrogen atom, having 1 to 3 carbon atoms.
  • R 5 and R 6 a hydrogen atom, a methyl group or a methoxymethyl group is particularly preferably used.
  • R 7 and R 8 are preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. preferable.
  • R 7 and R 8 a hydrogen atom or a methyl group is particularly preferably used.
  • the substituent is preferably a halogen atom, an alkyl group, a haloalkyl group or an alkoxy group, more preferably a halogen atom or an alkyl group having 1 to 3 carbon atoms.
  • the number of the substituents is preferably 1 to 3, more preferably 1 to 2.
  • Ar 2 is preferably a furan ring, a thiophene ring, a thiazole ring or a pyridine ring, and more preferably a furan ring, a thiophene ring or a thiazole ring.
  • a furan ring or a thiazole ring is particularly preferably used.
  • L is preferably an alkylene group or a cycloalkylene group, more preferably an alkylene group having 1 to 3 carbon atoms or a cycloalkylene group having 3 to 6 carbon atoms.
  • a methylene group, an ethylene group or a cyclohexylene group is particularly preferably used.
  • X represents an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminosulfonyl group, a monoalkylamino.
  • a sulfonyl group, a dialkylaminosulfonyl group, an alkoxyalkyleneoxy group or a heterocyclic group which may have a substituent is preferable, an alkoxy group having 1 to 3 carbon atoms, an amino group, or a carbon group having 1 to 3 carbon atoms. It is more preferably a monoalkylamino group, a dialkylamino group having 1 to 3 carbon atoms, an alkoxyalkyleneoxy group having 1 to 3 carbon atoms, or a heterocyclic group which may have a substituent.
  • the heterocyclic group of X is furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, pyridazine A ring, a pyrazine ring, an imidazo [1,2-a] pyridine ring, or any one of the formulas (III-1), (III-2) or (III-3) is preferred, and a furan ring, an oxazole ring, an oxadi An azole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, or any one of the formulas (III-1), (III-2), or (III-3) is more preferable.
  • the substituent is preferably a halogen atom, an alkyl group, a halogenoalkyl group, an alkoxy group or an alkoxyalkyl group, and is an alkyl group having 1 to 3 carbon atoms. It is more preferable.
  • the number of the substituents is more preferably 0 to 3, even more preferably 0 to 2.
  • unsubstituted or one is particularly preferably used.
  • n 1 , n 2 and n 3 are preferably integers of 0 to 3, more preferably integers of 0 to 2 preferable.
  • R 11 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • Y is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • Y a hydrogen atom, a methyl group or an ethyl group is particularly preferably used.
  • the compound represented by the formula (I) of the present invention can be produced, for example, by the following method.
  • Ar 1 , Ar 2 , L, X and Y are the same groups as defined in the formula (I).
  • M 1 , M 2 and M 3 are represented by the formula (A-1), the formula (A-3), the formula (B-1) or the formula (B-3).
  • R a and R b each independently represent a hydroxyl group, an alkoxy group, or the like, which are bonded together to form a cyclic group.
  • R c and R d each independently represents an alkyl group or a benzyl group.
  • the boron aryl reagent (A-1) having a corresponding Ar 1 can be converted into a boronic acid reagent (for example, R a and N 2 N-dimethylformamide) that can be coupled with a metal catalyst in a solvent such as N, N-dimethylformamide R b is a hydroxyl group) and is necessary in the presence of a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base such as sodium carbonate. Accordingly, the biaryl derivative (A-3) can be obtained by cooling and heating the reaction system.
  • a boronic acid reagent for example, R a and N 2 N-dimethylformamide
  • a metal catalyst in a solvent such as N, N-dimethylformamide R b is a hydroxyl group
  • a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferroc
  • the obtained biaryl derivative (A-3) is used in a solvent such as N, N-dimethylformamide in the presence of a corresponding ester derivative (A-4) having Ar 2 and a base such as potassium carbonate as necessary.
  • the ester derivative (A-5) can be obtained by cooling and heating the reaction system.
  • the resulting ester derivative (A-5) is cooled, heated or the like in the presence of a base such as sodium hydroxide in a solvent such as tetrahydrofuran or methanol, for example, to give a biarylcarboxylic acid.
  • a derivative (A-6) can be obtained.
  • the glycine derivative (B-3) can be obtained by cooling, heating and the like of the system.
  • the corresponding carboxylic acid derivative (A-6) can be derived into the amide ester derivative (C-2) using, for example, two production methods.
  • One is a production method using a condensing agent or the like.
  • Corresponding carboxylic acid derivative (A-6) such as, for example, corresponding glycine ester derivative (B-3) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride in a solvent such as dichloromethane
  • the amide ester derivative (C-2) can be obtained by cooling and heating the reaction system as necessary.
  • the corresponding carboxylic acid derivative (A-6) is cooled, heated, etc., if necessary, in the absence of a solvent or in the presence of an acid halogenating agent such as thionyl chloride in a solvent such as N, N-dimethylformamide.
  • the acid halogenated derivative (C-1) can be obtained by performing the above.
  • the obtained acid halogen derivative (C-1) is cooled and heated in a solvent such as dichloromethane in the presence of the corresponding glycine ester derivative (B-3) and a base such as diisopropylethylamine as necessary.
  • the amide ester derivative (C-2) can be obtained by performing etc.
  • the salt when the compound represented by the general formula (I) can form a salt form, the salt may be pharmaceutically acceptable, for example, an acidic group such as a carboxyl group in the formula
  • an acidic group such as a carboxyl group in the formula
  • salts with alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • aluminum salts such as calcium and magnesium
  • zinc salts triethylamine, ethanolamine
  • Examples thereof include salts with organic amines such as morpholine, piperidine and dicyclohexylamine, and salts with basic amino acids such as arginine and lysine.
  • sodium is preferable.
  • salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, benzoic acid
  • Organic carboxylic acids such as acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hybenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid
  • salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, among which hydrochloric acid and trifluoroacetic acid are preferably used.
  • the compound represented by the general formula (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersing agent, or a cation is obtained from other salt forms. It can also be obtained by exchange or anion exchange.
  • the compounds of the present invention also include solvates of compounds represented by general formula (I), such as hydrates, alcohol adducts and the like.
  • the compounds of the present invention can also be converted into prodrugs.
  • the prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention.
  • the active main body contains a carboxyl group or the like, an ester or amide thereof can be mentioned.
  • the active main body contains an amino group, its amide, carbamate and the like can be mentioned.
  • the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned.
  • the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.
  • the present invention includes all isotopes of the compound represented by the general formula (I).
  • the isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons).
  • Examples of isotopes contained in the compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, etc., and 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl and the like are included.
  • unstable radioisotopes that emit radioactivity and emit neutrons are useful in a tissue distribution test of pharmaceuticals or compounds.
  • Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity.
  • the isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
  • the pharmaceutical composition of the present invention can be suitably used for the treatment of diseases mediated by a decrease in glycogen synthase activity. In particular, it can be suitably used for the treatment of diabetes, especially type 2 diabetes and impaired glucose tolerance.
  • the pharmaceutical composition and glycogen synthase activator of the present invention vary depending on the administration subject, administration route, target disease, symptom, etc., but the administration route is preferably used by oral administration, and a single administration is effective.
  • the amount is preferably 1 mg to 1000 mg / person of the ingredient, more preferably 1 mg to 100 mg / person of the active ingredient, and it is desirable to administer this amount once to three times a day.
  • the pharmaceutical composition and the glycogen synthase activator of the present invention contain the compound represented by the above general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Various components used for example, pharmaceutically and physiologically acceptable solid or liquid carriers, additives and the like may be contained.
  • the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned.
  • additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.
  • the additive is not particularly limited as long as it is usually used for the purpose depending on the purpose. Specifically, for example, flavoring, sugar, sweetener, dietary fiber, vitamins, sodium glutamate Amino acids such as (MSG), nucleic acids such as inosine monophosphate (IMP), inorganic salts such as sodium chloride, and water.
  • the pharmaceutical composition and the glycogen synthase activator of the present invention can be used in a form that can be administered orally without any limitation on physical properties such as dry powder, paste, and solution.
  • examples of such orally administrable forms include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and troches.
  • the pharmaceutical composition and the glycogen synthase activator of the present invention can be used for injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions), and external preparations (eg, transdermal). Skin preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations, etc. .
  • injections eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions
  • external preparations eg, transdermal.
  • compositions and the glycogen synthase activator of the present invention include other diabetes therapeutic agents, diabetic complication therapeutic agents, hyperlipidemia therapeutic agents, antihypertensive agents, anti-obesity agents (hereinafter abbreviated as concomitant drugs). Can be used in combination.
  • concomitant drugs may be small molecules, high molecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), or vaccines. These concomitant drugs can be used alone or in combination of two or more.
  • the administration timing of the pharmaceutical composition, glycogen synthase activator, or concomitant drug of the present invention is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference.
  • Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, ⁇ -glucosidase, ⁇ -glucosidase , Acarbose, migli Tall, emiglitate), biguanides (eg, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues [sul
  • Step 2 Synthesis of Intermediate 1-A
  • the compound obtained in Step 1 (3.22 g, 12.8 mmol), ethyl 5-chloromethyl-2-furancarboxylate (2.42 g, 12.8 mmol), potassium carbonate ( 2.66 g, 19.3 mmol) was added N, N-dimethylformamide (hereinafter DMF) (100 mL), and the mixture was stirred overnight at room temperature.
  • DMF N, N-dimethylformamide
  • the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and thionyl chloride (10 mL) was added to the resulting residue, followed by stirring at room temperature for 2 hours.
  • the residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to give 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (2.80 g, 11.1 mmol), potassium carbonate (3.06 g, 22.2 mmol). ), Potassium iodide (catalytic amount) was added DMF (75 mL), and the mixture was stirred overnight at room temperature.
  • Step 2 Synthesis of Intermediate 4-A Compound (3.85 g, 15.2 mmol) obtained in Step 1, 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (3.85 g, 15. 2 mmol) and potassium carbonate (4.25 g, 30.8 mmol) were added DMF (75 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 2 Synthesis of 4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenol
  • the compound obtained in Step 1 (4.15 g, 18.4 mmol) was added to 1,4-dioxane (75 mL), Water (25 mL), 4-hydroxyphenylboronic acid (3.0 g, 22 mmol), sodium carbonate (3.9 g, 36.8 mmol) and PdCl 2 (dppf) (catalytic amount) were added and stirred at 100 ° C. for 2 hours. .
  • the insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain a residue.
  • Step 3 Synthesis of Intermediate 5-A
  • the compound obtained in Step 2 (2.0 g, 8.4 mmol), ethyl 2-bromomethylthiazole-4-carboxylate (2.1 g, 8.4 mmol), potassium carbonate ( DMF (75 mL) was added to 2.31 g (16.7 mmol) and stirred at room temperature overnight.
  • Step 2 Synthesis of Intermediate 6-A
  • the compound obtained in Step 1 (2.1 g, 8.1 mmol), ethyl 2-bromomethylthiazole-4-carboxylate (2.0 g, 8.1 mmol), potassium carbonate ( (2.33 g, 16.2 mmol) was added DMF (75 mL) and stirred at room temperature overnight.
  • the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • Methanol (30 mL), THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight.
  • Step 2 Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid ethyl ester 2-bromomethylthiazole-4-ethyl carboxylate (500 mg, 2 DMF (10 mL) was added to the compound obtained in Step 1 (524 mg, 2.00 mmol) and potassium carbonate (0.29 g, 2.1 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 3 Synthesis of Intermediate 7-A
  • the compound obtained in Step 2 (783 mg, 1.81 mmol) was dissolved in THF (14 mL) and methanol (4 mL), 1N aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred for 5 hours. did.
  • the residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
  • Step 2 Synthesis of Intermediate 8-A Ethyl 2-bromomethylthiazole-4-carboxylate (552 mg, 2.21 mmol), the compound obtained in Step 1 (676 mg, 2.21 mmol), potassium carbonate (0.32 g, 2.3 mmol) was added DMF (10 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate and hexane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 1 Synthesis of 2-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenoxy] methyl] thiazole-4-carboxylic acid ethyl ester 2-bromomethyl Ethyl thiazole-4-carboxylate (1.96 g, 7.83 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (1.90 g, 8 DMF (30 mL) was added to potassium carbonate (1.19 g, 8.61 mmol), and the mixture was stirred overnight at room temperature.
  • Step 2 Synthesis of Intermediate 9-A 7-Bromo-4,5-difluoro-benzofuran (100 mg, 0.257 mmol), compound obtained in Step 1 (48 mg, 0.214 mmol), PdCl 2 (dppf) (8 1.0 mg, 0.011 mmol) and 1,4-dioxane (2.3 ml) were added 1M aqueous potassium carbonate solution (0.78 mL), and the mixture was stirred at 100 ° C. for 1 hour. The mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 3 Synthesis of ethyl 2-[[4- (6,7-difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 2 (319 mg, 1.30 mmol) The compound obtained in Step 1 of Intermediate 4-A (358 mg, 1.43 mmol) was dissolved in DMF (13 mL).
  • Step 2 Synthesis of ethyl 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 1 (1.13 mg, 3.56 mmol) And the compound obtained in Step 1 of Intermediate 4-A (979 mg, 3.92 mmol) was dissolved in DMF (35 mL). To the solution was added potassium carbonate (1.20 g, 8.90 mmol), and the mixture was stirred at room temperature for 58 hours.
  • Step 3 Synthesis of Intermediate 11-A
  • the compound obtained in Step 2 (1.06 g, 2.61 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (6 mL), and 2N aqueous sodium hydroxide solution (2. 6 mL) was added and stirred at room temperature for 1.5 hours. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid (1.2 mL) and water (10 mL) were added to the resulting residue, and the resulting precipitate was filtered. The obtained precipitate was washed with water and dried to obtain the title compound.
  • the insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain a residue.
  • the obtained residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
  • Step 2 Synthesis of Intermediate 12-A
  • ethyl 5-chloromethyl-2-furancarboxylate (1.53 g, 8.5 mmol)
  • potassium carbonate 2.34 g, 17 mmol
  • DMF 75 mL
  • the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • Methanol (40 mL), THF (40 mL), 1N aqueous sodium hydroxide solution (40 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight.
  • the residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was washed with acetonitrile to give the title compound.
  • Step 2 Synthesis of Intermediate 17
  • thionyl chloride 5 mL
  • dichloromethane 30 mL
  • DIPEA diisopropylethylamine
  • Example 2 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 4 To A (98.4 mg, 0.250 mmol) was added 1 drop of thionyl chloride (1 mL) and DMF, and the mixture was stirred at 50 ° C. for 30 minutes. After removing the solvent under reduced pressure, the obtained residue was diluted with dichloromethane (2 mL), and the solution was diluted with DIPEA (0.044 mL, 0.25 mmol) and the compound obtained in Step 1 of Example 1 (112 mg,.
  • Step 2 2- [2- [tert-Butoxycarbonyl (methyl) amino] ethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] Synthesis of amino] acetic acid Intermediate 1-A (80.0 mg, 0.213 mmol) was dissolved in thionyl chloride (0.5 mL) and stirred at 40 ° C. for 1 hour. Intermediate 1-B was obtained by distilling off the solvent under reduced pressure.
  • Example 4 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.9 mL) was added, and the mixture was stirred at room temperature overnight. Further, 1N lithium hydroxide aqueous solution (0.4 mL) was added and stirred for 1 hour, and the reaction solution was neutralized with 1N trifluoroacetic acid aqueous solution. The solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Step 3 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[[5- (methoxymethyl) -1,2, Synthesis of 4-oxadiazol-3-yl] methyl] amino] benzyl acetate
  • the compound obtained in Step 2 (170 mg) was dissolved in DMF (1.5 mL) and 2-methoxyacetonitrile (0.180 mL, 2.
  • Example 5 Compound The compound obtained in Step 3 (10.5 mg, 0.0162 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.2 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution and distilling off the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound. Yield: 7.5 mg (0.0134 mmol) Yield: 83% MS (ESI) m / z 560 [M + H] +
  • Example 6 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (5 mL), 1N aqueous lithium hydroxide solution (2.5 mL) was added, and the mixture was stirred at room temperature for 50 minutes. Further, 1N lithium hydroxide aqueous solution (0.75 mL) and 1,4-dioxane (3 mL) were added and stirred at room temperature for 30 minutes, and the reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution.
  • Example 7 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid
  • the title compound was obtained in the same manner as in 4 except that intermediate 4-B was used instead of intermediate 1-B.
  • Example 9 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.213 mL) was added, and the mixture was stirred at room temperature overnight. Further, 1N aqueous lithium hydroxide solution (0.4 mL) was added and stirred overnight.
  • Example 10 2-[[4-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Intermediate 3 -A (51.0 mg, 0.130 mmol) was dissolved in thionyl chloride (0.5 mL) and stirred at 55 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and dichloromethane (2.6 mL) was added to the resulting residue to dissolve it.
  • Example 11 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(3-methyl-1,2,4- Oxadiazol-5-yl) methyl] amino] acetic acid
  • Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]- Synthesis of ethyl [(3-methyl-1,2,4-oxadiazol-5-yl) methyl] amino] acetate
  • DMF 5 mL
  • Example 11 Compound The compound obtained in Step 1 (48.6 mg, 0.0872 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.3 mL) was added and stirred at room temperature for 1 hour.
  • Example 12 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylpyrazol-3-yl) methyl Amino] acetic acid step 1 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylpyrazole-3- Synthesis of ethyl yl) methyl] amino] acetate Glycine ethyl ester hydrochloride (209 mg, 1.50 mmol) was dissolved in a mixture of THF (5 mL) and methanol (1.5 mL) to give 1-methylpyrazole-3-carbaldehyde.
  • Step 2 Synthesis of Compound of Example 12
  • the compound obtained in Step 1 (25.7 mg, 0.0463 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 13 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino] acetic acid step 1 Synthesis of benzyl 2- (tetrahydropyran-4-ylmethylamino) acetate Tetrahydropyran-4-ylmethanamine (0.184 mL, 1.50 mmol) was dissolved in acetonitrile (12 mL) and potassium carbonate (311 mg, 2.
  • Example 13 Compound The compound obtained in Step 2 (144 mg) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling. For 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 14 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoro Acetate Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid benzyl Synthesis of trifluoroacetate salt N, N-dimethyl-1,2-ethanediamine (44.1 mg, 0.500 mmol) was dissolved in acetonitrile (1.0 mL) and cooled to 0 ° C.
  • Example 16 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetic acid
  • the title compound was obtained by conducting the same operation as 15 using Intermediate 4-B instead of Intermediate 1-B.
  • Example 17 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetic acid
  • the title compound was obtained by the same procedures as for 15 except that intermediate 2-B was used instead of intermediate 1-B.
  • Example 18 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(3-methyl-1,2,4- Oxadiazol-5-yl) methyl] amino] acetic acid
  • Step 1 Synthesis of ethyl 2-[(3-methyl-1,2,4-oxadiazol-5-yl) methylamino] acetate
  • Glycine ethyl ester hydrochloride 5- (chloromethyl)-(68.5 mg, 0.491 mmol) was dissolved in acetonitrile (4 mL), potassium carbonate (204 mg, 1.47 mmol) was added, and the mixture was cooled to 0 ° C.
  • Example 18 Compound The compound obtained in Step 1 (60 mg, 0.25 mmol) was dissolved in dichloromethane (1 mL), and intermediate 4-B (82.2 mg, 0.200 mmol), DIPEA (0 .044 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, and the organic layer was washed with 0.5N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 19 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4- Oxadiazol-3-yl) methyl] amino] acetic acid
  • Step 1 Synthesis of ethyl 2-[[(5-methyl-1,2,4-oxadiazol-3-yl) methylamino] acetate
  • Example 20 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid
  • Step 1 Synthesis of benzyl 2- (pyrimidin-2-ylmethylamino) acetate
  • Glycine benzyl ester p-toluenesulfonate (506 mg, 1.50 mmol) was dissolved in a mixture of THF (5 mL) and methanol (1 mL) to give pyrimidyl- 2-Carbaldehyde (162 mg, 1.50 mmol) and a small amount of acetic acid were added, and the mixture was stirred overnight at room temperature.
  • Step 2 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate
  • the compound of Step 1 (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL), and Intermediate 1-B (94.8 mg, 0.240 mmol) and DIPEA (0.044 mL, 0.25 mmol) were added. Stir at room temperature for 2 hours.
  • Example 20 Compound The compound obtained in Step 2 (68.5 mg, 0.111 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.8 mL) and stirred at room temperature for 1 hour.
  • Example 21 Compound The compound of Step 1 (162 mg, 0.500 mmol) was dissolved in dichloromethane (5 mL), and Intermediate 1-B (80.0 mg, 0.200 mmol), DIPEA (0.044 mL, 0 .25 mmol) was added and stirred at room temperature for 1 hour.
  • the reaction solution was diluted with dichloromethane, and the organic layer was washed successively with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the residue obtained by removing the organic solvent under reduced pressure was dissolved in a mixed solution of dichloromethane (6 mL) and TFA (1 mL), and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 22 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid
  • Step 1 Synthesis of benzyl 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate
  • the compound obtained in Step 1 of 20 (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL), and intermediate 4-B (82.4 mg, 0.200 mmol), DIPEA (0.044 mL,.
  • Example 22 Compound The compound obtained in Step 1 (26 mg, 0.041 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution (0. 5 mL) was added and stirred at room temperature for 1 hour.
  • Example 23 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid
  • Step 1 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate 20
  • Step 1 compound (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL) and Intermediate 2-B (98.6 mg, 0.240 mmol), DIPEA (0.044 mL, 0.25 mmol) was added.
  • Example 23 Compound The compound obtained in Step 1 (45.6 mg, 0.0722 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour.
  • Example 24 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.205 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution, and the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 25 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid
  • Example 24 The title compound was obtained in the same manner as in the above except that Intermediate 4-B was used instead of Intermediate 1-B.
  • Example 26 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (0.8 mL), 1N aqueous lithium hydroxide solution (0.070 mL) was added, and the mixture was stirred at room temperature for 30 min. Furthermore, 1N lithium hydroxide aqueous solution (0.14 mL) was added and stirred. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • 1,4-dioxane 0.8 mL
  • 1N aqueous lithium hydroxide solution 0.070 mL
  • 1N lithium hydroxide aqueous solution (0.14 mL) was added and stirred.
  • the reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 27 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino ]
  • Acetic acid step 1 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (2-methoxyethoxy) ethyl] Synthesis of benzyl amino] acetate To a solution of 2- (2-methoxyethoxy) ethanamine (186 mg, 1.50 mmol) in acetonitrile (12 mL) was added potassium carbonate (207 mg, 1.50 mmol) and cooled to ⁇ 10 ° C.
  • Step 2 Synthesis of Example 27 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.8 mL) was added, and the mixture was stirred at room temperature for 1 hr. Furthermore, 1N lithium hydroxide aqueous solution (0.2 mL) was added and stirred. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 28 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino Acetic acid
  • the title compound was obtained in the same manner as the Example 27, except that the intermediate 4-B was used instead of the intermediate 1-B.
  • Example 29 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino Acetic acid
  • the title compound was obtained in the same manner as the Example 27, except that the intermediate 2-B was used instead of the intermediate 1-B.
  • Example 30 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(5-methyl-1,3,4- Oxadiazol-2-yl) methyl] amino] acetic acid
  • Step 1 Synthesis of benzyl 2-[(5-methyl-1,3,4-oxadiazol-2-yl) methylamino] acetate (5-methyl-1 , 3,4-oxadiazol-2-yl) methanamine (170 mg, 1.50 mmol) was dissolved in acetonitrile (12 mL), potassium carbonate (311 mg, 2.25 mmol) was added, and the mixture was cooled to ⁇ 10 ° C.
  • Example 30 Compound The compound obtained in Step 1 (54.6 mg, 0.103 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour.
  • Example 31 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylimidazol-4-yl) methyl ] Amino] acetic acid step 1 Synthesis of benzyl 2-[(1-methylimidazol-4-yl) methylamino] acetate 1-Methylimidazol-4-ylmethanamine (250 mg, 2.25 mmol) diluted with acetonitrile (10 mL) After adding potassium carbonate (466 mg, 3.37 mmol) and cooling to 0 ° C., benzyl 2-bromoacetate (0.390 mL, 2.47 mmol) diluted with acetonitrile (1 mL) was added dropwise and gradually added to room temperature.
  • Example 32 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-[(1-methylimidazol-4-yl) methyl Amino] acetic acid Intermediate 4-B (75.0 mg, 0.182 mmol) was dissolved in dichloromethane (2 mL). The compound obtained in Step 1 of Example 31 (96.5 mg, 0.372 mmol) and DIPEA (0.081 mL, 0.47 mmol) were added to the solution, and the mixture was stirred at room temperature for 16 hours.
  • Example 33 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoro Acetate Step 1 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid benzyl Synthesis of N, N-dimethyl-1,2-ethanediamine (54 ⁇ L, 0.50 mmol) was dissolved in acetonitrile (4 mL) and cooled to 0 ° C.
  • Example 33 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.173 mL) was added, and the mixture was stirred at room temperature for 40 minutes. After neutralizing the reaction solution, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 34 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetic acid Salt Step 1 4-[[(2-Benzyloxy-2-oxo-ethyl)-[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl Synthesis of tert-butyl] amino] methyl] piperidine-1-carboxylate Dissolve tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (107 mg, 0.50 mmol) in acetonitrile (4 mL) and bring to 0 ° C.
  • Step 2 2-[(1-tert-Butoxycarbonyl-4-piperidyl) methyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] Synthesis of amino] acetic acid
  • the compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 40 min.
  • Example 34 Compound To a dichloromethane solution (2 mL) of the compound obtained in Step 2, trifluoroacetic acid (0.103 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Step 2 2- [2- (tert-Butoxycarbonylamino) ethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] acetic acid
  • 1,4-dioxane 3 mL
  • 1N aqueous lithium hydroxide solution 0.8 mL
  • Example 35 Compound The compound obtained in Step 2 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (55 ⁇ L, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 36 2- [2-Aminoethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 35, using the intermediate 4-B instead of the intermediate 1-B.
  • the obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 38 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (ethylamino) ethyl] amino] acetic acid
  • Dichloromethane (2 mL) was added to trifluoroacetate intermediate 4-B (75.0 mg, 0.182 mmol) and dissolved.
  • the product obtained in Step 1 of Example 37 (91.8 mg, 0.273 mmol) and DIPEA (0.079 mL, 0.455 mmol) were added to the solution, and the mixture was stirred at room temperature for 18 hours.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to give a crude product (198 mg).
  • the obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.27 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form.
  • Example 39 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(imidazo [1,2-a] pyridine-6 -Ilmethyl) amino] acetic acid trifluoroacetate salt
  • Imidazo [1,2-a] pyridin-6-ylmethanamine 250 mg, 1.05 mmol was diluted with acetonitrile (6 mL) and potassium carbonate (218 mg, 1.58 mmol) After cooling to 0 ° C., benzyl 2-bromoacetate (0.18 mL, 1.6 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was stirred for 13 hours and a half while gradually returning to room temperature.
  • Example 40 2-[(2-Amino-2-methyl-propyl)-[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino ] Acetic acid trifluoroacetate step 1 Synthesis of benzyl 2-[[2- (tert-butoxycarbonylamino) -2-methyl-propyl] amino] acetate tert-butyl N- (2-amino-1,1-dimethyl- Ethyl) carbamate (250 mg, 1.33 mmol) was diluted with acetonitrile (6 mL), potassium carbonate (275 mg, 1.99 mmol) was added, cooled to 0 ° C., and then diluted with acetonitrile (1 mL) benzyl 2-bromoacetate (0.23 mL, 1.5 mmol) was added dropwise, and the mixture was stirred for 6 and a half hours while gradually returning to room
  • the obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 2 hours.
  • Example 41 2-[(2-Amino-2-methyl-propyl)-[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino ] Acetic acid trifluoroacetate Intermediate 4-B (75.0 mg, 0.182 mmol) was dissolved in dichloromethane (2 mL). To the solution, the product obtained in Step 1 of Example 40 (110 mg, 0.328 mmol) and DIPEA (0.095 mL, 0.55 mmol) were added and stirred at room temperature for 20 hours.
  • the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product.
  • the obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.28 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form.
  • Example 42 2-[(5-carbamoyl-2-thienyl) methyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino]
  • 5-formylthiophene-2-carboxylic acid (1.13 g, 7.24 mmol) was added THF (10 mL), oxalyl chloride (1.24 mL, 14.5 mmol), DMF (catalytic amount), and 2 hours at room temperature. Stir.
  • Step 2 2-[(1-tert-Butoxycarbonyl-4-piperidyl)-[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino Synthesis of acetic acid
  • the compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution, and the solvent was evaporated under reduced pressure.
  • Example 43 Compound To a dichloromethane solution (2 mL) of the compound obtained in Step 2, trifluoroacetic acid (0.104 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 44 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 43 by using the intermediate 4-B instead of the intermediate 1-B.
  • Example 45 2- [2-Diethylaminoethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] acetic acid trifluoroacetate step 1 Synthesis of benzyl 2- (2-diethylaminoethylamino) acetate N ′, N′-diethylethane-1,2-diamine (864 mg, 7.43 mmol) was diluted with acetonitrile (40 mL), and potassium carbonate (2.57 g , 18.6 mmol) After cooling to 0 ° C., benzyl 2-bromoacetate (1.28 mL, 8.18 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was stirred for 6 and a half hours while gradually returning to room temperature.
  • Example 46 2- [2-Diethylaminoethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate intermediate
  • Dichloromethane (2 mL) was added to 4-B (75.0 mg, 0.182 mmol) and dissolved, and the compound (86.6 mg, 0.328 mmol) obtained in Step 45 of Example 45 and DIPEA (0.079 mL) were dissolved. , 0.46 mmol) and stirred at room temperature for 15 hours.
  • the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product.
  • the obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.27 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 47 2-[[5-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Step 1 2- [ Synthesis of benzyl [5-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetate 7-Bromo-4,5- Difluoro-benzofuran (25 mg, 0.11 mmol), intermediate 16 (70 mg, 0.13 mmol), PdCl 2 (dppf) (5.0 mg, 0.0053 mmol) and 1,4-dioxane (1.2 ml) in 1M carbonic acid A potassium aqueous solution (0.4 ml) was added, and the mixture was stirred at 100 ° C.
  • Example 47 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.177 mL) was added, and the mixture was stirred at room temperature.
  • Example 48 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid As in Example 1 The title compound was obtained by performing the above procedure using Intermediate 9-B instead of Intermediate 1-B.
  • Example 49 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid As in Example 24 The title compound was obtained by performing the above procedure using Intermediate 9-B instead of Intermediate 1-B.
  • Example 50 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid
  • Example 4 The same operation was performed using intermediate 9-B instead of intermediate 1-B to give the title compound.
  • Example 51 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadi Azol-3-yl) methyl] amino] acetic acid
  • the title compound was obtained in the same manner as the Example 19 using the intermediate 9-B instead of the intermediate 4-B.
  • Example 52 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 33 using the intermediate 9-B instead of the intermediate 4-B.
  • Example 53 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Trifluoro Acetate step 1 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] benzyl acetate Synthesis of 2-pyrrolidin-1-ylethanamine (0.502 mL, 4.00 mmol) was diluted with acetonitrile (35 mL), potassium carbonate (552 mg, 4.00 mmol) was added, and the mixture was cooled to ⁇ 10 ° C.
  • Example 53 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (2 mL), 1N aqueous lithium hydroxide solution (0.81 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N trifluoroacetic acid and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 54 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Trifluoro Acetate
  • the title compound was obtained in the same manner as the Example 3 using the intermediate 9-B instead of the intermediate 1-B.
  • Example 55 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 34 using the intermediate 9-B instead of the intermediate 4-B.
  • Example 56 2-[[5-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 3 using the intermediate 14-B instead of the intermediate 1-B.
  • Example 57 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 53, except that the intermediate 6-B was used instead of the intermediate 9-B.
  • Example 58 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid
  • the title compound was obtained in the same manner as the Example 4 using the intermediate 6-B instead of the intermediate 1-B.
  • Example 59 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • thionyl chloride (1 mL) and DMF was added to Intermediate 13-A (90.8 mg, 0.250 mmol), and the mixture was stirred at 50 ° C. for 1 hr. After removing the solvent under reduced pressure, the obtained residue was diluted with dichloromethane (2 mL), and the solution was diluted with DIPEA (0.044 mL, 0.25 mmol) and the compound obtained in Step 1 of Example 1 (112 mg, 0.500 mmol).
  • Example 60 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 3 using the intermediate 13-B instead of the intermediate 1-B.
  • Example 61 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino ]
  • Acetic acid step 1 2-[[5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl)
  • benzyl amino] tetrahydropyran-4-ylmethanamine (461 mg, 4.00 mmol) was diluted with acetonitrile (35 mL), potassium carbonate (552 mg, 4.00 mmol) was added, and the mixture was cooled to ⁇ 10 ° C.
  • Example 62 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • the title compound was obtained by the same procedures as in Example 1, except that Intermediate 5-B was used instead of Intermediate 1-B.
  • Example 63 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid
  • the title compound was obtained in the same manner as the Example 4 using the intermediate 5-B instead of the intermediate 1-B.
  • Example 64 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] Acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 33, except that the intermediate 5-B was used instead of the intermediate 4-B.
  • Example 65 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid Trifluoroacetic acid salt
  • the title compound was obtained in the same manner as the Example 3 except that the intermediate 5-B was used instead of the intermediate 1-B.
  • Example 66 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetate
  • the title compound was obtained in the same manner as the Example 34, except that the intermediate 5-B was used instead of the intermediate 4-B.
  • Example 67 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 53, except that the intermediate 5-B was used instead of the intermediate 9-B.
  • Example 68 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid
  • the title compound was obtained in the same manner as the Example 24 using the intermediate 5-B instead of the intermediate 1-B.
  • Example 70 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(tetrahydropyran-4-ylmethyl) amino Acetic acid
  • the title compound was obtained in the same manner as the Example 61, except that the intermediate 5-B was used instead of the intermediate 13-B.
  • Example 71 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[(3-methyl-1,2 , 4-Oxadiazol-5-yl) methyl] amino] acetic acid
  • the title compound was obtained in the same manner as the example 18 except that the intermediate 5-B was used instead of the intermediate 4-B. .
  • Example 72 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2 , 4-Oxadiazol-3-yl) methyl] amino] acetic acid
  • the title compound was obtained in the same manner as the Example 19 using the intermediate 5-B instead of the intermediate 4-B. .
  • Example 73 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Example 1 The same operation was performed using intermediate 7-B instead of intermediate 1-B to obtain the title compound.
  • Example 74 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid
  • Example 24 The same operation was performed using intermediate 7-B instead of intermediate 1-B to obtain the title compound.
  • Example 75 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Tri Fluoroacetate
  • the title compound was obtained in the same manner as the Example 3 using the intermediate 7-B instead of the intermediate 1-B.
  • Example 76 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 34 using the intermediate 7-B instead of the intermediate 4-B.
  • Example 77 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Tri Fluoroacetate
  • the title compound was obtained in the same manner as the Example 53, using the intermediate 7-B instead of the intermediate 9-B.
  • Example 78 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid
  • Example 4 The title compound was obtained in the same manner as in 1 except that intermediate 7-B was used instead of intermediate 1-B.
  • Example 79 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxa Diazol-3-yl) methyl] amino] acetic acid
  • the title compound was obtained in the same manner as the Example 19 using the intermediate 7-B instead of the intermediate 4-B.
  • Example 80 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid
  • Example 20 The title compound was obtained in the same manner as in 1 except that intermediate 7-B was used instead of intermediate 1-B.
  • Example 81 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoroacetic acid Salt
  • the title compound was obtained in the same manner as the Example 33 using the intermediate 7-B instead of the intermediate 4-B.
  • Example 82 2- [2-Aminoethyl- [2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate
  • Example The title compound was obtained by the same operations as in 35, except that intermediate 7-B was used instead of intermediate 1-B.
  • Example 83 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) Amino] acetic acid step 1 2-[[2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxy Synthesis of ethyl) amino] benzyl acetate
  • Example 1 The compound obtained in step 1 of the compound was diluted with dichloromethane (4 mL) and DIPEA (30 ⁇ L, 0.17 mmol) and intermediate 8-B (50 mg, 0.11 mmol).
  • Example 83 Compound The compound obtained in Step 1 was dissolved in THF (1 mL) and methanol (0.2 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hr. . The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, and the residue obtained by evaporation under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
  • Example 84 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl ) Amino] acetic acid Trifluoroacetate
  • the title compound was obtained by carrying out the same operation as Example 33, using Intermediate 8-B instead of Intermediate 4-B.
  • Example 85 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidine-1 -Iylethyl) amino] acetic acid trifluoroacetate
  • the title compound was obtained by conducting the same operation as in Example 53, but using Intermediate 8-B instead of Intermediate 9-B.
  • Example 86 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino ) Ethyl] amino] acetic acid trifluoroacetic acid salt
  • the title compound was obtained by conducting the same operation as in Example 3, using Intermediate 8-B instead of Intermediate 1-B.
  • Example 87 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) Amino] acetic acid trifluoroacetate
  • the title compound was obtained in the same manner as the Example 34, except that the intermediate 8-B was used instead of the intermediate 4-B.
  • Example 88 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl ) Amino] acetic acid
  • the title compound was obtained in the same manner as in Example 4 except that intermediate 8-B was used instead of intermediate 1-B.
  • Example 90 2-[[2-[[4- (6,7-Difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 10-A (70.0 mg, 0.181 mmol) and the compound obtained in Step 1 of Example 1 (80.7 mg, 0.362 mmol) were dissolved in dichloromethane (2 mL), and WSC hydrochloride (69.5 mg, 0.362 mmol), HOBt ⁇ monohydrate (55.5 mg, 0.362 mmol) and DIPEA (0.095 mL, 0.54 mmol) were added, and the mixture was stirred at room temperature for 64 hours.
  • Example 91 2-[[5-[[4- (2-Cyano-4,5-difluoro-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Example 47 was performed using 7-bromo-4,5-difluoro-benzofuran-2-carbonitrile synthesized according to the method described in WO2013 / 065835 instead of 7-bromo-4,5-difluoro-benzofuran. To give the title compound.
  • Example 92 2-[[5-[[4- (4-Fluorobenzothiophen-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Similar to Example 47 The title compound was obtained by performing the procedure using 7-bromo-4-fluoro-benzothiophene instead of 7-bromo-4,5-difluoro-benzofuran.
  • Example 93 2-[[5-[[4- (7-Fluoro-1H-indol-4-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Example 47 The same operation was performed using 4-bromo-7-fluoro-1H-indole in place of 7-bromo-4,5-difluoro-benzofuran to obtain the title compound.
  • Example 94 2-[[5-[[4- (6,7-Difluoro-2-methyl-1H-indol-4-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino Acetic acid 4-Bromo-6,7-difluoro-2-methyl-1H—synthesized according to the method described in WO2013 / 065835 in place of 7-bromo-4,5-difluoro-benzofuran in the same manner as in Example 47 The title compound was obtained by using indole.
  • Example 95 2-[[2-[[4- (6,7-Difluoro-1-methyl-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • the compound (36.4 mg, 0.0726 mmol) was dissolved in THF (2 mL), sodium hydride (60% assay, 29 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 30 min. An excess amount of methyl iodide was added to the solution, and the mixture was stirred at room temperature for 1.5 hours.
  • Example 96 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid
  • Example 1 The same operation was performed using intermediate 11-B instead of intermediate 1-B to obtain the title compound.
  • Example 97 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid
  • Example 24 The same operation was performed using intermediate 11-B instead of intermediate 1-B to obtain the title compound.
  • Example 98 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Tri Fluoroacetate
  • the title compound was obtained in the same manner as the Example 53, using the intermediate 11-B instead of the intermediate 9-B.
  • Example 99 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Ethyl trifluoroacetate salt 1- (2-Aminoethyl) pyrrolidine (1.75 g, 15.3 mmol) was dissolved in acetonitrile (125 mL), potassium carbonate (2.12 g, 15.3 mmol) was added, Then, benzyl 2-bromoacetate (1.7 mL, 15 mmol) was added slowly. After stirring at the same temperature for 1 hour, the mixture was returned to room temperature and stirred overnight.
  • Example 101 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid ethyl trifluoroacetic acid Salt 4-Amino-1-tert-butoxycarbonylpiperidine (2.33 g, 11.6 mmol) was dissolved in acetonitrile (125 mL), potassium carbonate (1.6 g, 12 mmol) was added, and 2-bromo was added at ⁇ 20 ° C. Benzyl acetate (1.94 g, 11.6 mmol) was added slowly.
  • Example 103 Ethyl 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid hydrochloride
  • 4-amino-1-tert-butoxycarbonylpiperidine was replaced with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate and intermediate 4-B (474 mg, 1. 15 mmol) gave the trifluoroacetate salt of the title compound.
  • Example 104 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidylmethyl) amino] acetic acid ethyl hydrochloride
  • 4-amino-1-tert-butoxycarbonylpiperidine was replaced with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate, intermediate 1-B (454 mg, 1. 15 mmol) gave the trifluoroacetate salt of the title compound.
  • Test Example 1 Measurement of Glycogen Synthase Activity
  • Human GYS1 expression plasmid (pCDNA3.1 (+)-hGYS1) was constructed by the following method. Human GYS1 gene was amplified by PCR using human MTC Panel I (Takara Bio, 636742) as a template and using a cloning primer (Forward Primer: ATGCCTTTAAACCGCAC, Reverse Primer: TTAGTTACCGCTCTCGCGC).
  • the amplified human GYS1 sequence was used as a template, a restriction enzyme sequence was added by PCR using subcloning primers (Forward Primer: CCCTCGAGACCATGCCTTTAAAACCGCACTTT, Reverse Primer: GGTCTAGATTTAGTTTACGCTCTCTCGCCCAG), and then in vitro.
  • the human GYS1 gene was introduced into the Xho I site and Xba I site.
  • Glycogen synthase was prepared by the following method.
  • HEK293T cells derived from human kidney were seeded in a dish (Thermo Fisher Scientific, 168381) using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS, cultured overnight, and then Lipofectamine LTX (Invitrogen, 15338). ⁇ 100) and the human GYS1 expression vector was transfected according to the attached manual. After culturing at 37 ° C.
  • a lysis buffer 50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 2 mM EGTA, 100 mM NaF, 1 mM PMSF, 1 mM DTT, 1 ⁇ Complete (Roche, 1873580) And then homogenized, the mixture was centrifuged at 16000 ⁇ g and 4 ° C. for 15 minutes, and the precipitate fraction was re-dissolved by adding a lysis buffer and used for evaluation as glycogen synthase.
  • a lysis buffer 50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 2 mM EGTA, 100 mM NaF, 1 mM PMSF, 1 mM DTT, 1 ⁇ Complete (Roche, 1873580)
  • the mixture was centrifuged at 16000 ⁇ g and 4 ° C. for 15 minutes, and the precipitate fraction was re-dissolved by adding a lysis buffer and used for evaluation as glycogen synthas
  • glycogen synthase was measured by the following method. In a polystyrene 96-well plate, 30 mM glycylglycine (pH 7.3), 40 mM KCl, 20 mM MgCl 2 , 9.2% DMSO containing various concentrations of test compound, 10 mM Glucose-6-phosphate (Sigma Aldrich) , G7879) was added at 12 ⁇ L / well.
  • Test Example 2 PPAR- ⁇ Activity Measurement The activity of PPAR- ⁇ was measured according to a previous report (THE JOUNAL OF BIOLOGICAL CHEMISTRY Vol.270, No.22: 12953-12956, 1995).
  • the plasmid used for measuring the activity of PPAR- ⁇ was constructed as follows.
  • the PPAR- ⁇ receptor expression plasmid (hGR-GAL4-hPPAR ⁇ ) is the N-terminal region (1-76aa) of human GR at the Not I site and Sal I site of pExchange-1 Core Vector (Invitrogen, 21176), and GAL4 DNA of yeast.
  • the one into which the binding region (1-147aa) and the ligand binding region (167-468aa) of PPAR ⁇ were introduced was used.
  • the reporter assay was performed by the following method using CV-1 cells derived from African green monkey kidney.
  • CV-1 cells were seeded in a 96-well plate (Thermo Fisher Scientific, 4938) at 2 ⁇ 10 4 cells / well using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS. ° C., after 2 hours incubation under 5% CO 2, were transfected with plasmids. Transfection was performed using Lipofectamine LTX (Invitrogen, 15338-100) according to the attached manual. A plasmid solution was prepared by adding a mixed solution of a luciferase expression plasmid and a PPAR- ⁇ receptor expression plasmid to OPTI-MEM I (Invitrogen, 11058-021).
  • a test compound was added and cultured at 37 ° C. in the presence of 5% CO 2 for 18 to 20 hours. After completion of the culture, luciferase activity was measured by Luminescence JNR (ATTO) using Bright-Glo (Promega, E2620).
  • the PPAR- ⁇ induction magnification of the test compound was calculated by the following method. 100 (A / B) where A is the maximum PPAR- ⁇ activity at 3 ⁇ M, 10 ⁇ M, 30 ⁇ M, and 100 ⁇ M of the test compound, and B is the PPAR- ⁇ activity at 100 ⁇ M of the compound of WO / 2011/058154. ) As PPAR- ⁇ relative induction magnification (%). The results are shown in Tables 4-1 to 4-4.
  • Test Example 3 Evaluation of L6 Glycogen Accumulation Glycogen accumulation activity in skeletal muscle cells was evaluated according to the following method (ANALYTICAL BIOCHEMISTRY, Vol.261, 159-163, 1998) by the following method.
  • Rat skeletal muscle-derived L6 myoblasts (ATCC) were grown in 96-well collagen using growth medium ( ⁇ -MEM medium (Nacalai Tesque, 21444-05) containing 10% FBS) at 4 ⁇ 10 4 cells / 100 ⁇ L / well. After seeding on a coated plate (IWAKI, 4860-010) and culturing overnight at 37 ° C.
  • the culture medium is replaced with a differentiation medium ( ⁇ -MEM medium containing 2% FBS) and cultured for 3 days.
  • differentiation medium ⁇ -MEM medium containing 2% FBS
  • DMEM medium containing 0.1% BSA Gibco, 11966
  • test compound having a concentration twice the final evaluation concentration and 0.6%
  • Assay medium containing DMSO DMEM medium containing 0.1% BSA (Nacalai Tesque, 08456-65)
  • the assay medium containing / well was added at 15 ⁇ L / well to a final volume of 30 ⁇ L / well, and then incubated at 37 ° C.
  • the measured value (cpm) of a well containing only DMSO without a compound is A
  • the measured value of a well containing a compound and DMSO is B
  • WO / 2011/058154 Example 1
  • the measured value of a well containing 30 ⁇ M of the compound at a final concentration is shown.
  • the relative activity (%) was calculated as 100 ⁇ (BA) / (CA) with C.
  • the compound concentration causing an increase in activity by 50% was defined as EC50 and calculated by XLfit (idbs). The results are shown in Tables 5-1 and 5-2.
  • Test Example 4 Effect of Compound of the Present Invention on Glycogen Synthase Activity in Mouse Skeletal Muscle and Liver (Dose Response)
  • the dose-responsive activation effect of the compound of the present invention on glycogen synthase activity contained in mouse skeletal muscle and liver lysate was evaluated by the following method.
  • the animals used were C57BL / 6J mice (male) 8 to 14 weeks old, fasted overnight after habituation, skeletal muscle and liver were collected immediately, and stored at ⁇ 80 ° C. until the test was conducted. .
  • the tissue was crushed with 1 mL of 50 mM KF (pH 7.0), 10 mM EDTA (pH 7.0), and 10% Glycerol solution, and homogenated.
  • the compound of the present invention adjusted to each concentration, G6P (positive control, final concentration 3 mM), and UDP- [U-14C]
  • a reaction solution containing Glucose Perkin Elmer: NEC403 was added, and the reaction was performed at 30 ° C. for 20 minutes.
  • FIG. 1 shows the results of evaluation of the compound of Example 24 against glycogen synthase activity in mouse skeletal muscle
  • FIG. 2 shows glycogen synthase activity in mouse liver.
  • Test Example 5 Effect of Compound of the Present Invention on Glucose Tolerance Improvement Index (Dose Response) (Method)
  • the animals used were acclimated to 6-week-old C57BL / 6J (Lep ob / Lep ob ) mice (male), and then grouped using blood glucose level, body weight and the like as indices.
  • the body composition was analyzed by Echo MRI (Hitachi Aloka Medical Co., Ltd.) and used as the initial value.
  • FIG. 3 shows the Delta Fat mass of Result 1
  • FIG. 4 shows the Delta Lean mass of Result 1.
  • FIG. 5 shows the results of evaluation of the compound of Example 24 as result 2.
  • “*” indicates that p ⁇ 0.05, and “***” indicates that p ⁇ 0.001 (comparison with the vehicle-treated group by Dunnett's step-down method). by).
  • “##” indicates p ⁇ 0.01 (compared with the Vehicle-treated group by Student's t-test method).
  • FIG. 5 “*” indicates p ⁇ 0.05, and “**” indicates p ⁇ 0.01 (comparison with the Vehicle-treated group by Dunnett's step-down method). by).
  • “#” indicates p ⁇ 0.05, and “##” indicates p ⁇ 0.01 (comparison with the Vehicle-treated group by Student's t-test method). by).

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Abstract

The purpose of the present invention is to provide a novel compound that is capable of activating glycogen synthase but hardly activates receptor PPAR and shows high safety. Provided is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

Description

糖尿病治療用医薬組成物Pharmaceutical composition for the treatment of diabetes
　本発明は、グリコーゲンシンターゼ活性化作用を有する新規化合物及び該化合物を含有する糖尿病治療用医薬組成物に関する。 The present invention relates to a novel compound having an action of activating glycogen synthase and a pharmaceutical composition for treating diabetes containing the compound.
　糖尿病は、現代人にとって重要な病気であり、糖尿病の発生率は近年上昇傾向にある。糖尿病の発生のメカニズムにより多くの糖尿病治療薬が開発され、実際に使用されている。例えば、インスリン感受性増強剤、α－グリコシダーゼ阻害剤、インスリン分泌促進剤、インスリン製剤などが１種又は２種以上組み合わせて使用されている。
　このような状況下において、前記従来の糖尿病治療薬とは異なる新しいメカニズムであるグリコーゲンシンターゼを活性化させることによって、糖尿病を治療しようとする技術が開発されている。具体的には、グリコーゲンシンターゼを活性化できる化合物として、ビアリールオキシメチルアレーンカルボン酸が提案されている（特許文献１～１０、非特許文献１～２）。一方、新規な医薬的活性化合物については、病気治療についての所期の効果に加えて、副作用がないことなどの安全性が求められており、薬物の安全性評価として、ペルオキシソーム増殖薬－活性化受容体ＰＰＡＲ（peroxisome proliferator-activated receptor）について検討することが提案されている（非特許文献３）。これは、ラットなどの動物実験において、ある種の薬物投与によって肝肥大、肝内酵素の顕著な誘導、その薬物の長期投与によって肝癌が発生し、その変化の特徴は肝細胞内小器官ペルオキシソームの顕著な増殖である。薬物－肝ペルオキシソーム増殖－発肝癌の機構には、ペルオキシソーム増殖薬（PP）により活性化される受容体ＰＰＡＲ、とくにそのサブファミリーであるＰＰＡＲ－αが関与していることが明らかになっており、この現象は医薬品開発段階において、薬物の安全性評価（特に発癌性評価）において注目されているものである。 Diabetes is an important disease for modern people, and the incidence of diabetes has been increasing in recent years. Many antidiabetic drugs have been developed and actually used due to the mechanism of diabetes occurrence. For example, insulin sensitivity enhancers, α-glycosidase inhibitors, insulin secretagogues, insulin preparations and the like are used alone or in combination.
Under such circumstances, a technique for treating diabetes has been developed by activating glycogen synthase, which is a new mechanism different from the conventional antidiabetic drugs. Specifically, biaryloxymethylarene carboxylic acids have been proposed as compounds capable of activating glycogen synthase (Patent Documents 1 to 10, Non-Patent Documents 1 and 2). On the other hand, new pharmaceutically active compounds are required to have safety such as the absence of side effects in addition to their expected effects on disease treatment. Peroxisome proliferators-activated as a drug safety evaluation It has been proposed to examine the receptor PPAR (peroxisome proliferator-activated receptor) (Non-patent Document 3). In animal experiments such as in rats, hepatic hypertrophy, marked induction of enzymes in the liver, and long-term administration of the drug cause liver cancer. It is remarkable growth. It has been clarified that the mechanism of drug-hepatic peroxisome proliferation-hepatocarcinoma involves receptor PPAR activated by peroxisome proliferating drug (PP), in particular its subfamily PPAR-α, This phenomenon is attracting attention in drug safety evaluation (particularly carcinogenicity evaluation) in the drug development stage.
ＷＯ２００５／０００７８１WO2005 / 000781 ＷＯ２００６／０５８６４８WO2006 / 058648 ＷＯ２０１１／０５７９５６WO2011 / 057956 ＷＯ２０１１／０５７９５９WO2011 / 057959 ＷＯ２０１１／０５７９９３WO2011 / 057993 ＷＯ２０１１／０５８１２２WO2011 / 058122 ＷＯ２０１１／０５８１５４WO2011 / 058154 ＷＯ２０１１／０６７１７４WO2011 / 067174 ＷＯ２０１１／０６７２６６WO2011 / 067266 ＷＯ２０１３／０６５８３５WO2013 / 065835
　本発明は、グリコーゲンシンターゼ活性化能を有するが、受容体ＰＰＡＲが活性化されることが少なくて安全性が高い新規化合物を提供することを目的とする。
　本発明は、又、上記化合物を含有する医薬組成物を提供することを目的とする。
　本発明は、又、上記化合物を含有する糖尿病治療用医薬組成物を提供することを目的とする。
　本発明は、又、上記化合物を含有するグリコーゲンシンターゼ活性化剤を提供することを目的とする。 An object of the present invention is to provide a novel compound having glycogen synthase activating ability but having a high level of safety because the receptor PPAR is rarely activated.
Another object of the present invention is to provide a pharmaceutical composition containing the above compound.
Another object of the present invention is to provide a pharmaceutical composition for treating diabetes containing the above compound.
Another object of the present invention is to provide a glycogen synthase activator containing the above compound.
　本発明は、特許文献１～１０に記載のビアリールオキシメチルアレーンカルボン酸化合物について鋭意検討したところ、一方の末端に位置するビアリール環の末端アリール基として特定のアリール基を有し、かつ別の末端に位置するアリール基を特定の芳香族複素環に置換し、かつこの芳香族複素環がアミノ基として特定のアミノ基を有する化合物が、極めて高いグリコーゲンシンターゼ活性化能だけでなく、高いグリコーゲン蓄積作用を有することを見出し、これらの化合物を用いると上記課題を効率的に解決できるとの知見に基づいてなされたものである。
　すなわち、本発明は、下記［１］～［１０］を提供する。
［１］　下記一般式（Ｉ）で表される化合物又はその医薬上許容される塩。
　一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000004
 　（式中、Ａｒ1は、以下の式（II－１）～（II－５）のいずれかの環で表され、
Figure JPOXMLDOC01-appb-C000005
 The present invention has been intensively studied on the biaryloxymethylarene carboxylic acid compounds described in Patent Documents 1 to 10, and has a specific aryl group as the terminal aryl group of the biaryl ring located at one terminal, and another terminal. A compound in which the aryl group located at is substituted with a specific aromatic heterocycle and the aromatic heterocycle has a specific amino group as an amino group has not only a very high ability to activate glycogen synthase but also a high glycogen accumulation action It was made based on the knowledge that the above-mentioned problems can be solved efficiently by using these compounds.
That is, the present invention provides the following [1] to [10].
[1] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
Formula (I):
Figure JPOXMLDOC01-appb-C000004
 (Wherein Ar 1 is represented by any one of the following formulas (II-1) to (II-5):
Figure JPOXMLDOC01-appb-C000005
　これらの環は、同一又は異なっていてもよい、１又は複数の置換基を有していてもよく、該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基及びハロゲノアルコキシ基よりなる群から選択され；
　Ｒ1及びＲ2は、それぞれ独立して、水素原子、重水素で置換されていてもよいアルキル基、ハロゲノアルキル基、ヒドロキシアルキル基、アルコキシアルキル基又はアルキニル基を表し、
　Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、重水素で置換されていてもよいアルキル基、ハロゲノアルキル基、ヒドロキシアルキル基、アルコキシアルキル基又はアルキニル基を表し、
　Ａｒ2は、芳香族複素環を表し、
　Ｌは、結合、アルキレン基又はシクロアルキレン基を表し、
　Ｘは、水素原子、ハロゲン原子、ヒドロキシル基、アルコキシ基、ハロゲノアルキル基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アミノカルボニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アミノスルホニル基、モノアルキルアミノスルホニル基、ジアルキルアミノスルホニル基、アルキルスルホニル基、アルキルカルボニルアミノ基、アルキルスルホニルアミノ基、アルコキシアルキレンオキシ基又は置換基を有していてもよい、窒素原子、酸素原子及び硫黄原子から選ばれるヘテロ原子を少なくとも１つ有する５員～７員の複素環基を表し、
　これらの該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アルコキシアルキル基及びハロゲノアルコキシ基よりなる群から選択され；
　Ｙは、水素原子又はアルキル基で表される。） These rings may be the same or different and may have one or a plurality of substituents, and the substituents include a halogen atom, a hydroxyl group, an alkyl group, an acetamido group, an aminocarbonyl group, and an alkoxy group. , A cyano group, an amino group, a monoalkylamino group, a dialkylamino group and a halogenoalkoxy group;
R 1 and R 2 each independently represents a hydrogen atom, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group or an alkynyl group,
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxy Represents an alkyl group, an alkoxyalkyl group or an alkynyl group,
Ar 2 represents an aromatic heterocycle,
L represents a bond, an alkylene group or a cycloalkylene group,
X is a hydrogen atom, halogen atom, hydroxyl group, alkoxy group, halogenoalkyl group, cyano group, amino group, monoalkylamino group, dialkylamino group, aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group, amino A sulfonyl group, a monoalkylaminosulfonyl group, a dialkylaminosulfonyl group, an alkylsulfonyl group, an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxyalkyleneoxy group, or an optionally substituted nitrogen atom, oxygen atom and sulfur A 5- to 7-membered heterocyclic group having at least one heteroatom selected from atoms,
These substituents consist of a halogen atom, a hydroxyl group, an alkyl group, an acetamide group, an aminocarbonyl group, an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxyalkyl group, and a halogenoalkoxy group. Selected from the group;
Y is represented by a hydrogen atom or an alkyl group. )
［２］　一般式（Ｉ）中、Ｘの複素環基が、置換基を有していてもよい、フラン環、チオフェン環、オキサゾール環、イソオキサゾール環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、オキサジアゾール環、トリアゾール環、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、イミダゾ［１，２－ａ］ピリジン環、もしくは、以下の式（III－１）～（III－３）のいずれかの式で表わされ、
Figure JPOXMLDOC01-appb-C000006
 　（式中、Ｒ11が、水素原子、アルキル基又はアルキルカルボニル基で表され、
　ｎ1、ｎ2及びｎ3が、０～２の整数で表される。）
　これらの該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アルコキシアルキル基及びハロゲノアルコキシ基よりなる群から選択される［１］記載の化合物又はその医薬上許容される塩。 [2] In general formula (I), the heterocyclic group of X may have a substituent, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, Thiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, imidazo [1,2-a] pyridine ring, or the following formulas (III-1) to (III-3) Represented by any of the formulas
Figure JPOXMLDOC01-appb-C000006
 (In the formula, R 11 is represented by a hydrogen atom, an alkyl group or an alkylcarbonyl group;
n 1 , n 2 and n 3 are represented by integers of 0-2. )
These substituents consist of a halogen atom, a hydroxyl group, an alkyl group, an acetamide group, an aminocarbonyl group, an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxyalkyl group, and a halogenoalkoxy group. The compound according to [1] or a pharmaceutically acceptable salt thereof selected from the group.
［３］　一般式（Ｉ）中、Ａｒ2が、フラン環、チオフェン環、チアゾール環又はピリジン環である［１］又は［２］記載の化合物又はその医薬上許容される塩。
［４］　一般式（Ｉ）中、Ａｒ1が１又は２の置換基を有し、それらがハロゲン原子である［１］～［３］のいずれかに記載の化合物又はその医薬上許容される塩。
［５］　一般式（Ｉ）の式（II－１）～（II－５）中、
　Ｒ1及びＲ2が、水素原子、炭素数１～３のアルキル基又は重水素で１つ以上置換された炭素数１～３のアルキル基で表され、
　Ｒ3及びＲ5が、水素原子、ハロゲン原子又は炭素数１～３のアルキル基で表され、
　Ｒ4及びＲ6が、水素原子、炭素数１～３のアルキル基、シアノ基又はメトキシメチル基で表され、
　Ｒ7及びＲ8が、水素原子又は炭素数１～３のアルキル基を表す［１］～［４］のいずれかに記載の化合物又はその医薬上許容される塩。 [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein, in the general formula (I), Ar 2 is a furan ring, a thiophene ring, a thiazole ring or a pyridine ring.
[4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein Ar 1 has 1 or 2 substituents in general formula (I), and these are halogen atoms salt.
[5] In the formulas (II-1) to (II-5) of the general formula (I),
R 1 and R 2 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with one or more by deuterium;
R 3 and R 5 are each represented by a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,
R 4 and R 6 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, or a methoxymethyl group,
The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R 7 and R 8 represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
［６］　一般式（Ｉ）中、Ｌが、炭素数１～３のアルキレン基又は炭素数３～６のシクロアルキレン基を表す［１］～［５］のいずれかに記載の化合物又はその医薬上許容される塩。
［７］　一般式（Ｉ）の式（III－１）～（III－３）中、Ｒ11が水素原子であり、ｎ1、ｎ2及びｎ3が、０～１の整数である［１］～［６］のいずれかに記載の化合物又はその医薬上許容される塩。
［８］　下記の化合物からなる群から選択される［１］～［７］のいずれかに記載の化合物又はその医薬上許容される塩。
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピリジルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸、
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-フリルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、 [6] The compound according to any one of [1] to [5] or a pharmaceutical product thereof, wherein L in the general formula (I) represents an alkylene group having 1 to 3 carbon atoms or a cycloalkylene group having 3 to 6 carbon atoms Top acceptable salt.
[7] In the formulas (III-1) to (III-3) of the general formula (I), R 11 is a hydrogen atom, and n 1 , n 2, and n 3 are integers of 0 to 1 [1 ] To [6] or a pharmaceutically acceptable salt thereof.
[8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid,
2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid,
2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyridylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid,
2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid,
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
　2-[[5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid,
2-[[5-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid ,
2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid ,
2-[[2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
2-[[5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid,
2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid ,
2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid,
2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid,
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル) ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、及び
　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸
［９］　［１］～［８］のいずれかに記載の化合物又はその医薬上許容される塩を含有する医薬組成物。
［１０］　［１］～［８］のいずれかに記載の化合物又はその医薬上許容される塩を含有する糖尿病治療用医薬組成物。
［１１］　［１］～［８］のいずれかに記載の化合物又はその医薬上許容される塩を含有するグリコーゲンシンターゼ活性化剤。 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid ,
2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadiazole- 3-yl) methyl] amino] acetic acid,
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid ,
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid,
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid ,
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid,
2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid, and 2-[[2 -[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid [9] [1] to [8 ] The pharmaceutical composition containing the compound in any one of these, or its pharmaceutically acceptable salt.
[10] A pharmaceutical composition for treating diabetes comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
[11] A glycogen synthase activator comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
図１は、試験例４のマウス骨格筋におけるグリコーゲン合成酵素活性の評価結果を示すグラフである。FIG. 1 is a graph showing the evaluation results of glycogen synthase activity in mouse skeletal muscle of Test Example 4. 図２は、試験例４のマウス肝臓におけるグリコーゲン合成酵素活性の評価結果を示すグラフである。FIG. 2 is a graph showing the evaluation results of glycogen synthase activity in the mouse liver of Test Example 4. 図３は、試験例５におけるＤｅｌｔａ　Ｆａｔ　ｍａｓｓの結果を示すグラフである。FIG. 3 is a graph showing the results of Delta Fat mass in Test Example 5. 図４は、試験例５におけるＤｅｌｔａ　Ｌｅａｎ　ｍａｓｓの結果を示すグラフである。FIG. 4 is a graph showing the results of Delta Lean mass in Test Example 5. 図５は、試験例５におけるグルコース投与後の時間と血糖値との関係を示すグラフである。FIG. 5 is a graph showing the relationship between time after glucose administration and blood glucose level in Test Example 5.
　以下、式（Ｉ）の化合物の定義について説明する。
　本明細書中、「アルキル基」とは、重水素で置換されていてもよく、炭素数１～１２、好ましくは炭素数１～６の直鎖状および分枝鎖状の脂肪族炭化水素から任意の水素原子を１個除いて誘導される１価の基である。具体的には、メチル、エチル、イソプロピル、ブチル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔ－ブチル、ペンチル、イソペンチル、２，３－ジメチルプロピル、ヘキシルなどの基が挙げられる。好ましくは、炭素数１～４の アルキル基である。
　「アルキレン基」とは、重水素で置換されていてもよく、炭素数１～６の直鎖状および分岐鎖状の脂肪族炭化水素から任意の水素原子を２個除いて誘導される２価の基である。具体的には、メチレン、エチレン、プロピレン、ブチレンなどの基が挙げられる。好ましくは、炭素数１～３のアルキレン基であり、より好ましくは、メチレン又はエチレンである。
　「シクロアルキレン基」とは、炭素数３～８の環状の脂肪族炭化水素から任意の水素腹子を２個除いて誘導される２価の基である。具体的には、シクロプロピレン、シクロペンチレン、シクロへキシレンなどの基が挙げられる。好ましくは、シクロペンチレン又はシクロへキシレンである。
　「アルキニル基」とは、炭素数２～６の直鎖状または分枝鎖状の脂肪族炭化水素基のうち、少なくとも１個の三重結合（２個の隣接ＳＰ炭素原子）を有する、１価の基である。具体的には、エチニル、１－プロピニル、プロパルギル、３－ブチニルなどの基が挙げられる。好ましくは、炭素数２～３アルキニルであり、より好ましくは、プロパルギルである。
　「芳香族複素環」とは、酸素原子、硫黄原子、及び窒素原子から同一に又は異なって選択される１個以上の原子と１～６個の炭素原子からなる、５～７員の単環系非芳香族複素環又は酸素原子、硫黄原子、及び窒素原子から同一に又は異なって選択される１個以上の原子と１～１３個の炭素原子からなる、９～１４の原子から構成される縮合多環系芳香族環を意味する。具体的には、フラン環、チオフェン環、オキサゾール環、イソオキサゾール環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、オキサジアゾール環、オキサチアゾール環、トリアゾール環、テトラゾール環、ピリジン環、ピリジミン環、ピラジン環、キノリン環、イソキノリン環、ベンゾフラン環、ベンゾチオフェン環、イミダゾ［１，２－ａ］ピリジン環などが挙げられる。好ましくは、フラン環、チオフェン環、チアゾール環又はピリジン環であり、より好ましくは、フラン環、チオフェン環又はチアゾール環である。 Hereinafter, the definition of the compound of the formula (I) will be described.
In the present specification, an “alkyl group” may be substituted with deuterium, and may be a linear or branched aliphatic hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. It is a monovalent group derived by removing one arbitrary hydrogen atom. Specific examples include groups such as methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl and the like. Preferably, it is an alkyl group having 1 to 4 carbon atoms.
The “alkylene group” is a divalent group that may be substituted with deuterium and is derived by removing two arbitrary hydrogen atoms from linear and branched aliphatic hydrocarbons having 1 to 6 carbon atoms. It is the basis of. Specific examples include groups such as methylene, ethylene, propylene, butylene. An alkylene group having 1 to 3 carbon atoms is preferable, and methylene or ethylene is more preferable.
The “cycloalkylene group” is a divalent group derived by removing two arbitrary hydrogen halves from a cyclic aliphatic hydrocarbon having 3 to 8 carbon atoms. Specific examples include groups such as cyclopropylene, cyclopentylene and cyclohexylene. Preferably, it is cyclopentylene or cyclohexylene.
The “alkynyl group” is a monovalent having at least one triple bond (two adjacent SP carbon atoms) among a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms. It is the basis of. Specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl and the like. Preferred is alkynyl having 2 to 3 carbon atoms, and more preferred is propargyl.
“Aromatic heterocycle” means a 5- to 7-membered monocycle composed of one or more atoms selected from the oxygen atom, sulfur atom, and nitrogen atom, or the same or different, and 1 to 6 carbon atoms. Non-aromatic heterocycle or composed of 9 to 14 atoms consisting of one or more atoms selected from the same or different from oxygen, sulfur and nitrogen atoms and 1 to 13 carbon atoms A condensed polycyclic aromatic ring is meant. Specifically, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxadiazole ring, oxathiazole ring, triazole ring, tetrazole ring, pyridine ring, pyridimine Ring, pyrazine ring, quinoline ring, isoquinoline ring, benzofuran ring, benzothiophene ring, imidazo [1,2-a] pyridine ring and the like. A furan ring, a thiophene ring, a thiazole ring or a pyridine ring is preferable, and a furan ring, a thiophene ring or a thiazole ring is more preferable.
　「ハロゲン原子」とは、フッ素、塩素、臭素、ヨウ素原子などを意味する。
　「アルコキシ基」とは炭素数１～６のアルキル－Ｏ－を意味する。具体的には、メトキシ、エトキシ、１－プロポキシ、２－プロポキシ、ｎ－ブトキシ、ｉ－ブトキシ、ｓｅｃ－ブトキシ、ｔ－ブトキシ、１－ペンチルオキシ、２－ペンチルオキシ、３－ペンチルオキシ、２－メチル－１－ブチルオキシ、３－メチル－１－ブチルオキシ、２－メチル－２－ブチルオキシ、３－メチル－２－ブチルオキシ、２，２－ジメチル－１－プロピルオキシ、１－へキシルオキシ、２－へキシルオキシ、３－へキシルオキシなどの基が挙げられる。好ましくは炭素数１～３のアルコキシである。
　「ハロゲノアルキル基」とは、前記ハロゲン原子により置換された前記アルキル基を意味する。具体的には、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、モノフルオロエチル、トリフルオロエチルなどの基が挙げられる。好ましくは、ハロゲン原子が１～３付いた炭素数１～４の アルキル基であり、より好ましくは、トリフルオロメチルである。
　「ヒドロキシアルキル基」とは、ヒドロキシル基により置換された前記アルキル基を意味する。具体的には、ヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロキシペンチル、ヒドロキシへキシルなどの基が挙げられる。好ましくは、ヒドロキシ基がひとつ付いた炭素数１～３のアルキル基であり、より好ましくは、ヒドロキシメチルである。
　「アルコキシアルキル基」とは、前記アルコキシ基により置換された前記アルキル基を意味する。具体的には、メトキシメチル、メトキシエチル、メトキシプロピル、エトキシメチル、エトキシエチルなどの基が挙げられる。好ましくは、炭素数１及び２のアルコキシ基がひとつ付いた炭素数１～３のアルキル基であり、より好ましくは、メメトキシメチル又はメトキシエチル基である。 “Halogen atom” means a fluorine, chlorine, bromine, iodine atom or the like.
“Alkoxy group” means alkyl-O— having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2- Methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy , 3-hexyloxy and the like. Preferred is alkoxy having 1 to 3 carbon atoms.
The “halogenoalkyl group” means the alkyl group substituted with the halogen atom. Specific examples include groups such as monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl and trifluoroethyl. Preferred is an alkyl group having 1 to 4 carbon atoms with 1 to 3 halogen atoms, and more preferred is trifluoromethyl.
The “hydroxyalkyl group” means the alkyl group substituted with a hydroxyl group. Specific examples include groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypentyl, hydroxyhexyl and the like. Preferred is an alkyl group having 1 to 3 carbon atoms with one hydroxy group, and more preferred is hydroxymethyl.
The “alkoxyalkyl group” means the alkyl group substituted with the alkoxy group. Specific examples include groups such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, and ethoxyethyl. Preferred is an alkyl group having 1 to 3 carbon atoms with one alkoxy group having 1 or 2 carbon atoms, and more preferred is a memethoxymethyl group or a methoxyethyl group.
　「モノアルキルアミノ基」とは、窒素原子上の１個の水素原子が、前記アルキル基により置換されたアミノ基であり、アルキル－ＮH－を意味する。アルキル基は、前記の通りである。好ましくは、炭素数が１～３のアルキル基であるモノアルキルアミノ基である。
　「ジアルキルアミノ基」とは、窒素原子上の２個の水素原子が、前記アルキルによりそれぞれ置換されたアミノ基であり、（アルキル）2Ｎ－を意味する。アルキル基は同一または異なっていてもよい。具体的には、ジメチルアミノ、ジエチルアミノなどの基が挙げられる。好ましくは、それぞれのアルキル基の炭素数が１～４のジアルキルアミノである。 The “monoalkylamino group” is an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl group, and means alkyl-NH—. The alkyl group is as described above. Preferably, it is a monoalkylamino group that is an alkyl group having 1 to 3 carbon atoms.
The “dialkylamino group” is an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the alkyl, and means (alkyl) 2 N—. The alkyl groups may be the same or different. Specific examples include groups such as dimethylamino and diethylamino. Preferably, each alkyl group is a dialkylamino having 1 to 4 carbon atoms.
　「モノアルキルアミノカルボニル基」とは、窒素原子上の１個の水素原子が、前記アルキルにより置換されたアミノ基が付いたカルボニル基であり、アルキル－ＮＨ－Ｃ（Ｏ）－を意味する。具体的には、メチルアミノカルボニル、エチルアミノカルボニル等の基が挙げられる。好ましくは、アルキル基の炭素数が１～３のモノアルキルアミノカルボニル基である。
　「ジアルキルアミノカルボニル基」とは、窒素原子上の２個の水素原子が、前記アルキルによりそれぞれ置換されたアミノ基が付いたカルボニル基であり、（アルキル）2ＮＣ（Ｏ）－を意味する。アルキル基は同一または異なっていてもよい。具体的には、ジメチルアミノ、ジエチルアミノ等の基が付いたカルボニル基があげられる。また、アルキル同士が同じ炭素原子を共有し炭素数３～６の環を形成してもよく、具体的には、ピロリジニルカルボニル、ピペリジニルカルボニルなどの基が挙げられる。 The “monoalkylaminocarbonyl group” is a carbonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—C (O) —. Specific examples include groups such as methylaminocarbonyl and ethylaminocarbonyl. Preferably, it is a monoalkylaminocarbonyl group having 1 to 3 carbon atoms in the alkyl group.
The “dialkylaminocarbonyl group” is a carbonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted with the alkyl, and means (alkyl) 2 NC (O) —. The alkyl groups may be the same or different. Specific examples include carbonyl groups with groups such as dimethylamino and diethylamino. Further, alkyls may share the same carbon atom to form a ring having 3 to 6 carbon atoms, and specific examples thereof include pyrrolidinylcarbonyl, piperidinylcarbonyl and the like.
　「モノアルキルアミノスルホニル基」とは、窒素原子上の１個の水素原子が、前記アルキルにより置換されたアミノ基が付いたスルホニル基であり、アルキル－ＮＨ－ＳＯ2－を意味する。具体的には、メチルアミノスルホニル、エチルアミノスルホニル等の基が挙げられる。好ましくは、アルキル基の炭素数が１～３のモノアルキルアミノスルホニル基である。
　「ジアルキルアミノスルホニル基」とは、窒素原子上の２個の水素原子が、前記アルキルによりそれぞれ置換されたアミノ基が付いたスルホニル基であり、（アルキル）2－Ｎ－ＳＯ2－を意味する。アルキル基は同一または異なっていてもよい。具体的には、ジメチルアミノ、ジエチルアミノ等の基が付いたスルホニル基があげられる。また、アルキル同士が同じ炭素原子を共有し炭素数３～６の環を形成してもよく、具体的には、ピロリジニルスルホニル、ピペリジニルスルホニルなどの基が挙げられる。 The “monoalkylaminosulfonyl group” is a sulfonyl group having an amino group in which one hydrogen atom on a nitrogen atom is substituted with the alkyl, and means alkyl-NH—SO 2 —. Specific examples include groups such as methylaminosulfonyl and ethylaminosulfonyl. Preferably, it is a monoalkylaminosulfonyl group having 1 to 3 carbon atoms in the alkyl group.
The “dialkylaminosulfonyl group” is a sulfonyl group having an amino group in which two hydrogen atoms on a nitrogen atom are each substituted by the alkyl, and means (alkyl) 2 —N—SO 2 —. . The alkyl groups may be the same or different. Specific examples include sulfonyl groups with groups such as dimethylamino and diethylamino. In addition, alkyls may share the same carbon atom to form a ring having 3 to 6 carbon atoms, and specific examples include groups such as pyrrolidinylsulfonyl and piperidinylsulfonyl.
　「アルキルスルホニル基」とは、前記アルキルにより置換されたスルホニル基であり、アルキル－ＳＯ2－を意味する。アルキルは、前記の通りである。好ましくは、炭素数１～３のアルキルスルホニルである。
　「アルキルスルホニルアミノ基」とは、前記アルキルにより置換されたスルホニルアミノ基であり、アルキル－ＳＯ2－ＮＨ－を意味する。アルキルは、前記の通りである。好ましくは、炭素数１～３のアルキルスルホニルアミノである。
　「アルキルカルボニルアミノ基」とは、前記アルキルにより置換されたカルボニルアミノ基であり、アルキル－Ｃ（Ｏ）－ＮＨ－を意味する。アルキルは、前記の通りである。好ましくは、炭素数１～３のアルキルカルボニルアミノである。 The “alkylsulfonyl group” is a sulfonyl group substituted by the above alkyl and means alkyl-SO 2 —. Alkyl is as described above. Preferred is alkylsulfonyl having 1 to 3 carbon atoms.
The “alkylsulfonylamino group” is a sulfonylamino group substituted by the above alkyl and means alkyl-SO 2 —NH—. Alkyl is as described above. Preferred is alkylsulfonylamino having 1 to 3 carbon atoms.
The “alkylcarbonylamino group” is a carbonylamino group substituted by the above alkyl and means alkyl-C (O) —NH—. Alkyl is as described above. Preferable is alkylcarbonylamino having 1 to 3 carbon atoms.
　「アルコキシアルキレンオキシ基」とは、前記アルキレン基の一方に前記アルコシキ基が、もう一方に酸素原子が付いた基であり、アルキル－Ｏ－アルキレン－Ｏ－を意味する。アルキル基及びアルキレン基は、前記の通りである。好ましくは、アルコシキ基及びアルキレン基のそれぞれの炭素数が１～３のアルコキシアルキレンオキシ基であり、より好ましくは、メトキシエチレンオキシである。 The “alkoxyalkyleneoxy group” is a group in which the alkoxy group is attached to one of the alkylene groups and the oxygen atom is attached to the other, and means alkyl-O-alkylene-O—. The alkyl group and the alkylene group are as described above. Preferred is an alkoxyalkyleneoxy group having 1 to 3 carbon atoms in each of an alkoxy group and an alkylene group, and more preferred is methoxyethyleneoxy.
　「複素環基」とは、酸素原子、硫黄原子、及び窒素原子から同一に又は異なって選択される１～３個のヘテロ原子を含む５～７員の非芳香族複素環又は前記芳香族複素環から１個の水素原子を除いた基を意味する。非芳香族複素環基としては、具体的には、ピペリジン、ピペラジン、ピロリジン、テトラヒドロフラン、テトラヒドロピランなどから１個の水素原子を除いた基が挙げられる。芳香族複素環基としては、前記芳香族複素環を意味する。具体的には、チオフェン、フラン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、イミダゾール、ピラゾール、オキサジアゾール、オキサチアゾール、トリアゾール、ピリジン、ピリミジン、ピラジン、ピリダジンなどから１個の水素原子を除いた基が挙げられる。 The “heterocyclic group” is a 5- to 7-membered non-aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from the same or different from an oxygen atom, a sulfur atom, and a nitrogen atom, or the aromatic heterocyclic group. A group obtained by removing one hydrogen atom from a ring. Specific examples of the non-aromatic heterocyclic group include groups in which one hydrogen atom has been removed from piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and the like. The aromatic heterocyclic group means the aromatic heterocyclic ring. Specifically, a group in which one hydrogen atom is removed from thiophene, furan, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, oxathiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, etc. Is mentioned.
　以下、本発明の一般式（Ｉ）で表される化合物又はその医薬的に許容できる塩について説明する。
　一般式（Ｉ）において、Ａｒ1が、式（II－１）及び（II－２）である場合、Ｒ1及びＲ2は、水素原子、重水素で置換されていてもよいアルキル基であることが好ましく、水素原子、炭素数１～３の重水素で置換されていてもよいアルキル基がより好ましい。すなわち、Ｒ1及びＲ2としては、水素原子、メチル基又はＣＤ3基（ここで、Ｄは重水素原子を示す。）が特に好適に用いられる。
　Ａｒ1が式（II－３）～（II－５）である場合、以下の式（II－３－１）、（II－４－１）又は（II－５－１）であるのがより好ましい。
Figure JPOXMLDOC01-appb-C000007
 Hereinafter, the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof will be described.
In the general formula (I), when Ar 1 is a formula (II-1) or (II-2), R 1 and R 2 are a hydrogen atom or an alkyl group which may be substituted with deuterium. The alkyl group which may be substituted with a hydrogen atom or deuterium having 1 to 3 carbon atoms is more preferable. That is, as R 1 and R 2 , a hydrogen atom, a methyl group or a CD 3 group (where D represents a deuterium atom) is particularly preferably used.
When Ar 1 is a formula (II-3) to (II-5), it is more preferable that the following formula (II-3-1), (II-4-1) or (II-5-1) preferable.
Figure JPOXMLDOC01-appb-C000007
　式（II－３）及び（II－３－１）において、Ｒ3及びＲ4は、水素原子、アルキル基、シアノ基又はヒドロキシアルキル基であることが好ましく、水素原子、炭素数１～３のアルキル基、シアノ基又はヒドロキシアルキル基であることがより好ましい。Ｒ3およびＲ4としては、水素原子又はメチル基が特に好適に用いられる。
　式（II－４）及び（II－４－１）において、Ｒ5及びＲ6は、水素原子、アルキル基、シアノ基又はアルコキシアルキル基であることが好ましく、水素原子、炭素数１～３のアルキル基又はシアノ基又は炭素数１～３のアルコキシアルキル基であることがより好ましい。Ｒ5およびＲ6としては、水素原子、メチル基又はメトキシメチル基が特に好適に用いられる。
　式（II－５）及び（II－５－１）において、Ｒ7及びＲ8は、水素原子又はアルキル基であることが好ましく、水素原子又は炭素数１～３のアルキル基であることがより好ましい。Ｒ7およびＲ8としては、水素原子又はメチル基が特に好適に用いられる。
　Ａｒ1が置換基を有する場合、該置換基としては、ハロゲン原子、アルキル基、ハロアルキル基又はアルコキシ基がでることが好ましく、ハロゲン原子、炭素数１～３のアルキル基であることがより好ましい。該置換基の数は、１～３個が好ましく、１～２個がより好ましい。 In the formulas (II-3) and (II-3-1), R 3 and R 4 are preferably a hydrogen atom, an alkyl group, a cyano group, or a hydroxyalkyl group. More preferably, it is an alkyl group, a cyano group or a hydroxyalkyl group. As R 3 and R 4 , a hydrogen atom or a methyl group is particularly preferably used.
In the formulas (II-4) and (II-4-1), R 5 and R 6 are preferably a hydrogen atom, an alkyl group, a cyano group or an alkoxyalkyl group, and a hydrogen atom, having 1 to 3 carbon atoms. An alkyl group, a cyano group, or an alkoxyalkyl group having 1 to 3 carbon atoms is more preferable. As R 5 and R 6 , a hydrogen atom, a methyl group or a methoxymethyl group is particularly preferably used.
In the formulas (II-5) and (II-5-1), R 7 and R 8 are preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. preferable. As R 7 and R 8 , a hydrogen atom or a methyl group is particularly preferably used.
When Ar 1 has a substituent, the substituent is preferably a halogen atom, an alkyl group, a haloalkyl group or an alkoxy group, more preferably a halogen atom or an alkyl group having 1 to 3 carbon atoms. The number of the substituents is preferably 1 to 3, more preferably 1 to 2.
　一般式（Ｉ）において、Ａｒ2は、フラン環、チオフェン環、チアゾール環又はピリジン環であることが好ましく、フラン環、チオフェン環又はチアゾール環であることがより好ましい。Ａｒ2としては、フラン環又はチアゾール環が特に好適に用いられる。
　一般式（Ｉ）において、Ｌは、アルキレン基又はシクロアルキレン基であることが好ましい、炭素数１～３のアルキレン基又は炭素数３～６のシクロアルキレン基であることがより好ましい。Ｌとしては、メチレン基、エチレン基又はシクロへキシレン基が特に好適に用いられる。
　一般式（Ｉ）において、Ｘは、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アミノカルボニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アミノスルホニル基、モノアルキルアミノスルホニル基、ジアルキルアミノスルホニル基、アルコキシアルキレンオキシ基又は置換基を有していてもよい、複素環基であることが好ましく、炭素数１～３のアルコキシ基、アミノ基、炭素数１～３のモノアルキルアミノ基、それぞれ炭素数１～３のジアルキルアミノ基、それぞれ炭素数１～３のアルコキシアルキレンオキシ基又は置換基を有していてもよい、複素環基であることがより好ましい。 In the general formula (I), Ar 2 is preferably a furan ring, a thiophene ring, a thiazole ring or a pyridine ring, and more preferably a furan ring, a thiophene ring or a thiazole ring. As Ar 2 , a furan ring or a thiazole ring is particularly preferably used.
In the general formula (I), L is preferably an alkylene group or a cycloalkylene group, more preferably an alkylene group having 1 to 3 carbon atoms or a cycloalkylene group having 3 to 6 carbon atoms. As L, a methylene group, an ethylene group or a cyclohexylene group is particularly preferably used.
In the general formula (I), X represents an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an aminocarbonyl group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminosulfonyl group, a monoalkylamino. A sulfonyl group, a dialkylaminosulfonyl group, an alkoxyalkyleneoxy group or a heterocyclic group which may have a substituent is preferable, an alkoxy group having 1 to 3 carbon atoms, an amino group, or a carbon group having 1 to 3 carbon atoms. It is more preferably a monoalkylamino group, a dialkylamino group having 1 to 3 carbon atoms, an alkoxyalkyleneoxy group having 1 to 3 carbon atoms, or a heterocyclic group which may have a substituent.
　さらに、Ｘの複素環基は、フラン環、チオフェン環、オキサゾール環、イソオキサゾール環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、オキサジアゾール環、トリアゾール環、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、イミダゾ［１，２－ａ］ピリジン環、もしくは、式（III－１）、（III－２）又は（III－３）のいずれかが好ましく、フラン環、オキサゾール環、オキサジアゾール環、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、もしくは、式（III－１）、（III－２）又は（III－３）のいずれかがより好ましい。
　Ｘの複素環基が置換基を有する場合、該置換基としては、ハロゲン原子、アルキル基、ハロゲノアルキル基、アルコキシ基又はアルコキシアルキル基がでることが好ましく、炭素数１～３のアルキル基であることがより好ましい。該置換基の数は、０～３個がより好ましく、０～２個がさらにより好ましい。Ｘの複素環基としては、無置換又は１個が特に好適に用いられる。 Furthermore, the heterocyclic group of X is furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, pyridazine A ring, a pyrazine ring, an imidazo [1,2-a] pyridine ring, or any one of the formulas (III-1), (III-2) or (III-3) is preferred, and a furan ring, an oxazole ring, an oxadi An azole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, or any one of the formulas (III-1), (III-2), or (III-3) is more preferable.
When the heterocyclic group of X has a substituent, the substituent is preferably a halogen atom, an alkyl group, a halogenoalkyl group, an alkoxy group or an alkoxyalkyl group, and is an alkyl group having 1 to 3 carbon atoms. It is more preferable. The number of the substituents is more preferably 0 to 3, even more preferably 0 to 2. As the heterocyclic group for X, unsubstituted or one is particularly preferably used.
　Ｘが、式（III－１）、（III－２）及び（III－３）である場合、ｎ1、ｎ2及びｎ3は、０～３の整数が好ましく、０～２の整数がより好ましい。
　Ｘが、式（III－２）である場合、Ｒ11は、水素原子、アルキル基が好ましく、水素原子、炭素数１～３のアルキル基がより好ましい。
　一般式（Ｉ）において、Ｙは、水素原子又はアルキル基であることが好ましい、水素原子又は炭素数１～３のアルキル基であることがより好ましい。Ｙとしては、水素原子、メチル基又はエチル基が特に好適に用いられる。 When X is the formulas (III-1), (III-2) and (III-3), n 1 , n 2 and n 3 are preferably integers of 0 to 3, more preferably integers of 0 to 2 preferable.
When X is the formula (III-2), R 11 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
In general formula (I), Y is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. As Y, a hydrogen atom, a methyl group or an ethyl group is particularly preferably used.
　以下に、一般式（Ｉ）で表される化合物の好ましい具体例を列挙するが、本発明の化合物はこれらに限定されるものではない。
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸（実施例１）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸（実施例２）
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩（実施例３）
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸（実施例４）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸（実施例７）
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例９）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸（実施例２２）
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例２４）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例２５）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例３３） Although the preferable specific example of a compound represented by general formula (I) below is enumerated below, the compound of this invention is not limited to these.
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid (Example 1)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid (Example 2)
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid trifluoroacetic acid Salt (Example 3)
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid (Example 4)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid (Example 7)
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyridylmethyl) amino] acetic acid trifluoroacetate Example 9)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid (Example 22)
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] acetic acid (Example 24)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid (Example 25)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid trifluoroacetate ( Example 33)
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例３４）
　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジル)アミノ]酢酸　トリフルオロ酢酸塩（実施例４３）
　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジル)アミノ]酢酸　トリフルオロ酢酸塩（実施例４４）　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例４９）
　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例５３）
　2-[[5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩（実施例５６）
　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例５７）
　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸（実施例５８）
　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸（実施例５９） 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid trifluoroacetate Example 34)
2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidyl) amino] acetic acid trifluoroacetate (Examples) 43)
2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid trifluoroacetate (Examples) 44) 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid (Example 49)
2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid trifluoroacetate ( Example 53)
2-[[5-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Trifluoroacetate (Example 56)
2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Trifluoroacetate (Example 57)
2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid Example 58)
2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid (Examples) 59)
　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩（実施例６０）
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸（実施例６２）
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸（実施例６３）　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例６６）
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例６７）
　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例６８）
　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例７４）
　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸（実施例７９）
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸（実施例８３） 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Trifluoroacetate (Example 60)
2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid (Examples) 62)
2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid Example 63) 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetate (Example 66)
2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Trifluoroacetate (Example 67)
2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid (Examples) 68)
2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid (Example 74)
2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadiazole- 3-yl) methyl] amino] acetic acid (Example 79)
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid (Example 83)
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル) ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例８５）
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例８７）
　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸（実施例８８）
　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸（実施例９７）
　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩（実施例９８） 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid trifluoroacetate salt (Example 85)
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetate (Example 87)
2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid (Example 88)
2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid (Example 97)
2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid trifluoroacetate (Example 98)
　以下に、本発明化合物の製造法について記載する。
　本発明の式（Ｉ）で表される化合物は、例えば以下の方法によって製造することができる。
　以下の反応式において、Ａｒ1、Ａｒ2、Ｌ、Ｘ及びＹは、前記式（Ｉ）における定義と同一の基である。また、反応式（Ａ）～（Ｄ）において、Ｍ1、Ｍ2及びＭ3は、式（Ａ－１）、式（Ａ－３）、式（Ｂ－１）又は式（Ｂ－３）で表される化合物と結合できる官能基（例えば、ハロゲン原子を示す。）を示し、Ｒa及びＲbは、それぞれ独立して、ヒドロキシル基又はアルコキシ基などを示し、それらは一緒になって環状になってもよく、Ｒc及びＲdは、それぞれ独立して、アルキル基又はベンジル基などを示す。 Below, it describes about the manufacturing method of this invention compound.
The compound represented by the formula (I) of the present invention can be produced, for example, by the following method.
In the following reaction formula, Ar 1 , Ar 2 , L, X and Y are the same groups as defined in the formula (I). In the reaction formulas (A) to (D), M 1 , M 2 and M 3 are represented by the formula (A-1), the formula (A-3), the formula (B-1) or the formula (B-3). And R a and R b each independently represent a hydroxyl group, an alkoxy group, or the like, which are bonded together to form a cyclic group. R c and R d each independently represents an alkyl group or a benzyl group.
ビアリールカルボン酸誘導体（Ａ－６）の製造方法
（反応式Ａ）
Figure JPOXMLDOC01-appb-C000008
 Method for producing biarylcarboxylic acid derivative (A-6) (Scheme A)
Figure JPOXMLDOC01-appb-C000008
　対応するＡｒ1を有するハロゲンアリール試薬（Ａ－１）を、例えば、Ｎ，Ｎ－ジメチルホルムアミドなどの溶媒中、金属触媒などを用いてカップリング反応が可能なボロン酸試薬（例えば、Ｒa及びＲbがヒドロキシル基）であるフェノール誘導体（Ａ－２）と［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（II）などのパラジウム触媒と炭酸ナトリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、ビアリール誘導体（Ａ－３）を得ることができる。得られたビアリール誘導体（Ａ－３）を、例えば、Ｎ，Ｎ－ジメチルホルムアミドなどの溶媒中、対応するＡｒ2を有するエステル誘導体（Ａ－４）と炭酸カリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでエステル誘導体（Ａ－５）を得ることができる。得られたエステル誘導体（Ａ－５）を、例えば、テトラヒドロフラン及びメタノールなどの溶媒中、水酸化ナトリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、ビアリールカルボン酸誘導体（Ａ－６）を得ることができる。 The boron aryl reagent (A-1) having a corresponding Ar 1 can be converted into a boronic acid reagent (for example, R a and N 2 N-dimethylformamide) that can be coupled with a metal catalyst in a solvent such as N, N-dimethylformamide R b is a hydroxyl group) and is necessary in the presence of a palladium catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base such as sodium carbonate. Accordingly, the biaryl derivative (A-3) can be obtained by cooling and heating the reaction system. The obtained biaryl derivative (A-3) is used in a solvent such as N, N-dimethylformamide in the presence of a corresponding ester derivative (A-4) having Ar 2 and a base such as potassium carbonate as necessary. Then, the ester derivative (A-5) can be obtained by cooling and heating the reaction system. The resulting ester derivative (A-5) is cooled, heated or the like in the presence of a base such as sodium hydroxide in a solvent such as tetrahydrofuran or methanol, for example, to give a biarylcarboxylic acid. A derivative (A-6) can be obtained.
グリシンエステル誘導体（Ｂ－３）の製造方法
（反応式Ｂ）
Figure JPOXMLDOC01-appb-C000009
 　対応するアミン誘導体及びその塩（Ｂ－１）を、例えば、アセトニトリルなどの溶媒中、ブロモベンジル酢酸などの対応するエステル誘導体（Ｂ－２）と炭酸カリウムなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、グリシン誘導体（Ｂ－３）を得ることができる。 Glycine ester derivative (B-3) of the production how (Scheme B)
Figure JPOXMLDOC01-appb-C000009
 Reaction of the corresponding amine derivative and its salt (B-1) with a corresponding ester derivative (B-2) such as bromobenzylacetic acid in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, if necessary. The glycine derivative (B-3) can be obtained by cooling, heating and the like of the system.
アミドエステル誘導体（Ｃ－２）の製造方法
（反応式Ｃ）
Figure JPOXMLDOC01-appb-C000010
 Method for producing amide ester derivative (C-2) (reaction formula C)
Figure JPOXMLDOC01-appb-C000010
　対応するカルボン酸誘導体（Ａ－６）は、例えば２つの製造方法を用いてアミドエステル誘導体（Ｃ－２）へと誘導することができる。１つは縮合剤など用いて製造する方法である。対応するカルボン酸誘導体（Ａ－６）を、例えば、ジクロロメタンなどの溶媒中、対応するグリシンエステル誘導体（Ｂ－３）と１－エチル－３－（３－ジメチルアミノプロピル）－カルボジイミド　塩酸塩などの縮合剤とジイソプロピルエチルアミンなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでアミドエステル誘導体（Ｃ－２）を得ることができる。また、別の製造方法としては、酸ハロゲン化体（Ｃ－１）を経由して製造できる。対応するカルボン酸誘導体（Ａ－６）を、例えば、無溶媒又はＮ，Ｎ－ジメチルホルムアミドなどの溶媒中、塩化チオニルなどの酸ハロゲン化剤存在下、必要に応じて反応系を冷却、加熱等を行うことで酸ハロゲン化誘導体（Ｃ－１）を得ることができる。得られた酸ハロゲン誘導体（Ｃ－１）を、例えば、ジクロロメタンなどの溶媒中、対応するグリシンエステル誘導体（Ｂ－３）とジイソプロピルエチルアミンなどの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことでアミドエステル誘導体（Ｃ－２）を得ることができる。 The corresponding carboxylic acid derivative (A-6) can be derived into the amide ester derivative (C-2) using, for example, two production methods. One is a production method using a condensing agent or the like. Corresponding carboxylic acid derivative (A-6) such as, for example, corresponding glycine ester derivative (B-3) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride in a solvent such as dichloromethane In the presence of a condensing agent and a base such as diisopropylethylamine, the amide ester derivative (C-2) can be obtained by cooling and heating the reaction system as necessary. As another production method, it can be produced via an acid halide (C-1). The corresponding carboxylic acid derivative (A-6) is cooled, heated, etc., if necessary, in the absence of a solvent or in the presence of an acid halogenating agent such as thionyl chloride in a solvent such as N, N-dimethylformamide. The acid halogenated derivative (C-1) can be obtained by performing the above. The obtained acid halogen derivative (C-1) is cooled and heated in a solvent such as dichloromethane in the presence of the corresponding glycine ester derivative (B-3) and a base such as diisopropylethylamine as necessary. The amide ester derivative (C-2) can be obtained by performing etc.
アミドカルボン酸誘導体（Ｄ－１）の製造方法
（反応式Ｄ）
Figure JPOXMLDOC01-appb-C000011
 　対応するアミドエステル誘導体（Ｃ－２）を、例えば、テトラヒドロフラン及びメタノールなどの溶液中、水酸化ナトリウムまたは水酸化リチウム水溶液などの塩基存在下、必要に応じて反応系を冷却、加熱等を行うことで、アミドカルボン酸誘導体（Ｄ－１）を得ることができる。 Process for producing amidocarboxylic acid derivative (D-1) (reaction formula D)
Figure JPOXMLDOC01-appb-C000011
 The corresponding amide ester derivative (C-2) is cooled, heated, etc., if necessary, in a solution such as tetrahydrofuran and methanol in the presence of a base such as aqueous sodium hydroxide or lithium hydroxide. Thus, an amide carboxylic acid derivative (D-1) can be obtained.
　本発明において、一般式（Ｉ）で表される化合物が塩の形態を成し得る場合、その塩は医薬的に許容しうるものであればよく、例えば、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩が挙げられるが、中でもナトリウムを用いるのが好ましい。
　式中に塩基性基が存在する場合の塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸などの無機酸との塩、酢酸、トリフルオロ酢酸、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機スルホン酸との塩が挙げられるが、中でも塩酸、トリフルオロ酢酸を用いるのが好ましい。
　塩を形成する方法としては、一般式（Ｉ）で表される化合物と必要な酸または塩基とを適当な量比で溶媒、分散剤中で混合することや、他の塩の形より陽イオン交換または陰イオン交換を行うことによっても得られる。
　本発明の化合物には、一般式（Ｉ）で表される化合物の溶媒和物、例えば水和物、アルコール付加物等も含まれる。 In the present invention, when the compound represented by the general formula (I) can form a salt form, the salt may be pharmaceutically acceptable, for example, an acidic group such as a carboxyl group in the formula For acidic groups in the presence of ammonium salts, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, aluminum salts, zinc salts, triethylamine, ethanolamine, Examples thereof include salts with organic amines such as morpholine, piperidine and dicyclohexylamine, and salts with basic amino acids such as arginine and lysine. Among them, sodium is preferable.
When a basic group is present in the formula, for a basic group, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, benzoic acid Organic carboxylic acids such as acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hybenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid And salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, among which hydrochloric acid and trifluoroacetic acid are preferably used.
As a method for forming a salt, the compound represented by the general formula (I) and a necessary acid or base are mixed in an appropriate amount ratio in a solvent or a dispersing agent, or a cation is obtained from other salt forms. It can also be obtained by exchange or anion exchange.
The compounds of the present invention also include solvates of compounds represented by general formula (I), such as hydrates, alcohol adducts and the like.
　本発明の化合物は、プロドラッグ化することもできる。本発明におけるプロドラッグとは、体内で変換されて本発明の化合物を生成する化合物を表す。例えば、活性本体がカルボキシル基などを含む場合はそれらのエステル、アミド等が挙げられる。また、活性本体がアミノ基を含む場合にはそのアミド、カーバメート等が挙げられる。活性本体が水酸基を含む場合にはそのエステル、カーボネート、カーバメート等が挙げられる。本発明の化合物をプロドラッグ化する際にはアミノ酸、糖類と結合していてもよい。
　本発明は一般式（Ｉ）で表される化合物の全ての同位体を含む。本発明化合物の同位体は、少なくとも１の原子が、原子番号（陽子数）が同じで，質量数（陽子と中性子の数の和）が異なる原子で置換されたものである。本発明化合物に含まれる同位体の例としては、水素原子、炭素原子、窒素原子、酸素原子、リン原子、硫黄原子、フッ素原子、塩素原子などがあり、それぞれ、２Ｈ，３Ｈ，１３Ｃ，１４Ｃ，１５Ｎ，１７Ｏ，１８Ｏ，３１Ｐ，３２Ｐ，３５Ｓ，１８Ｆ，３６Ｃｌ等が含まれる。特に、３Ｈや１４Ｃのような、放射能を発して中性子を放つ不安定な放射性同位体は、医薬品あるいは化合物の体内組織分布試験等の際、有用である。安定同位体は、崩壊を起こさず、存在量がほとんど変わらず、放射能もないため、安全に使用することができる。本発明の化合物の同位体は、合成で用いている試薬を、対応する同位体を含む試薬に置き換えることにより、常法に従って変換することができる。
　本発明の医薬組成物は、グリコーゲン合成酵素活性の低下が介在する疾患の治療に好適に使用することができる。特に、糖尿病、中でも２型糖尿病や耐糖能異常の治療に好適に使用することができる。
　本発明の医薬組成物やグリコーゲンシンターゼ活性化剤は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、投与ルートとしては、経口投与で用いるのが好ましく、一回の投与を、有効成分１ｍｇ～１０００ｍｇ／人の量で行うのが好ましく、より好ましくは、有効成分１ｍｇ～１００ｍｇ／人の量であり、この量を１日１回乃至３回投与することが望ましい。 The compounds of the present invention can also be converted into prodrugs. The prodrug in the present invention refers to a compound that is converted in the body to produce the compound of the present invention. For example, when the active main body contains a carboxyl group or the like, an ester or amide thereof can be mentioned. Further, when the active main body contains an amino group, its amide, carbamate and the like can be mentioned. When the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned. When the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.
The present invention includes all isotopes of the compound represented by the general formula (I). The isotope of the compound of the present invention is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) and a different mass number (sum of the number of protons and neutrons). Examples of isotopes contained in the compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, a chlorine atom, etc., and 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl and the like are included. In particular, unstable radioisotopes that emit radioactivity and emit neutrons, such as 3H and 14C, are useful in a tissue distribution test of pharmaceuticals or compounds. Stable isotopes can be used safely because they do not decay, their abundances are almost unchanged, and there is no radioactivity. The isotope of the compound of the present invention can be converted according to a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
The pharmaceutical composition of the present invention can be suitably used for the treatment of diseases mediated by a decrease in glycogen synthase activity. In particular, it can be suitably used for the treatment of diabetes, especially type 2 diabetes and impaired glucose tolerance.
The pharmaceutical composition and glycogen synthase activator of the present invention vary depending on the administration subject, administration route, target disease, symptom, etc., but the administration route is preferably used by oral administration, and a single administration is effective. The amount is preferably 1 mg to 1000 mg / person of the ingredient, more preferably 1 mg to 100 mg / person of the active ingredient, and it is desirable to administer this amount once to three times a day.
　本発明の医薬組成物やグリコーゲンシンターゼ活性化剤は、有効成分として、上記一般式（Ｉ）で表される化合物及び/又はその医薬上許容される塩を含有するが、通常、経口投与薬剤に用いられている各種成分、例えば、医薬的や生理学的に許容される固体又は液体の担体、添加物等を含有させてもよい。
　上記担体としては、例えば、グルコース、乳糖、ショ糖、澱粉、マンニトール、デキストリン、脂肪酸グリセリド、ポリエチレングリコール、ヒドロキシエチルデンプン、エチレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル、ゼラチン、アルブミン、アミノ酸、水、生理食塩水等が挙げられる。また、必要に応じて、安定化剤、湿潤剤、乳化剤、結合剤、等張化剤等の慣用の添加剤を適宜添加することもできる。
　上記添加物としては、目的に応じて当該目的に対して通常用いられるものであれば特に制限されないが、具体的には、例えば、香料、糖類、甘味料、食物繊維類、ビタミン類、グルタミン酸ナトリウム（ＭＳＧ）などのアミノ酸類、イノシン一リン酸（ＩＭＰ）などの核酸類、塩化ナトリウムなどの無機塩類、水などが挙げられる。 The pharmaceutical composition and the glycogen synthase activator of the present invention contain the compound represented by the above general formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient. Various components used, for example, pharmaceutically and physiologically acceptable solid or liquid carriers, additives and the like may be contained.
Examples of the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned. Further, if necessary, conventional additives such as a stabilizer, a wetting agent, an emulsifier, a binder, and an isotonic agent can be appropriately added.
The additive is not particularly limited as long as it is usually used for the purpose depending on the purpose. Specifically, for example, flavoring, sugar, sweetener, dietary fiber, vitamins, sodium glutamate Amino acids such as (MSG), nucleic acids such as inosine monophosphate (IMP), inorganic salts such as sodium chloride, and water.
　本発明の医薬組成物やグリコーゲンシンターゼ活性化剤は、乾燥粉末、ペースト、溶液などの物性に制限なしに経口投与可能な形態で用いることができる。
　このような経口投与可能な形態としては、例えば、錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠を含む）、カプセル剤（ソフトカプセル、マイクロカプセルを含む）、顆粒剤、散剤、トローチ剤、シロップ剤、乳剤、懸濁剤、フィルム剤（例、口腔内崩壊フィルム）、凍結乾燥剤等が挙げられる。
　また、本発明の医薬組成物やグリコーゲンシンターゼ活性化剤は、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤、点滴剤）、外用剤（例、経皮製剤、軟膏剤）、坐剤（例、直腸坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤等の非経口剤での形態でも用いることができる。 The pharmaceutical composition and the glycogen synthase activator of the present invention can be used in a form that can be administered orally without any limitation on physical properties such as dry powder, paste, and solution.
Examples of such orally administrable forms include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and troches. Agents, syrups, emulsions, suspensions, films (eg, orally disintegrating films), lyophilizers and the like.
In addition, the pharmaceutical composition and the glycogen synthase activator of the present invention can be used for injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions), and external preparations (eg, transdermal). Skin preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations, etc. .
　これらはそれぞれ経口的あるいは非経口的（例、局所、直腸、静脈投与）に安全に投与できる。これらの製剤は、速放性製剤または徐放性製剤等の放出制御製剤（例、徐放性マイクロカプセル）であってもよい。これらの製剤は製剤上の常套手段により調製することができる。
　また、本発明の医薬組成物やグリコーゲンシンターゼ活性化剤は、他の糖尿病治療剤、糖尿病合併症治療剤、高脂血症治療剤、降圧剤、抗肥満剤（以下、併用薬剤と略記する）と組み合わせて用いることができる。これらの併用薬剤は、低分子であってもよく、また高分子のタンパク、ポリペプチド、抗体、核酸（アンチセンス核酸、ｓｉＲＮＡ、ｓｈＲＮＡを含む）であるか、あるいはワクチン等であってもよい。これらの併用薬剤は、１種又は２種以上と組み合わせて用いることができる。
　本発明の医薬組成物やグリコーゲンシンターゼ活性化剤、または併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与しても良い。 These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration). These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations. These preparations can be prepared by conventional means on the preparation.
In addition, the pharmaceutical composition and the glycogen synthase activator of the present invention include other diabetes therapeutic agents, diabetic complication therapeutic agents, hyperlipidemia therapeutic agents, antihypertensive agents, anti-obesity agents (hereinafter abbreviated as concomitant drugs). Can be used in combination. These concomitant drugs may be small molecules, high molecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), or vaccines. These concomitant drugs can be used alone or in combination of two or more.
The administration timing of the pharmaceutical composition, glycogen synthase activator, or concomitant drug of the present invention is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference.
　なお、糖尿病治療剤としては、インスリン製剤（例、ウシ、ブタの膵臓から抽出された動物インスリン製剤；大腸菌、イーストを用い遺伝子工学的に合成したヒ トインスリン製剤；インスリン亜鉛；プロタミンインスリン亜鉛；インスリンのフラグメントまたは誘導体（例、INS-1）、経口インスリン製剤）、インスリン抵抗性改善剤（例、ピオグリタゾンまたはその塩（好ましくは、塩酸塩）、ロシグリタゾンまたはその塩（好ましくは、マレイン酸塩）、テサグリタザール （Tesaglitazar）、ラガグリタザール（Ragaglitazar）、ムラグリタザール（Muraglitazar）、エダグリタゾン（Edaglitazone）、メタグリダセン（Metaglidasen）、ナベグリタザール（Naveglitazar）、AMG-131、THR- 0921）、α－グルコシダーゼ阻害剤（例、ボグリボース、アカルボース、ミグリトール、エミグリテート）、ビグアナイド剤（例、メトホルミン、ブホルミ ンまたはそれらの塩（例、塩酸塩、フマル酸塩、コハク酸塩））、インスリン分泌促進剤［スルホニルウレア剤（例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド、グリピザイド、グリブゾール）、レパグリニド、ナテグリニド、ミチグリニドまたはそのカルシウム塩水和物］、ジペプチジルペプチダーゼＩＶ阻害剤（例、アログリプチン（Alogliptin）、ヴィルダグリプチン（Vildagliptin）、シタグリプチン（Sitagliptin）、サクサグリプチン（Saxagliptin）、T-6666、TS-021）、β３アゴニスト（例、AJ-9677）、ＧＰＲ４０アゴニスト、ＧＰＲ１２０アゴニスト、ＧＬＰ－１受容体アゴニスト ［例、GLP-1、GLP-1MR剤、NN-2211、AC-2993（exendin-4）、BIM-51077、Aib(8,35)hGLP- 1(7,37)NH2、CJC-1131］、アミリンアゴニスト（例、プラムリンチド）、ホスホチロシンホスファターゼ阻害剤 （例、バナジン酸ナトリウム）、糖新生阻害剤（例、グリコーゲンホスホリラーゼ阻害剤、グルコース－６－ホスファターゼ阻害剤、グルカゴン拮抗剤）、 ＳＧＬＴ（sodium-glucose cotransporter）阻害剤（例、ダパグリフロジン、カナグリフロジン、イプラグリフロジン、BI-10773）、１１β－ヒドロキシステロイドデヒドロゲナーゼ阻害薬（例、BVT-3498）、アジポネクチンまたはその作動薬、ＩＫＫ阻害薬（例、AS-2868）、レプチン抵抗性改善薬、ソマトスタチン受容体作動薬、グルコキナーゼ活性化薬（例、Ro- 28-1675）、ＧＩＰ（Glucose-dependent insulinotropic peptide）等が挙げられる。
　さらに、サプリメントなどで用いられている顆粒や錠剤、又はゼラチンカプセルなどに上記一般式（Ｉ）で表される化合物及び/又はその医薬上許容される塩を収納した形態で用いてもよい。 Antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, α-glucosidase, α-glucosidase , Acarbose, migli Tall, emiglitate), biguanides (eg, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues [sulfonylsulfonylates (eg, tolbutamide, glibenclamide, gliclazide, Chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate], dipeptidyl peptidase IV inhibitor (eg, alogliptin, vildaglyg) Vitinagliptin, Sitagliptin, Saxagliptin, T-6666, TS-021), β3 agonist (eg, AJ-9677), GPR40 agonist, GPR120 agonist, GLP-1 receptor jaw Strike [eg, GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131] Amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist), SGLT (sodium- glucose cotransporter) inhibitors (eg, dapagliflozin, canagliflozin, ipragliflozin, BI-10773), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improver, somatostatin receptor agonist, glucokinase activator (eg, Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) It is.
Further, it may be used in a form in which the compound represented by the above general formula (I) and / or a pharmaceutically acceptable salt thereof is stored in granules, tablets, gelatin capsules and the like used in supplements.
　以下、本発明を実施例により詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
Figure JPOXMLDOC01-appb-I000012
中間体１－Ａ　5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボン酸の合成
工程１　4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノールの合成
　１－ブロモ－４，５－ジフルオロ－２－（メチルチオ）ベンゼン（１０．８ｇ，４５．０ｍｍｏｌ）に１，４－ジオキサン（７５ｍＬ）、水（２５ｍＬ）、４－ヒドロキシフェニルボロン酸（７．５ｇ，５４．３ｍｍｏｌ）、炭酸ナトリウム（９．６ｇ，９０ｍｍｏｌ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（II）（以下、ＰｄＣｌ2（ｄｐｐｆ））（触媒量）を加えて１００℃で２時間撹拌した。不溶物を濾別した後、減圧下溶媒を留去後、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：１１．３ｇ（４５．０ｍｍｏｌ） 収率：１００％ EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
Figure JPOXMLDOC01-appb-I000012
Intermediate 1-A Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carboxylic acid Step 1 4- (4,5- Synthesis of difluoro-2-methylsulfanyl-phenyl) phenol 1-Bromo-4,5-difluoro-2- (methylthio) benzene (10.8 g, 45.0 mmol) in 1,4-dioxane (75 mL), water (25 mL) ), 4-hydroxyphenylboronic acid (7.5 g, 54.3 mmol), sodium carbonate (9.6 g, 90 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (hereinafter, PdCl 2 (dppf)) (catalytic amount) was added and stirred at 100 ° C. for 2 hours. The insoluble material was filtered off, the solvent was distilled off under reduced pressure, diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 11.3 g (45.0 mmol) Yield: 100%
工程２　中間体１－Ａの合成
　工程１で得られた化合物（３．２２ｇ，１２．８ｍｍｏｌ）、５－クロロメチル－２－フランカルボン酸エチル（２．４２ｇ，１２．８ｍｍｏｌ）、炭酸カリウム（２．６６ｇ，１９．３ｍｍｏｌ）にＮ，Ｎ－ジメチルホルムアミド（以下、ＤＭＦ）（１００ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（７５ｍＬ）、テトラヒドロフラン（以下、ＴＨＦ）（５０ｍＬ）および１Ｎ　水酸化ナトリウム水溶液（５０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：３．６５ｇ（９．７０ｍｍｏｌ） 収率：７６％
Figure JPOXMLDOC01-appb-I000013
 Step 2 Synthesis of Intermediate 1-A The compound obtained in Step 1 (3.22 g, 12.8 mmol), ethyl 5-chloromethyl-2-furancarboxylate (2.42 g, 12.8 mmol), potassium carbonate ( 2.66 g, 19.3 mmol) was added N, N-dimethylformamide (hereinafter DMF) (100 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (75 mL), tetrahydrofuran (hereinafter referred to as THF) (50 mL) and 1N aqueous sodium hydroxide solution (50 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with acetonitrile.
Yield: 3.65 g (9.70 mmol) Yield: 76%
Figure JPOXMLDOC01-appb-I000013
中間体１－Ｂ　5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニルクロライドの合成
　中間体１－Ａ（３．６５ｇ、９．７１ｍｍｏｌ）にチオニルクロライド（１５ｍＬ）、ＤＭＦ（触媒量）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去して表題化合物を得た。
収量：３．３ｇ（８．４ｍｍｏｌ） 収率：８６％
Figure JPOXMLDOC01-appb-I000014
中間体２－Ａ　5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボン酸の合成
　２－ホルミルチオフェン－４－カルボン酸メチル（２．２２ｇ，１３．１ｍｍｏｌ）にメタノール（２０ｍＬ）を加えた後、水素化ホウ素ナトリウム（６００ｍｇ，１５．７ｍｍｏｌ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にチオニルクロライド（１０ｍＬ）加え、室温で２時間撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣に４－（４，５－ジフルオロ－２－メチルスルファニル－フェニル）フェノール（２．８０ｇ，１１．１ｍｍｏｌ）、炭酸カリウム（３．０６ｇ，２２．２ｍｍｏｌ）、ヨウ化カリウム（触媒量）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（２５ｍＬ）、ＴＨＦ（２５ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（２５ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：２．２ｇ（５．６ｍｍｏｌ） 収率：４３％
Figure JPOXMLDOC01-appb-I000015
 Intermediate 1-B Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl chloride Intermediate 1-A (3.65 g, 9.71 mmol) ) Were added with thionyl chloride (15 mL) and DMF (catalytic amount), and the mixture was stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 3.3 g (8.4 mmol) Yield: 86%
Figure JPOXMLDOC01-appb-I000014
Intermediate 2-A Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carboxylic acid 2-formylthiophene-4-carboxylate methyl (2. After adding methanol (20 mL) to 22 g, 13.1 mmol), sodium borohydride (600 mg, 15.7 mmol) was added and stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thionyl chloride (10 mL) was added to the resulting residue, followed by stirring at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (2.80 g, 11.1 mmol), potassium carbonate (3.06 g, 22.2 mmol). ), Potassium iodide (catalytic amount) was added DMF (75 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (25 mL), THF (25 mL), 1N aqueous sodium hydroxide solution (25 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with acetonitrile.
Yield: 2.2 g (5.6 mmol) Yield: 43%
Figure JPOXMLDOC01-appb-I000015
中間体２－Ｂ　5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボニルクロライドの合成
　中間体５－Ａ（２．２ｇ、５．６ｍｍｏｌ）にチオニルクロライド（１５ｍＬ）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去して表題化合物を得た。
収量：１．８５ｇ（４．５０ｍｍｏｌ） 収率：８１％
Figure JPOXMLDOC01-appb-I000016
中間体３－Ａ　4-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-2-カルボン酸の合成
　４－メチルチオフェン－２－カルボン酸メチル（５．０ｇ，６．４ｍｍｏｌ）、Ｎ－ブロモコハク酸イミド（以下、ＮＢＳ）（６．２５ｇ，７．０４ｍｍｏｌ）および触媒量の過酸化ベンゾイル（以下、ＢＰＯ）に、四塩化炭素（５０ｍＬ）を加え、一晩加熱還流した。室温に戻した後、不溶物を濾別し、減圧下溶媒を留去して得られた残渣に４－（４，５－ジフルオロ－２－メチルスルファニル－フェニル）フェノール（２．５８ｇ，５．１２ｍｍｏｌ）、炭酸カリウム（２．８２ｇ，１０．２ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（２５ｍＬ）、ＴＨＦ（２５ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（２５ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：４５０ｍｇ（１．１５ｍｍｏｌ） 収率：１７％
Figure JPOXMLDOC01-appb-I000017
 Intermediate 2-B Synthesis of 5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carbonyl chloride Intermediate 5-A (2.2 g, 5.6 mmol) ) Was added with thionyl chloride (15 mL), and the mixture was stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 1.85 g (4.50 mmol) Yield: 81%
Figure JPOXMLDOC01-appb-I000016
Intermediate 3-A Synthesis of 4 -[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carboxylic acid Methyl 4-methylthiophene-2-carboxylate (5. 0 g, 6.4 mmol), N-bromosuccinimide (hereinafter referred to as NBS) (6.25 g, 7.04 mmol) and a catalytic amount of benzoyl peroxide (hereinafter referred to as BPO), carbon tetrachloride (50 mL) was added. Refluxed overnight. After returning to room temperature, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure to give 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (2.58 g, 5. 12 mmol) and potassium carbonate (2.82 g, 10.2 mmol) were added DMF (75 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (25 mL), THF (25 mL), 1N aqueous sodium hydroxide solution (25 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by evaporating the solvent under reduced pressure and washing the resulting residue with acetonitrile.
Yield: 450 mg (1.15 mmol) Yield: 17%
Figure JPOXMLDOC01-appb-I000017
中間体３－Ｂ　4-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-2-カルボニルクロライドの合成
　中間体３－Ａ（４５０ｍｇ，１．１５ｍｍｏｌ）にチオニルクロライド（５ｍＬ）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去して表題化合物を得た。
収量：定量的
Figure JPOXMLDOC01-appb-I000018
中間体４－Ａ  2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　2-ブロモメチルチアゾール-4-カルボン酸エチルの合成
　２－メチルチアゾール－４－カルボン酸エチル（３．２６ｇ，１９．１ｍｍｏｌ）、ＮＢＳ（７．４６ｇ，４１．９ｍｍｏｌ）および触媒量のＢＰＯに、四塩化炭素（５０ｍＬ）を加え、一晩加熱還流した。室温に戻した後、不溶物を濾別し、５％チオ硫酸ナトリウム、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にＴＨＦ（５０ｍＬ）に溶解し、氷冷下、亜りん酸ジエチル（２．４６ｍＬ，１９．１ｍｍｏｌ）、ジイソプロピルエチルアミン（３．２７ｍＬ，１９．１ｍｍｏｌ）を加え、室温に戻して、２時間撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：３．８５ｇ（１５．２ｍｍｏｌ） 収率：８０％ Intermediate 3-B Synthesis of 4-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carbonyl chloride To intermediate 3-A (450 mg, 1.15 mmol) Thionyl chloride (5 mL) was added and stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain the title compound.
Yield: quantitative
Figure JPOXMLDOC01-appb-I000018
Intermediate 4-A Synthesis of 2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 2-Bromomethylthiazole-4 Synthesis of ethyl carboxylate Carbon 2-chloride (50 mL) was added to ethyl 2-methylthiazole-4-carboxylate (3.26 g, 19.1 mmol), NBS (7.46 g, 41.9 mmol) and catalytic amount of BPO. In addition, the mixture was heated to reflux overnight. After returning to room temperature, the insoluble material was filtered off, washed with 5% sodium thiosulfate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in THF (50 mL). Under ice cooling, diethyl phosphite (2.46 mL, 19.1 mmol), diisopropylethylamine (3.27 mL, 19.1 mmol) The mixture was returned to room temperature and stirred for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 3.85 g (15.2 mmol) Yield: 80%
工程２　中間体４－Ａの合成
　工程１で得られた化合物（３．８５ｇ，１５．２ｍｍｏｌ）、４－（４，５－ジフルオロ－２－メチルスルファニル－フェニル）フェノール（３．８５ｇ，１５．２ｍｍｏｌ）、炭酸カリウム（４．２５ｇ，３０．８ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（５０ｍＬ）、ＴＨＦ（５０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（５０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルと水（ｖ／ｖ＝１／１）の混合溶媒で洗浄することにより、表題化合物を得た。
収量：３．９ｇ（９．９ｍｍｏｌ） 収率：６５％
Figure JPOXMLDOC01-appb-I000019
 Step 2 Synthesis of Intermediate 4-A Compound (3.85 g, 15.2 mmol) obtained in Step 1, 4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenol (3.85 g, 15. 2 mmol) and potassium carbonate (4.25 g, 30.8 mmol) were added DMF (75 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (50 mL), THF (50 mL), 1N aqueous sodium hydroxide solution (50 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with a mixed solvent of acetonitrile and water (v / v = 1/1).
Yield: 3.9 g (9.9 mmol) Yield: 65%
Figure JPOXMLDOC01-appb-I000019
中間体４－Ｂ　2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸クロライドの合成
　中間体４－Ａ（３．９ｇ，９．９ｍｍｏｌ）にチオニルクロライド（２５ｍＬ）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去して表題化合物を得た。
収量：３．５７ｇ（８．６７ｍｍｏｌ） 収率：８８％
Figure JPOXMLDOC01-appb-I000020
中間体５－Ａ　2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　1-ブロモ-4,5-ジフルオロ-2-(トリデューテリオメトキシ)ベンゼンの合成
　２－ブロモ－４，５－ジフルオロフェノール（９．６４ｇ，４６．１ｍｍｏｌ）をＤＭＦ（７５ｍＬ）に溶解し、炭酸カリウム（７．６４ｇ，５５．４ｍｍｏｌ）、ヨウ化メタン－ｄ3（３．５２ｍＬ，５５．４ｍｍｏｌ）を加え室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：９．７４ｇ（４３．１ｍｍｏｌ） 収率：９３％ Intermediate 4-B Synthesis of 2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid chloride Intermediate 4-A (3.9 g, 9. 9 mmol) was added with thionyl chloride (25 mL) and stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 3.57 g (8.67 mmol) Yield: 88%
Figure JPOXMLDOC01-appb-I000020
Intermediate 5-A Synthesis of 2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carboxylic acid Step 1 1-Bromo- Synthesis of 4,5-difluoro-2- (triduteriomethoxy) benzene 2-Bromo-4,5-difluorophenol (9.64 g, 46.1 mmol) was dissolved in DMF (75 mL) and potassium carbonate (7. 64 g, 55.4 mmol), and stirred at room temperature overnight the iodomethane -d 3 (3.52mL, 55.4mmol). The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 9.74 g (43.1 mmol) Yield: 93%
工程２　4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノールの合成　工程１で得られた化合物（４．１５ｇ，１８．４ｍｍｏｌ）に１，４－ジオキサン（７５ｍＬ）、水（２５ｍＬ）、４－ヒドロキシフェニルボロン酸（３．０ｇ，２２ｍｍｏｌ）、炭酸ナトリウム（３．９ｇ，３６．８ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（触媒量）を加えて１００℃で２時間撹拌した。不溶物を濾別した後、減圧下溶媒を留去することで残渣を得た。得られた残渣を酢酸エチルで希釈した後、１Ｎ　塩酸および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：４．４ｇ（１８ｍｍｏｌ） 収率：１００％
工程３　中間体５－Ａの合成
　工程２で得られた化合物（２．０ｇ，８．４ｍｍｏｌ）、２－ブロモメチルチアゾール－４－カルボン酸エチル（２．１ｇ，８．４ｍｍｏｌ）、炭酸カリウム（２．３１ｇ，１６．７ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（３０ｍＬ）、ＴＨＦ（３０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（３０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルと水（ｖ／ｖ＝１／１）の混合溶媒で洗浄することにより、表題化合物を得た。
収量：２．３ｇ（６．０ｍｍｏｌ） 収率：７２％
Figure JPOXMLDOC01-appb-I000021
 Step 2 Synthesis of 4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenol The compound obtained in Step 1 (4.15 g, 18.4 mmol) was added to 1,4-dioxane (75 mL), Water (25 mL), 4-hydroxyphenylboronic acid (3.0 g, 22 mmol), sodium carbonate (3.9 g, 36.8 mmol) and PdCl 2 (dppf) (catalytic amount) were added and stirred at 100 ° C. for 2 hours. . The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 4.4 g (18 mmol) Yield: 100%
Step 3 Synthesis of Intermediate 5-A The compound obtained in Step 2 (2.0 g, 8.4 mmol), ethyl 2-bromomethylthiazole-4-carboxylate (2.1 g, 8.4 mmol), potassium carbonate ( DMF (75 mL) was added to 2.31 g (16.7 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (30 mL), THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with a mixed solvent of acetonitrile and water (v / v = 1/1).
Yield: 2.3 g (6.0 mmol) Yield: 72%
Figure JPOXMLDOC01-appb-I000021
中間体５－Ｂ　2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボン酸クロライドの合成
　中間体５－Ａ（２．３ｇ、６．０ｍｍｏｌ）にチオニルクロライド（２５ｍＬ）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去して表題化合物を得た。
収量：２．２ｇ（５．５ｍｍｏｌ） 収率：９２％
Figure JPOXMLDOC01-appb-I000022
中間体６－Ａ　2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノールの合成
　７－ブロモ－４，５－ジフルオロ－３－メチル－ベンゾフラン（２．１ｇ，８．５ｍｍｏｌ）に１，４－ジオキサン（７５ｍＬ）および水（２５ｍＬ）、４－ヒドロキシフェニルボロン酸（１．４ｇ，１０ｍｍｏｌ）、炭酸ナトリウム（１．８ｇ，１７ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（触媒量）を加えて１００℃で２時間撹拌した。不溶物を濾別した後、減圧下溶媒を留去することで残渣を得た。得られた残渣を酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．１ｇ（８．１ｍｍｏｌ） 収率：９５％ Intermediate 5-B Synthesis of 2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carboxylic acid chloride Intermediate 5-A (2.3 g , 6.0 mmol) was added with thionyl chloride (25 mL), and the mixture was stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 2.2 g (5.5 mmol) Yield: 92%
Figure JPOXMLDOC01-appb-I000022
Intermediate 6-A Synthesis of 2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4 , 5-Difluoro-3-methyl-benzofuran-7-yl) phenol 7-bromo-4,5-difluoro-3-methyl-benzofuran (2.1 g, 8.5 mmol) to 1,4-dioxane (75 mL) ) And water (25 mL), 4-hydroxyphenylboronic acid (1.4 g, 10 mmol), sodium carbonate (1.8 g, 17 mmol), PdCl 2 (dppf) (catalytic amount) were added, and the mixture was stirred at 100 ° C. for 2 hours. . The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 2.1 g (8.1 mmol) Yield: 95%
工程２　中間体６－Ａの合成
　工程１で得られた化合物（２．１ｇ，８．１ｍｍｏｌ）、２－ブロモメチルチアゾール－４－カルボン酸エチル（２．０ｇ，８．１ｍｍｏｌ）、炭酸カリウム（２．２３ｇ，１６．２ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（３０ｍＬ）、ＴＨＦ（３０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（３０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルと水（ｖ／ｖ＝１／１）の混合溶媒で洗浄することにより、表題化合物を得た。
収量：１．７ｇ（４．２ｍｍｏｌ） 収率：５２％
Figure JPOXMLDOC01-appb-I000023
 Step 2 Synthesis of Intermediate 6-A The compound obtained in Step 1 (2.1 g, 8.1 mmol), ethyl 2-bromomethylthiazole-4-carboxylate (2.0 g, 8.1 mmol), potassium carbonate ( (2.33 g, 16.2 mmol) was added DMF (75 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (30 mL), THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with a mixed solvent of acetonitrile and water (v / v = 1/1).
Yield: 1.7 g (4.2 mmol) Yield: 52%
Figure JPOXMLDOC01-appb-I000023
中間体６－Ｂ　2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
　中間体６－Ａ（７９０ｍｇ，１．９７ｍｍｏｌ）に塩化チオニル（４．６０ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４０分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000024
中間体７－Ａ　2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　4-（4,5-ジフルオロ-1-ベンゾチオフェン-7-イル）フェノールの合成
　７－ブロモ－４，５－ジフルオロ－１－ベンゾチオフェン（０．６５ｇ，２．６ｍｍｏｌ）、４－(４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル)フェノール（０．５７ｇ，２．６ｍｍｏｌ）、炭酸ナトリウム（０．８３ｇ，７．８ｍｍｏｌ）およびＰｄＣｌ2（ｄｐｐｆ）（０．３８g，０．５２ｍｍｏｌ）に１，４－ジオキサン（１２ｍＬ）および水（４ｍＬ）を加えてマイクロウェーブ装置にて１２５℃で３０分間攪拌した。反応液をろ過した後、ろ液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：１．１２ｇ（４．２７ｍｍｏｌ） 収率：６１％
1H NMR (400 MHz, CDCl3) δ 7.57 - 7.50 (m, 4H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.96 (d, J = 8.0Hz, 2H). Intermediate 6-B Synthesis of 2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 6-A (790 mg, 1. 97 mmol), thionyl chloride (4.60 mL) was added, a small amount of DMF was added dropwise, and the mixture was stirred at 55 ° C. for 40 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000024
Intermediate 7-A Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4,5-Difluoro Synthesis of 1-benzothiophen-7-yl) phenol 7-Bromo-4,5-difluoro-1-benzothiophene (0.65 g, 2.6 mmol), 4- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) phenol (0.57 g, 2.6 mmol), sodium carbonate (0.83 g, 7.8 mmol) and PdCl 2 (dppf) (0.38 g, 0.52 mmol) 1,4-Dioxane (12 mL) and water (4 mL) were added thereto, and the mixture was stirred at 125 ° C. for 30 minutes in a microwave apparatus. After the reaction solution was filtered, the filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 1.12 g (4.27 mmol) Yield: 61%
1 H NMR (400 MHz, CDCl 3 ) δ 7.57-7.50 (m, 4H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 6.96 (d, J = 8.0Hz, 2H).
工程２　2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルエステルの合成
　２－ブロモメチルチアゾール－４－カルボン酸エチル（５００ｍｇ，２．００ｍｍｏｌ）、　工程１で得られた化合物（５２４ｍｇ，２．００ｍｍｏｌ）、炭酸カリウム（０．２９ｇ，２．１ｍｍｏｌ）にＤＭＦ（１０ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：７８３ｍｇ（１．８１ｍｍｏｌ） 収率：９１％
1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.48 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H).
工程３　中間体７－Ａの合成
　工程２で得られた化合物（７８３ｍｇ，１．８１ｍｍｏｌ）をＴＨＦ（１４ｍL）およびメタノール（４ｍL）に溶解し、１Ｎ　水酸化ナトリウム水溶液（３ｍＬ）を加え５時間撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して、表題化合物を得た。
収量：７２１ｍｇ（１．７９ｍｍｏｌ） 収率：９９％
1H NMR (400 MHz, DMSO-d6) δ 13.20 - 12.99 (brs, 1H), 8.51 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H).
Figure JPOXMLDOC01-appb-I000025
 Step 2 Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid ethyl ester 2-bromomethylthiazole-4-ethyl carboxylate (500 mg, 2 DMF (10 mL) was added to the compound obtained in Step 1 (524 mg, 2.00 mmol) and potassium carbonate (0.29 g, 2.1 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 783 mg (1.81 mmol) Yield: 91%
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.54-7.50 (m, 2H), 7.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.48 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H).
Step 3 Synthesis of Intermediate 7-A The compound obtained in Step 2 (783 mg, 1.81 mmol) was dissolved in THF (14 mL) and methanol (4 mL), 1N aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred for 5 hours. did. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 721 mg (1.79 mmol) Yield: 99%
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.20-12.99 (brs, 1H), 8.51 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H).
Figure JPOXMLDOC01-appb-I000025
中間体７－Ｂ　2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
　中間体７－Ａ（４８４ｍｇ，１．２０ｍｍｏｌ）に塩化チオニル（３．００ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４５分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000026
中間体８－Ａ　2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　4-（4,5-ジフルオロ-2-メトキシメチル-1-ベンゾチオフェン-7-イル）フェノールの合成
　７－ブロモ－４，５－ジフルオロ－２－（メトキシメチル）－１－ベンゾチオフェン（５００ｍｇ，１．７１ｍｍｏｌ）、４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（３７５ｍｇ，１．７０ｍｍｏｌ）、炭酸ナトリウム（５４３ｍｇ，５．１２ｍｍｏｌ）およびＰｄＣｌ2（ｄｐｐｆ）（２５０ｍｇ，０．３４０ｍｍｏｌ）に１，４－ジオキサン（１２ｍＬ）および水（４ｍＬ）を加えてマイクロウェーブ装置にて１２５℃で３０分間攪拌した。反応液をろ過した後、ろ液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して、表題化合物を得た。
収量：４０１ｍｇ（２．３１ｍｍｏｌ） 収率：７７％
1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0Hz, 2H), 7.38 (s, 1H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.87 (s, 1H), 4.70 (s, 2H), 3.44 (s, 3H). Intermediate 7-B Synthesis of 2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 7-A (484 mg, 1.20 mmol) was chlorinated. Thionyl (3.00 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 45 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000026
Intermediate 8-A Synthesis of 2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4 Synthesis of-(4,5-difluoro-2-methoxymethyl-1-benzothiophen-7-yl) phenol 7-Bromo-4,5-difluoro-2- (methoxymethyl) -1-benzothiophene (500 mg, 1 .71 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (375 mg, 1.70 mmol), sodium carbonate (543 mg, 5.12 mmol) and PdCl 2 (dppf) (250 mg, 0.340 mmol) was added 1,4-dioxane (12 mL) and water (4 mL), and the mixture was stirred at 125 ° C. for 30 minutes in a microwave apparatus. After the reaction solution was filtered, the filtrate was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
Yield: 401 mg (2.31 mmol) Yield: 77%
1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J = 8.0Hz, 2H), 7.38 (s, 1H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 4.87 (s, 1H), 4.70 (s, 2H), 3.44 (s, 3H).
工程２　中間体８－Ａの合成
　２－ブロモメチルチアゾール－４－カルボン酸エチル（５５２ｍｇ，２．２１ｍｍｏｌ）、工程１で得られた化合物（６７６ｍｇ，２．２１ｍｍｏｌ）、炭酸カリウム（０．３２ｇ，２．３ｍｍｏｌ）にＤＭＦ（１０ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルとヘキサンで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をＴＨＦ（１０ｍL）およびメタノール（２ｍL）に溶解し、１Ｎ　水酸化ナトリウム水溶液（３ｍＬ）を加え３時間撹拌した。減圧下溶媒を留去して得られた残渣に酢酸エチルと１Ｎ　塩酸（３ｍＬ）を加えた。反応液をろ過した後、得られた固体を水で洗浄し、減圧乾燥して表題化合物を得た。
収量：７４１ｍｇ（１．６６ｍｍｏｌ） 収率：７５％
1H NMR (400 MHz, DMSO-d6) δ 13.22 - 12.97 (brs, 1H), 8.51 (s, 1H), 7.69 (d, J = 12.0 Hz, 2H), 7.57 (s, 1H), 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.25 (d, J = 12.0 Hz, 2H), 5.56 (s, 2H), 4.73 (s, 2H), 3.34 (s, 3H).
Figure JPOXMLDOC01-appb-I000027
 Step 2 Synthesis of Intermediate 8-A Ethyl 2-bromomethylthiazole-4-carboxylate (552 mg, 2.21 mmol), the compound obtained in Step 1 (676 mg, 2.21 mmol), potassium carbonate (0.32 g, 2.3 mmol) was added DMF (10 mL) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate and hexane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in THF (10 mL) and methanol (2 mL), 1N aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred for 3 hr. The solvent was distilled off under reduced pressure, and ethyl acetate and 1N hydrochloric acid (3 mL) were added to the resulting residue. After filtering the reaction solution, the obtained solid was washed with water and dried under reduced pressure to obtain the title compound.
Yield: 741 mg (1.66 mmol) Yield: 75%
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.22-12.97 (brs, 1H), 8.51 (s, 1H), 7.69 (d, J = 12.0 Hz, 2H), 7.57 (s, 1H), 7.52 ( dd, J = 8.0, 1.2 Hz, 1H), 7.25 (d, J = 12.0 Hz, 2H), 5.56 (s, 2H), 4.73 (s, 2H), 3.34 (s, 3H).
Figure JPOXMLDOC01-appb-I000027
中間体８－Ｂ　2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
　中間体８－Ａ（７００ｍｇ，１．４７ｍｍｏｌ）に塩化チオニル（３．０ｍＬ）を加え、５０℃で１時間撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000028
中間体９－Ａ　2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成 Intermediate 8-B Synthetic intermediate 8-A of 2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl chloride (700 mg , 1.47 mmol) was added with thionyl chloride (3.0 mL), and the mixture was stirred at 50 ° C. for 1 hour. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000028
Intermediate 9-A Synthesis of 2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carboxylic acid
工程１　2-[[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボラン-2-イル)フェノキシ]メチル]チアゾール-4-カルボン酸　エチルエステルの合成
　２－ブロモメチルチアゾール－４－カルボン酸エチル（１．９６ｇ，７．８３ｍｍｏｌ）、４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（１．９０ｇ，８．６３ｍｍｏｌ）、炭酸カリウム（１．１９ｇ，８．６１ｍｍｏｌ）にＤＭＦ（３０ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、水、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．７７ｇ（７．１２ｍｍｏｌ） 収率：９１％
1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 4.44 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.33 (s, 12H).
工程２　中間体９－Ａの合成
　７－ブロモ－４，５－ジフルオロ－ベンゾフラン（１００ｍｇ，０．２５７ｍｍｏｌ）、工程１で得られた化合物（４８ｍg，０．２１４ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（８．０ｍg，０．０１１ｍｍｏｌ）、および１，４－ジオキサン（２．３ｍｌ）に１Ｍ　炭酸カリウム水溶液（０．７８ｍＬ）を加え、１００℃で１時間撹拌した。ジクロロメタンで希釈し、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をアセトニトリルで洗浄し、シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、減圧濃縮した。ヘキサンと酢酸エチル（ｖ／ｖ＝１／１）の混合溶媒でスラリー洗浄を行った。得られた個体を１，４－ジオキサン（１ｍｌ）、少量のメタノールに懸濁させ、１Ｍ　水酸化リチウム水溶液（１８５μＬ）を加え１時間半撹拌した。１Ｍ　塩酸で弱酸性にし、減圧下溶媒を留去した。得られた残渣に水を加えスラリー洗浄を行い、真空乾燥させ表題化合物を得た。
収量：４９．０ｍｇ（０．１２６ｍｍｏｌ） 収率：４８％
MS (ESI) m/z 388 [M+H]+
Figure JPOXMLDOC01-appb-I000029
 Step 1 Synthesis of 2-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenoxy] methyl] thiazole-4-carboxylic acid ethyl ester 2-bromomethyl Ethyl thiazole-4-carboxylate (1.96 g, 7.83 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (1.90 g, 8 DMF (30 mL) was added to potassium carbonate (1.19 g, 8.61 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 2.77 g (7.12 mmol) Yield: 91%
1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 4.44 (q, J = 8.0 Hz, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.33 (s, 12H).
Step 2 Synthesis of Intermediate 9-A 7-Bromo-4,5-difluoro-benzofuran (100 mg, 0.257 mmol), compound obtained in Step 1 (48 mg, 0.214 mmol), PdCl 2 (dppf) (8 1.0 mg, 0.011 mmol) and 1,4-dioxane (2.3 ml) were added 1M aqueous potassium carbonate solution (0.78 mL), and the mixture was stirred at 100 ° C. for 1 hour. The mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was washed with acetonitrile, purified by silica gel chromatography (hexane / ethyl acetate), and concentrated under reduced pressure. The slurry was washed with a mixed solvent of hexane and ethyl acetate (v / v = 1/1). The obtained solid was suspended in 1,4-dioxane (1 ml) and a small amount of methanol, 1M aqueous lithium hydroxide solution (185 μL) was added, and the mixture was stirred for 1.5 hours. The solution was made weakly acidic with 1M hydrochloric acid, and the solvent was distilled off under reduced pressure. Water was added to the resulting residue for slurry washing, followed by vacuum drying to obtain the title compound.
Yield: 49.0 mg (0.126 mmol) Yield: 48%
MS (ESI) m / z 388 [M + H] +
Figure JPOXMLDOC01-appb-I000029
中間体９－Ｂ　2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
　中間体９－Ａ（３９２ｍｇ，１．０１ｍｍｏｌ）に塩化チオニル（３．５ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４０分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000030
中間体１０－Ａ　2-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　4-ブロモ-6,7-ジフルオロ-1H-インドールの合成
　５－ブロモ－１，２－ジフルオロ－３－ニトロ－ベンゼン（３．００ｇ，１２．６ｍｍｏｌ）をＴＨＦ（６０ｍＬ）に溶解し、－４０℃に冷却した。その溶液に、１Ｍ　ビニルマグネシウムブロマイドのＴＨＦ溶液（３８ｍＬ，３８ｍｍｏｌ）を１０分かけて加えて、－４０℃で２時間半撹拌した。反応液に酢酸エチルを加えて希釈し、有機層を飽和塩化アンモニア水溶液、水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：８８５ｍｇ（３．９８ｍｍｏｌ）　収率：　３１．６％
工程２　4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノールの合成 Intermediate 9-B Synthesis of 2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 9-A (392 mg, 1.01 mmol) was mixed with thionyl chloride. (3.5 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 40 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000030
Intermediate 10-A Synthesis of 2-[[4- (6,7-difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4-Bromo-6, Synthesis of 7-difluoro-1H-indole 5-Bromo-1,2-difluoro-3-nitro-benzene (3.00 g, 12.6 mmol) was dissolved in THF (60 mL) and cooled to −40 ° C. To the solution was added 1M vinylmagnesium bromide in THF (38 mL, 38 mmol) over 10 minutes, and the mixture was stirred at −40 ° C. for 2.5 hours. Ethyl acetate was added to the reaction solution for dilution, and the organic layer was washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 885 mg (3.98 mmol) Yield: 31.6%
Step 2 Synthesis of 4- (6,7-difluoro-1H-indol-4-yl) phenol
　工程１で得られた化合物（７００ｍｇ，２．４８ｍｍｏｌ）と４－ヒドロキシフェニルボロン酸　ピナコールエステル（５４６ｍｇ，２．４８ｍｍｏｌ）を１，４－ジオキサンと水（ｖ／ｖ＝４／１，２５ｍＬ）の混合溶媒に溶解した。その溶液に、ＰｄＣｌ2（ｄｐｐｆ）（１８２ｍｇ，０．２４８ｍｍｏｌ）及び炭酸ナトリウム（８３８ｍｇ，６．２１ｍｍｏｌ）を加えて、１２５℃で２時間撹拌した。反応溶液を室温に冷却後、酢酸エチルを加えて希釈し、炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄して無水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：３１９ｍｇ（１．３０ｍｍｏｌ）　収率：５３％
工程３　2-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルの合成
　工程２で得られた化合物（３１９ｍｇ，１．３０ｍｍｏｌ）と中間体４－Ａの工程１で得られた化合物（３５８ｍｇ，１．４３ｍｍｏｌ）をＤＭＦ（１３ｍＬ）に溶解した。その溶液に炭酸カリウム（４４９ｍｇ，３．２５ｍｍｏｌ）を加えて、室温で２２時間撹拌した。反応溶液に酢酸エチルを加えて希釈した後、水、炭酸水素ナトリウム水溶液及び飽和食塩水にて洗浄して無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：２３２ｍｇ（０．５６０ｍｍｏｌ）　収率：４３％
MS (ESI, m/z) 415 [M+H]+
工程４　中間体１０－Ａの合成
　工程３で得られた化合物（２３２ｍｇ，０．５６０ｍｍｏｌ）をＴＨＦ（３ｍＬ）及びメタノール（３ｍＬ）の混合溶媒に溶解し、２Ｎ　水酸化ナトリウム水溶液（０．５６ｍＬ）を加えて室温で２時間半撹拌した。減圧下溶媒を留去後、得られた残渣に１Ｎ　塩酸水溶液（１．２ｍＬ）及び水（１０ｍＬ）を加えることで生じた沈殿物を濾過した。得られた沈殿物を水で洗浄して、乾燥することで表題化合物を得た。
収量：　２１０ｍｇ（０．５４４ｍｍｏｌ）　収率：　９７％
MS (ESI) m/z 387 [M+H]+
Figure JPOXMLDOC01-appb-I000031
The compound obtained in Step 1 (700 mg, 2.48 mmol) and 4-hydroxyphenylboronic acid pinacol ester (546 mg, 2.48 mmol) were mixed with 1,4-dioxane and water (v / v = 4/1, 25 mL). Dissolved in the mixed solvent. To the solution, PdCl 2 (dppf) (182 mg, 0.248 mmol) and sodium carbonate (838 mg, 6.21 mmol) were added and stirred at 125 ° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 319 mg (1.30 mmol) Yield: 53%
Step 3 Synthesis of ethyl 2-[[4- (6,7-difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 2 (319 mg, 1.30 mmol) The compound obtained in Step 1 of Intermediate 4-A (358 mg, 1.43 mmol) was dissolved in DMF (13 mL). To the solution was added potassium carbonate (449 mg, 3.25 mmol), and the mixture was stirred at room temperature for 22 hours. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 232 mg (0.560 mmol) Yield: 43%
MS (ESI, m / z) 415 [M + H] +
Step 4 Synthesis of Intermediate 10-A The compound obtained in Step 3 (232 mg, 0.560 mmol) was dissolved in a mixed solvent of THF (3 mL) and methanol (3 mL), and 2N aqueous sodium hydroxide solution (0.56 mL) was dissolved. And stirred at room temperature for 2.5 hours. After evaporating the solvent under reduced pressure, the resulting precipitate was filtered by adding 1N aqueous hydrochloric acid (1.2 mL) and water (10 mL) to the resulting residue. The obtained precipitate was washed with water and dried to obtain the title compound.
Yield: 210 mg (0.544 mmol) Yield: 97%
MS (ESI) m / z 387 [M + H] +
Figure JPOXMLDOC01-appb-I000031
中間体１１－Ａ　2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸の合成
工程１　4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノールの合成
　１－ブロモ－４，５－ジフルオロ－２－メトキシ－ベンゼン（１．０ｇ，４．５ｍｍｏｌ）、４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（１．０９g，４．９３ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（３２８ｍg，０．４４８ｍｍｏｌ）、および炭酸ナトリウム（１．５１ｇ，１１．２ｍｍｏｌ）を１，４－ジオキサンと水の混合溶液（４０ｍＬ，ｖ／ｖ＝４／１）に加え、１００℃で１時間撹拌した。反応液を酢酸エチルで希釈し、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
収量：１．１３ｇ（３．５６ｍｍｏｌ）　収率：７９％
工程２　2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボン酸エチルの合成
　工程１で得られた化合物（１．１３ｍｇ，３．５６ｍｍｏｌ）と中間体４－Ａの工程１で得られた化合物（９７９ｍｇ，３．９２ｍｍｏｌ）をＤＭＦ（３５ｍＬ）に加えて溶解した。その溶液に炭酸カリウム（１．２０ｇ，８．９０ｍｍｏｌ）を加えて、室温で５８時間撹拌した。反応溶液に酢酸エチルを加えて希釈し、水、炭酸水素ナトリウム水溶液及び飽和食塩水にて洗浄して無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製し、表題化合物を得た。
収量：１．０６ｇ（２．６１ｍｍｏｌ）　収率：７３％
MS (ESI, m/z) 406 [M+H]+ Intermediate 11-A Synthesis of 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carboxylic acid Step 1 4- (4,5-Difluoro Synthesis of 2-methoxy-phenyl) phenol 1-bromo-4,5-difluoro-2-methoxy-benzene (1.0 g, 4.5 mmol), 4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) phenol (1.09 g, 4.93 mmol), PdCl 2 (dppf) (328 mg, 0.448 mmol), and sodium carbonate (1.51 g, 11.2 mmol) in 1, The mixture was added to a mixed solution of 4-dioxane and water (40 mL, v / v = 4/1), and stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 1.13 g (3.56 mmol) Yield: 79%
Step 2 Synthesis of ethyl 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carboxylate Compound obtained in Step 1 (1.13 mg, 3.56 mmol) And the compound obtained in Step 1 of Intermediate 4-A (979 mg, 3.92 mmol) was dissolved in DMF (35 mL). To the solution was added potassium carbonate (1.20 g, 8.90 mmol), and the mixture was stirred at room temperature for 58 hours. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 1.06 g (2.61 mmol) Yield: 73%
MS (ESI, m / z) 406 [M + H] +
工程３　中間体１１－Ａの合成
　工程２で得られた化合物（１．０６ｇ，２．６１ｍｍｏｌ）をＴＨＦ（６ｍＬ）及びメタノール（６ｍＬ）の混合溶媒に溶解し、２Ｎ　水酸化ナトリウム水溶液（２．６ｍＬ）を加えて室温で１時間半撹拌した。減圧下溶媒を留去後、得られた残渣に１Ｎ　塩酸水溶液（１．２ｍＬ）および水（１０ｍＬ）を加えることで生じた沈殿物を濾過した。得られた沈殿物を水で洗浄して、乾燥することで表題化合物を得た。
収量：９２３ｍｇ（２．４５ｍｍｏｌ）　収率：９４％
MS (ESI) m/z 378 [M+H]+
Figure JPOXMLDOC01-appb-I000032
中間体１１－Ｂ　2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニルクロリドの合成
　中間体１１－Ａ（１５０ｍｇ，０．３９７ｍｍｏｌ）に塩化チオニル（２．００ｍＬ）を加えＤＭＦを少量滴下し、５５℃で４５分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000033
 Step 3 Synthesis of Intermediate 11-A The compound obtained in Step 2 (1.06 g, 2.61 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (6 mL), and 2N aqueous sodium hydroxide solution (2. 6 mL) was added and stirred at room temperature for 1.5 hours. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid (1.2 mL) and water (10 mL) were added to the resulting residue, and the resulting precipitate was filtered. The obtained precipitate was washed with water and dried to obtain the title compound.
Yield: 923 mg (2.45 mmol) Yield: 94%
MS (ESI) m / z 378 [M + H] +
Figure JPOXMLDOC01-appb-I000032
Intermediate 11-B Synthesis of 2-[[4- (4,5-difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl chloride Intermediate 11-A (150 mg, 0.397 mmol) was chlorinated. Thionyl (2.00 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 45 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000033
中間体１２－Ａ　5-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボン酸の合成
工程１　4-(4,5-ジフルオロベンゾフラン-7-イル)フェノールの合成
　７－ブロモ－４，５－ジフルオロベンゾフラン（２．２ｇ，８．７ｍｍｏｌ）に１，４－ジオキサン（７５ｍＬ）および水（２５ｍＬ）、４－ヒドロキシフェニルボロン酸（１．４ｇ，１０．２ｍｍｏｌ）、炭酸ナトリウム（１．８ｇ，１７ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（触媒量）を加えて１００℃で２時間撹拌した。不溶物を濾別した後、減圧下溶媒を留去することで残渣を得た。得られた残渣を酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．１ｇ（８．５ｍｍｏｌ） 収率：９８％
工程２　中間体１２－Ａの合成
　工程１で得られた化合物（２．１ｇ，８．５ｍｍｏｌ）、５－クロロメチル－２－フランカルボン酸エチル（１．５３ｇ，８．５ｍｍｏｌ）、炭酸カリウム（２．３４ｇ，１７ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（３０ｍＬ）、ＴＨＦ（３０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（３０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルで洗浄することにより、表題化合物を得た。
収量：１．５ｇ（４．０ｍｍｏｌ） 収率：４８％
Figure JPOXMLDOC01-appb-I000034
 Intermediate 12-A Synthesis of 5-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carboxylic acid Step 1 4- (4,5-Difluorobenzofuran -7-yl) Phenol Synthesis 7-Bromo-4,5-difluorobenzofuran (2.2 g, 8.7 mmol) was added to 1,4-dioxane (75 mL) and water (25 mL), 4-hydroxyphenylboronic acid (1 0.4 g, 10.2 mmol), sodium carbonate (1.8 g, 17 mmol), and PdCl 2 (dppf) (catalytic amount) were added, and the mixture was stirred at 100 ° C. for 2 hours. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 2.1 g (8.5 mmol) Yield: 98%
Step 2 Synthesis of Intermediate 12-A The compound obtained in Step 1 (2.1 g, 8.5 mmol), ethyl 5-chloromethyl-2-furancarboxylate (1.53 g, 8.5 mmol), potassium carbonate ( 2.34 g, 17 mmol) was added DMF (75 mL) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (30 mL), THF (30 mL), 1N aqueous sodium hydroxide solution (30 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by washing the residue obtained by evaporating the solvent under reduced pressure with acetonitrile.
Yield: 1.5 g (4.0 mmol) Yield: 48%
Figure JPOXMLDOC01-appb-I000034
中間体１２－Ｂ　5-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニルクロリドの合成
　中間体１２－Ａ（７７ｍｇ，０．２０ｍｍｏｌ）に塩化チオニル（０．８０ｍＬ）を加えＤＭＦを少量滴下し、５５℃で３０分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000035
中間体１３－Ａ　5-[[4-[4,5-ジフルオロ-2-((トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボン酸の合成
　４－［４，５－ジフルオロ－２－（トリデューテリオメトキシ）フェニル］フェノール（０．９７ｇ，４．１ｍｍｏｌ）、５－クロロメチル－２－フランカルボン酸エチル（０．６２ｍｌ，４．１ｍｍｏｌ）、炭酸カリウム（１．１２ｇ，８．１２ｍｍｏｌ）にＤＭＦ（７５ｍＬ）を加え、室温で一晩撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（３０ｍＬ）、ＴＨＦ（３０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（３０ｍｌ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルと水（ｖ／ｖ＝１／１）の混合溶媒で洗浄することにより、表題化合物を得た。
収量：０．８０ｇ（２．２ｍｍｏｌ） 収率：５４％
Figure JPOXMLDOC01-appb-I000036
 Intermediate 12-B Synthesis of 5-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl chloride Intermediate 12-A (77 mg, 0.20 mmol) was mixed with thionyl chloride. (0.80 mL) was added and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 30 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000035
Intermediate 13-A Synthesis of 5-[[4- [4,5-difluoro-2-((trideteriomethoxy) phenyl] phenoxy] methyl] furan-2-carboxylic acid 4- [4,5-difluoro- 2- (triduteriomethoxy) phenyl] phenol (0.97 g, 4.1 mmol), ethyl 5-chloromethyl-2-furancarboxylate (0.62 ml, 4.1 mmol), potassium carbonate (1.12 g, 8 DMF (75 mL) was added to .12 mmol), and the mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (30 mL), THF (30 mL), 1N aqueous sodium hydroxide solution (30 ml) were added to the residue and stirred overnight, and the solvent was evaporated under reduced pressure to obtain ethyl acetate. After dilution, the mixture was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was a mixed solvent of acetonitrile and water (v / v = 1/1). The title compound was obtained by washing with
Yield: 0.80 g (2.2 mmol) Yield: 54%
Figure JPOXMLDOC01-appb-I000036
中間体１３－Ｂ　5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニルクロリドの合成
　中間体１３－Ａ（７３ｍｇ，０．２０ｍｍｏｌ）に塩化チオニル（０．８０ｍＬ）を加えＤＭＦを少量滴下し、５５℃で３０分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000037
中間体１４－Ａ　5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボン酸の合成
　中間体６－Ａと同様の操作を、２－ブロモメチルチアゾール－４－カルボン酸エチルの代わりに５－クロロメチル－２－フランカルボン酸エチルを用いて行うことにより、表題化合物を得た。
Figure JPOXMLDOC01-appb-I000038
 Intermediate 13-B Synthesis of 5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl chloride Intermediate 13-A (73 mg, 0. 20 mmol), thionyl chloride (0.80 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 30 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000037
Intermediate 14-A Synthesis of 5-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carboxylic acid The same procedure as in Intermediate 6-A was performed. The title compound was obtained by using ethyl 5-chloromethyl-2-furancarboxylate instead of ethyl 2-bromomethylthiazole-4-carboxylate.
Figure JPOXMLDOC01-appb-I000038
中間体１４－Ｂ　5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニルクロリドの合成
　中間体１４－Ａ（７７ｍｇ，０．２０ｍｍｏｌ）に塩化チオニル（０．８０ｍＬ）を加えＤＭＦを少量滴下し、５５℃で３０分撹拌した。冷却後、減圧濃縮し表題化合物を得た。
Figure JPOXMLDOC01-appb-I000039
中間体１５　5-[[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]メチル]フラン-2-カルボン酸の合成
　４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（２．０４ｇ，９．２７ｍｍｏｌ）、５－クロロメチル－２－フランカルボン酸エチル（１．７５ｇ，９．２７ｍｍｏｌ）、炭酸カリウム（２．５６ｇ，１８．５ｍｍｏｌ）にＤＭＦ（５０ｍＬ）を加え、室温で一晩撹拌した後、７５℃で４時間撹拌した。酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣にメタノール（４０ｍＬ）、ＴＨＦ（４０ｍＬ）、１Ｎ　水酸化ナトリウム水溶液（４０ｍＬ）を加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をアセトニトリルで洗浄し、表題化合物を得た。
Figure JPOXMLDOC01-appb-I000040
 Intermediate 14-B Synthesis intermediate 14-A of 5-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl chloride (77 mg, 0. 20 mmol), thionyl chloride (0.80 mL) was added, and a small amount of DMF was added dropwise, followed by stirring at 55 ° C. for 30 minutes. After cooling, the title compound was obtained by concentration under reduced pressure.
Figure JPOXMLDOC01-appb-I000039
Intermediate 15 Synthesis of 5-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl] furan-2-carboxylic acid 4- (4 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (2.04 g, 9.27 mmol), ethyl 5-chloromethyl-2-furancarboxylate (1.75 g, 9. 27 mmol) and potassium carbonate (2.56 g, 18.5 mmol) were added DMF (50 mL), and the mixture was stirred overnight at room temperature, and then stirred at 75 ° C. for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. Methanol (40 mL), THF (40 mL), 1N aqueous sodium hydroxide solution (40 mL) were added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with acetonitrile to give the title compound.
Figure JPOXMLDOC01-appb-I000040
中間体１６　2-[2-メトキシエチル-[5-[[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸ベンジルの合成
　中間体１５（２．０ｇ，５．８ｍｍｏｌ）にチオニルクロライド（１５ｍＬ）、ＤＭＦ（触媒量）を加え、５０℃で２時間撹拌した。冷却後、減圧下溶媒を留去後、ジクロロメタン（３０ｍＬ）に溶解し、２－（２－メトキシエチルアミノ）酢酸ベンジル（２．４ｇ，１１ｍｍｏｌ）、トリエチルアミン（１．６ｍＬ，１２ｍｍｏｌ）を加え、室温で２時間撹拌した。１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルクロマトグラフィーにて精製し、表題化合物を得た。
収量：２．３ｇ（４．１ｍｍｏｌ） 収率：７０％
Figure JPOXMLDOC01-appb-I000041
中間体１７　2-[2-[tert-ブトキシカルボニル(メチル)アミノ]エチル-[2-[[4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸ベンジルの合成
工程１　2-[2-[tert-ブトキシカルボニル(メチル)アミノ]エチルアミノ]酢酸ベンジルの合成
　Ｎ－（２－アミノエチル）－Ｎ－メチル－カルバミン酸 ｔｅｒｔ－ブチル（５２３ｍｇ，３．００ｍｍｏｌ）をアセトニトリル（１２ｍＬ）で希釈し、炭酸カリウム（６８４ｍｇ，４．９５ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（２ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．５１８ｍＬ，３．３０ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１５時間撹拌した。不溶物を濾別後、減圧下濃縮することで表題化合物を無精製で得た。
収量：８４９ｍｇ Intermediate 16 2- [2-Methoxyethyl- [5-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] methyl] furan-2- Thionyl chloride (15 mL) and DMF (catalytic amount) were added to synthesis intermediate 15 (2.0 g, 5.8 mmol) of carbonyl] amino] benzyl acetate , and the mixture was stirred at 50 ° C. for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane (30 mL), and benzyl 2- (2-methoxyethylamino) acetate (2.4 g, 11 mmol) and triethylamine (1.6 mL, 12 mmol) were added. For 2 hours. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain the title compound.
Yield: 2.3 g (4.1 mmol) Yield: 70%
Figure JPOXMLDOC01-appb-I000041
Intermediate 17 2- [2- [tert-Butoxycarbonyl (methyl) amino] ethyl- [2-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Synthesis of benzyl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetate Step 1 Synthesis of benzyl 2- [2- [tert-butoxycarbonyl (methyl) amino] ethylamino] acetate N- (2- Aminoethyl) -N-methyl-carbamate tert-butyl (523 mg, 3.00 mmol) was diluted with acetonitrile (12 mL), potassium carbonate (684 mg, 4.95 mmol) was added, and the mixture was cooled to 0 ° C., and then acetonitrile ( Benzyl 2-bromoacetate (0.518 mL, 3.30 mmol) diluted with 2 mL) was added dropwise, and the mixture was stirred for 15 hours while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 849 mg
工程２　中間体１７の合成
　中間体１７（１．１５ｇ，３．３４ｍｍｏｌ）にチオニルクロライド（５ｍＬ）を加えて、５０℃で３時間撹拌した。減圧下溶媒を留去して得られた残渣をジクロロメタン（３０ｍＬ）に溶解し、０℃に冷却した。その溶液に、工程１で得られた化合物（１．６１ｇ，５．０１ｍｍｏｌ）とジイソプロピルエチルアミン（以下、ＤＩＰＥＡ）（２．９ｍＬ，１７ｍｍｏｌ）を加え、徐々に室温に戻しながら、１６時間撹拌した。反応液をジクロロメタンで希釈し、飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を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（ヘキサン／酢酸エチル）で精製することで表題化合物を得た。
収量：６７７ｍｇ（１．０７ｍｍｏｌ）　収量：３２％
MS (ESI) m/z 650 [M+H]+ 
　上記実施例で得られた中間体の構造式を表１－１～１－３に示す。 Step 2 Synthesis of Intermediate 17 To intermediate 17 (1.15 g, 3.34 mmol) was added thionyl chloride (5 mL), and the mixture was stirred at 50 ° C. for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in dichloromethane (30 mL) and cooled to 0 ° C. To the solution were added the compound obtained in Step 1 (1.61 g, 5.01 mmol) and diisopropylethylamine (hereinafter DIPEA) (2.9 mL, 17 mmol), and the mixture was stirred for 16 hours while gradually returning to room temperature. The reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The title compound was obtained by purifying the residue obtained by evaporating the solvent under reduced pressure by silica gel column chromatography (hexane / ethyl acetate).
Yield: 677 mg (1.07 mmol) Yield: 32%
MS (ESI) m / z 650 [M + H] +
The structural formulas of intermediates obtained in the above examples are shown in Tables 1-1 to 1-3.
表１－１
Figure JPOXMLDOC01-appb-I000042
Table 1-1
Figure JPOXMLDOC01-appb-I000042
表１－２
Figure JPOXMLDOC01-appb-I000043
Table 1-2
Figure JPOXMLDOC01-appb-I000043
表１－３

Figure JPOXMLDOC01-appb-I000044
Table 1-3

Figure JPOXMLDOC01-appb-I000044
実施例１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
工程１　2-(2-メトキシエチル)アミノ]酢酸ベンジルの合成
　２－メトキシエタンアミン（０．１７３ｍＬ，２．００ｍｍｏｌ）をアセトニトリル（１２ｍＬ）で希釈し、炭酸カリウム（４１５ｍｇ，３．００ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（４ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．３２９ｍＬ，２．１０ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１２時間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで、表題化合物を無精製で得た。
収量：４５１ｍｇ
MS (ESI, m/z) 224 [M+H]+
工程２　実施例１化合物の合成
　中間体１－Ａ（９４．１ｍｇ，０．２５０ｍｍｏｌ）に塩化チオニル（１ｍＬ）とＤＭＦを１滴加えて、５０℃で３０分撹拌した。減圧下溶媒を留去することで、中間体１－Ｂを得た。得られた中間体１－Ｂをジクロロメタン（２ｍＬ）で希釈し、その溶液をＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）および工程１で得られた粗生成物（１１２ｍｇ，０．５００ｍｍｏｌ）を溶かしたジクロロメタン溶液（２ｍＬ）に氷冷下にて加えて室温で一晩撹拌した。反応溶液にジクロロメタンを加えて希釈し、有機層を１Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下濃縮後、得られた残渣をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１．０ｍＬ）を加え、室温で３０分撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣をＯＤＳを充填剤とする逆相ＨＰＬＣに付し、トリフルオロ酢酸０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶液で溶出し、目的のフラクションを凍結乾燥することにより、表題化合物を得た。
収量：９７．５ｍｇ（０．１９８ｍｍｏｌ）　収率：７９％
MS (ESI) m/z 492 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.1 - 12.4 (m, 1H), 7.40 - 7.26 (m, 4H), 7.16 - 6.96 (m, 3H), 6.76 (s, 1H), 5.27 - 5.06 (m, 2H), 4.46 - 4.06 (m, 2H), 3.82 - 3.41 (m, 4H), 3.23 (s, 3H), 2.39 (s, 3H). Example 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Step 1 2 Synthesis of benzyl-(2-methoxyethyl) amino] acetate 2-methoxyethanamine (0.173 mL, 2.00 mmol) was diluted with acetonitrile (12 mL), potassium carbonate (415 mg, 3.00 mmol) was added, and -10 After cooling to 0 ° C., benzyl 2-bromoacetate (0.329 mL, 2.10 mmol) diluted with acetonitrile (4 mL) was added dropwise, and the mixture was stirred for 12 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 451 mg
MS (ESI, m / z) 224 [M + H] +
Step 2 Synthesis of Compound of Example 1 To 1-A (94.1 mg, 0.250 mmol), 1 drop of thionyl chloride (1 mL) and DMF were added and stirred at 50 ° C. for 30 minutes. The solvent was removed under reduced pressure to obtain Intermediate 1-B. The resulting intermediate 1-B was diluted with dichloromethane (2 mL), and the solution was dissolved with DIPEA (0.044 mL, 0.25 mmol) and the crude product obtained in step 1 (112 mg, 0.500 mmol). The mixture was added to a dichloromethane solution (2 mL) under ice cooling and stirred overnight at room temperature. Dichloromethane was added to the reaction solution for dilution, and the organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N aqueous lithium hydroxide solution (1.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase HPLC using ODS as a filler, and water and acetonitrile containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solution of and lyophilizing the desired fraction.
Yield: 97.5 mg (0.198 mmol) Yield: 79%
MS (ESI) m / z 492 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.1-12.4 (m, 1H), 7.40-7.26 (m, 4H), 7.16-6.96 (m, 3H), 6.76 (s, 1H), 5.27-5.06 (m, 2H), 4.46-4.06 (m, 2H), 3.82-3.41 (m, 4H), 3.23 (s, 3H), 2.39 (s, 3H).
実施例２　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　中間体４－Ａ（９８．４ｍｇ，０．２５０ｍｍｏｌ）に塩化チオニル（１ｍＬ）とＤＭＦを１滴加えて、５０℃で３０分撹拌した。溶媒を減圧除去後、得られた残渣をジクロロメタン（２ｍＬ）で希釈し、その溶液を、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）および実施例１の工程１で得られた化合物（１１２ｍｇ，０．５００ｍｍｏｌ）を溶かしたジクロロメタン溶液（２ｍＬ）に氷冷下にて加えて室温で一晩撹拌した。反応溶液にジクロロメタンを加えて希釈し、有機層を１Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去後、得られた残渣をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で３０分撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７０．８ｍｇ（０．１３９ｍｍｏｌ）　収率：５６％
MS (ESI) m/z 509 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.32 - 8.10 (m, 1H), 7.47 - 7.23 (m, 4H), 7.20 - 7.03 (m, 2H), 5.61 - 5.40 (m, 2H), 4.66 - 4.06 (m, 2H), 3.79 - 3.48 (m, 4H), 3.28 - 3.16 (m, 3H), 2.39 (s, 3H). Example 2 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 4 To A (98.4 mg, 0.250 mmol) was added 1 drop of thionyl chloride (1 mL) and DMF, and the mixture was stirred at 50 ° C. for 30 minutes. After removing the solvent under reduced pressure, the obtained residue was diluted with dichloromethane (2 mL), and the solution was diluted with DIPEA (0.044 mL, 0.25 mmol) and the compound obtained in Step 1 of Example 1 (112 mg,. 500 mmol) was dissolved in a dichloromethane solution (2 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction solution for dilution, and the organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N aqueous lithium hydroxide solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 70.8 mg (0.139 mmol) Yield: 56%
MS (ESI) m / z 509 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.6 (s, 1H), 8.32-8.10 (m, 1H), 7.47-7.23 (m, 4H), 7.20-7.03 (m, 2H), 5.61-5.40 (m, 2H), 4.66-4.06 (m, 2H), 3.79-3.48 (m, 4H), 3.28-3.16 (m, 3H), 2.39 (s, 3H).
実施例３　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[2-[tert-ブトキシカルボニル(メチル)アミノ]エチルアミノ]酢酸ベンジルの合成
　Ｎ－（２－アミノエチル）－Ｎ－メチル－カルバミン酸 ｔｅｒｔ－ブチル（５２３ｍｇ，３．００ｍｍｏｌ）をアセトニトリル（１２ｍＬ）で希釈し、炭酸カリウム（６８４ｍｇ，４．９５ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（２ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．５１８ｍＬ，３．３０ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１５時間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで表題化合物を無精製で得た。
収量：８４９ｍｇ
工程２　2-[2-[tert-ブトキシカルボニル(メチル)アミノ]エチル-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸の合成
　中間体１－Ａ（８０．０ｍｇ，０．２１３ｍｍｏｌ）を塩化チオニル（０．５ｍＬ）に溶解して４０℃で１時間撹拌した。減圧下溶媒を留去することで中間体１－Ｂを得た。得られた残渣にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、工程１で得られた生成物（１０３ｍｇ，０．３１９ｍｍｏｌ）とＤＩＰＥＡ（０．１４８ｍＬ，０．８５２ｍｍｏｌ）を加えて、室温で１８時間半撹拌した。反応液を減圧下濃縮後、得られた残渣をＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（１．０ｍＬ）を加え、室温で３時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５４．９ｍｇ（０．０９３１ｍｍｏｌ）　収率：４４％
MS (ESI, m/z) 591 [M+H]+
工程３　実施例３化合物の合成
　工程２で得られた生成物（５４．９ｍｇ，０．０９３１ｍｍｏｌ）にＴＦＡ（１ｍＬ）とジクロロメタン（２ｍＬ）を加えた後、室温で３０分撹拌した。反応液を減圧下濃縮後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５８．８ｍｇ（０．０９３１ｍｍｏｌ）　収率：１００％
MS (ESI) m/z 491 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.27 (m, 2H), 7.44 - 7.24 (m, 4H), 7.20 - 6.74 (m, 4H), 5.34 - 5.05 (m, 2H), 4.54 - 4.04 (m, 2H), 4.00 - 3.66 (m, 2H), 3.22 - 3.09 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H). Example 3 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Trifluoroacetate Step 1 Synthesis of benzyl 2- [2- [tert-butoxycarbonyl (methyl) amino] ethylamino] acetate N- (2-aminoethyl) -N-methyl-carbamate tert-butyl (523 mg, 3 0.000 mmol) was diluted with acetonitrile (12 mL), potassium carbonate (684 mg, 4.95 mmol) was added, and the mixture was cooled to 0 ° C., and then diluted with acetonitrile (2 mL) benzyl 2-bromoacetate (0.518 mL, 3.95 mL). 30 mmol) was added dropwise and stirred for 15 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 849 mg
Step 2 2- [2- [tert-Butoxycarbonyl (methyl) amino] ethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] Synthesis of amino] acetic acid Intermediate 1-A (80.0 mg, 0.213 mmol) was dissolved in thionyl chloride (0.5 mL) and stirred at 40 ° C. for 1 hour. Intermediate 1-B was obtained by distilling off the solvent under reduced pressure. Dichloromethane (2 mL) was added to the resulting residue and dissolved. To the solution, the product obtained in Step 1 (103 mg, 0.319 mmol) and DIPEA (0.148 mL, 0.852 mmol) were added and stirred at room temperature for 18 and a half hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. did. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 54.9 mg (0.0931 mmol) Yield: 44%
MS (ESI, m / z) 591 [M + H] +
Step 3 Synthesis of Example 3 Compound TFA (1 mL) and dichloromethane (2 mL) were added to the product obtained in Step 2 (54.9 mg, 0.0931 mmol), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 58.8 mg (0.0931 mmol) Yield: 100%
MS (ESI) m / z 491 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89-8.27 (m, 2H), 7.44-7.24 (m, 4H), 7.20-6.74 (m, 4H), 5.34-5.05 (m, 2H), 4.54 -4.04 (m, 2H), 4.00-3.66 (m, 2H), 3.22-3.09 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H).
実施例４　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸エチルの合成
　オキサゾール－２－イルメタンアミン　塩酸塩（６９ｍｇ，０．５０ｍｍｏｌ）のアセトニトリル（３ｍＬ）溶液に、炭酸カリウム（１７３ｍｇ，１．２５ｍｍｏｌ）を加えて－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸エチル（０．０５５ｍＬ，０．５０ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去して得られた残渣を、ジクロロメタン（４ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７５ｍｇ，０．２０ｍｍｏｌ）を加えて室温で４５分撹拌した。反応液を減圧下で溶媒を留去し、表題化合物を無精製で得た。
MS (ESI) m/z 543 [M+H]+
工程２　実施例４化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．９ｍＬ）を加え、室温で一晩撹拌した。さらに１Ｎ　水酸化リチウム水溶液（０．４ｍＬ）を加え１時間撹拌し、反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した。減圧下溶媒を留去し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５０．８ｍｇ（０．０９８７ｍｍｏｌ）　収率：４９％
MS (ESI) m/z 515 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.43 - 7.00 (m, 8H), 6.77 (d, J = 3.5 Hz, 1H), 5.15 (s, 2H), 5.02 - 4.79 (m, 2H), 4.49 - 4.15 (m, 2H), 2.40 (s, 3H). Example 4 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid Step 1 Synthesis of ethyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(oxazol-2-ylmethyl) amino] acetate Oxazole- To a solution of 2-ylmethanamine hydrochloride (69 mg, 0.50 mmol) in acetonitrile (3 mL) was added potassium carbonate (173 mg, 1.25 mmol) and cooled to −10 ° C. to −15 ° C., then acetonitrile (1 mL) 2-Bromoacetic acid ethyl diluted (0.055 mL, 0.50 mmol) was added dropwise, and the mixture was gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off, and the residue obtained by evaporating the solvent under reduced pressure was diluted with dichloromethane (4 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (75 mg, 0.20 mmol) were diluted. And stirred at room temperature for 45 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain the title compound without purification.
MS (ESI) m / z 543 [M + H] +
Step 2 Synthesis of Example 4 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.9 mL) was added, and the mixture was stirred at room temperature overnight. Further, 1N lithium hydroxide aqueous solution (0.4 mL) was added and stirred for 1 hour, and the reaction solution was neutralized with 1N trifluoroacetic acid aqueous solution. The solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 50.8 mg (0.0987 mmol) Yield: 49%
MS (ESI) m / z 515 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (s, 1H), 7.43-7.00 (m, 8H), 6.77 (d, J = 3.5 Hz, 1H), 5.15 (s, 2H), 5.02- 4.79 (m, 2H), 4.49-4.15 (m, 2H), 2.40 (s, 3H).
実施例５　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[[5-(メトキシメチル)-1,2,4-オキサジアゾール-3-イル]メチル]アミノ]酢酸
工程１　2-[シアノメチル-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸ベンジルの合成
　シアノメタンアミン（１３９ｍｇ，１．５０ｍｍｏｌ）をアセトニトリル（５ｍＬ）で希釈し、炭酸カリウム（５１８ｍｇ，３．７５ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．２５９ｍＬ，１．６５ｍｍｏｌ）を滴下して一晩間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで残渣を得た。得られた残渣をジクロロメタン（５ｍＬ）で希釈し、氷冷下にてＤＩＰＥＡ（０．１７４ｍＬ，１．００ｍｍｏｌ）および中間体１－Ｂ（３８７ｍｇ，０．９８０ｍｍｏｌ）を加えた後、室温で６４時間撹拌した。反応溶液にジクロロメタンを加えて希釈し、有機層を０．５Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）を用いて精製することで表題化合物を得た。
収量：　２３０ｍｇ（０．４０９ｍｍｏｌ）　収率：　４２％
MS (ESI, m/z) 563 [M+H]+
工程２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(ヒドロキシアミノ)-2-イミノ-エチル]アミノ]酢酸ベンジルの合成
　工程１で得られた化合物（２３０ｍｇ，０．４０９ｍｍｏｌ）をエタノール（５ｍＬ）に溶解し、５０％　ヒドロキシアミン水溶液（０．０５４０ｍＬ，０．８１８ｍｍｏｌ）を加えて、９０℃で一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去することで表題化合物を無精製で得た。
収量：１７０ｍｇ
MS (ESI) m/z 596 [M+H]+ Example 5 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[[5- (methoxymethyl) -1,2 , 4-Oxadiazol-3-yl] methyl] amino] acetic acid Step 1 2- [cyanomethyl-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan Synthesis of -2-carbonyl] amino] benzyl acetate Cyanomethanamine (139 mg, 1.50 mmol) was diluted with acetonitrile (5 mL), potassium carbonate (518 mg, 3.75 mmol) was added, and the mixture was cooled to −10 ° C. Benzyl 2-bromoacetate (0.259 mL, 1.65 mmol) diluted with acetonitrile (1 mL) was added dropwise and stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to obtain a residue. The obtained residue was diluted with dichloromethane (5 mL), and DIPEA (0.174 mL, 1.00 mmol) and intermediate 1-B (387 mg, 0.980 mmol) were added under ice cooling, followed by 64 hours at room temperature. Stir. Dichloromethane was added to the reaction solution for dilution, and the organic layer was washed successively with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by purifying the residue obtained by distilling off the solvent under reduced pressure using silica gel column chromatography (hexane / ethyl acetate).
Yield: 230 mg (0.409 mmol) Yield: 42%
MS (ESI, m / z) 563 [M + H] +
Step 2 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (hydroxyamino) -2-imino-ethyl Synthesis of amino] benzyl acetate The compound obtained in Step 1 (230 mg, 0.409 mmol) was dissolved in ethanol (5 mL), 50% aqueous hydroxyamine solution (0.0540 mL, 0.818 mmol) was added, and 90 ° C. And stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 170mg
MS (ESI) m / z 596 [M + H] +
工程３　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[[5-(メトキシメチル)-1,2,4-オキサジアゾール-3-イル]メチル]アミノ]酢酸ベンジルの合成
　工程２で得られた化合物（１７０ｍｇ）をＤＭＦ（１．５ｍＬ）に溶解し、２－メトキシアセトニトリル（０．１８０ｍＬ，２．４０ｍｍｏｌ）、ｐ－トルエンスルホン酸・１水和物（１１．４ｍｇ，０．０６００ｍｍｏｌ），０．７Ｍ　亜鉛クロライドのＴＨＦ溶液（０．０８６ｍＬ，０．０６０ｍｍｏｌ）を加えて１００℃で２２時間撹拌した。反応液を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：　１０．５ｍｇ（０．０１６２ｍｍｏｌ）　収率：１３％（工程２から）
MS (ESI) m/z 650 [M+H]+
工程４　実施例５化合物の合成
　工程３で得られた化合物（１０．５ｍｇ，０．０１６２ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．２ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７．５ｍｇ（０．０１３４ｍｍｏｌ）　収率：８３％
MS (ESI) m/z 560 [M+H]+ Step 3 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[[5- (methoxymethyl) -1,2, Synthesis of 4-oxadiazol-3-yl] methyl] amino] benzyl acetate The compound obtained in Step 2 (170 mg) was dissolved in DMF (1.5 mL) and 2-methoxyacetonitrile (0.180 mL, 2. 40 mmol), p-toluenesulfonic acid monohydrate (11.4 mg, 0.0600 mmol), 0.7 M zinc chloride in THF (0.086 mL, 0.060 mmol) was added, and the mixture was stirred at 100 ° C. for 22 hours. . After the reaction solution was distilled off under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 10.5 mg (0.0162 mmol) Yield: 13% (from step 2)
MS (ESI) m / z 650 [M + H] +
Step 4 Synthesis of Example 5 Compound The compound obtained in Step 3 (10.5 mg, 0.0162 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.2 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution and distilling off the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 7.5 mg (0.0134 mmol) Yield: 83%
MS (ESI) m / z 560 [M + H] +
実施例６　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシプロピル)アミノ]酢酸
工程１　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシプロピル)アミノ]酢酸エチルの合成
　２－メトキシプロパン－１－アミン　塩酸塩（１２６ｍｇ，１．００ｍｍｏｌ）のアセトニトリル（７ｍＬ）溶液にトリエチルアミン（０．３０７ｍＬ，２．２０ｍｍｏｌ）を加えて－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸エチル（０．１１０ｍＬ，１．００ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣を、ジクロロメタン（６ｍＬ）で希釈し、ＤＩＰＥＡ（１７４μＬ，１．００ｍｍｏｌ）および中間体４－Ｂ（８１ｍｇ，０．２０ｍｍｏｌ）を加えて室温で１時間撹拌した。減圧下溶媒を留去し、表題化合物を無精製で得た。
MS (ESI) m/z 551 [M+H]+
工程２　実施例６化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（５ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（２．５ｍＬ）を加え、室温で５０分撹拌した。さらに１Ｎ　水酸化リチウム水溶液（０．７５ｍＬ）、１，４－ジオキサン（３ｍＬ）を加え室温で３０分撹拌し、反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した。減圧下溶媒を留去し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２５．２ｍｇ（０．０４８３ｍｍｏｌ）　収率：１９％
MS (ESI) m/z 523 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.46 - 7.04 (m, 6H), 5.62 - 5.38 (m, 2H), 4.71 - 4.43 (m, 1H), 4.32 - 4.03 (m, 1H), 3.82 - 3.56 (m, 2H), 3.36 - 3.27 (m, 1H), 3.26 - 3.15 (m, 3H), 2.39 (s, 3H), 1.15 - 0.92 (m, 3H). Example 6 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxypropyl) amino] acetic acid Step 1 2 Of 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxypropyl) amino] ethyl acetate 2-methoxypropane Triethylamine (0.307 mL, 2.20 mmol) was added to a solution of 1-amine hydrochloride (126 mg, 1.00 mmol) in acetonitrile (7 mL), cooled to −10 ° C. to −15 ° C., and then added with acetonitrile (1 mL). Diluted ethyl 2-bromoacetate (0.110 mL, 1.00 mmol) was added dropwise, and the mixture was gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane (6 mL), and DIPEA (174 μL, 1.00 mmol) and intermediate 4-B (81 mg, 0.20 mmol) were added. Stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain the title compound without purification.
MS (ESI) m / z 551 [M + H] +
Step 2 Synthesis of Example 6 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (5 mL), 1N aqueous lithium hydroxide solution (2.5 mL) was added, and the mixture was stirred at room temperature for 50 minutes. Further, 1N lithium hydroxide aqueous solution (0.75 mL) and 1,4-dioxane (3 mL) were added and stirred at room temperature for 30 minutes, and the reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution. The solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 25.2 mg (0.0483 mmol) Yield: 19%
MS (ESI) m / z 523 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.46-7.04 (m, 6H), 5.62-5.38 (m, 2H), 4.71-4.43 (m, 1H), 4.32-4.03 (m, 1H), 3.82-3.56 (m, 2H), 3.36-3.27 (m, 1H), 3.26-3.15 (m, 3H), 2.39 (s, 3H), 1.15-0.92 (m, 3H).
実施例７　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
MS (ESI) m/z 532 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.06 (d, J = 6.6 Hz, 1H), 7.47 - 7.03 (m, 7H), 5.47 (s, 2H), 5.27 - 4.76 (m, 2H), 4.67 - 4.14 (m, 2H), 2.39 (s, 3H).実施例８　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(1S)-2-メトキシ-1-メチル-エチル]アミノ]酢酸
　（２Ｓ）－１－メトキシプロパン－２－アミン　塩酸塩（５４０ｍｇ，４．９１ｍｍｏｌ）のアセトニトリル溶液に、炭酸カリウム（１．３６ｇ，９．８２ｍｍｏｌ）を加え、－２０℃下、２－ブロモ酢酸ベンジル（０．６９５ｍｌ，４．４２ｍｍｏｌ）をゆっくり加えた。同温下、１時間撹拌後、室温に戻して一晩撹拌した。不溶物を濾別した後、減圧下溶媒を留去し、得られた残渣をＴＨＦ、中間体１－Ｂ（２４２ｍｇ，０．６２０ｍｍｏｌ）、トリエチルアミン（０．２３０ｍＬ，１．６４ｍｍｏｌ）を加え室温で撹拌した後、１Ｎ　水酸化ナトリウム水溶液、メタノールを加え一晩撹拌した。減圧下溶媒を留去して得られた残渣を、酢酸エチルで希釈した後、１Ｎ　塩酸、および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た
収量：２７ｍｇ（０．０５３ｍｍｏｌ）　収率：８％
MS (ESI) m/z 506 [M+H]+ Example 7 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid The title compound was obtained in the same manner as in 4 except that intermediate 4-B was used instead of intermediate 1-B.
MS (ESI) m / z 532 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.06 (d, J = 6.6 Hz, 1H), 7.47-7.03 (m, 7H), 5.47 (s, 2H), 5.27- 4.76 (m, 2H), 4.67-4.14 (m, 2H), 2.39 (s, 3H) Example 8 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) Phenoxy] methyl] furan-2-carbonyl]-[(1S) -2-methoxy-1-methyl-ethyl] amino] acetic acid (2S) -1-methoxypropan-2-amine hydrochloride (540 mg, 4.91 mmol) To the acetonitrile solution, potassium carbonate (1.36 g, 9.82 mmol) was added, and 2-bromobenzyl acetate (0.695 ml, 4.42 mmol) was slowly added at −20 ° C. After stirring at the same temperature for 1 hour, the mixture was returned to room temperature and stirred overnight. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was added with THF, intermediate 1-B (242 mg, 0.620 mmol), triethylamine (0.230 mL, 1.64 mmol) at room temperature. After stirring, 1N aqueous sodium hydroxide solution and methanol were added and stirred overnight. The residue obtained by evaporating the solvent under reduced pressure was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound. Yield: 27 mg (0.053 mmol) Yield: 8%
MS (ESI) m / z 506 [M + H] +
実施例９　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピリジルメチル)アミノ]酢酸ベンジルの合成
　２－ピリジルメタンアミン（５２ｍｇ，０．５０ｍｍｏｌ）のアセトニトリル（４ｍＬ）溶液に、炭酸カリウム（６９ｍｇ，０．５０ｍｍｏｌ）を加えて－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．０７８ｍＬ，０．５０ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去して得られた残渣を、ジクロロメタン（４ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７５ｍｇ，０．２０ｍｍｏｌ）を加えて室温で１時間撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を無精製で得た。
MS (ESI) m/z 615 [M+H]+
工程２　実施例９化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．２１３ｍＬ）を加え、室温で一晩撹拌した。さらに１Ｎ　水酸化リチウム水溶液（０．４ｍＬ）を加え一晩撹拌した。減圧下溶媒留去し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２４．２ｍｇ（０．０３７６ｍｍｏｌ）　収率：１９％
MS (ESI) m/z 525 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.51 (m, 1H), 8.07 - 7.79 (m, 1H), 7.71 - 7.20 (m, 6H), 7.19 - 6.95 (m, 3H), 6.84 - 6.66 (m, 1H), 5.21 - 4.77 (m, 4H), 4.56 - 4.13 (m, 2H), 2.40 (s, 3H). Example 9 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyridylmethyl) amino] acetic acid Trifluoroacetic acid Salt Step 1 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyridylmethyl) amino] acetate To a solution of 2-pyridylmethanamine (52 mg, 0.50 mmol) in acetonitrile (4 mL) was added potassium carbonate (69 mg, 0.50 mmol), cooled to −10 ° C. to −15 ° C., and diluted with acetonitrile (1 mL). The 2-benzyl bromoacetate (0.078 mL, 0.50 mmol) was added dropwise, gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off, and the residue obtained by evaporating the solvent under reduced pressure was diluted with dichloromethane (4 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (75 mg, 0.20 mmol) were diluted. And stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound without purification.
MS (ESI) m / z 615 [M + H] +
Step 2 Synthesis of Example 9 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.213 mL) was added, and the mixture was stirred at room temperature overnight. Further, 1N aqueous lithium hydroxide solution (0.4 mL) was added and stirred overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 24.2 mg (0.0376 mmol) Yield: 19%
MS (ESI) m / z 525 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66-8.51 (m, 1H), 8.07-7.79 (m, 1H), 7.71-7.20 (m, 6H), 7.19-6.95 (m, 3H), 6.84 -6.66 (m, 1H), 5.21-4.77 (m, 4H), 4.56-4.13 (m, 2H), 2.40 (s, 3H).
実施例１０　2-[[4-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　中間体３－Ａ（５１．０ｍｇ，０．１３０ｍｍｏｌ）を塩化チオニル（０．５ｍＬ）に溶解して５５℃で１時間撹拌した。減圧下溶媒を留去し、得られた残渣にジクロロメタン（２．６ｍＬ）を加えて溶解した。その溶液に、実施例１の工程１で得られた生成物（４３．５ｍｇ，０．１９５ｍｍｏｌ）とＤＩＰＥＡ（０．０９１ｍＬ，０．５２ｍｍｏｌ）を加えて、室温で１３時間半撹拌した。減圧下溶媒を留去し、得られた残渣をＴＨＦ（１．５ｍＬ）およびメタノール（１．５ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．６５ｍＬ）を加え、室温で２時間半撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５１．５ｍｇ（０．１０１ｍｍｏｌ）　収率：７８％
MS (ESI) m/z 508 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.80 (brs, 1H), 7.70 - 7.23 (m, 5H), 7.07 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H), 4.45 - 4.04 (m, 2H), 3.82 - 3.49 (m, 4H), 3.25 (s, 3H), 2.39 (s, 3H). Example 10 2-[[4-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 3 -A (51.0 mg, 0.130 mmol) was dissolved in thionyl chloride (0.5 mL) and stirred at 55 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and dichloromethane (2.6 mL) was added to the resulting residue to dissolve it. The product obtained in Step 1 of Example 1 (43.5 mg, 0.195 mmol) and DIPEA (0.091 mL, 0.52 mmol) were added to the solution, and the mixture was stirred at room temperature for 13 and a half hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in a mixed solvent of THF (1.5 mL) and methanol (1.5 mL), 1N aqueous sodium hydroxide solution (0.65 mL) was added under ice cooling, and For 2 and a half hours. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 51.5 mg (0.101 mmol) Yield: 78%
MS (ESI) m / z 508 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (brs, 1H), 7.70-7.23 (m, 5H), 7.07 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H), 4.45- 4.04 (m, 2H), 3.82-3.49 (m, 4H), 3.25 (s, 3H), 2.39 (s, 3H).
実施例１１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(3-メチル-1,2,4-オキサジアゾール-5-イル)メチル]アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(3-メチル-1,2,4-オキサジアゾール-5-イル)メチル]アミノ]酢酸エチルの合成
　グリシンエチルエステル　塩酸塩（６９．８ｍｇ，０．５００ｍｍｏｌ）をＤＭＦ（５ｍＬ）に溶解し、炭酸カリウム（２０７ｍｇ，１．５０ｍｍｏｌ）を加えて０℃に冷却した後、ＤＭＦ（１ｍＬ）で希釈した５－（クロロメチル）－３－メチル－１，２，４－オキサジアゾール（６９．６ｍｇ，０．５２５ｍｍｏｌ）、ヨウ化ナトリウムを少量加えて、徐々に室温に戻しながら１６時間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで残渣を得た。得られた残渣をジクロロメタン（５ｍＬ）に溶解し、中間体１－Ｂ（０．２５０ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて、室温で２時間半撹拌した。減圧下溶媒を留去し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４８．６ｍｇ（０．０８７２ｍｍｏｌ）　収率：３５％
MS (ESI, m/z) 558 [M+H]+
工程２　実施例１１化合物の合成
　工程１で得られた化合物（４８．６ｍｇ，０．０８７２ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．３ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４１．３ｍｇ（０．０７８ｍｍｏｌ）　収率：８９％
MS (ESI) m/z 530 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.24 (m, 4H), 7.16 - 6.99 (m, 3H), 6.82 - 6.73 (m, 1H), 5.30 - 4.85 (m, 4H), 4.67 - 4.16 (m, 2H), 2.39 (s, 3H), 2.34 - 2.22 (m, 3H). Example 11 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(3-methyl-1,2,4- Oxadiazol-5-yl) methyl] amino] acetic acid Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]- Synthesis of ethyl [(3-methyl-1,2,4-oxadiazol-5-yl) methyl] amino] acetate Glycine ethyl ester hydrochloride (69.8 mg, 0.500 mmol) was dissolved in DMF (5 mL). Then, potassium carbonate (207 mg, 1.50 mmol) was added and cooled to 0 ° C., and then diluted with DMF (1 mL), 5- (chloromethyl) -3-methyl-1,2,4-oxadiazole (69. 6 mg, 0.525 mmol), a small amount of sodium iodide was added, and the mixture was stirred for 16 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to obtain a residue. The obtained residue was dissolved in dichloromethane (5 mL), intermediate 1-B (0.250 mmol) and DIPEA (0.044 mL, 0.25 mmol) were added, and the mixture was stirred at room temperature for 2.5 hr. The solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 48.6 mg (0.0872 mmol) Yield: 35%
MS (ESI, m / z) 558 [M + H] +
Step 2 Synthesis of Example 11 Compound The compound obtained in Step 1 (48.6 mg, 0.0872 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.3 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 41.3 mg (0.078 mmol) Yield: 89%
MS (ESI) m / z 530 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43-7.24 (m, 4H), 7.16-6.99 (m, 3H), 6.82-6.73 (m, 1H), 5.30-4.85 (m, 4H), 4.67 -4.16 (m, 2H), 2.39 (s, 3H), 2.34-2.22 (m, 3H).
実施例１２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(1-メチルピラゾール-3-イル)メチル]アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(1-メチルピラゾール-3-イル)メチル]アミノ]酢酸エチルの合成
　グリシンエチルエステル　塩酸塩（２０９ｍｇ，１．５０ｍｍｏｌ）をＴＨＦ（５ｍＬ）およびメタノール（１．５ｍＬ）の混合液に溶解し、１－メチルピラゾール－３－カルバルデヒド（１６５ｍｇ，１．５０ｍｍｏｌ）、酢酸を少量加えて、室温で一晩撹拌した。減圧下溶媒を留去し、得られた残渣をＴＨＦ（１０ｍＬ）に懸濁させて、トリアセトキシ水素化ホウ素ナトリウム（９５４ｍｇ，４．５０ｍｍｏｌ）を加えて室温で３時間撹拌した。反応液を酢酸エチルで希釈し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去後、得られた残渣をジクロロメタン（４ｍＬ）に溶解し、中間体１－Ｂ（１５２ｍｇ，０．３８６ｍｍｏｌ）、ＤＩＰＥＡ（０．０８８ｍＬ，０．５０ｍｍｏｌ）を加えて室温で一晩撹拌した。減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２５．７ｍｇ（０．０４６３ｍｍｏｌ）　収率：１２％
MS (ESI, m/z) 556 [M+H]+
工程２　実施例１２化合物の合成
　工程１で得られた化合物（２５．７ｍｇ，０．０４６３ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１５．７ｍｇ（０．０２９８ｍｍｏｌ）　収率：６４％
MS (ESI) m/z 528 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.8 (brs, 1H), 7.69 - 7.58 (m, 1H), 7.42 - 7.24 (m, 4H), 7.20 - 6.96 (m, 3H), 6.83 - 6.71 (m, 1H), 6.33 - 6.07 (m, 1H), 5.26 - 5.08 (m, 2H), 4.77 - 4.48 (m, 2H), 4.34 - 3.96 (m, 2H), 3.87 - 3.72 (m, 3H), 2.39 (s, 3H). Example 12 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylpyrazol-3-yl) methyl Amino] acetic acid step 1 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylpyrazole-3- Synthesis of ethyl yl) methyl] amino] acetate Glycine ethyl ester hydrochloride (209 mg, 1.50 mmol) was dissolved in a mixture of THF (5 mL) and methanol (1.5 mL) to give 1-methylpyrazole-3-carbaldehyde. (165 mg, 1.50 mmol) and a small amount of acetic acid were added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, the resulting residue was suspended in THF (10 mL), sodium triacetoxyborohydride (954 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in dichloromethane (4 mL), intermediate 1-B (152 mg, 0.386 mmol) and DIPEA (0.088 mL, 0.50 mmol) were added, and the mixture was stirred at room temperature. Stir overnight. The residue obtained by evaporating the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 25.7 mg (0.0463 mmol) Yield: 12%
MS (ESI, m / z) 556 [M + H] +
Step 2 Synthesis of Compound of Example 12 The compound obtained in Step 1 (25.7 mg, 0.0463 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 15.7 mg (0.0298 mmol) Yield: 64%
MS (ESI) m / z 528 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.8 (brs, 1H), 7.69-7.58 (m, 1H), 7.42-7.24 (m, 4H), 7.20-6.96 (m, 3H), 6.83-6.71 (m, 1H), 6.33-6.07 (m, 1H), 5.26-5.08 (m, 2H), 4.77-4.48 (m, 2H), 4.34-3.96 (m, 2H), 3.87-3.72 (m, 3H) , 2.39 (s, 3H).
実施例１３　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(テトラヒドロピラン-4-イルメチル)アミノ]酢酸
工程１　2-(テトラヒドロピラン-4-イルメチルアミノ)酢酸ベンジルの合成
　テトラヒドロピラン－４－イルメタンアミン（０．１８４ｍＬ，１．５０ｍｍｏｌ）をアセトニトリル（１２ｍＬ）に溶解し、炭酸カリウム（３１１ｍｇ，２．２５ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（３ｍＬ）で希釈した２－ブロモ酢酸ベンジルエステル（０．２５９ｍＬ，１．６５ｍｍｏｌ）を加えて、徐々に室温に戻しながら１５時間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで表題化合物を無精製で得た。
収量：４１８ｍｇ
MS (ESI) m/z 264 [M+H]+
工程２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(テトラヒドロピラン-4-イルメチル)アミノ]酢酸ベンジルの合成
　中間体１－Ｂ（９５．０ｍｇ，０．２４１ｍｍｏｌ）にジクロロメタン（５ｍＬ）を加えて溶解し、工程１で得られた化合物（１３９ｍｇ，０．５００ｍｍｏｌ）とＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて、室温で１７時間撹拌した。減圧下溶媒を留去後、得られた残渣を酢酸エチルで希釈し、有機層を０．５Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することで、表題化合物を無精製で得た。
収量：１４４ｍｇ
MS (ESI) m/z 622 [M+H]+
工程３　実施例１３化合物の合成
　工程２で得られた化合物（１４４ｍｇ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（１ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６１．７ｍｇ（０．１１６ｍｍｏｌ）　収率：４８％　（工程２から）
MS (ESI) m/z 532 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.7 (brs, 1H), 7.41 - 7.26 (m, 4H), 7.14 - 6.95 (m, 3H), 6.84 - 6.69 (m, 1H), 5.28 - 5.05 (m, 2H), 4.49 - 4.00 (m, 2H), 3.89 - 3.10 (m, 4H), 2.39 (s, 3H), 1.98 - 1.76 (m, 1H), 1.64 - 1.45 (m, 2H), 1.36 - 1.04 (m, 2H). Example 13 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino] acetic acid step 1 Synthesis of benzyl 2- (tetrahydropyran-4-ylmethylamino) acetate Tetrahydropyran-4-ylmethanamine (0.184 mL, 1.50 mmol) was dissolved in acetonitrile (12 mL) and potassium carbonate (311 mg, 2. 25 mmol), and cooled to −10 ° C., 2-bromoacetic acid benzyl ester (0.259 mL, 1.65 mmol) diluted with acetonitrile (3 mL) was added, and the mixture was stirred for 15 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 418 mg
MS (ESI) m / z 264 [M + H] +
Step 2 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino] acetate Synthesis Intermediate 1-B (95.0 mg, 0.241 mmol) was dissolved by adding dichloromethane (5 mL), and the compound obtained in Step 1 (139 mg, 0.500 mmol) and DIPEA (0.044 mL, 0.25 mmol) were dissolved. ) And stirred at room temperature for 17 hours. After evaporating the solvent under reduced pressure, the obtained residue was diluted with ethyl acetate, and the organic layer was washed successively with 0.5N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound without purification.
Yield: 144mg
MS (ESI) m / z 622 [M + H] +
Step 3 Synthesis of Example 13 Compound The compound obtained in Step 2 (144 mg) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling. For 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 61.7 mg (0.116 mmol) Yield: 48% (from step 2)
MS (ESI) m / z 532 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.7 (brs, 1H), 7.41-7.26 (m, 4H), 7.14-6.95 (m, 3H), 6.84-6.69 (m, 1H), 5.28-5.05 (m, 2H), 4.49-4.00 (m, 2H), 3.89-3.10 (m, 4H), 2.39 (s, 3H), 1.98-1.76 (m, 1H), 1.64-1.45 (m, 2H), 1.36 -1.04 (m, 2H).
実施例１４　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸ベンジル　トリフルオロ酢酸塩の合成
　Ｎ，Ｎ－ジメチル－１，２－エタンジアミン（４４．１ｍｇ，０．５００ｍｍｏｌ）をアセトニトリル（１．０ｍＬ）に溶解し、０℃に冷却した。その溶液に炭酸カリウム（１０４ｍｇ，０．５５０ｍｍｏｌ）を加え、その後、２－ブロモ酢酸ベンジル（１２６ｍｇ，０．５５０ｍｍｏｌ）を加えて，自然昇温しながら室温で１５時間撹拌した。不溶物を濾別後、減圧下溶媒を留去して得られた残渣をジクロロメタン（３ｍＬ）に溶解し、中間体１－Ｂ（９０．１ｍｇ，０．２２８ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で２時間撹拌した。反応液をジクロロメタンで希釈し、有機層を水、０．５Ｎ　水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去することで、表題化合物を無精製で得た。
収量：１１１ｍｇ
MS (ESI, m/z) 595 [M+H]+
工程２　実施例１４化合物の合成
　工程１で得られた化合物（１１１ｍｇ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４６．７ｍｇ（０．０７５５ｍｍｏｌ）　収率：３３％
MS (ESI) m/z 505 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 10.2 - 8.91 (m, 1H), 7.42 - 7.25 (m, 4H), 7.22 - 7.00 (m, 3H), 6.87 - 6.73 (m, 1H), 5.39 - 5.01 (m, 2H), 4.55 - 4.07 (m, 2H), 4.07 - 3.73 (m, 2H), 3.59 - 3.22 (m, 2H), 2.85 (s, 6H), 2.40 (s, 3H). Example 14 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoro Acetate Step 1 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid benzyl Synthesis of trifluoroacetate salt N, N-dimethyl-1,2-ethanediamine (44.1 mg, 0.500 mmol) was dissolved in acetonitrile (1.0 mL) and cooled to 0 ° C. To the solution was added potassium carbonate (104 mg, 0.550 mmol), and then benzyl 2-bromoacetate (126 mg, 0.550 mmol) was added, and the mixture was stirred at room temperature for 15 hours while naturally heating. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (3 mL). Intermediate 1-B (90.1 mg, 0.228 mmol), DIPEA (0.044 mL, 0 .25 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, and the organic layer was washed with water, 0.5N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound without purification.
Yield: 111mg
MS (ESI, m / z) 595 [M + H] +
Step 2 Synthesis of Example 14 Compound The compound obtained in Step 1 (111 mg) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N lithium hydroxide aqueous solution (1 mL) was added under ice-cooling. For 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 46.7 mg (0.0755 mmol) Yield: 33%
MS (ESI) m / z 505 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.2-8.91 (m, 1H), 7.42-7.25 (m, 4H), 7.22-7.00 (m, 3H), 6.87-6.73 (m, 1H), 5.39 -5.01 (m, 2H), 4.55-4.07 (m, 2H), 4.07-3.73 (m, 2H), 3.59-3.22 (m, 2H), 2.85 (s, 6H), 2.40 (s, 3H).
実施例１５　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(ピリミジン-4-イルメチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(ピリミジン-4-イルメチル)アミノ]酢酸エチルの合成
　ピリミジン－４－イルメタンアミン（５５ｍｇ，０．５０ｍｍｏｌ）のアセトニトリル（４ｍＬ）溶液に、炭酸カリウム（６９ｍｇ，０．５０ｍｍｏｌ）を加え－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸エチル（５５μＬ，０．５０ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去して得られた残渣をジクロロメタン（４ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７６ｍｇ，０．２０ｍｍｏｌ）を加えて室温で一晩撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
収量：６７．７ｍｇ（０．１２２ｍｍｏｌ）　収率：６１％
MS (ESI) m/z 554 [M+H]+
工程２　実施例１５化合物の合成
　工程１で得られた化合物（６７．７ｍｇ，０．１２２ｍｍｏｌ）を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．１９６ｍＬ）を加え、室温で１時間撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、減圧下溶媒留去して得られた残渣を実施例の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４１．４ｍｇ（０．０７８７ｍｍｏｌ）　収率：６４％
MS (ESI) m/z 526 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 7.54 (dd, J = 21.9, 5.3 Hz, 1H), 7.45 - 7.23 (m, 4H), 7.17 - 6.93 (m, 3H), 6.73 (dd, J = 36.7, 3.5 Hz, 1H), 5.21 - 4.66 (m, 4H), 4.61 - 4.14 (m, 2H), 2.40 (s, 3H). Example 15 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetic acid Step 1 Synthesis of ethyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetate pyrimidine- To a solution of 4-ylmethanamine (55 mg, 0.50 mmol) in acetonitrile (4 mL) was added potassium carbonate (69 mg, 0.50 mmol), cooled to −10 ° C. to −15 ° C., and then diluted with acetonitrile (1 mL). 2-Bromoethyl acetate (55 μL, 0.50 mmol) was added dropwise, and the mixture was gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was diluted with dichloromethane (4 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (76 mg, 0.20 mmol) were added. In addition, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.
Yield: 67.7 mg (0.122 mmol) Yield: 61%
MS (ESI) m / z 554 [M + H] +
Step 2 Synthesis of Example 15 Compound The compound obtained in Step 1 (67.7 mg, 0.122 mmol) was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.196 mL) was added, Stir at room temperature for 1 hour. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution, and the solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of the Example to obtain the title compound.
Yield: 41.4 mg (0.0787 mmol) Yield: 64%
MS (ESI) m / z 526 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 7.54 (dd, J = 21.9, 5.3 Hz, 1H), 7.45-7.23 ( m, 4H), 7.17-6.93 (m, 3H), 6.73 (dd, J = 36.7, 3.5 Hz, 1H), 5.21-4.66 (m, 4H), 4.61-4.14 (m, 2H), 2.40 (s, 3H).
実施例１６　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-4-イルメチル)アミノ]酢酸
　実施例１５と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
収量：４４．８ｍｇ（０．０８２５ｍｍｏｌ）　収率：４１％
MS (ESI) m/z 543 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.88 - 12.65 (m, 1H), 9.11 (s, 1H), 8.81 - 8.67 (m, 1H), 8.38 - 8.22 (m, 1H), 7.57 - 7.47 (m, 1H), 7.47 - 7.22 (m, 4H), 7.14 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.56 - 5.29 (m, 2H), 5.15 - 4.74 (m, 2H), 4.74 - 4.15 (m, 2H), 2.39 (s, 3H).
実施例１７　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボニル]-(ピリミジン-4-イルメチル)アミノ]酢酸
　実施例１５と同様の操作を、中間体１－Ｂの代わりに中間体２－Ｂを用いて行うことにより、表題化合物を得た。
収量：３８．３ｍｇ（０．０７０８ｍｍｏｌ）　収率：３７％
MS (ESI) m/z 542 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.24 - 9.06 (m, 1H), 8.77 (dd, J = 11.6, 5.2 Hz, 1H), 7.86 - 7.63 (m, 1H), 7.62 - 7.47 (m, 1H), 7.47 - 7.18 (m, 5H), 7.07 (dd, J = 19.6, 8.3 Hz, 2H), 5.44 - 5.19 (m, 2H), 4.86 - 4.62 (m, 2H), 4.36 - 4.03 (m, 2H), 2.39 (s, 3H). Example 16 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetic acid The title compound was obtained by conducting the same operation as 15 using Intermediate 4-B instead of Intermediate 1-B.
Yield: 44.8 mg (0.0825 mmol) Yield: 41%
MS (ESI) m / z 543 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.88-12.65 (m, 1H), 9.11 (s, 1H), 8.81-8.67 (m, 1H), 8.38-8.22 (m, 1H), 7.57-7.47 (m, 1H), 7.47-7.22 (m, 4H), 7.14 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.56-5.29 (m, 2H), 5.15- 4.74 (m, 2H), 4.74-4.15 (m, 2H), 2.39 (s, 3H).
Example 17 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-4-ylmethyl) amino] acetic acid The title compound was obtained by the same procedures as for 15 except that intermediate 2-B was used instead of intermediate 1-B.
Yield: 38.3 mg (0.0708 mmol) Yield: 37%
MS (ESI) m / z 542 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.24-9.06 (m, 1H), 8.77 (dd, J = 11.6, 5.2 Hz, 1H), 7.86-7.63 (m, 1H), 7.62-7.47 (m , 1H), 7.47-7.18 (m, 5H), 7.07 (dd, J = 19.6, 8.3 Hz, 2H), 5.44-5.19 (m, 2H), 4.86-4.62 (m, 2H), 4.36-4.03 (m , 2H), 2.39 (s, 3H).
実施例１８　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(3-メチル-1,2,4-オキサジアゾール-5-イル)メチル]アミノ]酢酸
工程１　2-[(3-メチル-1,2,4-オキサジアゾール-5-イル)メチルアミノ]酢酸エチルの合成　グリシンエチルエステル　塩酸塩（６８．５ｍｇ，０．４９１ｍｍｏｌ）をアセトニトリル（４ｍＬ）に溶解し、炭酸カリウム（２０４ｍｇ，１．４７ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した５－（クロロメチル）－３－メチル－１，２，４－オキサジアゾール（６５．０ｍｇ，０．４９１ｍｍｏｌ）、ヨウ化ナトリウム（７４ｍｇ，０．４９ｍｍｏｌ）を加えて、徐々に室温に戻しながら１６時間撹拌した。不溶物を濾別後、減圧下溶媒を留去することで表題化合物を無精製で得た。
収量：１２２ｍｇ
MS (ESI) m/z 200 [M+H]+
工程２　実施例１８化合物の合成
　工程１にて得られた化合物（６０ｍｇ，０．２５ｍｍｏｌ）をジクロロメタン（１ｍＬ）に溶解し、中間体４－Ｂ（８２．２ｍｇ，０．２００ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で３時間撹拌した。反応液をジクロロメタンで希釈し、有機層を０．５Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機溶媒を減圧除去した後、得られた残渣をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６２．６ｍｇ（０．１１５ｍｍｏｌ）　収率：５７％
MS (ESI) m/z 547 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.42 - 8.35 (m, 1H), 7.41 - 7.26 (m, 4H), 7.17 - 7.04 (m, 2H), 5.56 - 5.37 (m, 2H), 5.37 - 4.91 (m, 2H), 4.77 - 4.22 (m, 2H), 2.39 (s, 3H), 2.35 - 2.27 (m, 3H). Example 18 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(3-methyl-1,2,4- Oxadiazol-5-yl) methyl] amino] acetic acid Step 1 Synthesis of ethyl 2-[(3-methyl-1,2,4-oxadiazol-5-yl) methylamino] acetate Glycine ethyl ester hydrochloride ( 5- (chloromethyl)-(68.5 mg, 0.491 mmol) was dissolved in acetonitrile (4 mL), potassium carbonate (204 mg, 1.47 mmol) was added, and the mixture was cooled to 0 ° C. and diluted with acetonitrile (1 mL). 3-Methyl-1,2,4-oxadiazole (65.0 mg, 0.491 mmol) and sodium iodide (74 mg, 0.49 mmol) were added, and the mixture was stirred for 16 hours while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 122mg
MS (ESI) m / z 200 [M + H] +
Step 2 Synthesis of Example 18 Compound The compound obtained in Step 1 (60 mg, 0.25 mmol) was dissolved in dichloromethane (1 mL), and intermediate 4-B (82.2 mg, 0.200 mmol), DIPEA (0 .044 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, and the organic layer was washed with 0.5N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the organic solvent was removed under reduced pressure, the obtained residue was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N lithium hydroxide aqueous solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 62.6 mg (0.115 mmol) Yield: 57%
MS (ESI) m / z 547 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42-8.35 (m, 1H), 7.41-7.26 (m, 4H), 7.17-7.04 (m, 2H), 5.56-5.37 (m, 2H), 5.37 -4.91 (m, 2H), 4.77-4.22 (m, 2H), 2.39 (s, 3H), 2.35-2.27 (m, 3H).
実施例１９　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸
工程１　2-[[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチルアミノ]酢酸エチルの合成
　グリシンエチルエステル　塩酸塩（１０５ｍｇ，０．７５４ｍｍｏｌ）をアセトニトリル（１０ｍＬ）に溶解し、炭酸カリウム（３１３ｍｇ，２．２６ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した３－（クロロメチル）－５－メチル－１，２，４－オキサジアゾール（１００ｍｇ，０．７５４ｍｍｏｌ）、ヨウ化ナトリウム（１１３ｍｇ，０．７５４ｍｍｏｌ）を加えて、徐々に室温に戻しながら一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去することで、表題化合物を無精製で得た。
収量：２７２ｍｇ
MS (ESI) m/z 200 [M+H]+
工程２　実施例１９化合物の合成
　工程１にて得られた化合物（９０ｍｇ，０．２５ｍｍｏｌ）をジクロロメタン（１ｍＬ）に溶解し、中間体４－Ｂ（８２．２ｍｇ，０．２００ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で３時間撹拌した。反応液をジクロロメタンで希釈し、有機層を０．５Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機溶媒を減圧除去した後、得られた残渣をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３９．７ｍｇ（０．０７２６ｍｍｏｌ）　収率：３６％
MS (ESI) m/z 547 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.8 (brs, 1H), 8.37 - 8.29 (m, 1H), 7.42 - 7.25 (m, 4H), 7.16 - 7.09 (m, 2H), 5.55 - 5.42 (m, 2H), 5.25 - 4.74 (m, 2H), 4.69 - 4.11 (m, 1H), 3.33 - 3.11 (m, 1H), 2.62 - 2.53 (m, 3H), 2.39 (s, 3H). Example 19 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4- Oxadiazol-3-yl) methyl] amino] acetic acid Step 1 Synthesis of ethyl 2-[[(5-methyl-1,2,4-oxadiazol-3-yl) methylamino] acetate Glycine ethyl ester hydrochloride 3- (Chloromethyl) -5 diluted with acetonitrile (1 mL) after dissolving (105 mg, 0.754 mmol) in acetonitrile (10 mL), adding potassium carbonate (313 mg, 2.26 mmol) and cooling to 0 ° C. -Methyl-1,2,4-oxadiazole (100 mg, 0.754 mmol) and sodium iodide (113 mg, 0.754 mmol) were added, and the mixture was stirred overnight while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 272 mg
MS (ESI) m / z 200 [M + H] +
Step 2 Synthesis of Example 19 Compound The compound obtained in Step 1 (90 mg, 0.25 mmol) was dissolved in dichloromethane (1 mL), and intermediate 4-B (82.2 mg, 0.200 mmol), DIPEA (0 .044 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, and the organic layer was washed with 0.5N hydrochloric acid aqueous solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the organic solvent was removed under reduced pressure, the obtained residue was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N lithium hydroxide aqueous solution (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 39.7 mg (0.0726 mmol) Yield: 36%
MS (ESI) m / z 547 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.8 (brs, 1H), 8.37-8.29 (m, 1H), 7.42-7.25 (m, 4H), 7.16-7.09 (m, 2H), 5.55-5.42 (m, 2H), 5.25-4.74 (m, 2H), 4.69-4.11 (m, 1H), 3.33-3.11 (m, 1H), 2.62-2.53 (m, 3H), 2.39 (s, 3H).
実施例２０　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸
工程１　2-(ピリミジン-2-イルメチルアミノ)酢酸ベンジルの合成
　グリシンベンジルエステル　ｐ－トルエンスルホン酸塩（５０６ｍｇ，１．５０ｍｍｏｌ）をＴＨＦ（５ｍＬ）およびメタノール（１ｍＬ）の混合液に溶解し、ピリミジル－２－カルバルデヒド（１６２ｍｇ，１．５０ｍｍｏｌ）、酢酸を少量加えて、室温で一晩撹拌した。反応液を減圧除去後、得られた残渣をＴＨＦ（１０ｍＬ）に懸濁させて、トリアセトキシ水素化ホウ素ナトリウム（９５４ｍｇ，４．５０ｍｍｏｌ）を加えて室温で５時間撹拌した。反応液を酢酸エチルで希釈し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。有機溶媒を減圧除去することで、表題化合物を無精製で得た。
収量：２７１ｍｇ
MS (ESI) m/z 258 [M+H]+
工程２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸ベンジルの合成
　工程１の化合物（９０．０ｍｇ，０．５００ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、中間体１－Ｂ（９４．８ｍｇ，０．２４０ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で２時間撹拌した。反応液を減圧除去後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６８．５ｍｇ（０．１１１ｍｍｏｌ）　収率：４６％
MS (ESI, m/z) 616 [M+H]+
工程３　実施例２０化合物の合成
　工程２で得られた化合物（６８．５ｍｇ，０．１１１ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．８ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３７．４ｍｇ（０．０７１２ｍｍｏｌ）　収率：６４％
MS (ESI) m/z 526 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.74 (m, 2H), 7.43 - 7.25 (m, 5H), 7.16 - 7.07 (m, 1H), 7.04 - 6.95 (m, 2H), 6.81 - 6.64 (m, 1H), 5.20 - 5.05 (m, 2H), 5.05 - 4.80 (m, 2H), 4.59 - 4.17 (m, 2H), 2.40 (s, 3H). Example 20 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid Step 1 Synthesis of benzyl 2- (pyrimidin-2-ylmethylamino) acetate Glycine benzyl ester p-toluenesulfonate (506 mg, 1.50 mmol) was dissolved in a mixture of THF (5 mL) and methanol (1 mL) to give pyrimidyl- 2-Carbaldehyde (162 mg, 1.50 mmol) and a small amount of acetic acid were added, and the mixture was stirred overnight at room temperature. After removing the reaction solution under reduced pressure, the obtained residue was suspended in THF (10 mL), sodium triacetoxyborohydride (954 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure to obtain the title compound without purification.
Yield: 271 mg
MS (ESI) m / z 258 [M + H] +
Step 2 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate The compound of Step 1 (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL), and Intermediate 1-B (94.8 mg, 0.240 mmol) and DIPEA (0.044 mL, 0.25 mmol) were added. Stir at room temperature for 2 hours. After removing the reaction solution under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 68.5 mg (0.111 mmol) Yield: 46%
MS (ESI, m / z) 616 [M + H] +
Step 3 Synthesis of Example 20 Compound The compound obtained in Step 2 (68.5 mg, 0.111 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.8 mL) and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 37.4 mg (0.0712 mmol) Yield: 64%
MS (ESI) m / z 526 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81-8.74 (m, 2H), 7.43-7.25 (m, 5H), 7.16-7.07 (m, 1H), 7.04-6.95 (m, 2H), 6.81 -6.64 (m, 1H), 5.20-5.05 (m, 2H), 5.05-4.80 (m, 2H), 4.59-4.17 (m, 2H), 2.40 (s, 3H).
実施例２１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩工程１　4-[[(2-tert-ブトキシ-2-オキソ-エチル)アミノ]メチル]ピペリジン-1-カルボン酸 tert-ブチルの合成
　４－（アミノメチル）ピペリジン－１－カルボン酸 ｔｅｒｔ－ブチル（１０７ｍｇ，０．５００ｍｍｏｌ）をアセトニトリル（４ｍＬ）に溶解し、炭酸カリウム（１３８ｍｇ，０．７５０ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジルエステル（０．０８１ｍＬ，０．５５０ｍｍｏｌ）を加えて、徐々に室温に戻しながら一晩撹拌した。不溶物を濾別後、減圧下溶媒を留去することで表題化合物を無精製で得た。
収量：１６２ｍｇ
MS (ESI) m/z 329 [M+H]+ 
工程２　実施例２１化合物の合成
　工程１の化合物（１６２ｍｇ，０．５００ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、中間体１－Ｂ（８０．０ｍｇ，０．２００ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で１時間撹拌した。反応液をジクロロメタンで希釈し、有機層を０．５Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。有機溶媒を減圧除去することで得られた残渣を、ジクロロメタン（６ｍＬ）およびＴＦＡ（１ｍＬ）の混合溶液に溶解し、室温で２時間撹拌した。減圧下溶媒を留去後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６１．２ｍｇ（０．０９４９ｍｍｏｌ）　収率：３８％
MS (ESI) m/z 531 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.9 (brs, 1H), 8.50 (brs, 1H), 8.19 (brs, 1H), 7.43 - 7.24 (m, 4H), 7.17 - 6.96 (m, 3H), 6.83 - 6.71 (m, 1H), 5.28 - 5.05 (m, 2H), 4.48 - 4.02 (m, 2H), 3.70 - 3.17 (m, 4H), 2.91 - 2.71 (m, 2H), 2.40 (s, 3H), 2.05 - 1.87 (m, 1H), 1.87 - 1.73 (m, 2H), 1.44 - 1.19 (m, 2H). Example 21 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetic acid Salt Step 1 Synthesis of tert-butyl 4-[[(2-tert-butoxy-2-oxo-ethyl) amino] methyl] piperidine-1-carboxylate 4- (aminomethyl) piperidine-1-carboxylic acid tert-butyl (107 mg, 0.500 mmol) was dissolved in acetonitrile (4 mL), potassium carbonate (138 mg, 0.750 mmol) was added, cooled to −10 ° C., and then diluted with acetonitrile (1 mL) 2-bromoacetic acid benzyl ester ( 0.081 mL, 0.550 mmol) was added, and the mixture was stirred overnight while gradually returning to room temperature. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound without purification.
Yield: 162mg
MS (ESI) m / z 329 [M + H] +
Step 2 Synthesis of Example 21 Compound The compound of Step 1 (162 mg, 0.500 mmol) was dissolved in dichloromethane (5 mL), and Intermediate 1-B (80.0 mg, 0.200 mmol), DIPEA (0.044 mL, 0 .25 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, and the organic layer was washed successively with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by removing the organic solvent under reduced pressure was dissolved in a mixed solution of dichloromethane (6 mL) and TFA (1 mL), and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 61.2 mg (0.0949 mmol) Yield: 38%
MS (ESI) m / z 531 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.9 (brs, 1H), 8.50 (brs, 1H), 8.19 (brs, 1H), 7.43-7.24 (m, 4H), 7.17-6.96 (m, 3H ), 6.83-6.71 (m, 1H), 5.28-5.05 (m, 2H), 4.48-4.02 (m, 2H), 3.70-3.17 (m, 4H), 2.91-2.71 (m, 2H), 2.40 (s , 3H), 2.05-1.87 (m, 1H), 1.87-1.73 (m, 2H), 1.44-1.19 (m, 2H).
実施例２２　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸
工程１　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸ベンジルの合成
　実施例２０の工程１で得られた化合物（９０．０ｍｇ，０．５００ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、中間体４－Ｂ（８２．４ｍｇ，０．２００ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で６０時間撹拌した。反応液を減圧除去後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２５．９ｍｇ（０．０４１ｍｍｏｌ）　収率：２０％
MS (ESI) m/z 633 [M+H]+
工程２　実施例２２化合物の合成
　工程１で得られた化合物（２６ｍｇ，０．０４１ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１８．４ｍｇ（０．０３３９ｍｍｏｌ）　収率：８３％
MS (ESI) m/z 543 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.73 (m, 2H), 8.32 - 8.19 (m, 1H), 7.46 - 7.25 (m, 5H), 7.19 - 6.99 (m, 2H), 5.56 - 5.29 (m, 2H), 5.29 - 4.84 (m, 2H), 4.74 - 4.18 (m, 2H), 2.39 (s, 3H). Example 22 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid Step 1 Synthesis of benzyl 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate The compound obtained in Step 1 of 20 (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL), and intermediate 4-B (82.4 mg, 0.200 mmol), DIPEA (0.044 mL,. 25 mmol) was added and stirred at room temperature for 60 hours. After removing the reaction solution under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 25.9 mg (0.041 mmol) Yield: 20%
MS (ESI) m / z 633 [M + H] +
Step 2 Synthesis of Example 22 Compound The compound obtained in Step 1 (26 mg, 0.041 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution (0. 5 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 18.4 mg (0.0339 mmol) Yield: 83%
MS (ESI) m / z 543 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82-8.73 (m, 2H), 8.32-8.19 (m, 1H), 7.46-7.25 (m, 5H), 7.19-6.99 (m, 2H), 5.56 -5.29 (m, 2H), 5.29-4.84 (m, 2H), 4.74-4.18 (m, 2H), 2.39 (s, 3H).
実施例２３　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸ベンジルの合成
　実施例２０の工程１の化合物（９０．０ｍｇ，０．５００ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、中間体２－Ｂ（９８．６ｍｇ，０．２４０ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で１時間撹拌した。反応液を減圧除去後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を無精製で得た。
収量：４５．６ｍｇ（０．０７２２ｍｍｏｌ）　収率：３０％
MS (ESI) m/z 632 [M+H]+ 
工程２　実施例２３化合物の合成
　工程１で得られた化合物（４５．６ｍｇ，０．０７２２ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２８．４ｍｇ（０．０５２４ｍｍｏｌ）　収率：７３％
MS (ESI) m/z 542 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.88 - 8.74 (m, 2H), 7.84 - 7.69 (m, 1H), 7.52 - 7.40 (m, 1H), 7.40 - 7.25 (m, 5H), 7.13 - 7.03 (m, 2H), 5.41 - 5.27 (m, 2H), 4.88 - 4.78 (m, 2H), 4.33 - 4.09 (m, 2H), 2.39 (s, 3H). Example 23 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid Step 1 Synthesis of benzyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophen-3-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetate 20 Step 1 compound (90.0 mg, 0.500 mmol) was dissolved in dichloromethane (2 mL) and Intermediate 2-B (98.6 mg, 0.240 mmol), DIPEA (0.044 mL, 0.25 mmol) was added. In addition, the mixture was stirred at room temperature for 1 hour. After removing the reaction solution under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound without purification.
Yield: 45.6 mg (0.0722 mmol) Yield: 30%
MS (ESI) m / z 632 [M + H] +
Step 2 Synthesis of Example 23 Compound The compound obtained in Step 1 (45.6 mg, 0.0722 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 28.4 mg (0.0524 mmol) Yield: 73%
MS (ESI) m / z 542 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.88-8.74 (m, 2H), 7.84-7.69 (m, 1H), 7.52-7.40 (m, 1H), 7.40-7.25 (m, 5H), 7.13 -7.03 (m, 2H), 5.41-5.27 (m, 2H), 4.88-4.78 (m, 2H), 4.33-4.09 (m, 2H), 2.39 (s, 3H).
実施例２４　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-フリルメチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-フリルメチル)アミノ]酢酸エチルの合成
　２－フリルメタンアミン（０．１３９ｍＬ，１．５０ｍｍｏｌ）のアセトニトリル（１２ｍＬ）溶液に、炭酸カリウム（２０７ｍｇ，１．５０ｍｍｏｌ）加え－１０℃～－１５℃に冷却した後、アセトニトリル（１．５ｍＬ）で希釈した２－ブロモ酢酸エチル（１６５μＬ，１．５０ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣の３分の１をジクロロメタン（２ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７９ｍｇ，０．２０ｍｍｏｌ）を加えて室温で３０分撹拌した。反応液を減圧濃縮し、表題化合物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
MS (ESI) m/z 542 [M+H]+
工程２　実施例２４化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．２０５ｍＬ）を加え、室温で一晩撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５５．６ｍｇ（０．１０８ｍｍｏｌ）　収率：５４％
MS (ESI) m/z 514 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.70 - 6.37 (m, 11H), 5.28 - 5.07 (m, 2H), 4.91 - 4.59 (m, 2H), 4.39 - 3.98 (m, 2H), 2.39 (s, 3H). Example 24 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] acetic acid Step 1 2 Of 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] ethyl acetate 2-furylmethane To a solution of amine (0.139 mL, 1.50 mmol) in acetonitrile (12 mL) was added potassium carbonate (207 mg, 1.50 mmol), cooled to −10 ° C. to −15 ° C., and then diluted with acetonitrile (1.5 mL) 2 -Ethyl bromoacetate (165 μL, 1.50 mmol) was added dropwise, gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off and concentrated under reduced pressure. A third of the resulting residue was diluted with dichloromethane (2 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (79 mg, 0.20 mmol) were diluted. ) And stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the title compound was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound.
MS (ESI) m / z 542 [M + H] +
Step 2 Synthesis of Example 24 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.205 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution, and the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 55.6 mg (0.108 mmol) Yield: 54%
MS (ESI) m / z 514 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.70-6.37 (m, 11H), 5.28-5.07 (m, 2H), 4.91-4.59 (m, 2H), 4.39-3.98 (m, 2H), 2.39 (s, 3H).
実施例２５　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸
　実施例２４と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
収量：４８．７ｍｇ（０．０９１８ｍｍｏｌ）　収率：４６％
MS (ESI) m/z 531 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.20 (m, 1H), 7.60 (d, J = 10.7 Hz, 1H), 7.46 - 7.00 (m, 6H), 6.47 - 6.30 (m, 2H), 5.61 - 5.42 (m, 2H), 5.05 - 4.66 (m, 2H), 4.50 - 4.02 (m, 2H), 2.39 (s, 3H).
実施例２６　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(チアゾール-4-イルメチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(チアゾール-4-イルメチル)アミノ]酢酸エチルの合成
　チアゾール－４－イルメタンアミン　塩酸塩（１００ｍｇ，０．６６４ｍｍｏｌ）のアセトニトリル（３ｍＬ）溶液に、炭酸カリウム（２２９ｍｇ，１．６６ｍｍｏｌ）およびＤＭＦ（２ｍＬ）を加え－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸エチル（７３μＬ，０．６６ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣の半分をジクロロメタン（２ｍＬ）で希釈し、ＤＩＰＥＡ（６１μＬ，０．３５ｍｍｏｌ）および中間体１－Ｂ（４０ｍｇ，０．１０ｍｍｏｌ）を加えて室温で３０分撹拌した。反応液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
MS (ESI) m/z 559 [M+H]+
工程２　実施例２６化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（０．８ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．０７０ｍＬ）を加え、室温で３０分撹拌した。さらに１Ｎ　水酸化リチウム水溶液（０．１４ｍＬ）を加え撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１３．１ｍｇ（０．０２４６ｍｍｏｌ）　収率：２５％
MS (ESI) m/z 531 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.19 - 9.03 (m, 1H), 7.78 - 6.97 (m, 8H), 6.75 (s, 1H), 5.25 - 5.04 (m, 2H), 5.02 - 4.74 (m, 2H), 4.49 - 4.06 (m, 2H), 2.39 (s, 3H). Example 25 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid Example 24 The title compound was obtained in the same manner as in the above except that Intermediate 4-B was used instead of Intermediate 1-B.
Yield: 48.7 mg (0.0918 mmol) Yield: 46%
MS (ESI) m / z 531 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37-8.20 (m, 1H), 7.60 (d, J = 10.7 Hz, 1H), 7.46-7.00 (m, 6H), 6.47-6.30 (m, 2H ), 5.61-5.42 (m, 2H), 5.05-4.66 (m, 2H), 4.50-4.02 (m, 2H), 2.39 (s, 3H).
Example 26 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(thiazol-4-ylmethyl) amino] acetic acid Step 1 Synthesis of ethyl 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(thiazol-4-ylmethyl) amino] acetate thiazole- To a solution of 4-ylmethanamine hydrochloride (100 mg, 0.664 mmol) in acetonitrile (3 mL) was added potassium carbonate (229 mg, 1.66 mmol) and DMF (2 mL), and the mixture was cooled to −10 ° C. to −15 ° C. 2-Bromoethyl acetate (73 μL, 0.66 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was gradually warmed to room temperature and stirred overnight. Insoluble material was filtered off and concentrated under reduced pressure. Half of the obtained residue was diluted with dichloromethane (2 mL), and DIPEA (61 μL, 0.35 mmol) and intermediate 1-B (40 mg, 0.10 mmol) were added. And stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound.
MS (ESI) m / z 559 [M + H] +
Step 2 Synthesis of Example 26 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (0.8 mL), 1N aqueous lithium hydroxide solution (0.070 mL) was added, and the mixture was stirred at room temperature for 30 min. Furthermore, 1N lithium hydroxide aqueous solution (0.14 mL) was added and stirred. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 13.1 mg (0.0246 mmol) Yield: 25%
MS (ESI) m / z 531 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.19-9.03 (m, 1H), 7.78-6.97 (m, 8H), 6.75 (s, 1H), 5.25-5.04 (m, 2H), 5.02-4.74 (m, 2H), 4.49-4.06 (m, 2H), 2.39 (s, 3H).
実施例２７　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(2-メトキシエトキシ)エチル]アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(2-メトキシエトキシ)エチル]アミノ]酢酸ベンジルの合成　２－（２－メトキシエトキシ）エタンアミン（１８６ｍｇ，１．５０ｍｍｏｌ）のアセトニトリル（１２ｍＬ）溶液に、炭酸カリウム（２０７ｍｇ，１．５０ｍｍｏｌ）を加え－１０℃～－１５℃に冷却した後、アセトニトリル（１．５ｍＬ）で希釈した２－ブロモ酢酸ベンジル（２３５μＬ，１．５ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣の３分の１をジクロロメタン（２ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７９ｍｇ，０．２０ｍｍｏｌ）を加えて室温で３０分撹拌した。反応液を減圧濃縮し、表題化合物を無精製で得た。
工程２　実施例２７化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．８ｍＬ）を加え、室温で１時間撹拌した。さらに１Ｎ　水酸化リチウム水溶液（０．２ｍＬ）を加え撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６２．３ｍｇ（０．１１７ｍｍｏｌ）　収率：５９％
MS (ESI) m/z 536 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.49 - 6.93 (m, 7H), 6.83 - 6.69 (m, 1H), 5.27 - 5.06 (m, 2H), 4.51 - 4.09 (m, 2H), 3.80 - 3.45 (m, 8H), 3.27 - 3.18 (m, 3H), 2.39 (s, 3H). Example 27 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino ] Acetic acid step 1 2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (2-methoxyethoxy) ethyl] Synthesis of benzyl amino] acetate To a solution of 2- (2-methoxyethoxy) ethanamine (186 mg, 1.50 mmol) in acetonitrile (12 mL) was added potassium carbonate (207 mg, 1.50 mmol) and cooled to −10 ° C. to −15 ° C. After that, benzyl 2-bromoacetate (235 μL, 1.5 mmol) diluted with acetonitrile (1.5 mL) was added dropwise, and the mixture was gradually raised to room temperature and stirred overnight. The insoluble material was filtered off and concentrated under reduced pressure. A third of the resulting residue was diluted with dichloromethane (2 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (79 mg, 0.20 mmol) were diluted. ) And stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound without purification.
Step 2 Synthesis of Example 27 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.8 mL) was added, and the mixture was stirred at room temperature for 1 hr. Furthermore, 1N lithium hydroxide aqueous solution (0.2 mL) was added and stirred. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 62.3 mg (0.117 mmol) Yield: 59%
MS (ESI) m / z 536 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.49-6.93 (m, 7H), 6.83-6.69 (m, 1H), 5.27-5.06 (m, 2H), 4.51-4.09 (m, 2H), 3.80 -3.45 (m, 8H), 3.27-3.18 (m, 3H), 2.39 (s, 3H).
実施例２８　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(2-メトキシエトキシ)エチル]アミノ]酢酸
　実施例２７と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
収量：５２．４ｍｇ（０．０９４８ｍｍｏｌ）　収率：４７％
MS (ESI) m/z 553 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.16 (m, 1H), 7.44 - 7.24 (m, 4H), 7.24 - 7.08 (m, 2H), 5.62 - 5.40 (m, 2H), 4.62 - 4.09 (m, 2H), 3.82 - 3.34 (m, 8H), 3.27 - 3.18 (m, 3H), 2.39 (s, 3H).
実施例２９　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チオフェン-3-カルボニル]-[2-(2-メトキシエトキシ)エチル]アミノ]酢酸
　実施例２７と同様の操作を、中間体１－Ｂの代わりに中間体２－Ｂを用いて行うことにより、表題化合物を得た。
収量：６４．１ｍｇ（０．１１６ｍｍｏｌ）　収率：５８％
MS (ESI) m/z 552 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.97 - 12.41 (m, 1H), 7.98 - 7.01 (m, 8H), 5.44 - 5.25 (m, 2H), 4.24 - 4.04 (m, 2H), 3.66 - 3.41 (m, 8H), 3.24 (s, 3H), 2.39 (s, 3H) Example 28 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino Acetic acid The title compound was obtained in the same manner as the Example 27, except that the intermediate 4-B was used instead of the intermediate 1-B.
Yield: 52.4 mg (0.0948 mmol) Yield: 47%
MS (ESI) m / z 553 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33-8.16 (m, 1H), 7.44-7.24 (m, 4H), 7.24-7.08 (m, 2H), 5.62-5.40 (m, 2H), 4.62 -4.09 (m, 2H), 3.82-3.34 (m, 8H), 3.27-3.18 (m, 3H), 2.39 (s, 3H).
Example 29 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiophene-3-carbonyl]-[2- (2-methoxyethoxy) ethyl] amino Acetic acid The title compound was obtained in the same manner as the Example 27, except that the intermediate 2-B was used instead of the intermediate 1-B.
Yield: 64.1 mg (0.116 mmol) Yield: 58%
MS (ESI) m / z 552 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97-12.41 (m, 1H), 7.98-7.01 (m, 8H), 5.44-5.25 (m, 2H), 4.24-4.04 (m, 2H), 3.66 -3.41 (m, 8H), 3.24 (s, 3H), 2.39 (s, 3H)
実施例３０　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(5-メチル-1,3,4-オキサジアゾール-2-イル)メチル]アミノ]酢酸
工程１　2-[(5-メチル-1,3,4-オキサジアゾール-2-イル)メチルアミノ]酢酸ベンジルの合成
　（５－メチル－１，３，４－オキサジアゾール－２－イル)メタンアミン（１７０ｍｇ，１．５０ｍｍｏｌ）をアセトニトリル（１２ｍＬ）に溶解し、炭酸カリウム（３１１ｍｇ，２．２５ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（３ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．２５９ｍＬ，１．６５ｍｍｏｌ）を加えて、徐々に室温に戻しながら一晩撹拌した。不溶物を濾別後、減圧下濃縮することで表題化合物を無精製で得た。
収量：３７２ｍｇ
MS (ESI) m/z 262 [M+H]+
工程２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(5-メチル-1,3,4-オキサジアゾール-2-イル)メチル]アミノ]酢酸ベンジルの合成
　工程１で得られた化合物（１２４ｍｇ，０．５００ｍｍｏｌ）をジクロロメタン（３ｍＬ）に溶解し、中間体１－Ｂ（９８．８ｍｇ，０．２４０ｍｍｏｌ）、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧除去後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５６．７ｍｇ（０．０８９２ｍｍｏｌ）　収率：２１％
MS (ESI, m/z) 620 [M+H]+ 
工程３　実施例３０化合物の合成
　工程１で得られた化合物（５４．６ｍｇ，０．１０３ｍｍｏｌ）をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４２．７ｍｇ（０．０７８１ｍｍｏｌ）　収率：８８％
MS (ESI) m/z 530 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.25 (m, 4H), 7.23 - 6.93 (m, 3H), 6.81 - 6.72 (m, 1H), 5.23 - 4.81 (m, 4H), 4.55 - 4.07 (m, 2H), 2.49 - 2.36 (m, 6H). Example 30 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(5-methyl-1,3,4- Oxadiazol-2-yl) methyl] amino] acetic acid Step 1 Synthesis of benzyl 2-[(5-methyl-1,3,4-oxadiazol-2-yl) methylamino] acetate (5-methyl-1 , 3,4-oxadiazol-2-yl) methanamine (170 mg, 1.50 mmol) was dissolved in acetonitrile (12 mL), potassium carbonate (311 mg, 2.25 mmol) was added, and the mixture was cooled to −10 ° C. Benzyl 2-bromoacetate (0.259 mL, 1.65 mmol) diluted with acetonitrile (3 mL) was added, and the mixture was stirred overnight while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 372 mg
MS (ESI) m / z 262 [M + H] +
Step 2 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(5-methyl-1,3,4-oxa Synthesis of benzyl diazol-2-yl) methyl] amino] acetate The compound obtained in step 1 (124 mg, 0.500 mmol) was dissolved in dichloromethane (3 mL) and intermediate 1-B (98.8 mg, 0. 240 mmol) and DIPEA (0.044 mL, 0.25 mmol) were added and stirred overnight at room temperature. After removing the reaction solution under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 56.7 mg (0.0892 mmol) Yield: 21%
MS (ESI, m / z) 620 [M + H] +
Step 3 Synthesis of Example 30 Compound The compound obtained in Step 1 (54.6 mg, 0.103 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and 1N aqueous lithium hydroxide solution ( 0.5 mL) was added and stirred at room temperature for 1 hour. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 42.7 mg (0.0781 mmol) Yield: 88%
MS (ESI) m / z 530 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.40-7.25 (m, 4H), 7.23-6.93 (m, 3H), 6.81-6.72 (m, 1H), 5.23-4.81 (m, 4H), 4.55 -4.07 (m, 2H), 2.49-2.36 (m, 6H).
実施例３１　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[(1-メチルイミダゾール-4-イル)メチル]アミノ]酢酸
工程１　2-[(1-メチルイミダゾール-4-イル)メチルアミノ]酢酸ベンジルの合成
　１－メチルイミダゾール－４－イルメタンアミン（２５０ｍｇ，２．２５ｍｍｏｌ）をアセトニトリル（１０ｍＬ）で希釈し、炭酸カリウム（４６６ｍｇ，３．３７ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．３９０ｍＬ，２．４７ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１４時間撹拌した。不溶物を濾別後、減圧下濃縮することで表題化合物を無精製で得た。
収量：３５０ｍｇ
MS (ESI) m/z 260 [M+H]+ 
工程２　実施例３１化合物の合成
　中間体１－Ｂ（７５．０ｍｇ，０．１９０ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、工程１で得られた化合物（９６．５ｍｇ，０．３７２ｍｍｏｌ）とＤＩＰＥＡ（０．０８１ｍＬ，０．４７ｍｍｏｌ）を加えて、室温で１６時間撹拌した。反応液を減圧下濃縮後、得られた残渣をＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．４８ｍＬ）を加え、室温で３時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３０．４ｍｇ（０．０５７６ｍｍｏｌ）　収率：３０％
MS (ESI) m/z 528 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.69 (m, 1H), 7.61 - 7.44 (m, 1H), 7.36 - 7.16 (m, 4H), 7.12 - 6.94 (m, 3H), 6.72 (d, J = 3.44 Hz, 1H), 5.18 - 5.01 (m, 2H), 4.88 - 4.55 (m, 2H), 4.45 - 3.95 (m, 2H), 3.79 - 3.64 (m, 3H), 2.33 (s, 3H). Example 31 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[(1-methylimidazol-4-yl) methyl ] Amino] acetic acid step 1 Synthesis of benzyl 2-[(1-methylimidazol-4-yl) methylamino] acetate 1-Methylimidazol-4-ylmethanamine (250 mg, 2.25 mmol) diluted with acetonitrile (10 mL) After adding potassium carbonate (466 mg, 3.37 mmol) and cooling to 0 ° C., benzyl 2-bromoacetate (0.390 mL, 2.47 mmol) diluted with acetonitrile (1 mL) was added dropwise and gradually added to room temperature. The mixture was stirred for 14 hours. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 350mg
MS (ESI) m / z 260 [M + H] +
Step 2 Synthesis of Compound of Example 31 Dichloromethane (2 mL) was added to Intermediate 1-B (75.0 mg, 0.190 mmol) and dissolved. The compound obtained in Step 1 (96.5 mg, 0.372 mmol) and DIPEA (0.081 mL, 0.47 mmol) were added to the solution, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.48 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. did. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 30.4 mg (0.0576 mmol) Yield: 30%
MS (ESI) m / z 528 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92-8.69 (m, 1H), 7.61-7.44 (m, 1H), 7.36-7.16 (m, 4H), 7.12-6.94 (m, 3H), 6.72 (d, J = 3.44 Hz, 1H), 5.18-5.01 (m, 2H), 4.88-4.55 (m, 2H), 4.45-3.95 (m, 2H), 3.79-3.64 (m, 3H), 2.33 (s , 3H).
実施例３２　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(1-メチルイミダゾール-4-イル)メチル]アミノ]酢酸　中間体４－Ｂ（７５．０ｍｇ，０．１８２ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、実施例３１の工程１で得られた化合物（９６．５ｍｇ，０．３７２ｍｍｏｌ）とＤＩＰＥＡ（０．０８１ｍＬ，０．４７ｍｍｏｌ）を加えて、室温で１６時間撹拌した。反応液を減圧下濃縮後、得られた残渣をＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．４８ｍＬ）を加え、室温で３時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２７．４ｍｇ（０．０５０３ｍｍｏｌ）　収率：２７．６％
MS (ESI) m/z 545 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.76 (m, 1H), 8.36 - 8.24 (m, 1H), 7.61 - 7.48 (m, 1H), 7.36 - 7.16 (m, 4H), 7.09 - 7.00 (m, 2H), 5.52 - 5.36 (m, 2H), 4.96 - 4.59 (m, 2H), 4.57 - 3.97 (m, 2H), 3.75 (s, 3H), 2.33 (s, 3H). Example 32 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-[(1-methylimidazol-4-yl) methyl Amino] acetic acid Intermediate 4-B (75.0 mg, 0.182 mmol) was dissolved in dichloromethane (2 mL). The compound obtained in Step 1 of Example 31 (96.5 mg, 0.372 mmol) and DIPEA (0.081 mL, 0.47 mmol) were added to the solution, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.48 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. did. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 27.4 mg (0.0503 mmol) Yield: 27.6%
MS (ESI) m / z 545 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92-8.76 (m, 1H), 8.36-8.24 (m, 1H), 7.61-7.48 (m, 1H), 7.36-7.16 (m, 4H), 7.09 -7.00 (m, 2H), 5.52-5.36 (m, 2H), 4.96-4.59 (m, 2H), 4.57-3.97 (m, 2H), 3.75 (s, 3H), 2.33 (s, 3H).
実施例３３　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸ベンジルの合成
　Ｎ，Ｎ－ジメチル－１，２－エタンジアミン（５４μＬ，０．５０ｍｍｏｌ）をアセトニトリル（４ｍＬ）に溶解し、０℃に冷却した。その溶液に炭酸カリウム（６９ｍｇ， ０．５０ｍｍｏｌ）を加え、その後、２－ブロモ酢酸ベンジル（７８μＬ，０．５０ｍｍｏｌ）を加えて，自然昇温しながら室温で一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣をジクロロメタン（２ｍＬ）で希釈し、室温でＤＩＰＥＡ（０．０８７ｍＬ，０．５０ｍｍｏｌ）および中間体４－Ｂ（８７ｍｇ，０．２０ｍｍｏｌ）を加えて室温で１時間半撹拌した。減圧下溶媒を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（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
MS (ESI) m/z 612 [M+H]+ 
工程２　実施例３３化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．１７３ｍＬ）を加え、室温で４０分撹拌した。反応液を中和後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４２．６ｍｇ（０．０６７０ｍｍｏｌ）　収率：３３％
MS (ESI) m/z 522 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.13 - 12.61 (m, 1H), 9.54 - 9.10 (m, 1H), 8.41 - 8.28 (m, 1H), 7.48 - 7.04 (m, 6H), 5.61 - 5.41 (m, 2H), 4.62 - 4.12 (m, 2H), 4.02 - 3.80 (m, 2H), 3.39 - 3.27 (m, 2H), 2.92 - 2.79 (m, 6H), 2.40 (s, 3H). Example 33 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoro Acetate Step 1 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid benzyl Synthesis of N, N-dimethyl-1,2-ethanediamine (54 μL, 0.50 mmol) was dissolved in acetonitrile (4 mL) and cooled to 0 ° C. Potassium carbonate (69 mg, 0.50 mmol) was added to the solution, and then benzyl 2-bromoacetate (78 μL, 0.50 mmol) was added, and the mixture was stirred overnight at room temperature with natural temperature rise. The insoluble material was filtered off, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane (2 mL), and DIPEA (0.087 mL, 0.50 mmol) and intermediate 4-B (87 mg, 0.20 mmol) were diluted at room temperature. And stirred at room temperature for 1.5 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound.
MS (ESI) m / z 612 [M + H] +
Step 2 Synthesis of Example 33 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.173 mL) was added, and the mixture was stirred at room temperature for 40 minutes. After neutralizing the reaction solution, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 42.6 mg (0.0670 mmol) Yield: 33%
MS (ESI) m / z 522 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.13-12.61 (m, 1H), 9.54-9.10 (m, 1H), 8.41-8.28 (m, 1H), 7.48-7.04 (m, 6H), 5.61 -5.41 (m, 2H), 4.62-4.12 (m, 2H), 4.02-3.80 (m, 2H), 3.39-3.27 (m, 2H), 2.92-2.79 (m, 6H), 2.40 (s, 3H) .
実施例３４　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
工程１　4-[[(2-ベンジルオキシ-2-オキソ-エチル)-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]メチル]ピペリジン-1-カルボン酸 tert-ブチルの合成
　４－（アミノメチル）ピペリジン－１－カルボン酸 ｔｅｒｔ－ブチル（１０７ｍｇ，０．５０ｍｍｏｌ）をアセトニトリル（４ｍＬ）に溶解し、０℃に冷却した。その溶液に炭酸カリウム（６９ｍｇ， ０．５０ｍｍｏｌ）を加え、その後、２－ブロモ酢酸ベンジル（７８μＬ，０．５０ｍｍｏｌ）を加えて，自然昇温しながら室温で一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣をジクロロメタン（２ｍＬ）で希釈し、室温でＤＩＰＥＡ（０．０８７ｍＬ，０．５０ｍｍｏｌ）および中間体４－Ｂ（８７ｍｇ，０．２０ｍｍｏｌ）を加えて室温で１時間半撹拌した。減圧下溶媒を留去することで、表題化合物を無精製で得た。
MS (ESI) m/z 738 [M+H]+
工程２　2-[(1-tert-ブトキシカルボニル-4-ピペリジル)メチル-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸の合成
　工程１で得られた化合物を１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で４０分撹拌した。反応液を中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
MS (ESI) m/z 649 [M+H]+
工程３　実施例３４化合物の合成
　工程２で得られた化合物のジクロロメタン溶液（２ｍＬ）に、トリフルオロ酢酸（０．１０３ｍＬ）を滴下し室温で３時間撹拌した。反応液を減圧濃縮し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７５．４ｍｇ（０．１１４ｍｍｏｌ）　収率：３３％
MS (ESI) m/z 548 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.89 - 12.43 (m, 1H), 8.54 - 8.35 (m, 1H), 8.35 - 7.98 (m, 2H), 7.51 - 7.05 (m, 6H), 5.61 - 5.43 (m, 2H), 4.57 - 4.07 (m, 2H), 3.71 - 3.16 (m, 4H), 2.92 - 2.75 (m, 2H), 2.40 (s, 3H), 2.04 - 1.71 (m, 3H), 1.45 - 1.12 (m, 2H). Example 34 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetic acid Salt Step 1 4-[[(2-Benzyloxy-2-oxo-ethyl)-[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl Synthesis of tert-butyl] amino] methyl] piperidine-1-carboxylate Dissolve tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (107 mg, 0.50 mmol) in acetonitrile (4 mL) and bring to 0 ° C. Cooled down. Potassium carbonate (69 mg, 0.50 mmol) was added to the solution, and then benzyl 2-bromoacetate (78 μL, 0.50 mmol) was added, and the mixture was stirred overnight at room temperature with natural temperature rise. The insoluble material was filtered off, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane (2 mL), and DIPEA (0.087 mL, 0.50 mmol) and intermediate 4-B (87 mg, 0.20 mmol) were diluted at room temperature. And stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure to obtain the title compound without purification.
MS (ESI) m / z 738 [M + H] +
Step 2 2-[(1-tert-Butoxycarbonyl-4-piperidyl) methyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] Synthesis of amino] acetic acid The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 40 min. After neutralizing the reaction solution, the residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
MS (ESI) m / z 649 [M + H] +
Step 3 Synthesis of Example 34 Compound To a dichloromethane solution (2 mL) of the compound obtained in Step 2, trifluoroacetic acid (0.103 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 75.4 mg (0.114 mmol) Yield: 33%
MS (ESI) m / z 548 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.89-12.43 (m, 1H), 8.54-8.35 (m, 1H), 8.35-7.98 (m, 2H), 7.51-7.05 (m, 6H), 5.61 -5.43 (m, 2H), 4.57-4.07 (m, 2H), 3.71-3.16 (m, 4H), 2.92-2.75 (m, 2H), 2.40 (s, 3H), 2.04-1.71 (m, 3H) , 1.45-1.12 (m, 2H).
実施例３５　2-[2-アミノエチル-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[2-(tert-ブトキシカルボニルアミノ)エチル-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸ベンジルの合成
　Ｎ－（２－アミノエチル）カルバミン酸 ｔｅｒｔ－ブチル（１５９μＬ，１．００ｍｍｏｌ）のアセトニトリル（８ｍＬ）溶液に、炭酸カリウム（１３８ｍｇ，１．００ｍｍｏｌ）を加え－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（１５７μＬ，１．００ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣の半分をジクロロメタン（２ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７９ｍｇ，０．２０ｍｍｏｌ）を加えて室温で１時間撹拌した。反応液を減圧濃縮することで、表題化合物を無精製で得た。
MS (ESI) m/z 667 [M+H]+
工程２　2-[2-(tert-ブトキシカルボニルアミノ)エチル-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸の合成　工程１で得られた化合物を１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．８ｍＬ）を加え、室温で４０分撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
MS (ESI) m/z 577 [M+H]+
工程３　実施例３５化合物の合成
　工程２で得られた化合物をジクロロメタン（１ｍＬ）に溶解し、トリフルオロ酢酸（５５μＬ，０．７２ｍｍｏｌ）を加え、室温で３時間撹拌した。反応液を減圧濃縮した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２７．５ｍｇ（０．０４６６ｍｍｏｌ）　収率：２３％
MS (ESI) m/z 477 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.62 (m, 3H), 7.46 - 6.75 (m, 8H), 5.28 - 5.07 (m, 2H), 4.51 - 4.06 (m, 2H), 3.91 - 3.61 (m, 2H), 3.22 - 2.97 (m, 2H), 2.40 (s, 3H). Example 35 2- [2-Aminoethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] acetic acid trifluoroacetate step 1 2- [2- (tert-Butoxycarbonylamino) ethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] benzyl acetate Synthesis of tert-butyl N- (2-aminoethyl) carbamate (159 μL, 1.00 mmol) in acetonitrile (8 mL) was added potassium carbonate (138 mg, 1.00 mmol) and cooled to −10 ° C. to −15 ° C. After that, benzyl 2-bromoacetate (157 μL, 1.00 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was gradually raised to room temperature and stirred overnight. Insoluble material was filtered off and concentrated under reduced pressure. Half of the resulting residue was diluted with dichloromethane (2 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (79 mg, 0.20 mmol) were added. And stirred at room temperature for 1 hour. The title compound was obtained without purification by concentrating the reaction solution under reduced pressure.
MS (ESI) m / z 667 [M + H] +
Step 2 2- [2- (tert-Butoxycarbonylamino) ethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] acetic acid The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (0.8 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
MS (ESI) m / z 577 [M + H] +
Step 3 Synthesis of Example 35 Compound The compound obtained in Step 2 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (55 μL, 0.72 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 27.5 mg (0.0466 mmol) Yield: 23%
MS (ESI) m / z 477 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92-7.62 (m, 3H), 7.46-6.75 (m, 8H), 5.28-5.07 (m, 2H), 4.51-4.06 (m, 2H), 3.91 -3.61 (m, 2H), 3.22-2.97 (m, 2H), 2.40 (s, 3H).
実施例３６　2-[2-アミノエチル-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３５と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
収量：３３．７ｍｇ（０．０５５４ｍｍｏｌ）　収率：２８％
MS (ESI) m/z 494 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.90 - 7.64 (m, 3H), 7.44 - 7.23 (m, 4H), 7.20 - 7.06 (m, 2H), 5.62 - 5.41 (m, 2H), 4.60 - 4.09 (m, 2H), 3.85 - 3.66 (m, 2H), 3.23 - 3.01 (m, 2H), 2.40 (s, 3H).
実施例３７　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(エチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[2-[tert-ブトキシカルボニル(エチル)アミノ]エチルアミノ]酢酸ベンジルの合成
　ｔｅｒｔ－ブチル Ｎ－（２－アミノエチル）－Ｎ－エチル－カルバメイト（２５０ｍｇ，１．３３ｍｍｏｌ）をアセトニトリル（６ｍＬ）で希釈し、炭酸カリウム（２７５ｍｇ，１．９９ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．２３ｍＬ，１．４６ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１６時間半撹拌した。不溶物を濾別後、減圧下濃縮することで表題化合物を無精製で得た。
収量：４４０ｍｇ
MS (ESI) m/z 337 [M+H]+ 
工程２　実施例３７化合物の合成
　中間体１－Ｂ（７５．０ｍｇ，０．１９０ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、工程１で得られた化合物（９５．８ｍｇ，０．２８５ｍｍｏｌ）とＤＩＰＥＡ（０．０８３ｍＬ，０．４８ｍｍｏｌ）を加えて、室温で１８時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物（１９０ｍｇ）を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２９ｍＬ）を加え、室温で２時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、Ｂｏｃ体を得た。そのＢｏｃ体にＴＦＡ（０．５ｍＬ）およびジクロロメタン（１ｍＬ）を加えて、室温で１時間半撹拌した。有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５１．７ｍｇ（０．０８３６ｍｍｏｌ）　収率：４４％
MS (ESI) m/z 505 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.79 - 8.13 (m, 2H), 7.57 - 7.23 (m, 4H), 7.23 - 6.65 (m, 4H), 5.46 - 4.91 (m, 2H), 4.61 - 4.04 (m, 2H), 4.04 - 3.64 (m, 2H), 3.22 - 3.07 (m, 2H), 3.07 - 2.80 (m, 2H), 2.40 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). Example 36 2- [2-Aminoethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 35, using the intermediate 4-B instead of the intermediate 1-B.
Yield: 33.7 mg (0.0554 mmol) Yield: 28%
MS (ESI) m / z 494 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 7.90-7.64 (m, 3H), 7.44-7.23 (m, 4H), 7.20-7.06 (m, 2H), 5.62-5.41 (m, 2H), 4.60-4.09 (m, 2H), 3.85-3.66 (m, 2H), 3.23-3.01 (m, 2H), 2.40 (s, 3H).
Example 37 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (ethylamino) ethyl] amino] acetic acid Trifluoroacetate Step 1 Synthesis of benzyl 2- [2- [tert-butoxycarbonyl (ethyl) amino] ethylamino] acetate tert-butyl N- (2-aminoethyl) -N-ethyl-carbamate (250 mg, 1. 33 mmol) was diluted with acetonitrile (6 mL), potassium carbonate (275 mg, 1.99 mmol) was added, cooled to 0 ° C., and then diluted with acetonitrile (1 mL) benzyl 2-bromoacetate (0.23 mL, 1.46 mmol). ) Was added dropwise and stirred for 16 and a half hours while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 440 mg
MS (ESI) m / z 337 [M + H] +
Step 2 Synthesis of Example 37 Compound Dichloromethane (2 mL) was added to Intermediate 1-B (75.0 mg, 0.190 mmol) and dissolved. To the solution, the compound obtained in Step 1 (95.8 mg, 0.285 mmol) and DIPEA (0.083 mL, 0.48 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to give a crude product (190 mg). The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 1.5 hours. After distilling off the organic solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 51.7 mg (0.0836 mmol) Yield: 44%
MS (ESI) m / z 505 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79-8.13 (m, 2H), 7.57-7.23 (m, 4H), 7.23-6.65 (m, 4H), 5.46-4.91 (m, 2H), 4.61 -4.04 (m, 2H), 4.04-3.64 (m, 2H), 3.22-3.07 (m, 2H), 3.07-2.80 (m, 2H), 2.40 (s, 3H), 1.16 (t, J = 7.2 Hz , 3H).
実施例３８　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(エチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
　中間体４－Ｂ（７５．０ｍｇ，０．１８２ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、実施例３７の工程１で得られた生成物（９１．８ｍｇ，０．２７３ｍｍｏｌ）とＤＩＰＥＡ（０．０７９ｍＬ，０．４５５ｍｍｏｌ）を加えて、室温で１８時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物（１９８ｍｇ）を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２７ｍＬ）を加え、室温で２時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、Ｂｏｃ体を得た。そのＢｏｃ体にＴＦＡ（０．５ｍＬ）およびジクロロメタン（１ｍＬ）を加えて、室温で１時間半撹拌した。有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５７．５ｍｇ（０．０９０５ｍｍｏｌ）　収率：５０％
MS (ESI) m/z 522 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.36 (m, 2H), 8.34 (s, 1H), 7.51 - 7.22 (m, 4H), 7.22 - 7.00 (m, 2H), 5.60 - 5.38 (m, 2H), 4.71 - 4.06 (m, 2H), 3.96 - 3.64 (m, 2H), 3.27 - 3.11 (m, 2H), 3.08 - 2.84 (m, 2H), 2.40 (s, 3H), 1.32 - 0.99 (m, 3H). Example 38 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (ethylamino) ethyl] amino] acetic acid Dichloromethane (2 mL) was added to trifluoroacetate intermediate 4-B (75.0 mg, 0.182 mmol) and dissolved. The product obtained in Step 1 of Example 37 (91.8 mg, 0.273 mmol) and DIPEA (0.079 mL, 0.455 mmol) were added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to give a crude product (198 mg). The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.27 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 1.5 hours. After distilling off the organic solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 57.5 mg (0.0905 mmol) Yield: 50%
MS (ESI) m / z 522 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69-8.36 (m, 2H), 8.34 (s, 1H), 7.51-7.22 (m, 4H), 7.22-7.00 (m, 2H), 5.60-5.38 (m, 2H), 4.71-4.06 (m, 2H), 3.96-3.64 (m, 2H), 3.27-3.11 (m, 2H), 3.08-2.84 (m, 2H), 2.40 (s, 3H), 1.32 -0.99 (m, 3H).
実施例３９　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(イミダゾ[1,2-a]ピリジン-6-イルメチル)アミノ]酢酸　トリフルオロ酢酸塩
　イミダゾ［１，２－ａ］ピリジン－６－イルメタンアミン（２５０ｍｇ，１．０５ｍｍｏｌ）をアセトニトリル（６ｍＬ）で希釈し、炭酸カリウム（２１８ｍｇ，１．５８ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．１８ｍＬ，１．６ｍｍｏｌ）を滴下して、徐々に室温に戻しながら１３時間半撹拌した。不溶物を濾別後、減圧下濃縮することで残渣を得た。
　得られた残渣にジクロロメタン（２ｍＬ）を加えて溶解し、中間体４－Ｂ（７５．０ｍｇ，０．１９１ｍｍｏｌ）とＤＩＰＥＡ（０．０８３ｍＬ，０．４８ｍｍｏｌ）を加えて、室温で２４時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２９ｍＬ）を加え、室温で２０時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１５．１ｍｇ（０．０２１７ｍｍｏｌ）　収率：１１％
MS (ESI) m/z 581 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.73 (m, 1H), 8.44 - 8.34 (m, 1H), 8.34 - 8.19 (m, 1H), 7.95 - 7.71 (m, 2H), 7.47 - 7.18 (m, 6H), 7.20 - 7.01 (m, 2H), 5.59 - 5.46 (m, 2H), 5.27 - 4.84 (m, 3H), 4.73 - 4.12 (m, 2H), 2.39 (s, 3H). Example 39 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(imidazo [1,2-a] pyridine-6 -Ilmethyl) amino] acetic acid trifluoroacetate salt Imidazo [1,2-a] pyridin-6-ylmethanamine (250 mg, 1.05 mmol) was diluted with acetonitrile (6 mL) and potassium carbonate (218 mg, 1.58 mmol) After cooling to 0 ° C., benzyl 2-bromoacetate (0.18 mL, 1.6 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was stirred for 13 hours and a half while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give a residue.
Dichloromethane (2 mL) was added to the resulting residue for dissolution, intermediate 4-B (75.0 mg, 0.191 mmol) and DIPEA (0.083 mL, 0.48 mmol) were added, and the mixture was stirred at room temperature for 24 hours. . The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 20 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 15.1 mg (0.0217 mmol) Yield: 11%
MS (ESI) m / z 581 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.91-8.73 (m, 1H), 8.44-8.34 (m, 1H), 8.34-8.19 (m, 1H), 7.95-7.71 (m, 2H), 7.47 -7.18 (m, 6H), 7.20-7.01 (m, 2H), 5.59-5.46 (m, 2H), 5.27-4.84 (m, 3H), 4.73-4.12 (m, 2H), 2.39 (s, 3H) .
実施例４０　2-[(2-アミノ-2-メチル-プロピル)-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-[[2-(tert-ブトキシカルボニルアミノ)-2-メチル-プロピル]アミノ]酢酸ベンジルの合成
　ｔｅｒｔ－ブチル Ｎ－（２－アミノ－１，１－ジメチル－エチル）カルバメイト（２５０ｍｇ，１．３３ｍｍｏｌ）をアセトニトリル（６ｍＬ）で希釈し、炭酸カリウム（２７５ｍｇ，１．９９ｍｍｏｌ）を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．２３ｍＬ，１．５ｍｍｏｌ）を滴下して、徐々に室温に戻しながら６時間半撹拌した。不溶物を濾別後、減圧下濃縮することで工程１の粗生成物を得た。
収量：４８３ｍｇ
MS (ESI) m/z 337 [M+H]+ 
工程２　実施例４０化合物の合成
　中間体１－Ｂ（７５．０ｍｇ，０．１９０ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、工程１で得られた化合物（１１５ｍｇ，０．３４２ｍｍｏｌ）とＤＩＰＥＡ（０．０９９ｍＬ，０．５７ｍｍｏｌ）を加えて、室温で２０時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２９ｍＬ）を加え、室温で３時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、Ｂｏｃ体を得た。そのＢｏｃ体にＴＦＡ（０．５ｍＬ）およびジクロロメタン（１ｍＬ）を加えて、室温で２時間撹拌した。有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：６１．８ｍｇ（０．０９９９ｍｍｏｌ）　収率：５３％
MS (ESI) m/z 505 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.68 (m, 3H), 7.42 - 7.24 (m, 4H), 7.16 - 7.07 (m, 3H), 6.79 (d, J = 3.47 Hz, 1H), 5.14 (s, 2H), 4.50 (s, 2H), 3.62 (s, 2H), 2.40 (s, 3H), 1.27 (s, 6H). Example 40 2-[(2-Amino-2-methyl-propyl)-[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino ] Acetic acid trifluoroacetate step 1 Synthesis of benzyl 2-[[2- (tert-butoxycarbonylamino) -2-methyl-propyl] amino] acetate tert-butyl N- (2-amino-1,1-dimethyl- Ethyl) carbamate (250 mg, 1.33 mmol) was diluted with acetonitrile (6 mL), potassium carbonate (275 mg, 1.99 mmol) was added, cooled to 0 ° C., and then diluted with acetonitrile (1 mL) benzyl 2-bromoacetate (0.23 mL, 1.5 mmol) was added dropwise, and the mixture was stirred for 6 and a half hours while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to obtain the crude product of Step 1.
Yield: 483 mg
MS (ESI) m / z 337 [M + H] +
Step 2 Synthesis of Compound of Example 40 Dichloromethane (2 mL) was added to Intermediate 1-B (75.0 mg, 0.190 mmol) and dissolved. To the solution, the compound obtained in Step 1 (115 mg, 0.342 mmol) and DIPEA (0.099 mL, 0.57 mmol) were added and stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 2 hours. After distilling off the organic solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 61.8 mg (0.0999 mmol) Yield: 53%
MS (ESI) m / z 505 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84-7.68 (m, 3H), 7.42-7.24 (m, 4H), 7.16-7.07 (m, 3H), 6.79 (d, J = 3.47 Hz, 1H ), 5.14 (s, 2H), 4.50 (s, 2H), 3.62 (s, 2H), 2.40 (s, 3H), 1.27 (s, 6H).
実施例４１　2-[(2-アミノ-2-メチル-プロピル)-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
　中間体４－Ｂ（７５．０ｍｇ，０．１８２ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、実施例４０の工程１で得られた生成物（１１０ｍｇ，０．３２８ｍｍｏｌ）とＤＩＰＥＡ（０．０９５ｍＬ，０．５５ｍｍｏｌ）を加えて、室温で２０時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２８ｍＬ）を加え、室温で３時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、Ｂｏｃ体を得た。そのＢｏｃ体にＴＦＡ（０．５ｍＬ）及びジクロロメタン（１ｍＬ）を加えて、室温で２時間撹拌した。有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７３．５ｍｇ（０．１１６ｍｍｏｌ）　収率：６４％
MS (ESI) m/z 522 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.38 - 8.32 (m, 1H), 7.78 (s, 3H), 7.42 - 7.24 (m, 4H), 7.20 - 7.05 (m, 2H), 5.48 (s, 2H), 4.65 (s, 2H), 4.11 - 3.61 (m, 2H), 2.40 (s, 3H), 1.29 (s, 6H). Example 41 2-[(2-Amino-2-methyl-propyl)-[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino ] Acetic acid trifluoroacetate Intermediate 4-B (75.0 mg, 0.182 mmol) was dissolved in dichloromethane (2 mL). To the solution, the product obtained in Step 1 of Example 40 (110 mg, 0.328 mmol) and DIPEA (0.095 mL, 0.55 mmol) were added and stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.28 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the Boc form. TFA (0.5 mL) and dichloromethane (1 mL) were added to the Boc body, and the mixture was stirred at room temperature for 2 hours. After distilling off the organic solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 73.5 mg (0.116 mmol) Yield: 64%
MS (ESI) m / z 522 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38-8.32 (m, 1H), 7.78 (s, 3H), 7.42-7.24 (m, 4H), 7.20-7.05 (m, 2H), 5.48 (s , 2H), 4.65 (s, 2H), 4.11-3.61 (m, 2H), 2.40 (s, 3H), 1.29 (s, 6H).
実施例４２　2-[(5-カルバモイル-2-チエニル)メチル-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸
　５－ホルミルチオフェン－２－カルボン酸（１．１３ｇ、７．２４ｍｍｏｌ）にＴＨＦ（１０ｍＬ）、オキザリルクロライド（１．２４ｍＬ、１４．５ｍｍｏｌ）、ＤＭＦ（触媒量）を加え、室温で２時間撹拌した。溶媒を減圧下留去した後、得られた残渣に酢酸エチル（１０ｍＬ）、アンモニア水（２ｍＬ）を加え、室温で２時間撹拌した。溶媒を減圧下留去した後、得られた残渣を酢酸エチルで希釈し、水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣（３３０ｍｇ、２．１０ｍｍｏｌ）にジクロロメタン（１０ｍＬ）、酢酸（０．２４ｍＬ、４．２ｍｍｏｌ）、グリシンエチルエステル　塩酸塩（３５０ｍｇ、２．５２ｍｍｏｌ）を加え、室温で３０分間撹拌後、ナトリウムトリアセトキシボロハイドライド（５３０ｍｇ、２．５１ｍｍｏｌ）を加え、室温で一晩撹拌した。減圧下溶媒を留去して得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製した。得られた化合物（５００ｍｇ、１．４０ｍｍｏｌ）、中間体４－Ｂ（４８０ｍｇ、１．１７ｍｍｏｌ）、トリエチルアミン（０．３２ｍＬ、２．３ｍｍｏｌ）を加え、室温で２時間撹拌後、２Ｎ　塩酸にて中性にした後、減圧下溶媒を留去して得られた残渣に４Ｎ　塩酸ジオキサン溶液を0℃下加え、同温下２時間撹拌した。減圧下溶媒を留去して得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製した。得られた化合物の一部（３５ｍｇ、０．０７０ｍｍｏｌ）に１Ｎ　水酸化ナトリウム水溶液（５ｍＬ）、メタノール（５ｍＬ）、ＴＨＦ(５ｍＬ)を加え一晩撹拌した。２Ｎ　塩酸にて中性にした後、減圧下溶媒を留去して得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１５ｍｇ（０．０３２ｍｍｏｌ）　収率：４５％
MS (ESI) m/z 590 [M+H]+ Example 42 2-[(5-carbamoyl-2-thienyl) methyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino] To acetic acid 5-formylthiophene-2-carboxylic acid (1.13 g, 7.24 mmol) was added THF (10 mL), oxalyl chloride (1.24 mL, 14.5 mmol), DMF (catalytic amount), and 2 hours at room temperature. Stir. After the solvent was distilled off under reduced pressure, ethyl acetate (10 mL) and aqueous ammonia (2 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Dichloromethane (10 mL), acetic acid (0.24 mL, 4.2 mmol) and glycine ethyl ester hydrochloride (350 mg, 2.52 mmol) were added to the residue (330 mg, 2.10 mmol) obtained by evaporating the solvent under reduced pressure. After stirring for 30 minutes at room temperature, sodium triacetoxyborohydride (530 mg, 2.51 mmol) was added and stirred overnight at room temperature. The residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1. The obtained compound (500 mg, 1.40 mmol), intermediate 4-B (480 mg, 1.17 mmol) and triethylamine (0.32 mL, 2.3 mmol) were added, and the mixture was stirred at room temperature for 2 hours, and then with 2N hydrochloric acid. Then, 4N hydrochloric acid dioxane solution was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at the same temperature for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1. To a portion of the obtained compound (35 mg, 0.070 mmol), 1N aqueous sodium hydroxide solution (5 mL), methanol (5 mL), and THF (5 mL) were added and stirred overnight. After neutralizing with 2N hydrochloric acid, the solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 15 mg (0.032 mmol) Yield: 45%
MS (ESI) m / z 590 [M + H] +
実施例４３　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジル)アミノ]酢酸　トリフルオロ酢酸塩
工程１　4-[(2-ベンジルオキシ-2-オキソ-エチル)-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]ピペリジン-1-カルボン酸 tert-ブチルの合成
　４－アミノピペリジン－１－カルボン酸 ｔｅｒｔ－ブチル（８０１ｍｇ，４．００ｍｍｏｌ）をアセトニトリル（３５ｍＬ）で希釈し、炭酸カリウム（５５２ｍｇ，４．００ｍｍｏｌ）を加えて－１０℃～－１５℃に冷却した後、アセトニトリル（３ｍＬ）で希釈した２－ブロモ酢酸ベンジル（６２７μＬ，４．００ｍｍｏｌ）を滴下し、徐々に室温に上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣の一部（１５１ｍｇ）をジクロロメタン（２ｍＬ）で希釈し、ＤＩＰＥＡ（８７μＬ，０．５０ｍｍｏｌ）および中間体１－Ｂ（７９ｍｇ，０．２０ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧濃縮し、表題化合物を無精製で得た。
工程２　2-[(1-tert-ブトキシカルボニル-4-ピペリジル)-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸の合成
　工程１で得られた化合物を１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（１．６ｍＬ）を加え室温で１時間撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和後、減圧下溶媒を留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
MS (ESI) m/z 617 [M+H]+
工程３　実施例４３化合物の合成
　工程２で得られた化合物のジクロロメタン溶液（２ｍＬ）に、トリフルオロ酢酸（０．１０４ｍＬ）を滴下し室温で３時間撹拌した。反応液を減圧濃縮し、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７２．５ｍｇ（０．１１５ｍｍｏｌ）　収率：５７％
MS (ESI) m/z 517 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.46 (m, 1H), 8.17 - 7.94 (m, 1H), 7.48 - 6.97 (m, 6H), 6.78 (s, 1H), 5.33 - 5.02 (m, 2H), 4.60 - 4.16 (m, 2H), 4.06 - 3.27 (m, 3H), 3.15 - 2.87 (m, 2H), 2.40 (s, 3H), 2.11 - 1.71 (m, 4H). Example 43 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidyl) amino] acetic acid trifluoroacetate Step 1 4-[(2-Benzyloxy-2-oxo-ethyl)-[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino ] Synthesis of tert-butyl piperidine-1-carboxylate Tert-butyl 4-aminopiperidine-1-carboxylate (801 mg, 4.00 mmol) was diluted with acetonitrile (35 mL), and potassium carbonate (552 mg, 4.00 mmol) was added. In addition, after cooling to −10 ° C. to −15 ° C., benzyl 2-bromoacetate (627 μL, 4.00 mmol) diluted with acetonitrile (3 mL) was added dropwise, gradually warmed to room temperature and stirred overnight. An insoluble material was filtered off, and the residue (151 mg) obtained by concentration under reduced pressure was diluted with dichloromethane (2 mL), and DIPEA (87 μL, 0.50 mmol) and intermediate 1-B (79 mg, 0. 20 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the title compound without purification.
Step 2 2-[(1-tert-Butoxycarbonyl-4-piperidyl)-[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino Synthesis of acetic acid The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution, and the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
MS (ESI) m / z 617 [M + H] +
Step 3 Synthesis of Example 43 Compound To a dichloromethane solution (2 mL) of the compound obtained in Step 2, trifluoroacetic acid (0.104 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 72.5 mg (0.115 mmol) Yield: 57%
MS (ESI) m / z 517 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71-8.46 (m, 1H), 8.17-7.94 (m, 1H), 7.48-6.97 (m, 6H), 6.78 (s, 1H), 5.33-5.02 (m, 2H), 4.60-4.16 (m, 2H), 4.06-3.27 (m, 3H), 3.15-2.87 (m, 2H), 2.40 (s, 3H), 2.11-1.71 (m, 4H).
実施例４４　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例４３と同様の操作を、中間体１－Ｂの代わりに中間体４－Ｂを用いて行うことにより、表題化合物を得た。
収量：７５．４ｍｇ（０．１１６ｍｍｏｌ）　収率：５８％
MS (ESI) m/z 534 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.03 - 12.48 (m, 1H), 8.62 - 8.49 (m, 1H), 8.33 - 8.18 (m, 1H), 8.16 - 7.92 (m, 1H), 7.45 - 7.09 (m, 6H), 5.62 - 5.37 (m, 2H), 4.59 - 3.96 (m, 3H), 3.11 - 2.78 (m, 2H), 2.40 (s, 3H), 2.10 - 1.72 (m, 4H).
実施例４５　2-[2-ジエチルアミノエチル-[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
工程１　2-(2-ジエチルアミノエチルアミノ)酢酸ベンジルの合成
　Ｎ’，Ｎ’－ジエチルエタン－１，２－ジアミン（８６４ｍｇ，７．４３ｍｍｏｌ）をアセトニトリル（４０ｍＬ）で希釈し、炭酸カリウム（２．５７ｇ，１８．６ｍｍｏｌ）
を加えて０℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（１．２８ｍＬ，８．１８ｍｍｏｌ）を滴下して、徐々に室温に戻しながら６時間半撹拌した。不溶物を濾別後、減圧下濃縮することで表題化合物を無精製で得た。
収量：１．９５ｇ
MS (ESI) m/z 265 [M+H]+ 
工程２　実施例４５化合物の合成
　中間体１－Ｂ（７５．０ｍｇ，０．１９０ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解した。その溶液に、工程１で得られた化合物（９０．４ｍｇ，０．３４２ｍｍｏｌ）とＤＩＰＥＡ（０．０８３ｍＬ，０．４８ｍｍｏｌ）を加えて、室温で１５時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物を得た。得られた粗生成物にＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２９ｍＬ）を加え、室温で２時間撹拌した。反応液を中和後、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５１．４ｍｇ（０．０７９５ｍｍｏｌ）　収率：４２％
MS (ESI) m/z 533 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.24 (m, 4H), 7.23 - 6.99 (m, 3H), 6.89 - 6.71 (m, 1H), 5.28 - 5.07 (m, 2H), 4.47 - 4.08 (m, 2H), 4.08 - 3.74 (m, 2H), 3.33 - 3.08 (m, 6H), 2.40 (s, 3H), 1.28 - 1.06 (m, 6H). Example 44 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 43 by using the intermediate 4-B instead of the intermediate 1-B.
Yield: 75.4 mg (0.116 mmol) Yield: 58%
MS (ESI) m / z 534 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03-12.48 (m, 1H), 8.62-8.49 (m, 1H), 8.33-8.18 (m, 1H), 8.16-7.92 (m, 1H), 7.45 -7.09 (m, 6H), 5.62-5.37 (m, 2H), 4.59-3.96 (m, 3H), 3.11-2.78 (m, 2H), 2.40 (s, 3H), 2.10-1.72 (m, 4H) .
Example 45 2- [2-Diethylaminoethyl- [5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl] amino] acetic acid trifluoroacetate step 1 Synthesis of benzyl 2- (2-diethylaminoethylamino) acetate N ′, N′-diethylethane-1,2-diamine (864 mg, 7.43 mmol) was diluted with acetonitrile (40 mL), and potassium carbonate (2.57 g , 18.6 mmol)
After cooling to 0 ° C., benzyl 2-bromoacetate (1.28 mL, 8.18 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the mixture was stirred for 6 and a half hours while gradually returning to room temperature. The insoluble material was filtered off and concentrated under reduced pressure to give the title compound without purification.
Yield: 1.95 g
MS (ESI) m / z 265 [M + H] +
Step 2 Synthesis of Example 45 Compound Dichloromethane (2 mL) was added to Intermediate 1-B (75.0 mg, 0.190 mmol) and dissolved. The compound obtained in Step 1 (90.4 mg, 0.342 mmol) and DIPEA (0.083 mL, 0.48 mmol) were added to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.29 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 51.4 mg (0.0795 mmol) Yield: 42%
MS (ESI) m / z 533 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.43-7.24 (m, 4H), 7.23-6.99 (m, 3H), 6.89-6.71 (m, 1H), 5.28-5.07 (m, 2H), 4.47 -4.08 (m, 2H), 4.08-3.74 (m, 2H), 3.33-3.08 (m, 6H), 2.40 (s, 3H), 1.28-1.06 (m, 6H).
実施例４６　2-[2-ジエチルアミノエチル-[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
　中間体４－Ｂ（７５．０ｍｇ，０．１８２ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加えて溶解し、実施例４５の工程１で得られた化合物（８６．６ｍｇ，０．３２８ｍｍｏｌ）とＤＩＰＥＡ（０．０７９ｍＬ，０．４６ｍｍｏｌ）を加えて、室温で１５時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで、粗生成物を得た。得られた粗生成物をＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化ナトリウム水溶液（０．２７ｍＬ）を加え、室温で２時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５０．６ｍｇ（０．０７６２ｍｍｏｌ）　収率：４２％
MS (ESI) m/z 550 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.44 - 8.23 (m, 1H), 7.45 - 7.24 (m, 4H), 7.20 - 7.08 (m, 2H), 5.60 - 5.42 (m, 2H), 4.58 - 4.11 (m, 2H), 4.05 - 3.75 (m, 2H), 3.24 - 3.08 (m, 6H), 2.44 - 2.35 (m, 3H), 1.20 (dt, J = 7.20, 14.54 Hz, 6H). Example 46 2- [2-Diethylaminoethyl- [2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate intermediate Dichloromethane (2 mL) was added to 4-B (75.0 mg, 0.182 mmol) and dissolved, and the compound (86.6 mg, 0.328 mmol) obtained in Step 45 of Example 45 and DIPEA (0.079 mL) were dissolved. , 0.46 mmol) and stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in a mixed solvent of THF (1 mL) and methanol (1 mL), 1N aqueous sodium hydroxide solution (0.27 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 50.6 mg (0.0762 mmol) Yield: 42%
MS (ESI) m / z 550 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44-8.23 (m, 1H), 7.45-7.24 (m, 4H), 7.20-7.08 (m, 2H), 5.60-5.42 (m, 2H), 4.58 -4.11 (m, 2H), 4.05-3.75 (m, 2H), 3.24-3.08 (m, 6H), 2.44-2.35 (m, 3H), 1.20 (dt, J = 7.20, 14.54 Hz, 6H).
実施例４７　2-[[5-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
工程１　2-[[5-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸ベンジルの合成
　７－ブロモ－４，５－ジフルオロ－ベンゾフラン（２５ｍｇ，０．１１ｍｍｏｌ）、中間体１６（７０ｍg，０．１３ｍｍｏｌ）、ＰｄＣｌ2（ｄｐｐｆ）（５．０ｍg，０．００５３ｍｍｏｌ）および１，４－ジオキサン（１．２ｍｌ）に１Ｍ　炭酸カリウム水溶液（０．４ｍｌ）を加え、１００℃で１時間撹拌した。ジクロロメタンで希釈し、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去後、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物を得た。
MS (ESI) m/z 576 [M+H]+
工程２　実施例４７化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．１７７ｍＬ）を加え、室温で撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２２．４ｍｇ（０．０４６１ｍｍｏｌ）　収率：４３％
MS (ESI) m/z 486 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 12.3, 7.7 Hz, 1H), 7.34 - 6.93 (m, 4H), 6.84 - 6.66 (m, 1H), 5.34 - 5.07 (m, 2H), 4.47 - 4.07 (m, 2H), 3.65 - 3.41 (m, 4H), 3.23 (s, 3H). Example 47 2-[[5-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Step 1 2- [ Synthesis of benzyl [5-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetate 7-Bromo-4,5- Difluoro-benzofuran (25 mg, 0.11 mmol), intermediate 16 (70 mg, 0.13 mmol), PdCl 2 (dppf) (5.0 mg, 0.0053 mmol) and 1,4-dioxane (1.2 ml) in 1M carbonic acid A potassium aqueous solution (0.4 ml) was added, and the mixture was stirred at 100 ° C. for 1 hour. The mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound.
MS (ESI) m / z 576 [M + H] +
Step 2 Synthesis of Example 47 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.177 mL) was added, and the mixture was stirred at room temperature. The reaction solution was neutralized with 1N aqueous trifluoroacetic acid solution and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 22.4 mg (0.0461 mmol) Yield: 43%
MS (ESI) m / z 486 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 12.3, 7.7 Hz, 1H) , 7.34-6.93 (m, 4H), 6.84-6.66 (m, 1H), 5.34-5.07 (m, 2H), 4.47-4.07 (m, 2H), 3.65-3.41 (m, 4H), 3.23 (s, 3H).
実施例４８　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例１と同様の操作を、中間体１－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：２７．０ｍｇ（０．０５３８ｍｍｏｌ）　収率：４３％
MS (ESI) m/z 503 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.27 - 8.17 (m, 2H), 7.90 - 7.78 (m, 2H), 7.68 - 7.58 (m, 1H), 7.29 - 7.17 (m, 3H), 5.76 - 5.38 (m, 2H), 4.61 - 4.12 (m, 2H), 3.82 - 3.49 (m, 4H), 3.29 - 3.15 (m, 3H).
実施例４９　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸
　実施例２４と同様の操作を、中間体１－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：５３．６ｍｇ（０．１０２ｍｍｏｌ）　収率：８１％
MS (ESI) m/z 525 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.15 (m, 2H), 7.89 - 7.79 (m, 2H), 7.68 - 7.55 (m, 2H), 7.29 - 7.17 (m, 3H), 6.47 - 6.33 (m, 2H), 5.64 - 5.47 (m, 2H), 5.05 - 4.65 (m, 2H), 4.52 - 4.01 (m, 2H). Example 48 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid As in Example 1 The title compound was obtained by performing the above procedure using Intermediate 9-B instead of Intermediate 1-B.
Yield: 27.0 mg (0.0538 mmol) Yield: 43%
MS (ESI) m / z 503 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27-8.17 (m, 2H), 7.90-7.78 (m, 2H), 7.68-7.58 (m, 1H), 7.29-7.17 (m, 3H), 5.76 -5.38 (m, 2H), 4.61-4.12 (m, 2H), 3.82-3.49 (m, 4H), 3.29-3.15 (m, 3H).
Example 49 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid As in Example 24 The title compound was obtained by performing the above procedure using Intermediate 9-B instead of Intermediate 1-B.
Yield: 53.6 mg (0.102 mmol) Yield: 81%
MS (ESI) m / z 525 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36-8.15 (m, 2H), 7.89-7.79 (m, 2H), 7.68-7.55 (m, 2H), 7.29-7.17 (m, 3H), 6.47 -6.33 (m, 2H), 5.64-5.47 (m, 2H), 5.05-4.65 (m, 2H), 4.52-4.01 (m, 2H).
実施例５０　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：１０．２ｍｇ（０．０１９４ｍｍｏｌ）　収率：１５％
MS (ESI) m/z 526 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.42 - 8.28 (m, 1H), 8.28 - 8.15 (m, 1H), 8.15 - 8.00 (m, 1H), 7.90 - 7.76 (m, 2H), 7.62 (dd, J = 12.0, 7.9 Hz, 1H), 7.33 - 7.11 (m, 4H), 5.52 (s, 2H), 5.28 - 4.77 (m, 2H), 4.66 - 4.13 (m, 2H).
実施例５１　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸　実施例１９と同様の操作を、中間体４－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：２８．１ｍｇ（０．０５２０ｍｍｏｌ）　収率：４１％
MS (ESI) m/z 541 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.23 - 8.15 (m, 1H), 7.90 - 7.78 (m, 2H), 7.63 (dd, J = 12.0, 8.0 Hz, 1H), 7.28 - 7.17 (m, 3H), 5.52 (s, 2H), 5.25 - 4.73 (m, 2H), 4.69 - 4.12 (m, 2H), 2.62 - 2.53 (m, 3H). Example 50 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid Example 4 The same operation was performed using intermediate 9-B instead of intermediate 1-B to give the title compound.
Yield: 10.2 mg (0.0194 mmol) Yield: 15%
MS (ESI) m / z 526 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42-8.28 (m, 1H), 8.28-8.15 (m, 1H), 8.15-8.00 (m, 1H), 7.90-7.76 (m, 2H), 7.62 (dd, J = 12.0, 7.9 Hz, 1H), 7.33-7.11 (m, 4H), 5.52 (s, 2H), 5.28-4.77 (m, 2H), 4.66-4.13 (m, 2H).
Example 51 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadi Azol-3-yl) methyl] amino] acetic acid The title compound was obtained in the same manner as the Example 19 using the intermediate 9-B instead of the intermediate 4-B.
Yield: 28.1 mg (0.0520 mmol) Yield: 41%
MS (ESI) m / z 541 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 8.23-8.15 (m, 1H), 7.90-7.78 (m, 2H), 7.63 (dd, J = 12.0, 8.0 Hz, 1H ), 7.28-7.17 (m, 3H), 5.52 (s, 2H), 5.25-4.73 (m, 2H), 4.69-4.12 (m, 2H), 2.62-2.53 (m, 3H).
実施例５２　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸 トリフルオロ酢酸塩
　実施例３３と同様の操作を、中間体４－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：１８．８ｍｇ（０．０２９８ｍｍｏｌ）　収率：２４％
MS (ESI) m/z 516 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.00 - 12.75 (m, 1H), 9.41 - 9.04 (m, 1H), 8.41 - 8.28 (m, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.70 - 7.53 (m, 1H), 7.32 - 7.13 (m, 3H), 5.65 - 5.42 (m, 2H), 4.64 - 4.12 (m, 2H), 4.04 - 3.17 (m, 4H), 2.92 - 2.76 (m, 6H).
実施例５３　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩工程１　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸ベンジルの合成
　２－ピロリジン－１－イルエタンアミン（０．５０２ｍＬ，４．００ｍｍｏｌ）をアセトニトリル（３５ｍＬ）で希釈し、炭酸カリウム（５５２ｍｇ，４．００ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（３ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．６２７ｍＬ，４．００ｍｍｏｌ）を滴下して一晩間撹拌した。不溶物を濾別後、減圧下濃縮することで残渣を得た。得られた残渣の一部（６６ｍｇ）をジクロロメタン（１ｍＬ）で希釈し、ＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）および中間体９－Ｂ（５１ｍｇ，０．１３ｍｍｏｌ）を加えた後、室温で３０分撹拌した。反応溶液を減圧下濃縮することで、表題化合物を無精製で得た。
MS (ESI) m/z 632 [M+H]+
工程２　実施例５３化合物の合成
　工程１で得られた化合物に１，４－ジオキサン（２ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．８１ｍＬ）を加え、室温で一晩撹拌した。反応液を１Ｎ　トリフルオロ酢酸で中和した後、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３１．３ｍｇ（０．０４７７ｍｍｏｌ）　収率：３８％
MS (ESI) m/z 542 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.04 - 12.68 (m, 1H), 9.53 - 9.29 (m, 1H), 8.41 - 8.29 (m, 1H), 8.27 - 8.14 (m, 1H), 7.94 - 7.77 (m, 2H), 7.70 - 7.53 (m, 1H), 7.31 - 7.15 (m, 3H), 5.64 - 5.48 (m, 2H), 4.67 - 4.11 (m, 2H), 4.02 - 3.78 (m, 2H), 3.76 - 2.99 (m, 6H), 2.14 - 1.72 (m, 4H). Example 52 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 33 using the intermediate 9-B instead of the intermediate 4-B.
Yield: 18.8 mg (0.0298 mmol) Yield: 24%
MS (ESI) m / z 516 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00-12.75 (m, 1H), 9.41-9.04 (m, 1H), 8.41-8.28 (m, 1H), 8.20 (d, J = 2.2 Hz, 1H ), 7.93-7.79 (m, 2H), 7.70-7.53 (m, 1H), 7.32-7.13 (m, 3H), 5.65-5.42 (m, 2H), 4.64-4.12 (m, 2H), 4.04-3.17 (m, 4H), 2.92-2.76 (m, 6H).
Example 53 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Trifluoro Acetate step 1 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] benzyl acetate Synthesis of 2-pyrrolidin-1-ylethanamine (0.502 mL, 4.00 mmol) was diluted with acetonitrile (35 mL), potassium carbonate (552 mg, 4.00 mmol) was added, and the mixture was cooled to −10 ° C. Benzyl 2-bromoacetate (0.627 mL, 4.00 mmol) diluted with (3 mL) was added dropwise and stirred overnight. The insoluble material was filtered off and concentrated under reduced pressure to give a residue. Part of the resulting residue (66 mg) was diluted with dichloromethane (1 mL) and DIPEA (0.044 mL, 0.25 mmol) and intermediate 9-B (51 mg, 0.13 mmol) were added, followed by 30 at room temperature. Stir for minutes. The title compound was obtained without purification by concentrating the reaction solution under reduced pressure.
MS (ESI) m / z 632 [M + H] +
Step 2 Synthesis of Example 53 Compound The compound obtained in Step 1 was dissolved in 1,4-dioxane (2 mL), 1N aqueous lithium hydroxide solution (0.81 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N trifluoroacetic acid and then purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 31.3 mg (0.0477 mmol) Yield: 38%
MS (ESI) m / z 542 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04-12.68 (m, 1H), 9.53-9.29 (m, 1H), 8.41-8.29 (m, 1H), 8.27-8.14 (m, 1H), 7.94 -7.77 (m, 2H), 7.70-7.53 (m, 1H), 7.31-7.15 (m, 3H), 5.64-5.48 (m, 2H), 4.67-4.11 (m, 2H), 4.02-3.78 (m, 2H), 3.76-2.99 (m, 6H), 2.14-1.72 (m, 4H).
実施例５４　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：４７．７ｍｇ（０．０７７５ｍｍｏｌ）　収率：７７％
MS (ESI) m/z 502 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.25 (m, 3H), 8.26 - 8.17 (m, 1H), 7.92 - 7.80 (m, 2H), 7.68 - 7.56 (m, 1H), 7.32 - 7.18 (m, 3H), 5.66 - 5.47 (m, 2H), 4.64 - 4.11 (m, 2H), 3.97 - 3.71 (m, 2H), 3.32 - 3.12 (m, 2H), 2.64 - 2.55 (m, 3H).
実施例５５　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３４と同様の操作を、中間体４－Ｂの代わりに中間体９－Ｂを用いて行うことにより、表題化合物を得た。
収量：４１．６ｍｇ（０．０６３５ｍｍｏｌ）　収率：７０％
MS (ESI) m/z 542 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.37 (m, 1H), 8.31 - 8.03 (m, 3H), 7.91 - 7.79 (m, 2H), 7.69 - 7.56 (m, 1H), 7.32 - 7.18 (m, 3H), 5.64 - 5.46 (m, 2H), 4.60 - 4.05 (m, 2H), 3.91 - 3.16 (m, 4H), 2.90 - 2.71 (m, 2H), 2.07 - 1.68 (m, 3H), 1.46 - 1.13 (m, 2H). Example 54 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Trifluoro Acetate The title compound was obtained in the same manner as the Example 3 using the intermediate 9-B instead of the intermediate 1-B.
Yield: 47.7 mg (0.0775 mmol) Yield: 77%
MS (ESI) m / z 502 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43-8.25 (m, 3H), 8.26-8.17 (m, 1H), 7.92-7.80 (m, 2H), 7.68-7.56 (m, 1H), 7.32 -7.18 (m, 3H), 5.66-5.47 (m, 2H), 4.64-4.11 (m, 2H), 3.97-3.71 (m, 2H), 3.32-3.12 (m, 2H), 2.64-2.55 (m, 3H).
Example 55 2-[[2-[[4- (4,5-Difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 34 using the intermediate 9-B instead of the intermediate 4-B.
Yield: 41.6 mg (0.0635 mmol) Yield: 70%
MS (ESI) m / z 542 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52-8.37 (m, 1H), 8.31-8.03 (m, 3H), 7.91-7.79 (m, 2H), 7.69-7.56 (m, 1H), 7.32 -7.18 (m, 3H), 5.64-5.46 (m, 2H), 4.60-4.05 (m, 2H), 3.91-3.16 (m, 4H), 2.90-2.71 (m, 2H), 2.07-1.68 (m, 3H), 1.46-1.13 (m, 2H).
実施例５６　2-[[5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体１４－Ｂを用いて行うことにより、表題化合物を得た。
収量：２２．４ｍｇ（０．０３６６ｍｍｏｌ）　収率：１８％
MS (ESI) m/z 499 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.07 (m, 2H), 8.05 - 7.69 (m, 3H), 7.59 (dd, J = 12.3, 7.7 Hz, 1H), 7.33 - 6.70 (m, 4H), 5.35 - 5.06 (m, 2H), 4.53 - 4.05 (m, 2H), 3.90 - 3.60 (m, 2H), 3.33 - 3.07 (m, 2H), 2.64 - 2.55 (m, 3H), 2.35 (s, 3H).
実施例５７　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例５３と同様の操作を、中間体９－Ｂの代わりに中間体６－Ｂを用いて行うことにより、表題化合物を得た。
収量：４７．６ｍｇ（０．０７１０ｍｍｏｌ）　収率：３０％
MS (ESI) m/z 556 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.95 - 12.78 (m, 1H), 9.46 - 9.23 (m, 1H), 8.40 - 8.32 (m, 1H), 7.95 - 7.76 (m, 3H), 7.63 - 7.54 (m, 1H), 7.28 - 7.15 (m, 2H), 5.62 - 5.46 (m, 2H), 4.67 - 4.12 (m, 2H), 4.04 - 3.80 (m, 2H), 3.71 - 2.76 (m, 6H), 2.35 (s, 3H), 2.08 - 1.77 (m, 4H). Example 56 2-[[5-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 3 using the intermediate 14-B instead of the intermediate 1-B.
Yield: 22.4 mg (0.0366 mmol) Yield: 18%
MS (ESI) m / z 499 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56-8.07 (m, 2H), 8.05-7.69 (m, 3H), 7.59 (dd, J = 12.3, 7.7 Hz, 1H), 7.33-6.70 (m , 4H), 5.35-5.06 (m, 2H), 4.53-4.05 (m, 2H), 3.90-3.60 (m, 2H), 3.33-3.07 (m, 2H), 2.64-2.55 (m, 3H), 2.35 (s, 3H).
Example 57 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 53, except that the intermediate 6-B was used instead of the intermediate 9-B.
Yield: 47.6 mg (0.0710 mmol) Yield: 30%
MS (ESI) m / z 556 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.95-12.78 (m, 1H), 9.46-9.23 (m, 1H), 8.40-8.32 (m, 1H), 7.95-7.76 (m, 3H), 7.63 -7.54 (m, 1H), 7.28-7.15 (m, 2H), 5.62-5.46 (m, 2H), 4.67-4.12 (m, 2H), 4.04-3.80 (m, 2H), 3.71-2.76 (m, 6H), 2.35 (s, 3H), 2.08-1.77 (m, 4H).
実施例５８　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体６－Ｂを用いて行うことにより、表題化合物を得た。
収量：１５．５ｍｇ（０．０２８７ｍｍｏｌ）　収率：１４％
MS (ESI) m/z 540 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.27 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.87 - 7.75 (m, 2H), 7.64 - 7.52 (m, 1H), 7.25 - 7.10 (m, 3H), 5.57 - 5.46 (m, 2H), 5.27 - 4.78 (m, 2H), 4.67 - 4.14 (m, 2H), 2.34 (s, 3H).
実施例５９　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　中間体１３－Ａ（９０．８ｍｇ，０．２５０ｍｍｏｌ）に塩化チオニル（１ｍＬ）とＤＭＦを１滴加えて、５０℃で１時間撹拌した。溶媒を減圧除去後、得られた残渣をジクロロメタン（２ｍＬ）で希釈し、その溶液をＤＩＰＥＡ（０．０４４ｍＬ，０．２５ｍｍｏｌ）および実施例１の工程１で得られた化合物（１１２ｍｇ，０．５００ｍｍｏｌ）を溶かしたジクロロメタン溶液（２ｍＬ）に氷冷下にて加えて室温で一晩撹拌した。反応溶液にジクロロメタンを加えて希釈し、有機層を１Ｎ　塩酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。減圧下濃縮後、得られた残渣をＴＨＦ（２ｍＬ）およびメタノール（２ｍＬ）の混合溶媒に溶解し、氷冷下１Ｎ　水酸化リチウム水溶液（１．０ｍＬ）を加え、室温で３０分撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：７４．０ｍｇ（０．１５５ｍｍｏｌ）　収率：６２％
MS (ESI) m/z 479 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.23 (m, 4H), 7.23 - 7.00 (m, 3H), 6.78 (d, J = 3.6 Hz, 1H), 5.25 - 4.05 (m, 6H), 2.48 - 2.37 (m, 3H).
実施例６０　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体１３－Ｂを用いて行うことにより、表題化合物を得た。
収量：２９．２ｍｇ（０．０４９３ｍｍｏｌ）　収率：２５％
MS (ESI) m/z 478 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.50 - 8.13 (m, 2H), 7.50 - 7.30 (m, 3H), 7.25 (dd, J = 13.0, 7.1 Hz, 1H), 7.06 (dd, J = 14.1, 6.0 Hz, 3H), 6.88 - 6.72 (m, 1H), 5.26 - 5.04 (m, 2H), 4.45 - 4.07 (m, 2H), 3.97 - 3.63 (m, 2H), 3.33 - 3.04 (m, 2H), 2.64 - 2.56 (m, 3H). Example 58 2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid The title compound was obtained in the same manner as the Example 4 using the intermediate 6-B instead of the intermediate 1-B.
Yield: 15.5 mg (0.0287 mmol) Yield: 14%
MS (ESI) m / z 540 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37-8.27 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.87-7.75 ( m, 2H), 7.64-7.52 (m, 1H), 7.25-7.10 (m, 3H), 5.57-5.46 (m, 2H), 5.27-4.78 (m, 2H), 4.67-4.14 (m, 2H), 2.34 (s, 3H).
Example 59 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid One drop of thionyl chloride (1 mL) and DMF was added to Intermediate 13-A (90.8 mg, 0.250 mmol), and the mixture was stirred at 50 ° C. for 1 hr. After removing the solvent under reduced pressure, the obtained residue was diluted with dichloromethane (2 mL), and the solution was diluted with DIPEA (0.044 mL, 0.25 mmol) and the compound obtained in Step 1 of Example 1 (112 mg, 0.500 mmol). Was added to a dichloromethane solution (2 mL) in which the solution was dissolved under ice-cooling, and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction solution for dilution, and the organic layer was washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), 1N aqueous lithium hydroxide solution (1.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 74.0 mg (0.155 mmol) Yield: 62%
MS (ESI) m / z 479 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.45-7.23 (m, 4H), 7.23-7.00 (m, 3H), 6.78 (d, J = 3.6 Hz, 1H), 5.25-4.05 (m, 6H ), 2.48-2.37 (m, 3H).
Example 60 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 3 using the intermediate 13-B instead of the intermediate 1-B.
Yield: 29.2 mg (0.0493 mmol) Yield: 25%
MS (ESI) m / z 478 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50-8.13 (m, 2H), 7.50-7.30 (m, 3H), 7.25 (dd, J = 13.0, 7.1 Hz, 1H), 7.06 (dd, J = 14.1, 6.0 Hz, 3H), 6.88-6.72 (m, 1H), 5.26-5.04 (m, 2H), 4.45-4.07 (m, 2H), 3.97-3.63 (m, 2H), 3.33-3.04 (m , 2H), 2.64-2.56 (m, 3H).
実施例６１　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(テトラヒドロピラン-4-イルメチル)アミノ]酢酸工程１　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(テトラヒドロピラン-4-イルメチル)アミノ]酢酸ベンジルの合成
　テトラヒドロピラン－４－イルメタンアミン（４６１ｍｇ，４．００ｍｍｏｌ）をアセトニトリル（３５ｍＬ）で希釈し、炭酸カリウム（５５２ｍｇ，４．００ｍｍｏｌ）を加えて－１０℃に冷却した後、アセトニトリル（３ｍＬ）で希釈した２－ブロモ酢酸ベンジル（０．６２７ｍＬ，４．００ｍｍｏｌ）を滴下し、徐々に室温に上げ４晩間撹拌した。不溶物を濾別後、減圧下濃縮することで残渣を得た。得られた残渣の一部（１０５ｍｇ）をジクロロメタン（１ｍＬ）で希釈し、ＤＩＰＥＡ（０．８７ｍＬ，０．５０ｍｍｏｌ）および中間体１３－Ｂ（５１ｍｇ，０．１３ｍｍｏｌ）を加えた後、室温で３０分撹拌した。反応溶液を減圧下濃縮することで、表題化合物を無精製で得た。
MS (ESI) m/z 609 [M+H]+
工程２　実施例６１化合物の合成
　工程１で得られた化合物に１，４－ジオキサン（３ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（１ｍＬ）を加え、室温で一晩撹拌した。反応液を１Ｎ　トリフルオロ酢酸で中和し、有機溶媒を減圧下留去した後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５２．２ｍｇ（０．１４５ｍｍｏｌ）　収率：７３％
MS (ESI) m/z 519 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.31 (m, 3H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.18 - 6.93 (m, 3H), 6.83 - 6.70 (m, 1H), 5.25 - 5.05 (m, 2H), 4.47 - 4.04 (m, 2H), 3.87 - 3.10 (m, 6H), 1.97 - 1.80 (m, 1H), 1.62 - 1.46 (m, 2H), 1.29 - 1.06 (m, 2H). Example 61 2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) amino ] Acetic acid step 1 2-[[5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(tetrahydropyran-4-ylmethyl) Synthesis of benzyl amino] tetrahydropyran-4-ylmethanamine (461 mg, 4.00 mmol) was diluted with acetonitrile (35 mL), potassium carbonate (552 mg, 4.00 mmol) was added, and the mixture was cooled to −10 ° C. Benzyl 2-bromoacetate (0.627 mL, 4.00 mmol) diluted with acetonitrile (3 mL) was added dropwise, gradually raised to room temperature and stirred for 4 nights. The insoluble material was filtered off and concentrated under reduced pressure to give a residue. A part of the obtained residue (105 mg) was diluted with dichloromethane (1 mL), and DIPEA (0.87 mL, 0.50 mmol) and intermediate 13-B (51 mg, 0.13 mmol) were added, followed by 30 at room temperature. Stir for minutes. The title compound was obtained without purification by concentrating the reaction solution under reduced pressure.
MS (ESI) m / z 609 [M + H] +
Step 2 Synthesis of Compound in Example 61 The compound obtained in Step 1 was dissolved in 1,4-dioxane (3 mL), 1N aqueous lithium hydroxide solution (1 mL) was added, and the mixture was stirred overnight at room temperature. The reaction solution was neutralized with 1N trifluoroacetic acid and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 52.2 mg (0.145 mmol) Yield: 73%
MS (ESI) m / z 519 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.49-7.31 (m, 3H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.18-6.93 (m, 3H), 6.83-6.70 (m , 1H), 5.25-5.05 (m, 2H), 4.47-4.04 (m, 2H), 3.87-3.10 (m, 6H), 1.97-1.80 (m, 1H), 1.62-1.46 (m, 2H), 1.29 -1.06 (m, 2H).
実施例６２　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例１と同様の操作を、中間体１－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：７４．４ｍｇ（０．１５０ｍｍｏｌ）　収率：７５％
MS (ESI) m/z 496 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.27 - 8.19 (m, 1H), 7.48 - 7.33 (m, 3H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.15 - 7.06 (m, 2H), 5.57 - 5.41 (m, 2H), 4.59 - 4.13 (m, 2H), 3.79 - 3.61 (m, 2H), 3.56 - 3.39 (m, 2H), 3.27 - 3.18 (m, 3H).
実施例６３　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：２２．４ｍｇ（０．０４３２ｍｍｏｌ）　収率：２２％
MS (ESI) m/z 519 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.27 (m, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.48 - 7.05 (m, 7H), 5.47 (s, 2H), 5.31 - 4.76 (m, 2H), 4.72 - 4.12 (m, 2H).
実施例６４　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３３と同様の操作を、中間体４－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：６６．５ｍｇ（０．１０７ｍｍｏｌ）　収率：５３％
MS (ESI) m/z 509 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.50 - 9.03 (m, 1H), 8.46 - 8.25 (m, 1H), 7.60 - 6.98 (m, 6H), 5.65 - 5.35 (m, 2H), 4.67 - 3.64 (m, 6H), 3.03 - 2.74 (m, 6H). Example 62 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid The title compound was obtained by the same procedures as in Example 1, except that Intermediate 5-B was used instead of Intermediate 1-B.
Yield: 74.4 mg (0.150 mmol) Yield: 75%
MS (ESI) m / z 496 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27-8.19 (m, 1H), 7.48-7.33 (m, 3H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.15-7.06 (m , 2H), 5.57-5.41 (m, 2H), 4.59-4.13 (m, 2H), 3.79-3.61 (m, 2H), 3.56-3.39 (m, 2H), 3.27-3.18 (m, 3H).
Example 63 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid The title compound was obtained in the same manner as the Example 4 using the intermediate 5-B instead of the intermediate 1-B.
Yield: 22.4 mg (0.0432 mmol) Yield: 22%
MS (ESI) m / z 519 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37-8.27 (m, 1H), 8.07 (d, J = 7.1 Hz, 1H), 7.48-7.05 (m, 7H), 5.47 (s, 2H), 5.31-4.76 (m, 2H), 4.72-4.12 (m, 2H).
Example 64 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] Acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 33, except that the intermediate 5-B was used instead of the intermediate 4-B.
Yield: 66.5 mg (0.107 mmol) Yield: 53%
MS (ESI) m / z 509 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.50-9.03 (m, 1H), 8.46-8.25 (m, 1H), 7.60-6.98 (m, 6H), 5.65-5.35 (m, 2H), 4.67 -3.64 (m, 6H), 3.03-2.74 (m, 6H).
実施例６５　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酸酢酸塩
　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：３０．７ｍｇ（０．０５０５ｍｍｏｌ）　収率：２５％
MS (ESI) m/z 495 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.38 - 8.27 (m, 2H), 7.52 - 7.03 (m, 6H), 5.59 - 5.44 (m, 2H), 4.62 - 4.10 (m, 2H), 3.94 - 3.72 (m, 2H), 3.33 - 3.12 (m, 2H), 2.64 - 2.58 (m, 3H).
実施例６６　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３４と同様の操作を、中間体４－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：５４．１ｍｇ（０．０８３４ｍｍｏｌ）　収率：４２％
MS (ESI) m/z 535 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.52 - 8.02 (m, 3H), 7.52 - 7.04 (m, 6H), 5.58 - 5.39 (m, 2H), 4.54 - 4.09 (m, 2H), 3.69 - 3.37 (m, 2H), 3.33 - 3.17 (m, 2H), 2.90 - 2.72 (m, 2H), 2.03 - 1.72 (m, 3H), 1.43 - 1.12 (m, 2H). Example 65 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] Amino] acetic acid Trifluoroacetic acid salt The title compound was obtained in the same manner as the Example 3 except that the intermediate 5-B was used instead of the intermediate 1-B.
Yield: 30.7 mg (0.0505 mmol) Yield: 25%
MS (ESI) m / z 495 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.90 (s, 1H), 8.38-8.27 (m, 2H), 7.52-7.03 (m, 6H), 5.59-5.44 (m, 2H), 4.62-4.10 (m, 2H), 3.94-3.72 (m, 2H), 3.33-3.12 (m, 2H), 2.64-2.58 (m, 3H).
Example 66 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid Trifluoroacetate The title compound was obtained in the same manner as the Example 34, except that the intermediate 5-B was used instead of the intermediate 4-B.
Yield: 54.1 mg (0.0834 mmol) Yield: 42%
MS (ESI) m / z 535 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52-8.02 (m, 3H), 7.52-7.04 (m, 6H), 5.58-5.39 (m, 2H), 4.54-4.09 (m, 2H), 3.69 -3.37 (m, 2H), 3.33-3.17 (m, 2H), 2.90-2.72 (m, 2H), 2.03-1.72 (m, 3H), 1.43-1.12 (m, 2H).
実施例６７　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例５３と同様の操作を、中間体９－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：３４．０ｍｇ（０．０５２５ｍｍｏｌ）　収率：２６％
MS (ESI) m/z 535 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 12.97 - 12.80 (m, 1H), 9.50 - 9.30 (m, 1H), 8.41 - 8.27 (m, 1H), 7.51 - 7.05 (m, 6H), 5.59 - 5.43 (m, 2H), 4.63 - 4.16 (m, 2H), 4.02 - 3.79 (m, 2H), 3.09 (s, 6H), 2.09 - 1.79 (m, 4H).
実施例６８　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸
　実施例２４と同様の操作を、中間体１－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：４４．０ｍｇ（０．０８５１ｍｍｏｌ）　収率：４３％
MS (ESI) m/z 518 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.23 (m, 1H), 7.67 - 7.56 (m, 1H), 7.54 - 7.02 (m, 6H), 6.45 - 6.32 (m, 2H), 5.60 - 5.43 (m, 2H), 5.06 - 4.65 (m, 2H), 4.50 - 3.98 (m, 2H). Example 67 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 53, except that the intermediate 5-B was used instead of the intermediate 9-B.
Yield: 34.0 mg (0.0525 mmol) Yield: 26%
MS (ESI) m / z 535 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.97-12.80 (m, 1H), 9.50-9.30 (m, 1H), 8.41-8.27 (m, 1H), 7.51-7.05 (m, 6H), 5.59 -5.43 (m, 2H), 4.63-4.16 (m, 2H), 4.02-3.79 (m, 2H), 3.09 (s, 6H), 2.09-1.79 (m, 4H).
Example 68 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid The title compound was obtained in the same manner as the Example 24 using the intermediate 5-B instead of the intermediate 1-B.
Yield: 44.0 mg (0.0851 mmol) Yield: 43%
MS (ESI) m / z 518 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33-8.23 (m, 1H), 7.67-7.56 (m, 1H), 7.54-7.02 (m, 6H), 6.45-6.32 (m, 2H), 5.60 -5.43 (m, 2H), 5.06-4.65 (m, 2H), 4.50-3.98 (m, 2H).
実施例６９　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-エトキシエチル)アミノ]酢酸
工程１　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-エトキシエチル)アミノ]酢酸ベンジルの合成
　２－エトキシエタンアミン（１０５μＬ，１．００ｍｍｏｌ）のアセトニトリル（８ｍＬ）溶液に、炭酸カリウム（１３８ｍｇ，１．００ｍｍｏｌ）を加え－１０℃～－１５℃に冷却した後、アセトニトリル（１ｍＬ）で希釈した２－ブロモ酢酸ベンジル（１５７μＬ，１．００ｍｍｏｌ）を滴下し、徐々に室温へ上げ一晩撹拌した。不溶物を濾別後、減圧下濃縮して得られた残渣をジクロロメタン（４ｍＬ）で希釈し、ＤＩＰＥＡ（１７４μＬ，１．００ｍｍｏｌ）および中間体５－Ｂ（１１５ｍｇ，０．２８８ｍｍｏｌ）を加えて室温で撹拌した。反応液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、減圧下溶媒を留去することにより、表題化合物を得た。
MS (ESI) m/z 600 [M+H]+
工程２　実施例６９化合物の合成
　工程１で得られた化合物を１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ　水酸化リチウム水溶液（０．１５７ｍＬ）を加え、室温で２時間撹拌した。反応液を１Ｎ　トリフルオロ酢酸水溶液で中和後、減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：４２．４ｍｇ（０．０８３１ｍｍｏｌ）　収率：２９％
MS (ESI) m/z 510 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.27 - 8.17 (m, 1H), 7.53 - 7.30 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.18 - 7.04 (m, 2H), 5.57 - 5.40 (m, 2H), 4.61 - 4.13 (m, 2H), 3.77 - 3.58 (m, 2H), 3.48 - 3.34 (m, 4H), 1.14 - 0.94 (m, 3H). Example 69 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-ethoxyethyl) amino] acetic acid Step 1 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-ethoxyethyl) amino] acetic acid benzyl Synthesis of 2-ethoxyethanamine (105 μL, 1.00 mmol) in acetonitrile (8 mL) was added potassium carbonate (138 mg, 1.00 mmol), cooled to −10 ° C. to −15 ° C., and then acetonitrile (1 mL) Diluted benzyl 2-bromoacetate (157 μL, 1.00 mmol) was added dropwise, and the mixture was gradually warmed to room temperature and stirred overnight. The insoluble material was filtered off, and the residue obtained by concentration under reduced pressure was diluted with dichloromethane (4 mL), and DIPEA (174 μL, 1.00 mmol) and intermediate 5-B (115 mg, 0.288 mmol) were added to room temperature. Stir with. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate), and the solvent was evaporated under reduced pressure to give the title compound.
MS (ESI) m / z 600 [M + H] +
Step 2 Synthesis of Compound in Example 69 The compound obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), 1N aqueous lithium hydroxide solution (0.157 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N aqueous trifluoroacetic acid solution and evaporated under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 42.4 mg (0.0831 mmol) Yield: 29%
MS (ESI) m / z 510 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27-8.17 (m, 1H), 7.53-7.30 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.18-7.04 (m , 2H), 5.57-5.40 (m, 2H), 4.61-4.13 (m, 2H), 3.77-3.58 (m, 2H), 3.48-3.34 (m, 4H), 1.14-0.94 (m, 3H).
実施例７０　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(テトラヒドロピラン-4-イルメチル)アミノ]酢酸
　実施例６１と同様の操作を、中間体１３－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：９０．３ｍｇ（０．１６９ｍｍｏｌ）　収率：８４％
MS (ESI) m/z 536 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.24 - 8.11 (m, 1H), 7.48 - 7.31 (m, 3H), 7.31 - 7.19 (m, 1H), 7.19 - 7.06 (m, 2H), 5.57 - 5.41 (m, 2H), 4.54 - 4.07 (m, 2H), 3.89 - 3.73 (m, 2H), 3.64 - 3.13 (m, 4H), 2.00 - 1.77 (m, 1H), 1.63 - 1.43 (m, 2H), 1.31 - 1.15 (m, 1H), 1.09 - 0.95 (m, 1H).
実施例７１　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-[(3-メチル-1,2,4-オキサジアゾール-5-イル)メチル]アミノ]酢酸
　実施例１８と同様の操作を、中間体４－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：８７．６ｍｇ（０．１６４ｍｍｏｌ）　収率：８２％
MS (ESI) m/z 534 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.33 (m, 1H), 7.49 - 7.29 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.17 - 6.98 (m, 2H), 5.52 - 4.88 (m, 4H), 4.79 - 4.23 (m, 2H), 2.36 - 2.25 (m, 3H). Example 70 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(tetrahydropyran-4-ylmethyl) amino Acetic acid The title compound was obtained in the same manner as the Example 61, except that the intermediate 5-B was used instead of the intermediate 13-B.
Yield: 90.3 mg (0.169 mmol) Yield: 84%
MS (ESI) m / z 536 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.24-8.11 (m, 1H), 7.48-7.31 (m, 3H), 7.31-7.19 (m, 1H), 7.19-7.06 (m, 2H), 5.57 -5.41 (m, 2H), 4.54-4.07 (m, 2H), 3.89-3.73 (m, 2H), 3.64-3.13 (m, 4H), 2.00-1.77 (m, 1H), 1.63-1.43 (m, 2H), 1.31-1.15 (m, 1H), 1.09-0.95 (m, 1H).
Example 71 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[(3-methyl-1,2 , 4-Oxadiazol-5-yl) methyl] amino] acetic acid The title compound was obtained in the same manner as the example 18 except that the intermediate 5-B was used instead of the intermediate 4-B. .
Yield: 87.6 mg (0.164 mmol) Yield: 82%
MS (ESI) m / z 534 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43-8.33 (m, 1H), 7.49-7.29 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.17-6.98 (m , 2H), 5.52-4.88 (m, 4H), 4.79-4.23 (m, 2H), 2.36-2.25 (m, 3H).
実施例７２　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸
　実施例１９と同様の操作を、中間体４－Ｂの代わりに中間体５－Ｂを用いて行うことにより、表題化合物を得た。
収量：５５．４ｍｇ（０．１０４ｍｍｏｌ）　収率：５２％
MS (ESI) m/z 534 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.50 - 7.32 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.19 - 7.04 (m, 2H), 5.47 (s, 2H), 5.25 - 4.75 (m, 2H), 4.69 - 4.12 (m, 2H), 2.61 - 2.53 (m, 3H).
実施例７３　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例１と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：４８．３ｍｇ（０．０９３１ｍｍｏｌ）　収率：４７％
MS (ESI) m/z 519 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.14 (m, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.77 - 7.61 (m, 3H), 7.53 (dd, J = 11.6, 7.1 Hz, 1H), 7.36 - 7.16 (m, 2H), 5.63 - 5.47 (m, 2H), 4.63 - 4.13 (m, 2H), 3.82 - 3.60 (m, 2H), 3.60 - 3.48 (m, 2H), 3.29 - 3.14 (m, 3H). Example 72 2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2 , 4-Oxadiazol-3-yl) methyl] amino] acetic acid The title compound was obtained in the same manner as the Example 19 using the intermediate 5-B instead of the intermediate 4-B. .
Yield: 55.4 mg (0.104 mmol) Yield: 52%
MS (ESI) m / z 534 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (s, 1H), 7.50-7.32 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.19-7.04 (m, 2H ), 5.47 (s, 2H), 5.25-4.75 (m, 2H), 4.69-4.12 (m, 2H), 2.61-2.53 (m, 3H).
Example 73 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Example 1 The same operation was performed using intermediate 7-B instead of intermediate 1-B to obtain the title compound.
Yield: 48.3 mg (0.0931 mmol) Yield: 47%
MS (ESI) m / z 519 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32-8.14 (m, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.77-7.61 (m, 3H), 7.53 (dd, J = 11.6 , 7.1 Hz, 1H), 7.36-7.16 (m, 2H), 5.63-5.47 (m, 2H), 4.63-4.13 (m, 2H), 3.82-3.60 (m, 2H), 3.60-3.48 (m, 2H ), 3.29-3.14 (m, 3H).
実施例７４　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸
　実施例２４と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：７５．１ｍｇ（０．１３９ｍｍｏｌ）　収率：６９％
MS (ESI) m/z 541 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.34 - 8.25 (m, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.76 - 7.45 (m, 5H), 7.32 - 7.20 (m, 2H), 6.48 - 6.32 (m, 2H), 5.65 - 5.48 (m, 2H), 5.05 - 4.66 (m, 2H), 4.51 - 4.02 (m, 2H).
実施例７５　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：４０．６ｍｇ（０．０６４３ｍｍｏｌ）　収率：３２％
MS (ESI) m/z 518 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.25 (m, 3H), 8.01 (d, J = 5.6 Hz, 1H), 7.77 - 7.58 (m, 3H), 7.58 - 7.48 (m, 1H), 7.33 - 7.20 (m, 2H), 5.68 - 5.47 (m, 2H), 4.61 - 4.12 (m, 2H), 3.97 - 3.71 (m, 2H), 3.34 - 3.09 (m, 2H), 2.67 - 2.55 (m, 3H). Example 74 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid Example 24 The same operation was performed using intermediate 7-B instead of intermediate 1-B to obtain the title compound.
Yield: 75.1 mg (0.139 mmol) Yield: 69%
MS (ESI) m / z 541 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34-8.25 (m, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.76-7.45 (m, 5H), 7.32-7.20 (m, 2H ), 6.48-6.32 (m, 2H), 5.65-5.48 (m, 2H), 5.05-4.66 (m, 2H), 4.51-4.02 (m, 2H).
Example 75 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid Tri Fluoroacetate The title compound was obtained in the same manner as the Example 3 using the intermediate 7-B instead of the intermediate 1-B.
Yield: 40.6 mg (0.0643 mmol) Yield: 32%
MS (ESI) m / z 518 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48-8.25 (m, 3H), 8.01 (d, J = 5.6 Hz, 1H), 7.77-7.58 (m, 3H), 7.58-7.48 (m, 1H ), 7.33-7.20 (m, 2H), 5.68-5.47 (m, 2H), 4.61-4.12 (m, 2H), 3.97-3.71 (m, 2H), 3.34-3.09 (m, 2H), 2.67-2.55 (m, 3H).
実施例７６　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３４と同様の操作を、中間体４－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：５５．５ｍｇ（０．０８２６ｍｍｏｌ）　収率：４１％
MS (ESI) m/z 558 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.39 (m, 1H), 8.29 - 8.05 (m, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.76 - 7.62 (m, 3H), 7.59 - 7.48 (m, 1H), 7.33 - 7.20 (m, 2H), 5.66 - 5.43 (m, 2H), 4.62 - 4.06 (m, 2H), 3.77 - 3.17 (m, 4H), 2.91 - 2.73 (m, 2H), 2.07 - 1.72 (m, 3H), 1.45 - 1.15 (m, 2H).
実施例７７　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例５３と同様の操作を、中間体９－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：３７．４ｍｇ（０．０５５６ｍｍｏｌ）　収率：２８％
MS (ESI) m/z 558 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.56 - 9.29 (m, 1H), 8.42 - 8.30 (m, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.76 - 7.60 (m, 3H), 7.60 - 7.48 (m, 1H), 7.32 - 7.20 (m, 2H), 5.63 - 5.49 (m, 2H), 4.69 - 4.13 (m, 2H), 4.04 - 3.78 (m, 2H), 3.64 - 3.02 (m, 6H), 2.11 - 1.74 (m, 4H). Example 76 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 34 using the intermediate 7-B instead of the intermediate 4-B.
Yield: 55.5 mg (0.0826 mmol) Yield: 41%
MS (ESI) m / z 558 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54-8.39 (m, 1H), 8.29-8.05 (m, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.76-7.62 (m, 3H ), 7.59-7.48 (m, 1H), 7.33-7.20 (m, 2H), 5.66-5.43 (m, 2H), 4.62-4.06 (m, 2H), 3.77-3.17 (m, 4H), 2.91-2.73 (m, 2H), 2.07-1.72 (m, 3H), 1.45-1.15 (m, 2H).
Example 77 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Tri Fluoroacetate The title compound was obtained in the same manner as the Example 53, using the intermediate 7-B instead of the intermediate 9-B.
Yield: 37.4 mg (0.0556 mmol) Yield: 28%
MS (ESI) m / z 558 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.56-9.29 (m, 1H), 8.42-8.30 (m, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.76-7.60 (m, 3H ), 7.60-7.48 (m, 1H), 7.32-7.20 (m, 2H), 5.63-5.49 (m, 2H), 4.69-4.13 (m, 2H), 4.04-3.78 (m, 2H), 3.64-3.02 (m, 6H), 2.11-1.74 (m, 4H).
実施例７８　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：２９．７ｍｇ（０．０５４９ｍｍｏｌ）　収率：４４％
MS (ESI) m/z 542 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.39 - 8.31 (m, 1H), 8.07 (d, J = 6.9 Hz, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.73 - 7.59 (m, 3H), 7.58 - 7.49 (m, 1H), 7.30 - 7.20 (m, 2H), 7.20 - 7.15 (m, 1H), 5.53 (s, 2H), 5.26 - 4.80 (m, 2H), 4.68 - 4.14 (m, 2H).
実施例７９　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸
　実施例１９と同様の操作を、中間体４－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：１４．５ｍｇ（０．０２６１ｍｍｏｌ）　収率：１８％
MS (ESI) m/z 557 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.73 - 7.63 (m, 3H), 7.53 (dd, J = 11.5, 7.1 Hz, 1H), 7.29 - 7.19 (m, 2H), 5.53 (s, 2H), 5.23 - 4.78 (m, 2H), 4.69 - 4.13 (m, 2H), 2.60 - 2.54 (m, 3H). Example 78 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid Example 4 The title compound was obtained in the same manner as in 1 except that intermediate 7-B was used instead of intermediate 1-B.
Yield: 29.7 mg (0.0549 mmol) Yield: 44%
MS (ESI) m / z 542 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39-8.31 (m, 1H), 8.07 (d, J = 6.9 Hz, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.73-7.59 ( m, 3H), 7.58-7.49 (m, 1H), 7.30-7.20 (m, 2H), 7.20-7.15 (m, 1H), 5.53 (s, 2H), 5.26-4.80 (m, 2H), 4.68- 4.14 (m, 2H).
Example 79 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxa Diazol-3-yl) methyl] amino] acetic acid The title compound was obtained in the same manner as the Example 19 using the intermediate 7-B instead of the intermediate 4-B.
Yield: 14.5 mg (0.0261 mmol) Yield: 18%
MS (ESI) m / z 557 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.73-7.63 (m, 3H), 7.53 (dd, J = 11.5, 7.1 Hz, 1H), 7.29-7.19 (m, 2H), 5.53 (s, 2H), 5.23-4.78 (m, 2H), 4.69-4.13 (m, 2H), 2.60-2.54 (m, 3H).
実施例８０　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸
　実施例２０と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：１９．１ｍｇ（０．０３４６ｍｍｏｌ）　収率：２４％
MS (ESI) m/z 553 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.72 (m, 2H), 8.32 - 8.21 (m, 1H), 8.03 - 7.96 (m, 1H), 7.74 - 7.59 (m, 3H), 7.59 - 7.49 (m, 1H), 7.45 - 7.36 (m, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 5.57 - 5.34 (m, 2H), 5.26 - 4.85 (m, 2H), 4.71 - 4.21 (m, 2H).
実施例８１　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩　実施例３３と同様の操作を、中間体４－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：４５．８ｍｇ（０．０７０９ｍｍｏｌ）　収率：５６％
MS (ESI) m/z 532 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.12 - 12.62 (m, 1H), 9.50 - 9.07 (m, 1H), 8.42 - 8.30 (m, 1H), 8.03 - 7.94 (m, 1H), 7.76 - 7.61 (m, 3H), 7.61 - 7.46 (m, 1H), 7.34 - 7.16 (m, 2H), 5.69 - 5.47 (m, 2H), 4.65 - 4.13 (m, 2H), 4.04 - 3.78 (m, 2H), 3.50 - 3.23 (m, 2H), 2.96 - 2.74 (m, 6H). Example 80 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid Example 20 The title compound was obtained in the same manner as in 1 except that intermediate 7-B was used instead of intermediate 1-B.
Yield: 19.1 mg (0.0346 mmol) Yield: 24%
MS (ESI) m / z 553 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82-8.72 (m, 2H), 8.32-8.21 (m, 1H), 8.03-7.96 (m, 1H), 7.74-7.59 (m, 3H), 7.59 -7.49 (m, 1H), 7.45-7.36 (m, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 5.57-5.34 (m, 2H), 5.26-4.85 (m, 2H), 4.71-4.21 (m, 2H).
Example 81 2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid Trifluoroacetic acid Salt The title compound was obtained in the same manner as the Example 33 using the intermediate 7-B instead of the intermediate 4-B.
Yield: 45.8 mg (0.0709 mmol) Yield: 56%
MS (ESI) m / z 532 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.12-12.62 (m, 1H), 9.50-9.07 (m, 1H), 8.42-8.30 (m, 1H), 8.03-7.94 (m, 1H), 7.76 -7.61 (m, 3H), 7.61-7.46 (m, 1H), 7.34-7.16 (m, 2H), 5.69-5.47 (m, 2H), 4.65-4.13 (m, 2H), 4.04-3.78 (m, 2H), 3.50-3.23 (m, 2H), 2.96-2.74 (m, 6H).
実施例８２　2-[2-アミノエチル-[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３５と同様の操作を、中間体１－Ｂの代わりに中間体７－Ｂを用いて行うことにより、表題化合物を得た。
収量：４１．５ｍｇ（０．０６７１ｍｍｏｌ）　収率：５３％
MS (ESI) m/z 504 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.05 - 12.75 (m, 1H), 8.34 (s, 1H), 8.03 - 7.97 (m, 1H), 7.84 - 7.60 (m, 6H), 7.58 - 7.48 (m, 1H), 7.30 - 7.20 (m, 2H), 5.68 - 5.47 (m, 2H), 4.60 - 4.12 (m, 2H), 3.86 - 3.66 (m, 2H), 3.22 - 3.02 (m, 2H).
実施例８３　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
工程１　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸ベンジルの合成
　実施例１化合物の工程１で得られた化合物をジクロロメタン（４ｍＬ）で希釈し、ＤＩＰＥＡ（３０μＬ，０．１７ｍｍｏｌ）および中間体８－Ｂ（５０ｍｇ，０．１１ｍｍｏｌ）を加えて室温で１時間半撹拌した。反応液を減圧濃縮し、表題化合物を無精製で得た。
MS (ESI) m/z 653 [M+H]+
工程２　実施例８３化合物の合成
　工程１で得られた化合物をＴＨＦ（１ｍＬ）とメタノール（０．２ｍL）に溶解し、１Ｎ　水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温で２時間撹拌した。反応液を１Ｎ　塩酸水溶液で中和後、減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：１８．０ｍｇ（０．０３２ｍｍｏｌ）　収率：３０％
MS (ESI) m/z 563 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 12.72 - 12.56 (m, 1H), 8.26 - 8.21 (m, 1H), 7.70 - 7.65 (m, 2H), 7.57 (s, 1H), 7.51 (dd, J = 12.0, 8.0 Hz, 1H), 7.28 - 7.21 (m, 2H), 5.60 - 5.49 (m, 2H), 4.73 (s, 2H), 4.59 - 3.49 (m, 6H), 3.34 (s, 3H), 3.26 - 3.17 (m, 3H). Example 82 2- [2-Aminoethyl- [2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl] amino] acetic acid trifluoroacetate Example The title compound was obtained by the same operations as in 35, except that intermediate 7-B was used instead of intermediate 1-B.
Yield: 41.5 mg (0.0671 mmol) Yield: 53%
MS (ESI) m / z 504 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.05-12.75 (m, 1H), 8.34 (s, 1H), 8.03-7.97 (m, 1H), 7.84-7.60 (m, 6H), 7.58-7.48 (m, 1H), 7.30-7.20 (m, 2H), 5.68-5.47 (m, 2H), 4.60-4.12 (m, 2H), 3.86-3.66 (m, 2H), 3.22-3.02 (m, 2H) .
Example 83 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) Amino] acetic acid step 1 2-[[2-[[4- [4,5-difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxy Synthesis of ethyl) amino] benzyl acetate Example 1 The compound obtained in step 1 of the compound was diluted with dichloromethane (4 mL) and DIPEA (30 μL, 0.17 mmol) and intermediate 8-B (50 mg, 0.11 mmol). And stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound without purification.
MS (ESI) m / z 653 [M + H] +
Step 2 Synthesis of Example 83 Compound The compound obtained in Step 1 was dissolved in THF (1 mL) and methanol (0.2 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hr. . The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, and the residue obtained by evaporation under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 18.0 mg (0.032 mmol) Yield: 30%
MS (ESI) m / z 563 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.72-12.56 (m, 1H), 8.26-8.21 (m, 1H), 7.70-7.65 (m, 2H), 7.57 (s, 1H), 7.51 (dd , J = 12.0, 8.0 Hz, 1H), 7.28-7.21 (m, 2H), 5.60-5.49 (m, 2H), 4.73 (s, 2H), 4.59-3.49 (m, 6H), 3.34 (s, 3H ), 3.26-3.17 (m, 3H).
実施例８４　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３３と同様の操作を、中間体４－Ｂの代わりに中間体８－Ｂを用いて行うことにより、表題化合物を得た。
収量：３８．０ｍｇ（０．０５５ｍｍｏｌ）　収率：２６％
MS (ESI) m/z 576 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 13.00 - 12.78 (m, 1H), 9.43 - 9.04 (m, 1H), 8.42 - 8.32 (m, 1H), 7.74 - 7.64 (m, 2H), 7.58 (s, 1H), 7.55 - 7.47 (m, 1H), 7.28 - 7.21 (m, 2H), 5.63 - 5.48 (m, 2H), 4.73 (s, 2H), 4.63 - 3.44 (m, 6H), 3.34 (s, 3H), 2.90 - 2.80 (m, 6H).
実施例８５　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル) ベンゾチオフェン-7-イル] フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例５３と同様の操作を、中間体９－Ｂの代わりに中間体８－Ｂを用いて行うことにより、表題化合物を得た。
収量：４７．０ｍｇ（０．０６６ｍｍｏｌ）　収率：２４％
MS (ESI) m/z 602 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 13.03 - 12.70 (m, 1H), 9.50 - 9.27 (m, 1H), 8.40 - 8.34 (m, 1H), 7.73 - 7.61 (m, 2H), 7.57 (s, 1H), 7.56 - 7.47 (m, 1H), 7.29 - 7.22 (m, 2H), 5.62 - 5.49 (m, 2H), 4.73 (s, 2H), 4.64 - 3.37 (m, 8H), 3.34 (s, 3H), 3.16 - 3.02 (m, 2H), 2.08 - 1.76 (m, 4H). Example 84 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl ) Amino] acetic acid Trifluoroacetate The title compound was obtained by carrying out the same operation as Example 33, using Intermediate 8-B instead of Intermediate 4-B.
Yield: 38.0 mg (0.055 mmol) Yield: 26%
MS (ESI) m / z 576 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.00-12.78 (m, 1H), 9.43-9.04 (m, 1H), 8.42-8.32 (m, 1H), 7.74-7.64 (m, 2H), 7.58 (s, 1H), 7.55-7.47 (m, 1H), 7.28-7.21 (m, 2H), 5.63-5.48 (m, 2H), 4.73 (s, 2H), 4.63-3.44 (m, 6H), 3.34 (s, 3H), 2.90-2.80 (m, 6H).
Example 85 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidine-1 -Iylethyl) amino] acetic acid trifluoroacetate The title compound was obtained by conducting the same operation as in Example 53, but using Intermediate 8-B instead of Intermediate 9-B.
Yield: 47.0 mg (0.066 mmol) Yield: 24%
MS (ESI) m / z 602 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03-12.70 (m, 1H), 9.50-9.27 (m, 1H), 8.40-8.34 (m, 1H), 7.73-7.61 (m, 2H), 7.57 (s, 1H), 7.56-7.47 (m, 1H), 7.29-7.22 (m, 2H), 5.62-5.49 (m, 2H), 4.73 (s, 2H), 4.64-3.37 (m, 8H), 3.34 (s, 3H), 3.16-3.02 (m, 2H), 2.08-1.76 (m, 4H).
実施例８６　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸　トリフルオロ酢酸塩
　実施例３と同様の操作を、中間体１－Ｂの代わりに中間体８－Ｂを用いて行うことにより、表題化合物を得た。
MS (ESI) m/z 562 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 12.91 - 12.85 (m, 1H), 8.40 - 8.29 (m, 3H), 7.73 - 7.65 (m, 2H), 7.57 (s, 1H), 7.56 - 7.46 (m, 1H), 7.29 - 7.20 (m, 2H), 5.64 - 5.48 (m, 2H), 4.73 (s, 2H), 4.60 - 3.71 (m, 4H), 3.34 (s, 3H), 3.32 - 3.14 (m, 2H), 2.65 - 2.57 (m, 3H).
実施例８７　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸　トリフルオロ酢酸塩
　実施例３４と同様の操作を、中間体４－Ｂの代わりに中間体８－Ｂを用いて行うことにより、表題化合物を得た。
収量：５８．０ｍｇ（０．０８１０ｍｍｏｌ）　収率：７６％
MS (ESI) m/z 602 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 12.80 - 12.63 (m, 1H), 8.52 - 8.38 (m, 1H), 8.26 - 8.23 (m, 1H), 7.72 - 7.65 (m, 2H), 7.57 (s, 1H), 7.55 - 7.48 (m, 1H), 7.29 - 7.21 (m, 2H), 5.60 - 5.49 (m, 2H), 4.73 (s, 2H), 4.55 - 3.40 (m, 4H), 3.34 (s, 3H), 3.33 - 3.16 (m, 2H), 2.91 - 2.71 (m, 2H), 2.05 - 1.74 (m, 3H), 1.46 - 1.10 (m, 2H). Example 86 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-[2- (methylamino ) Ethyl] amino] acetic acid trifluoroacetic acid salt The title compound was obtained by conducting the same operation as in Example 3, using Intermediate 8-B instead of Intermediate 1-B.
MS (ESI) m / z 562 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.91-12.85 (m, 1H), 8.40-8.29 (m, 3H), 7.73-7.65 (m, 2H), 7.57 (s, 1H), 7.56-7.46 (m, 1H), 7.29-7.20 (m, 2H), 5.64-5.48 (m, 2H), 4.73 (s, 2H), 4.60-3.71 (m, 4H), 3.34 (s, 3H), 3.32-3.14 (m, 2H), 2.65-2.57 (m, 3H).
Example 87 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) Amino] acetic acid trifluoroacetate The title compound was obtained in the same manner as the Example 34, except that the intermediate 8-B was used instead of the intermediate 4-B.
Yield: 58.0 mg (0.0810 mmol) Yield: 76%
MS (ESI) m / z 602 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.80-12.63 (m, 1H), 8.52-8.38 (m, 1H), 8.26-8.23 (m, 1H), 7.72-7.65 (m, 2H), 7.57 (s, 1H), 7.55-7.48 (m, 1H), 7.29-7.21 (m, 2H), 5.60-5.49 (m, 2H), 4.73 (s, 2H), 4.55-3.40 (m, 4H), 3.34 (s, 3H), 3.33-3.16 (m, 2H), 2.91-2.71 (m, 2H), 2.05-1.74 (m, 3H), 1.46-1.10 (m, 2H).
実施例８８　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸
　実施例４と同様の操作を、中間体１－Ｂの代わりに中間体８－Ｂを用いて行うことにより、表題化合物を得た。
収量：２５．０ｍｇ（０．０４３ｍｍｏｌ）　収率：４０％
MS (ESI) m/z 586 [M+H]+ 
1H NMR (400 MHz, DMSO-d6) δ 13.10 - 12.40 (m, 1H), 8.36 - 8.32 (m, 1H), 8.09 - 8.04 (m, 1H), 7.70 - 7.63 (m, 2H), 7.57 (s, 1H), 7.55 - 7.47 (m, 1H), 7.28 - 7.20 (m, 2H), 7.18 - 7.14 (m, 1H), 5.52 (s, 2H), 5.25 - 4.79 (m, 2H), 4.73 (s, 2H), 4.67 - 4.15 (m, 2H), 3.34 (s, 3H).
実施例８９　2-[[5-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例４７と同様の操作を、７－ブロモ－４，５－ジフルオロ－ベンゾフランの代わりにＷＯ２０１３／０６５８３５の記載方法に従い合成した４－ブロモ－６，７－ジフルオロ－１Ｈ－インドールを用いて行うことにより、表題化合物を得た。
収量：６７．２ｍｇ（０．１３９ｍｍｏｌ）　収率：２９％
MS (ESI) m/z 485 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.67 - 7.54 (m, 2H), 7.48 (t, 1H), 7.27 - 6.91 (m, 4H), 6.86 - 6.69 (m, 1H), 6.67 - 6.53 (m, 1H), 5.31 - 5.03 (m, 2H), 4.46 - 4.07 (m, 2H), 3.80 - 3.46 (m, 4H), 3.23 (s, 3H) Example 88 2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl ) Amino] acetic acid The title compound was obtained in the same manner as in Example 4 except that intermediate 8-B was used instead of intermediate 1-B.
Yield: 25.0 mg (0.043 mmol) Yield: 40%
MS (ESI) m / z 586 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.10-12.40 (m, 1H), 8.36-8.32 (m, 1H), 8.09-8.04 (m, 1H), 7.70-7.63 (m, 2H), 7.57 (s, 1H), 7.55-7.47 (m, 1H), 7.28-7.20 (m, 2H), 7.18-7.14 (m, 1H), 5.52 (s, 2H), 5.25-4.79 (m, 2H), 4.73 (s, 2H), 4.67-4.15 (m, 2H), 3.34 (s, 3H).
Example 89 2-[[5-[[4- (6,7-Difluoro-1H-indol-4-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid 47, by using 4-bromo-6,7-difluoro-1H-indole synthesized according to the method described in WO2013 / 065835 instead of 7-bromo-4,5-difluoro-benzofuran, The title compound was obtained.
Yield: 67.2 mg (0.139 mmol) Yield: 29%
MS (ESI) m / z 485 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 7.67-7.54 (m, 2H), 7.48 (t, 1H), 7.27-6.91 (m, 4H), 6.86-6.69 (m , 1H), 6.67-6.53 (m, 1H), 5.31-5.03 (m, 2H), 4.46-4.07 (m, 2H), 3.80-3.46 (m, 4H), 3.23 (s, 3H)
実施例９０　2-[[2-[[4-(6,7-ジフルオロ-1H-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　中間体１０－Ａ（７０．０ｍｇ，０．１８１ｍｍｏｌ）と実施例１の工程１で得られた化合物（８０．７ｍｇ，０．３６２ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解し、ＷＳＣ　塩酸塩（６９．５ｍｇ，０．３６２ｍｍｏｌ）、ＨＯＢｔ・１水和物（５５．５ｍｇ，０．３６２ｍｍｏｌ）およびＤＩＰＥＡ（０．０９５ｍＬ，０．５４ｍｍｏｌ）を加えて、室温で６４時間撹拌した。溶媒を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）にて精製することで粗生成物を得た。得られた粗生成物をＴＨＦ（１ｍＬ）およびメタノール（１ｍＬ）に溶解し、２Ｎ　水酸化ナトリウム水溶液（０．２７ｍＬ）を加えて室温で２時間撹拌した。反応液を中和後、有機溶媒を減圧下留去して得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：５６．４ｍｇ（０．１１２ｍｍｏｌ）　収率：６２％
MS (ESI) m/z 502 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.30 - 8.17 (m, 1H), 7.69 - 7.54 (m, 2H), 7.53 - 7.45 (m, 1H), 7.27 - 7.15 (m, 2H), 7.14 - 7.02 (m, 1H), 6.64 - 6.53 (m, 1H), 5.62 - 5.44 (m, 2H), 4.63 - 4.09 (m, 2H), 3.82 - 3.49 (m, 4H), 3.27 - 3.16 (m, 3H). Example 90 2-[[2-[[4- (6,7-Difluoro-1H-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Intermediate 10-A (70.0 mg, 0.181 mmol) and the compound obtained in Step 1 of Example 1 (80.7 mg, 0.362 mmol) were dissolved in dichloromethane (2 mL), and WSC hydrochloride (69.5 mg, 0.362 mmol), HOBt · monohydrate (55.5 mg, 0.362 mmol) and DIPEA (0.095 mL, 0.54 mmol) were added, and the mixture was stirred at room temperature for 64 hours. After the solvent was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain a crude product. The obtained crude product was dissolved in THF (1 mL) and methanol (1 mL), 2N aqueous sodium hydroxide solution (0.27 mL) was added, and the mixture was stirred at room temperature for 2 hr. After neutralizing the reaction solution, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 56.4 mg (0.112 mmol) Yield: 62%
MS (ESI) m / z 502 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 8.30-8.17 (m, 1H), 7.69-7.54 (m, 2H), 7.53-7.45 (m, 1H), 7.27-7.15 (m, 2H), 7.14-7.02 (m, 1H), 6.64-6.53 (m, 1H), 5.62-5.44 (m, 2H), 4.63-4.09 (m, 2H), 3.82-3.49 (m, 4H) , 3.27-3.16 (m, 3H).
実施例９１　2-[[5-[[4-(2-シアノ-4,5-ジフルオロ-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例４７と同様の操作を、７－ブロモ－４，５－ジフルオロ－ベンゾフランの代わりにＷＯ２０１３／０６５８３５の記載方法に従い合成した７－ブロモ－４，５－ジフルオロ－ベンゾフラン－２－カルボニトリルを用いて行うことにより、表題化合物を得た。
収量：２．８ｍｇ（０．００５５ｍｍｏｌ）　収率：５％
MS (ESI) m/z 511 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.02 - 7.78 (m, 3H), 7.33 - 6.91 (m, 3H), 6.84 - 6.70 (m, 1H), 5.35 - 5.12 (m, 2H), 4.50 - 4.07 (m, 2H), 3.83 - 3.30 (m, 4H), 3.23 (s, 3H).
実施例９２　2-[[5-[[4-(4-フルオロベンゾチオフェン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例４７と同様の操作を、７－ブロモ－４，５－ジフルオロ－ベンゾフランの代わりに７－ブロモ－４－フルオロ-ベンゾチオフェンを用いて行うことにより、表題化合物を得た。
収量：２３．７ｍｇ（０．０４９０ｍｍｏｌ）　収率：４６％
MS (ESI) m/z 484 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.82 (m, 1H), 7.76 - 7.54 (m, 3H), 7.52 - 6.95 (m, 5H), 6.86 - 6.71 (m, 1H), 5.32 - 5.11 (m, 2H), 4.49 - 4.04 (m, 2H), 3.78 - 3.47 (m, 4H), 3.23 (s, 3H). Example 91 2-[[5-[[4- (2-Cyano-4,5-difluoro-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid The same operation as in Example 47 was performed using 7-bromo-4,5-difluoro-benzofuran-2-carbonitrile synthesized according to the method described in WO2013 / 065835 instead of 7-bromo-4,5-difluoro-benzofuran. To give the title compound.
Yield: 2.8 mg (0.0055 mmol) Yield: 5%
MS (ESI) m / z 511 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.02-7.78 (m, 3H), 7.33-6.91 (m, 3H), 6.84-6.70 (m, 1H), 5.35-5.12 (m, 2H), 4.50-4.07 (m, 2H), 3.83-3.30 (m, 4H), 3.23 (s, 3H).
Example 92 2-[[5-[[4- (4-Fluorobenzothiophen-7-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Similar to Example 47 The title compound was obtained by performing the procedure using 7-bromo-4-fluoro-benzothiophene instead of 7-bromo-4,5-difluoro-benzofuran.
Yield: 23.7 mg (0.0490 mmol) Yield: 46%
MS (ESI) m / z 484 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.97-7.82 (m, 1H), 7.76-7.54 (m, 3H), 7.52-6.95 (m, 5H), 6.86-6.71 (m, 1H), 5.32 -5.11 (m, 2H), 4.49-4.04 (m, 2H), 3.78-3.47 (m, 4H), 3.23 (s, 3H).
実施例９３　2-[[5-[[4-(7-フルオロ-1H-インドール-4-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例４７と同様の操作を、７－ブロモ－４，５－ジフルオロ－ベンゾフランの代わりに４－ブロモ－７－フルオロ－１Ｈ－インドールを用いて行うことにより、表題化合物を得た。
収量：９０．２ｍｇ（０．１９３ｍｍｏｌ）　収率：４２％
MS (ESI) m/z 467 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.64 - 7.53 (m, 2H), 7.46 (t, J = 2.8 Hz, 1H), 7.28 - 6.93 (m, 5H), 6.82 - 6.70 (m, 1H), 6.64 - 6.55 (m, 1H), 5.31 - 5.09 (m, 2H), 4.49 - 4.08 (m, 2H), 3.81 - 3.49 (m, 4H), 3.23 (s, 3H).
実施例９４　2-[[5-[[4-(6,7-ジフルオロ-2-メチル-1H-インドール-4-イル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例４７と同様の操作を、７－ブロモ－４，５－ジフルオロ－ベンゾフランの代わりにＷＯ２０１３／０６５８３５の記載方法に従い合成した４－ブロモ－６，７－ジフルオロ－２－メチル－１Ｈ－インドールを用いて行うことにより、表題化合物を得た。
収量：７７．６ｍｇ（０．１５６ｍｍｏｌ）　収率：３４％
MS (ESI) m/z 499 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.65 - 7.47 (m, 2H), 7.28 - 6.91 (m, 4H), 6.85 - 6.66 (m, 1H), 6.37 - 6.22 (m, 1H), 5.28 - 5.09 (m, 2H), 4.50 - 4.04 (m, 2H), 3.83 - 3.47 (m, 4H), 3.23 (s, 3H), 2.39 (s, 3H). Example 93 2-[[5-[[4- (7-Fluoro-1H-indol-4-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid Example 47 The same operation was performed using 4-bromo-7-fluoro-1H-indole in place of 7-bromo-4,5-difluoro-benzofuran to obtain the title compound.
Yield: 90.2 mg (0.193 mmol) Yield: 42%
MS (ESI) m / z 467 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.73 (s, 1H), 7.64-7.53 (m, 2H), 7.46 (t, J = 2.8 Hz, 1H), 7.28-6.93 (m, 5H), 6.82-6.70 (m, 1H), 6.64-6.55 (m, 1H), 5.31-5.09 (m, 2H), 4.49-4.08 (m, 2H), 3.81-3.49 (m, 4H), 3.23 (s, 3H ).
Example 94 2-[[5-[[4- (6,7-Difluoro-2-methyl-1H-indol-4-yl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino Acetic acid 4-Bromo-6,7-difluoro-2-methyl-1H—synthesized according to the method described in WO2013 / 065835 in place of 7-bromo-4,5-difluoro-benzofuran in the same manner as in Example 47 The title compound was obtained by using indole.
Yield: 77.6 mg (0.156 mmol) Yield: 34%
MS (ESI) m / z 499 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.68 (s, 1H), 7.65-7.47 (m, 2H), 7.28-6.91 (m, 4H), 6.85-6.66 (m, 1H), 6.37-6.22 (m, 1H), 5.28-5.09 (m, 2H), 4.50-4.04 (m, 2H), 3.83-3.47 (m, 4H), 3.23 (s, 3H), 2.39 (s, 3H).
実施例９５　2-[[2-[[4-(6,7-ジフルオロ-1-メチル-インドール-4-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例９０化合物（３６．４ｍｇ，０．０７２６ｍｍｏｌ）をＴＨＦ（２ｍＬ）に溶解し、水素化ナトリウム（６０％assay，２９ｍｇ，０．７３ｍｍｏｌ）を加えて室温で３０分撹拌した。その溶液に過剰量のヨウ化メチルを加えて、室温で１時間半撹拌した。溶媒を減圧濃縮後、得られた残渣を実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３３．４ｍｇ（０．０６４８ｍｍｏｌ）　収率：８９％
MS (ESI) m/z 516 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.19 (m, 1H), 7.64 - 7.54 (m, 2H), 7.45 - 7.37 (m, 1H), 7.27 - 7.13 (m, 2H), 7.13 - 7.02 (m, 1H), 6.60 - 6.43 (m, 1H), 5.60 - 5.43 (m, 2H), 4.63 - 4.09 (m, 2H), 4.05 - 3.92 (m, 3H), 3.82 - 3.49 (m, 4H), 3.27 - 3.14 (m, 3H).
実施例９６　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸
　実施例１と同様の操作を、中間体１－Ｂの代わりに中間体１１－Ｂを用いて行うことにより、表題化合物を得た。
収量：３４．７ｍｇ（０．０７０４ｍｍｏｌ）　収率：５３％
MS (ESI) m/z 493 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.25 - 8.17 (m, 1H), 7.47 - 7.39 (m, 2H), 7.42 - 7.31 (m, 1H), 7.24 (dd, J = 13.0, 7.1 Hz, 1H), 7.14 - 7.04 (m, 2H), 5.56 - 5.42 (m, 2H), 4.35 (d, J = 164.8 Hz, 2H), 3.81 - 3.69 (m, 3H), 3.66 - 3.45 (m, 4H), 3.29 - 3.14 (m, 3H). Example 95 2-[[2-[[4- (6,7-Difluoro-1-methyl-indol-4-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Example 90 The compound (36.4 mg, 0.0726 mmol) was dissolved in THF (2 mL), sodium hydride (60% assay, 29 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 30 min. An excess amount of methyl iodide was added to the solution, and the mixture was stirred at room temperature for 1.5 hours. After concentrating the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 33.4 mg (0.0648 mmol) Yield: 89%
MS (ESI) m / z 516 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28-8.19 (m, 1H), 7.64-7.54 (m, 2H), 7.45-7.37 (m, 1H), 7.27-7.13 (m, 2H), 7.13 -7.02 (m, 1H), 6.60-6.43 (m, 1H), 5.60-5.43 (m, 2H), 4.63-4.09 (m, 2H), 4.05-3.92 (m, 3H), 3.82-3.49 (m, 4H), 3.27-3.14 (m, 3H).
Example 96 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid Example 1 The same operation was performed using intermediate 11-B instead of intermediate 1-B to obtain the title compound.
Yield: 34.7 mg (0.0704 mmol) Yield: 53%
MS (ESI) m / z 493 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25-8.17 (m, 1H), 7.47-7.39 (m, 2H), 7.42-7.31 (m, 1H), 7.24 (dd, J = 13.0, 7.1 Hz , 1H), 7.14-7.04 (m, 2H), 5.56-5.42 (m, 2H), 4.35 (d, J = 164.8 Hz, 2H), 3.81-3.69 (m, 3H), 3.66-3.45 (m, 4H ), 3.29-3.14 (m, 3H).
実施例９７　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸
　実施例２４と同様の操作を、中間体１－Ｂの代わりに中間体１１－Ｂを用いて行うことにより、表題化合物を得た。
収量：４７．１ｍｇ（０．０９１６ｍｍｏｌ）　収率：６９％
MS (ESI) m/z 515 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.24 (m, 1H), 7.60 (d, J = 10.2 Hz, 1H), 7.45 - 7.30 (m, 3H), 7.23 (dd, J = 13.0, 7.1 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.44 - 6.33 (m, 2H), 5.60 - 5.42 (m, 2H), 5.03 - 4.65 (m, 2H), 4.49 - 4.02 (m, 2H), 3.75 (s, 3H).
実施例９８　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸　トリフルオロ酢酸塩　実施例５３と同様の操作を、中間体９－Ｂの代わりに中間体１１－Ｂを用いて行うことにより、表題化合物を得た。
収量：２０．６ｍｇ（０．０３１９ｍｍｏｌ）　収率：２４％
MS (ESI) m/z 532 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.54 - 9.25 (m, 1H), 8.41 - 8.30 (m, 1H), 7.50 - 7.29 (m, 3H), 7.25 (dd, J = 13.0, 7.1 Hz, 1H), 7.18 - 7.05 (m, 2H), 5.57 - 5.40 (m, 2H), 4.66 - 4.11 (m, 2H), 4.00 - 3.78 (m, 2H), 3.76 (s, 3H), 3.62 - 3.35 (m, 4H), 3.18 - 2.96 (m, 2H), 2.09 - 1.73 (m, 4H). Example 97 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid Example 24 The same operation was performed using intermediate 11-B instead of intermediate 1-B to obtain the title compound.
Yield: 47.1 mg (0.0916 mmol) Yield: 69%
MS (ESI) m / z 515 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31-8.24 (m, 1H), 7.60 (d, J = 10.2 Hz, 1H), 7.45-7.30 (m, 3H), 7.23 (dd, J = 13.0 , 7.1 Hz, 1H), 7.15-7.06 (m, 2H), 6.44-6.33 (m, 2H), 5.60-5.42 (m, 2H), 5.03-4.65 (m, 2H), 4.49-4.02 (m, 2H ), 3.75 (s, 3H).
Example 98 2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Tri Fluoroacetate The title compound was obtained in the same manner as the Example 53, using the intermediate 11-B instead of the intermediate 9-B.
Yield: 20.6 mg (0.0319 mmol) Yield: 24%
MS (ESI) m / z 532 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 9.54-9.25 (m, 1H), 8.41-8.30 (m, 1H), 7.50-7.29 (m, 3H), 7.25 (dd, J = 13.0, 7.1 Hz , 1H), 7.18-7.05 (m, 2H), 5.57-5.40 (m, 2H), 4.66-4.11 (m, 2H), 4.00-3.78 (m, 2H), 3.76 (s, 3H), 3.62-3.35 (m, 4H), 3.18-2.96 (m, 2H), 2.09-1.73 (m, 4H).
実施例９９　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸エチル　トリフルオロ酢酸塩
　１－（２－アミノエチル）ピロリジン（１．７５ｇ，１５．３ｍｍｏｌ）をアセトニトリル（１２５ｍＬ）に溶解後、炭酸カリウム（２．１２ｇ，１５．３ｍｍｏｌ）を加え、－２０℃下、２－ブロモ酢酸ベンジル（１．７ｍＬ，１５ｍｍｏｌ）をゆっくり加えた。同温下、１時間撹拌後、室温に戻して一晩撹拌した。不溶物を濾別した後、溶媒を減圧下留去して得られた残渣の一部（５９０ｍｇ，２．９５ｍｍｏｌ）をＴＨＦ(２５ｍＬ)に溶解し、中間体４－Ｂ（６００ｍｇ，１．４８ｍｍｏｌ）、トリエチルアミン（０．４１ｍＬ，３．０ｍｍｏｌ）を加え、室温で２時間撹拌した。減圧下溶媒を留去後、得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：３２０ｍｇ（０．４６０ｍｍｏｌ）　収率：３１％
MS (ESI) m/z 576 [M+H]+
実施例１００　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸エチル　トリフルオロ酢酸塩
　実施例９９と同様の操作を、中間体４－Ｂの代わりに中間体１－Ｂ（４１４ｍｇ，１．０５ｍｍｏｌ）を用いて行うことにより、表題化合物を得た。
収量：２３０ｍｇ（０．３４０ｍｍｏｌ）　収率：３３％
MS (ESI) m/z 559 [M+H]+ Example 99 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Ethyl trifluoroacetate salt 1- (2-Aminoethyl) pyrrolidine (1.75 g, 15.3 mmol) was dissolved in acetonitrile (125 mL), potassium carbonate (2.12 g, 15.3 mmol) was added, Then, benzyl 2-bromoacetate (1.7 mL, 15 mmol) was added slowly. After stirring at the same temperature for 1 hour, the mixture was returned to room temperature and stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. A part of the resulting residue (590 mg, 2.95 mmol) was dissolved in THF (25 mL) to obtain intermediate 4-B (600 mg, 1.48 mmol). ), Triethylamine (0.41 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 320 mg (0.460 mmol) Yield: 31%
MS (ESI) m / z 576 [M + H] +
Example 100 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid Ethyl trifluoroacetate The title compound was obtained in the same manner as the Example 99, except that the intermediate 1-B (414 mg, 1.05 mmol) was used instead of the intermediate 4-B.
Yield: 230 mg (0.340 mmol) Yield: 33%
MS (ESI) m / z 559 [M + H] +
実施例１０１　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジル)アミノ]酢酸エチル　トリフルオロ酢酸塩
　４－アミノ－１－ｔｅｒｔ－ブトキシカルボニルピペリジン（２．３３ｇ，１１．６ｍｍｏｌ）をアセトニトリル（１２５ｍＬ）に溶解後、炭酸カリウム（１．６ｇ，１２ｍｍｏｌ）を加え、－２０℃下、２－ブロモ酢酸ベンジル（１．９４ｇ，１１．６ｍｍｏｌ）をゆっくり加えた。同温下、１時間撹拌後、室温に戻して一晩撹拌した。不溶物を濾別した後、溶媒を減圧下留去して得られた残渣の一部（４６０ｍｇ，１．６０ｍｍｏｌ）をＴＨＦ(２５ｍＬ)に溶解し、中間体４－Ｂ（３３０ｍｇ，０．８００ｍｍｏｌ）、トリエチルアミン（０．２３ｍＬ，１．６ｍｍｏｌ）を加え、室温で２時間撹拌した。減圧下溶媒を留去して得られた残渣を、ＴＦＡ（１０ｍＬ）に溶解し、室温で２時間撹拌した。減圧下溶媒を留去して得られた残渣を、実施例１の工程２と同様に逆相ＨＰＬＣで精製し、表題化合物を得た。
収量：２７０ｍｇ（０．４００ｍｍｏｌ）　収率：５０％
MS (ESI) m/z 562 [M+H]+
実施例１０２　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジル)アミノ]酢酸エチル　トリフルオロ酢酸塩　実施例１０１と同様な操作を、中間体４－Ｂの代わりに中間体１－Ｂ（３００ｍｇ、０．７６０ｍｍｏｌ）を用いて行うことにより、表題化合物を得た。
収量：１６０ｍｇ（０．２４０ｍｍｏｌ）　収率：３２％
MS (ESI) m/z 545 [M+H]+ Example 101 2-[[2-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid ethyl trifluoroacetic acid Salt 4-Amino-1-tert-butoxycarbonylpiperidine (2.33 g, 11.6 mmol) was dissolved in acetonitrile (125 mL), potassium carbonate (1.6 g, 12 mmol) was added, and 2-bromo was added at −20 ° C. Benzyl acetate (1.94 g, 11.6 mmol) was added slowly. After stirring at the same temperature for 1 hour, the mixture was returned to room temperature and stirred overnight. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. A part of the resulting residue (460 mg, 1.60 mmol) was dissolved in THF (25 mL) to obtain intermediate 4-B (330 mg, 0.800 mmol). ), Triethylamine (0.23 mL, 1.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in TFA (10 mL) and stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by reverse phase HPLC in the same manner as in Step 2 of Example 1 to obtain the title compound.
Yield: 270 mg (0.400 mmol) Yield: 50%
MS (ESI) m / z 562 [M + H] +
Example 102 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidyl) amino] acetic acid ethyl trifluoroacetic acid Salt The title compound was obtained in the same manner as the Example 101 using the intermediate 1-B (300 mg, 0.760 mmol) instead of the intermediate 4-B.
Yield: 160 mg (0.240 mmol) Yield: 32%
MS (ESI) m / z 545 [M + H] +
実施例１０３　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸エチル　塩酸塩
　実施例１０１と同様の操作を、４－アミノ－１－ｔｅｒｔ－ブトキシカルボニルピペリジンを４－（アミノメチル）ピペリジン－１－カルボン酸 ｔｅｒｔ－ブチルに代えて、中間体４－Ｂ（４７４ｍｇ，１．１５ｍｍｏｌ）を用いて行うことにより、表題化合物のトリフルオロ酢酸塩を得た。得られた化合物に１Ｎ 塩酸水溶液（１．２ｍＬ）および水（１５ｍＬ）を加えて凍結乾燥することにより、表題化合物を得た。
収量：３１９ｍｇ（０．５２１ｍｍｏｌ） 収率：４５％
MS (ESI) m/z 576 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.40 (m, 2H), 8.33 - 8.21 (m, 1H), 7.44 - 7.24 (m, 4H), 7.23 - 7.06 (m, 2H), 5.64 - 5.37 (m, 2H), 4.61 - 4.16 (m, 2H), 4.17 - 4.05 (m, 2H), 3.76 - 3.40 (m, 2H), 3.31 - 3.14 (m, 2H), 2.90 - 2.68 (m, 2H), 2.46 - 2.34 (m, 3H), 2.06 - 1.86 (m, 1H), 1.87 - 1.68 (m, 2H), 1.50 - 1.27 (m, 2H), 1.26 - 1.11 (m, 3H).
実施例１０４　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸エチル　塩酸塩
　実施例１０２と同様の操作を、４－アミノ－１－ｔｅｒｔ－ブトキシカルボニルピペリジンを４－（アミノメチル）ピペリジン－１－カルボン酸 ｔｅｒｔ－ブチルに代えて、中間体１－Ｂ（４５４ｍｇ，１．１５ｍｍｏｌ）を用いて行うことにより、表題化合物のトリフルオロ酢酸塩を得た。得られた化合物に１Ｎ 塩酸水溶液（１．２ｍＬ）および水（１５ｍＬ）を加えて凍結乾燥することにより、表題化合物を得た。
収量：３１４ｍｇ（０．５２８ｍｍｏｌ） 収率：４６％
MS (ESI) m/z 559 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.27 (m, 2H), 7.45 - 7.22 (m, 4H), 7.17 - 7.00 (m, 3H), 6.87 - 6.68 (m, 1H), 5.43 - 4.80 (m, 2H), 4.64 - 4.13 (m, 2H), 4.14 - 4.01 (m, 2H), 3.68 - 3.37 (m, 2H), 3.30 - 3.15 (m, 2H), 2.88 - 2.70 (m, 2H), 2.40 (s, 3H), 2.02 - 1.87 (m, 1H), 1.86 - 1.70 (m, 2H), 1.47 - 1.26 (m, 2H), 1.26 - 1.02 (m, 3H). Example 103 Ethyl 2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid hydrochloride The same operation as that of Example 101 was carried out except that 4-amino-1-tert-butoxycarbonylpiperidine was replaced with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate and intermediate 4-B (474 mg, 1. 15 mmol) gave the trifluoroacetate salt of the title compound. The title compound was obtained by adding 1N aqueous hydrochloric acid (1.2 mL) and water (15 mL) to the obtained compound and lyophilizing.
Yield: 319 mg (0.521 mmol) Yield: 45%
MS (ESI) m / z 576 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.91-8.40 (m, 2H), 8.33-8.21 (m, 1H), 7.44-7.24 (m, 4H), 7.23-7.06 (m, 2H), 5.64 -5.37 (m, 2H), 4.61-4.16 (m, 2H), 4.17-4.05 (m, 2H), 3.76-3.40 (m, 2H), 3.31-3.14 (m, 2H), 2.90-2.68 (m, 2H), 2.46-2.34 (m, 3H), 2.06-1.86 (m, 1H), 1.87-1.68 (m, 2H), 1.50-1.27 (m, 2H), 1.26-1.11 (m, 3H).
Example 104 2-[[5-[[4- (4,5-Difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidylmethyl) amino] acetic acid ethyl hydrochloride The same operation as in Example 102 was carried out except that 4-amino-1-tert-butoxycarbonylpiperidine was replaced with tert-butyl 4- (aminomethyl) piperidine-1-carboxylate, intermediate 1-B (454 mg, 1. 15 mmol) gave the trifluoroacetate salt of the title compound. The title compound was obtained by adding 1N aqueous hydrochloric acid (1.2 mL) and water (15 mL) to the obtained compound and lyophilizing.
Yield: 314 mg (0.528 mmol) Yield: 46%
MS (ESI) m / z 559 [M + H] +
1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82-8.27 (m, 2H), 7.45-7.22 (m, 4H), 7.17-7.00 (m, 3H), 6.87-6.68 (m, 1H), 5.43 -4.80 (m, 2H), 4.64-4.13 (m, 2H), 4.14-4.01 (m, 2H), 3.68-3.37 (m, 2H), 3.30-3.15 (m, 2H), 2.88-2.70 (m, 2H), 2.40 (s, 3H), 2.02-1.87 (m, 1H), 1.86-1.70 (m, 2H), 1.47-1.26 (m, 2H), 1.26-1.02 (m, 3H).
　上記実施例で得られた化合物の構造式を表２－１～表２－１８に示す。
表２－１
Figure JPOXMLDOC01-appb-I000045
The structural formulas of the compounds obtained in the above Examples are shown in Tables 2-1 to 2-18.
Table 2-1.
Figure JPOXMLDOC01-appb-I000045
表２－２
Figure JPOXMLDOC01-appb-I000046
Table 2-2
Figure JPOXMLDOC01-appb-I000046
表２－３
Figure JPOXMLDOC01-appb-I000047
Table 2-3
Figure JPOXMLDOC01-appb-I000047
表２－４
Figure JPOXMLDOC01-appb-I000048
Table 2-4
Figure JPOXMLDOC01-appb-I000048
表２－５
Figure JPOXMLDOC01-appb-I000049
Table 2-5
Figure JPOXMLDOC01-appb-I000049
表２－６
Figure JPOXMLDOC01-appb-I000050
Table 2-6
Figure JPOXMLDOC01-appb-I000050
表２－７
Figure JPOXMLDOC01-appb-I000051
Table 2-7
Figure JPOXMLDOC01-appb-I000051
表２－８
Figure JPOXMLDOC01-appb-I000052
Table 2-8
Figure JPOXMLDOC01-appb-I000052
表２－９
Figure JPOXMLDOC01-appb-I000053
Table 2-9
Figure JPOXMLDOC01-appb-I000053
表２－１０
Figure JPOXMLDOC01-appb-I000054
Table 2-10
Figure JPOXMLDOC01-appb-I000054
表２－１１
Figure JPOXMLDOC01-appb-I000055
Table 2-11
Figure JPOXMLDOC01-appb-I000055
表２－１２
Figure JPOXMLDOC01-appb-I000056
Table 2-12
Figure JPOXMLDOC01-appb-I000056
表２－１３
Figure JPOXMLDOC01-appb-I000057
Table 2-13
Figure JPOXMLDOC01-appb-I000057
表２－１４
Figure JPOXMLDOC01-appb-I000058
Table 2-14
Figure JPOXMLDOC01-appb-I000058
表２－１５
Figure JPOXMLDOC01-appb-I000059
Table 2-15
Figure JPOXMLDOC01-appb-I000059
表２－１６
Figure JPOXMLDOC01-appb-I000060
Table 2-16
Figure JPOXMLDOC01-appb-I000060
表２－１７
Figure JPOXMLDOC01-appb-I000061
Table 2-17
Figure JPOXMLDOC01-appb-I000061
表２－１８
Figure JPOXMLDOC01-appb-I000062
Table 2-18
Figure JPOXMLDOC01-appb-I000062
試験例１　グリコーゲンシンターゼ活性測定
　ヒトＧＹＳ１発現プラスミド（ｐＣＤＮＡ３．１（＋）－ｈＧＹＳ１）は、次の方法で構築した。Ｈｕｍａｎ　ＭＴＣ　Ｐａｎｅｌ Ｉ（タカラバイオ、６３６７４２）のヒト骨格筋ｃＤＮＡをテンプレートとして用い、クローニングプライマー（Ｆｏｒｗａｒｄ　Ｐｒｉｍｅｒ：ＡＴＧＣＣＴＴＴＡＡＡＣＣＧＣＡＣ、Ｒｅｖｅｒｓｅ　Ｐｒｉｍｅｒ：ＴＴＡＧＴＴＡＣＧＣＴＣＣＴＣＧＣ）を用いたＰＣＲ法で、ヒトＧＹＳ１遺伝子を増幅した。増幅したヒトＧＹＳ１配列をテンプレートとして用い、サブクローニングプライマー（Ｆｏｒｗａｒｄ　Ｐｒｉｍｅｒ：ＣＣＣＴＣＧＡＧＡＣＣＡＴＧＣＣＴＴＴＡＡＡＣＣＧＣＡＣＴＴ、Ｒｅｖｅｒｓｅ　Ｐｒｉｍｅｒ：ＧＧＴＣＴＡＧＡＴＴＡＧＴＴＡＣＧＣＴＣＣＴＣＧＣＣＣＡＧ）を用いたＰＣＲ法により制限酵素配列を付加した後、ｐＣＤＮＡ３．１（＋）（インビトロジェン、Ｖ７９０－２０）のＸｈｏ Ｉサイト、Ｘｂａ ＩサイトにヒトＧＹＳ１遺伝子を導入した。
　グリコーゲンシンターゼの調製は次の方法で行った。ヒト腎臓由来のＨＥＫ２９３Ｔ細胞を、１０％ＦＢＳを含むＤＭＥＭ（ナカライテスク、０８４５８７４）培地を用い、ディッシュ（サーモフィッシャーサイエンティフィック、１６８３８１）に播種し、一晩培養した後、Ｌｉｐｏｆｅｃｔａｍｉｎｅ　ＬＴＸ（インビトロジェン、１５３３８－１００）を用い、添付のマニュアルに準じてヒトＧＹＳ１発現ベクターのトランスフェクションを行った。３７℃、５％ＣＯ2条件下で２日間培養した後、リシスバッファー（５０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ８．０）、１０ｍＭ　ＥＤＴＡ、２ｍＭ　ＥＧＴＡ、１００ｍＭ　ＮａＦ、１ｍＭ　ＰＭＳＦ、1ｍＭ　ＤＴＴ、１ｘＣｏｍｐｌｅｔｅ（ロシュ、１８７３５８０））に溶解し、ホモジェナイズした後、１６０００ｘｇ、４℃、１５分間の遠心分離を行い、沈殿画分にリシスバッファーを加えて再溶解したものをグリコーゲンシンターゼとして評価に用いた。 Test Example 1 Measurement of Glycogen Synthase Activity A human GYS1 expression plasmid (pCDNA3.1 (+)-hGYS1) was constructed by the following method. Human GYS1 gene was amplified by PCR using human MTC Panel I (Takara Bio, 636742) as a template and using a cloning primer (Forward Primer: ATGCCTTTAAACCGCAC, Reverse Primer: TTAGTTACCGCTCTCGCGC). The amplified human GYS1 sequence was used as a template, a restriction enzyme sequence was added by PCR using subcloning primers (Forward Primer: CCCTCGAGACCATGCCTTTAAAACCGCACTTT, Reverse Primer: GGTCTAGATTTAGTTTACGCTCTCTCGCCCAG), and then in vitro. The human GYS1 gene was introduced into the Xho I site and Xba I site.
Glycogen synthase was prepared by the following method. HEK293T cells derived from human kidney were seeded in a dish (Thermo Fisher Scientific, 168381) using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS, cultured overnight, and then Lipofectamine LTX (Invitrogen, 15338). −100) and the human GYS1 expression vector was transfected according to the attached manual. After culturing at 37 ° C. under 5% CO 2 for 2 days, a lysis buffer (50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 2 mM EGTA, 100 mM NaF, 1 mM PMSF, 1 mM DTT, 1 × Complete (Roche, 1873580) And then homogenized, the mixture was centrifuged at 16000 × g and 4 ° C. for 15 minutes, and the precipitate fraction was re-dissolved by adding a lysis buffer and used for evaluation as glycogen synthase.
　グリコーゲンシンターゼの活性測定は次の方法で行った。ポリスチレン９６ウエルプレートに、３０ｍＭのグリシルグリシン（ｐＨ７．３）、４０ｍＭのＫＣｌ、２０ｍＭのＭｇＣｌ2、各種濃度の被検化合物を含む９．２％ＤＭＳＯ、1０ｍＭのＧｌｕｃｏｓｅ－６－ｐｈｏｓｐｈａｔｅ（シグマアルドリッチ、Ｇ７８７９）を含む溶液を１２μＬ／ウェル加えた。
　次に、３０ｍＭのグリシルグリシン（ｐＨ７．３）、４．３ｍｇ/ｍＬのグリコーゲン（シグマアルドリッチ、Ｇ８８７６）、２１．６ｍＭのＵＤＰ－グルコース（シグマアルドリッチ、Ｕ４６２５）、２１．６ｍＭのホスホエノールピルビン酸（シグマアルドリッチ、Ｐ０５６４）および４．０５ｍＭのＮＡＤＨ（シグマアルドリッチ、Ｎ８１２９）を含む基質溶液を１８μＬ／ウェル加えた。
　さらに、５０ｍＭのＴｒｉｓ－ＨＣｌ（ｐＨ８．０）、２７ｍＭのＤＴＴ（ナカライテスク、１４１２８－０４）、０．２ｍｇ／ｍＬのウシ血清アルブミン、０．１７ｍｇ/ｍＬのグリコーゲンシンターゼ、１．５μＬのピルベートキナーゼ／ラクテートデヒドロゲナーゼ溶液（シグマアルドリッチ、Ｐ０２９４）を含む酵素溶液を１８μＬ／ウェル加え、反応溶液とした。反応溶液をインキュベート（実施例１、２、５～１０４は３７℃、２５分、実施例３、４は３７℃、２０分、ＷＯ／２０１３／０６５８３５の実施例１５化合物は３０℃、２５分）した後、Ｂｅｎｃｈｍａｒｋ　Ｐｌｕｓ（バイオラッドラボラトリーズ）を用いて３４０ｎｍの吸光度を測定した。
　被検化合物の活性の算出は次の方法で行った。化合物を含まずＤＭＳＯのみを含む反応溶液の３４０ｎｍの吸光度から、化合物およびＤＭＳＯを含む反応溶液の３４０ｎｍの吸光度を引くことによって、吸光度変化（ΔＡ３４０）を算出した。ＷＯ／２０１１／０５８１５４実施例１化合物を最終濃度で１０μＭ含む反応溶液のΔＡ３４０を１００％とし、被検化合物の各種濃度における相対活性（％）を算出した。５０％の相対活性の上昇を起こす化合物濃度をＥＣ５０とし、ＸＬｆｉｔ（ｉｄｂｓ）により算出した。結果を表３－１～表３－４に示す。 The activity of glycogen synthase was measured by the following method. In a polystyrene 96-well plate, 30 mM glycylglycine (pH 7.3), 40 mM KCl, 20 mM MgCl 2 , 9.2% DMSO containing various concentrations of test compound, 10 mM Glucose-6-phosphate (Sigma Aldrich) , G7879) was added at 12 μL / well.
Next, 30 mM glycylglycine (pH 7.3), 4.3 mg / mL glycogen (Sigma Aldrich, G8876), 21.6 mM UDP-glucose (Sigma Aldrich, U4625), 21.6 mM phosphoenolpyruvate A substrate solution containing (Sigma Aldrich, P0564) and 4.05 mM NADH (Sigma Aldrich, N8129) was added at 18 μL / well.
In addition, 50 mM Tris-HCl (pH 8.0), 27 mM DTT (Nacalai Tesque, 14128-04), 0.2 mg / mL bovine serum albumin, 0.17 mg / mL glycogen synthase, 1.5 μL pyruvate An enzyme solution containing a kinase / lactate dehydrogenase solution (Sigma Aldrich, P0294) was added at 18 μL / well to obtain a reaction solution. Incubate the reaction solution (Examples 1, 2, 5 to 104 are 37 ° C., 25 minutes, Examples 3 and 4 are 37 ° C., 20 minutes, Example 15 compound of WO / 2013/065835 is 30 ° C., 25 minutes) Then, absorbance at 340 nm was measured using Benchmark Plus (BioRad Laboratories).
The activity of the test compound was calculated by the following method. The absorbance change (ΔA340) was calculated by subtracting the absorbance at 340 nm of the reaction solution containing the compound and DMSO from the absorbance at 340 nm of the reaction solution containing only DMSO but not the compound. WO / 2011/058154 Example 1 The relative activity (%) at various concentrations of the test compound was calculated by setting ΔA340 of a reaction solution containing 10 μM of the compound at the final concentration to 100%. The compound concentration causing an increase in relative activity of 50% was defined as EC50, and calculated by XLfit (idbs). The results are shown in Tables 3-1 to 3-4.
表３－１
Figure JPOXMLDOC01-appb-I000063
Table 3-1.
Figure JPOXMLDOC01-appb-I000063
表３－２
Figure JPOXMLDOC01-appb-I000064
Table 3-2
Figure JPOXMLDOC01-appb-I000064
表３－３
Figure JPOXMLDOC01-appb-I000065
Table 3-3
Figure JPOXMLDOC01-appb-I000065
表３－４
Figure JPOXMLDOC01-appb-I000066
　ＷＯ２０１３/０６５８３５の実施例１５は、下記の構造式１の化合物を有する。
構造式１：
Figure JPOXMLDOC01-appb-I000067
Table 3-4
Figure JPOXMLDOC01-appb-I000066
Example 15 of WO2013 / 065835 has a compound of structural formula 1 below.
Structural formula 1:
Figure JPOXMLDOC01-appb-I000067
試験例２　ＰＰＡＲ－α活性測定
　ＰＰＡＲ－αの活性測定は、既報（ＴＨＥ　ＪＯＵＮＡＬ　ＯＦ　ＢＩＯＬＯＧＩＣＡＬ　ＣＨＥＭＩＳＴＲＹ　Ｖｏｌ．２７０，Ｎｏ．２２，：１２９５３-１２９５６,１９９５）に準じて行った。
　ＰＰＡＲ－αの活性測定に用いたプラスミドは次のように構築した。ルシフェラーゼ発現プラスミド（ＵＡＳｘ５－ＴＫ－Ｌｕｃ）は、ｐＴＡＬ－Ｌｕｃ(タカラバイオ、６２５２－１)のチミジンキナーゼプロモーター上流に、酵母のＧＡＬ４結合配列が５個タンデムに連結した配列を導入したものを用いた。ＰＰＡＲ－α受容体発現プラスミド（ｈＧＲ－ＧＡＬ４－ｈＰＰＡＲα）は、ｐＥｘｃｈａｎｇｅ－１　Ｃｏｒｅ　Ｖｅｃｔｏｒ（インビトロジェン、２１１１７６)のＮｏｔ ＩサイトとＳａｌ ＩサイトにヒトＧＲのＮ末領域（１－７６ａａ)、酵母のＧＡＬ４ＤＮＡ結合領域（１－１４７ａａ）及びＰＰＡＲαのリガンド結合領域（１６７－４６８ａａ）を導入したものを用いた。
　レポーターアッセイはアフリカミドリザル腎由来のＣＶ－１細胞を用いて、次の方法で行った。ＣＶ－１細胞を、１０％ＦＢＳを含むＤＭＥＭ（ナカライテスク、０８４５８７４）培地を用い、２×１０4細胞／ウェルとなるように９６ウエルプレート（サーモフィッシャーサイエンティフィック、４９３８）に播種し、３７℃、５％ＣＯ2条件下で２時間培養した後、プラスミドのトランスフェクションを行った。トランスフェクションはＬｉｐｏｆｅｃｔａｍｉｎｅ　ＬＴＸ（インビトロジェン、１５３３８－１００）を用い、添付のマニュアルに準じて行った。プラスミド溶液は、ルシフェラーゼ発現プラスミドおよびＰＰＡＲ－α受容体発現プラスミドの混合溶液をＯＰＴＩ－ＭＥＭ Ｉ（インビトロジェン、１１０５８－０２１）に添加して調製した。トランスフェクションを行った後、被検化合物を添加し、３７℃、５％ＣＯ2存在下で１８～２０時間培養した。培養終了後に、Ｂｒｉｇｈｔ－Ｇｌｏ(プロメガ、Ｅ２６２０)を用い、Ｌｕｍｉｎｅｓｃｅｎｓｏｒ　ＪＮＲ（ＡＴＴＯ）によりルシフェラーゼ活性を測定した。
　被検化合物のＰＰＡＲ－α誘導倍率は次の方法で算出した。被検化合物の３μＭ、１０μＭ、３０μＭ、１００μＭにおけるＰＰＡＲ－α活性の中の最大値をＡ、ＷＯ／２０１１／０５８１５４の化合物の１００μＭにおけるＰＰＡＲ－α活性をＢとしたときの、１００（Ａ／Ｂ）をＰＰＡＲ－α相対誘導倍率（％）とした。
　結果を表４－１～４－４に示す。 Test Example 2 PPAR-α Activity Measurement The activity of PPAR-α was measured according to a previous report (THE JOUNAL OF BIOLOGICAL CHEMISTRY Vol.270, No.22: 12953-12956, 1995).
The plasmid used for measuring the activity of PPAR-α was constructed as follows. As the luciferase expression plasmid (UASx5-TK-Luc), a plasmid in which a sequence in which five GAL4-binding sequences of yeast were linked in tandem upstream of the thymidine kinase promoter of pTAL-Luc (Takara Bio, 6252-1) was used. . The PPAR-α receptor expression plasmid (hGR-GAL4-hPPARα) is the N-terminal region (1-76aa) of human GR at the Not I site and Sal I site of pExchange-1 Core Vector (Invitrogen, 21176), and GAL4 DNA of yeast. The one into which the binding region (1-147aa) and the ligand binding region (167-468aa) of PPARα were introduced was used.
The reporter assay was performed by the following method using CV-1 cells derived from African green monkey kidney. CV-1 cells were seeded in a 96-well plate (Thermo Fisher Scientific, 4938) at 2 × 10 4 cells / well using DMEM (Nacalai Tesque, 0845874) medium containing 10% FBS. ° C., after 2 hours incubation under 5% CO 2, were transfected with plasmids. Transfection was performed using Lipofectamine LTX (Invitrogen, 15338-100) according to the attached manual. A plasmid solution was prepared by adding a mixed solution of a luciferase expression plasmid and a PPAR-α receptor expression plasmid to OPTI-MEM I (Invitrogen, 11058-021). After the transfection, a test compound was added and cultured at 37 ° C. in the presence of 5% CO 2 for 18 to 20 hours. After completion of the culture, luciferase activity was measured by Luminescence JNR (ATTO) using Bright-Glo (Promega, E2620).
The PPAR-α induction magnification of the test compound was calculated by the following method. 100 (A / B) where A is the maximum PPAR-α activity at 3 μM, 10 μM, 30 μM, and 100 μM of the test compound, and B is the PPAR-α activity at 100 μM of the compound of WO / 2011/058154. ) As PPAR-α relative induction magnification (%).
The results are shown in Tables 4-1 to 4-4.
表４－１
Figure JPOXMLDOC01-appb-I000068
Table 4-1
Figure JPOXMLDOC01-appb-I000068
表４－２
Figure JPOXMLDOC01-appb-I000069
Table 4-2
Figure JPOXMLDOC01-appb-I000069
表４－３
Figure JPOXMLDOC01-appb-I000070
Table 4-3
Figure JPOXMLDOC01-appb-I000070
表４－４
Figure JPOXMLDOC01-appb-I000071
Table 4-4
Figure JPOXMLDOC01-appb-I000071
試験例３　Ｌ６グリコーゲン蓄積評価
　骨格筋細胞におけるグリコーゲン蓄積活性評価は、既報（ＡＮＡＬＹＴＩＣＡＬ　ＢＩＯＣＨＥＭＩＳＴＲＹ，Ｖｏｌ．２６１，：１５９－１６３,１９９８）に準じ、次の方法で行った。ラット骨格筋由来Ｌ６筋芽細胞（ＡＴＣＣ）を、増殖培地（１０％ＦＢＳを含むα‐ＭＥＭ培地（ナカライテスク、２１４４４－０５））を用いて４ｘ１０4細胞／１００μＬ／ウェルの条件で９６ウエルコラーゲンコートプレート（ＩＷＡＫＩ、４８６０－０１０）に播種し、３７℃、５%ＣＯ2条件下で一晩培養した後、分化培地（２％ＦＢＳを含むα‐ＭＥＭ培地）に置換し、３日間培養することにより筋管細胞への分化を行った。評価当日に、グルコース飢餓培地（０．１％ＢＳＡを含むＤＭＥＭ培地（Ｇｉｂｃｏ、１１９６６））に置換して４時間培養した後、最終評価濃度の２倍濃度の被検化合物および０．６％のＤＭＳＯを含むアッセイ培地（０．１％ＢＳＡを含むＤＭＥＭ培地（ナカライテスク、０８４５６－６５））　１５μＬ／ウェルに置換し、さらにＤ－［Ｕ－Ｃ１４］グルコース（パーキンエルマー、ＮＥＣ０４２Ｖ）を１．９μＬ／ウェル含むアッセイ培地を１５μＬ／ウェル添加して、最終ボリューム３０μＬ／ウェルとした後、３７℃、５%ＣＯ2条件下で３時間のインキュベーションを行った。インキュベーション後に培地をアスピレータにより吸引除去し、ＰＢＳを用いて２００μＬ／ウェル、2回の洗浄を行った後、１Ｎ　ＮａＯＨを５０μＬ／ウェル添加し、６０℃、１０分間のインキュベーションにより細胞の溶解を行った。溶解した細胞を室温に戻した後、予め１００％エタノールを１００μＬ／ウェル添加したＭｕｌｔｉｓｃｒｅｅｎＨＴＳ (ミリポア、ＭＳＦＣＮ６Ｂ)に、全溶解細胞および１０ｍｇ／ｍｇ　グリコーゲン（シグマアルドリッチ、Ｇ８８７６）　５μＬ／ウェルを添加し、４℃、２０分間のインキュベーションを行った。インキュベーション後にＭｕｌｔｉｓｃｒｅｅｎＨＴＳ　Ｖａｃｕｕｍ　Ｍａｎｉｆｏｌｄ（ミリポア）による吸引を行い、６６％エタノールで２００μＬ／ウェル、２回の洗浄を行った。乾燥によりフィルターに残存するエタノールを完全に除去した後、ＭｉｃｒｏＳｃｉｎｔ４０（パーキンエルマー）を５０μＬ／ウェル添加し、ＴｏｐＣｏｕｎｔＮＸＴ（パーキンエルマー）により［１４Ｃ］グリコーゲン量を測定した。
　被検化合物の活性の算出は次の方法で行った。化合物を含まずＤＭＳＯのみを含むウェルの測定値（ｃｐｍ）をＡ、化合物およびＤＭＳＯを含むウェルの測定値をＢ、ＷＯ／２０１１／０５８１５４実施例１化合物を最終濃度で３０μＭ含むウェルの測定値をＣとしたときの、１００×（Ｂ－Ａ）／（Ｃ－Ａ）として相対活性（％）を算出した。５０％の活性上昇を起こす化合物濃度をＥＣ５０とし、ＸＬｆｉｔ（ｉｄｂｓ）により算出した。
結果を表５－１と５－２に示す。 Test Example 3 Evaluation of L6 Glycogen Accumulation Glycogen accumulation activity in skeletal muscle cells was evaluated according to the following method (ANALYTICAL BIOCHEMISTRY, Vol.261, 159-163, 1998) by the following method. Rat skeletal muscle-derived L6 myoblasts (ATCC) were grown in 96-well collagen using growth medium (α-MEM medium (Nacalai Tesque, 21444-05) containing 10% FBS) at 4 × 10 4 cells / 100 μL / well. After seeding on a coated plate (IWAKI, 4860-010) and culturing overnight at 37 ° C. and 5% CO 2 , the culture medium is replaced with a differentiation medium (α-MEM medium containing 2% FBS) and cultured for 3 days. Thus, differentiation into myotube cells was performed. On the day of evaluation, the medium was replaced with glucose starvation medium (DMEM medium containing 0.1% BSA (Gibco, 11966)) and cultured for 4 hours, and then the test compound having a concentration twice the final evaluation concentration and 0.6% Assay medium containing DMSO (DMEM medium containing 0.1% BSA (Nacalai Tesque, 08456-65)) Replaced with 15 μL / well, and 1.9 μL of D- [U-C14] glucose (PerkinElmer, NEC042V) The assay medium containing / well was added at 15 μL / well to a final volume of 30 μL / well, and then incubated at 37 ° C. under 5% CO 2 for 3 hours. After the incubation, the medium was removed by suction with an aspirator, washed twice with PBS at 200 μL / well, 1N NaOH was added at 50 μL / well, and cells were lysed by incubation at 60 ° C. for 10 minutes. . After returning the lysed cells to room temperature, 5 μL / well of total lysed cells and 10 mg / mg glycogen (Sigma Aldrich, G8876) were added to Multiscreen HTS (Millipore, MSFCN6B) to which 100% ethanol was added in advance at 100 μL / well. Incubation at 20 ° C. for 20 minutes was performed. After the incubation, suction with Multiscreen HTS Vacuum Manifold (Millipore) was performed, and washing was performed twice with 66% ethanol at 200 μL / well. After the ethanol remaining on the filter was completely removed by drying, 50 μL / well of MicroScint40 (Perkin Elmer) was added, and the amount of [14C] glycogen was measured by TopCount NXT (Perkin Elmer).
The activity of the test compound was calculated by the following method. The measured value (cpm) of a well containing only DMSO without a compound is A, the measured value of a well containing a compound and DMSO is B, and WO / 2011/058154 Example 1 The measured value of a well containing 30 μM of the compound at a final concentration is shown. The relative activity (%) was calculated as 100 × (BA) / (CA) with C. The compound concentration causing an increase in activity by 50% was defined as EC50 and calculated by XLfit (idbs).
The results are shown in Tables 5-1 and 5-2.
表５－１
Figure JPOXMLDOC01-appb-I000072
Table 5-1
Figure JPOXMLDOC01-appb-I000072
表５－２
Figure JPOXMLDOC01-appb-I000073
Table 5-2
Figure JPOXMLDOC01-appb-I000073
試験例４　マウス骨格筋、肝臓におけるグリコーゲン合成酵素活性に対する本発明化合物の効果（用量反応性）
　マウス骨格筋、肝臓のライセートに含まれるグリコーゲン合成酵素活性に対する本発明化合物の用量反応性活性化作用を、下記の方法により評価した。
（方法）
　使用動物は８週齢～１４週齢のＣ５７ＢＬ／６Ｊマウス（オス）を用い、馴化後一晩絶食処理し、速やかに骨格筋と肝臓を採取し、試験実施時まで－８０℃にて保管した。試験実施時に使用する組織重量を測定した後に、１ｍＬの５０ｍＭ　ＫＦ（ｐＨ７．０），１０ｍＭ　ＥＤＴＡ（ｐＨ７．０），１０％　Ｇｌｙｃｅｒｏｌ溶液にて破砕し、ホモジネート処理をした。数回の遠心分離により、上清を酵素源として抽出後、この酵素源に対し、各濃度に調整した本発明化合物とＧ６Ｐ（陽性対照、終濃度３ｍＭ）、ならびに、ＵＤＰ－［Ｕ－１４Ｃ］Ｇｌｕｃｏｓｅ（Ｐｅｒｋｉｎ Ｅｌｍｅｒ：ＮＥＣ４０３）を含む反応液を添加し、３０℃で２０分間の反応を行った。反応終了後、速やかに７５μＬの反応液を濾紙に点着し、氷冷６６％エタノール溶液にて３回洗浄した。洗浄後、濾紙をよく乾固した後に、バイアル瓶に移し、４ｍＬのＬｕｍａ　Ｓａｆｅ　Ｐｌｕｓ（Ｐｅｒｋｉｎ ｅｌｍｅｒ：３０９７）を添加後よく混和し、シンチレーションカウンタを用いてＲＩ強度をｄ．ｐ．ｍにて測定した。図１にマウス骨格筋におけるグリコーゲン合成酵素活性を、図２にマウス肝臓におけるグリコーゲン合成酵素活性に対する、実施例２４化合物の評価結果を示す。 Test Example 4 Effect of Compound of the Present Invention on Glycogen Synthase Activity in Mouse Skeletal Muscle and Liver (Dose Response)
The dose-responsive activation effect of the compound of the present invention on glycogen synthase activity contained in mouse skeletal muscle and liver lysate was evaluated by the following method.
(Method)
The animals used were C57BL / 6J mice (male) 8 to 14 weeks old, fasted overnight after habituation, skeletal muscle and liver were collected immediately, and stored at −80 ° C. until the test was conducted. . After measuring the tissue weight used at the time of the test, the tissue was crushed with 1 mL of 50 mM KF (pH 7.0), 10 mM EDTA (pH 7.0), and 10% Glycerol solution, and homogenated. After extracting the supernatant as an enzyme source by several times of centrifugation, the compound of the present invention adjusted to each concentration, G6P (positive control, final concentration 3 mM), and UDP- [U-14C] A reaction solution containing Glucose (Perkin Elmer: NEC403) was added, and the reaction was performed at 30 ° C. for 20 minutes. Immediately after completion of the reaction, 75 μL of the reaction solution was spotted on a filter paper and washed three times with an ice-cold 66% ethanol solution. After washing, the filter paper is thoroughly dried and then transferred to a vial. After adding 4 mL of Luma Safe Plus (Perkin elmer: 3097), mix well, and use a scintillation counter to adjust the RI strength to d. p. Measured in m. FIG. 1 shows the results of evaluation of the compound of Example 24 against glycogen synthase activity in mouse skeletal muscle, and FIG. 2 shows glycogen synthase activity in mouse liver.
試験例５　耐糖能改善指標における本発明化合物の効果（用量反応性）
（方法）
　使用動物は、6週齢のＣ５７ＢＬ／６Ｊ（Ｌｅｐob／Ｌｅｐob）マウス（オス）を馴化させた後、血糖値、体重などを指標とし、群わけを行った。投与開始前日に体組成をＥｃｈｏＭＲＩ（日立アロカメディカル株式会社）にて分析し、初期値とした。Ｖｅｈｉｃｌｅ（Ｖｅｈ）ならびに本発明化合物の３、１０ｍｇ／ｋｇ、陽性対照化合物としてＰｉｏｇｌｉｔａｚｏｎｅ（Ｐｉｏ、東京化成：１１２５２９－１５－４）をそれぞれ１日２回（９時、１６時）、４週間投与した。投与４週間目に体組成をＥｃｈｏＭＲＩで測定し、初期値からの脂肪体積の変動値をＤｅｌｔａ Ｆａｔ ｍａｓｓ、除脂肪体積の変動値をＤｅｌｔａ Ｌｅａｎ ｍａｓｓとした（結果１）。
　４週間投与後、１６時間絶食処理を行い、本発明化合物、陽性対照化合物ならびに食餌の影響を排除した後に、１ｇのグルコース負荷によるＯＧＴＴ（Ｏｒａｌ　ｇｌｕｃｏｓｅ　ｔｏｌｅｒａｎｃｅ　ｔｅｓｔ）を行った（結果２）。
　図３に結果１のＤｅｌｔａ　Ｆａｔ　ｍａｓｓを、図４に結果１のＤｅｌｔａ　Ｌｅａｎ　ｍａｓｓを示す。図５に、結果２として、実施例２４化合物を評価した結果を示す。
　尚、図３中、「＊」はｐ＜０．０５であることを、「＊＊＊」はｐ＜０．００１であることを示す（Ｄｕｎｎｅｔｔのステップダウン法によるＶｅｈｉｃｌｅ－処置群との比較による）。また、図３中、「＃＃」は、ｐ＜０．０１であることを示す（ステューデントのｔ－テスト法によるＶｅｈｉｃｌｅ－処置群との比較による）。
　また、図５中、「＊」は、ｐ＜０．０５であることを、「＊＊」はｐ＜０．０１であることを示す（Ｄｕｎｎｅｔｔのステップダウン法によるＶｅｈｉｃｌｅ－処置群との比較による）。また、図５中、「＃」はｐ＜０．０５であることを、「＃＃」はｐ＜０．０１であることを示す（ステューデントのｔ－テスト法によるＶｅｈｉｃｌｅ－処置群との比較による）。 Test Example 5 Effect of Compound of the Present Invention on Glucose Tolerance Improvement Index (Dose Response)
(Method)
The animals used were acclimated to 6-week-old C57BL / 6J (Lep ob / Lep ob ) mice (male), and then grouped using blood glucose level, body weight and the like as indices. On the day before the start of administration, the body composition was analyzed by Echo MRI (Hitachi Aloka Medical Co., Ltd.) and used as the initial value. Vehicle (Veh) and 3, 10 mg / kg of the compound of the present invention and Pioglitazone (Pio, Tokyo Kasei: 112529-15-4) as a positive control compound were each administered twice a day (9 o'clock and 16 o'clock) for 4 weeks. . At 4 weeks after administration, body composition was measured by Echo MRI, and the fluctuation value of fat volume from the initial value was defined as Delta Fat mass, and the fluctuation value of lean body volume was defined as Delta Lean mass (Result 1).
After administration for 4 weeks, fasting treatment was performed for 16 hours, and after removing the influence of the compound of the present invention, the positive control compound and the diet, OGTT (Oral glucose tolerance test) with 1 g glucose load was performed (Result 2).
FIG. 3 shows the Delta Fat mass of Result 1, and FIG. 4 shows the Delta Lean mass of Result 1. FIG. 5 shows the results of evaluation of the compound of Example 24 as result 2.
In FIG. 3, “*” indicates that p <0.05, and “***” indicates that p <0.001 (comparison with the vehicle-treated group by Dunnett's step-down method). by). In FIG. 3, “##” indicates p <0.01 (compared with the Vehicle-treated group by Student's t-test method).
In FIG. 5, “*” indicates p <0.05, and “**” indicates p <0.01 (comparison with the Vehicle-treated group by Dunnett's step-down method). by). Further, in FIG. 5, “#” indicates p <0.05, and “##” indicates p <0.01 (comparison with the Vehicle-treated group by Student's t-test method). by).

Claims (11)

  1. 　下記一般式（Ｉ）で表される化合物又はその医薬上許容される塩。
    　一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     　（式中、Ａｒ1は、以下の式（II－１）～（II－５）のいずれかの環で表され、
    Figure JPOXMLDOC01-appb-C000002
     　これらの環は、同一又は異なっていてもよい、１又は複数の置換基を有していてもよく、該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基及びハロゲノアルコキシ基よりなる群から選択され；
    　Ｒ1及びＲ2は、それぞれ独立して、水素原子、重水素で置換されていてもよいアルキル基、ハロゲノアルキル基、ヒドロキシアルキル基、アルコキシアルキル基又はアルキニル基を表し、
    　Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、重水素で置換されていてもよいアルキル基、ハロゲノアルキル基、ヒドロキシアルキル基、アルコキシアルキル基又はアルキニル基を表し、
    　Ａｒ2は、芳香族複素環を表し、
    　Ｌは、結合、アルキレン基又はシクロアルキレン基を表し、
    　Ｘは、水素原子、ハロゲン原子、ヒドロキシル基、アルコキシ基、ハロゲノアルキル基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アミノカルボニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アミノスルホニル基、モノアルキルアミノスルホニル基、ジアルキルアミノスルホニル基、アルキルスルホニル基、アルキルカルボニルアミノ基、アルキルスルホニルアミノ基、アルコキシアルキレンオキシ基又は置換基を有していてもよい、窒素原子、酸素原子及び硫黄原子から選ばれるヘテロ原子を少なくとも１つ有する５員～７員の複素環基を表し、
    　これらの該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アルコキシアルキル基及びハロゲノアルコキシ基よりなる群から選択され；
    　Ｙは、水素原子又はアルキル基で表される。）     A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     (Wherein Ar 1 is represented by any one of the following formulas (II-1) to (II-5):
    Figure JPOXMLDOC01-appb-C000002
     These rings may be the same or different and may have one or a plurality of substituents, and the substituents include a halogen atom, a hydroxyl group, an alkyl group, an acetamido group, an aminocarbonyl group, and an alkoxy group. , A cyano group, an amino group, a monoalkylamino group, a dialkylamino group and a halogenoalkoxy group;
    R 1 and R 2 each independently represents a hydrogen atom, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group or an alkynyl group,
    R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group optionally substituted with deuterium, a halogenoalkyl group, a hydroxy Represents an alkyl group, an alkoxyalkyl group or an alkynyl group,
    Ar 2 represents an aromatic heterocycle,
    L represents a bond, an alkylene group or a cycloalkylene group,
    X is a hydrogen atom, halogen atom, hydroxyl group, alkoxy group, halogenoalkyl group, cyano group, amino group, monoalkylamino group, dialkylamino group, aminocarbonyl group, monoalkylaminocarbonyl group, dialkylaminocarbonyl group, amino A sulfonyl group, a monoalkylaminosulfonyl group, a dialkylaminosulfonyl group, an alkylsulfonyl group, an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxyalkyleneoxy group, or an optionally substituted nitrogen atom, oxygen atom and sulfur A 5- to 7-membered heterocyclic group having at least one heteroatom selected from atoms,
    These substituents consist of a halogen atom, a hydroxyl group, an alkyl group, an acetamide group, an aminocarbonyl group, an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxyalkyl group, and a halogenoalkoxy group. Selected from the group;
    Y is represented by a hydrogen atom or an alkyl group. )
  2. 　一般式（Ｉ）中、Ｘの複素環基が、置換基を有していてもよい、フラン環、チオフェン環、オキサゾール環、イソオキサゾール環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、オキサジアゾール環、トリアゾール環、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、イミダゾ［１，２－ａ］ピリジン環、もしくは、以下の式（III－１）～（III－３）のいずれかの式で表わされ、
    Figure JPOXMLDOC01-appb-C000003
     　（式中、Ｒ11が、水素原子、アルキル基又はアルキルカルボニル基で表され、
    　ｎ1、ｎ2及びｎ3が、０～２の整数で表される。）
    　これらの該置換基は、ハロゲン原子、ヒドロキシル基、アルキル基、アセトアミド基、アミノカルボニル基、アルコキシ基、シアノ基、アミノ基、モノアルキルアミノ基、ジアルキルアミノ基、アルコキシアルキル基及びハロゲノアルコキシ基よりなる群から選択される請求項１記載の化合物又はその医薬上許容される塩。     In general formula (I), the heterocyclic group of X may have a substituent, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, Oxadiazole ring, triazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, imidazo [1,2-a] pyridine ring, or any of the following formulas (III-1) to (III-3) Represented by the formula
    Figure JPOXMLDOC01-appb-C000003
     (In the formula, R 11 is represented by a hydrogen atom, an alkyl group or an alkylcarbonyl group;
    n 1 , n 2 and n 3 are represented by integers of 0-2. )
    These substituents consist of a halogen atom, a hydroxyl group, an alkyl group, an acetamide group, an aminocarbonyl group, an alkoxy group, a cyano group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxyalkyl group, and a halogenoalkoxy group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group.
  3. 　一般式（Ｉ）中、Ａｒ2が、フラン環、チオフェン環、チアゾール環又はピリジン環である請求項１又は２記載の化合物又はその医薬上許容される塩。 In general formula (I), Ar 2 is a furan ring, a thiophene ring, a thiazole ring or a pyridine ring, or a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.
  4. 　一般式（Ｉ）中、Ａｒ1が１又は２の置換基を有し、それらがハロゲン原子である請求項１～３のいずれか１項記載の化合物又はその医薬上許容される塩。 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), Ar 1 has 1 or 2 substituents, which are halogen atoms.
  5. 　一般式（Ｉ）の式（II－１）～（II－５）中、
    　Ｒ1及びＲ2が、水素原子、炭素数１～３のアルキル基又は重水素で１つ以上置換された炭素数１～３のアルキル基で表され、
    　Ｒ3及びＲ5が、水素原子、ハロゲン原子又は炭素数１～３のアルキル基で表され、
    　Ｒ4及びＲ6が、水素原子、炭素数１～３のアルキル基、シアノ基又はメトキシメチル基で表され、
    　Ｒ7及びＲ8が、水素原子又は炭素数１～３のアルキル基を表す請求項１～４のいずれか１項記載の化合物又はその医薬上許容される塩。     In formulas (II-1) to (II-5) of general formula (I),
    R 1 and R 2 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with one or more by deuterium;
    R 3 and R 5 are each represented by a hydrogen atom, a halogen atom or an alkyl group having 1 to 3 carbon atoms,
    R 4 and R 6 are each represented by a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cyano group, or a methoxymethyl group,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 7 and R 8 represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  6. 　一般式（Ｉ）中、Ｌが、炭素数１～３のアルキレン基又は炭素数３～６のシクロアルキレン基を表す請求項１～５のいずれか１項記載の化合物又はその医薬上許容される塩。 In the general formula (I), L represents a C 1-3 alkylene group or a C 3-6 cycloalkylene group, or a pharmaceutically acceptable compound thereof. salt.
  7. 　一般式（Ｉ）の式（III－１）～（III－３）中、Ｒ11が水素原子であり、ｎ1、ｎ2及びｎ3が、０～１の整数である請求項１～６のいずれか１項記載の化合物又はその医薬上許容される塩。 In formulas (III-1) to (III-3) of general formula (I), R 11 is a hydrogen atom, and n 1 , n 2 and n 3 are integers of 0 to 1. Or a pharmaceutically acceptable salt thereof.
  8. 　下記の化合物からなる群から選択される請求項１～７のいずれか１項記載の化合物又はその医薬上許容される塩。
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-ピリジルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(ピリミジン-2-イルメチル)アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(2-フリルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ジメチルアミノエチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]フラン-2-カルボニル]-(4-ピペリジル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メチルスルファニル-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
    　2-[[5-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-3-メチル-ベンゾフラン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
    　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
    　2-[[5-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]フラン-2-カルボニル]-[2-(メチルアミノ)エチル]アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(トリデューテリオメトキシ)フェニル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロベンゾチオフェン-7-イル)フェノキシ]メチル]チアゾール-4-カルボニル]-[(5-メチル-1,2,4-オキサジアゾール-3-イル)メチル]アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-メトキシエチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル) ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(4-ピペリジルメチル)アミノ]酢酸、
    　2-[[2-[[4-[4,5-ジフルオロ-2-(メトキシメチル)ベンゾチオフェン-7-イル]フェノキシ]メチル]チアゾール-4-カルボニル]-(オキサゾール-2-イルメチル)アミノ]酢酸、
    　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-フリルメチル)アミノ]酢酸、及び
    　2-[[2-[[4-(4,5-ジフルオロ-2-メトキシ-フェニル)フェノキシ]メチル]チアゾール-4-カルボニル]-(2-ピロリジン-1-イルエチル)アミノ]酢酸     The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds:
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid,
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid,
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-pyridylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazol-4-carbonyl]-(pyrimidin-2-ylmethyl) amino] acetic acid,
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(2-furylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-dimethylaminoethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid,
    2-[[5-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] furan-2-carbonyl]-(4-piperidyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluorobenzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid,
    2-[[5-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid ,
    2-[[2-[[4- (4,5-Difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid ,
    2-[[2-[[4- (4,5-difluoro-3-methyl-benzofuran-7-yl) phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
    2-[[5-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-(2-methoxyethyl) amino] acetic acid,
    2-[[5-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] furan-2-carbonyl]-[2- (methylamino) ethyl] amino] acetic acid ,
    2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid,
    2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] acetic acid,
    2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid,
    2-[[2-[[4- [4,5-Difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid ,
    2-[[2-[[4- [4,5-difluoro-2- (triduteriomethoxy) phenyl] phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid,
    2-[[2-[[4- (4,5-Difluorobenzothiophen-7-yl) phenoxy] methyl] thiazole-4-carbonyl]-[(5-methyl-1,2,4-oxadiazole- 3-yl) methyl] amino] acetic acid,
    2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(2-methoxyethyl) amino] acetic acid ,
    2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(2-pyrrolidin-1-ylethyl) Amino] acetic acid,
    2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazole-4-carbonyl]-(4-piperidylmethyl) amino] acetic acid ,
    2-[[2-[[4- [4,5-Difluoro-2- (methoxymethyl) benzothiophen-7-yl] phenoxy] methyl] thiazol-4-carbonyl]-(oxazol-2-ylmethyl) amino] Acetic acid,
    2-[[2-[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-furylmethyl) amino] acetic acid, and 2-[[2 -[[4- (4,5-Difluoro-2-methoxy-phenyl) phenoxy] methyl] thiazole-4-carbonyl]-(2-pyrrolidin-1-ylethyl) amino] acetic acid
  9. 　請求項１～８のいずれか１項記載の化合物又はその医薬上許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　請求項１～８のいずれか１項記載の化合物又はその医薬上許容される塩を含有する糖尿病治療用医薬組成物。 A pharmaceutical composition for treating diabetes, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  11. 　請求項１～８のいずれか１項記載の化合物又はその医薬上許容される塩を含有するグリコーゲンシンターゼ活性化剤。 A glycogen synthase activator comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
PCT/JP2015/069031 2014-07-01 2015-07-01 Medicinal composition for treating diabetes WO2016002853A1 (en)

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