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WO2010001869A1 - Composé de benzène tétrasubstitué et son utilisation - Google Patents

Composé de benzène tétrasubstitué et son utilisation Download PDF

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Publication number
WO2010001869A1
WO2010001869A1 PCT/JP2009/061887 JP2009061887W WO2010001869A1 WO 2010001869 A1 WO2010001869 A1 WO 2010001869A1 JP 2009061887 W JP2009061887 W JP 2009061887W WO 2010001869 A1 WO2010001869 A1 WO 2010001869A1
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WIPO (PCT)
Prior art keywords
group
compound
optionally substituted
methyl
reaction
Prior art date
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Ceased
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PCT/JP2009/061887
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English (en)
Japanese (ja)
Inventor
政宏 竃浦
健太郎 力丸
広士 井元
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2010001869A1 publication Critical patent/WO2010001869A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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
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    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a 4-substituted benzene compound and a therapeutic agent for diabetes using the same.
  • Peroxisome proliferator-responsive receptor gamma is a member of the nuclear hormone receptor superfamily represented by steroid hormone receptors and thyroid hormone receptors, and its expression is induced very early in adipocyte differentiation. It plays an important role in the differentiation of adipocytes as a master regulator. PPAR ⁇ forms a dimer with retinoid X receptor (RXR) by binding to a ligand, and binds to a responsive site of a target gene in the nucleus to directly control (activate) transcription efficiency.
  • RXR retinoid X receptor
  • 15-deoxy- ⁇ 12.14 prostaglandin J2 which is a metabolite of prostaglandin D2 may be an endogenous ligand of PPAR ⁇ , and a kind of insulin sensitivity represented by thiazolidinedione derivatives. It has been found that the potentiating agent has PPAR ⁇ ligand activity, and its strength is in parallel with blood glucose lowering action or adipocyte differentiation promoting action (Non-patent Documents 1 to 3).
  • PPAR ⁇ is expressed in cultured cells derived from human liposarcoma, and its growth is stopped by addition of PPAR ⁇ ligand (Non-patent Document 4); 2) Nonsteroidal anti-inflammatory typified by indomethacin and fenoprofen The drug has PPAR ⁇ ligand activity (Non-Patent Document 5); 3) PPAR ⁇ is highly expressed in activated macrophages, and the addition of the ligand inhibits transcription of genes involved in inflammation (Non-Patent Document 6). 4) It has been found that PPAR ⁇ ligand suppresses the production of inflammatory cytokines (TNF ⁇ , IL-1 ⁇ , IL-6) by monocytes (Non-patent Document 7).
  • Patent Document 1 as a PPAR ⁇ agonist or partial agonist, the formula:
  • X is a bond, O, S (O) n , CO, etc .
  • Y is —CH ⁇ CH—, —CH (OH) CH (OH) —, etc .
  • Z is —CO 2 H or tetrazolyl
  • A is hydrogen atom, C 1-4 alkyl or the like
  • R 2 is optionally C 1-4 alkyl and optionally substituted by a halogen atom
  • R 3 is 3-benzisoxazolyl, 3-benzisothiazolyl or the like
  • R 4 represents a halogen atom, C 1-3 alkyl, OC 1-5 alkyl or the like.
  • Patent Document 2 As a PPAR ⁇ agonist or partial agonist, the formula:
  • R 1 represents (a) -X-aryl-YZ, (b) -X-heteroaryl-YZ, etc .;
  • X represents a bond, O, CH 2 , CH (CH 3 ), etc .;
  • Z represents —CO 2 H or tetrazolyl;
  • A represents C 1-4 alkyl, C 1-4 alkenyl, etc .;
  • R 2 represents a halogen atom Optionally substituted C 1-4 alkyl;
  • R 3 represents benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, aryl, and the like;
  • R 4 represents a halogen atom, C 1-5 alkyl, and the like.
  • the compound represented by these is described.
  • Patent Document 4 discloses ((2R) -2- (2-chloro-5- ⁇ [3- (4-chlorobenzoyl) -2-methyl-6- (trifluoromethoxy) -1H-) as a PPAR ⁇ partial agonist. Indol-1-yl] methyl ⁇ phenoxy) propanoic acid, (2S) -2- (4-chloro-3- ⁇ [1- (6-chloro-1,2-benzisoxazol-3-yl) -2- Methyl-5- (trifluoromethoxy) -1H-indol-3-yl] oxy ⁇ phenoxy) propanoic acid and the like are described.
  • Non-Patent Document 8 describes an N-benzylindole derivative having a benzoyl group or a benzisoxazolyl group at the 3-position and an indole derivative having a phenoxy group at the 3-position as PPAR ⁇ modulators.
  • Patent Document 5 as a plant growth regulator, a formula:
  • Patent Document 6 describes a 3-phenoxypyrazole derivative as a compound having herbicidal activity
  • Patent Document 7 describes a 3- (4-nitrophenoxy) pyrazole derivative as a compound having herbicidal activity
  • Patent Document 8 discloses a pyridyloxyphenoxyalkanecarboxylic acid derivative as a compound having herbicidal activity.
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • R 2 represents an optionally substituted C 1-6 alkyl group
  • R 3 and R 4 independently represent a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-10 cycloalkyl group
  • a 1 is an oxygen atom, —CR a R b — (R a and R b independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group), —NR c — (R c is A hydrogen atom or a C 1-6 alkyl group) or —S (O) m — (m represents an integer of 0 to 2);
  • a 2 represents an oxygen atom, —CR d R e — (R d and R e independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group), —NR f — (R f is A hydrogen
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 is a halogen atom
  • R 4 is a halogen atom
  • a 1 is an oxygen atom
  • a 2 is an oxygen atom or —CH 2 —
  • R 5 is (1) a halogen atom, (2) a cyano group, (3) a carboxy group, (4) a hydroxy group, (5) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (7) 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups, respectively.
  • the present invention provides a preventive or therapeutic agent for diabetes with few side effects such as weight gain, adipocyte accumulation, cardiac hypertrophy.
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified.
  • C 1-6 alkoxy group in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
  • C 1-6 alkoxy-carbonyl group in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
  • C 1-6 alkyl-carbonyl group in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified.
  • R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group.
  • R 2 represents an optionally substituted C 1-6 alkyl group.
  • R 3 and R 4 independently represent a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-10 cycloalkyl group.
  • Examples of the “C 3-10 cycloalkyl group” of the “optionally substituted C 3-10 cycloalkyl group” represented by R 3 or R 4 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] ] Nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.
  • the C 3-10 cycloalkyl group may be condensed with a benzene ring, and examples of such a condensed ring group include indanyl, tetrahydronaphthyl, fluorenyl and the like.
  • a substituent for example, (1) C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) a halogen atom, and (e) a C 1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy)
  • a C 6-14 aryl group eg, phenyl, naphthyl
  • a member of an aromatic heterocyclic group (4) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) an oxo group, and (e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms; (5) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 6-14 aryl group (eg, phenyl), (E) a C 6-14 aryl-carbonyl
  • a substituent selected from: (6) amid
  • the “C 3-10 cycloalkyl group” in the “optionally substituted C 3-10 cycloalkyl group” represented by R 3 or R 4 has 1 to 3 substituents at substitutable positions. It may be.
  • a substituent for example, (1) the groups exemplified as the substituents that the aforementioned C 1-6 alkyl group may have; (2) (a) a halogen atom, (B) a carboxyl group, (C) a hydroxy group, (D) a C 1-6 alkoxy group, (E) a C 1-6 alkoxy-carbonyl group, (F) C 1-6 alkyl - carbonyl group (e.g., acetyloxy, tert- butylcarbonyloxy) (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group, (H) a carbamoyl group, (I) a carbamoyloxy group optionally mono- or di-substi
  • Examples of the aromatic heterocyclic group in the above substituent include 4 to 7 members (preferably 5 to 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Or a 6-membered) monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
  • Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • aromatic heterocyclic group examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl ( Examples: 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4- Pyrazolyl
  • non-aromatic heterocyclic group in the substituent examples include 4 to 7 members (preferably containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom).
  • condensed non-aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring
  • a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
  • benzene ring examples thereof include a condensed non-aromatic heterocyclic group and a group obtained by partial saturation of the group.
  • non-aromatic heterocyclic group examples include oxetanyl (eg, 2-oxetanyl, 3-oxetanyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidyl (eg, piperidino, 2-piperidyl, 3 -Piperidyl, 4-piperidyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimine) -1-yl), oxazolidinyl (eg, oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), imidazolidinyl (eg, imidazolidin-2),
  • R 1 is preferably (1) a hydrogen atom; (2) (a) a C 1-6 alkoxy group (preferably methoxy, ethoxy) optionally substituted with a C 1-6 alkoxy group (preferably methoxy), (B) a carbamoyl group (preferably diethylcarbamoyl) optionally mono- or di-substituted with a C 1-6 alkyl group, (C) a C 1-6 alkoxy-carbonyl group, (D) a carboxyl group, (E) a hydroxy group, (F) a cyano group, (G) a C 1-6 alkyl-carbonyloxy group (preferably acetyloxy), (H) C 1-6 alkyl - is also C 1-6 alkyl group (preferably optionally substituted by 1 to selected from carbonyl group 3 substituents, methyl, ethyl, propyl, isopropyl, butyl, tert -Butyl); Etc.
  • R 1 is more preferably (1) a hydrogen atom; (2) (a) a C 1-6 alkoxy group (preferably methoxy, ethoxy), (B) a C 1-6 alkoxy-carbonyl group, (C) a carboxyl group, (D) a hydroxy group, (E) a cyano group, (F) a C 1-6 alkyl-carbonyloxy group (preferably acetyloxy), (G) C 1-6 alkyl - is also C 1-6 alkyl group (preferably optionally substituted by 1 to selected from carbonyl group 3 substituents, methyl, ethyl, propyl, isopropyl, butyl, tert -Butyl); Etc.
  • R 1 is more preferably (1) a hydrogen atom; (2) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl); Etc.
  • R 2 is preferably (A) a C 1-6 alkoxy group, (B) a halogen atom, (C) a hydroxy group, (D) a cyano group, (E) a C 1-6 alkylthio group (preferably methylthio), (F) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from a carbamoyl group and the like; Etc.
  • R 2 is more preferably (A) a C 1-6 alkoxy group, (B) a halogen atom, (C) a hydroxy group, (D) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group and the like; Etc.
  • R 2 is more preferably a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) or the like.
  • R 3 and R 4 are preferably independently a halogen atom or (1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) a halogen atom, and (e) a C 1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy) A C 6-14 aryl group (eg, phenyl, naphthyl) optionally substituted with 1 to 3 substituents selected from: (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to
  • a member of an aromatic heterocyclic group (4) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) an oxo group, and (e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms, (5) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 6-14 aryl group (eg, phenyl), (E) a C 6-14 aryl-carbonyl
  • a carbamoyl group which may be mono- or di-substituted with a substituent selected from: (10) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (11) a carboxyl group, (12) a hydroxy group, (13) (a) a halogen atom, (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (eg, phenyl), (G) a 4- to 14-membered aromatic heterocyclic group which may be substituted with a C 1-6 alkyl group, (H)
  • R 3 and R 4 are more preferably independently (1) a halogen atom (preferably a fluorine atom or a chlorine atom); (2) (a) a C 1-6 alkoxy group, (B) a halogen atom, (C) a hydroxy group, (D) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from a cyano group and the like; Etc.
  • a halogen atom preferably a fluorine atom or a chlorine atom
  • B a halogen atom
  • C a hydroxy group
  • D a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from a
  • R 3 and R 4 are more preferably independently (1) a halogen atom (preferably a fluorine atom or a chlorine atom); (2) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl); Etc.
  • a halogen atom preferably a fluorine atom or a chlorine atom
  • a C 1-6 alkyl group preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl
  • R 3 and R 4 are still more preferably independently A halogen atom (preferably a fluorine atom or a chlorine atom); Etc.
  • a 1 represents an oxygen atom, —CR a R b —, —NR c —, or —S (O) m —.
  • R a and R b independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group
  • R c represents a hydrogen atom or a C 1-6 alkyl group
  • m represents an integer of 0-2.
  • a 1 is preferably (1) oxygen atom; (2) —CR a R b — (R a and R b are preferably independently (i) a hydrogen atom; or (ii) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, tert-butyl)); (3) —NR c — (R c is preferably a hydrogen atom); Etc.
  • a 1 is more preferably (1) oxygen atom; (2) —CH 2 —; (3) —NH—; Etc.
  • a 1 is more preferably (1) oxygen atom; (2) —CH 2 —; Etc.
  • a 1 is still more preferably (1) oxygen atom; It is.
  • a 2 represents an oxygen atom, —CR d R e —, —NR f —, or —S (O) n —.
  • R d and R e independently represent a hydrogen atom, a halogen atom or a C 1-6 alkyl group
  • R f represents a hydrogen atom or a C 1-6 alkyl group
  • n represents an integer of 0-2.
  • a 2 is preferably (1) oxygen atom; (2) —CR d R e — (R d and R e are preferably independently (i) a hydrogen atom; or (ii) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, tert-butyl)); (3) —NR f — (R f is preferably a hydrogen atom); Etc.
  • a 2 is more preferably (1) oxygen atom; (2) —CH 2 —; (3) —NH—; Etc.
  • a 2 is more preferably (1) oxygen atom; (2) —CH 2 —; Etc.
  • a 2 is still more preferably (1) —CH 2 —; It is.
  • R 5 represents an optionally substituted imidazolyl group (the imidazolyl group may be condensed) or an optionally substituted pyrazol-4-yl group (the pyrazol-4-yl group is condensed). Is also possible.
  • the “optionally substituted imidazolyl group represented by R 5 (the imidazolyl group may be condensed)” means “optionally substituted imidazolyl group” and “optionally substituted condensed Imidazolyl group ".
  • the “condensed imidazolyl group” for example, a 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms in the imidazole ring (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) And a group in which 1 to 2 groups selected from a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene) and a benzene ring are condensed.
  • Benzimidazolyl eg, benzimidazol-1-yl, benzimidazol-2-yl
  • imidazopyridyl eg, 1H-imidazo [4,5-b] pyridin-1-yl, 1H-imidazo [4,5-c ] Pyridin-1-yl, 3H-imidazo [4,5-b] pyridin-3-yl, 3H-imidazo [4,5-c] pyridin-3-yl, imidazo [1,2-a] pyridine-3 -Yl
  • imidazopyrazinyl eg, 1H-imidazo [4,5-b] pyrazin-2-yl
  • Etc e.g, 1H-imidazo [4,5-b] pyrazin-2-yl
  • the “optionally substituted pyrazol-4-yl group (the pyrazol-4-yl group may be condensed)” represented by R 5 is “an optionally substituted pyrazol-4-yl group”.
  • the “condensed pyrazol-4-yl group” is, for example, a 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 nitrogen atoms in the pyrazol-4-yl group (eg, pyrrole, imidazole).
  • pyrazol-4-yl group Pyrazolopyridyl (eg, pyrazolo [1,5-a] pyridin-3-yl), pyrazolotriazinyl (eg, pyrazolo [1,5-a] [1,3,5] triazin-8-yl) , Pyrazolothiazolyl (eg, pyrazolo [5,1-b] [1,3] thiazol-7-yl); Etc.
  • Pyrazolopyridyl eg, pyrazolo [1,5-a] pyridin-3-yl
  • pyrazolotriazinyl eg, pyrazolo [1,5-a] [1,3,5] triazin-8-yl
  • Pyrazolothiazolyl eg, pyrazolo [5,1-b] [1,3] thiazol-7-yl
  • the group may be condensed) ”, ie,“ pyrazol-4-yl group ”and“ fused pyrazol-4-yl group ”have 1 to 3 substituents at substitutable positions. May be. Examples of such a substituent include those similar to the substituent which may be possessed by the “optionally substituted C 3-10 cycloalkyl group” represented by R 3 or R 4. . When there are two or more substituents, each substituent may be the same or different.
  • Examples of the “imidazolyl group (the imidazolyl group may be condensed)” in the “optionally substituted imidazolyl group (the imidazolyl group may be condensed)” represented by R 5 include, for example, imidazolyl Benzimidazolyl, imidazopyridyl, imidazopyrazinyl and the like are preferable.
  • the group may be condensed ” is preferably, for example, pyrazol-4-yl, pyrazolopyridyl, pyrazolotriazinyl, pyrazolothiazolyl and the like.
  • a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a halogen atom (preferably a fluorine atom)
  • a C 6-14 aryl group preferably phenyl, naphthyl
  • substituents selected from: (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to 3 halogen atoms, and (d) 4 to 14 that may be substituted with 1 to 3 substituents selected from halogen atoms.
  • aromatic heterocyclic groups preferably thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl, imidazolyl; (4) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to 3 halogen atoms, and (d) 4 to 14 that may be substituted with 1 to 3 substituents selected from halogen atoms.
  • non-aromatic heterocyclic groups preferably oxetanyl, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1,3-dihydro-2-benzofuranyl, thiazolidinyl; (5) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 6-14 aryl group (preferably phenyl), (E) a C 6-14 aryl-carbonyl group (preferably benzoyl), and (f) a C 7-13 aralkyl-carbonyl group (preferably
  • a substituent selected from: (6) a C 1-6 alkyl-carbonyl group (preferably acet
  • a carbamoyl group optionally mono- or di-substituted with a substituent selected from: (9) carboxyl group; (10) hydroxy group; (11) (a) a halogen atom (preferably a fluorine atom), (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (preferably phenyl), (G) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl) optionally substituted by a C 1-6 alkyl group (preferably methyl), (H) a C 3-10
  • (1) a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a halogen atom (preferably a fluorine atom)
  • a C 6-14 aryl group preferably phenyl, naphthyl
  • substituents selected from: (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 3-10 cycloalkyl group (preferably
  • a substituent selected from: (4) a C 1-6 alkyl-carbonyl group (preferably acet
  • a carbamoyl group optionally mono- or di-substituted with a substituent selected from: (7) carboxyl group; (8) hydroxy group; (9) (a) a halogen atom (preferably a fluorine atom), (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (preferably phenyl), (G) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl) optionally substituted by a C 1-6 alkyl group (preferably methyl), (H) a substituent selected
  • R 5 is preferably (1) a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a halogen atom (preferably a fluorine atom) A C 6-14 aryl group (preferably phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from: (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to 3 halogen atoms, and (d) 4 to 14 that may be substituted with 1 to 3 substituents selected from halogen atoms.
  • aromatic heterocyclic groups preferably thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl, imidazolyl; (4) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to 3 halogen atoms, and (d) 4 to 14 that may be substituted with 1 to 3 substituents selected from halogen atoms.
  • non-aromatic heterocyclic groups preferably oxetanyl, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1,3-dihydro-2-benzofuranyl, thiazolidinyl; (5) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 6-14 aryl group (preferably phenyl), (E) a C 6-14 aryl-carbonyl group (preferably benzoyl), and (f) a C 7-13 aralkyl-carbonyl group (preferably
  • a substituent selected from: (6) a C 1-6 alkyl-carbonyl group (preferably acet
  • a carbamoyl group optionally mono- or di-substituted with a substituent selected from: (9) carboxyl group; (10) hydroxy group; (11) (a) a halogen atom (preferably a fluorine atom), (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (preferably phenyl), (G) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl) optionally substituted by a C 1-6 alkyl group (preferably methyl), (H) a C 3-10
  • R 5 is more preferably (1) a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a halogen atom (preferably a fluorine atom)
  • a C 6-14 aryl group (preferably phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from: (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a
  • a substituent selected from: (4) a C 1-6 alkyl-carbonyl group (preferably acet
  • a carbamoyl group optionally mono- or di-substituted with a substituent selected from: (7) carboxyl group; (8) hydroxy group; (9) (a) a halogen atom (preferably a fluorine atom), (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (preferably phenyl), (G) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl) optionally substituted by a C 1-6 alkyl group (preferably methyl), (H) a substituent selected
  • R 5 is preferably an imidazolyl group which may be substituted (the imidazolyl group may be condensed) or the like.
  • R 5 is more preferably (1) a halogen atom; (2) a cyano group; (3) a carboxy group; (4) hydroxy group; (5) (a) a halogen atom, (B) a hydroxy group, 1 to 3 selected from (c) a cyano group, and (d) a carbamoyloxy group optionally mono- or di-substituted by a C 1-6 alkyl group optionally substituted by a C 3-10 cycloalkyl group A C 1-6 alkyl group which may be substituted with a substituent of: (6) (a) a halogen atom, (B) a C 6-14 aryl group, (C) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, triazolyl, thiazolyl, isoxazolyl) optionally substituted with a C 1-6 alkyl group, (D) optionally substituted with 1 to 3 substituents selected from a C 3-10
  • R 5 is more preferably (1) a halogen atom; (2) a cyano group; (3) a carboxy group; (4) hydroxy group; (5) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (6) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms; (7) a C 1-6 alkoxy-carbonyl group; And an imidazolyl group optionally substituted with 1 to 3 substituents selected from the above (the imidazolyl group may be condensed) (preferably an imidazolyl group or a benzimidazolyl group).
  • R 1 is (1) a hydrogen atom; or (2) (a) a C 1-6 alkoxy group (preferably methoxy, ethoxy), (B) a C 1-6 alkoxy-carbonyl group, (C) a carboxyl group, (D) a hydroxy group, (E) a cyano group, (F) a C 1-6 alkyl-carbonyloxy group (preferably acetyloxy), and (g) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl-carbonyl groups 1-6 alkyl groups (preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl); Is; R 2 is (A) a C 1-6 alkoxy group, (B) a halogen atom, (C) a C 1-6 alkyl group (preferably methyl, ethyl,
  • a substituent selected from: (4) a C 1-6 alkyl-carbonyl group (preferably acet
  • a carbamoyl group optionally mono- or di-substituted with a substituent selected from: (7) carboxyl group; (8) hydroxy group; (9) (a) a halogen atom (preferably a fluorine atom), (B) a carboxyl group, (C) a C 1-6 alkoxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) an amino group optionally mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group, (F) a C 6-14 aryl group (preferably phenyl), (G) a 4- to 14-membered aromatic heterocyclic group (preferably pyridyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl) optionally substituted by a C 1-6 alkyl group (preferably methyl), (H) a substituent selected
  • R 1 is (1) a hydrogen atom; or (2) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl); Is; R 2 is a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl); R 3 and R 4 are independently (1) a halogen atom (preferably a fluorine atom, a chlorine atom); or (2) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl); Is; A 1 is, (1) oxygen atom; (2) —CH 2 —; or (3) —NH—; Is; A 2 is, (1) oxygen atom; (2) —CH 2 —; or (3) —NH—; Compound (I) wherein
  • R 1 is (1) a hydrogen atom; or (2) a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl); Is; R 2 is a C 1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl); R 3 and R 4 are independently a halogen atom (preferably a fluorine atom or a chlorine atom); A 1 is, (1) an oxygen atom; or (2) —CH 2 —; Is; A 2 is, (1) an oxygen atom; or (2) —CH 2 —; Compound (I) wherein R 5 is the same as [Compound A].
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 and R 4 are each independently a halogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1-6 cycloalkyl group
  • a 1 is an oxygen atom
  • a 2 is an oxygen atom or —CH 2 — (preferably —CH 2 —)
  • R 5 is (1) a halogen atom, (2) a cyano group, (3) a carboxy group, (4) a hydroxy group, (5) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (7) a substituent substituted with 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups
  • Compound (I) which may be an imidazolyl group (which may be conden
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 and R 4 are independently a halogen atom, or (1) a C 3-10 cycloalkyl group
  • (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) a halogen atom, and (e) a C 6-14 aryl group optionally substituted with 1 to 3 substituents selected from a C 1-6 alkylsulfonyloxy group, (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group that may be substituted with 1 to 3 halogen atoms, and (
  • a member of an aromatic heterocyclic group (4) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, (B) a hydroxy group, (C) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (D) an oxo group, and (e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms, (5) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (B) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms, (C) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms, (D) a C 6-14 aryl group, (E) a C 6-14 aryl-carbonyl group, (F) a C
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 is a halogen atom
  • R 4 is a halogen atom
  • a 1 is an oxygen atom
  • a 2 is an oxygen atom or —CH 2 — (preferably —CH 2 —)
  • R 5 is (1) a halogen atom, (2) a cyano group, (3) a carboxy group, (4) a hydroxy group, (5) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (6) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (7) 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl group, respectively.
  • Compound (I) which may be an imidazolyl group or a benzimidazolyl group.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 is a halogen atom
  • R 4 is a halogen atom
  • a 1 is an oxygen atom
  • a 2 is —CH 2 —
  • R 5 is (1) a halogen atom, (2) a cyano group, (3) a carboxy group, (4) a hydroxy group, (5) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (7) a substituent substituted with 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups
  • Compound (I) which may be an imidazolyl group.
  • R 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 2 is a C 1-6 alkyl group
  • R 3 is a halogen atom
  • R 4 is a halogen atom
  • a 1 is an oxygen atom
  • a 2 is —CH 2 —
  • R 5 is (1) a halogen atom, (2) a cyano group, (3) a carboxy group, (4) a hydroxy group, (5) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (6) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (7) a substituent substituted with 1 to 3 substituents selected from C 1-6 alkoxy-carbonyl groups
  • Compound (I) which may be a benzimidazolyl group.
  • the salt of the compound represented by the formula (I) is preferably a pharmacologically acceptable salt.
  • a salt with an inorganic base a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid And salts with basic or acidic amino acids.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
  • salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation
  • Compound (I) can be a crystal, and the crystal form of the crystal may be single or plural. Crystals can be produced using a crystallization method known per se. In the present specification, the melting point is measured using, for example, a micro melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
  • the melting point may vary depending on the measurement equipment, measurement conditions, and the like.
  • the crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
  • the crystals of compound (I) are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug efficacy), pharmaceuticals As extremely useful.
  • Compound (I) may be a solvate (eg, hydrate) or non-solvate (eg, non-hydrate), and these are all encompassed in compound (I).
  • the A compound labeled with an isotope eg, 3 H, 14 C, 35 S, 125 I
  • a deuterium converter obtained by converting 1 H into 2 H (D) are also encompassed in compound (I).
  • Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) is toxic (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity) ) Is low, as it is, or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition, so that mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig) , Monkeys) can be used as a prophylactic / therapeutic agent for various diseases described later or an insulin resistance improving agent.
  • mammals eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig
  • Monkeys can be used as a prophylactic / therapeutic agent for various diseases described later or an insulin resistance improving agent.
  • the pharmacologically acceptable carrier various conventional organic or inorganic carrier materials are used as the formulation material, and excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
  • the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
  • Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
  • the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate;
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • Preferable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
  • buffer solutions such as a phosphate, acetate, carbonate, a citrate, etc. are mentioned, for example.
  • the soothing agent include benzyl alcohol.
  • the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, ⁇ -carotene, chlorophyll, bengara) and the like.
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges.
  • Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.
  • Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration). These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • the compound of the present invention has a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, an insulin sensitivity enhancing action and a peroxisome proliferator-responsive receptor (hereinafter sometimes abbreviated as PPAR) ⁇ (GenBank Accession No. L40904) Has agonist (activation) action.
  • PPAR ⁇ is one of retinoid X receptor (hereinafter sometimes abbreviated as RXR) ⁇ (GenBank Accession No. X52773), RXR ⁇ (GenBank Accession No. M84820) or RXR ⁇ (GenBank Accession No. U38480).
  • RXR retinoid X receptor
  • a heterodimeric receptor may be formed.
  • the compound of the present invention has a selective partial agonist (partial agonist) action particularly on PPAR ⁇ .
  • the compound of the present invention is, for example, a prophylactic / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes); hyperlipidemia (eg, hypertriglyceride (TG) emia, hypercholesterolemia) Prevention, treatment of insulin disease, high LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia); insulin resistance improver; insulin sensitivity enhancer; impaired glucose tolerance [IGT (Impaired Glucose Tolerance)] -It can be used as a therapeutic agent; and an inhibitor of the transition from impaired glucose tolerance to diabetes.
  • diabetes eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes
  • hyperlipidemia eg, hypertriglyceride (TG) emia, hypercholesterolemia
  • TG hypertriglyceride
  • hypercholesterolemia hypercholesterolemia
  • Prevention treatment of insulin disease, high LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • glucose level in venous plasma is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, or a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) of 200 mg / dl or more. It is the state which shows.
  • impaired glucose tolerance is a state in which the 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 140 mg / dl or more and less than 200 mg / dl.
  • IFG Impaired Fasting Glucose
  • WHO calls the IFG (Impaired Fasting Glucose) an IFG (Impaired Fasting Glycaemia) with a fasting blood glucose level (glucose concentration in venous plasma) of 110 mg / dl or more and less than 126 mg / dl.
  • the compound of the present invention is also used as a preventive / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycaemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycaemia) to diabetes.
  • the compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, Urinary tract infection, digestive tract infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], obesity, osteoporosis, cachexia ( Examples: Cancer cachexia, tuberculosis cachex, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious cachexia or cachexia due to acquired immune deficiency syndrome), fatty liver, hypertension , Polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease), muscular dystrophy, myocardial infarction,
  • the compound of the present invention can also be used to improve symptoms such as peptic ulcer, acute or chronic gastritis, biliary dyskinesia, abdominal pain associated with cholecystitis, nausea, vomiting and upper abdominal discomfort.
  • the compound of the present invention is also used as a prophylactic / therapeutic agent for inflammatory diseases involving TNF- ⁇ .
  • an inflammatory disease involving TNF- ⁇ is an inflammatory disease that develops due to the presence of TNF- ⁇ and can be treated through a TNF- ⁇ inhibitory effect.
  • inflammatory diseases include diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorders), rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery -Post-traumatic inflammation, swelling, neuralgia, sore throat, cystitis, hepatitis, pneumonia, gastric mucosal damage (including gastric mucosal damage caused by aspirin), etc.
  • the compound of the present invention has an apoptosis-inhibiting action and is also used as a prophylactic / therapeutic agent for diseases involving the promotion of apoptosis.
  • diseases associated with the promotion of apoptosis include viral diseases (eg, AIDS, fulminant hepatitis), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa).
  • Cerebellar degeneration spinal dysplasia disease (eg, aplastic anemia), ischemic disease (eg, myocardial infarction, stroke), liver disease (eg, alcoholic hepatitis, hepatitis B, hepatitis C), joint disease (Eg, osteoarthritis), atherosclerosis and the like.
  • ischemic disease eg, myocardial infarction, stroke
  • liver disease eg, alcoholic hepatitis, hepatitis B, hepatitis C
  • joint disease eg, osteoarthritis
  • the compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary metabolism, prevents cardiovascular complications It is also used for treatment, prevention and treatment of heart failure complications, blood remnant reduction, anovulation prevention and treatment, hirsutism prevention and treatment, hyperandrogenemia prevention and treatment, etc.
  • the compound of the present invention is also used for secondary prevention and suppression of progression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when orally administered to an adult diabetic patient, it is usually about 0.005 to 50 mg / kg body weight as a single dose.
  • the dose is preferably 0.01 to 2 mg / kg body weight, more preferably 0.025 to 0.5 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
  • the compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis, It can be used in combination with drugs (hereinafter abbreviated as concomitant drugs) such as dementia drugs, erectile dysfunction-improving drugs, urinary incontinence / frequent urination drugs, and dysuria drugs.
  • concomitant drugs may be low molecular compounds, high molecular proteins, polypeptides, antibodies, or vaccines.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • dosage forms include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration by different administration routes of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different administration routes (for example, administration in the order of the compound of the present invention and the concomitant drug, or Administration in reverse order) Et
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering 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) ), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN- 2034, GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO Compounds described in 2008/099794), ⁇ -glucosidase inhibitors (eg, voglibose, vo
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increase drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-Methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-Fe) Nasyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg,
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt)
  • Squalene synthase inhibitors eg, compounds described in pamphlet of WO97 / 10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5 -(2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds ( E.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (e.g.
  • antihypertensive agent examples include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan, medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, nicardipine, amlodipine, sinodidipine, etc.), ⁇ -blockers (eg, metoprolol, atenolol, propranolol, propranolol) Pindolol), clonidine and
  • anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor , GABA modulators (eg, topiramate), neuropeptide Y antagonists (eg, beneperit), cannabinoid receptor antagonists (eg, rimonabant, taranaban), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitor Drugs, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, Orlistat, cetilistat), ⁇ 3 agonists (eg,
  • FGF21 preparations eg, animals extracted from bovine, porcine pancreas FGF21 preparations; human FGF21 preparations synthesized by genetic engineering using E. coli and yeast; FGF21 fragments or derivatives)
  • antifeedants eg, P-57
  • diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflux.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide, etc.
  • Azosemide is
  • chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin) Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furtulon or neoflutulon are preferred.
  • alkylating agents eg, cyclophosphamide, ifosfamide
  • antimetabolites eg, methotrexate, 5-fluorouracil and derivatives thereof
  • anticancer antibiotics eg, mitomycin, adriamycin
  • Plant-derived anticancer agents eg, vincristine, vindesine, taxol
  • cisplatin carb
  • immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like, and interleukins such as IL-1, IL-2 and IL-12 are preferred.
  • microorganisms or bacterial components eg, muramyl dipeptide derivatives, picibanil
  • polysaccharides having immunopotentiating activity eg, lentinan, schizophyllan, krestin
  • cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)
  • colony stimulating factor eg, granulocyte colony stimulating
  • antithrombotic agents examples include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban ( aragatroban), dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504), thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase (pamiteplase)), platelet aggregation inhibitors (eg, Ticlopidine hydrochloride, clopidogrel, prasugrel, E
  • osteoporosis therapeutic agents examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, risedronate disodium (risedronate) disodium), pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.
  • anti-dementia agent examples include tacrine, donepezil, rivastigmine, galanthamine and the like.
  • the erectile dysfunction ameliorating agent examples include apomorphine, sildenafil citrate, and the like.
  • urinary incontinence / frequent urination therapeutic agent examples include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
  • dysuria therapeutic agent examples include acetylcholinesterase inhibitors (eg, distigmine).
  • Concomitant drugs include drugs that have been shown to improve cachexia in animal models and clinically, ie cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, Dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF- ⁇ , LIF, IL -6, an antibody against Oncostatin M, and the like.
  • cyclooxygenase inhibitors eg, indomethacin
  • progesterone derivatives eg, megesterol acetate
  • carbohydrate steroids eg, Dexamethasone
  • metoclopramide drugs etrahydrocannabinol drugs
  • fat metabolism improvers eg, eico
  • the concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), ⁇ 2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.
  • nerve regeneration promoters eg, Y-128,
  • the combination drug is preferably an insulin preparation, an insulin resistance improving agent, an ⁇ -glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
  • the insulin resistance improving agent, insulin secretagogue and biguanide can be reduced from the usual dose.
  • the adverse effects that would be caused by these agents can be safely prevented.
  • the dosage of diabetic complication therapeutics, hyperlipidemia therapeutics, antihypertensives can be reduced, and the adverse effects that would be caused by these agents can be effectively prevented.
  • Compound (I) can be produced by a method known per se, for example, the following methods A to T or a method analogous thereto.
  • the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound (I) are used.
  • examples of the “alkyl group” include a C 1-6 alkyl group.
  • examples of the “cycloalkyl group” include those exemplified as the “C 3-10 cycloalkyl group” of the “optionally substituted C 3-10 cycloalkyl group” represented by R 3 or R 4 .
  • examples of the “aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like.
  • heteroaryl group examples include those exemplified as the aromatic heterocyclic group in the substituent of the “optionally substituted C 1-6 alkyl group” represented by R 1 or R 2 .
  • aromatic ring includes an aromatic heterocyclic group in the ring corresponding to the above “aryl group”, the substituent of “optionally substituted C 1-6 alkyl group” represented by R 1 or R 2. Corresponding rings and the like can be mentioned.
  • alkyl group may each be substituted.
  • substituent of the “alkyl group” include those exemplified as the substituent of the “optionally substituted C 1-6 alkyl group” represented by R 1 or R 2 .
  • compound (I) wherein A 1 is O can be produced, for example, by the following method A. [Method A]
  • R 101 represents a hydrogen atom, an alkyl group or an alkoxy group
  • Ua represents a leaving group or a hydroxy group
  • R 101 is preferably a hydrogen atom, methyl, methoxy or the like.
  • Examples of the “leaving group” represented by Ua include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • compound (III) can be produced from compound (II).
  • This reaction is carried out using a method known per se, for example, a method of treating with an acid, a method of subjecting to a hydrogenation reaction, or the like.
  • the reaction may be performed in a solvent that does not adversely affect the reaction.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trichloride and boron tribromide; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid; hydrogen chloride gas as methanol and ethyl acetate And hydrogen chloride-methanol, hydrogen chloride-ethyl acetate and the like dissolved in the above solvent.
  • the amount of the acid to be used is generally 0.01 to 500 mol, preferably 0.01 to 50 mol, per 1 mol of compound (II).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Alcohols such as methanol and ethanol; Ketones such as acetone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • this reaction is performed according to a conventional method in the presence of a metal catalyst and a hydrogen source in a solvent that does not adversely influence the reaction.
  • This reaction adversely affects the reaction in the presence of a metal catalyst such as palladium-carbon, palladium-carbon ethylenediamine complex, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and a hydrogen source.
  • a metal catalyst such as palladium-carbon, palladium-carbon ethylenediamine complex, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and a hydrogen source.
  • the amount of the metal catalyst to be used is generally 0.001 to 1000 mol, preferably 0.01 to 100 mol, per 1 mol of compound (II).
  • Examples of the hydrogen source include hydrogen gas, formic acid, formic acid amine salt, phosphinate, hydrazine and the like.
  • Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane; alcohols such as methanol and ethanol; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 100 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (I-2) can be produced by reacting compound (III) with compound (IV).
  • Ua is a leaving group
  • this reaction is performed in the presence of a base in a solvent that does not adversely influence the reaction.
  • the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • Alkali metal salts such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; potassium hydride and sodium hydride Metal hydrides such as alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (III).
  • the amount of compound (IV) to be used is preferably about 1 to about 10 mol per 1 mol of compound (III).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 40 hours.
  • this reaction is carried out by a method known per se, for example, the method described in Synthesis page 1 (1981) or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely influence the reaction.
  • organic phosphorus compound include triphenylphosphine and tributylphosphine.
  • electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azodicarbonyldipiperidine, and the like.
  • the amount of the organophosphorus compound and electrophilic agent used is preferably about 1 to about 5 moles per 1 mole of compound (III).
  • the amount of compound (IV) to be used is preferably about 1 to about 5 mol per 1 mol of compound (III).
  • Examples of the solvent that does not adversely influence the reaction include the same solvents as described above.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 40 hours.
  • Compound (II) used as a raw material compound in the above-mentioned method A is, for example, C method, D method, F method, G method, H method, I method, K method, L method, M method, N method, or It can be produced according to a method according to these.
  • Compound (IV) can also be produced according to a method known per se, or Reference Example 24 and Reference Example 49 described later.
  • compound (I) in which A 1 is O and R 1 is a hydrogen atom can be produced, for example, by the following Method B. [Method B]
  • R 1a represents an alkyl group, and other symbols are as defined above.
  • R 1a is preferably methyl, ethyl, tert-butyl or the like.
  • compound (I-3) can be produced by subjecting compound (I-2a) to a hydrolysis reaction.
  • This reaction is carried out according to a conventional method in the presence of an acid or a base in a solvent that does not adversely influence the reaction.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trichloride and boron tribromide; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid.
  • the amount of the acid to be used is preferably about 0.01 to about 50 mol per 1 mol of compound (I-2a).
  • the base examples include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metals such as magnesium hydroxide, calcium hydroxide and barium hydroxide.
  • the amount of the base to be used is preferably about 1 to about 10 mol per 1 mol of compound (I-2a).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Alcohols such as methanol and ethanol; Ketones such as acetone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (I-2a) used as the starting compound in the above-mentioned method B is, for example, the above-mentioned method A, method J described later, method K, method N, method P, method R, method S, or the like. It can be manufactured according to the method.
  • compound (II) in which A 2 is CH 2 , R 3 and R 4 are chlorine atoms, and R 5 is R 5a can be produced, for example, by the following Method C it can. [Method C]
  • R 5a represents an optionally substituted imidazolyl group which may be substituted at the 2-position, 4-position and 5-position, Ub and Uc each independently represents a leaving group, and other symbols. Is as defined above.
  • R 5a is preferably 2,4-dimethyl-1H-imidazol-1-yl, 4-iodo-2,5-dimethyl-1H-imidazol-1-yl, 4-chloro-2,5-dimethyl-1H- Imidazol-1-yl, 4,5-dichloro-2-methyl-1H-imidazol-1-yl, 2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl, 2-methyl-4- Phenyl-1H-imidazol-1-yl, 5- (methoxycarbonyl) -2-methyl-1H-benzimidazol-1-yl, 5-iodo-2-methyl-1H-benzimidazol-1-yl, and the like.
  • Examples of the “leaving group” represented by Ub or Uc include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. It is done.
  • compound (VI) can be produced from compound (V).
  • This reaction is carried out in a solvent that does not adversely influence the reaction, for example, using a method of treating with sulfuryl chloride.
  • the amount of sulfuryl chloride to be used is generally 0.5-5 mol, preferably 1-3 mol, per 1 mol of compound (V).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. . These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (VIII) can be produced by reacting compound (VI) with compound (VII).
  • This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline and 4-dimethylaminopyridine; alkali metals such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate Salt; Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Metal such as potassium hydride and sodium hydride Hydrides; and alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (VI).
  • the amount of compound (VII) to be used is preferably about 1 to about 10 mol per 1 mol of compound (VI).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Step 3 compound (IX) can be produced from compound (VIII).
  • This reaction is performed using a method of treating with alkylsulfonyl chloride or arylsulfonyl chloride in the presence of a base. Alkali metal halide salts may also be added. The reaction is carried out in a solvent that does not adversely affect the reaction.
  • the base those exemplified in Step 2 above can be used.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (VIII).
  • alkylsulfonyl chloride examples include methanesulfonyl chloride, and examples of the arylsulfonyl chloride include benzenesulfonyl chloride.
  • the amount of alkylsulfonyl chloride or arylsulfonyl chloride to be used is preferably 1 to 3 mol per 1 mol of compound (VIII).
  • alkali metal halide salt include lithium chloride, lithium bromide, sodium bromide, sodium iodide, potassium iodide and the like.
  • the amount of the alkali metal halide salt to be used is preferably 1 to 3 mol per 1 mol of compound (VIII).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. . These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • this reaction may be performed by a method of treating with carbon tetrabromide in the presence of an organic phosphorus reagent.
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • organic phosphorus reagent triphenylphosphine, tributylphosphine, or the like is used.
  • the amount of the organophosphorus reagent to be used is preferably about 1 to about 5 mol per 1 mol of compound (VIII).
  • the amount of carbon tetrabromide to be used is preferably 1 to 5 mol per 1 mol of compound (VIII).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. . These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (II-2) can be produced by reacting compound (IX) with compound (X). This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • a base those exemplified in Step 2 above can be used.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (IX).
  • Examples of the compound (X) include 2,4-dimethyl-1H-imidazole, 4-iodo-2,5-dimethyl-1H-imidazole, 4-chloro-2,5-dimethyl-1H-imidazole, 4,5 Imidazoles such as 2-dichloro-2-methyl-1H-imidazole, 2-methyl-4- (trifluoromethyl) -1H-imidazole, 2-methyl-4-phenyl-1H-imidazole; 2-methyl-1H-benz And benzimidazoles such as methyl imidazole-5-carboxylate and 5-iodo-2-methyl-1H-benzimidazole.
  • the amount of compound (X) to be used is preferably about 0.5 to about 2 mol per 1 mol of compound (IX).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (V) and the compound (VII) used as raw material compounds in the method C can be produced according to a method known per se.
  • Compound (X) can also be produced according to a method known per se, Method Q described later or a method analogous thereto, or the method described in Reference Example 28.
  • Compound (II-5) which is (R 102 and R 103 are as described later) can be produced, for example, by the following method D. [Method D]
  • R 102 and R 103 are each independently a hydrogen atom or an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., Xa is a halogen atom, The symbols are as defined above.
  • R 102 and R 103 are preferably each independently a hydrogen atom, methyl, ethyl, phenyl, 2-pyridyl, trifluoromethyl, cyclopropyl or the like.
  • compound (II-4) can be produced by reacting compound (II-3) with a halogenating agent. This reaction is performed in a solvent that does not adversely influence the reaction.
  • a halogenating agent include bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, xenon difluoride and the like.
  • the amount of the halogenating agent to be used is preferably about 1 to about 3 mol per 1 mol of compound (II-3).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Carboxylic acids such as acetic acid; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (II-5) can be produced from compound (II-4).
  • This reaction is carried out using a method known per se, for example, a method of treating with copper cyanide or a method of treating with cyanide in the presence of a palladium catalyst.
  • the reaction is carried out in a solvent that does not adversely affect the compound.
  • the amount of copper cyanide to be used is preferably 1 to 10 mol per 1 mol of compound (II-4).
  • the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about 0 to about 250 ° C., preferably about 0 to about 180 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • cyanide When cyanide is used in the production of compound (II-5) in the presence of a palladium catalyst, the reaction is carried out in a solvent that does not adversely affect the compound.
  • the palladium catalyst include tetrakis (triphenylphosphine) palladium (0).
  • the amount of the palladium catalyst to be used is generally 0.001 to 10 mol, preferably 0.001 to 0.3 mol, per 1 mol of compound (II-4).
  • the cyanide include zinc cyanide, sodium cyanide, potassium cyanide and the like. The amount of cyanide to be used is preferably 1 to 10 mol per 1 mol of compound (II-4).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about 0 to about 250 ° C., preferably about 0 to about 180 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (II-3) used as the starting compound in the above method D can be produced, for example, according to the above-mentioned method C or a method analogous thereto.
  • R 5b may have a substituent and may be condensed with an imidazolyl group or a pyrazol-4-yl group, Xb represents a halogen atom, and other symbols are as defined above.
  • R 5b is preferably 1,3,5-trimethyl-1H-pyrazol-4-yl, 2-methylimidazo [1,2-a] pyridin-3-yl, and the like.
  • Xb is preferably a chlorine atom, a bromine atom or an iodine atom.
  • compound (XI) can be produced by oxidizing compound (VIII-2).
  • This reaction is performed in the presence of an oxidizing agent in a solvent that does not adversely influence the reaction.
  • the oxidizing agent include manganese dioxide, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (desmartin reagent), and the like.
  • the amount of the oxidizing agent to be used is preferably about 1 to about 10 mol per 1 mol of compound (VIII-2).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Nitriles; Amides such as N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (XIII) can be produced by reacting compound (XII) with compound (XI) after lithiation with an alkyllithium reagent. This reaction is performed in a solvent that does not adversely influence the reaction.
  • the alkyl lithium reagent include n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and the like.
  • the amount of the alkyl lithium reagent to be used is preferably about 1 to about 3 mol per 1 mol of compound (XII).
  • the compound (XII) include 4-bromo-1,3,5-trimethyl-1H-pyrazole, 3-bromo-2-methylimidazo [1,2-a] pyridine and the like.
  • the amount of compound (XII) to be used is preferably about 0.5 to about 2 mol per 1 mol of compound (XI).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 100 to about 100 ° C., preferably about ⁇ 80 to about 30 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (III-2) can be produced by reacting compound (XIII) with trialkylsilane in the presence of trifluoroacetic acid. This reaction may be performed in a solvent that does not adversely influence the reaction.
  • the amount of trifluoroacetic acid to be used is generally about 1-about 1000 mol, preferably about 1-about 100 mol, per 1 mol of compound (XIII).
  • Examples of the trialkylsilane include triethylsilane.
  • the amount of the trialkylsilane to be used is preferably about 1 to about 10 mol per 1 mol of compound (XIII).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. . These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (VIII-2) used as a starting compound in the above-mentioned method E can be produced according to a method known per se, for example, the above-mentioned method C or a method analogous thereto.
  • Compound (II-6), which is R 104 and ring A as described later, can be produced, for example, by the following Method F. [F method]
  • R 104 represents an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., Ud represents a leaving group, and ring A represents an optionally substituted aromatic ring, Other symbols are as defined above.
  • R 104 is preferably methyl, trifluoromethyl, ethyl, phenyl, 2-pyridyl and the like.
  • Examples of the “leaving group” represented by Ud include a chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • Ring A is preferably a benzene ring, a pyridine ring or the like.
  • compound (XV) can be produced by reacting compound (XIV) with an acylating agent.
  • This reaction is performed in a solvent that does not adversely influence the reaction. Moreover, you may carry out in presence of a base.
  • the acylating agent include acid halides such as acetyl chloride, acetyl bromide, benzoyl chloride, and propionyl chloride; acid anhydrides such as acetic anhydride and trifluoroacetic anhydride.
  • the amount of the acylating agent to be used is preferably about 1 to about 3 mol per 1 mol of compound (XIV).
  • solvents such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Nitriles; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio.
  • Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline and 4-dimethylaminopyridine; alkali metals such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate Salt; Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Metal such as potassium hydride and sodium hydride Hydrides; and alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • alkali metals such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate Salt
  • Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide
  • Alkaline earth metal such as magnesium hydroxide, calcium hydroxide and barium hydroxide
  • the amount of the base to be used is preferably 0 to about 5 mol per 1 mol of compound (XIV).
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (XVI) can be produced by reacting compound (XV) with compound (IX-2). This reaction is carried out according to the above-mentioned Method C, Step 4.
  • compound (II-6) can be produced from compound (XVI).
  • This reaction is performed using a method of treating with iron powder in the presence of an acid.
  • the reaction is carried out in a solvent that does not adversely affect the reaction.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid and p-toluenesulfonic acid; hydrogen chloride-methanol in which hydrogen chloride gas is dissolved in a solvent such as methanol and ethyl acetate; Examples include hydrogen chloride-ethyl acetate.
  • the amount of the acid to be used is generally 0.01-1000 mol, preferably 0.01-200 mol, per 1 mol of compound (XVI).
  • the amount of iron powder to be used is preferably 1 to 10 mol per 1 mol of compound (XVI).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; methanol and ethanol Alcohols such as acetone; ketones such as acetone; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about 0 to about 200 ° C, preferably about 0 to about 130 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • step 4 In this method, compound (XVII) can be produced from compound (XV). This reaction is performed according to the above step 3.
  • compound (II-6) can be produced by reacting compound (XVII) with compound (IX-2). This reaction is carried out according to the above-mentioned Method C, Step 4.
  • the compound (XIV) used as a raw material compound in the method F can be produced according to a method known per se.
  • Compound (XV) can also be produced according to a method known per se.
  • Compound (II-6) can also be produced, for example, by the following method G. [G method]
  • compound (XIX) can be produced from compound (XVIII) and compound (IX-2). This reaction is carried out according to the above-mentioned Method C, Step 4.
  • compound (II-6) can be produced from compound (XIX).
  • This reaction is performed in the presence of an acid in a solvent that does not adversely affect the reaction.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid, trifluoroacetic acid and p-toluenesulfonic acid; hydrogen chloride-methanol in which hydrogen chloride gas is dissolved in a solvent such as methanol and ethyl acetate; Examples include hydrogen chloride-ethyl acetate.
  • the amount of the acid to be used is generally 0.01-1000 mol, preferably 0.01-200 mol, per 1 mol of compound (XIX).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; methanol and ethanol Alcohols such as acetone; ketones such as acetone; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about 0 to about 200 ° C, preferably about 0 to about 130 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (XVIII) used as a raw material compound in the above G method can be produced according to a method known per se.
  • Compound (II-8) can be produced, for example, by the following Method H. [Method H]
  • Xc represents a halogen atom, and other symbols are as defined above.
  • Xc is preferably a chlorine atom, a bromine atom or an iodine atom.
  • compound (II-8) can be produced from compound (II-7). This reaction is carried out according to the above-mentioned Method D, Step 2.
  • the compound (II-7) used as a raw material compound in the above-mentioned method H can be produced, for example, according to the above-mentioned method C, method F, method G, the following method K, method N, or a method analogous thereto. it can.
  • R 105 represents an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc.
  • R 106 represents a hydrogen atom, an alkyl group, or an alkoxy group
  • Xd represents a halogen atom, and the like.
  • the symbol represents the same meaning as described above.
  • R 105 is preferably methyl, ethyl, phenyl, 2-pyridyl, trifluoromethyl, cyclopropyl or the like.
  • R 106 is preferably a hydrogen atom, methyl, methoxy or the like.
  • compound (II-9) can be produced from compound (XX) and compound (XXI).
  • This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • a base those exemplified in Step 2 of Method C can be used.
  • the amount of the base to be used is preferably about 1 to about 3 mol per 1 mol of compound (XX).
  • the amount of compound (XXI) to be used is preferably about 1 to about 3 mol per 1 mol of compound (XX).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide and 1-methyl-2-pyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually about ⁇ 80 to about 250 ° C., preferably about ⁇ 10 to about 200 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (XX) and the compound (XXI) used as raw material compounds in the above method I can be produced according to a method known per se.
  • compound (I) wherein A 1 is O, A 2 is CH 2 and R 5 is R 5c can be produced, for example, by the following Method J. [J method]
  • R 5c is an optionally substituted imidazolyl group which may be substituted at the 2-position, 4-position and 5-position, and other symbols are as defined above. .
  • Examples of the “leaving group” represented by Ue include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • R 5c is preferably 2-methyl-1H-imidazol-1-yl, 2-methyl-1H-benzimidazol-1-yl, 2- (trifluoromethyl) -1H-benzimidazol-1-yl, or the like.
  • compound (XXII) can be produced by reacting compound (VI-2) with compound (IV). This reaction is carried out according to the above-mentioned Method A, Step 2.
  • the compound (VI-2) used as a starting compound in the above-mentioned method J can be produced according to a method known per se, for example, the above-mentioned method C or a method analogous thereto.
  • Compound (X-2) can also be produced according to a method known per se, a method Q described later or a method analogous thereto, or a method described in Reference Example 28.
  • Compound (I-7), which is R 107 and R 108 as described later, can be produced, for example, by the following K method. [K method]
  • R 107 represents an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc.
  • R 108 represents an optionally substituted alkyl group, etc.
  • Uf represents a leaving group.
  • R 107 is preferably methyl, trifluoromethyl, ethyl, phenyl, 2-pyridyl and the like.
  • R 108 is preferably methyl, ethyl, n-butyl, 2-fluoroethyl, 2-pyridylmethyl, 2- (1H-1,2,4-triazol-1-yl) ethyl and the like.
  • Examples of the “leaving group” represented by Uf include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • compound (XXV) can be produced by reacting compound (XXIV) with benzyl alcohol. This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • the amount of benzyl alcohol to be used is preferably about 1 to about 5 mol per 1 mol of compound (XXIV).
  • Examples of the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline and 4-dimethylaminopyridine; alkali metals such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate Salt; Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline earth metal such as magnesium hydroxide, calcium hydroxide and barium hydroxide; Metal such as potassium hydride and sodium hydride Hydrides; and alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • alkali metals such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate Salt
  • Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide
  • Alkaline earth metal such as magnesium hydroxide, calcium hydroxide and barium hydroxide
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (XXIV).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 40 hours.
  • compound (XXVII) can be produced from compound (XXVI) and compound (IX-3). This reaction is carried out according to the above-mentioned Method F, Step 2.
  • compound (I-5) can be produced from compound (III-3) and compound (IV). This reaction is carried out according to the above-mentioned Method A, Step 2.
  • compound (I-6) can be produced from compound (I-5). This reaction is carried out according to Step 1 of Method A above.
  • compound (I-7) can be produced from compound (I-6) and compound (XXVIII).
  • This reaction is carried out by a method known per se, for example, the method described in Synthesis page 1 (1981) or a method analogous thereto. That is, this reaction is usually performed in the presence of an organic phosphorus compound and an electrophilic agent in a solvent that does not adversely influence the reaction.
  • the organic phosphorus compound include triphenylphosphine and tributylphosphine.
  • the electrophilic agent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azodicarbonyldipiperidine, and the like.
  • the amount of the organophosphorus compound and electrophilic agent used is preferably about 1 to about 5 mol per 1 mol of compound (I-6).
  • the amount of compound (XXVIII) to be used is preferably about 1 to about 5 mol per 1 mol of compound (I-6).
  • the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • the compound (IX-3) used as a raw material compound in the above-mentioned method K can be produced, for example, according to the above-mentioned method C or a method analogous thereto.
  • Compound (XXIV) and compound (XXVIII) can be produced according to a method known per se.
  • R 109 and R 110 are each independently an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., Ug is a leaving group, and other symbols are those described above. Is equivalent to ] R 109 and R 110 are preferably each independently methyl, trifluoromethyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • Examples of the “leaving group” represented by Ug include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • compound (XXX) can be produced by reacting compound (XXIX) with compound (XXI). This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction.
  • a base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • Alkali metal salts such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; potassium hydride and sodium hydride Metal hydrides such as alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (XXIX).
  • the amount of compound (XXI) to be used is preferably about 0.3 to about 3 mol per 1 mol of compound (XXIX).
  • Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (II-11) can be produced by reacting compound (XXX) with compound (XXXI). This reaction is performed in a solvent that does not adversely influence the reaction.
  • the amount of compound (XXXI) to be used is preferably about 1 to about 3 mol per 1 mol of compound (XXX).
  • the solvent that does not adversely influence the reaction include alkanoic acids such as acetic acid and propionic acid; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; benzene, toluene and xylene.
  • Aromatic hydrocarbons Amides such as N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Alcohols such as methanol and ethanol. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Compound (II-13) which is R 111 , R 113 and R 114 as described later can be produced, for example, by the following Method M. [M method]
  • R 111 and R 113 are each independently an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., and R 112 and R 114 are each independently alkyl.
  • Group, Uh is a leaving group, and other symbols are as defined above.
  • R 111 is preferably methyl, trifluoromethyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • R 113 is preferably methyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • R 112 and R 114 are preferably each independently methyl, ethyl or the like.
  • Examples of the “leaving group” represented by Uh include a chlorine atom, a bromine atom, an iodine atom, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.
  • compound (XXXIII) can be produced by reacting compound (XXXII) with compound (IX-2). This reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction. Alkali metal halide salts may also be added.
  • the base include amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • Alkali metal salts such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; potassium hydride and sodium hydride Metal hydrides such as alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
  • the amount of the base to be used is preferably about 1 to about 5 mol per 1 mol of compound (XXXII).
  • the amount of compound (IX-2) to be used is preferably about 0.2 to about 5 mol per 1 mol of compound (XXXII).
  • alkali metal halide salt examples include lithium chloride, lithium bromide, sodium bromide, sodium iodide, potassium iodide and the like.
  • the amount of the alkali metal halide salt to be used is preferably 0.2 to 5 mol per 1 mol of compound (XXXII).
  • the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 40 hours.
  • compound (II-12) can be produced from compound (XXXIII) and compound (XXXI-2). This reaction is carried out according to the above-mentioned Method L, Step 2.
  • step 3 In this method, compound (II-13) can be produced from compound (II-12) and compound (XXXIV). This reaction is carried out according to the above step 1.
  • the compound (XXXII), the compound (XXXI-2), and the compound (XXXIV) used as starting compounds in the above Method M can be produced according to a method known per se.
  • R 115 , R 117 and R 118 are each independently a hydrogen atom or an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., and R 116 is a hydrogen atom. , Alkyl group, and other symbols are as defined above.
  • R 115 is preferably methyl, trifluoromethyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • R 116 is preferably a hydrogen atom, methyl, ethyl or the like.
  • R 117 and R 118 are preferably each independently a hydrogen atom, methyl, ethyl, cyclopropylmethyl, phenyl, 2-pyridyl or the like.
  • compound (II-15) can be produced from compound (II-14) by using a reducing agent.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • the reducing agent include metal hydride compounds such as sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride; sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride and the like.
  • the amount of the reducing agent to be used is generally 1 to 20 mol per 1 mol of compound (II-14).
  • Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol and tert-butanol; aromatic hydrocarbons such as benzene, toluene and xylene; hexane, Aliphatic hydrocarbons such as heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone Amides such as; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature
  • compound (III-4) can be produced from compound (II-15). This reaction is carried out according to Step 1 of Method A above.
  • compound (I-8) can be produced from compound (III-4) and compound (IV). This reaction is carried out according to the above-mentioned Method A, Step 2.
  • compound (I-9) can be produced by reacting compound (I-8) with alkyl isocyanate, cycloalkyl isocyanate, aryl isocyanate, or heteroaryl isocyanate.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • alkyl isocyanate, cycloalkyl isocyanate, aryl isocyanate, or heteroaryl isocyanate (which may each be substituted) include, for example, ethyl isocyanate, cyclopropyl isocyanate, phenyl isocyanate, 2-isocyanate And pyridyl.
  • the amount of alkyl isocyanate, aryl isocyanate, cycloalkyl isocyanate or heteroaryl isocyanate to be used is generally 1 to 5 mol per 1 mol of compound (I-8).
  • the solvent that does not adversely influence the reaction include pyridines such as pyridine and lutidine; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, ethers such as tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; dichloromethane, chloroform, 1,2-dichloroethane, And halogenated hydrocarbons such as 1,1,2,2-t
  • N, N′-carbonyldiimidazole and compound (I-8) are reacted and then reacted with a primary or secondary amine to produce compound (I-9). You can also.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • the amount of N, N′-carbonyldiimidazole to be used is generally 1 to 3 mol per 1 mol of compound (I-8).
  • Examples of the primary or secondary amine include cyclopropylmethylamine and diethylamine.
  • the amount of the primary or secondary amine to be used is generally 1 to 5 mol per 1 mol of compound (I-8).
  • Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane and dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; Dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2- And halogenated hydrocarbons such as tetrachloroethane. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 70 to 150 ° C., preferably ⁇ 20 to 100 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.
  • Compound (II-14) used as a starting compound in Method N can be produced, for example, according to the aforementioned Method C, Method F, Method G, Method H, or a method analogous thereto.
  • a 1 is O
  • a 2 is CH 2
  • R 1 is a hydrogen atom
  • R 5 is
  • R 119 represents a hydrogen atom or an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc.
  • R 120 represents an alkyl group, etc., and other symbols are as defined above. Indicates.
  • R 119 is preferably methyl, trifluoromethyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • R 120 is preferably methyl, ethyl or the like.
  • compound (I-11) can be produced by subjecting compound (I-10) to a hydrolysis reaction. This reaction is carried out according to the above-mentioned method B.
  • Compound (I-10) used as a starting compound in Method O can be produced, for example, according to the aforementioned Method A, Method B, Method J, Method K, Method N, or a method analogous thereto.
  • Compound (I-14) which is (R 121 , R 122 and R 123 are as described later) can be produced, for example, by the following method P. [P method]
  • R 121 , R 122 and R 123 are each independently an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., Xe is a halogen atom, and other symbols are The meaning is the same as above.
  • R 121 and R 122 are preferably each independently methyl, trifluoromethyl, ethyl, cyclopropyl, phenyl, 2-pyridyl and the like.
  • R 123 is preferably methyl, cyclopropyl, phenyl, 4-fluorophenyl, 2-furyl, 2-thienyl and the like.
  • Step 2 In this step, arylboric acid, heteroarylboric acid, cycloalkylboric acid or alkylboric acid (which may be each substituted) is coupled to compound (I-13) in the presence of a transition metal catalyst and a base.
  • compound (I-14) can be produced.
  • This reaction is performed in a solvent that does not adversely influence the reaction under an inert gas atmosphere according to a conventional method.
  • the inert gas include argon and nitrogen.
  • transition metal catalyst examples include tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (2) dichloride, tris (dibenzylideneacetone) 2palladium (0). And a mixture of 4 molar equivalents of 2- (dicyclohexylphosphino) -2 ′, 6′-dimethoxybiphenyl.
  • the amount of the transition metal catalyst to be used is generally 0.001 to 2 mol, preferably 0.01 to 0.1 mol, per 1 mol of compound (I-13).
  • the base examples include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Amines such as undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal C 1-6 alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Carboxylates such as potassium acetate, sodium acetate and sodium formate; alkali metal fluorides such as potassium fluoride and sodium fluoride; The amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (I-13).
  • alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate
  • pyridine triethy
  • Examples of the aryl boric acid include phenyl boric acid and 4-fluorophenyl boric acid.
  • Examples of the heteroaryl boric acid include 2-furyl boric acid and 2-thienyl boric acid.
  • Examples of the cycloalkyl boric acid include cyclopropyl boric acid.
  • examples of the alkyl boric acid include methyl boric acid.
  • the amount of the arylboric acid, heteroarylboric acid, cycloalkylboric acid or alkylboric acid to be used is generally 1-10 mol, preferably 1-3 mol, per 1 mol of compound (I-13).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; Acetonitrile, etc. Nitriles; sulfoxides such as dimethyl sulfoxide; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about 0 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Compound (I-12) used as a raw material compound in Method P can be produced, for example, according to the aforementioned Method A, Method B, Method J, or a method analogous thereto.
  • Compound (X-4) which is a raw material of compound (I) can be produced, for example, by the following method Q. [Q method]
  • R 124 and R 125 each independently represent a hydrogen atom or an optionally substituted alkyl group, cycloalkyl group, aryl group, heteroaryl group, etc., and Xf represents a halogen atom.
  • R 124 and R 125 are preferably each independently a hydrogen atom, methyl, ethyl, phenyl, 2-pyridyl, trifluoromethyl, cyclopropyl or the like.
  • compound (X-4) can be produced from compound (X-3). This reaction is carried out according to the above-mentioned Method D, Step 1.
  • the compound (X-3) used as a raw material compound in the above Q method can be produced according to a method known per se.
  • Compound (I-17) which is (R 126 is as described later) can be produced, for example, by the following R method. [R method]
  • R 126 represents an alkyl group, an aryl group or the like, and other symbols are as defined above.
  • R 126 is preferably methyl, ethyl, phenyl or the like.
  • compound (I-16) can be produced by reacting compound (I-15) with an organometallic reagent.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • the organometallic reagent include methyl magnesium chloride, ethyl magnesium bromide, phenyl lithium and the like.
  • the amount of the organometallic reagent to be used is generally 1-50 mol, preferably 1-5 mol, per 1 mol of compound (I-15).
  • Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Examples include ethers such as dioxane and dimethoxyethane; halogenated hydrocarbons such as chloroform and dichloromethane. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 100 to about 150 ° C., preferably about ⁇ 80 to about 40 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Compound (I-19) can be produced, for example, by the following Method S. [S method]
  • Ui represents a leaving group, and other symbols are as defined above.
  • Examples of the “leaving group” represented by Ui include chlorine atom, bromine atom, iodine atom, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • compound (I-19) can be produced by reacting compound (I-18) with an alkali metal cyanide.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • an additive may be added.
  • the alkali metal cyanide include potassium cyanide and sodium cyanide.
  • the amount of the alkali metal cyanide to be used is preferably 1 to 5 mol per 1 mol of compound (I-18).
  • Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Nitriles; Amides such as N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide and the like. These solvents may be mixed and used at an appropriate ratio.
  • Examples of the additive include crown ethers such as 18-crown-6.
  • the amount of the additive to be used is preferably 0.1 to 2 mol per 1 mol of compound (I-18).
  • the reaction temperature is generally about ⁇ 100 to about 150 ° C., preferably about ⁇ 80 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • Compound (I) can also be produced, for example, by the following T method. [T method]
  • compound (I-20) can be produced from compound (XXXV).
  • This reaction is carried out using a method known per se, for example, a method of allowing an oxidizing agent to act.
  • the reaction is carried out in a solvent that does not adversely influence the reaction.
  • the oxidizing agent include Jones reagent, potassium dichromate, pyridinium dichromate, and the like.
  • the amount of the oxidizing agent to be used is generally 1 to 20 mol, preferably 1 to 6 mol, per 1 mol of compound (XXXV).
  • the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide; ketones such as acetone; water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually about ⁇ 40 to about 150 ° C., preferably about ⁇ 10 to about 50 ° C.
  • the reaction time is usually about 0.5 to about 20 hours.
  • compound (I) can be produced by reacting compound (I-20) with compound (XXXVI).
  • This reaction may be carried out in the presence of an acid in a solvent that does not adversely influence the reaction.
  • the acid include mineral acids such as hydrochloric acid and sulfuric acid; organic acids such as trifluoroacetic acid and p-toluenesulfonic acid.
  • the amount of the acid to be used is preferably about 0.01 to about 50 mol per 1 mol of compound (I-20).
  • compound (XXXVI) include methanol, ethanol and the like.
  • the amount of compound (XXXVI) to be used is generally about 1-about 1000 mol, preferably about 1-about 100 mol, per 1 mol of compound (I-20).
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Ketones such as acetone and 2-butanone; Water and the like. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is generally about ⁇ 80 to about 150 ° C., preferably about ⁇ 10 to about 100 ° C.
  • the reaction time is usually about 0.5 to about 40 hours.
  • the compound (XXXV) used as a raw material compound in the T method is, for example, a method known per se, or the above-described A method, C method, D method, E method, F method, G method, H method, I method, It can be produced according to a method according to the J method, K method, L method, M method, N method, O method, P method, R method, and S method.
  • Compound (XXXVI) can be produced according to a method known per se.
  • a protective group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C 7-10 aralkyl-carbonyl group eg, benzylcarbonyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • the method for removing the protecting group described above can be carried out according to a method known per se, for example, the method described in Protective Group in Organic Synthesis, published by John Wiley and Sons (1980), etc. . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.
  • a method known per se for example, the method described in Protective Group in Organic Synthesis, published by John Wiley and Sons (1980), etc. .
  • the compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like.
  • each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above.
  • a commercially available product can be used as it is.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and they are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product.
  • compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
  • the room temperature means a temperature of 1 to 30 ° C. unless otherwise specified.
  • Reference Example 5 1- [5- (Benzyloxy) -2,4-dichlorobenzyl] -5-iodo-2,4-dimethyl-1H-imidazole Obtained in Reference Example 1 cooled to 0 ° C. in an ice bath. While stirring a solution of 4-iodo-2,5-dimethyl-1H-imidazole (1.75 g, 7.88 mmol) in N, N-dimethylformamide (10 mL), 60% sodium hydride (315 mg, 7.88 mmol) was added. added. The ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours and then cooled again to 0 ° C. with an ice bath.
  • the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred at room temperature for 10 min. After removing the precipitate by filtration, the two layers were separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was purified with a preparative HPLC apparatus under the conditions shown below, and crystallized from hexane-ethyl acetate to give the title compound (190 mg, yield 31%) as pale brown crystals.
  • Reference Example 17 1- [5- (Benzyloxy) -2,4-dichlorobenzyl] -5-bromo-2,4-dimethyl-1H-imidazole 5- (benzyloxy) -2 chloride obtained in Reference Example 4 , 4-dichlorobenzyl and 4-bromo-2,5-dimethyl-1H-imidazole hydrochloride obtained in Reference Example 15 were used to obtain the title compound in the same manner as in Reference Example 10.
  • Reference Example 29 1- [5- (Benzyloxy) -2,4-dichlorobenzyl] -2-methyl-4-phenyl-1H-imidazole 5- (benzyloxy) -2,4 chloride obtained in Reference Example 4
  • the title compound was obtained from 2-dichlorobenzyl and 2-methyl-4-phenyl-1H-imidazole hydrochloride obtained in Reference Example 28 in the same manner as in Reference Example 5.
  • Reference Example 44 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-b] pyridin-1-yl) methyl] phenol N- (2-nitropyridin-3-yl) acetamide and From 1- (benzyloxy) -2,4-dichloro-5-[(methanesulfonyloxy) methyl] benzene obtained in Reference Example 43, a method similar to Reference Example 40, Reference Example 41, and Reference Example 42 was used. The title compound was obtained.
  • Reference Example 45 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-c] pyridin-1-yl) methyl] phenol N- (3-nitropyridin-4-yl) acetamide and From 1- (benzyloxy) -2,4-dichloro-5-[(methanesulfonyloxy) methyl] benzene obtained in Reference Example 43, a method similar to Reference Example 40, Reference Example 41, and Reference Example 42 was used. The title compound was obtained.
  • reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A pale yellow solid was obtained. This was recrystallized from hexane-tetrahydrofuran to give the title compound (144 mg, yield 91%) as colorless crystals.
  • the reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 95: 5-40: 60, v / v) to give the title compound (4.31 g, yield 32%) as a pale yellow solid. Recrystallization from hexane-ethyl acetate gave pale brown crystals.
  • Methylhydrazine (0.92 5 mL, 34.9 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 2 hours and at 80 ° C. for 3 hours.
  • methylhydrazine (0.595 mL, 22.5 mmol) was added to a solution of the yellow solid (2.51 g) obtained above in acetic acid (20 mL), and the mixture was stirred at room temperature for 24 hours.
  • Methylhydrazine (0.595 mL, 22.5 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 2 hours and at 80 ° C. for 3 hours.
  • the two reaction liquids were mixed and concentrated under reduced pressure.
  • Reference Example 82 4- [5- (Benzyloxy) -2,4-dichlorobenzyl] -5-methoxy-1-methyl-3- (trifluoromethyl) -1H-pyrazole 4- [5] obtained in Reference Example 81 5- (Benzyloxy) -2,4-dichlorobenzyl] -1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol (1.92 g, 4.45 mmol), potassium carbonate (900 mg, 6.51 mmol) ), Methyl iodide (0.350 mL, 5.42 mmol) and N, N-dimethylformamide (10 mL) were stirred at room temperature for 12 hours.
  • Reference Example 96 1- ⁇ 2,4-Dichloro-5-[(4-methoxybenzyl) oxy] benzyl ⁇ -2,6-bis (trifluoromethyl) -1H-benzimidazole
  • Reference Example 97 1- ⁇ 2,4 -Dichloro-5-[(4-methoxybenzyl) oxy] benzyl ⁇ -2-methyl-6- (trifluoromethyl) -1H-benzimidazole N- ⁇ 2,4-dichloro-5 obtained in Reference Example 95 -[(4-Methoxybenzyl) oxy] benzyl ⁇ -2,2,2-trifluoro-N- [2-nitro-5- (trifluoromethyl) phenyl] acetamide (1.93 g, 3.23 mmol) and acetic acid (4.4 mL) in ethanol (20 mL) was added reduced iron (1.80 g, 32.3 mmol), and the suspension was stirred at 80 ° C.
  • Example 2 (2S) -2- ⁇ 2,4-Dichloro-5-[(4-chloro-2,5-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Reference Example 12 2,4-dichloro-5-[(4-chloro-2,5-dimethyl-1H-imidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4 The title compound was obtained from methyl-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 3 (2S) -2- ⁇ 2,4-Dichloro-5-[(5-chloro-2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Reference Example 11 2,4-dichloro-5-[(5-chloro-2,4-dimethyl-1H-imidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4 The title compound was obtained from methyl-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 5 (2S) -2- ⁇ 5-[(4-Bromo-2,5-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ propanoic acid obtained in Reference Example 18 5-[(4-Bromo-2,5-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenol and (2R) -2- ⁇ [(4 The title compound was obtained from methyl-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 6 (2S) -2- ⁇ 5-[(5-Bromo-2,4-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ propanoic acid obtained in Reference Example 19 5-[(5-Bromo-2,4-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenol and (2R) -2- ⁇ [(4 The title compound was obtained from methyl-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 8 (2S) -2- ⁇ 2,4-Dichloro-5-[(5-iodo-2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 7 (2S) -2- ⁇ 2,4-Dichloro-5-[(2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoate methyl (800 mg, 2.24 mmol) in acetonitrile (20 To the solution, N-iodosuccinimide (504 mg, 2.24 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours and at room temperature for 40 hours.
  • Example 9 (2S) -2- ⁇ 2,4-Dichloro-5-[(2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid (2S) obtained in Example 7 -2- ⁇ 2,4-dichloro-5-[(2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate (500 mg) in tetrahydrofuran (7 mL) and water (3 mL ) And was cooled to 0 ° C. Lithium hydroxide monohydrate (117 mg) was added, and the mixture was stirred at 0 ° C. for 2 hr.
  • Example 10 (2S) -2- ⁇ 5-[(5-Bromo-2,4-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ methyl propanoate Obtained in Example 7 (2S) -2- ⁇ 2,4-dichloro-5-[(2,4-dimethyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl ester (300 mg, 0.840 mmol) in acetonitrile ( 10 mL) solution was added N-bromosuccinimide (149 mg, 0.840 mmol) at 0 ° C. and stirred at 0 ° C. for 2 hours.
  • N-bromosuccinimide 149 mg, 0.840 mmol
  • Example 11 (2S) -2- (2,4-Dichloro-5- ⁇ [5- (4-fluorophenyl) -2,4-dimethyl-1H-imidazol-1-yl] methyl ⁇ phenoxy) propanoic acid tri Fluoroacetate (2S) -2- ⁇ 5-[(5-Bromo-2,4-dimethyl-1H-imidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ propane obtained in Example 10 A mixture of methyl acid (322 mg, 0.738 mmol), 4-fluorophenylboronic acid (108 mg, 0.775 mmol), potassium carbonate (321 mg, 2.33 mmol), and toluene (15 mL) under an argon atmosphere at room temperature For 0.5 hour.
  • Example 12 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate
  • Reference Example 23 2,4-dichloro-5- ⁇ [2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenol obtained in 1) and (2R) -2 obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 7 from methyl ⁇ -([(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 13 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 12 Obtained methyl (2S) -2- (2,4-dichloro-5- ⁇ [2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenoxy) propanoate (600 mg , 1.46 mmol) was dissolved in a mixed solvent of tetrahydrofuran (7 mL) and water (3 mL) and cooled to 0 ° C.
  • Example 14 (2S) -2- (2,4-Dichloro-5- ⁇ [5-chloro-2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • the title compound was obtained from methyl and N-chlorosuccinimide in the same manner as in Example 8.
  • Example 15 (2S) -2- (2,4-Dichloro-5- ⁇ [5-cyano-2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenoxy) propanoic acid 2,4-Dichloro-5- ⁇ [5-cyano-2-methyl-4- (trifluoromethyl) -1H-imidazol-1-yl] methyl ⁇ phenol obtained in Reference Example 27 and obtained in Reference Example 24 The title compound was obtained in the same manner as in Example 1 from the obtained methyl (2R) -2- ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 16 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate Obtained in Reference Example 30 2,2-Dichloro-5-[(2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4-methylphenyl) obtained in Reference Example 24 The title compound was obtained from methyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 7.
  • Example 17 (2S) -2- ⁇ 2,4-Dichloro-5-[(5-chloro-2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid
  • Example 16 The resulting methyl (2S) -2- ⁇ 2,4-dichloro-5-[(2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoate and N-chlorosuccinimide
  • the title compound was obtained in the same manner as in Example 8.
  • Example 18 (2S) -2- ⁇ 2,4-dichloro-5-[(5-cyano-2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid
  • Reference Example 33 The obtained 2,4-dichloro-5-[(5-cyano-2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenol and (2R) -2-
  • the title compound was obtained from methyl ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 19 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 16 ( 2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-4-phenyl-1H-imidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate in the same manner as in Example 13, The title compound was obtained.
  • Example 20 (2S) -2- ⁇ 2,4-Dichloro-5-[(1,3,5-trimethyl-1H-pyrazol-4-yl) methyl] phenoxy ⁇ propanoic acid 2 obtained in Reference Example 36 , 4-Dichloro-5-[(1,3,5-trimethyl-1H-pyrazol-4-yl) methyl] phenol and (2R) -2- ⁇ [(4-methylphenyl) phenol obtained in Reference Example 24 The title compound was obtained from methyl sulfonyl] oxy ⁇ propanoate in the same manner as in Example 1.
  • Example 23 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-b] pyridin-1-yl) methyl] phenoxy ⁇ methyl propanoate
  • Reference Example 44 2,4-dichloro-5-[(2-methyl-1H-imidazo [4,5-b] pyridin-1-yl) methyl] phenol obtained in 1) and (2R) -2 obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 7 from methyl ⁇ -([(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 24 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-b] pyridin-1-yl) methyl] phenoxy ⁇ propanoic acid
  • Example 23 Performed from the obtained methyl (2S) -2- ⁇ 2,4-dichloro-5-[(2-methyl-1H-imidazo [4,5-b] pyridin-1-yl) methyl] phenoxy ⁇ propanoate In the same manner as in Example 13, the title compound was obtained.
  • Example 25 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-c] pyridin-1-yl) methyl] phenoxy ⁇ methyl propanoate
  • Reference Example 45 2,4-dichloro-5-[(2-methyl-1H-imidazo [4,5-c] pyridin-1-yl) methyl] phenol obtained in 1) and (2R) -2 obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 7 from methyl ⁇ -([(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 26 (2S) -2- ⁇ 2,4-Dichloro-5-[(2-methyl-1H-imidazo [4,5-c] pyridin-1-yl) methyl] phenoxy ⁇ propanoic acid
  • Example 25 Performed from the resulting methyl (2S) -2- ⁇ 2,4-dichloro-5-[(2-methyl-1H-imidazo [4,5-c] pyridin-1-yl) methyl] phenoxy ⁇ propanoate In the same manner as in Example 13, the title compound was obtained.
  • Example 28 (2S) -1- ⁇ 5-[(1S) -2-tert-butoxy-1-methyl-2-oxoethoxy] -2,4-dichlorobenzyl ⁇ -2-methyl-1H-benzimidazole- Methyl 5-carboxylate Obtained in methyl 1- (2,4-dichloro-5-hydroxybenzyl) -2-methyl-1H-benzimidazole-5-carboxylate obtained in Reference Example 48 and Reference Example 49 ( The title compound was obtained in the same manner as in Example 7 from tert-butyl 2R) -2- ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 29 (2S) -2- (2,4-Dichloro-5- ⁇ [5- (methoxycarbonyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 28 The obtained (2S) -1- ⁇ 5-[(1S) -2-tert-butoxy-1-methyl-2-oxoethoxy] -2,4-dichlorobenzyl ⁇ -2-methyl-1H-benzimidazole-
  • a mixture of methyl 5-carboxylate (78 mg, 0.16 mmol) and trifluoroacetic acid (0.1 mL) was stirred at 50 ° C. for 2 hours.
  • Example 30 1- ⁇ 5-[(1S) -1-carboxyethoxy] -2,4-dichlorobenzyl ⁇ -2-methyl-1H-benzimidazole-5-carboxylic acid (2S) obtained in Example 29 2- (2,4-Dichloro-5- ⁇ [5- (methoxycarbonyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid in the same manner as in Example 13. The title compound was obtained.
  • Example 31 1- ⁇ 5-[(1S) -2-tert-butoxy-1-methyl-2-oxoethoxy] -2,4-dichlorobenzyl ⁇ -2-methyl-1H-benzimidazole-6-carboxylic acid Methyl 1- (2,4-dichloro-5-hydroxybenzyl) -2-methyl-1H-benzimidazole-6-carboxylate obtained in Reference Example 52 and (2R) -2 obtained in Reference Example 49 The title compound was obtained in the same manner as in Example 7 from tert-butyl- ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 32 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (methoxycarbonyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 31 1- ⁇ 5-[(1S) -2-tert-butoxy-1-methyl-2-oxoethoxy] -2,4-dichlorobenzyl ⁇ -2-methyl-1H-benzimidazole-6-carboxylic acid obtained The title compound was obtained from methyl in the same manner as in Example 29.
  • Example 33 (2S) -2- ⁇ 2,4-Dichloro-5-[(5-methoxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Reference Example 53 2,2-Dichloro-5-[(5-methoxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4-methyl The title compound was obtained in the same manner as in Example 1 from methyl phenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 34 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-methoxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Reference Example 54 2,2-Dichloro-5-[(6-methoxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4-methyl The title compound was obtained in the same manner as in Example 1 from methyl phenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 35 (2S) -2- ⁇ 2,4-Dichloro-5-[(5-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Reference Example 60 2,2-Dichloro-5-[(5-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4-methyl The title compound was obtained in the same manner as in Example 1 from methyl phenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 36 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate Obtained in Reference Example 61 2,4-dichloro-5-[(6-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4- The title compound was obtained in the same manner as in Example 7 from methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 37 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 36 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-cyano-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl method similar to Example 13 Gave the title compound.
  • Example 41 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (hydroxymethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate
  • Reference Example 70 ⁇ 1- (2,4-dichloro-5-hydroxybenzyl) -2-methyl-1H-benzimidazol-6-yl ⁇ methanol obtained in 1) and (2R) -2- ⁇ [ The title compound was obtained as colorless crystals from methyl (4-methylphenyl) sulfonyl] oxy ⁇ propanoate in the same manner as in Example 7.
  • Example 43 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (hydroxymethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 41 Obtained methyl (2S) -2- (2,4-dichloro-5- ⁇ [6- (hydroxymethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoate (500 mg , 1.18 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL) and cooled to 0 ° C.
  • Example 44 (2S) -2- ⁇ 2,4-Dichloro-5-[(6- ⁇ [(ethylcarbamoyl) oxy] methyl ⁇ -2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇
  • Propanoic acid (2S) -2- ⁇ 2,4-dichloro-5-[(6- ⁇ [(ethylcarbamoyl) oxy] methyl ⁇ -2-methyl-1H-benzimidazole-1- obtained in Example 42
  • the title compound was obtained as colorless crystals from methyl yl) methyl] phenoxy ⁇ propanoate.
  • Example 46 (2S) -2- (2,4-Dichloro-5- ⁇ [(6-benzyloxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate
  • Reference Example 77 2,4-dichloro-5- ⁇ [6- (benzyloxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenol obtained in 1) and (2R) -2 obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 7 from methyl ⁇ -([(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 47 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate Obtained in Example 46 (2S) -2- (2,4-Dichloro-5- ⁇ [(6-benzyloxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate (11.4 g, 22.8 mmol), water-containing 10% palladium carbon (5.00 g), and ethanol (300 mL) were stirred under a hydrogen atmosphere for 6 hours.
  • Example 48 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-ethoxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 47 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate (180 mg, 0.440 mmol), ethanol (203 mg, 4.40 mmol), tri-n-butylphosphine (258 mg, 1.28 mmol), and tetrahydrofuran (10 mL) were added to 1,1 '-(azodicarbonyl) dipiperidine (333 mg, 1.32 mmol).
  • Example 50 (2S) -2- ⁇ 2,4-Dichloro-5-[(1,3,5-trimethyl-1H-pyrazol-4-yl) oxy] phenoxy ⁇ propanoic acid obtained in Example 49 ( 2S) -2- ⁇ 2,4-Dichloro-5-[(1,3,5-trimethyl-1H-pyrazol-4-yl) oxy] phenoxy ⁇ propanoic acid methyl ester in the same manner as in Example 13, The title compound was obtained.
  • Example 52 (2S) -2- (2,4-Dichloro-5- ⁇ [5-methoxy-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl ⁇ phenoxy) propanoic acid (2S) -2- (2,4-Dichloro-5- ⁇ [5-methoxy-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl ⁇ obtained in Example 51 The title compound was obtained from methyl phenoxy) propanoate in the same manner as in Example 13.
  • Example 54 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-fluoro-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 53 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-fluoro-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl method similar to Example 13 Gave the title compound.
  • Example 55 (2S) -2- [2,4-dichloro-5-( ⁇ 2-methyl-6- [2- (1H-1,2,4-triazol-1-yl) ethoxy] -1H-benz (Imidazol-1-yl ⁇ methyl) phenoxy] propanoic acid (2S) -2- ⁇ 2,4-dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazole-1) obtained in Example 47 The title compound was obtained in the same manner as in Example 48 from -yl) methyl] phenoxy ⁇ propanoate methyl and 2- (1H-1,2,4-triazol-1-yl) ethanol.
  • Example 56 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (2-fluoroethoxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid (2S) -2- ⁇ 2,4-dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl and 2-fluoro obtained in 47
  • the title compound was obtained from ethanol in the same manner as in Example 48.
  • Example 57 (2S) -2- (5- ⁇ [6- (Benzyloxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) propanoic acid
  • Example 46 Performed from the resulting methyl (2S) -2- (2,4-dichloro-5- ⁇ [(6-benzyloxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoate In the same manner as in Example 13, the title compound was obtained.
  • Example 58 (2S) -2- ⁇ 2,4-Dichloro-5-[(2,6-dimethyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ methyl propanoate 2 obtained in Reference Example 84 , 4-Dichloro-5-[(2,6-dimethyl-1H-benzimidazol-1-yl) methyl] phenol and (2R) -2- ⁇ [(4-methylphenyl) sulfonyl obtained in Reference Example 24 The title compound was obtained from methyl oxy ⁇ propanoate in the same manner as in Example 7.
  • Example 59 (2S) -2- ⁇ 2,4-Dichloro-5-[(2,6-dimethyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 58 (2S ) -2- ⁇ 2,4-dichloro-5-[(2,6-dimethyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl ester in the same manner as in Example 13 Got.
  • Example 60 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (cyclopropylmethoxy) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 47 (2S) -2- ⁇ 2,4-Dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid methyl and cyclopropylmethyl alcohol obtained in Thus, the title compound was obtained in the same manner as in Example 48.
  • Example 62 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (1,3-thiazol-2-ylmethoxy) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy )
  • Propanoic acid (2S) -2- ⁇ 2,4-dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoic acid obtained in Example 47
  • the title compound was obtained in the same manner as in Example 48 from methyl and (1,3-thiazol-2-yl) methanol.
  • Example 64 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (pyridin-2-ylmethoxy) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid Methyl (2S) -2- ⁇ 2,4-dichloro-5-[(6-hydroxy-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoate obtained in Example 47 and 2- The title compound was obtained from pyridylmethanol in the same manner as in Example 48.
  • Example 66 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (1-hydroxyethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate Methyl (2S) -2- ⁇ 2,4-dichloro-5-[(6-formyl-2-methyl-1H-benzimidazol-1-yl) methyl] phenoxy ⁇ propanoate obtained in Example 65 (500 mg , 1.19 mmol) in tetrahydrofuran (10 mL) was cooled to ⁇ 78 ° C. in a dry ice acetone bath.
  • methylmagnesium bromide (3 mol / L ethyl ether solution, 0.43 mL) was added, and the reaction mixture was stirred at ⁇ 78 ° C. for 1.5 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated.
  • Example 68 (2S) -2- ⁇ 5-[(6-Acetyl-2-methyl-1H-benzimidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ propanoic acid obtained in Example 67 (2S) -2- ⁇ 5-[(6-Acetyl-2-methyl-1H-benzimidazol-1-yl) methyl] -2,4-dichlorophenoxy ⁇ propanoate in the same manner as in Example 13. The title compound was obtained.
  • This mixture (500 mg) was dissolved in dimethyl sulfoxide (5 mL), 18-crown-6 (130 mg, 0.49 mmol) and potassium cyanide (130 mg, 2.00 mmol) were added, and the mixture was stirred at room temperature for 18 hours.
  • the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Example 70 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (cyanomethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid Obtained in Example 69
  • Example 2 from methyl (2S) -2- (2,4-dichloro-5- ⁇ [6- (cyanomethyl) -2-methyl-1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoate In the same manner as described above, the title compound was obtained as colorless crystals.
  • Example 71 (2S) -2- (2,4-Dichloro-5- ⁇ [6-cyano-2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Reference Example 89 1- (2,4-Dichloro-5-hydroxybenzyl) -2- (trifluoromethyl) -1H-benzimidazole-6-carbonitrile obtained in 1) and (2R) -2- obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 1 from methyl ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 72 (2S) -2- (5- ⁇ [6- (Benzyloxy) -2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) propanoic acid Methyl 5- ⁇ [6- (Benzyloxy) -2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenol obtained in Reference Example 93 and Reference Example 24 The title compound was obtained in the same manner as in Example 7 from the obtained methyl (2R) -2- ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 73 (2S) -2- (5- ⁇ [6- (Benzyloxy) -2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) propanoic acid (2S) -2- (5- ⁇ [6- (Benzyloxy) -2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichloro obtained in Example 72 The title compound was obtained from methyl phenoxy) propanoate in the same manner as in Example 13.
  • Example 75 (2S) -2- (2,4-Dichloro-5- ⁇ [6- (cyclopropylmethoxy) -2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propane Acid (2S) -2- (2,4-Dichloro-5- ⁇ [6-hydroxy-2- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) obtained in Example 74 The title compound was obtained in the same manner as in Example 48 from methyl propanoate and cyclopropanemethanol.
  • Example 76 (2S) -2- [2,4-dichloro-5-( ⁇ 6- [2- (1H-1,2,4-triazol-1-yl) ethoxy] -2- (trifluoromethyl) -1H-benzimidazol-1-yl ⁇ methyl) phenoxy] propanoic acid (2S) -2- (2,4-dichloro-5- ⁇ [6-hydroxy-2- (trifluoromethyl) obtained in Example 74 ) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate and 2- (1H-1,2,4-triazol-1-yl) ethanol in the same manner as in Example 48 and the title compound Got.
  • Example 77 Methyl (2S) -2- (5- ⁇ [2,6-bis (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) methyl propanoate
  • Reference Example 98 5- ⁇ [2,6-bis (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenol obtained in 1) and (2R) -2 obtained in Reference Example 24
  • the title compound was obtained in the same manner as in Example 7 from methyl ⁇ -([(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 78 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) methyl propanoate
  • the title compound was obtained from methyl -2- ⁇ [(4-methylphenyl) sulfonyl] oxy ⁇ propanoate.
  • Example 79 (2S) -2- (5- ⁇ [2,6-Bis (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) propanoic acid
  • Example 77 Performed from the obtained methyl (2S) -2- (5- ⁇ [2,6-bis (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ -2,4-dichlorophenoxy) propanoate In the same manner as in Example 13, the title compound was obtained.
  • Example 80 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy) propanoic acid
  • Example 78 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy)
  • Example 78 (2S) -2- (2,4-Dichloro-5- ⁇ [2-methyl-6- (trifluoromethyl) -1H-benzimidazol-1-yl] methyl ⁇ phenoxy
  • Test Example 1 (PPAR ⁇ -RXR ⁇ heterodimeric ligand activity) Ham F12 medium [Life Technologies, Inc.] containing 10% fetal bovine serum (Life Technologies, Inc., USA) containing PPAR ⁇ : RXR ⁇ : 4ERPP / CHO-K1 cells described in WO03 / 099793. Inc.), USA], and then seeded in a 96-well white half area plate [Corning Coster Corporation, USA] at 1 ⁇ 10 4 cells / well, and then carbonated at 37 ° C. Incubate overnight in gas incubator.
  • the induction ratio was calculated from the luciferase activity of each test compound when the luciferase activity of the test compound non-administered group was 1.
  • concentration of the test compound and the value of induction ratio using Prism (manufactured by GraphPad Software, Inc., USA)
  • EC 50 value of the test compound maximal induction ratio
  • Compound concentration showing 50% of the value was calculated. The results are shown in Table 1.
  • Examples 2 to 6, 8, 13, 14, 20, 21, 23, 25, 27, 29, 32 to 34, 36, 37, 40 to 42, 44, 48, 49, 53, 54, 56, 58-61, 65-68, 70, 71, 75, 76, 79 and 80 were subjected to the same test as in Test Example 1.
  • the EC 50 value was 1 nM to 1 ⁇ M. .
  • the compounds of the present invention were shown to have excellent PPAR ⁇ -RXR ⁇ heterodimeric ligand activity.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg 60mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 (Manufacture of tablets) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) Corn starch 15g 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1g 1000 tablets total 140g The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
  • the compound of the present invention is useful as a preventive or therapeutic agent for diabetes with few side effects such as weight gain, fat cell accumulation, cardiac hypertrophy.

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Abstract

L'invention porte sur un composé qui est utile comme agent prophylactique ou thérapeutique pour le diabète et ne provoque guère d'effet secondaire défavorable tel qu'une augmentation du poids corporel, une accumulation d'adipocytes et une hypertrophie du cœur. De façon spécifique, l'invention porte sur un composé représenté par la formule (I) [dans laquelle chaque symbole est tel que défini dans la description], un sel du composé, ou un promédicament du composé ou du sel, qui est utile comme agent prophylactique ou thérapeutique pour le diabète et ne provoque guère d'effet secondaire défavorable tel qu'une augmentation du poids corporel, une accumulation d'adipocytes et une hypertrophie du cœur.
PCT/JP2009/061887 2008-06-30 2009-06-29 Composé de benzène tétrasubstitué et son utilisation Ceased WO2010001869A1 (fr)

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JP2008-171784 2008-06-30
JP2008171784 2008-06-30
JP2008-193338 2008-07-28
JP2008193338 2008-07-28

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WO2010001869A1 true WO2010001869A1 (fr) 2010-01-07

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JP2015519381A (ja) * 2012-06-11 2015-07-09 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ−アルファ調節ベンゾイミダゾール
US20160039790A1 (en) * 2013-03-15 2016-02-11 Wenying Chai 1,2,6-substituted benzimidazoles as flap modulators
US20160355509A1 (en) * 2013-12-09 2016-12-08 Ucb Biopharma Sprl Imidazopyridine Derivatives as Modulators of TNF Activity
US9682972B2 (en) 2013-03-15 2017-06-20 Janssen Pharmaceutica Nv 1,2,5-substituted benzimidazoles as flap modulators
JP2018536015A (ja) * 2015-09-16 2018-12-06 メタクリン，インク． ファルネソイドｘ受容体アゴニストとその使用
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof

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JPH02193976A (ja) * 1988-11-21 1990-07-31 Monsanto Co ３―フェノキシピラゾール誘導体、その製造法およびその使用
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015519381A (ja) * 2012-06-11 2015-07-09 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ−アルファ調節ベンゾイミダゾール
US9682971B2 (en) 2013-03-15 2017-06-20 Janssen Pharmaceutica Nv 1,2,5-Substituted benzimidazoles as flap modulators
US20160039790A1 (en) * 2013-03-15 2016-02-11 Wenying Chai 1,2,6-substituted benzimidazoles as flap modulators
US9695149B2 (en) * 2013-03-15 2017-07-04 Janssen Pharmaceutica Nv 1,2,6-substituted benzimidazoles as flap modulators
US9682972B2 (en) 2013-03-15 2017-06-20 Janssen Pharmaceutica Nv 1,2,5-substituted benzimidazoles as flap modulators
JP2016539981A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリジン誘導体
US20160355509A1 (en) * 2013-12-09 2016-12-08 Ucb Biopharma Sprl Imidazopyridine Derivatives as Modulators of TNF Activity
US9890154B2 (en) * 2013-12-09 2018-02-13 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
JP2018536015A (ja) * 2015-09-16 2018-12-06 メタクリン，インク． ファルネソイドｘ受容体アゴニストとその使用
US11214538B2 (en) 2015-09-16 2022-01-04 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10961198B2 (en) 2017-03-15 2021-03-30 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11773094B2 (en) 2018-09-18 2023-10-03 Organovo, Inc. Farnesoid X receptor agonists and uses thereof

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