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WO2016002853A1 - Composition médicinale destinée au traitement du diabète - Google Patents

Composition médicinale destinée au traitement du diabète 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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WIPO (PCT)
Prior art keywords
group
methyl
amino
mmol
phenoxy
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English (en)
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
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority claimed from JP2014247621A external-priority patent/JP2017149647A/ja
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Publication of WO2016002853A1 publication Critical patent/WO2016002853A1/fr
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    • A—HUMAN NECESSITIES
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    • 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
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    • 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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    • A61K31/40—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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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • 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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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'objectif de la présente invention est de fournir un nouveau composé qui est capable d'activer la glycogène synthase, mais qui active à peine le récepteur PPAR et présente une haute innocuité. L'invention concerne un composé représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de ce dernier.
PCT/JP2015/069031 2014-07-01 2015-07-01 Composition médicinale destinée au traitement du diabète Ceased WO2016002853A1 (fr)

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JP2014136017 2014-07-01
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JP2014247621A JP2017149647A (ja) 2014-07-01 2014-12-08 糖尿病治療用医薬組成物

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149941A (zh) * 2020-01-22 2021-07-23 中国科学院上海药物研究所 醚类化合物及其在防治糖尿病及代谢综合征中的药学用途

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000781A1 (fr) * 2003-06-24 2005-01-06 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
WO2006058648A2 (fr) * 2004-12-03 2006-06-08 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
WO2011057956A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Analogues de benzisoxazole en tant qu'activateurs de glycogène synthase
WO2011057959A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Dérivés d'indole et d'indazole en tant qu'activateurs de glycogène synthase
WO2011058154A1 (fr) * 2009-11-16 2011-05-19 F. Hoffmann-La Roche Ag Acides biphénylcarboxyliques et bioisostères comme activateurs du glycogène synthase
WO2011058122A1 (fr) * 2009-11-16 2011-05-19 F. Hoffmann-La Roche Ag Analogues de pipéridine en tant qu'activateurs de la glycogène synthase
WO2011057993A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Dérivés indazolone en tant qu'activateurs de glycogène synthase
WO2011067174A1 (fr) * 2009-12-01 2011-06-09 F. Hoffmann-La Roche Ag Analogues de l'aniline comme activateurs de la glycogène synthase
WO2011067266A1 (fr) * 2009-12-04 2011-06-09 F. Hoffmann-La Roche Ag Analogues d'acides carboxyliques comme activateurs de la glycogène synthase
WO2013065835A1 (fr) * 2011-11-04 2013-05-10 味の素株式会社 Composition pharmaceutique destinée au traitement du diabète

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000781A1 (fr) * 2003-06-24 2005-01-06 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
WO2006058648A2 (fr) * 2004-12-03 2006-06-08 F. Hoffmann-La Roche Ag Acides biaryloxymethylarenecarboxyliques
WO2011057956A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Analogues de benzisoxazole en tant qu'activateurs de glycogène synthase
WO2011057959A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Dérivés d'indole et d'indazole en tant qu'activateurs de glycogène synthase
WO2011057993A1 (fr) * 2009-11-11 2011-05-19 F. Hoffmann-La Roche Ag Dérivés indazolone en tant qu'activateurs de glycogène synthase
WO2011058154A1 (fr) * 2009-11-16 2011-05-19 F. Hoffmann-La Roche Ag Acides biphénylcarboxyliques et bioisostères comme activateurs du glycogène synthase
WO2011058122A1 (fr) * 2009-11-16 2011-05-19 F. Hoffmann-La Roche Ag Analogues de pipéridine en tant qu'activateurs de la glycogène synthase
WO2011067174A1 (fr) * 2009-12-01 2011-06-09 F. Hoffmann-La Roche Ag Analogues de l'aniline comme activateurs de la glycogène synthase
WO2011067266A1 (fr) * 2009-12-04 2011-06-09 F. Hoffmann-La Roche Ag Analogues d'acides carboxyliques comme activateurs de la glycogène synthase
WO2013065835A1 (fr) * 2011-11-04 2013-05-10 味の素株式会社 Composition pharmaceutique destinée au traitement du diabète

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149941A (zh) * 2020-01-22 2021-07-23 中国科学院上海药物研究所 醚类化合物及其在防治糖尿病及代谢综合征中的药学用途

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