WO2019054430A1 - Amide compound having aromatic heterocycle - Google Patents

Amide compound having aromatic heterocycle Download PDF

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Publication number
WO2019054430A1
WO2019054430A1 PCT/JP2018/033912 JP2018033912W WO2019054430A1 WO 2019054430 A1 WO2019054430 A1 WO 2019054430A1 JP 2018033912 W JP2018033912 W JP 2018033912W WO 2019054430 A1 WO2019054430 A1 WO 2019054430A1
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WIPO (PCT)
Prior art keywords
methyl
group
mmol
triazol
disorder
Prior art date
Application number
PCT/JP2018/033912
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French (fr)
Japanese (ja)
Inventor
亨 谷口
理 岩本
啓志 齋藤
勝義 中島
泰之 小川
青木　一真
伸也 栗川
田中　伸治
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第一三共株式会社
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Publication of WO2019054430A1 publication Critical patent/WO2019054430A1/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound having a specific chemical structure having peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof, a method for producing the same, and the like.
  • the present invention also relates to the mechanism of action of the compound or a pharmacologically acceptable salt thereof, a pharmaceutical composition, a method for producing, preventing and / or treating the pharmaceutical composition, and the like.
  • Non-Patent Documents 1 and 2 It has been reported that stress increases the production of inflammatory cytokines from microglia and that blood cytokines (TNF ⁇ etc.) levels are high in mental disease patients (depression, schizophrenia etc.), and brain inflammation in mental diseases Involvement of is suggested.
  • TNF ⁇ etc. blood cytokines
  • brain inflammation in mental diseases Involvement of is suggested.
  • proteins considered to be the cause cause inflammation in the brain by activation of microglia it has also been suggested that proteins considered to be the cause cause inflammation in the brain by activation of microglia.
  • the present invention relates to a compound having a specific chemical structure having anti-inflammatory activity, useful as an active ingredient for the prevention and / or treatment of inflammatory diseases, a pharmacologically acceptable salt thereof, or a novel preparation thereof
  • a compound having a specific chemical structure having anti-inflammatory activity useful as an active ingredient for the prevention and / or treatment of inflammatory diseases
  • a pharmacologically acceptable salt thereof or a novel preparation thereof
  • the compounds of the present invention and their pharmacologically acceptable salts are considered to be useful as novel pharmaceuticals because they have different properties from existing anti-inflammatory agents in various aspects.
  • the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has been found that it has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
  • the present inventors have intensively studied for the purpose of developing a compound useful as an active ingredient for the prevention and / or treatment of an inflammatory disease, a pharmacologically acceptable salt thereof and the like, and as a result, the compound of the present invention We found pharmacologically acceptable salts etc. That is, the present invention is as described below.
  • X any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
  • Y may form a
  • Substituent group Y 1 Hydroxyl group, Amino group, Nitro group, Cyano group, Halogen atom, A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ; A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; 5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2
  • Substituent group Y 2 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3
  • Substituent group Y 3 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
  • E is -O-, n 1 is 0, and n 2 is 1.
  • G is any one selected from the following.
  • n 3 is 0, [1] - a compound or a pharmacologically acceptable salt thereof according to any one of [5].
  • Y is any group (Note selected from the following, Y may be substituted with same or different 1-3 groups selected from Substituent Group Y 1.
  • Substituent group Y 1 is The compound or pharmacologically acceptable salt thereof according to any of [1]-[6], which is as defined in [1].
  • Y Either group selected from the following (Note, Y may be substituted with same or different 1-3 groups selected from substituent group Y 1 substituent group Y 1 is [ As defined in 1).)
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C6 alkyl group, or a halo C1-C6 alkoxy group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R5c and R5d each independently a hydrogen atom or a C1-C6 alkyl group]
  • a pharmaceutical composition comprising the compound according to any one of [1]-[9] or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [11] which is for the prevention and / or treatment of an inflammatory disease.
  • the pharmaceutical composition according to [12], wherein the inflammatory disease is a peripheral inflammatory disease.
  • the pharmaceutical composition according to [12], wherein the inflammatory disease is a central inflammatory disease.
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, celiac disease, ⁇ ⁇ , radiation enteritis, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, peripheral neuritis , Ankylosing spondylitis, eczema (acute, subacute, chronic), contact dermatitis, sun (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrhoeic dermatitis,
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary Sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, sun (ultraviolet) dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, alopecia areata, pemphigus, erythema, acne
  • Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spine
  • the pharmaceutical composition according to [13] which is any one selected from the group consisting of inflammation, wounds, intractable stomatitis, glossitis and Behcet's disease.
  • [twenty two] [11] A method for preventing and / or treating an inflammatory disease, which comprises administering an effective amount of the pharmaceutical composition according to [11].
  • the compound having a specific chemical structure having a peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof of the present invention has properties different from anti-inflammatory agents existing in various aspects from the past. It is considered to be useful as a new medicine because of In addition, the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
  • One embodiment of the present invention is a compound of the general formula (1) or a pharmacologically acceptable salt thereof.
  • X any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
  • Y may form a
  • Substituent group Y 1 Hydroxyl group, Amino group, Nitro group, Cyano group, Halogen atom, A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ; A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ; 5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
  • Substituent group Y 2 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group, An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ; 4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3 ;
  • Substituent group Y 3 Hydroxyl group, Halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group
  • R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
  • R 3 hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
  • R 4 hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
  • R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
  • Preferred embodiments of the present invention are the compounds described in the examples or pharmacologically acceptable salts thereof.
  • the “5-membered aromatic heterocycle optionally having sulfur atom, nitrogen atom or oxygen atom” in G is a 5-membered member, and atoms constituting the ring are nitrogen atom, oxygen atom, and An aromatic ring containing 1 to 4 atoms selected from the group consisting of sulfur atoms, such as a ring shown below (having two or more bonds).
  • it is a 5-membered aromatic heterocycle having a bond as follows.
  • the "halogen atom” in the present specification is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
  • the "C1-C6 alkyl group” in the present specification is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or an isobutyl group. It is a group.
  • the "C1-C6 alkoxy group” in the present specification is a group in which a C1-C6 alkyl group is bonded to an oxygen atom, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or an isobutoxy group. is there.
  • the "C3-C8 cycloalkyl group” in the present specification is a cyclic alkyl group having 3 to 8 carbon atoms, and preferably represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the group as shown below is also included.
  • C3-C8 cycloalkoxy group in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to an oxygen atom, and preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or And cyclohexyloxy.
  • the "halo C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkyl group is substituted by an appropriate number of halogen atoms, and preferably a difluoromethyl group, a trifluoromethyl group or a difluoroethyl group. is there.
  • halo C1-C6 alkoxy group in the present specification is a group in which an appropriate number of halogen atoms are substituted to a C1-C6 alkoxy group, and preferably a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group. is there.
  • amino C1-C6 alkyl group in the present specification is a group in which an amino group is bonded to a C1-C6 alkyl group, and is preferably an aminomethyl group, an aminoethyl group or an aminopropyl group.
  • the “di C1-C6 alkylamino group” in the present specification is a group in which two identical or different C1-C6 alkyl groups are bonded to an amino group, and preferably a dimethylamino group or a diethylamino group.
  • the “5-6 membered aromatic heterocyclic group” in the present specification is a 5- or 6-membered, 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. It refers to a monocyclic aromatic cyclic group contained, for example, a group having one bond in the ring as shown below.
  • the "4-7 membered saturated heterocyclic group" in the present specification is a 4-7 member, and contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a monocyclic saturated cyclic group is, for example, a group having one bond in the ring as shown below.
  • the "C1-C6 alkyl carbonyl group” in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and is preferably an acetyl group, an ethyl carbonyl group or a propyl carbonyl group.
  • the “C1-C6 alkoxycarbonyl group” in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a methoxycarbonyl group, an ethoxycarbonyl group or a t-butoxycarbonyl group.
  • C3-C8 cycloalkyl carbonyl group in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to a carbonyl group, and preferably a cyclopropyl carbonyl group, a cyclobutyl carbonyl group or a cyclopentyl carbonyl group. is there.
  • C3-C8 cycloalkoxycarbonyl group in the present specification is a group in which a C3-C8 cycloalkoxy group is bonded to a carbonyl group, and preferably a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group It is.
  • the "halo C1-C6 alkyl carbonyl group” in the present specification is a group in which a halo C1-C6 alkyl group is bonded to a carbonyl group, and preferably a difluoromethyl carbonyl group, a trifluoromethyl carbonyl group, a difluoroethyl carbonyl group.
  • halo C1-C6 alkoxycarbonyl group in the present specification is a group in which a halo C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a difluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group, a difluoroethoxycarbonyl group. It is a group.
  • the "phenyl carbonyl group” in the present specification is a group in which a phenyl group is bonded to a carbonyl group.
  • phenoxycarbonyl group in the present specification is a group in which a phenoxy group is bonded to a carbonyl group.
  • the pharmacologically acceptable salt indicates a salt that can be used as a pharmaceutical.
  • a salt thereof is shown because it can be converted to a basic salt or an acidic salt by reacting with a base or an acid.
  • the pharmacologically acceptable “basic salt” of the compound is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; Methyl morpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salts such as picoline salt or glycine salt, lysine salt, They are amino acid salts such as arginine salts, ornithine salts, glutamates and aspartates, preferably alkali metal salts.
  • alkali metal salt such as sodium salt, potassium salt or lithium salt
  • an alkaline earth metal salt such as magnesium salt or calcium salt
  • Methyl morpholine salt triethylamine salt, tributylamine salt, diisopropylethylamine
  • the pharmacologically acceptable “acid salt” of the compound is preferably a hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, nitrate, Inorganic acid salts such as chlorate, sulfate and phosphate; methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonate such as ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid Allyl sulfonates such as salts, acetates, malates, fumarates, succinates, citrates, citrates, ascorbates, tartrates, borates, borates, maleates and the like; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, and most preferably hydrohalide (especially
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become hydrate upon standing in the air or recrystallization.
  • the present invention also encompasses compounds of such various hydrates, solvates and crystalline polymorphs.
  • the compounds of the present invention may be cis isomer, geometric isomer such as trans isomer, tautomer or d isomer, l isomer etc. While various isomers such as optical isomers of may exist, the compounds include all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio, unless otherwise specified. It is Mixtures of these isomers can be separated by known resolution means.
  • the compounds of the present invention also include labels, that is, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2H, 3H, 13C, 14C, 35S, etc.).
  • the invention also encompasses so-called prodrugs.
  • the prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, Prog. Med., Vol. 5, pp. 2157-2161 (1985).
  • the prodrug (1)
  • an amino group is present in the compound, Compounds in which the amino group is acylated, alkylated or phosphorylated (eg, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4- (4) And the like, and compounds such as methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylated compounds, etc.
  • the hydroxyl group is acylated, alkylated, phosphorylated, borated compound (eg, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, analylated, dimethylaminomethylcarbonylated Compounds, etc.) and the like.
  • a carboxy group is present in the compound, A compound in which the carboxy group is esterified or amidated (eg, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl ester And the like), and the like.
  • Method A is a method of producing the compound (A-IV) of the present invention.
  • Step A1 A step of deprotecting an amino group This step is to obtain a compound (A-III) by deprotecting an amino group from the compound (AI).
  • the protecting group is a tert-butoxycarbonyl group
  • compound (A-III) can be obtained by dissolving compound (AI) in a solvent and adding an acid.
  • the reaction temperature is about ⁇ 20 to 100 ° C.
  • the reaction time is about 1 to 24 hours.
  • an acid to be used trifluoroacetic acid, hydrochloric acid and the like can be mentioned.
  • the solvent to be used dichloromethane, chloroform, methanol, ethyl acetate, 1,4-dioxane etc., or a mixture thereof can be mentioned.
  • Step A2 A step of reducing a nitro group to an amino group From the compound (A-II), a step of obtaining a compound (A-III) by hydrogenation in the presence of a metal catalyst such as 10% palladium carbon is there.
  • the solvent to be used may be terhydrohydrofuran, 1,4-dioxane, methanol, ethanol or the like, or a mixture thereof, and the reaction temperature is usually about room temperature to 60 ° C., and the reaction time is 0.5 to 24. It is about time.
  • this step can also be carried out by heating under reflux in an ethanol / water solvent a reduction reaction between iron powder and ammonium chloride.
  • Step A3 A step of forming an amide by condensation (i) Activate carboxylic acid as acid chloride and then react with compound (A-III) to produce compound (A-IV), or (ii) Carboxylic acid
  • the acid and the compound (A-III) are reacted in the presence of a condensing agent to produce a compound (A-IV).
  • a condensing agent for example, oxalyl chloride and a small amount of dimethylformamide are added to a dichloromethane solution of a carboxylic acid at 0 ° C. to room temperature, and after standing for a while, the compound ( Compound (A-IV) can be obtained by adding A-III) and a base such as pyridine.
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • a base and a condensing agent can be added to a solution of a carboxylic acid and a compound (A-III) in dimethylformamide or dichloromethane to obtain a compound (A-IV).
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • tertiary amines such as diisopropylethylamine can be mentioned.
  • G is the following 1,2,4-triazole
  • Method E Can be produced, for example, by using the following method B to produce a compound corresponding to the compound (A-I) and the compound (A-II) used in the method A. Further, a compound corresponding to the compound (A-IV) of Method A can be produced using Method E below.
  • Method B is a method for producing (B-III) (the compound corresponding to Compound (AI) and Compound (A-II) used in Method A).
  • N 1 represents P n NH- or NO 2- .
  • Step B1 Step of Forming Triazole Ring Compound (BI) is reacted with an alkylating agent such as methyl iodide to convert it into the corresponding thioimidate, and reacted with compound (B-II) to give compound (B-III) Manufacturing process.
  • an alkylating agent such as methyl iodide
  • compound (B-II) to give compound (B-III) Manufacturing process.
  • Tetrahydrofuran, 1,4-dioxane, etc. can be mentioned as a solvent used in the reaction of compound (BI) and methyl iodide, and the reaction temperature is usually about room temperature to 80 ° C., and the reaction time is 1 to 24 hours. It is an extent.
  • examples of the solvent used in the reaction of thioimidate with the compound (B-II) include tetrahydrofuran and 1,4-dioxane, and the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is from 1 to It is about 24 hours.
  • Method C is a method of producing a compound (C-III) (a compound corresponding to the compound (BI) used in the method B).
  • Step C1 A step of forming an amide by condensation This is a step of producing a compound (C-II) from a compound (CI) which can be synthesized by a commercially available method or a known method under the same conditions as in the step A3 step.
  • Step C2 Step of Thiocarbonylation This is a step of reacting compound (C-II) with a sulfurizing agent such as Lawesson's reagent in a solvent to obtain compound (C-III).
  • a sulfurizing agent such as Lawesson's reagent
  • the solvent to be used hydrochlorohydrofuran, 1,4-dioxane, etc., or a mixture thereof can be mentioned.
  • the reaction temperature is about 0 to 100 ° C.
  • the reaction time is about 0.5 to 24 hours. .
  • Method D is a method of producing a compound (D-II) (a compound corresponding to the compound (B-II) used in the method B).
  • P C represents a group that protects a carboxy group.
  • Step D1 A step of forming a hydrazide This is a step of heating a compound (DI) which can be synthesized by a commercially available method or a known method with hydrazine in a solvent to produce a compound (D-II).
  • a solvent to be used methanol, ethanol, water and the like, or a mixture thereof can be mentioned.
  • the reaction temperature is about room temperature to 100 ° C.
  • the reaction time is about 0.5 to 24 hours.
  • Method E is a method of producing the compound (E-VIII) of the present invention (the compound corresponding to the compound (A-IV) of Method A).
  • P 2 O represents a group that protects a hydroxyl group.
  • Step E1 A step of forming a hydrazide This is a step of producing a compound (E-II) from a compound (EI) which can be synthesized by a known method, under the same conditions as in the step D1.
  • Step E2 A step of forming a triazole ring Compound (E-II) and compound (E-III) (a compound corresponding to (C-III) in Method C) to compound B (Compound B) under the same conditions as in Method B1.
  • E-IV is produced.
  • Step E3 A step of reducing a nitro group to an amino group This is a step of producing a compound (EV) from compound (E-IV) under the same conditions as in Step A2.
  • Step E4 A step of forming an amide by condensation This is a step of producing a compound (E-VI) from the compound (EV) and a corresponding carboxylic acid under the same conditions as in the method A3 step.
  • Step E5 Step for Deprotection This is a step for obtaining compound (E-VII) by deprotecting a hydroxyl group from compound (E-VI).
  • the protecting group is a tetrahydropyranyl group
  • compound (E-VI) can be dissolved in a solvent and acid can be added to give compound (E-VII).
  • the reaction temperature is about 0 to 80 ° C.
  • the reaction time is about 0.5 to 24 hours.
  • Step E6 A step of etherifying by Mitsunobu reaction This is a step of obtaining compound (E-VIII) from compound (E-VII) using a corresponding alcohol in the presence of phosphine and azodicarboxylic acid ester or diazodicarboxamide.
  • phosphine to be used triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
  • azodicarboxylate ester or diazodicarboxamide to be used include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipyridine and the like.
  • the solvent to be used include terehydrofuran, 1,4-dioxane, toluene and the like, or a mixture thereof.
  • the reaction temperature is about 0 to 100 ° C.
  • the reaction time is about 0.5 to 24 hours. is there.
  • G is the following pyrazole
  • Method F is a method of producing a compound (F-II) (a compound corresponding to the compound (A-II) used in the method A).
  • Step F1 Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (F-II) from compound (FI) commercially available or which can be synthesized by a known method under the same conditions as in step E6 of method E.
  • G is the following 1,2,4-triazole
  • Method G is a method of producing a compound (G-III) (a compound corresponding to the compound (A-II) used in the method A).
  • Step G1 A step of reducing an ester to form an alcohol This is a step of producing a compound (G-II) from a compound (GI) which can be synthesized by a known method, under the same conditions as in the step J2 of step J2.
  • Step G2 A step of etherifying by Mitsunobu reaction This is a step of producing a compound (G-III) from the compound (G-II) under the same conditions as in the step E6.
  • G is the following imidazole
  • Method H is a method of producing a compound (H-III) (a compound corresponding to the compound (AI) used in the method A).
  • Step H1 A step of etherifying by Mitsunobu reaction A step of producing compound (H-II) from compound (HI) and a corresponding alcohol which can be synthesized by a commercially available method or a known method under the same conditions as in step E6 step It is.
  • triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), hydrogen carbonate Potassium, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, sodium phosphate and the like can be mentioned.
  • the solvent to be used methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, N, N-dimethylformamide, dimethylsulfoxide, toluene, etc., or a mixture thereof can be mentioned, and usually the reaction temperature Is about 60 to 120.degree. C., and the reaction time is about 0.5 to 24 hours.
  • G is the following isoxazole
  • Method I is a method of producing a compound (I-II) (a compound corresponding to the compound (A-II) used in the method A).
  • Step I1 A step of etherifying by Mitsunobu reaction A step of producing compound (I-II) from compound (II) which can be synthesized by a commercially available method or a known method and an alcohol corresponding thereto, under the same conditions as in Step E6. It is.
  • G is the following pyrazole
  • Method J is a method of producing a compound (J-IV) (a compound corresponding to the compound (A-II) used in the method A).
  • Step J1 The step of protecting the amino group of pyrazole This is a step of producing compound (J-II) from compound (JI) which can be synthesized by a known method, by introducing a protecting group into the amino group of pyrazole. .
  • compound (JI) is reacted with 3,4-dihydro-2H-pyran in a solvent under acidic conditions to give compound (J-II).
  • the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
  • Step J2 A step of reducing an ester to form an alcohol This is a step of producing a compound (J-III) by reacting the compound (J-II) with a reducing agent in a solvent.
  • a reducing agent to be used lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL), etc.
  • Step J3 Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (J-IV) from compound (J-III) and an alcohol corresponding thereto, under the same conditions as Step E6.
  • Method K when G of compound (KI) contains a protecting group P n , the protecting group is deprotected to give a compound (K-II) of the present invention (the compound used in Method A (A-IV) And the corresponding compound).
  • Step K1 Step for Deprotection This is a step for obtaining compound (K-II) by performing deprotection from compound (KI).
  • the protecting group is a tetrahydropyranyl group
  • the compound (KI) is dissolved in a solvent, and an acid is added to give a compound (K-II).
  • the reaction temperature is about room temperature to 80 ° C.
  • the reaction time is about 1 to 24 hours.
  • the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.
  • the solvent methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and the like or mixtures thereof can be mentioned.
  • optical isomers can be isolated and purified by known methods such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
  • optical isomers can be isolated and purified by a conventional method such as fractional recrystallization (salt resolution) or recrystallization with an appropriate salt.
  • fractional recrystallization salt resolution
  • recrystallization with an appropriate salt.
  • Administration is orally using tablets, pills, capsules, granules, powders, solutions, etc., or injections for intraarticular, intravenous, intramuscular etc., suppositories, eye drops, eye ointments, for transdermal use It may be in any form of parenteral administration by liquid solution, ointment, transdermal patch, transmucosal liquid, transmucosal patch, inhalant and the like.
  • Such solid compositions may comprise one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl piriddon And / or magnesium metasilicate magnesium aluminate and the like.
  • the solid composition contains, according to a conventional method, an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium ruboxymethylstarch, a stabilizer, and a solubilizer. It may be done.
  • the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.
  • liquid composition for oral administration Pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like are used. To such liquid compositions it is possible to add generally used inert diluents such as purified water or ethanol.
  • the liquid composition may contain, in addition to an inert diluent, solubilizers, adjuvants such as wetting agents, sweetening agents, flavoring agents, fragrances, preservatives.
  • the aqueous solvent includes, for example, distilled water for injection or physiological saline.
  • Nonaqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or Polysorbate 80.
  • Such an injection composition may further contain a tonicity agent, preservative, wetting agent, emulsifying agent, dispersing agent, stabilizing agent, or solubilizing agent.
  • These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, incorporation of a bactericide or irradiation.
  • these injection compositions can be used to prepare sterile solid compositions and to be dissolved or suspended in sterile water or sterile injectable solvent prior to use.
  • Ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like are used.
  • These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
  • ointment or lotion base polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauro macrogol, sorbitan sesquioleate, etc. used.
  • Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semisolid form, and can be produced according to a conventionally known method.
  • known excipients pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
  • devices suitable for inhalation or insufflation can be used as the method of administration.
  • the compounds may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and dry powder or powder containing capsules may be used.
  • a suitable propellant may be used.
  • it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroaluminum, hydrofluoroaluminum or carbon dioxide.
  • the daily dose is suitably about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg of body weight, once Or divided into two or more doses.
  • the appropriate daily dose is about 0.0001-10 mg / kg of body weight, which is administered once or several times daily.
  • about 0.001 to 100 mg / kg of body weight is administered in one or more divided doses a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
  • combination In the present invention, it can be used in combination with various therapeutic or preventive agents for diseases which are considered to show its efficacy.
  • the combination may be administered simultaneously, or separately separately, continuously, or at desired time intervals.
  • Co-administered formulations may be formulated or formulated separately.
  • Formulation Example 1 Powdered Powder A powder is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 895 g of lactose and 100 g of corn starch in a blender.
  • Formulation Example 2 Granules After 5 g of the compound of the present invention or a salt thereof, 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose are mixed, 300 g of a 10% aqueous solution of hydroxypropyl cellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • Formulation Example 3 Tablet A compound is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender and tableting with a tableting machine.
  • IL-10 increase rate 100 mg / kg of test substance suspended in 0.5% (w / v) methyl cellulose was orally administered to mice, and 1 hour later, lipopolysaccharide (LPS, Sigma-Aldrich, L2630 (trade name) 0.4 mg / kg was intraperitoneally administered to cause inflammation.
  • LPS lipopolysaccharide
  • IL-10 increase rate (% control ratio) (IL-10 amount in compound administration group) x 100 / (IL-10 amount in 0.5% (w / v) methyl cellulose administration group)
  • Example 3 4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridyl] oxymethyl] -1,2,4-triazole-3- [I] Phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridinyl] oxymethyl] -1,2,4-triazol-3-yl] phenyl] benzamide
  • Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.2 g, 0.55 mmol) is dissolved in N, N-dimethylformamide (4 mL) and 2-chloro-4- (trifluoro) pyridine (A
  • Example 4 4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] benzamide
  • Example 2 (2e): 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.15 g (0.41 mmol) is suspended in 1,4-dioxane (3 mL) and cyanomethylene tributylphosphorane (0.21 mL, 0.82 mmol), 3- (propan-2-yloxy) phenol (Enamine catalog
  • Example 5 4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] benzamide (5a) tert-Butyl N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] carbamate tert-butyl N- [4- [4-methyl-5- (2-phenylethyl) -1,2,4-triazol-3-yl] carbamate The tert-butyl N- [4- (methylcarbamothiol) phenyl] carbamate (200 mg, 0.75 mmol) of Example 1 (1b) was dissolved in tetrahydrofuran (1 mL), methyl iodide (0.93 mL, 15 mmol) ) was added and stirred at room temperature for 3 hours.
  • Example 9 After distilling off the solvent under reduced pressure and azeotroping with toluene twice, the residue is dissolved in pyridine (3 mL) and dichloromethane (3 mL), and 5- [4-methyl-5- of Example 9 (9 d) is obtained. [[3- (Trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-2-amine (0.2 g, 0.57 mmol) was added and stirred at room temperature for 2 hours.
  • Example 10 4-[(Dimethylamino) methyl] -N- [4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] phenyl] benzamide (10a) 4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole 4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole Dissolve [1- (4-nitrophenyl) imidazol-4-yl] methanol (CAS Registry Number: 85102-89-2, Synthesis, 1983, 47-49) (790 mg, 3.6 mmol) in dichloromethane (30 mL) Then, 3-isopropylphenol (780 mg, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were added.
  • diethyl azodicarboxylate (2.2 M solution in toluene, 0.42 mL, 0.94 mmol) was slowly added dropwise and stirred at room temperature for 17 hours.
  • Example 13 4-[(Dimethylamino) methyl] -N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] Tetrahydropyran-3-yl] benzamide (13a) Methyl 2- (3-isopropylphenoxy) acetate methyl 2- (3-isopropylphenoxy) acetate Dissolve 3-isopropylphenol (10 g, 73 mmol) in N, N-dimethylformamide (100 mL) and add potassium carbonate (20 g, 147 mmol), methyl bromoacetate (Tokyo Chemical Industry Co., Ltd.
  • Example 14 1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine-4-carboxamide 1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4-carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (32 mg, 68 mmol) of Example 1 (1 d) And 1-methylpiperidine-4-carboxylic acid (Combi-blocks catalog code: SS-5926) (0.025 g, 0.17 mmol) are dissolved in dehydrated N, N-dimethylformamide (1 mL), 4- (4,6,4 -Dimethoxy-1
  • Example 15 4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide 4-cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.4 g, 1.15 mmol) of Example 1 (1d) 4-cyano-2-methyl-benzoic acid (Combi-blocks catalog code: SH-5948) (0.22 mg, 1.38 mmol) in dichloromethane (2.3 mL) solution of 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydro
  • Example 16 4-[(Dimethylamino) methyl] -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- [I] Phenyl] benzamide (16a) 4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl ] Benzamide 4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide 4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl of Example 15 To
  • Example 17 4-[(1S) -1- (azetidin-1-yl) ethyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole -3-yl] cyclohexyl] benzamide (17a) tert-Butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] carbamate tert-butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] carbamate
  • the methyl 4- (tert-butoxycarbonylamino) -N-methyl-cyclohexanecarboximidothioate (1.4 g, 4.9 mmol) of Example 7 (7b) was methyl
  • the reaction solution is quenched with aqueous sodium thiosulfate solution, extracted three times with ethyl acetate, the organic layer is dried over magnesium sulfate, filtered and concentrated, and the obtained residue is dissolved in methanol (4 mL) and hydrogenated Sodium boron (78 mg, 0.21 mmol) was added at 0 ° C. and stirred for 30 minutes. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain 91.4 mg (yield: 94%) of the title compound as a white solid.
  • Example 20 1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] pyrazole-4-carboxamide 1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyrazole-4-carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.1 g, 0.29 mmol) of Example 1 (1d) Is dissolved in dichloromethane (0.6 mL), 1-methyl-1H-pyrazole-4-carboxylic acid (Combi-blocks catalog code: HC-3334) (0.0434 g, 0.34 mmol), 1-ethyl-3- (3-) Dimethylamino
  • Example 22b 4-[(3-Fluoroazetidin-1-yl) methyl] benzoic acid 4-[(3-fluoroazetidin-1-yl) methyl] benzoic acid
  • the methyl 4-[(3-fluoroazetidin-1-yl) methyl] benzoate (0.29 g, 1.3 mmol) of Example 22 (22a) was dissolved in a mixed solvent of tetrahydrofuran (1.3 mL) and methanol (1.3 mL) A solution of sodium hydroxide (0.26 g, 6.5 mmol) in water (1.5 mL) was added, and the mixture was stirred at room temperature for 5 hours.
  • Example 23 4-[(3-hydroxyazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide
  • 23a 4-formyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide
  • the reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the organic layer was washed with brine and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 28 mg (yield: 50%) of the title compound as a colorless solid.
  • Example 26 4-[(Dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide 4-[(dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
  • Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( Suspend 0.15 g (0.41 mmol) in acetonitrile (5 mL) and add 3-fluorophenol (Tokyo Chemical Industry Catalog No .: F0159) (0.055 g, 0.49 mmol) and cyanomethylenetributyl
  • Example 30 4-Fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine- 4-carboxamide 4-fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4- carboxamide 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (50 mg, 0.14 mmol) of Example 1 (1d) And 4-fluoro-1-methyl-piperidine-4-carboxylic acid hydrochloride (ZERENEX catalog code: ZXH001982) (34 mg, 0.17 mmol) in a solution of dehydrated N, N-dimethylformamide (1
  • Example 31 4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide
  • 31a tert-Butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridyl] carbamate tert-butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridine] carbamate
  • Example 8b tert-butyl N- [6- (methylcarbamothiol) -3-pyridyl] carbamate (1.7 g, 6.4 mmol) was dissolved in te
  • Example 13 Example 13 (13b) was added, and the mixture was stirred at 100 ° C. for 6 hours.
  • Example 32 6-[(Dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine- 3-carboxamide 6-[(dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine-3- carboxamide
  • Example 35 4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] phenyl] benzamide (35a) 3-[(3-Isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole 3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole Dissolve methyl 5- (4-nitrophenyl) isoxazole-3-carboxylate (CAS Registry Number: 487034-01-5, Organic Letters, 2006, 8, 713-716) (300 mg, 1.2 mmol) in ethanol, Sodium borohydride (92 mg, 2.4 mmol) was added at room temperature and stirred at 50 ° C.
  • the mixture was diluted with dichloromethane, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure is dissolved in acetonitrile, 3-isopropylphenol (0.17 mL, 1.2 mmol) and cesium carbonate (1 g, 3.1 mmol) are added, and the mixture is stirred at room temperature for 12 hours did.
  • the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure to give 530 mg (yield: quantitative) of the title compound as a yellow solid.

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Abstract

The purpose of the present invention is to provide a compound having an anti-inflammatory action, a pharmacologically acceptable salt thereof, etc. A solving means of the present invention is a compound of general formula (1) or a pharmacologically acceptable salt thereof. [Symbols in the formula are defined below: A1, A2 and A3 are -CH=, etc.; E is -CH2-, etc.; G is a 5-membered aromatic heterocycle, etc.; X is a benzene ring, etc.; Y is C1-C6 alkyl group, etc.; R1 and R2 are a hydrogen atom, etc.; R3 is a hydrogen atom, etc.; R4 is a hydrogen atom, etc.; R5a, R5b, R5c and R5d are a hydrogen atom, etc.; n1, n2 and n3 are 1, etc.]

Description

芳香族複素環を有するアミド化合物Amide compound having an aromatic heterocycle
　本発明は、末梢性及び/又は中枢性の抗炎症作用を有する特定の化学構造を有する化合物又はその薬理上許容される塩及びその製造方法等に関する。また、本発明は、該化合物又はその薬理上許容される塩の作用メカニズム、医薬組成物、該医薬組成物の製造、予防及び/又は治療方法等に関する。 The present invention relates to a compound having a specific chemical structure having peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof, a method for producing the same, and the like. The present invention also relates to the mechanism of action of the compound or a pharmacologically acceptable salt thereof, a pharmaceutical composition, a method for producing, preventing and / or treating the pharmaceutical composition, and the like.
　特許文献１において以下に示す5員芳香族複素環化合物が報告されているが、これらの化合物の抗炎症作用は知られていない。 Although the 5-membered aromatic heterocyclic compounds shown below are reported in Patent Document 1, the anti-inflammatory action of these compounds is not known.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　近年、研究の進展とともに、精神疾患、神経変性疾患と炎症との関連性が報告されている（非特許文献1、2）。
　ストレスによってミクログリアから炎症性サイトカインの産生が増加することや、精神疾患患者（うつ、統合失調症など）において血中サイトカイン（TNFα等）レベルが高いことが報告されており、精神疾患における脳内炎症の関与が示唆されている。またアルツハイマー病に代表される神経変性疾患では、その原因と考えられる蛋白がミクログリアの活性化によって脳内炎症を惹起することも示唆されている。 In recent years, with the progress of research, the association between mental diseases and neurodegenerative diseases and inflammation has been reported (Non-Patent Documents 1 and 2).
It has been reported that stress increases the production of inflammatory cytokines from microglia and that blood cytokines (TNFα etc.) levels are high in mental disease patients (depression, schizophrenia etc.), and brain inflammation in mental diseases Involvement of is suggested. In addition, in neurodegenerative diseases represented by Alzheimer's disease, it has also been suggested that proteins considered to be the cause cause inflammation in the brain by activation of microglia.
WO2010/001946WO 2010/001946
　本発明は、抗炎症作用を有する特定の化学構造を有する、炎症性の疾患の予防及び/又は治療のための有効成分として有用な化合物、その薬理上許容される塩等、又はその新規な製造方法及び中間体を提供する。本発明の化合物及びその薬理上許容される塩は、様々な面からこれまでに存する抗炎症剤とは異なる特性を有していることから新規な医薬品として有用であると考えられる。
　また、本発明の化合物及びその薬理上許容される塩は、抗炎症活性、生物学的利用能、in vitro活性、in vivo活性、薬効発現の早さ、薬効の持続性、物理的安定性、薬物相互作用、毒性等の点で優れた性質を有し、医薬として有用であることを見出した。 The present invention relates to a compound having a specific chemical structure having anti-inflammatory activity, useful as an active ingredient for the prevention and / or treatment of inflammatory diseases, a pharmacologically acceptable salt thereof, or a novel preparation thereof Provided are methods and intermediates. The compounds of the present invention and their pharmacologically acceptable salts are considered to be useful as novel pharmaceuticals because they have different properties from existing anti-inflammatory agents in various aspects.
In addition, the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has been found that it has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
　本発明者らは、炎症性の疾患の予防及び/又は治療のための有効成分として有用な化合物、その薬理上許容される塩等の開発を目的に鋭意研究した結果、本発明の化合物、その薬理上許容される塩等を見出した。すなわち、本発明は以下に説明するとおりである。 The present inventors have intensively studied for the purpose of developing a compound useful as an active ingredient for the prevention and / or treatment of an inflammatory disease, a pharmacologically acceptable salt thereof and the like, and as a result, the compound of the present invention We found pharmacologically acceptable salts etc. That is, the present invention is as described below.
[1]
　一般式(1)の化合物又はその薬理上許容される塩。 [1]
The compound of General formula (1) or its pharmacologically acceptable salt.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
[式中の記号は以下に定義される。
A1、A2、A3：それぞれ独立して、-CH=、又は、-N=
E：-CH2-、又は、-O-
G：硫黄原子、窒素原子、又は、酸素原子を有していてもよい5員芳香族複素環（当該環は2つ以上の結合手を有する）
但し、以下の5員芳香族複素環（左右の向きも記載のとおり）は除く。 [The symbols in the formula are defined below.
A 1 , A 2 and A 3 : each independently, -CH = or -N =
E: -CH 2- or -O-
G: 5-membered aromatic heterocycle which may have a sulfur atom, nitrogen atom or oxygen atom (the ring has two or more bonds)
However, the following five-membered aromatic heterocycle (the direction of right and left is also as described) is excluded.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
X：以下から選択されるいずれかの環（当該環は2つ以上の結合手を有し、2つの環が縮環した場合や、架橋した場合も含む） X: any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　A4、A5：それぞれ独立して、-CH=、又は、-N=
　A6：-CH2-、-O-、又は、-NH-
　ｍは、0、1、又は、2
Y：
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいフェニル基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基（架橋構造を有する場合がある）、又は、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基（架橋構造を有する場合がある）
なお、Yは連結するアミド部分と一緒になってラクタムを形成する場合がある。すなわち、以下の左に示す鎖状アミドの部分構造が、以下の右に示す環状アミドの部分構造になる場合がある。 A 4 and A 5 : each independently, -CH = or -N =
A 6 : -CH 2- , -O-, or -NH-
m is 0, 1 or 2
Y:
C1-C6 alkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
A phenyl group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
A C3-C8 cycloalkyl group (which may have a crosslinked structure) optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 1 or
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent group Y 1 (may have a crosslinked structure)
In addition, Y may form a lactam together with the linked amide moiety. That is, the partial structure of the linear amide shown on the left below may be the partial structure of the cyclic amide shown on the right below.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
置換基群Y1：
水酸基、
アミノ基、
ニトロ基、
シアノ基、
ハロゲン原子、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルコキシ基、
置換基群Y2から選択される同一または異なる1-2の基で置換されていてもよいアミノC1-C6アルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基 Substituent group Y 1 :
Hydroxyl group,
Amino group,
Nitro group,
Cyano group,
Halogen atom,
A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ;
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2
置換基群Y2：
水酸基、
ハロゲン原子、
C1-C6アルキル基、
C1-C6アルコキシ基、
置換基群Y3から選択される同一または異なる1-2の基で置換されていてもよいアミノ基、
置換基群Y3から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基 Substituent group Y 2 :
Hydroxyl group,
Halogen atom,
C1-C6 alkyl group,
C1-C6 alkoxy group,
An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ;
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3
置換基群Y3：
水酸基、
ハロゲン原子、
C1-C6アルキル基、
C1-C6アルコキシ基 Substituent group Y 3 :
Hydroxyl group,
Halogen atom,
C1-C6 alkyl group,
C1-C6 alkoxy group
R1、R2：それぞれ独立して、水素原子、シアノ基、ハロゲン原子、C1-C6アルキル基、C1-C6アルコキシ基、C3-C8シクロアルキル基、C3-C8シクロアルコキシ基、ハロC1-C6アルキル基、ハロC1-C6アルコキシ基、フェニル基、5-6員芳香族複素環基、C1-C6アルキルカルボニル基、C1-C6アルコキシカルボニル基、C3-C8シクロアルキルカルボニル基、C3-C8シクロアルコキシカルボニル基、ハロC1-C6アルキルカルボニル基、ハロC1-C6アルコキシカルボニル基、フェニルカルボニル基、又は、フェノキシカルボニル基 R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
R3：水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、又は、C3-C8シクロアルキル基
R4：水素原子、ハロゲン原子、又は、C1-C6アルキル基
R5a、R5b、R5c、R5d：それぞれ独立して水素原子、又は、C1-C6アルキル基
n1、n2、n3：それぞれ独立して、0、1、又は、2]
[2]
A1、A2、及び、A3のいずれもが同一であり、-CH=； 又は、いずれか１個が-N=である[1]に記載の一般式(1)の化合物又はその薬理上許容される塩。
[3]
Eが、-O-であり、n1が0であり、n2が、1である[1]又は[2]に記載の一般式(1)の化合物又はその薬理上許容される塩。
[4]
Gが、以下から選択されるいずれかである、[1]-[3]のいずれかに記載の化合物又はその薬理上許容される塩。 R 3 : hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
R 4 : hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group
n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
[2]
The compound of the general formula (1) or the pharmacology thereof described in [1], wherein all of A 1 , A 2 and A 3 are the same and -CH =; or any one is -N = Top acceptable salt.
[3]
A compound of the general formula (1) or a pharmacologically acceptable salt thereof according to [1] or [2], wherein E is -O-, n 1 is 0, and n 2 is 1.
[Four]
The compound or pharmacologically acceptable salt thereof according to any one of [1] to [3], wherein G is any one selected from the following.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
[5]
Xが、以下から選択されるいずれかである、[1]-[4]のいずれかに記載の化合物又はその薬理上許容される塩。 [Five]
The compound or pharmacologically acceptable salt thereof according to any one of [1] to [4], wherein X is any one selected from the following.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
[6]
n3が、0である、[1]-[5]のいずれかに記載の化合物又はその薬理上許容される塩。
[7]
Yが、以下から選択されるいずれかの基（なお、Yは、置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい。置換基群Y1は、[1]で定義のとおり。）である、[1]-[6]のいずれかに記載の化合物又はその薬理上許容される塩。 [6]
n 3 is 0, [1] - a compound or a pharmacologically acceptable salt thereof according to any one of [5].
[7]
Y is any group (Note selected from the following, Y may be substituted with same or different 1-3 groups selected from Substituent Group Y 1. Substituent group Y 1 is The compound or pharmacologically acceptable salt thereof according to any of [1]-[6], which is as defined in [1].
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
[8]
　一般式(1a)の化合物又はその薬理上許容される塩。 [8]
The compound of General formula (1a) or its pharmacologically acceptable salt.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
[式中の記号は以下に定義される。
A1、A2、及び、A3：いずれもが同一であり、-CH=； 又は、いずれか１個が-N=である
G：以下から選択されるいずれかの5員芳香族複素環 [The symbols in the formula are defined below.
A 1 , A 2 and A 3 : all are the same, -CH =; or any one is -N =
G: any 5-membered aromatic heterocycle selected from the following:
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
X：以下から選択されるいずれかの環 X: any ring selected from the following
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
Y：以下から選択されるいずれかの基（なお、Yは、置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい。置換基群Y1は、[1]で定義のとおり。） Y:. Either group selected from the following (Note, Y may be substituted with same or different 1-3 groups selected from substituent group Y 1 substituent group Y 1 is [ As defined in 1).)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
R1、R2：それぞれ独立して、水素原子、シアノ基、ハロゲン原子、C1-C6アルキル基、C1-C6アルコキシ基、ハロC1-C6アルキル基、又は、ハロC1-C6アルコキシ基、
R3：水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、又は、C3-C8シクロアルキル基
R4：水素原子、ハロゲン原子、又は、C1-C6アルキル基
R5c、R5d：それぞれ独立して水素原子、又は、C1-C6アルキル基] R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C6 alkyl group, or a halo C1-C6 alkoxy group,
R 3 : hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
R 4 : hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
R5c and R5d : each independently a hydrogen atom or a C1-C6 alkyl group]
[9]
以下から選択されるいずれかの化合物又はその薬理上許容される塩。
4-[(ジメチルアミノ)メチル]-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]-1,2,3,4-テトラヒドロイソキノリン-6-カルボキサミド
4-フルオロ-1-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ピペリジン-4-カルボキサミド
4-シアノ-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
4-[(ジメチルアミノ)メチル]-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
N-(4-[5-[(3-クロロフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル)-4-[(ジメチルアミノ)メチル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[トランス-4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-41,2,4-トリアゾール-3-イル)シクロヘキシル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[6-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ピリジン-3-イル]ベンズアミド
(2S,5R)-5-(ジメチルアミノ)-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]テトラハイドロ-2H-ピラン-2-カルボキサミド
4-[(3-フルオロアゼチジン-1-イル)メチル]-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[トランス-4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)シクロヘキシル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-({[4-(トリフルオロメチル)ピリジン-2-イル]オキシ)メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
4-(アゼチジン-1-イルメチル)-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
3-フルオロ-1-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ピペリジン-3-カルボキサミド
4-[(ジメチルアミノ)メチル]-N-{4-[4-メチル-5-([[6-メチル-4-(トリフルオロメチル)ピリジン-2-イル]オキシ]メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[4-(4-[[3-(プロパン-2-イル)フェノキシ]メチル]-イミダゾール-1-イル)フェニル]ベンズアミド
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-({[4-(プロパン-2-イル)ピリジン-2-イル]オキシ]メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
4-(アゼチジン-1-イルメチル)-2-フルオロ-N-[6-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ピリジン-3-イル]ベンズアミド
N-[4-[(ジメチルアミノ)メチル]フェニル]-4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ベンズアミド
[10]
IL10を増加させるための[1]-[9]のいずれかに記載の化合物又はその薬理上許容される塩。
[11]
[1]-[9]のいずれかに記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
[12]
炎症性疾患の予防及び/又は治療用である、[11]に記載の医薬組成物。
[13]
炎症性疾患が、末梢性炎症性疾患である、[12]に記載の医薬組成物。
[14]
炎症性疾患が、中枢性炎症性疾患である、[12]に記載の医薬組成物。 [9]
Any compound selected from the following or a pharmacologically acceptable salt thereof.
4-[(Dimethylamino) methyl] -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] Benzamide
2-Methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] -1,2,3 , 4-Tetrahydroisoquinoline-6-carboxamide
4-Fluoro-1-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] piperidine- 4-carboxamide
4-Cyano-2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] benzamide
4-[(Dimethylamino) methyl] -2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) phenyl] benzamide
4-[(Dimethylamino) methyl] -N- [4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazol-3-yl) Phenyl] benzamide
N- (4- [5-[(3-chlorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl) -4-[(dimethylamino) methyl] benzamide
4-[(Dimethylamino) methyl] -N- [trans-4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -41,2,4-triazol-3-yl) Cyclohexyl] benzamide
4-[(Dimethylamino) methyl] -N- [6- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) pyridine- 3-yl] benzamide
(2S, 5R) -5- (Dimethylamino) -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl ) Phenyl] Tetrahydro-2H-pyran-2-carboxamide
4-[(3-Fluoroazetidin-1-yl) methyl] -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl) phenyl] benzamide
4-[(Dimethylamino) methyl] -N- [trans-4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazole-3-) I) cyclohexyl] benzamide
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-({[4- (trifluoromethyl) pyridin-2-yl] oxy) methyl) -1,2,4-triazole -3-yl] phenyl} benzamide
4- (Azetidin-1-ylmethyl) -2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) phenyl] benzamide
3-Fluoro-1-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] piperidine- 3-carboxamide
4-[(Dimethylamino) methyl] -N- {4- [4-methyl-5-([[6-methyl-4- (trifluoromethyl) pyridin-2-yl] oxy] methyl) -1,2 , 4-Triazol-3-yl] phenyl} benzamide
4-[(Dimethylamino) methyl] -N- [4- (4-[[3- (propan-2-yl) phenoxy] methyl] -imidazol-1-yl) phenyl] benzamide
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-({[4- (propan-2-yl) pyridin-2-yl] oxy] methyl) -1,2,4 -Triazol-3-yl] phenyl} benzamide
4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) pyridin-3-yl] benzamide
N- [4-[(Dimethylamino) methyl] phenyl] -4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazole-3- I) benzamide
[Ten]
The compound or pharmacologically acceptable salt thereof according to any of [1] to [9] for increasing IL10.
[11]
A pharmaceutical composition comprising the compound according to any one of [1]-[9] or a pharmacologically acceptable salt thereof as an active ingredient.
[12]
The pharmaceutical composition according to [11], which is for the prevention and / or treatment of an inflammatory disease.
[13]
The pharmaceutical composition according to [12], wherein the inflammatory disease is a peripheral inflammatory disease.
[14]
The pharmaceutical composition according to [12], wherein the inflammatory disease is a central inflammatory disease.
[15]
末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、強皮症、気管支喘息、喘息性気管支炎、びまん性間質性肺炎、慢性閉塞性肺疾患、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、急性肝炎、慢性肝炎、劇症肝炎、自己免疫性肝炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、アルコール性肝炎、非アルコール性脂肪性肝炎、肝硬変、末梢神経炎、強直性脊椎炎、湿疹（急性・亜急性・慢性）、接触皮膚炎、日光（紫外線）皮膚炎、放射線皮膚炎、アトピー皮膚炎、脂漏性皮膚炎、尋常性乾癬、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、扁平苔癬、紅斑症、酒さ、蕁麻疹、円形脱毛症、天疱瘡群、紅皮症、尋常性ざ瘡、褥瘡、創傷、熱傷、結膜炎，角膜炎，強膜炎，急性・慢性中耳炎、通年性アレルギー性鼻炎、花粉症、副鼻腔炎、喉頭炎、食道炎、難治性口内炎及、舌炎、急性・慢性唾液腺炎、口角炎、口唇炎、ベーチェット病、多発性硬化症、I型糖尿病、II型糖尿病、アテローム性動脈硬化症、膵炎、及び、慢性心不全からなる群より選択されるいずれかである、[13]に記載の医薬組成物。
[16]
末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、気管支喘息、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、急性肝炎、自己免疫性肝炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、アルコール性肝炎、非アルコール性脂肪性肝炎、強直性脊椎炎、接触皮膚炎、日光（紫外線）皮膚炎、アトピー皮膚炎、脂漏性皮膚炎、尋常性乾癬、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、扁平苔癬、紅斑症、酒さ、円形脱毛症、天疱瘡群、紅皮症、尋常性ざ瘡、褥瘡、創傷、熱傷、副鼻腔炎、喉頭炎、食道炎、難治性口内炎、舌炎、急性・慢性唾液腺炎、口角炎、及び、口唇炎及びベーチェット病からなる群より選択されるいずれかである、[13]に記載の医薬組成物。
[17]
末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、自己免疫性肝炎、アルコール性肝炎、非アルコール性脂肪性肝炎、強直性脊椎炎、創傷、難治性口内炎、舌炎、及び、ベーチェット病からなる群より選択されるいずれかである、[13]に記載の医薬組成物。
[18]
中枢性炎症性疾患が、
アルツハイマー病、パーキンソン病、レビー小体型認知症、多系統萎縮症、ピック病、進行性核上性麻痺、大脳皮質基底核変性症、前頭側頭葉変性症、ハンチントン病、筋萎縮性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、脊髄小脳変性症、多発性硬化症、クロイツフェルト・ヤコブ病、致死性家族性不眠症、ゲルストマン・ストロイスラー・シャインカー症候群、ダウン症侯群 、ニーマン－ピック病、脳アミロイド血管症、HIV脳症、インフルエンザ脳症、肝性脳症、進行性多巣性白質脳症、抗NMDA受容体抗体脳炎、脳血管障害、外傷性脳損傷、脊髄損傷、低酸素脳症、てんかん、視神経炎、先天性代謝性脳疾患、ウェルニッケ脳症、自閉スペクトラム障害、注意欠如・多動性障害、チック障害、統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害、心的外傷およびストレス因関連障害、摂食障害、概日リズム睡眠・覚醒障害、ナルコレプシー、物質関連障害（アルコール依存、薬物依存）、衝動制御障害、せん妄、パーソナリティ障害、レット症候群
からなる群より選択されるいずれかである、[14]に記載の医薬組成物。
[19]
中枢性炎症性疾患が、
アルツハイマー病、パーキンソン病、レビー小体型認知症、多系統萎縮症、ピック病、進行性核上性麻痺、大脳皮質基底核変性症、前頭側頭葉変性症、ハンチントン病、筋萎縮性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、脊髄小脳変性症、多発性硬化症、クロイツフェルト・ヤコブ病、統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害、心的外傷およびストレス因関連障害、摂食障害、概日リズム睡眠・覚醒障害、ナルコレプシー、物質関連障害（アルコール依存、薬物依存等）、衝動制御障害、せん妄、パーソナリティ障害、レット症候群
からなる群より選択されるいずれかである、[14]に記載の医薬組成物。
[20]
中枢性炎症性疾患が、
統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害
からなる群より選択されるいずれかである、[14]に記載の医薬組成物。
[21]
炎症性疾患の治療における使用のための[1]-[9]のいずれかに記載の化合物又はその薬理上許容される塩。
[22]
[11]に記載の医薬組成物の有効量を投与する炎症性疾患の予防及び/又は治療方法。 [15]
Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, celiac disease,痔 瘻, radiation enteritis, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, peripheral neuritis , Ankylosing spondylitis, eczema (acute, subacute, chronic), contact dermatitis, sun (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis, Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, urticaria, alopecia areata, pemphigus, erythema, acne vulgaris, acne, wounds, burns, conjunctivitis, keratitis , Scleritis, acute / chronic otitis media, perennial allergic Inflammation, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, intractable glossitis, acute / chronic sialadenitis, canker sores, lipitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes The pharmaceutical composition according to [13], which is any one selected from the group consisting of atherosclerosis, pancreatitis, and chronic heart failure.
[16]
Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary Sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, sun (ultraviolet) dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, alopecia areata, pemphigus, erythema, acne vulgaris, acne, wounds, burns, sinusitis, laryngitis [13] The pharmaceutical composition according to [13], which is any one selected from the group consisting of esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, cankerulitis, and colitis and Behcet's disease.
[17]
Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spine The pharmaceutical composition according to [13], which is any one selected from the group consisting of inflammation, wounds, intractable stomatitis, glossitis and Behcet's disease.
[18]
Central inflammatory disease,
Alzheimer's disease, Parkinson's disease, Lewy body type dementia, multiple system atrophy, Pick's disease, progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, frontotemporal lobar degeneration, Huntington's disease, amyotrophic lateral sclerosis Disease, bulbar and spinal muscular atrophy, spinal muscular atrophy, spinocerebellar degeneration, multiple sclerosis, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann Stroisler Shinker syndrome, Down syndrome group , Niemann-Pick disease, cerebral amyloid angiopathy, HIV encephalopathy, influenza encephalopathy, hepatic encephalopathy, progressive multifocal leukoencephalopathy, anti-NMDA receptor antibody encephalitis, cerebrovascular disorder, traumatic brain injury, spinal cord injury, hypoxia Encephalopathy, epilepsy, optic neuritis, congenital metabolic brain disease, Wernicke's encephalopathy, autism spectrum disorder, attention deficit / hyperactivity disorder, tic disorder, schizophrenia, bipolar disorder, major depression Harm (treatment-resistant depression, postpartum depression), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, obsessive compulsive disorder, trauma and stress related disorder Eating disorder, circadian rhythm sleep and awakening disorder, narcolepsy, substance related disorder (alcoholic and drug dependent), impulse control disorder, delirium, personality disorder, Rett syndrome, any one selected from the group consisting of 14] pharmaceutical composition.
[19]
Central inflammatory disease,
Alzheimer's disease, Parkinson's disease, Lewy body type dementia, multiple system atrophy, Pick's disease, progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, frontotemporal lobar degeneration, Huntington's disease, amyotrophic lateral sclerosis Disorders, spinal muscular atrophy, spinal muscular atrophy, spinocerebellar degeneration, multiple sclerosis, Creutzfeldt-Jakob disease, schizophrenia, bipolar disorder, major depressive disorder (treatment-resistant depression, Postpartum depression), persistent depressive disorder (thymic disorder), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, obsessive compulsive disorder, trauma and stress related disorder, eating disorder, circadian It is described in [14] which is any one selected from the group consisting of rhythm sleep and awakening disorder, narcolepsy, substance related disorder (alcohol dependence, drug dependence etc), impulse control disorder, delirium, personality disorder, Rett syndrome Pharmaceutical composition.
[20]
Central inflammatory disease,
Schizophrenia, bipolar disorder, major depressive disorder (treatment resistant depression, postpartum depression), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, The pharmaceutical composition according to [14], which is any one selected from the group consisting of obsessive compulsive disorder.
[twenty one]
The compound or pharmacologically acceptable salt thereof according to any one of [1] to [9] for use in the treatment of inflammatory diseases.
[twenty two]
[11] A method for preventing and / or treating an inflammatory disease, which comprises administering an effective amount of the pharmaceutical composition according to [11].
　本発明の末梢性及び/又は中枢性の抗炎症作用を有する特定の化学構造を有する化合物又はその薬理上許容される塩は、様々な面からこれまでに存する抗炎症剤とは異なる特性を有していることから新規な医薬品として有用であると考えられる。
　また、本発明の化合物及びその薬理上許容される塩は、抗炎症活性、生物学的利用能、in vitro活性、in vivo活性、薬効発現の早さ、薬効の持続性、物理的安定性、薬物相互作用、毒性等の点で優れた性質を有し、医薬として有用である。 The compound having a specific chemical structure having a peripheral and / or central anti-inflammatory activity or a pharmacologically acceptable salt thereof of the present invention has properties different from anti-inflammatory agents existing in various aspects from the past. It is considered to be useful as a new medicine because of
In addition, the compound of the present invention and pharmacologically acceptable salts thereof have anti-inflammatory activity, bioavailability, in vitro activity, in vivo activity, rapid onset of drug efficacy, sustained efficacy, physical stability, It has excellent properties in terms of drug interaction, toxicity, etc. and is useful as a medicine.
　以下に本発明について詳細に説明する。 The present invention will be described in detail below.
(置換基、用語の説明等)
　本発明の態様の一つとしては、一般式(1)の化合物又はその薬理上許容される塩である。 (Substituents, explanation of terms, etc.)
One embodiment of the present invention is a compound of the general formula (1) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
[式中の記号は以下に定義される。
A1、A2、A3：それぞれ独立して、-CH=、又は、-N=
E：-CH2-、又は、-O-
G：硫黄原子、窒素原子、又は、酸素原子を有していてもよい5員芳香族複素環（当該環は２つ以上の結合手を有する）
但し、以下の5員芳香族複素環（左右の向きも記載のとおり）は除く。 [The symbols in the formula are defined below.
A 1 , A 2 and A 3 : each independently, -CH = or -N =
E: -CH 2- or -O-
G: 5-membered aromatic heterocycle which may have a sulfur atom, nitrogen atom or oxygen atom (the ring has two or more bonds)
However, the following five-membered aromatic heterocycle (the direction of right and left is also as described) is excluded.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
X：以下から選択されるいずれかの環（当該環は２つ以上の結合手を有し、２つの環が縮環した場合や、架橋した場合も含む） X: any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　A4、A5：それぞれ独立して、-CH=、又は、-N=
　A6：-CH2-、-O-、又は、-NH-
　ｍは、0、1、又は、2
Y：
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいフェニル基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基（架橋構造を有する場合がある）、又は、
置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基（架橋構造を有する場合がある）
なお、Yは連結するアミド部分と一緒になってラクタムを形成する場合がある。すなわち、以下の左に示す鎖状アミドの部分構造が、以下の右に示す環状アミドの部分構造になる場合がある。 A 4 and A 5 : each independently, -CH = or -N =
A 6 : -CH 2- , -O-, or -NH-
m is 0, 1 or 2
Y:
C1-C6 alkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
A phenyl group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
A C3-C8 cycloalkyl group (which may have a crosslinked structure) optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 1 or
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent group Y 1 (may have a crosslinked structure)
In addition, Y may form a lactam together with the linked amide moiety. That is, the partial structure of the linear amide shown on the left below may be the partial structure of the cyclic amide shown on the right below.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
置換基群Y1：
水酸基、
アミノ基、
ニトロ基、
シアノ基、
ハロゲン原子、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルコキシ基、
置換基群Y2から選択される同一または異なる1-2の基で置換されていてもよいアミノC1-C6アルキル基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基、
置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基、 Substituent group Y 1 :
Hydroxyl group,
Amino group,
Nitro group,
Cyano group,
Halogen atom,
A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ;
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
置換基群Y2：
水酸基、
ハロゲン原子、
C1-C6アルキル基、
C1-C6アルコキシ基、
置換基群Y3から選択される同一または異なる1-2の基で置換されていてもよいアミノ基、
置換基群Y3から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基、 Substituent group Y 2 :
Hydroxyl group,
Halogen atom,
C1-C6 alkyl group,
C1-C6 alkoxy group,
An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ;
4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3 ;
置換基群Y3：
水酸基、
ハロゲン原子、
C1-C6アルキル基、
C1-C6アルコキシ基 Substituent group Y 3 :
Hydroxyl group,
Halogen atom,
C1-C6 alkyl group,
C1-C6 alkoxy group
R1、R2：それぞれ独立して、水素原子、シアノ基、ハロゲン原子、C1-C6アルキル基、C1-C6アルコキシ基、C3-C8シクロアルキル基、C3-C8シクロアルコキシ基、ハロC1-C6アルキル基、ハロC1-C6アルコキシ基、フェニル基、5-6員芳香族複素環基、C1-C6アルキルカルボニル基、C1-C6アルコキシカルボニル基、C3-C8シクロアルキルカルボニル基、C3-C8シクロアルコキシカルボニル基、ハロC1-C6アルキルカルボニル基、ハロC1-C6アルコキシカルボニル基、フェニルカルボニル基、又は、フェノキシカルボニル基 R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
R3：水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、又は、C3-C8シクロアルキル基
R4：水素原子、ハロゲン原子、又は、C1-C6アルキル基
R5a、R5b、R5c、R5d：それぞれ独立して水素原子、又は、C1-C6アルキル基
n1、n2、n3：それぞれ独立して、0、1、又は、2］ R 3 : hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
R 4 : hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group
n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
　本発明の好適な態様としては、実施例に記載の化合物又はその薬理上許容される塩である。 Preferred embodiments of the present invention are the compounds described in the examples or pharmacologically acceptable salts thereof.
Gにおける「硫黄原子、窒素原子、又は、酸素原子を有していてもよい5員芳香族複素環」とは、5員であり、その環を構成する原子に窒素原子、酸素原子、及び、硫黄原子からなる群より選択される1-4個の原子を含んでいる芳香族環をいう、例えば、以下に示すような環である（結合手を２つ以上有するものとする）。 The “5-membered aromatic heterocycle optionally having sulfur atom, nitrogen atom or oxygen atom” in G is a 5-membered member, and atoms constituting the ring are nitrogen atom, oxygen atom, and An aromatic ring containing 1 to 4 atoms selected from the group consisting of sulfur atoms, such as a ring shown below (having two or more bonds).
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
好適には、以下のように結合手を有する5員芳香族複素環である。 Preferably, it is a 5-membered aromatic heterocycle having a bond as follows.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
(R3は、上記と同一の意味を有する。)
Xにおける「環」とは、例えば、以下のような環を示す。 (R 3 has the same meaning as above.)
The "ring" in X represents, for example, the following rings.
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
(R4は、上記と同一の意味を有する。)
本明細書における「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、又は、ヨウ素原子であり、好適には、フッ素原子又は塩素原子である。
本明細書における「C1-C6アルキル基」とは、炭素数1-6個の直鎖若しくは分枝鎖アルキル基であり、好適には、メチル基、エチル基、プロピル基、イソプロピル基又は、イソブチル基である。
本明細書における「C1-C6アルコキシ基」とは、酸素原子にC1-C6アルキル基が結合した基であり、好適には、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基又は、イソブトキシ基である。
本明細書における「C3-C8シクロアルキル基」とは、炭素数3-8個の環状アルキル基であり、好適には、シクロプロピル基、シクロブチル基、シクロペンチル基、又は、シクロヘキシル基を示す。また架橋構造を有する基としては、以下に示すような基も含む。 (R 4 has the same meaning as above.)
The "halogen atom" in the present specification is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
The "C1-C6 alkyl group" in the present specification is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or an isobutyl group. It is a group.
The "C1-C6 alkoxy group" in the present specification is a group in which a C1-C6 alkyl group is bonded to an oxygen atom, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or an isobutoxy group. is there.
The "C3-C8 cycloalkyl group" in the present specification is a cyclic alkyl group having 3 to 8 carbon atoms, and preferably represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Moreover, as group which has a crosslinked structure, the group as shown below is also included.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
本明細書における「C3-C8シクロアルコキシ基」とは、酸素原子にC3-C8シクロアルキル基が結合した基であり、好適には、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、又は、シクロヘキシルオキシ基である。
本明細書における「ハロC1-C6アルキル基」とは、C1-C6アルキル基に適当数のハロゲン原子が置換した基であり、好適には、ジフルオロメチル基、トリフルオロメチル基、ジフルオロエチル基である。
本明細書における「ハロC1-C6アルコキシ基」とは、C1-C6アルコキシ基に適当数のハロゲン原子が置換した基であり、好適には、ジフルオロメトキシ基、トリフルオロメトキシ基、ジフルオロエトキシ基である。
本明細書における「アミノC1-C6アルキル基」とは、C1-C6アルキル基にアミノ基が結合した基であり、好適には、アミノメチル基、アミノエチル基、アミノプロピル基である。
本明細書における「ジC1-C6アルキルアミノ基」とは、アミノ基に2つの同一又は異なるC1-C6アルキル基が結合した基であり、好適には、ジメチルアミノ基、ジエチルアミノ基である。
本明細書における「5-6員芳香族複素環基」とは、5員又は6員であり、窒素原子、酸素原子、及び、硫黄原子からなる群より選択される1-4個の原子を含有する単環性の芳香族環状基をいう、例えば、以下に示すような環に1つの結合手を有する基である。 The "C3-C8 cycloalkoxy group" in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to an oxygen atom, and preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or And cyclohexyloxy.
The "halo C1-C6 alkyl group" in the present specification is a group in which a C1-C6 alkyl group is substituted by an appropriate number of halogen atoms, and preferably a difluoromethyl group, a trifluoromethyl group or a difluoroethyl group. is there.
The "halo C1-C6 alkoxy group" in the present specification is a group in which an appropriate number of halogen atoms are substituted to a C1-C6 alkoxy group, and preferably a difluoromethoxy group, a trifluoromethoxy group, a difluoroethoxy group. is there.
The "amino C1-C6 alkyl group" in the present specification is a group in which an amino group is bonded to a C1-C6 alkyl group, and is preferably an aminomethyl group, an aminoethyl group or an aminopropyl group.
The “di C1-C6 alkylamino group” in the present specification is a group in which two identical or different C1-C6 alkyl groups are bonded to an amino group, and preferably a dimethylamino group or a diethylamino group.
The “5-6 membered aromatic heterocyclic group” in the present specification is a 5- or 6-membered, 1-4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. It refers to a monocyclic aromatic cyclic group contained, for example, a group having one bond in the ring as shown below.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
本明細書における「4-7員飽和複素環基」とは、4-7員であり、窒素原子、酸素原子、及び、硫黄原子からなる群より選択される1-3個の原子を含有する単環性の飽和環状基をいう、例えば、以下に示すような環に1つの結合手を有する基である。 The "4-7 membered saturated heterocyclic group" in the present specification is a 4-7 member, and contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. A monocyclic saturated cyclic group is, for example, a group having one bond in the ring as shown below.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
本明細書における「C1-C6アルキルカルボニル基」とは、カルボニル基にC1-C6アルキル基が結合した基であり、好適には、アセチル基、エチルカルボニル基、プロピルカルボニル基である。
本明細書における「C1-C6アルコキシカルボニル基」とは、カルボニル基にC1-C6アルコキシ基が結合した基であり、好適には、メトキシカルボニル基、エトキシカルボニル基、t-ブトキシカルボニル基である。
本明細書における「C3-C8シクロアルキルカルボニル基」とは、カルボニル基にC3-C8シクロアルキル基が結合した基であり、好適には、シクロプロピルカルボニル基、シクロブチルカルボニル基、シクロペンチルカルボニル基である。
本明細書における「C3-C8シクロアルコキシカルボニル基」とは、カルボニル基にC3-C8シクロアルコキシ基が結合した基であり、好適には、シクロプロポキシカルボニル基、シクロブトキシカルボニル基、シクロペンチルオキシカルボニル基である。
本明細書における「ハロC1-C6アルキルカルボニル基」とは、カルボニル基にハロC1-C6アルキル基が結合した基であり、好適には、ジフルオロメチルカルボニル基、トリフルオロメチルカルボニル基、ジフルオロエチルカルボニル基である。
本明細書における「ハロC1-C6アルコキシカルボニル基」とは、カルボニル基にハロC1-C6アルコキシ基が結合した基であり、好適には、ジフルオロメトキシカルボニル基、トリフルオロメトキシカルボニル基、ジフルオロエトキシカルボニル基である。
本明細書における「フェニルカルボニル基」とは、カルボニル基にフェニル基が結合した基である。
本明細書における「フェノキシカルボニル基」とは、カルボニル基にフェノキシ基が結合した基である。 The "C1-C6 alkyl carbonyl group" in the present specification is a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and is preferably an acetyl group, an ethyl carbonyl group or a propyl carbonyl group.
The “C1-C6 alkoxycarbonyl group” in the present specification is a group in which a C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a methoxycarbonyl group, an ethoxycarbonyl group or a t-butoxycarbonyl group.
The "C3-C8 cycloalkyl carbonyl group" in the present specification is a group in which a C3-C8 cycloalkyl group is bonded to a carbonyl group, and preferably a cyclopropyl carbonyl group, a cyclobutyl carbonyl group or a cyclopentyl carbonyl group. is there.
The "C3-C8 cycloalkoxycarbonyl group" in the present specification is a group in which a C3-C8 cycloalkoxy group is bonded to a carbonyl group, and preferably a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group It is.
The "halo C1-C6 alkyl carbonyl group" in the present specification is a group in which a halo C1-C6 alkyl group is bonded to a carbonyl group, and preferably a difluoromethyl carbonyl group, a trifluoromethyl carbonyl group, a difluoroethyl carbonyl group. It is a group.
The “halo C1-C6 alkoxycarbonyl group” in the present specification is a group in which a halo C1-C6 alkoxy group is bonded to a carbonyl group, and preferably a difluoromethoxycarbonyl group, a trifluoromethoxycarbonyl group, a difluoroethoxycarbonyl group. It is a group.
The "phenyl carbonyl group" in the present specification is a group in which a phenyl group is bonded to a carbonyl group.
The "phenoxycarbonyl group" in the present specification is a group in which a phenoxy group is bonded to a carbonyl group.
　「その薬理上許容される塩」とは、医薬として使用することができる塩を示す。化合物では、酸性基または塩基性基を有する場合に、塩基又は酸と反応させることにより、塩基性塩又は酸性塩にすることができるので、その塩を示す。 "The pharmacologically acceptable salt" indicates a salt that can be used as a pharmaceutical. When the compound has an acidic group or a basic group, a salt thereof is shown because it can be converted to a basic salt or an acidic salt by reacting with a base or an acid.
　化合物の薬理上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩；N-メチルモルホリン塩、トリエチルアミン塩、トリブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、N-メチルピペリジン塩、ピリジン塩、4-ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。 The pharmacologically acceptable “basic salt” of the compound is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; Methyl morpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salts such as picoline salt or glycine salt, lysine salt, They are amino acid salts such as arginine salts, ornithine salts, glutamates and aspartates, preferably alkali metal salts.
　化合物の薬理上許容される「酸性塩」としては、好適には、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩のようなアリ-ルスルホン酸塩、酢酸塩、リンゴ酸塩、フマ-ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、最も好適には、ハロゲン化水素酸塩(特に、塩酸塩)である。 The pharmacologically acceptable “acid salt” of the compound is preferably a hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydroiodide, nitrate, nitrate, Inorganic acid salts such as chlorate, sulfate and phosphate; methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonate such as ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid Allyl sulfonates such as salts, acetates, malates, fumarates, succinates, citrates, citrates, ascorbates, tartrates, borates, borates, maleates and the like; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate, and most preferably hydrohalide (especially, hydrochloride).
　本発明の化合物又はその薬理上許容される塩は、大気中に放置したり又は再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となったりする場合があり、本発明には、そのような各種の水和物、溶媒和物及び結晶多形の化合物も包含する。 The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become hydrate upon standing in the air or recrystallization. The present invention also encompasses compounds of such various hydrates, solvates and crystalline polymorphs.
　本発明の化合物、その薬理上許容される塩又はそれらの溶媒和物は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、互変異性体又はd体、l体等の光学異性体等の各種異性体が存在し得るが、化合物は、特に限定していない場合はそれら全ての異性体、立体異性体及びいずれの比率のこれら異性体及び立体異性体混合物をも包含するものである。これらの異性体の混合物は、公知の分割手段により分離することができる。
　本発明の化合物は、ラベル体、すなわち、化合物の1又は2以上の原子を同位元素(例えば、2H、3H、13C、14C、35S等)で置換した化合物も含まれる。 The compounds of the present invention, their pharmacologically acceptable salts or solvates thereof, depending on the kind and combination of substituents, may be cis isomer, geometric isomer such as trans isomer, tautomer or d isomer, l isomer etc. While various isomers such as optical isomers of may exist, the compounds include all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio, unless otherwise specified. It is Mixtures of these isomers can be separated by known resolution means.
The compounds of the present invention also include labels, that is, compounds in which one or more atoms of the compound are substituted with an isotope (eg, 2H, 3H, 13C, 14C, 35S, etc.).
　また、本発明には、いわゆる、プロドラッグも包含される。プロドラッグとは、加水分解により、若しくは、生理学的条件下で、化合物のアミノ基、水酸基、カルボキシル基等に変換し得る基を有する化合物であり、このようなプロドラッグを形成する基としては、Prog. Med.、第5巻、2157-2161ページ、1985年等に記載の基である。当該プロドラッグとして、より具体的には、
(1)化合物に、アミノ基が存在する場合には、
そのアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、そのアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物等である）等を挙げることができ、
(2)化合物に、水酸基が存在する場合には、
その水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例えば、その水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等である。）等を挙げることができる。
(3)また、化合物に、カルボキシ基が存在する場合には、
そのカルボキシ基がエステル化、アミド化された化合物（例えば、そのカルボキシ基がエチル　エステル化、フェニル　エステル化、カルボキシメチル　エステル化、ジメチルアミノメチル　エステル化、ピバロイルオキシメチル　エステル化、エトキシカルボニルオキシエチル　エステル化、アミド化又はメチルアミド化された化合物等である。）等が挙げられる。 The invention also encompasses so-called prodrugs. The prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, Prog. Med., Vol. 5, pp. 2157-2161 (1985). More specifically, as the prodrug,
(1) When an amino group is present in the compound,
Compounds in which the amino group is acylated, alkylated or phosphorylated (eg, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4- (4) And the like, and compounds such as methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylated compounds, etc.
(2) When a hydroxyl group is present in the compound,
The hydroxyl group is acylated, alkylated, phosphorylated, borated compound (eg, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, analylated, dimethylaminomethylcarbonylated Compounds, etc.) and the like.
(3) Also, if a carboxy group is present in the compound,
A compound in which the carboxy group is esterified or amidated (eg, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl ester And the like), and the like.
(製造方法)
　以下に製造方法について述べる。ただし、本発明は、下記の方法に何ら限定されるものではない。 (Production method)
The manufacturing method is described below. However, the present invention is not limited to the following method.
[A法]
A法は、本発明の化合物(A-IV)を製造する方法である。 [Method A]
Method A is a method of producing the compound (A-IV) of the present invention.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
［式中、使用されている記号は、上記と同様の意味を示す。Pnは、アミノ基を保護する基を示す。］ [Wherein the symbols used have the same meanings as described above. P n represents a group protecting an amino group. ]
(A1工程)アミノ基の脱保護をする工程
　化合物(A-I)からアミノ基の脱保護をすることで、化合物(A-III)を得る工程である。保護基がtert-ブトキシカルボニル基の場合、化合物(A-I)を溶媒に溶解し、酸を加えることで化合物(A-III)を得ることができる。通常、反応温度は-20～100℃程度であり、反応時間は1～24時間程度である。
　使用する酸としては、トリフルオロ酢酸、塩酸等を挙げることができる。
　使用する溶媒としては、ジクロロメタン、クロロホルム、メタノール、酢酸エチル、1,4-ジオキサン等、またはこれらの混合物を挙げることができる。 (Step A1) A step of deprotecting an amino group This step is to obtain a compound (A-III) by deprotecting an amino group from the compound (AI). When the protecting group is a tert-butoxycarbonyl group, compound (A-III) can be obtained by dissolving compound (AI) in a solvent and adding an acid. Usually, the reaction temperature is about −20 to 100 ° C., and the reaction time is about 1 to 24 hours.
As an acid to be used, trifluoroacetic acid, hydrochloric acid and the like can be mentioned.
As the solvent to be used, dichloromethane, chloroform, methanol, ethyl acetate, 1,4-dioxane etc., or a mixture thereof can be mentioned.
(A2工程)ニトロ基を還元してアミノ基とする工程
　化合物(A-II)から10％パラジウム炭素等の金属触媒の存在下、水素添加を行うことで化合物(A-III)を得る工程である。
　使用する溶媒としては、テ卜ラヒドロフラン、1,4-ジオキサン、メタノール、エタノール等、またはこれらの混合物を挙げることができ、通常、反応温度は室温～60℃程度であり、反応時間は0.5～24時間程度である。
　また、本工程は、鉄粉と塩化アンモニウムによる還元反応を、エタノール／水溶媒中で還流加熱することによっても行うことができる。 (Step A2) A step of reducing a nitro group to an amino group From the compound (A-II), a step of obtaining a compound (A-III) by hydrogenation in the presence of a metal catalyst such as 10% palladium carbon is there.
The solvent to be used may be terhydrohydrofuran, 1,4-dioxane, methanol, ethanol or the like, or a mixture thereof, and the reaction temperature is usually about room temperature to 60 ° C., and the reaction time is 0.5 to 24. It is about time.
In addition, this step can also be carried out by heating under reflux in an ethanol / water solvent a reduction reaction between iron powder and ammonium chloride.
(A3工程)縮合によりアミドを形成する工程
　(i)カルボン酸を酸クロリドとして活性化してから、化合物(A-III)と反応させて化合物(A-IV)を製造するか、(ii)カルボン酸と化合物(A-III)を縮合剤の存在下、反応させて化合物(A-IV)を製造する工程である。
　(i)の場合には、例えば、カルボン酸のジクロロメタン溶液中に、オキザリルクロリドと少量のジメチルホルムアミドを0℃～室温にて加えて、しばらく放置してから、0℃～室温にて化合物(A-III)とピリジン等の塩基を加えることで化合物(A-IV)を得ることができる。通常、反応温度は室温～80℃程度であり、反応時間は1～24時間程度である。
　(ii)の場合には、例えば、カルボン酸及び化合物(A-III)のジメチルホルムアミド又はジクロロメタン溶液に、塩基及び縮合剤を加えて化合物(A-IV)を得ことができる。通常、反応温度は室温～80℃程度であり、反応時間は1～24時間程度である。
　使用する塩基としては、ジイソプロピルエチルアミン等の3級アミンを挙げることができる。
　使用する縮合剤としては、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(DMT-MM)、N,N,N’,N’-テトラメチル-O-(ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート(HBTU)、ヘキサフルオロりん酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム(HATU)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(EDCI)等を挙げることができる。 (Step A3) A step of forming an amide by condensation (i) Activate carboxylic acid as acid chloride and then react with compound (A-III) to produce compound (A-IV), or (ii) Carboxylic acid In this step, the acid and the compound (A-III) are reacted in the presence of a condensing agent to produce a compound (A-IV).
In the case of (i), for example, oxalyl chloride and a small amount of dimethylformamide are added to a dichloromethane solution of a carboxylic acid at 0 ° C. to room temperature, and after standing for a while, the compound ( Compound (A-IV) can be obtained by adding A-III) and a base such as pyridine. Usually, the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
In the case of (ii), for example, a base and a condensing agent can be added to a solution of a carboxylic acid and a compound (A-III) in dimethylformamide or dichloromethane to obtain a compound (A-IV). Usually, the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
As a base to be used, tertiary amines such as diisopropylethylamine can be mentioned.
As the condensing agent to be used, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), N, N, N ', N '-Tetramethyl-O- (benzotriazol-1-yl) uronium hexafluorophosphate (HBTU), hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium (HATU), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and the like can be mentioned.
　Gが下記1,2,4-トリアゾール G is the following 1,2,4-triazole
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
　で表せる場合には、例えば、下記B法を用いてA法で使用される化合物(A-I)及び化合物(A-II)に相当する化合物を製造できる。また、下記E法を用いてA法の化合物(A-IV)に相当する化合物を製造できる。 Can be produced, for example, by using the following method B to produce a compound corresponding to the compound (A-I) and the compound (A-II) used in the method A. Further, a compound corresponding to the compound (A-IV) of Method A can be produced using Method E below.
[B法]
B法は、(B-III)(A法で使用される化合物(A-I)及び化合物(A-II)に相当する化合物)を製造する方法である。 [Method B]
Method B is a method for producing (B-III) (the compound corresponding to Compound (AI) and Compound (A-II) used in Method A).
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
［式中、使用されている記号は、上記と同様の意味を示す。N1は、PnNH-、又は、NO2-を示す。］ [Wherein the symbols used have the same meanings as described above. N 1 represents P n NH- or NO 2- . ]
　(B1工程)トリアゾール環を形成する工程
　化合物(B-I)をヨウ化メチル等のアルキル化剤と反応させ、対応するチオイミデートに変換し、化合物(B-II)と反応させて化合物(B-III)を製造する工程である。
　化合物(B-I)とヨウ化メチルの反応において使用する溶媒として、テトラヒドロフラン、1,4-ジオキサン等を挙げることができ、通常、反応温度は室温～80℃程度であり、反応時間は1～24時間程度である。
　また、チオイミデートと化合物(B-II)の反応において使用する溶媒として、テトラヒドロフラン、1,4-ジオキサン等を挙げることができ、通常、反応温度は室温～120℃程度であり、反応時間は1～24時間程度である。 (Step B1) Step of Forming Triazole Ring Compound (BI) is reacted with an alkylating agent such as methyl iodide to convert it into the corresponding thioimidate, and reacted with compound (B-II) to give compound (B-III) Manufacturing process.
Tetrahydrofuran, 1,4-dioxane, etc. can be mentioned as a solvent used in the reaction of compound (BI) and methyl iodide, and the reaction temperature is usually about room temperature to 80 ° C., and the reaction time is 1 to 24 hours. It is an extent.
Further, examples of the solvent used in the reaction of thioimidate with the compound (B-II) include tetrahydrofuran and 1,4-dioxane, and the reaction temperature is usually from room temperature to 120 ° C., and the reaction time is from 1 to It is about 24 hours.
[C法]
C法は、化合物(C-III)(B法で使用される化合物(B-I)に相当する化合物)を製造する方法である。 [Method C]
Method C is a method of producing a compound (C-III) (a compound corresponding to the compound (BI) used in the method B).
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
　(C1工程)縮合によりアミドを形成する工程
　市販または既知の方法により合成可能な化合物(C-I)からA法A3工程と同様の条件により、化合物(C-II)を製造する工程である。
　(C2工程)チオカルボニル化する工程
　化合物(C-II)を溶媒中、ローソン試薬等の硫化剤と反応させることで化合物(C-III)を得る工程である。
　使用する溶媒としては、テ卜ラヒドロフラン、1,4-ジオキサン等、またはこれらの混合物を挙げることができ、通常、反応温度は0～100℃程度であり、反応時間は0.5～24時間程度である。 (Step C1) A step of forming an amide by condensation This is a step of producing a compound (C-II) from a compound (CI) which can be synthesized by a commercially available method or a known method under the same conditions as in the step A3 step.
(Step C2) Step of Thiocarbonylation This is a step of reacting compound (C-II) with a sulfurizing agent such as Lawesson's reagent in a solvent to obtain compound (C-III).
As the solvent to be used, hydrochlorohydrofuran, 1,4-dioxane, etc., or a mixture thereof can be mentioned. Usually, the reaction temperature is about 0 to 100 ° C., and the reaction time is about 0.5 to 24 hours. .
[D法]
D法は、化合物(D-II)(B法で使用される化合物(B-II)に相当する化合物)を製造する方法である。 [Method D]
Method D is a method of producing a compound (D-II) (a compound corresponding to the compound (B-II) used in the method B).
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
［式中、使用されている記号は、上記と同様の意味を示す。PCは、カルボキシ基を保護する基を示す。］ [Wherein the symbols used have the same meanings as described above. P C represents a group that protects a carboxy group. ]
　(D1工程)ヒドラジドを形成する工程
　市販または既知の方法により合成可能な化合物(D-I)を溶媒中ヒドラジンと加熱し、化合物(D-II)を製造する工程である。
　使用する溶媒としては、メタノール、エタノール、水等、またはこれらの混合物を挙げることができ、通常、反応温度は室温～100℃程度であり、反応時間は0.5～24時間程度である。 (Step D1) A step of forming a hydrazide This is a step of heating a compound (DI) which can be synthesized by a commercially available method or a known method with hydrazine in a solvent to produce a compound (D-II).
As the solvent to be used, methanol, ethanol, water and the like, or a mixture thereof can be mentioned. Usually, the reaction temperature is about room temperature to 100 ° C., and the reaction time is about 0.5 to 24 hours.
[E法]
E法は、本発明の化合物(E-VIII)(A法の化合物(A-IV)に相当する化合物)を製造する方法である。 [Method E]
Method E is a method of producing the compound (E-VIII) of the present invention (the compound corresponding to the compound (A-IV) of Method A).
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
［式中、使用されている記号は、上記と同様の意味を示す。POは、水酸基を保護する基を示す。］ [Wherein the symbols used have the same meanings as described above. P 2 O represents a group that protects a hydroxyl group. ]
(E1工程)ヒドラジドを形成する工程
　既知の方法により合成可能な化合物(E-I)から、D法D1工程と同様の条件により、化合物(E-II)を製造する工程である。
(E2工程)トリアゾール環を形成する工程
　化合物(E-II)と化合物(E-III)(C法の(C-III)に相当する化合物)からB法B1工程と同様の条件により、化合物(E-IV)を製造する工程である。
(E3工程)ニトロ基を還元してアミノ基とする工程
　化合物(E-IV)から、A法A2工程と同様の条件により、化合物(E-V)を製造する工程である。
(E4工程)縮合によりアミドを形成する工程
　化合物(E-V)と対応するカルボン酸からA法A3工程と同様の条件により、化合物(E-VI)を製造する工程である。
(E5工程)脱保護を行なう工程
　化合物(E-VI)から水酸基の脱保護をすることで、化合物(E-VII)を得る工程である。保護基がテトラヒドロピラニル基の場合、化合物(E-VI)を溶媒に溶解し、酸を加えることで化合物(E-VII)を得ることができる。通常、反応温度は0～80℃程度であり、反応時間は0.5～24時間程度である。
　酸としては、塩酸、硫酸、酢酸、p-トルエンスルホン酸、またはp-トルエンスルホン酸ピリジニウム等が挙げられる。
　溶媒としては、メタノール、エタノール、テトラヒドロフラン、1,4-ジオキサン、酢酸エチル、水、またはこれらの混合物等を挙げることができる。
(E6工程)光延反応によってエーテル化する工程
　化合物(E-VII)からホスフィンおよびアゾジカルボン酸エステルまたはジアゾジカルボキサミド存在下、対応するアルコールを用いて、化合物(E-VIII)を得る工程である。
　使用するホスフィンとしては、トリフェニルホスフィン、トリ-n-ブチルホスフィン等を挙げることができる。
　使用するアゾジカルボン酸エステルまたはジアゾジカルボキサミドとしては、アゾジカルボン酸ジエチル、アゾジカルボン酸ジ-tert-ブチル、1,1’-(アゾジカルボニル)ジピリジン等を挙げることができる。
　使用する溶媒としては、テ卜ラヒドロフラン、1,4-ジオキサン、トルエン等、またはこれらの混合物を挙げることができ、通常、反応温度は0～100℃程度で、反応時間は0.5～24時間程度である。 (Step E1) A step of forming a hydrazide This is a step of producing a compound (E-II) from a compound (EI) which can be synthesized by a known method, under the same conditions as in the step D1.
(Step E2) A step of forming a triazole ring Compound (E-II) and compound (E-III) (a compound corresponding to (C-III) in Method C) to compound B (Compound B) under the same conditions as in Method B1. E-IV) is produced.
(Step E3) A step of reducing a nitro group to an amino group This is a step of producing a compound (EV) from compound (E-IV) under the same conditions as in Step A2.
(Step E4) A step of forming an amide by condensation This is a step of producing a compound (E-VI) from the compound (EV) and a corresponding carboxylic acid under the same conditions as in the method A3 step.
(Step E5) Step for Deprotection This is a step for obtaining compound (E-VII) by deprotecting a hydroxyl group from compound (E-VI). When the protecting group is a tetrahydropyranyl group, compound (E-VI) can be dissolved in a solvent and acid can be added to give compound (E-VII). Usually, the reaction temperature is about 0 to 80 ° C., and the reaction time is about 0.5 to 24 hours.
Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, or pyridinium p-toluenesulfonate.
As the solvent, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, water, or a mixture thereof can be mentioned.
(Step E6) A step of etherifying by Mitsunobu reaction This is a step of obtaining compound (E-VIII) from compound (E-VII) using a corresponding alcohol in the presence of phosphine and azodicarboxylic acid ester or diazodicarboxamide.
As the phosphine to be used, triphenyl phosphine, tri-n-butyl phosphine and the like can be mentioned.
Examples of the azodicarboxylate ester or diazodicarboxamide to be used include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipyridine and the like.
Examples of the solvent to be used include terehydrofuran, 1,4-dioxane, toluene and the like, or a mixture thereof. Usually, the reaction temperature is about 0 to 100 ° C., and the reaction time is about 0.5 to 24 hours. is there.
　Gが下記ピラゾール G is the following pyrazole
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　で表せる場合には、例えば、下記F法を用いて、A法で使用される化合物(A-II)に相当する化合物を製造できる。 Can be produced, for example, using the following method F to produce a compound corresponding to the compound (A-II) used in method A.
[F法]
F法は、化合物(F-II)(A法で使用される化合物(A-II)に相当する化合物)を製造する方法である。 [Method F]
Method F is a method of producing a compound (F-II) (a compound corresponding to the compound (A-II) used in the method A).
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
(F1工程)光延反応によってエーテル化する工程
　市販または既知の方法により合成可能な化合物(F-I)からE法E6工程と同様の条件により、化合物(F-II)を製造する工程である。 (Step F1) Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (F-II) from compound (FI) commercially available or which can be synthesized by a known method under the same conditions as in step E6 of method E.
　Gが下記1,2,4-トリアゾール G is the following 1,2,4-triazole
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　で表せる場合には、例えば、下記G法を用いて、A法で使用される化合物(A-II)に相当する化合物を製造できる。 Can be produced, for example, using the following method G to produce a compound corresponding to the compound (A-II) used in method A.
[G法]
G法は、化合物(G-III)(A法で使用される化合物(A-II)に相当する化合物)を製造する方法である。 [G method]
Method G is a method of producing a compound (G-III) (a compound corresponding to the compound (A-II) used in the method A).
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
(G1工程)エステルを還元し、アルコールを形成する工程
　既知の方法により合成可能な化合物(G-I)から、J法J2工程と同様の条件により、化合物(G-II)を製造する工程である。
(G2工程)光延反応によってエーテル化する工程
　化合物(G-II)から、E法E6工程と同様の条件により、化合物(G-III)を製造する工程である。 (Step G1) A step of reducing an ester to form an alcohol This is a step of producing a compound (G-II) from a compound (GI) which can be synthesized by a known method, under the same conditions as in the step J2 of step J2.
(Step G2) A step of etherifying by Mitsunobu reaction This is a step of producing a compound (G-III) from the compound (G-II) under the same conditions as in the step E6.
　Gが下記イミダゾール G is the following imidazole
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
　で表せる場合には、例えば、下記H法を用いて、A法で使用される化合物(A-I)に相当する化合物を製造できる。 Can be produced, for example, using the following Method H to produce a compound corresponding to the compound (A-I) used in Method A.
[H法]
H法は、化合物(H-III)(A法で使用される化合物(A-I)に相当する化合物)を製造する方法である。 [Method H]
Method H is a method of producing a compound (H-III) (a compound corresponding to the compound (AI) used in the method A).
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
［式中、使用されている記号は、上記と同様の意味を示す。Lは、脱離基を示し、Bhは、ボロン酸又はボロン酸ピナコールエステル等を示し、Bocは、t-ブトキシカルボニル基を示す。］
(H1工程)光延反応によってエーテル化する工程
　市販または既知の方法により合成可能な化合物(H-I)と対応するアルコールから、E法E6工程と同様の条件により、化合物(H-II)を製造する工程である。
(H2工程)遷移金属触媒を用いてカップリング反応を行なう工程
　化合物(H-II)から塩基存在下、パラジウム触媒と対応するボロン酸又はボロン酸ピナコールエステルを用いて、化合物(H-III)を得る工程である。
　使用するパラジウム触媒としては、テ卜ラキス(卜リフェニルホスフィン)パラジウム、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム、卜リス(ジベンジリデンアセトン)ジパラジウム、酢酸パラジウム、アセチルアセトンパラジウム、ビス(卜リフェニルホスフィン)パラジウムジクロリド等を挙げることができる。
　使用する塩基としては卜リエチルアミン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(DBU)、1,5-ジアザビシクロ[4.3.0]-5-ノネン(DBN)、炭酸水素カリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸ナトリウム、水酸化カリウム、水酸化ナトリウム、リン酸カリウム、またはリン酸ナトリウム等を挙げることができる。
　使用する溶媒としては、メタノール、エタノール、テ卜ラヒドロフラン、1,4-ジオキサン、水、N,N-ジメチルホルムアミド、ジメチルスルホキシド、卜ルエン等、またはこれらの混合物を挙げることができ、通常、反応温度は60～120℃程度であり、反応時間は0.5～24時間程度である。 [Wherein the symbols used have the same meanings as described above. L represents a leaving group, B h represents a boronic acid or a boronic acid pinacol ester, etc., and Boc represents a t-butoxycarbonyl group. ]
(Step H1) A step of etherifying by Mitsunobu reaction A step of producing compound (H-II) from compound (HI) and a corresponding alcohol which can be synthesized by a commercially available method or a known method under the same conditions as in step E6 step It is.
(H2 step) Step of conducting coupling reaction using transition metal catalyst Compound (H-III) can be prepared from compound (H-II) using palladium catalyst and corresponding boronic acid or boronic acid pinacol ester in the presence of a base Is the process of
As the palladium catalyst to be used, tetrakis (triphenylphosphine) palladium, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium acetylacetonate And bis (triphenylphosphine) palladium dichloride and the like.
As a base to be used, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), hydrogen carbonate Potassium, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, sodium phosphate and the like can be mentioned.
As the solvent to be used, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, N, N-dimethylformamide, dimethylsulfoxide, toluene, etc., or a mixture thereof can be mentioned, and usually the reaction temperature Is about 60 to 120.degree. C., and the reaction time is about 0.5 to 24 hours.
　Gが下記イソキサゾール G is the following isoxazole
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　で表せる場合には、例えば、下記I法を用いて、A法で使用される化合物(A-II)に相当する化合物を製造できる。 Can be produced, for example, using the following method I to produce a compound corresponding to the compound (A-II) used in method A.
[I法]
I法は、化合物(I-II)(A法で使用される化合物(A-II)に相当する化合物)を製造する方法である。 [Method I]
Method I is a method of producing a compound (I-II) (a compound corresponding to the compound (A-II) used in the method A).
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
(I1工程)光延反応によってエーテル化する工程
　市販または既知の方法によって合成可能な化合物(I-I)と対応するアルコールから、E法E6工程と同様の条件により、化合物(I-II)を製造する工程である。 (Step I1) A step of etherifying by Mitsunobu reaction A step of producing compound (I-II) from compound (II) which can be synthesized by a commercially available method or a known method and an alcohol corresponding thereto, under the same conditions as in Step E6. It is.
　Gが下記ピラゾール G is the following pyrazole
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　で表せる場合には、例えば、下記J法を用いて、A法で使用される化合物(A-II)に相当する化合物を製造できる。 Can be produced, for example, using the following Method J to produce a compound corresponding to the compound (A-II) used in Method A.
[J法]
J法は、化合物(J-IV)(A法で使用される化合物(A-II)に相当する化合物)を製造する方法である。 [Method J]
Method J is a method of producing a compound (J-IV) (a compound corresponding to the compound (A-II) used in the method A).
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
(J1工程)ピラゾールのアミノ基を保護する工程
　既知の方法により合成可能な化合物(J-I)から、ピラゾールのアミノ基に保護基を導入する事によって、化合物(J-II)を製造する工程である。保護基として、テトラヒドロピラニル基を用いる場合、化合物(J-I)を溶媒中、酸性条件下3,4-ジヒドロ-2H-ピランと反応させることで化合物(J-II)が得られる。通常、反応温度は室温～80℃程度であり、反応時間は1～24時間程度である。
　使用する酸としては塩酸、硫酸、酢酸、p-トルエンスルホン酸、またはp-トルエンスルホン酸ピリジニウム等を挙げることができる。
　溶媒としては、トルエン、テトラヒドロフラン、1,4-ジオキサン等、またはこれらの混合物を挙げることができる。
(J2工程)エステルを還元し、アルコールを形成する工程
　化合物(J-II)を溶媒中、還元剤と反応させることで化合物(J-III)を製造する工程である。
　使用する還元剤としては、リチウムアルミニウムヒドリド(LAH)、ジイソブチルアルミニウムヒドリド(DIBAL)等を挙げることができる。
　使用する溶媒としては、トルエン、ジエチルエーテル、テトラヒドロフラン等、またはこれらの混合物を挙げることができ、通常、反応温度は-78～100℃程度であり、反応時間は0.5～24時間程度である。
(J3工程)光延反応によってエーテル化する工程
　化合物(J-III)と対応するアルコールから、E法E6工程と同様の条件により、化合物(J-IV)を製造する工程である。 (Step J1) The step of protecting the amino group of pyrazole This is a step of producing compound (J-II) from compound (JI) which can be synthesized by a known method, by introducing a protecting group into the amino group of pyrazole. . When a tetrahydropyranyl group is used as a protecting group, compound (JI) is reacted with 3,4-dihydro-2H-pyran in a solvent under acidic conditions to give compound (J-II). Usually, the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
Examples of the acid to be used include hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate and the like.
As the solvent, toluene, tetrahydrofuran, 1,4-dioxane and the like, or a mixture thereof can be mentioned.
(Step J2) A step of reducing an ester to form an alcohol This is a step of producing a compound (J-III) by reacting the compound (J-II) with a reducing agent in a solvent.
As a reducing agent to be used, lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL), etc. can be mentioned.
As the solvent to be used, toluene, diethyl ether, tetrahydrofuran or the like, or a mixture thereof can be mentioned. Usually, the reaction temperature is about −78 to 100 ° C., and the reaction time is about 0.5 to 24 hours.
(Step J3) Step of Etherifying by Mitsunobu Reaction This is a step of producing compound (J-IV) from compound (J-III) and an alcohol corresponding thereto, under the same conditions as Step E6.
[K法]
K法は、化合物(K-I)のGに保護基Pnが含まれるとき、その保護基を脱保護して本発明の化合物(K-II)(A法で使用される化合物(A-IV)に相当する化合物)を製造する方法である。 [Method K]
In Method K, when G of compound (KI) contains a protecting group P n , the protecting group is deprotected to give a compound (K-II) of the present invention (the compound used in Method A (A-IV) And the corresponding compound).
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
［式中、使用されている記号は、上記と同様の意味を示す。］ [Wherein the symbols used have the same meanings as described above. ]
(K1工程)脱保護を行なう工程
　化合物(K-I)から脱保護をする事によって、化合物(K-II)を得る工程である。保護基がテトラヒドロピラニル基の場合、化合物(K-I)を溶媒に溶解し、酸を加えることで化合物(K-II)が得られる。通常、反応温度は室温～80℃程度であり、反応時間は1～24時間程度である。
　酸としては、塩酸、硫酸、p-トルエンスルホン酸、またはp-トルエンスルホン酸ピリジニウム等を挙げることができる。
　溶媒としては、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、1,4-ジオキサン、水等またはこれらの混合物を挙げることができる。 (Step K1) Step for Deprotection This is a step for obtaining compound (K-II) by performing deprotection from compound (KI). When the protecting group is a tetrahydropyranyl group, the compound (KI) is dissolved in a solvent, and an acid is added to give a compound (K-II). Usually, the reaction temperature is about room temperature to 80 ° C., and the reaction time is about 1 to 24 hours.
Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate.
As the solvent, methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water and the like or mixtures thereof can be mentioned.
　上記の方法で製造された化合物は、公知の方法、例えば、抽出、沈殿、蒸留、クロマトグラフィー、分別再結晶、再結晶等により単離、精製することができる。
　また、化合物又は製造の中間体が不斉炭素を有する場合には光学異性体が存在する。これらの光学異性体は、適切な塩と再結晶する分別再結晶(塩分割)やカラムクロマトグラフィー等の常法によって、それぞれの異性体を単離、精製することができる。ラセミ体から光学異性体を分割する方法の参考文献としては、J.Jacquesらの「Enantiomers,Racemates and Resolution,John Wiley And Sons,Inc.」を挙げることができる。 The compounds produced by the above methods can be isolated and purified by known methods such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like.
In addition, when the compound or intermediate of production has asymmetric carbon, optical isomers exist. These optical isomers can be isolated and purified by a conventional method such as fractional recrystallization (salt resolution) or recrystallization with an appropriate salt. As a reference for the method of resolving an optical isomer from a racemate, mention may be made of J. Jacques et al., "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.".
(投与形態)
　投与は錠剤、丸剤、力プセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等用の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 (Administration form)
Administration is orally using tablets, pills, capsules, granules, powders, solutions, etc., or injections for intraarticular, intravenous, intramuscular etc., suppositories, eye drops, eye ointments, for transdermal use It may be in any form of parenteral administration by liquid solution, ointment, transdermal patch, transmucosal liquid, transmucosal patch, inhalant and the like.
　経口投与のための固体組成物としては、
錠剤、散剤、顆粒剤等が用いられる。このような固体組成物は、1種又は2種以上の有効成分と、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピ口リドン、及び/又はメタケイ酸アルミン酸マグネシウム等とからなる。その固体組成物には、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤や力ルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は、必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。 As solid compositions for oral administration,
Tablets, powders, granules and the like are used. Such solid compositions may comprise one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl piriddon And / or magnesium metasilicate magnesium aluminate and the like. The solid composition contains, according to a conventional method, an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium ruboxymethylstarch, a stabilizer, and a solubilizer. It may be done. The tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.
　経口投与のための液体組成物としては、
薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等が用いられる。このような液体組成物には、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを添加することが可能である。その液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 As a liquid composition for oral administration,
Pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like are used. To such liquid compositions it is possible to add generally used inert diluents such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, solubilizers, adjuvants such as wetting agents, sweetening agents, flavoring agents, fragrances, preservatives.
　非経口投与のための注射剤としては、
無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤等が用いられる。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液等がある。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール又はオリーブ油のような植物油、エタノールのようなアルコール類、又はボリソルベート80等がある。このような注射剤組成物には、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでいてもよい。これら注射剤組成物は、例えばバクテリア保留フィルターを通すろ過、殺菌剤の配合又は照射によって無菌化することが可能である。また、これら注射剤組成物は、無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 As an injection for parenteral administration,
Sterile aqueous or non-aqueous solutions, suspensions, emulsions or the like are used. The aqueous solvent includes, for example, distilled water for injection or physiological saline. Nonaqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or Polysorbate 80. Such an injection composition may further contain a tonicity agent, preservative, wetting agent, emulsifying agent, dispersing agent, stabilizing agent, or solubilizing agent. These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, incorporation of a bactericide or irradiation. In addition, these injection compositions can be used to prepare sterile solid compositions and to be dissolved or suspended in sterile water or sterile injectable solvent prior to use.
　外用剤としては、
軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等が用いられる。これらの外用剤は、一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が使用される。 For external use,
Ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like are used. These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like. For example, as an ointment or lotion base, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauro macrogol, sorbitan sesquioleate, etc. used.
　吸入剤や経鼻剤等の経粘膜剤は固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。これらの経粘膜剤では、その投与方法として、適当な吸入又は吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のテバイスや噴霧器を使用して、化合物を単独で又は処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液又は懸濁液として投与することができる。乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有力プセルを使用することができる。あるいは、適当な駆出剤を使用することもできる。例えば、クロロフルオロアル力ン、ヒドロフルオロアル力ン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。 Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semisolid form, and can be produced according to a conventionally known method. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. With these transmucosal agents, devices suitable for inhalation or insufflation can be used as the method of administration. For example, the compounds may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices. be able to. The dry powder inhaler or the like may be for single or multiple administration, and dry powder or powder containing capsules may be used. Alternatively, a suitable propellant may be used. For example, it may be in the form of a pressurized aerosol spray using a suitable gas such as chlorofluoroaluminum, hydrofluoroaluminum or carbon dioxide.
(投与量)
　通常経口投与の場合、1日の投与量は、体重当たり約0.001-100mg/kg、好ましくはO.1-30mg/kg、更に好ましくは0.1-10mg/kgが適当であり、これを1回で、あるいは2回以上に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.0001-10mg/kgが適当で、1日1回または複数回に分けて投与する。また、経粘膜剤としては、体重当たり約0.001-100mg/kgを1日1回または複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 (Dose)
In the case of ordinary oral administration, the daily dose is suitably about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg of body weight, once Or divided into two or more doses. When administered intravenously, the appropriate daily dose is about 0.0001-10 mg / kg of body weight, which is administered once or several times daily. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg of body weight is administered in one or more divided doses a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
(併用)
　本発明では、その有効性を示すと考えられる疾患の種々の治療剤又は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 (In combination)
In the present invention, it can be used in combination with various therapeutic or preventive agents for diseases which are considered to show its efficacy. The combination may be administered simultaneously, or separately separately, continuously, or at desired time intervals. Co-administered formulations may be formulated or formulated separately.
(製剤例1) 散剤
　本発明の化合物又はその塩 5g、乳糖 895gおよびトウモロコシデンプン 100gをブレンダーで混合することにより、散剤が得られる。
(製剤例2) 顆粒剤
　本発明の化合物又はその塩 5g、乳糖865gおよび低置換度ヒドロキシプロピルセルロース100gを混合した後、10%ヒドロキシプロピルセルロース水溶液 300gを加えて練合する。これを押出造粒機を用いて造粒し、乾燥すると顆粒剤が得られる。
(製剤例3) 錠剤
　本発明の化合物又はその塩 5g、乳糖 90g、トウモロコシデンプン 34g、結晶セルロース 20gおよびステアリン酸マグネシウム 1gをブレンダーで混合した後、打錠機で打錠することにより、錠剤が得られる。 Formulation Example 1 Powdered Powder A powder is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 895 g of lactose and 100 g of corn starch in a blender.
Formulation Example 2 Granules After 5 g of the compound of the present invention or a salt thereof, 865 g of lactose and 100 g of low substituted hydroxypropyl cellulose are mixed, 300 g of a 10% aqueous solution of hydroxypropyl cellulose is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
Formulation Example 3 Tablet A compound is obtained by mixing 5 g of the compound of the present invention or a salt thereof, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender and tableting with a tableting machine. Be
　本発明の化合物又はその薬理上許容される塩の薬理活性は、以下の試験により確認した。
(試験例)IL-10増加率の測定
　0.5%(w/v)のmethyl cellulose に懸濁した被験物質100 mg/kgをマウスに経口投与し、1時間後、lipopolysaccharide(LPS, Sigma-Aldrich, L2630(商品名))0.4mg/kgを腹腔内投与して炎症を惹起した。LPSを投与してから1時間後、イソフルラン麻酔下にて大静脈から採血し、血清分離剤入りチューブに採取した。室温で20-30分間静置した後、12,000 rpmで5分間、4度で遠心分離し、血清を採取した。その後、Mouse IL-10 Quantikine ELISA Kit (R&D systems, M1000B(商品名))あるいは、Mouse IL-10 Immunoassay kit (PerkinElmer, AL502(商品名)) を用い、本キットのプロトコルに従って、血清中のIL-10の量を測定した。血清は、キット付属の希釈液で10倍希釈して用いた。化合物のIL-10増加率(%コントロール比)については、以下の数式から算出した。
IL-10増加率(％コントロール比)＝(化合物投与群のIL-10量)×100/(0.5%(w/v)methyl cellulose投与群のIL-10量) The pharmacological activity of the compound of the present invention or a pharmacologically acceptable salt thereof was confirmed by the following test.
(Test Example) Measurement of IL-10 increase rate 100 mg / kg of test substance suspended in 0.5% (w / v) methyl cellulose was orally administered to mice, and 1 hour later, lipopolysaccharide (LPS, Sigma-Aldrich, L2630 (trade name) 0.4 mg / kg was intraperitoneally administered to cause inflammation. One hour after administration of LPS, blood was collected from the vena cava under isoflurane anesthesia and collected in a tube containing a serum separating agent. After standing at room temperature for 20-30 minutes, the serum was collected by centrifugation at 12,000 rpm for 5 minutes at 4 degrees. Then, using the Mouse IL-10 Quantikine ELISA Kit (R & D systems, M1000B (trade name)) or the Mouse IL-10 Immunoassay kit (PerkinElmer, AL502 (trade name)), according to the protocol of this kit, IL- The amount of 10 was measured. The serum was used after being diluted 10-fold with the dilution solution attached to the kit. The IL-10 increase rate (% control ratio) of the compound was calculated from the following formula.
IL-10 increase rate (% control ratio) = (IL-10 amount in compound administration group) x 100 / (IL-10 amount in 0.5% (w / v) methyl cellulose administration group)
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
　本試験結果より、本発明の化合物又はその薬理上許容される塩が、炎症性疾患の予防及び/又は治療に有効であることが示された。 From the test results, it was shown that the compound of the present invention or a pharmacologically acceptable salt thereof is effective for the prevention and / or treatment of inflammatory diseases.
　以下、実施例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
　以下の実施例において、核磁気共鳴（以下、1H NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。分裂パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をm、ブロードをbrで示した。 Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto.
In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR) spectra were described using δ values (ppm) as chemical shift values with tetramethylsilane as a standard substance. The split pattern is indicated by s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad.
（実施例1）
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド Example 1
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] Benzamide
（1a）
2-[3-(トリフルオロメチル)フェノキシ]アセトヒドラジド
2-[3-(trifluoromethyl)phenoxy]acetohydrazide
メチル 2-[3-(トリフルオロメチル)フェノキシ]アセテート(CAS Registry Number: 588-26-1, WO2008078291) (3 g, 13 mmol)をエタノール(15 mL)に溶解し、ヒドラジン一水和物(9.7 g, 192 mmol)を加え、加熱還流下にて8時間攪拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル］にて精製し、標記化合物1.2 g(収率：40%）を白色固体として得た。 (1a)
2- [3- (Trifluoromethyl) phenoxy] acetohydrazide
2- [3- (Trifluoromethyl) phenoxy] acetohydrazide
Methyl 2- [3- (trifluoromethyl) phenoxy] acetate (CAS Registry Number: 588-26-1, WO2008078291) (3 g, 13 mmol) was dissolved in ethanol (15 mL), and hydrazine monohydrate ( 9.7 g (192 mmol) was added, and the mixture was stirred for 8 hours while heating under reflux.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography [eluting solvent: methanol / ethyl acetate] to obtain 1.2 g of the title compound (yield: 40%) was obtained as a white solid.
（1b）
tert-ブチル N-[4-(メチルカルバモチオイル)フェニル]カルバメート
tert-butyl N-[4-(methylcarbamothioyl)phenyl]carbamate
tert-ブチル N-[4-(メチルカルバモイル)フェニル]カルバメート(CAS Registry Number: 179625-42-4, WO1996013485) (1 g, 4.0 mmol)をテトラヒドロフラン(20 mL)に溶解し、ローソン試薬(1.8 g, 4.4 mmol)を加え、室温で4時間撹拌した。
1N水酸化ナトリウム水溶液を加え、反応混合物をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、ジエチルエーテルでトリチュレーションし、標記化合物800 mg（収率：80%）を黄白色固体として得た。 (1b)
tert-Butyl N- [4- (methylcarbamothiol) phenyl] carbamate
tert-butyl N- [4- (methylcarbamothiol) phenyl] carbamate
tert-Butyl N- [4- (methylcarbamoyl) phenyl] carbamate (CAS Registry Number: 179625-42-4, WO1996013485) (1 g, 4.0 mmol) is dissolved in tetrahydrofuran (20 mL), and Lawesson's reagent (1.8 g) , 4.4 mmol) was added and stirred at room temperature for 4 hours.
Aqueous 1 N sodium hydroxide solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether to give 800 mg (yield: 80%) of the title compound as a pale yellow solid.
（1c）
tert-ブチル N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバメート
tert-butyl N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamate
実施例1(1b)のtert-ブチル N-[4-(メチルカルバモチオイル)フェニル]カルバメート(200 mg, 0.75 mmol)をテトラヒドロフラン(1 mL)に溶解し、ヨウ化メチル(0.93 mL, 15 mmol)を加え、室温にて3時間撹拌した。
減圧下にて溶媒を留去した後、残渣をエタノール(3 mL)に溶解し、実施例1(1a)の2-[3-(トリフルオロメチル)フェノキシ]アセトヒドラジド(352 mg, 1.5 mmol)を加え、100℃にて6時間攪拌した。
反応温度を室温に戻した後、不溶物を濾過し、減圧下にて溶媒を留去した。残渣をジクロロメタンでトリチュレーションし、標記化合物230 mg（収率：68%）を黄白色固体として得た。 (1c)
tert-Butyl N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] carbamate
tert-butyl N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] carbamate
The tert-butyl N- [4- (methylcarbamothiol) phenyl] carbamate (200 mg, 0.75 mmol) of Example 1 (1b) was dissolved in tetrahydrofuran (1 mL), methyl iodide (0.93 mL, 15 mmol) ) Was added and stirred at room temperature for 3 hours.
After evaporating the solvent under reduced pressure, the residue is dissolved in ethanol (3 mL), and 2- [3- (trifluoromethyl) phenoxy] acetohydrazide (352 mg, 1.5 mmol) of Example 1 (1a) Was added and stirred at 100 ° C. for 6 hours.
After the reaction temperature was returned to room temperature, the insolubles were filtered and the solvent was distilled off under reduced pressure. The residue was triturated with dichloromethane to give 230 mg (yield: 68%) of the title compound as a pale yellow solid.
（1d）
4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン
4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]aniline
実施例1(1c)のtert-ブチル N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバメート(230 mg, 0.51 mmol)を2N塩酸-メタノール(3 mL)に溶解し、室温にて18時間攪拌した。
減圧下にて溶媒を留去した後、炭酸カリウム水溶液を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、標記化合物170 mg（収率：95%）を白色固体として得た。 (1d)
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline
4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline
Tert-Butyl N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl of Example 1 (1c) The carbamate (230 mg, 0.51 mmol) was dissolved in 2N hydrochloric acid-methanol (3 mL) and stirred at room temperature for 18 hours.
After evaporating the solvent under reduced pressure, aqueous potassium carbonate solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 170 mg (yield: 95%) of the title compound as a white solid.
（1e）
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(50 mg, 0.15 mmol)および4-ジメチルアミノメチル安息香酸(Fluorochem カタログコード: 058811) (0.031 g, 0.17 mmol)を脱水N,N-ジメチルホルムアミド(1 mL)に溶解し、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(60 mg, 0.22 mmol)を加え、室温にて24時間撹拌した。
反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝1/50-1/4(V/V)］にて精製し、標記化合物25 mg（収率：34%）を白色固体として得た。 (1e)
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] Benzamide
4-[(dimethylamino) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (50 mg, 0.15 mmol) of Example 1 (1d) And 4-dimethylaminomethylbenzoic acid (Fluorochem catalog code: 058811) (0.031 g, 0.17 mmol) are dissolved in dehydrated N, N-dimethylformamide (1 mL) to give 4- (4,6-dimethoxy-1,3 5, 5-Triazin-2-yl) -4-methylmorpholinium chloride (60 mg, 0.22 mmol) was added and stirred at room temperature for 24 hours.
Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 1 / 50-1 / 4 (V / V)] to give the title compound 25 mg (yield: 34%) were obtained as a white solid.
（実施例2）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド (Example 2)
4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
（2a）
2-テトラヒドロピラン-2-イロキシアセトヒドラジド
2-tetrahydropyran-2-yloxyacetohydrazide
エチル 2-テトラヒドロピラン-2-イルオキシアセテート(CAS Registry Number: 61675-94-3, WO2013003383) (16.5 g, 87.7 mmol)をエタノール(170 mL)に溶解し、ヒドラジン一水和物(12.8 mL, 263 mmol)を加え90℃にて9時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物10.2 g（収率：67％）を白色固体として得た。 (2a)
2-Tetrahydropyran-2-yloxyacetohydrazide
2-tetrahydropyran-2-yloxyacetohydrazide
Ethyl 2-tetrahydropyran-2-yloxy acetate (CAS Registry Number: 61675-94-3, WO2013003383) (16.5 g, 87.7 mmol) is dissolved in ethanol (170 mL), hydrazine monohydrate (12.8 mL, 263 mmol) was added and stirred at 90 ° C. for 9 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 10.2. g (yield: 67%) was obtained as a white solid.
（2b）
4-メチル-3-(4-ニトロフェニル)-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール
4-methyl-3-(4-nitrophenyl)-5-(tetrahydropyran-2-yloxymethyl)-1,2,4-triazole
実施例2(2a)の2-テトラヒドロピラン-2-イロキシアセトヒドラジド(10.2 g, 58.6 mmol)をトルエン(100 mL)に懸濁させ、トリエチルアミン(24.5 mL, 176 mmol)、N-メチル-4-ニトロ-ベンズイミドイル クロリド(CAS Registry Number: 64594-45-2, Journal of Organic Chemistry, 1984, 49, 546-547) (11.6 g, 58.6 mmol)を加え、90℃にて4時間撹拌した。
反応混合物に酢酸エチル-エタノール混合液及び水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物12.2 g（収率：66％）を白色固体として得た。 (2b)
4-Methyl-3- (4-nitrophenyl) -5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazole
4-methyl-3- (4-nitrophenyl) -5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazole
The 2-tetrahydropyran-2-yloxyacetohydrazide (10.2 g, 58.6 mmol) of Example 2 (2a) is suspended in toluene (100 mL), triethylamine (24.5 mL, 176 mmol), N-methyl-4 -Nitro-benzimidoyl chloride (CAS Registry Number: 64594-45-2, Journal of Organic Chemistry, 1984, 49, 546-547) (11.6 g, 58.6 mmol) was added and stirred at 90 ° C for 4 hours.
To the reaction mixture were added ethyl acetate-ethanol mixture solution and water, and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 12.2. g (yield: 66%) was obtained as a white solid.
（2c）
4-[4-メチル-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール-3-イル]アニリン
4-[4-methyl-5-(tetrahydropyran-2-yloxymethyl)-1,2,4-triazol-3-yl]aniline
実施例2(2b)の4-メチル-3-(4-ニトロフェニル)-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール(12.2 g, 38.3 mmol)をエタノール(100 mL)、テトラヒドロフラン(50 mL)、水(100 mL)の混合溶媒に溶解し、鉄粉(21.4 g, 383 mmol)、塩化アンモニウム(4.1 g, 76.7 mmol)を加え、70℃にて8時間撹拌した。終夜室温で放置し、さらに70℃にて9時間撹拌した。
反応温度を室温に戻した後、セライト濾過にて不溶物を除去した。減圧下にて溶媒を留去して得られた残渣をジクロロメタンに溶解し、有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-95/5(V/V)］にて精製し、標記化合物6 g（収率：54%）を白色固体として得た。 (2c)
4- [4-Methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] aniline
4- [4-methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] aniline
4-methyl-3- (4-nitrophenyl) -5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazole (12.2 g, 38.3 mmol) of Example 2 (2b) in ethanol (100 mL) ), Dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (100 mL), added with iron powder (21.4 g, 383 mmol) and ammonium chloride (4.1 g, 76.7 mmol), and stirred at 70 ° C. for 8 hours . It was left at room temperature overnight and further stirred at 70 ° C. for 9 hours.
After the reaction temperature was returned to room temperature, insolubles were removed by celite filtration. The residue obtained by evaporation of the solvent under reduced pressure was dissolved in dichloromethane, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0-95 / 5 (V / V)] to give the title compound 6 g (Yield: 54%) was obtained as a white solid.
（2d）
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[4-methyl-5-(tetrahydropyran-2-yloxymethyl)-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2c)の4-[4-メチル-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール-3-イル]アニリン(3 g, 10 mmol)をN,N-ジメチルホルムアミド(5 mL)に溶解し、3H-1,2,3-トリアゾロ[4,5-b]ピリジン-3-オール(1.4 g, 10 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(2.99 g, 15.6 mmol)、4-[(ジメチルアミノ)メチル]安息香酸(2.2 g, 12 mmol)、トリエチルアミン(7.3 mL, 52 mmol)を加え60℃にて4時間撹拌した。
反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物3.4 g（収率：73%）を白色固体として得た。 (2d)
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [4-methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] benzamide
Example 2 (2c) 4- [4-Methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] aniline (3 g, 10 mmol) was N, N- Dissolved in dimethylformamide (5 mL), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol (1.4 g, 10 mmol), 1-ethyl-3- (3-dimethylamino) Propyl) carbodiimide hydrochloride (2.99 g, 15.6 mmol), 4-[(dimethylamino) methyl] benzoic acid (2.2 g, 12 mmol), triethylamine (7.3 mL, 52 mmol) were added and stirred at 60 ° C. for 4 hours .
Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 3.4 g (yield: 73%) were obtained as a white solid.
（2e）
4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-(hydroxymethyl)-4-methyl-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2d)の4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-(テトラヒドロピラン-2-イロキシメチル)-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(3.3 g, 7.3 mmol)をエタノール(30 mL)、水(10 mL)の混合溶媒に溶解しp-トルエンスルホン酸一水和物(3.5 g, 18 mmol)を加え、室温にて終夜放置した。
飽和重曹水で中和しジクロロメタンで3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物2.7 g（収率：定量的）を白色固体として得た。 (2e)
4-[(Dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
Example 2 (2d) 4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (tetrahydropyran-2-yloxymethyl) -1,2,4-triazol-3-yl] Phenyl] benzamide (3.3 g, 7.3 mmol) is dissolved in a mixed solvent of ethanol (30 mL) and water (10 mL), p-toluenesulfonic acid monohydrate (3.5 g, 18 mmol) is added, and the mixture is stirred at room temperature It was left overnight.
It was neutralized with saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 2.7 g (yield: quantitative) were obtained as a white solid.
（2f）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.15 g, 0.41 mmol)を1,4-ジオキサン(3 mL)に懸濁させ、シアノメチレントリブチルホスホラン(0.32 mL, 1.2 mmol)、3-イソプロピルフェノール(Combi-blocks カタログコード：YF-6400) (0.17 mL, 1.2 mmol)を加え、110℃にて6時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物85 mg（収率：43%）を白色固体として得た。 (2f)
4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] benzylamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.15 g (0.41 mmol) is suspended in 1,4-dioxane (3 mL), cyanomethylene tributylphosphorane (0.32 mL, 1.2 mmol), 3-isopropylphenol (Combi-blocks catalog code: YF-6400) ( 0.17 mL, 1.2 mmol) was added and stirred at 110 ° C. for 6 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 85 mg (yield: 43%) were obtained as a white solid.
（実施例3）
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-[[4-(トリフルオロメチル)-2-ピリジル]オキシメチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[4-methyl-5-[[4-(trifluoromethyl)-2-pyridyl]oxymethyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.2 g, 0.55 mmol)をN,N-ジメチルホルムアミド(4 mL)に溶解し2-クロロ-4-(トリフルオロ)ピリジン(Ark Pharm カタログコード: AK-26346) (0.12 g, 0.66 mmol)、水素化ナトリウム(0.029 g, 0.66 mmol)を加え室温にて終夜放置した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物165 mg（収率：59％）を白色固体として得た。 (Example 3)
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridyl] oxymethyl] -1,2,4-triazole-3- [I] Phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [4-methyl-5-[[4- (trifluoromethyl) -2-pyridinyl] oxymethyl] -1,2,4-triazol-3-yl] phenyl] benzamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.2 g, 0.55 mmol) is dissolved in N, N-dimethylformamide (4 mL) and 2-chloro-4- (trifluoro) pyridine (Ark Pharm catalog code: AK-26346) (0.12 g, 0.66 mmol), hydrogen Sodium fluoride (0.029 g, 0.66 mmol) was added and left at room temperature overnight.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 165 mg (yield: 59%) were obtained as a white solid.
（実施例4）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロポキシフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-[(3-isopropoxyphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド (0.15 g, 0.41 mmol)を1,4-ジオキサン (3 mL)に懸濁し、シアノメチレントリブチルホスホラン(0.21 mL, 0.82 mmol)、3-(プロパン-2-イルオキシ)フェノール(Enamine カタログコード: EN300-72009) (0.126 g, 0.82 mmol)を加え110℃にて5時間撹拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物60 mg（収率：29％）を白色固体として得た。 (Example 4)
4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropoxyphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] benzamide
Example 2 (2e): 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.15 g (0.41 mmol) is suspended in 1,4-dioxane (3 mL) and cyanomethylene tributylphosphorane (0.21 mL, 0.82 mmol), 3- (propan-2-yloxy) phenol (Enamine catalog code: EN300- 72009) (0.126 g, 0.82 mmol) was added and stirred at 110 ° C. for 5 hours.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure, and the residue thus obtained is subjected to NH silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V The resulting compound was purified by the) to give 60 mg (yield: 29%) of the title compound as a white solid.
（実施例5）
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
 (5a)
tert-ブチル N-[4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]フェニル]カルバメート
tert-butyl N-[4-[4-methyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]phenyl]carbamate
実施例1(1b)のtert-ブチル N-[4-(メチルカルバモチオイル)フェニル]カルバメート(200 mg, 0.75 mmol)をテトラヒドロフラン(1 mL)に溶解し、ヨウ化メチル(0.93 mL, 15 mmol)を加え室温にて3時間撹拌した。
減圧下にて溶媒を留去した後、残渣をエタノール(3 mL)に溶解し、3-フェニルプロパンヒドラジド(CAS Registry Number: 3538-68-9, Journal of Medicinal Chemistry 2016, 59, 9942-9959) (246 mg, 1.5 mmol)を加え、100℃にて6時間攪拌した。
反応温度を室温に戻した後、不溶物を濾過し、減圧下にて溶媒を留去した。残渣をジクロロメタンでトリチュレーションし、標記化合物282 mg（収率：99%）を黄色固体として得た。 (Example 5)
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] benzamide (5a)
tert-Butyl N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] carbamate
tert-butyl N- [4- [4-methyl-5- (2-phenylethyl) -1,2,4-triazol-3-yl] carbamate
The tert-butyl N- [4- (methylcarbamothiol) phenyl] carbamate (200 mg, 0.75 mmol) of Example 1 (1b) was dissolved in tetrahydrofuran (1 mL), methyl iodide (0.93 mL, 15 mmol) ) Was added and stirred at room temperature for 3 hours.
After evaporating the solvent under reduced pressure, the residue is dissolved in ethanol (3 mL) and 3-phenylpropanehydrazide (CAS Registry Number: 3538-68-9, Journal of Medicinal Chemistry 2016, 59, 9942-9959) (246 mg, 1.5 mmol) was added and stirred at 100 ° C. for 6 hours.
After the reaction temperature was returned to room temperature, the insolubles were filtered and the solvent was distilled off under reduced pressure. The residue was triturated with dichloromethane to give 282 mg (yield: 99%) of the title compound as a yellow solid.
（5b）
4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]アニリン
4-[4-methyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]aniline
実施例5(5a)のtert-ブチル N-[4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]フェニル]カルバメート(282 mg, 0.75 mmol)をメタノール(3 mL)に溶解し、4N塩酸-1,4-ジオキサン(3 mL)を加え室温にて18時間撹拌した。
反応混合物に炭酸カリウム水溶液を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィーにて精製し、標記化合物135 mg（収率：65％）を白色固体として得た。 (5b)
4- [4-Methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] aniline
4- [4-methyl-5- (2-phenylethyl) -1,2,4-triazol-3-yl] aniline
Tert-Butyl N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] carbamate of Example 5 (5a) (282 mg, 0.75 mmol) The residue was dissolved in methanol (3 mL), 4N hydrochloric acid-1,4-dioxane (3 mL) was added, and the mixture was stirred at room temperature for 18 hours.
To the reaction mixture was added aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 135 mg (yield: 65%) of the title compound as a white solid.
(5c)
4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[4-methyl-5-(2-phenylethyl)-1,2,4-triazol-3-yl]phenyl]benzamide
実施例5(5b)の4-[4-メチル-5-(2-フェネチル)-1,2,4-トリアゾール-3-イル]アニリン(50 mg, 0.18 mmol)を脱水N,N-ジメチルホルムアミド(1 mL)に溶解し、4-ジメチルアミノメチル安息香酸(39 mg, 0.22 mmol)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(75 mg, 0.27 mmol)を加え室温にて24時間撹拌した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた固体をジエチルエーテルでトリチュレーションし、沈殿物を濾取する事で標記化合物53 mg（収率：67％）を白色固体として得た。 (5c)
4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [4-methyl-5- (2-phenylethyl) -1,2,4-triazol-3-yl] phenyl] benzamide
Dehydrated N, N-dimethylformamide of 4- [4-methyl-5- (2-phenethyl) -1,2,4-triazol-3-yl] aniline (50 mg, 0.18 mmol) of Example 5 (5b) Dissolved in (1 mL), 4-dimethylaminomethylbenzoic acid (39 mg, 0.22 mmol), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine The reaction mixture was added with sodium chloride (75 mg, 0.27 mmol) and stirred at room temperature for 24 hours.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was triturated with diethyl ether, and the precipitate was collected by filtration to obtain 53 mg (yield: 67%) of the title compound as a white solid.
（実施例6）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
（6a）
メチル 2-(3-イソプロピルフェノキシ)プロパノエート
methyl 2-(3-isopropylphenoxy)propanoate
3-イソプロピルフェノール(1.0 mL, 7.3 mmol)をN,N-ジメチルホルムアミド (10 mL)に溶解し炭酸カリウム(3.0 g, 22 mmol)、メチル 2-ブロモプロピオネート(シグマ-アルドリッチ カタログ番号: 167185) (1.6 mL, 15 mmol)を加え、室温にて3時間撹拌した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝10/0-7/3(V/V)］にて精製し、標記化合物1.6 g (収率：98％)を白色固体として得た。 (Example 6)
4-[(Dimethylamino) methyl] -N- [4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 6a)
Methyl 2- (3-isopropylphenoxy) propanoate
methyl 2- (3-isopropylphenoxy) propanoate
Dissolve 3-isopropylphenol (1.0 mL, 7.3 mmol) in N, N-dimethylformamide (10 mL) and potassium carbonate (3.0 g, 22 mmol), methyl 2-bromopropionate (Sigma-Aldrich Catalog number: 167185 ) (1.6 mL, 15 mmol) was added and stirred at room temperature for 3 hours.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 10 / 0-7 / 3 (V / V)] to obtain the title compound 1.6. g (yield: 98%) was obtained as a white solid.
（6b）
2-(3-イソプロピルフェノキシ)プロパンヒドラジド
2-(3-isopropylphenoxy)propanehydrazide
実施例6(6a)のメチル 2-(3-イソプロピルフェノキシ)プロパノエート(1.6 g, 7.2 mmol)をエタノール(150 mL)に溶解し、ヒドラジン一水和物(1.0 mL, 22 mmol)を加え3時間撹拌した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1(V/V)］にて精製し、標記化合物1.35 g（収率：84％）を白色固体として得た。 (6b)
2- (3-isopropylphenoxy) propane hydrazide
2- (3-isopropylphenoxy) propanehydrazide
The methyl 2- (3-isopropylphenoxy) propanoate (1.6 g, 7.2 mmol) of Example 6 (6a) is dissolved in ethanol (150 mL), hydrazine monohydrate (1.0 mL, 22 mmol) is added, and 3 hours It stirred.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1 (V / V)] to obtain the title compound 1.35. g (yield: 84%) was obtained as a white solid.
（6c）
3-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-5-(4-ニトロフェニル)-1,2,4-トリアゾール
3-[1-(3-isopropylphenoxy)ethyl]-4-methyl-5-(4-nitrophenyl)-1,2,4-triazole
実施例6(6b)の2-(3-イソプロピルフェノキシ)プロパンヒドラジド(1.35 g, 6.1 mmol)をトルエン(20 mL)に溶解しトリエチルアミン(8.5 mL, 61 mmol)、N-メチル-4-ニトロ-ベンズイミドイル クロリド(1.21 g, 6.1 mmol)を加え90℃にて4時間撹拌した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝10/0-7/3(V/V)］にて精製し、標記化合物1.4 g（収率：63％）を白色固体として得た。 (6c)
3- [1- (3-Isopropylphenoxy) ethyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole
3- [1- (3-isopropylphenoxy) ethyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole
Example 6 (6b) 2- (3-isopropylphenoxy) propane hydrazide (1.35 g, 6.1 mmol) was dissolved in toluene (20 mL) Benzimidoyl chloride (1.21 g, 6.1 mmol) was added and stirred at 90 ° C. for 4 hours.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 10 / 0-7 / 3 (V / V)] to give the title compound 1.4 g (yield: 63%) was obtained as a white solid.
（6d）
4-[5-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-1,2,4-トリアゾール-3-イル]アニリン
4-[5-[1-(3-isopropylphenoxy)ethyl]-4-methyl-1,2,4-triazol-3-yl]aniline
実施例6(6c)の3-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-5-(4-ニトロフェニル)-1,2,4-トリアゾール(1.4 g, 3.8 mmol)をテトラヒドロフラン(5 mL)、エタノール(15 mL)、水(5 mL)の混合溶媒に溶解し鉄粉(2.1 g, 38 mmol)、塩化アンモニウム(0.61 g, 11 mmol)を加え70℃にて4時間撹拌した。
反応温度を室温に戻した後、不溶物を濾過で取り除き濾液を濃縮し、水を加え、反応混合物をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物400 mg（収率：31%）を白色固体として得た。 (6d)
4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] aniline
4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] aniline
Example 6 (6c) 3- [1- (3-isopropylphenoxy) ethyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole (1.4 g, 3.8 mmol) in tetrahydrofuran Dissolve in a mixed solvent of (5 mL), ethanol (15 mL) and water (5 mL), add iron powder (2.1 g, 38 mmol), ammonium chloride (0.61 g, 11 mmol) and stir at 70 ° C for 4 hours did.
After the reaction temperature was returned to room temperature, insolubles were removed by filtration, the filtrate was concentrated, water was added, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 400 mg (yield: 31%) was obtained as a white solid.
（6e）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-[1-(3-isopropylphenoxy)ethyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]benzamide
実施例6(6d)の4-[5-[1-(3-イソプロピルフェノキシ)エチル]-4-メチル-1,2,4-トリアゾール-3-イル]アニリン(150 mg, 0.45 mmol)をN,N-ジメチルホルムアミド(3 mL)に溶解し、4-ジメチルアミノメチル安息香酸(104 mg, 0.58 mmol)、3H-1,2,3-トリアゾロ[4,5-b]ピリジン-3-オール(60 mg, 0.45 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(128 mg, 0.67 mmol)を加え90℃にて4時間撹拌した。
反応温度を室温に戻した後、反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物60 mg（収率：27％）を白色固体として得た。 (6e)
4-[(Dimethylamino) methyl] -N- [4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] benzamide
Example 6 (6d) 4- [5- [1- (3-isopropylphenoxy) ethyl] -4-methyl-1,2,4-triazol-3-yl] aniline (150 mg, 0.45 mmol) was N-treated , Dissolved in N-dimethylformamide (3 mL), 4-dimethylaminomethylbenzoic acid (104 mg, 0.58 mmol), 3H-1,2,3-triazolo [4,5-b] pyridin-3-ol ( 60 mg, 0.45 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (128 mg, 0.67 mmol) were added, and the mixture was stirred at 90 ° C. for 4 hours.
After returning the reaction temperature to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 60 mg (yield: 27%) were obtained as a white solid.
（実施例7）
4-[(ジメチルアミノ)メチル]-N-[トランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキシル]ベンズアミド
（7a）
tert-ブチル N-[トランス-4-(メチルカルバモチオイル)シクロヘキシル]カルバメート
tert-butyl N-[trans-4-(methylcarbamothioyl)cyclohexyl]carbamate
tert-ブチル N-[トランス-4-(メチルカルバモイル)シクロヘキシル]カルバメート(CAS Registry Number: 1013111-97-1, WO2015103453) (2.16 g, 8.26 mmol)をテトラヒドロフラン(40 mL)に溶解しローソン試薬(3.67 g, 9.08 mmol)を加え、80℃にて6時間撹拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝7/3-3/7(V/V)］にて精製し、標記化合物1.54 g(収率：69％)を薄灰色固体として得た。 (Example 7)
4-[(Dimethylamino) methyl] -N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] Cyclohexyl] benzamide (7a)
tert-Butyl N- [trans-4- (methylcarbamothiol) cyclohexyl] carbamate
tert-butyl N- [trans-4- (methylcarbamothiol) cyclohexyl] carbamate
Dissolve tert-butyl N- [trans-4- (methylcarbamoyl) cyclohexyl] carbamate (CAS Registry Number: 1013111-97-1, WO2015103453) (2.16 g, 8.26 mmol) in tetrahydrofuran (40 mL) and use Lawesson's reagent (3.67) g, 9.08 mmol) was added and stirred at 80 ° C. for 6 hours.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure and the residue thus obtained is subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 7 / 3-3 / 7 (V / V) To give 1.54 g (yield: 69%) of the title compound as a light gray solid.
（7b）
メチル トランス-4-(tert-ブトキシカルボニルアミノ)-N-メチル-シクロヘキサンカルボキシイミドチオエート
methyl trans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboximidothioate
実施例7(7a)のtert-ブチル N-[トランス-4-(メチルカルバモチオイル)シクロヘキシル]カルバメート(1.5 g, 5.7 mmol)をテトラヒドロフラン(30 mL)に溶解し炭酸カリウム(1.6 g, 11 mmol)及びヨウ化メチル(1.2 g, 8.5 mmol)を加え、過熱還流下8時間撹拌した。
反応温度を室温に戻した後、反応混合物を濾過し、減圧下にて溶媒を留去し、標記化合物1.6 g(収率：96％)を白色固体として得た。 (7b)
Methyl trans-4- (tert-butoxycarbonylamino) -N-methyl-cyclohexanecarboximidothioate
methyl trans-4- (tert-butylcarbonylamino) -N-methyl-cyclohexanecarboximidothioate
Example 7 (7a) tert-Butyl N- [trans-4- (methylcarbamothiol) cyclohexyl] carbamate (1.5 g, 5.7 mmol) was dissolved in tetrahydrofuran (30 mL) and potassium carbonate (1.6 g, 11 mmol) ) And methyl iodide (1.2 g, 8.5 mmol) were added and stirred for 8 hours under heating and reflux.
After the reaction temperature was returned to room temperature, the reaction mixture was filtered and the solvent was evaporated under reduced pressure to obtain 1.6 g (yield: 96%) of the title compound as a white solid.
（7c）
tert-ブチル N-[トランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキシル]カルバメート
tert-butyl N-[trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexyl]carbamate
実施例7(7b)のメチル トランス-4-(tert-ブトキシカルボニルアミノ)-N-メチル-シクロヘキサンカルボキシイミドチオエート(200 mg, 0.70 mmol)をN,N-ジメチルホルムアミド(3 mL)に溶解し実施例1(1a)の2-[3-(トリフルオロメチル)フェノキシ]アセトヒドラジド(164 mg, 0.70 mmol)を加え、110℃にて8時間撹拌した。
反応温度を室温に戻した後、反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1、酢酸エチル/メタノール＝7/3(V/V)］にて精製し、標記化合物216 mg (収率：68％)を白色固体として得た。 (7c)
tert-Butyl N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexyl] carbamate
tert-Butyl N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexacarbamate
The methyl trans-4- (tert-butoxycarbonylamino) -N-methyl-cyclohexanecarboximidothioate (200 mg, 0.70 mmol) of Example 7 (7b) was dissolved in N, N-dimethylformamide (3 mL) The 2- [3- (trifluoromethyl) phenoxy] acetohydrazide (164 mg, 0.70 mmol) of Example 1 (1a) was added, and the mixture was stirred at 110 ° C. for 8 hours.
After returning the reaction temperature to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1, ethyl acetate / methanol = 7/3 (V / V) The title compound (216 mg, yield: 68%) was obtained as a white solid.
（7d）
トランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン
trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexanamine
実施例7(7c)のtert-ブチル N-[トランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキシル]カルバメート(216 mg, 0.48 mmol)をジクロロメタン(3 mL)に溶解しトリフルオロ酢酸(3 mL, 39 mmol)を加え、室温にて27時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、メタノール（5 mL）に溶解し、Amberlyst A-26(OH)にて脱塩した。溶出液を濾過した後、減圧下にて溶媒を留去し、標記化合物160 mg (収率：95％)を無色油状物質として得た。 (7d)
Trans-4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexanamine
trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexanamine
Tert-Butyl N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl of Example 7 (7c) Cyclohexyl] carbamate (216 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL, 39 mmol) was added, and the mixture was stirred at room temperature for 27 hours.
The residue obtained by evaporation of the solvent under reduced pressure was dissolved in methanol (5 mL) and desalted with Amberlyst A-26 (OH). The eluate was filtered, and the solvent was evaporated under reduced pressure to give 160 mg (yield: 95%) of the title compound as a colorless oil.
（7e）
4-[(ジメチルアミノ)メチル]-N-[トランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキシル]ベンズアミド
4-[(dimethylamino)methyl]-N-[trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexyl]benzamide
実施例7(7d)のトランス-4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン(160 mg, 0.45 mmol)をジクロロメタン(5 mL)に溶解し4-[(ジメチルアミノ)メチル]安息香酸(97 mg, 0.54 mmol)、N,N-ジイソプロピルエチルアミン(0.16 mL, 0.90 mmol), N,N,N’,N’-テトラメチル-O-(ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート(205 mg, 0.54 mmol)を加え、室温にて21時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝10/0-9/1(V/V)］にて精製し、標記化合物87 mg (収率：37％)を白色固体として得た。 (7e)
4-[(Dimethylamino) methyl] -N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] Cyclohexyl] benzamide
4-[(dimethylamino) methyl] -N- [trans-4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexyl] benzamide
Trans 4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] cyclohexanamine of Example 7 (7d) (160 mg, In a solution of 0.45 mmol) in dichloromethane (5 mL), 4-[(dimethylamino) methyl] benzoic acid (97 mg, 0.54 mmol), N, N-diisopropylethylamine (0.16 mL, 0.90 mmol), N, N, N ', N'-Tetramethyl-O- (benzotriazol-1-yl) uronium hexafluorophosphate (205 mg, 0.54 mmol) was added and stirred at room temperature for 21 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / methanol = 10 / 0-9 / 1 (V / V)] to give the title compound 87 mg (yield: 37%) were obtained as a white solid.
（実施例8）
4-[(ジメチルアミノ)メチル]-N-[6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-3-ピリジル]ベンズアミド
（8a）
tert-ブチル N-[6-(メチルカルバモイル)-3-ピリジル]カルバメート
tert-butyl N-[6-(methylcarbamoyl)-3-pyridyl]carbamate
メチル 5-(tert-ブトキシカルボニルアミノ)ピリジン-2-カルボキシレート(CAS Registry Number: 131052-40-9, WO2016033445) (0.9 g, 3.6 mmol)を40%メチルアミン-メタノール溶液(約9.8mol/L) (30 mL, 290 mmol)に溶解し80℃にて3時間撹拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた固体を、酢酸エチルおよびヘキサンの混合溶媒で洗浄し、標記化合物600 mg (収率：70 %)を白色固体として得た。 (Example 8)
4-[(Dimethylamino) methyl] -N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide (8a)
tert-Butyl N- [6- (methylcarbamoyl) -3-pyridyl] carbamate
tert-butyl N- [6- (methylcarbamoyl) -3-pyridine] carbamate
Methyl 5- (tert-butoxycarbonylamino) pyridine-2-carboxylate (CAS Registry Number: 131052-40-9, WO201603345) (0.9 g, 3.6 mmol) in 40% methylamine-methanol solution (about 9.8 mol / L) The mixture was dissolved in (30 mL, 290 mmol) and stirred at 80 ° C. for 3 hours.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure, and the obtained solid is washed with a mixed solvent of ethyl acetate and hexane, and the title compound 600 mg (yield: 70%) as a white solid Got as.
（8b）
tert-ブチル N-[6-(メチルカルバモチオイル)-3-ピリジル]カルバメート
tert-butyl N-[6-(methylcarbamothioyl)-3-pyridyl]carbamate
実施例8(8a)のtert-ブチル N-[6-(メチルカルバモイル)-3-ピリジル]カルバメート(0.6 g, 2.4 mmol)をテトラヒドロフラン(10 mL)に溶解しローソン試薬(1.1 g, 2.6 mmol)を加え室温にて終夜放置した。さらにローソン試薬(1.1 g, 2.6 mmol)を加え室温にて終夜放置した。更にローソン試薬(1.06 g, 2.6 mmol)を加え室温にて4日間放置した。
反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝10/0-7/3(V/V)］にて精製し、標記化合物480 mg (収率：75 %)を白色固体として得た。 (8b)
tert-Butyl N- [6- (methylcarbamothiol) -3-pyridyl] carbamate
tert-butyl N- [6- (methylcarbamothiol) -3-pyridine] carbamate
The Lawesson's reagent (1.1 g, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL) by dissolving tert-butyl N- [6- (methylcarbamoyl) -3-pyridyl] carbamate (0.6 g, 2.4 mmol) of Example 8 (8a). And left overnight at room temperature. Furthermore, Lawesson's reagent (1.1 g, 2.6 mmol) was added and left at room temperature overnight. Furthermore, Lawesson's reagent (1.06 g, 2.6 mmol) was added and left at room temperature for 4 days.
The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 10 / 0-7 / 3 (V / V)], and the title compound 480 is obtained. mg (yield: 75%) was obtained as a white solid.
（8c）
tert-ブチル N-[6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-3-ピリジル]カルバメート
tert-butyl N-[6-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]-3-pyridyl]carbamate
実施例8(8b)のtert-ブチル N-[6-(メチルカルバモチオイル)-3-ピリジル]カルバメート(0.48 g, 1.8 mmol)をテトラヒドロフラン(10 mL)に溶解し、炭酸カリウム(0.25 g, 1.8 mmol)、ヨウ化メチル(1.1 mL, 18 mmol)を加え室温にて終夜放置した。
不溶物を濾過で取り除き濾液を減圧下濃縮した。残渣をエタノール(5 mL)に溶解し実施例1(1a)の2-[3-(トリフルオロメチル)フェノキシ]アセトヒドラジド(0.5 g, 2.2 mmol)を加え90℃にて5時間撹拌した。
反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物120 mg(収率：15 %)を白色固体として得た。 (8c)
tert-Butyl N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -3-pyridyl] carbamate
tert-butyl N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] carbamate
The tert-butyl N- [6- (methylcarbamothiol) -3-pyridyl] carbamate (0.48 g, 1.8 mmol) of Example 8 (8b) was dissolved in tetrahydrofuran (10 mL) and potassium carbonate (0.25 g, 1.8 mmol) and methyl iodide (1.1 mL, 18 mmol) were added and left at room temperature overnight.
The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (5 mL), 2- [3- (trifluoromethyl) phenoxy] acetohydrazide (0.5 g, 2.2 mmol) of Example 1 (1a) was added, and the mixture was stirred at 90 ° C. for 5 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 120 mg (yield: 15%) was obtained as a white solid.
（8d）
6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]ピリジン-3-アミン
6-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]pyridin-3-amine
実施例8(8c)のtert-ブチル N-[6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-3-ピリジル]カルバメート(0.12 g, 0.27 mmol)をジクロロメタン(4 mL)、トリフルオロ酢酸(1 mL)に溶解し室温にて3時間撹拌した。
減圧下にて溶媒を留去後、トルエンで2回共沸し、標記化合物102 mg(収率：定量的)を白色固体として得た。 (8d)
6- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-3-amine
6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridine-3-amine
Tert-Butyl N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -3 of Example 8 (8c) -Pyridyl] carbamate (0.12 g, 0.27 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours.
After evaporating the solvent under reduced pressure, the residue was azeotroped twice with toluene to obtain 102 mg (yield: quantitative) of the title compound as a white solid.
（8e）
4-[(ジメチルアミノ)メチル]-N-[6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-3-ピリジル]ベンズアミド
4-[(dimethylamino)methyl]-N-[6-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]-3-pyridyl]benzamide
4-ジメチルアミノメチル安息香酸(0.077 g, 0.43 mmol)をジクロロメタン(5 mL)に懸濁し、チオニルクロリド (0.042 mL, 0.57 mmol)、N,N-ジメチルホルムアミド(0.1 mL)を加え、室温にて2時間撹拌した。
減圧下溶媒を留去し、トルエンで2回共沸した後、残渣をピリジン(3 mL)に溶解し、実施例8(8d)の6-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]ピリジン-3-アミン(0.1 g, 0.29 mmol)のジクロロメタン(3 mL)溶液を加え、室温にて2時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物25 mg (収率：17%)を白色固体として得た。 (8e)
4-[(Dimethylamino) methyl] -N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide
4-[(dimethylamino) methyl] -N- [6- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -3-pyridyl] benzamide
4-Dimethylaminomethylbenzoic acid (0.077 g, 0.43 mmol) is suspended in dichloromethane (5 mL), and thionyl chloride (0.042 mL, 0.57 mmol), N, N-dimethylformamide (0.1 mL) are added, and the mixture is stirred at room temperature. Stir for 2 hours.
The solvent was evaporated under reduced pressure, and the residue was azeotroped twice with toluene, and the residue was dissolved in pyridine (3 mL) to obtain 6- [4-methyl-5-[[3- (triyl) of Example 8 (8d). A solution of fluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-3-amine (0.1 g, 0.29 mmol) in dichloromethane (3 mL) was added and stirred at room temperature for 2 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 25 mg (yield: 17%) were obtained as a white solid.
（実施例9）
4-[(ジメチルアミノ)メチル]-N-[5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル-2-ピリジル]ベンズアミド
（9a）
tert-ブチル N-[5-(メチルカルバモイル)-2-ピリジル]カルバメート
tert-butyl N-[5-(methylcarbamoyl)-2-pyridyl]carbamate
メチル 6-(tert-ブトキシカルボニルアミノ)ピリジン-3-カルボキシレート(CAS Registry Number: 144186-11-8, WO2016033445) (0.5 g, 2.0 mmol)をメチルアミン(40%メタノール溶液, 約9.8 mol/L) (0.30 mL, 3.0 mmol)に溶解し80℃にて4時間撹拌した。
減圧下にて溶媒を留去して得られた固体を、酢酸エチルとヘキサンの混合溶媒で洗浄し、標記化合物495 mg (収率：99%)を白色固体として得た。 (Example 9)
4-[(Dimethylamino) methyl] -N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl-2- Pyridyl] benzamide (9a)
tert-Butyl N- [5- (methylcarbamoyl) -2-pyridyl] carbamate
tert-butyl N- [5- (methylcarbamoyl) -2-pyridine] carbamate
Methyl 6- (tert-butoxycarbonylamino) pyridine-3-carboxylate (CAS Registry Number: 144186-11-8, WO201603345) (0.5 g, 2.0 mmol) with methylamine (40% methanol solution, about 9.8 mol / L The mixture was dissolved in (0.30 mL, 3.0 mmol) and stirred at 80 ° C. for 4 hours.
The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to obtain 495 mg (yield: 99%) of the title compound as a white solid.
（9b）
tert-ブチル N-[5-(メチルカルバモチオイル)-2-ピリジル]カルバメート
tert-butyl N-[5-(methylcarbamothioyl)-2-pyridyl]carbamate
実施例9(9a)のtert-ブチル N-[5-(メチルカルバモイル)-2-ピリジル]カルバメート(2.8 g, 11 mmol)をテトラヒドロフラン(10 mL)に溶解し、ローソン試薬(5.0 g, 12 mmol)を加え、室温にて終夜放置した。
反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/0-1/1(V/V)］にて精製し、標記化合物2.1 g (収率：70%)を白色固体として得た。 (9b)
tert-Butyl N- [5- (methylcarbamothiol) -2-pyridyl] carbamate
tert-butyl N- [5- (methylcarbamothiol) -2-pyridine] carbamate
The tert-butyl N- [5- (methylcarbamoyl) -2-pyridyl] carbamate (2.8 g, 11 mmol) of Example 9 (9a) was dissolved in tetrahydrofuran (10 mL), and Lawesson's reagent (5.0 g, 12 mmol) was used. ) Was added and left at room temperature overnight.
Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 0-1 / 1 (V / V)] to obtain the title compound 2.1. g (yield: 70%) was obtained as a white solid.
（9c）
tert-ブチル N-[5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-2-ピリジル]カルバメート
tert-butyl N-[5-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]-2-pyridyl]carbamate
実施例9(9b)のtert-ブチル N-[5-(メチルカルバモチオイル)-2-ピリジル]カルバメート(2.1 g, 7.9 mmol)をテトラヒドロフラン(40 mL)に溶解しヨウ化メチル(4.9 mL, 79 mmol)、炭酸カリウム(1.1 g, 7.9 mmol)を加え室温にて終夜放置した。
不溶物を濾過で取り除きテトラヒドロフランで洗浄した。減圧下にて溶媒を留去して、残渣をエタノール(5 mL)に溶解し、実施例1(1a)の2-[3-(トリフルオロメチル)フェノキシ]アセトヒドラジド(2.2 g, 9.4 mmol)を加え90℃にて4時間撹拌した。
反応混合物に水を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物2.8 g (収率：79%)を白色固体として得た。 (9c)
tert-Butyl N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -2-pyridyl] carbamate
tert-Butyl N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] carbamate
Example 9 (9b): tert-butyl N- [5- (methylcarbamothioyl) -2-pyridyl] carbamate (2.1 g, 7.9 mmol) was dissolved in tetrahydrofuran (40 mL) and methyl iodide (4.9 mL, 79 mmol) and potassium carbonate (1.1 g, 7.9 mmol) were added and left at room temperature overnight.
The insolubles were removed by filtration and washed with tetrahydrofuran. The solvent was evaporated under reduced pressure, the residue was dissolved in ethanol (5 mL), and 2- [3- (trifluoromethyl) phenoxy] acetohydrazide of Example 1 (1a) (2.2 g, 9.4 mmol) Was added and stirred at 90.degree. C. for 4 hours.
Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 2.8 g (yield: 79%) was obtained as a white solid.
（9d）
5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]ピリジン-2-アミン
5-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]pyridin-2-amine
実施例9(9c)のtert-ブチル N-[5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]-2-ピリジル]カルバメート(2.8 g, 6.2 mmol)をジクロロメタン(45 mL)に溶解し、トリフルオロ酢酸(5 mL)を加え、室温にて2時間撹拌した。
飽和重曹水で中和しジクロロメタンで反応混合物を抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物1.5 g(収率：69%)を白色固体として得た。 (9d)
5- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-2-amine
5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridine-2-amine
Tert-Butyl N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -2 of Example 9 (9c) -Pyridyl] carbamate (2.8 g, 6.2 mmol) was dissolved in dichloromethane (45 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 1.5 g (yield: 69%) were obtained as a white solid.
（9e）
4-[(ジメチルアミノ)メチル]-N-[5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル-2-ピリジル]ベンズアミド
4-[(dimethylamino)methyl]-N-[5-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]-2-pyridyl]benzamide
4-ジメチルアミノメチル安息香酸(0.15 g, 0.86 mmol)をジクロロメタン(5 mL)に懸濁しチオニルクロリド(0.08 mL, 1.1 mmol)、N,N-ジメチルホルムアミド(0.1 mL)を加え、室温にて2時間撹拌した。
減圧下溶媒を留去し、トルエンで2回共沸した後、残渣をピリジン(3 mL)、ジクロロメタン (3 mL)に溶解し、実施例9(9d)の5-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]ピリジン-2-アミン(0.2 g, 0.57 mmol)を加え、室温にて2時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物135 mg (収率：46%)を白色固体として得た。 (9e)
4-[(Dimethylamino) methyl] -N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl-2- Pyridyl] benzamide
4-[(dimethylamino) methyl] -N- [5- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -2-pyridyl] benzamide
4-Dimethylaminomethylbenzoic acid (0.15 g, 0.86 mmol) is suspended in dichloromethane (5 mL), thionyl chloride (0.08 mL, 1.1 mmol), N, N-dimethylformamide (0.1 mL) are added, and Stir for hours.
After distilling off the solvent under reduced pressure and azeotroping with toluene twice, the residue is dissolved in pyridine (3 mL) and dichloromethane (3 mL), and 5- [4-methyl-5- of Example 9 (9 d) is obtained. [[3- (Trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyridin-2-amine (0.2 g, 0.57 mmol) was added and stirred at room temperature for 2 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)] to give the title compound 135 mg (yield: 46%) were obtained as a white solid.
（実施例10）
4-[(ジメチルアミノ)メチル]-N-[4-[4-[(3-イソプロピルフェノキシ)メチル]イミダゾール-1-イル]フェニル]ベンズアミド
（10a）
4-[(3-イソプロピルフェノキシ)メチル]-1-(4-ニトロフェニル)イミダゾール
4-[(3-isopropylphenoxy)methyl]-1-(4-nitrophenyl)imidazole
 [1-(4-ニトロフェニル)イミダゾール-4-イル]メタノール(CAS Registry Number: 85102-89-2, Synthesis, 1983, 47-49) (790 mg, 3.6 mmol)をジクロロメタン(30 mL)に溶解し、3-イソプロピルフェノール(780 mg, 5.7 mmol)、トリフェニルホスフィン(1.5 g, 5.7 mmol)を加えた。続いて2.2Mアゾジカルボン酸ジエチル-トルエン溶液(2.6 mL, 5.7 mmol)をゆっくり滴下し、室温にて17時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝3/7-4/6(V/V)］にて精製し、標記化合物315 mg（収率：26%）を白色固体として得た。 (Example 10)
4-[(Dimethylamino) methyl] -N- [4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] phenyl] benzamide (10a)
4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole
4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole
Dissolve [1- (4-nitrophenyl) imidazol-4-yl] methanol (CAS Registry Number: 85102-89-2, Synthesis, 1983, 47-49) (790 mg, 3.6 mmol) in dichloromethane (30 mL) Then, 3-isopropylphenol (780 mg, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were added. Subsequently, a 2.2 M solution of diethyl azodicarboxylate (2.6 mL, 5.7 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 17 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: ethyl acetate / hexane = 3 / 7-4 / 6 (V / V)] to give the title compound 315 mg (yield: 26%) was obtained as a white solid.
（10b）
4-[4-[(3-イソプロピルフェノキシ)メチル]イミダゾール-1-イル]アニリン
4-[4-[(3-isopropylphenoxy)methyl]imidazol-1-yl]aniline
実施例10(10a)の4-[(3-イソプロピルフェノキシ)メチル]-1-(4-ニトロフェニル)イミダゾール(89 mg, 0.26 mmol)をメタノール(6 mL)に溶解し、塩化ニッケル(II)六水和物(125 mg, 0.52 mmol)を加えた。氷冷後、水素化ホウ素ナトリウム(40 mg, 1.0 mmol)を加え、0℃にて1時間攪拌した。
減圧下にて溶媒を留去し、酢酸エチル、炭酸水素ナトリウム水溶液を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝3/7-10/0(V/V)］にて精製し、標記化合物76 mg （収率：94%）を無色オイルとして得た。 (10b)
4- [4-[(3-Isopropylphenoxy) methyl] imidazol-1-yl] aniline
4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] aniline
Example 10 (10a) 4-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) imidazole (89 mg, 0.26 mmol) was dissolved in methanol (6 mL), and nickel chloride (II) was used. Hexahydrate (125 mg, 0.52 mmol) was added. After ice cooling, sodium borohydride (40 mg, 1.0 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour.
The solvent was evaporated under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 3 / 7-10 / 0 (V / V)] to give the title compound 76 mg (yield: 94%) were obtained as a colorless oil.
（10c）
4-[(ジメチルアミノ)メチル]-N-[4-[4-[(3-イソプロピルフェノキシ)メチル]イミダゾール-1-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[4-[(3-isopropylphenoxy)methyl]imidazol-1-yl]phenyl]benzamide
実施例10(10b)の4-[4-[(3-イソプロピルフェノキシ)メチル]イミダゾール-1-イル]アニリン(74 mg, 0.24 mmol)および4-ジメチルアミノメチル安息香酸(54 mg, 0.25 mmol)を脱水N,N-ジメチルホルムアミド(8 mL)に溶解し、トリエチルアミン(61 mg, 0.6 mmol)を加えた。氷冷後、ヘキサフルオロりん酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム(114 mg, 0.3 mmol)を加え、室温にて20時間撹拌した。
反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝1/1-1/0、メタノール/酢酸エチル=1/9(V/V)］にて精製し、標記化合物38 mg （収率：34%）を白色固体として得た。 (10c)
4-[(Dimethylamino) methyl] -N- [4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] phenyl] benzamide
4- [4-[(3-isopropylphenoxy) methyl] imidazol-1-yl] aniline (74 mg, 0.24 mmol) and 4-dimethylaminomethylbenzoic acid (54 mg, 0.25 mmol) of Example 10 (10b) Was dissolved in dry N, N-dimethylformamide (8 mL), and triethylamine (61 mg, 0.6 mmol) was added. After ice cooling, add hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (114 mg, 0.3 mmol), and add 20 Stir for hours.
Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to NH silica gel column chromatography [eluent: ethyl acetate / hexane = 1 / 1-1 / 0, methanol / ethyl acetate = 1/9 (V / V ) To give 38 mg (yield: 34%) of the title compound as a white solid.
（実施例11）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]-1,2,4-トリアゾール-1-イル]フェニル]ベンズアミド
（11a）
メチル 1-(4-ニトロフェニル)-1,2,4-トリアゾール-3-カルボキシレート
methyl 1-(4-nitrophenyl)-1,2,4-triazole-3-carboxylate
メチル 1H-1,2,4-トリアゾール-3-カルボキシレート(シグマ-アルドリッチ カタログ番号: 530352) (1.27 g, 10 mmol)を1-メチルピロリジン-2-オン(10 mL)に溶解し、氷冷後、水素化ナトリウム(55%, 480 mg, 11 mmol)の1-メチルピロリジン-2-オン(10 mL)溶液を滴下した。20分間攪拌後、1-フルオロ-4-ニトロ-ベンゼン(東京化成工業 カタログ番号: F0105) (1.41 g, 10 mmol)の1-メチルピロリジン-2-オン(10 mL)溶液を滴下し、室温にて1時間、60℃にて2時間攪拌した。
冷却後、反応混合物に水、1N塩酸を加え、攪拌後、析出物を濾取した。濾取した固体を水、イソプロピルエーテルで洗浄し、標記化合物1.5 g（収率：60%）を白色固体として得た。 (Example 11)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] phenyl] benzamide (11a)
Methyl 1- (4-nitrophenyl) -1,2,4-triazole-3-carboxylate
methyl 1- (4-nitrophenyl) -1,2,4-triazole-3-carboxylate
Dissolve methyl 1H-1,2,4-triazole-3-carboxylate (Sigma-Aldrich catalog number: 530352) (1.27 g, 10 mmol) in 1-methylpyrrolidin-2-one (10 mL) and ice-cool After that, a solution of sodium hydride (55%, 480 mg, 11 mmol) in 1-methylpyrrolidin-2-one (10 mL) was added dropwise. After stirring for 20 minutes, a solution of 1-fluoro-4-nitro-benzene (Tokyo Chemical Industry Co., Ltd. catalog number: F0105) (1.41 g, 10 mmol) in 1-methylpyrrolidin-2-one (10 mL) was added dropwise to room temperature. The mixture was stirred for 1 hour at 60.degree. C. for 2 hours.
After cooling, water and 1 N hydrochloric acid were added to the reaction mixture, and after stirring, the precipitate was collected by filtration. The collected solid was washed with water and isopropyl ether to give 1.5 g (yield: 60%) of the title compound as a white solid.
（11b）
[1-(4-ニトロフェニル)-1,2,4-トリアゾール-3-イル]メタノール
[1-(4-nitrophenyl)-1,2,4-triazol-3-yl]methanol
実施例11(11a)のメチル 1-(4-ニトロフェニル)-1,2,4-トリアゾール-3-カルボキシレート(420 mg, 1.7 mmol)をテトラヒドロフラン（25 mL）に懸濁し、水素化ほう素リチウム(80 mg, 3.6 mmol)を加え、1.5時間加熱還流した。
冷却後、反応混合物に1N塩酸を加え、反応混合物を酢酸エチルで抽出した。有機層を重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝1/1-1/0、アセトン/酢酸エチル=1/9(V/V)］にて精製し、標記化合物132 mg（収率：35%）を赤色固体として得た。 (11b)
[1- (4-Nitrophenyl) -1,2,4-triazol-3-yl] methanol
[1- (4-nitrophenyl) -1,2,4-triazol-3-yl] methanol
The methyl 1- (4-nitrophenyl) -1,2,4-triazole-3-carboxylate (420 mg, 1.7 mmol) of Example 11 (11a) was suspended in tetrahydrofuran (25 mL) and boron hydride was used. Lithium (80 mg, 3.6 mmol) was added and the mixture was heated to reflux for 1.5 hours.
After cooling, 1N hydrochloric acid was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography [eluent: ethyl acetate / hexane = 1 / 1-1 / 0, acetone / ethyl acetate = 1/9 (V / V) The resulting compound was purified by using the formula to obtain 132 mg (yield: 35%) of the title compound as a red solid.
（11c）
4-[3-[(3-イソプロピルフェノキシ)メチル]-1,2,4-トリアゾール-1-イル]アニリン
4-[3-[(3-isopropylphenoxy)methyl]-1,2,4-triazol-1-yl]aniline
実施例11(11b)の[1-(4-ニトロフェニル)-1,2,4-トリアゾール-3-イル]メタノール(122 mg, 0.55 mmol)をジクロロメタン(10 mL)に溶解し、3-イソプロピルフェノール(128 mg, 0.94 mmol)、トリフェニルホスフィン(246 mg, 0.94 mmol) を加えた。続いてアゾジカルボン酸ジエチル(2.2Mトルエン溶液, 0.42 mL, 0.94 mmol)をゆっくり滴下し、室温にて17時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝25/75-55/45(V/V)］にて精製し、3-[(3-イソプロピルフェノキシ)メチル]-1-(4-ニトロフェニル)-1,2,4-トリアゾール102 mgを白色固体として得た。
この3-[(3-イソプロピルフェノキシ)メチル]-1-(4-ニトロフェニル)-1,2,4-トリアゾール(106 mg, 0.31 mmol)をメタノール(6 mL)とテトラヒドロフラン(3 mL)の混合溶媒に溶解し、塩化ニッケル(II)六水和物(149 mg, 0.62 mmol)を加えた。氷冷後、水素化ホウ素ナトリウム(47 mg, 1.24 mmol)を加え、0℃にて1時間攪拌した。
減圧下にて溶媒を留去し、酢酸エチル、炭酸水素ナトリウム水溶液を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝3/7-8/2(V/V)］にて精製し、標記化合物81 mg（収率：84%）を無色オイルとして得た。 (11c)
4- [3-[(3-Isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] aniline
4- [3-[(3-isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] aniline
Example 11 (11b) of [1- (4-nitrophenyl) -1,2,4-triazol-3-yl] methanol (122 mg, 0.55 mmol) was dissolved in dichloromethane (10 mL), 3-isopropyl Phenol (128 mg, 0.94 mmol) and triphenylphosphine (246 mg, 0.94 mmol) were added. Subsequently, diethyl azodicarboxylate (2.2 M solution in toluene, 0.42 mL, 0.94 mmol) was slowly added dropwise and stirred at room temperature for 17 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: ethyl acetate / hexane = 25 / 75-55 / 45 (V / V)], and then 3- [3 102 mg of (3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) -1,2,4-triazole were obtained as a white solid.
A mixture of methanol (6 mL) and tetrahydrofuran (3 mL) with this 3-[(3-isopropylphenoxy) methyl] -1- (4-nitrophenyl) -1,2,4-triazole (106 mg, 0.31 mmol) It was dissolved in a solvent and nickel chloride (II) hexahydrate (149 mg, 0.62 mmol) was added. After ice cooling, sodium borohydride (47 mg, 1.24 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour.
The solvent was evaporated under reduced pressure, ethyl acetate and aqueous sodium hydrogen carbonate solution were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 3 / 7-8 / 2 (V / V)] to give the title compound 81 mg (yield: 84%) was obtained as a colorless oil.
（11d）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]-1,2,4-トリアゾール-1-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[3-[(3-isopropylphenoxy)methyl]-1,2,4-triazol-1-yl]phenyl]benzamide
実施例11(11c)の4-[3-[(3-イソプロピルフェノキシ)メチル]-1,2,4-トリアゾール-1-イル]アニリン(80 mg, 0.26 mmol)および4-ジメチルアミノメチル安息香酸(59 mg, 0.28 mmol)を脱水N,N-ジメチルホルムアミド(8 mL)に溶解し、トリエチルアミン(61 mg, 0.6 mmol)を加えた。氷冷後、ヘキサフルオロりん酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム(114 mg, 0.3 mmol)を加え、室温にて5時間撹拌した。
反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝25/75-100/0、メタノール/酢酸エチル=1/9(V/V)］にて精製し、標記化合物60 mg （収率：49%）を白色固体として得た。 (11d)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] phenyl] benzamide
4- [3-[(3-isopropylphenoxy) methyl] -1,2,4-triazol-1-yl] aniline (80 mg, 0.26 mmol) and 4-dimethylaminomethylbenzoic acid of Example 11 (11c) (59 mg, 0.28 mmol) was dissolved in dehydrated N, N-dimethylformamide (8 mL) and triethylamine (61 mg, 0.6 mmol) was added. After ice cooling, add hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (114 mg, 0.3 mmol), and add 5 Stir for hours.
Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to NH silica gel column chromatography [eluent: ethyl acetate / hexane = 25 / 75-100 / 0, methanol / ethyl acetate = 1/9 (V / V ], And 60 mg (yield: 49%) of the title compound was obtained as a white solid.
（実施例12）
4-[(ジメチルアミノ)メチル]-N-[4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]フェニル]ベンズアミド
（12a）
5-ブロモ-2-[(3-イソプロピルフェノキシ)メチル]-1-メチル-イミダゾール
5-bromo-2-[(3-isopropylphenoxy)methyl]-1-methyl-imidazole
 (5-ブロモ-1-メチル-イミダゾール-2-イル)メタノール(東京化成工業 カタログ番号: M2368) (302 mg, 1.6 mmol)をジクロロメタン (10 mL)に溶解し、トリエチルアミン(0.4 mL, 2.9 mmol)およびメシルクロリド(239 mg, 2.1 mmol)を加え、室温にて1時間撹拌した。
反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し得られた残渣を脱水N,N-ジメチルホルムアミド(10 mL)に溶解し、3-イソプロピルフェノール(260 mg, 1.9 mmol)、炭酸セシウム(1.0 g, 3.2 mmol)を加え、70℃にて2時間撹拌した。
反応混合物に1N塩酸を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝2/8-4/6 (V/V)］にて精製し、標記化合物314 mg（収率：64%）を白色固体として得た。 (Example 12)
4-[(Dimethylamino) methyl] -N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] phenyl] benzamide (12a)
5-bromo-2-[(3-isopropylphenoxy) methyl] -1-methyl-imidazole
5-bromo-2-[(3-isopropylphenoxy) methyl] -1-methyl-imidazole
(5-bromo-1-methyl-imidazol-2-yl) methanol (Tokyo Chemical Industry catalog number: M2368) (302 mg, 1.6 mmol) is dissolved in dichloromethane (10 mL) and triethylamine (0.4 mL, 2.9 mmol) And mesyl chloride (239 mg, 2.1 mmol) were added and stirred at room temperature for 1 hour.
Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is dissolved in dehydrated N, N-dimethylformamide (10 mL), and 3-isopropylphenol (260 mg, 1.9 mmol), cesium carbonate (1.0 g, 3.2 mmol) Was added and stirred at 70 ° C. for 2 hours.
To the reaction mixture was added 1N hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: ethyl acetate / hexane = 2 / 8-4 / 6 (V / V)], and the title compound 314 is obtained. mg (yield: 64%) was obtained as a white solid.
（12b）
tert-ブチル N-[4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]フェニル]カルバメート
tert-butyl N-[4-[2-[(3-isopropylphenoxy)methyl]-3-methyl-imidazol-4-yl]phenyl]carbamate
実施例12(12a)の5-ブロモ-2-[(3-イソプロピルフェノキシ)メチル]-1-メチル-イミダゾール(312 mg, 1.0 mmol)をジオキサン(10 mL)と水(2 mL)の混合溶媒に溶解し、リン酸カリウム(460 mg, 2 mmol)、[4-(tert-ブトキシカルボニルアミノ)フェニル]ボロン酸(シグマ-アルドリッチ カタログ番号: 565814) (284 mg, 1.2 mmol)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド(81 mg, 0.1 mmol)を加え、窒素雰囲気下100℃にて3時間撹拌した。
反応温度を室温に戻し、反応混合物を酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝2/8-4/6 (V/V)］にて精製し、標記化合物389 mg（収率：92%）を赤色オイルとして得た。 (12b)
tert-Butyl N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] phenyl] carbamate
tert-butyl N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] carbamate
A mixed solvent of 5-bromo-2-[(3-isopropylphenoxy) methyl] -1-methyl-imidazole (312 mg, 1.0 mmol) of Example 12 (12a) in dioxane (10 mL) and water (2 mL) Dissolved in potassium phosphate (460 mg, 2 mmol), [4- (tert-butoxycarbonylamino) phenyl] boronic acid (Sigma-Aldrich Cat. No: 565814) (284 mg, 1.2 mmol), [1,1 '-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride (81 mg, 0.1 mmol) was added, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere.
The reaction temperature was returned to room temperature, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 2 / 8-4 / 6 (V / V)] to give the title compound 389 mg (yield: 92%) were obtained as a red oil.
（12c）
4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]アニリン
tert-butyl 4-[2-[(3-isopropylphenoxy)methyl]-3-methyl-imidazol-4-yl]aniline
実施例12(12b)のtert-ブチル N-[4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]フェニル]カルバメート(392 mg, 0.26 mmol)を4N塩酸-ジオキサン(3 mL)に溶解し、室温にて2時間攪拌した。
減圧下にて溶媒を留去した後、重曹水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝2/8-3/7 (V/V)］にて精製し、標記化合物243 mg（収率：82%）を無色オイルとして得た。 (12c)
4- [2-[(3-Isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] aniline
tert-butyl 4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] aniline
Example 12 (12b) of tert-butyl N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] phenyl] carbamate (392 mg, 0.26 mmol) in 4N It was dissolved in hydrochloric acid-dioxane (3 mL) and stirred at room temperature for 2 hours.
After evaporation of the solvent under reduced pressure, aqueous sodium bicarbonate solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 2 / 8-3 / 7 (V / V)] to give the title compound 243 mg (yield: 82%) were obtained as a colorless oil.
（12d）
4-[(ジメチルアミノ)メチル]-N-[4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[2-[(3-isopropylphenoxy)methyl]-3-methyl-imidazol-4-yl]phenyl]benzamide
実施例12(12c)の4-[2-[(3-イソプロピルフェノキシ)メチル]-3-メチル-イミダゾール-4-イル]アニリン(242 mg, 0.75 mmol)および4-ジメチルアミノメチル安息香酸(171 mg, 0.80 mmol)を脱水N,N-ジメチルホルムアミド(10 mL)に溶解し、トリエチルアミン(190 mg, 1.9 mmol)を加えた。氷冷後、ヘキサフルオロりん酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム(400 mg, 1.05 mmol)を加え、室温にて16時間撹拌した。
反応混合物に水を加え、反応混合物をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝2/8-10/0 (V/V)］にて精製し、標記化合物196 mg（収率：54%）を白色固体として得た。 (12d)
4-[(Dimethylamino) methyl] -N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] phenyl] benzamide
4- [2-[(3-isopropylphenoxy) methyl] -3-methyl-imidazol-4-yl] aniline (242 mg, 0.75 mmol) and 4-dimethylaminomethylbenzoic acid (171) of Example 12 (12c) mg, 0.80 mmol) was dissolved in dehydrated N, N-dimethylformamide (10 mL) and triethylamine (190 mg, 1.9 mmol) was added. After ice cooling, add hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (400 mg, 1.05 mmol), and add 16 Stir for hours.
Water was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 2 / 8-10 / 0 (V / V)], and the title compound is obtained. 196 mg (yield: 54%) was obtained as a white solid.
（実施例13）
4-[(ジメチルアミノ)メチル]-N-[(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-イル]ベンズアミド
（13a）
メチル 2-(3-イソプロピルフェノキシ)アセテート
methyl 2-(3-isopropylphenoxy)acetate
3-イソプロピルフェノール(10 g, 73 mmol)をN,N-ジメチルホルムアミド(100 mL)に溶解し炭酸カリウム(20 g, 147 mmol)、メチル ブロモアセテート(東京化成工業 カタログ番号: B0533)(7.4 mL, 81 mmol)を加え、室温にて3日間放置した。
反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝10/0-7/3(V/V)］にて精製し、標記化合物14.4 g(収率：94％)を白色固体として得た。 (Example 13)
4-[(Dimethylamino) methyl] -N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] Tetrahydropyran-3-yl] benzamide (13a)
Methyl 2- (3-isopropylphenoxy) acetate
methyl 2- (3-isopropylphenoxy) acetate
Dissolve 3-isopropylphenol (10 g, 73 mmol) in N, N-dimethylformamide (100 mL) and add potassium carbonate (20 g, 147 mmol), methyl bromoacetate (Tokyo Chemical Industry Co., Ltd. catalog number: B0533) (7.4 mL , 81 mmol) was added and left at room temperature for 3 days.
The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 10 / 0-7 / 3 (V / V)] to give the title compound 14.4. g (yield: 94%) was obtained as a white solid.
（13b）
2-(3-イソプロピルフェノキシ)アセトヒドラジド
2-(3-isopropylphenoxy)acetohydrazide
実施例13（13a）のメチル 2-(3-イソプロピルフェノキシ)アセテート(14.4 g, 69.1 mmol)をエタノール(150 mL)に溶解し、ヒドラジン一水和物(10.4 g, 207 mmol)を加え、3時間撹拌した。
反応液を約半分に濃縮し、水200 mlを加え、析出した固体を濾取し、水で洗浄した。得られた固体を乾燥し、標記化合物12.6 g(収率：63％)を白色固体として得た。 (13b)
2- (3-isopropylphenoxy) acetohydrazide
2- (3-isopropylphenoxy) acetohydrazide
The methyl 2- (3-isopropylphenoxy) acetate (14.4 g, 69.1 mmol) of Example 13 (13a) is dissolved in ethanol (150 mL), hydrazine monohydrate (10.4 g, 207 mmol) is added, 3 Stir for hours.
The reaction solution was concentrated to about half, 200 ml of water was added, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried to give 12.6 g (yield: 63%) of the title compound as a white solid.
（13c）
tert-ブチル N-[(3R,6S)-6-(メチルカルバモチオイル)テトラヒドロピラン-3-イル]カルバメート
tert-butyl N-[(3R,6S)-6-(methylcarbamothioyl)tetrahydropyran-3-yl]carbamate
tert-ブチル N-[(3R,6S)-6-(メチルカルバモイル)テトラヒドロピラン-3-イル]カルバメート(CAS Registry Number: 1398570-72-3, WO2012121361) (914 mg, 3.5 mmol)をテトラヒドロフラン(20 mL)に溶解しローソン試薬(1.6 g, 3.9 mmol)を加え、80℃にて15時間撹拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝7/3-3/7(V/V)］にて精製し、標記化合物580 mg (収率：59％)を白色固体として得た。 (13c)
tert-Butyl N-[(3R, 6S) -6- (methylcarbamothiol) tetrahydropyran-3-yl] carbamate
tert-butyl N-[(3R, 6S) -6- (methylcarbamothiol) tetrahydropyran-3-yl] carbamate
tert-Butyl N-[(3R, 6S) -6- (methylcarbamoyl) tetrahydropyran-3-yl] carbamate (CAS Registry Number: 1398570-72-3, WO2012121361) (914 mg, 3.5 mmol) in tetrahydrofuran (20 mg) After dissolving in mL), Lawesson's reagent (1.6 g, 3.9 mmol) was added, and the mixture was stirred at 80 ° C. for 15 hours.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure and the residue thus obtained is subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 7 / 3-3 / 7 (V / V) The reaction mixture was purified by filtration to obtain 580 mg (yield: 59%) of the title compound as a white solid.
（13d）
tert-ブチル N-[(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-イル]カルバメート
N-[(3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-yl]carbamate
実施例13(13c)のtert-ブチル N-[(3R,6S)-6-(メチルカルバモチオイル)テトラヒドロピラン-3-イル]カルバメート(580 mg, 2.1 mmol)をテトラヒドロフラン(15 mL)に溶解し炭酸カリウム(351 mg, 2.5 mmol)及びヨウ化メチル(600 mg, 4.2 mmol)を加え、過熱還流下23時間撹拌した。
反応温度を室温に戻した後、反応混合物を濾過し、減圧下にて溶媒を留去して得られた残渣をジオキサン(20 mL)に溶解し、実施例13(13b)の2-(3-イソプロピルフェノキシ)アセトヒドラジド(441mg, 2.1 mmol)を加え、110℃にて30分間撹拌した。
冷却後、減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/10-1/9(V/V)］にて精製し、標記化合物499 mg(収率：63％)を無色オイルとして得た。 (13d)
tert-Butyl N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran-3-yl] Carbamate
N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran-3-yl] carbamate
Example 13 Dissolution of tert-butyl N-[(3R, 6S) -6- (methylcarbamothioyl) tetrahydropyran-3-yl] carbamate (580 mg, 2.1 mmol) of 13 (13c) in tetrahydrofuran (15 mL) To this solution was added potassium carbonate (351 mg, 2.5 mmol) and methyl iodide (600 mg, 4.2 mmol), and the mixture was stirred for 23 hours under reflux of heating.
After returning the reaction temperature to room temperature, the reaction mixture is filtered, the solvent is evaporated under reduced pressure, and the obtained residue is dissolved in dioxane (20 mL) to give 2- (3b) of Example 13 (13b) -Isopropylphenoxy) acetohydrazide (441 mg, 2.1 mmol) was added and stirred at 110 ° C. for 30 minutes.
After cooling, the residue obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography [elution solvent: methanol / ethyl acetate = 0 / 10-1 / 9 (V / V)], 499 mg (yield: 63%) of the title compound were obtained as a colorless oil.
（13e）
(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-アミン
(3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-amine
実施例13(13d)のtert-ブチル N-[(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-イル]カルバメート(499 mg, 1.6 mmol)をジクロロメタン(5 mL)に溶解し、トリフルオロ酢酸(5 mL)を加え、室温にて1時間攪拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-4/6(V/V)］にて精製し、標記化合物377 mg（収率：98%）を無色オイルとして得た。 (13e)
(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran-3-amine
(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran-3-amine
Example 13 tert-Butyl N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] of 13 (13d) Tetrahydropyran-3-yl] carbamate (499 mg, 1.6 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hour.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-4 / 6 (V / V)] to give the title compound 377 mg (yield: 98%) were obtained as a colorless oil.
（13f）
4-[(ジメチルアミノ)メチル]-N-[(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-イル]ベンズアミド
4-[(dimethylamino)methyl]-N-[(3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-yl]benzamide
実施例13(13e)の(3R,6S)-6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]テトラヒドロピラン-3-アミン(50 mg, 0.15 mmol)および4-ジメチルアミノメチル安息香酸(0.041 g, 0.23 mmol)を脱水N,N-ジメチルホルムアミド(2 mL)に溶解し、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド (86 mg, 0.3 mmol)を加え、室温にて14時間撹拌した。
反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-2/8 (V/V)］にて精製し、標記化合物50 mg（収率：68%）を白色固体として得た。 (13f)
4-[(Dimethylamino) methyl] -N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] Tetrahydropyran-3-yl] benzamide
4-[(dimethylamino) methyl] -N-[(3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran- 3-yl] benzamide
Example 13 (13e) (3R, 6S) -6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] tetrahydropyran-3-amine Dissolve (50 mg, 0.15 mmol) and 4-dimethylaminomethylbenzoic acid (0.041 g, 0.23 mmol) in dehydrated N, N-dimethylformamide (2 mL), 4- (4,6-dimethoxy-1,3 5, 5-Triazin-2-yl) -4-methylmorpholinium chloride (86 mg, 0.3 mmol) was added and stirred at room temperature for 14 hours.
Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-2 / 8 (V / V)] to give the title compound 50 mg (yield: 68%) were obtained as a white solid.
（実施例14）
1-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-4-カルボキサミド
1-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]piperidine-4-carboxamide 
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(32 mg, 68 mmol)および1-メチルピペリジン-4-カルボン酸(Combi-blocks カタログコード：SS-5926) (0.025 g, 0.17 mmol)を脱水N,N-ジメチルホルムアミド(1 mL)に溶解し、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(25 mg, 0.37 mmol)を加え、室温にて24時間撹拌した。
反応混合物に水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣にジエチルエーテルを加え、生じた固体をトリチュレーションし、標記化合物32 mg（収率：47%）を白色固体として得た。 (Example 14)
1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine-4-carboxamide
1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4-carboxamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (32 mg, 68 mmol) of Example 1 (1 d) And 1-methylpiperidine-4-carboxylic acid (Combi-blocks catalog code: SS-5926) (0.025 g, 0.17 mmol) are dissolved in dehydrated N, N-dimethylformamide (1 mL), 4- (4,6,4 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (25 mg, 0.37 mmol) was added and stirred at room temperature for 24 hours.
Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diethyl ether was added to the obtained residue, and the resulting solid was triturated to obtain 32 mg (yield: 47%) of the title compound as a white solid.
（実施例15）
4-シアノ-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-cyano-2-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.4 g, 1.15 mmol)のジクロロメタン(2.3 mL)溶液に4-シアノ-2-メチル-安息香酸(Combi-blocks カタログコード：SH-5948) (0.22 mg, 1.38 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩 (0.66 g, 3.45 mmol)、ジメチルアミノピリジン(0.21 mg, 1.72 mmol)を加えて室温にて4時間攪拌した。
反応混合物に飽和重曹水を加え、反応混合物をジクロロメタンで抽出した。有機層を1N塩酸、飽和重曹水および飽和食塩水にて洗浄後に、有機層を無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝9/1-0/1(V/V)］にて精製した後、ジクロロメタンおよびヘキサンの混合溶媒により固化させて、標記化合物536 mg（収率：95%）を白色固体として得た。 (Example 15)
4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide
4-cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.4 g, 1.15 mmol) of Example 1 (1d) 4-cyano-2-methyl-benzoic acid (Combi-blocks catalog code: SH-5948) (0.22 mg, 1.38 mmol) in dichloromethane (2.3 mL) solution of 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (0.66 g, 3.45 mmol) and dimethylaminopyridine (0.21 mg, 1.72 mmol) were added and stirred at room temperature for 4 hours.
Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 9 / 1-0 / 1 (V / V)], then dichloromethane and The solid was solidified with a mixed solvent of hexane to give 536 mg (yield: 95%) of the title compound as a white solid.
（実施例16）
4-[(ジメチルアミノ)メチル]-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
（16a）
4-(アミノメチル)-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-(aminomethyl)-2-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例15の4-シアノ-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.15 g, 0.31 mmol)のメタノール(3 mL)溶液に、氷冷下にて塩化コバルト(II)(0.15 g, 0.61 mmol)を加えて攪拌し、続けて水素化ホウ素ナトリウム(0.069 g, 1.8 mmol)を加えた後に、室温にて1.5時間攪拌した。
氷冷下にて、28%アンモニア水(2 mL)を加えて、室温にて30分間攪拌後、セライト濾過してメタノールで洗浄した。濾液を減圧下にて濃縮して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-9/1(V/V)］にて精製し、標記化合物111 mg（収率：74%）を白色固体として得た。 (Example 16)
4-[(Dimethylamino) methyl] -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- [I] Phenyl] benzamide (16a)
4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl ] Benzamide
4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide
4-Cyano-2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl of Example 15 To a solution of phenyl] benzamide (0.15 g, 0.31 mmol) in methanol (3 mL) was added cobalt (II) chloride (0.15 g, 0.61 mmol) under ice-cooling and stirring was continued, followed by sodium borohydride (0.069) After adding g, 1.8 mmol), the mixture was stirred at room temperature for 1.5 hours.
Under ice-cooling, 28% aqueous ammonia (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes, filtered through celite and washed with methanol. The filtrate is concentrated under reduced pressure, and the resulting residue is purified by NH silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-9 / 1 (V / V)] to give the title compound 111 mg. (Yield: 74%) was obtained as a white solid.
（16b）
4-[(ジメチルアミノ)メチル]-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-2-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例16(16a)の4-(アミノメチル)-2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.09 g, 0.18 mmol)のジクロロメタン(0.36 mL)溶液にホルムアルデヒド液(37%) (0.054 mL, 0.73 mmol)を加えて、室温にて5分間攪拌した。反応混合物に、ナトリウムトリアセトキシボロヒドリド(95%) (0.24 g, 1.1 mmol)を加えて、室温にて終夜放置した。
反応混合物に飽和重曹水を加え、反応混合物をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-19/1(V/V)］にて精製し、標記化合物74 mg（収率：78%）を白色固体として得た。 (16b)
4-[(Dimethylamino) methyl] -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- [I] Phenyl] benzamide
4-[(dimethylamino) methyl] -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl ] benzamide
Example 16 (16a) 4- (aminomethyl) -2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4- Formaldehyde solution (37%) (0.054 mL, 0.73 mmol) was added to a solution of triazol-3-yl] phenyl] benzamide (0.09 g, 0.18 mmol) in dichloromethane (0.36 mL), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture, sodium triacetoxyborohydride (95%) (0.24 g, 1.1 mmol) was added and left at room temperature overnight.
Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-19 / 1 (V / V)], and the title compound 74 is obtained. mg (yield: 78%) was obtained as a white solid.
（実施例17）
4-[(1S)-1-(アゼチジン-1-イル)エチル]-N-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]ベンズアミド
（17a）
tert-ブチル N-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]カルバメート
tert-butyl N-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]carbamate
実施例7(7b)のメチル 4-(tert-ブトキシカルボニルアミノ)-N-メチル-シクロヘキサンカルボキシイミドチオエート(1.4 g, 4.9 mmol)をジオキサン(10 mL)に溶解し実施例13(13b)の2-(3-イソプロピルフェノキシ)アセトヒドラジド(1.0 g, 4.9 mmol)を加え、110℃にて8時間撹拌した。
反応温度を室温に戻した後、反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1、酢酸エチル/メタノール＝7/3(V/V)］にて精製し、標記化合物1.2 g(収率：57％)を白色固体として得た。 (Example 17)
4-[(1S) -1- (azetidin-1-yl) ethyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole -3-yl] cyclohexyl] benzamide (17a)
tert-Butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] carbamate
tert-butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] carbamate
The methyl 4- (tert-butoxycarbonylamino) -N-methyl-cyclohexanecarboximidothioate (1.4 g, 4.9 mmol) of Example 7 (7b) was dissolved in dioxane (10 mL) to obtain Example 13 (13b). 2- (3-isopropylphenoxy) acetohydrazide (1.0 g, 4.9 mmol) was added and stirred at 110 ° C. for 8 hours.
After returning the reaction temperature to room temperature, the reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1, ethyl acetate / methanol = 7/3 (V / V) To give 1.2 g (yield: 57%) of the title compound as a white solid.
（17b）
トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン
trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexanamine
実施例17(17a)のtert-ブチル N-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]カルバメート(1.2 g, 2.8 mmol)をジクロロメタン(5 mL)に溶解し、トリフルオロ酢酸(5 mL)を加え、室温にて3時間攪拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝9/1-1/1(V/V)］にて精製し、標記化合物981 mg （収率：定量的）を無色油状物質として得た。 (17b)
Trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexanamine
trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexanamine
Example 17 tert-butyl N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] carbamate of Example 17 (17a) 1.2 g (2.8 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 3 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: ethyl acetate / methanol = 9 / 1-1 / 1 (V / V)], 981 mg (yield: quantitative) was obtained as a colorless oil.
（17c）
メチル 4-[(1S)-1-(アゼチジン-1-イル)エチル]ベンゾエート
methyl 4-[(1S)-1-(azetidin-1-yl)ethyl]benzoate
メチル 4-[(1S)-1-アミノエチル]ベンゾエート(OAKWOOD カタログコード: 060717) (500 mg, 2.8 mmol)をアセトニトリル(28 mL)に溶解し、トリエチルアミン(1 mL, 7 mmol)、テトラ-n-ブチルアンモニウム ヨージド(103 mg, 0.28 mmol)および1,3-ジブロモプロパン(0.28 mL, 2.8 mmol)を室温で加え、100℃で還流下、8時間攪拌した。反応溶液を室温に冷却し一晩放置した後、再び反応溶液を100℃で還流下攪拌した。
反応溶液を室温に冷却し、濃縮後、残渣をNHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝1/1-1/0(V/V)］で精製し、標記化合物355 mg（収率：58%）を黄色油状物質として得た。 (17c)
Methyl 4-[(1S) -1- (azetidin-1-yl) ethyl] benzoate
methyl 4-[(1S) -1- (azetidin-1-yl) ethyl] benzoate
Methyl 4-[(1S) -1-aminoethyl] benzoate (OAKWOOD catalog code: 060717) (500 mg, 2.8 mmol) is dissolved in acetonitrile (28 mL), triethylamine (1 mL, 7 mmol), tetra-n -Butyl ammonium iodide (103 mg, 0.28 mmol) and 1,3-dibromopropane (0.28 mL, 2.8 mmol) were added at room temperature and stirred at 100 ° C. under reflux for 8 hours. The reaction solution was cooled to room temperature and allowed to stand overnight, and then the reaction solution was again stirred at 100 ° C. under reflux.
The reaction solution is cooled to room temperature and concentrated, and the residue is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 1 / 1-1 / 0 (V / V)] to obtain 355 mg of the title compound (yield Rate: 58%) as a yellow oil.
（17d）
4-[(1S)-1-(アゼチジン1-イル)エチル]-N-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]ベンズアミド
4-[(1S)-1-(azetidin-1-yl)ethyl]-N-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]benzamide
実施例17(17c)のメチル 4-[(1S)-1-(アゼチジン-1-イル)エチル]ベンゾエート(355 mg, 1.6 mmol)をメタノール(8 mL)に溶解し、2N水酸化ナトリウム水溶液(0.8 mL)を室温で加え13時間攪拌した。反応溶液に1N塩酸(1.6 mL)を室温で加え、濃縮、乾燥し4-[(1S)-1-(アゼチジン-1-イル)エチル]安息香酸444 mgを粗生成物として得た。
この粗生成物48 mgをジクロロメタン(2 mL)に溶解し、実施例17(17b)のトランス-4-[5-[(3イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン(50 mg, 0.15 mmol)、ジイソプロピルエチルアミン(0.08 mL, 0.46 mmol)およびN,N,N’,N’-テトラメチル-O-(ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート(87 mg, 0.23 mmol)を室温で加え、18時間攪拌した。
反応溶液を濃縮し、残渣をNHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/19(V/V)］で精製し、標記化合物59 mg（収率：75%）を白色固体として得た。 (17d)
4-[(1S) -1- (azetidine 1-yl) ethyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole- 3-yl] cyclohexyl] benzamide
4-[(1S) -1- (azetidin-1-yl) ethyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol- 3-yl] cyclohexyl] benzamide
The methyl 4-[(1S) -1- (azetidin-1-yl) ethyl] benzoate (355 mg, 1.6 mmol) of Example 17 (17c) was dissolved in methanol (8 mL), and 2N aqueous solution of sodium hydroxide ( 0.8 mL) was added at room temperature and stirred for 13 hours. To the reaction solution was added 1N hydrochloric acid (1.6 mL) at room temperature, concentrated and dried to give 444 mg of 4-[(1S) -1- (azetidin-1-yl) ethyl] benzoic acid as a crude product.
This crude product (48 mg) was dissolved in dichloromethane (2 mL) and trans-4- [5-[(3 isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole of Example 17 (17b) -3-yl] cyclohexanamine (50 mg, 0.15 mmol), diisopropylethylamine (0.08 mL, 0.46 mmol) and N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium Hexafluorophosphate (87 mg, 0.23 mmol) was added at room temperature and stirred for 18 hours.
The reaction solution is concentrated, and the residue is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 19 (V / V)] to give 59 mg of the title compound (yield: 75%) Was obtained as a white solid.
（実施例18）
5-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ピリジン-2-カルボキサミド
（18a）
3-[(3-イソプロピルフェノキシ)メチル]-4-メチル-5-(4-ニトロフェニル)-1,2,4-トリアゾール
3-[(3-isopropylphenoxy)methyl]-4-methyl-5-(4-nitrophenyl)-1,2,4-triazole
N-メチル-4-ニトロ-ベンズイミドイル クロリド(18 g, 85 mmol)をトルエン(300 mL)に溶解しトリエチルアミン(59 mL, 423 mmol)、実施例13(13b)の2-(3-イソプロピルフェノキシ)アセトヒドラジド(19 g, 91 mmol)を加え90℃にて6時間撹拌した。
反応液を濃縮後酢酸エチル-エタノール混合液に溶解し水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1(V/V)］にて精製し、標記化合物28.1 g（収率：67％）を無色油状物質として得た。 (Example 18)
5-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] pyridine-2- Carboxamide (18a)
3-[(3-Isopropylphenoxy) methyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole
3-[(3-isopropylphenoxy) methyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole
N-methyl-4-nitro-benzimidoyl chloride (18 g, 85 mmol) is dissolved in toluene (300 mL) and triethylamine (59 mL, 423 mmol), 2- (3-isopropylphenoxy) of Example 13 (13 b) Acetohydrazide (19 g, 91 mmol) was added and stirred at 90 ° C. for 6 hours.
The reaction mixture was concentrated, dissolved in an ethyl acetate-ethanol mixed solution, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1 (V / V)] to give the title compound 28.1. g (yield: 67%) was obtained as a colorless oil.
（18b）
4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]アニリン
4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]aniline
実施例18(18a)の3-[(3-イソプロピルフェノキシ)メチル]-4-メチル-5-(4-ニトロフェニル)-1,2,4-トリアゾール(12 g, 34 mmol)をエタノール(100 mL)、ジクロロメタン(20 mL)に溶解し10%パラジウム炭素触媒(1.2 g, 11 mmol)を加え、水素雰囲気下1.5時間撹拌した。
窒素置換後、パラジウム-炭素を濾別してエタノールで洗浄し、減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/9(V/V)］にて精製し、標記化合物7.4 g（収率：67％）を無色油状物質として得た。 (18b)
4- [5-[(3-Isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] aniline
4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] aniline
Example 18 (18a) 3-[(3-isopropylphenoxy) methyl] -4-methyl-5- (4-nitrophenyl) -1,2,4-triazole (12 g, 34 mmol) with ethanol (100 g) The solution was dissolved in dichloromethane (20 mL), 10% palladium on carbon catalyst (1.2 g, 11 mmol) was added, and the mixture was stirred for 1.5 hours under a hydrogen atmosphere.
After nitrogen substitution, palladium-carbon is separated by filtration and washed with ethanol, and the solvent is distilled off under reduced pressure. 9 (V / V)] to give 7.4 g (yield: 67%) of the title compound as a colorless oil.
（18c）
メチル 5-[(ジメチルアミノ)メチル]ピリジン-2-カルボキシレート
methyl 5-[(dimethylamino)methyl]pyridine-2-carboxylate
メチル 5-(アミノメチル)ピリジン-2-カルボン酸 二塩酸塩(JW-PHARMLAB カタログコード: 69R0956S) (2 g, 8.4 mmol)をテトラヒドロフラン(40 mL)に溶解し、ホルムアルデヒド液(37%) (3.1 mL, 42 mmol)及びナトリウムトリアセトキシボロヒドリド(95%) (5.3 g, 25 mmol)を室温で加え10日間攪拌した。
反応溶液を濃縮した後、残渣をNHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝7/3-1/0(V/V)］で精製し、標記化合物1.45 g（収率：89％）を無色油状物質として得た。 (18c)
Methyl 5-[(dimethylamino) methyl] pyridine-2-carboxylate
methyl 5-[(dimethylamino) methyl] pyridine-2-carboxylate
Dissolve methyl 5- (aminomethyl) pyridine-2-carboxylic acid dihydrochloride (JW-PHARMLAB catalog code: 69R0956S) (2 g, 8.4 mmol) in tetrahydrofuran (40 mL) mL, 42 mmol) and sodium triacetoxyborohydride (95%) (5.3 g, 25 mmol) were added at room temperature and stirred for 10 days.
The reaction solution is concentrated, and the residue is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 7 / 3-1 / 0 (V / V)] to give 1.45 g of the title compound (yield: 89% ) As a colorless oil.
（18d）
5-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ピリジン-2-カルボキサミド
5-[(dimethylamino)methyl]-N-[4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]pyridine-2-carboxamide
実施例18(18c)のメチル 5-[(ジメチルアミノ)メチル]ピリジン-2-カルボキシレート(1.45 g, 7.47 mmol)をメタノール(20 mL)に溶解し2N水酸化ナトリウム水溶液(3.7 mL)を室温で加え14時間攪拌した。
反応溶液に1N塩酸(3.7 mL)を室温で加え、濃縮、乾燥し5-[(ジメチルアミノ)メチル]ピリジン-2-カルボン酸1.78 gを粗生成物として得た。
この粗生成物44 mgをN,N-ジメチルホルムアミド(1 mL)に溶解し、実施例18(18b)の4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]アニリン(50 mg, 0.16 mmol)、N,N-ジイソプロピルエチルアミン (0.1 mL, 0.6 mmol)およびN,N,N’,N’-テトラメチル-O-(ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート (88 mg, 0.23 mmol)を室温で加え、50℃にて7時間攪拌した。
反応温度を室温に戻した後、反応溶液を酢酸エチルで希釈した後、水で2回、飽和食塩水で1回洗浄した。有機層を硫酸マグネシウムで乾燥し、濾過した後濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝7/3-1/0、メタノール/酢酸エチル＝1/9(V/V)］で精製し、標記化合物51 mg（収率：66%）を白色固体として得た。 (18d)
5-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] pyridine-2- Carboxamide
5-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] pyridine-2-carboxamide
The methyl 5-[(dimethylamino) methyl] pyridine-2-carboxylate (1.45 g, 7.47 mmol) of Example 18 (18c) is dissolved in methanol (20 mL), and a 2 N aqueous solution of sodium hydroxide (3.7 mL) at room temperature And stirred for 14 hours.
To the reaction solution was added 1N hydrochloric acid (3.7 mL) at room temperature, concentrated and dried to give 1.78 g of 5-[(dimethylamino) methyl] pyridine-2-carboxylic acid as a crude product.
44 mg of this crude product was dissolved in N, N-dimethylformamide (1 mL) to give 4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2 of Example 18 (18b). , 4-Triazol-3-yl] aniline (50 mg, 0.16 mmol), N, N-diisopropylethylamine (0.1 mL, 0.6 mmol) and N, N, N ', N'-Tetramethyl-O- (benzotriazole) -1-yl) uronium hexafluorophosphate (88 mg, 0.23 mmol) was added at room temperature and stirred at 50 ° C. for 7 hours.
After the reaction temperature was returned to room temperature, the reaction solution was diluted with ethyl acetate and then washed twice with water and once with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 7 / 3-1 / 0, methanol / ethyl acetate = 1/9 (V / V)] to give 51 mg of the title compound (yield: 66%) was obtained as a white solid.
（実施例19）
5-(アゼチジン-1-イルメチル)-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン
（19a）
5-ブロモ-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン
5-bromo-2-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]isoindolin-1-one
実施例17(17b)のトランス-4-[5-[(3イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン(163 mg, 0.5 mmol)を脱水テトラヒドロフラン(3 mL)と酢酸(3 mL)の混合溶液に溶解し、メチル 4-ブロモ-2-ホルミルベンゾエート(Enamine カタログコード: EN300-156449) (362 mg, 1.5 mmol)を室温で加え40分間攪拌した。上記の混合物にナトリウムトリアセトキシボロヒドリド(95%) (210 mg, 0.99 mmol)を室温で加え15分攪拌した後、70℃に昇温し、23時間攪拌した。
反応溶液を室温に冷却し、濃縮した後、残渣をNHカラムクロマトグラフィー[溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1(V/V)]で精製し標記化合物183 mg（収率：70%）を白色固体として得た。 (Example 19)
5- (Azetidin-1-ylmethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindoline -1- on (19a)
5-bromo-2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindoline-1-one
5-bromo-2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindolin-1-one
Dehydration of trans-4- [5-[(3 isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexanamine (163 mg, 0.5 mmol) of Example 17 (17b) Dissolve in a mixed solution of tetrahydrofuran (3 mL) and acetic acid (3 mL), add methyl 4-bromo-2-formylbenzoate (Enamine catalog code: EN300-156449) (362 mg, 1.5 mmol) at room temperature and stir for 40 minutes did. To the above mixture was added sodium triacetoxyborohydride (95%) (210 mg, 0.99 mmol) at room temperature, and the mixture was stirred for 15 minutes, heated to 70 ° C., and stirred for 23 hours.
The reaction solution is cooled to room temperature and concentrated, and then the residue is purified by NH column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1 (V / V)] to give the title compound 183 mg (yield 70%) as a white solid.
（19b）
2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]-5-ビニル-イソインドリン-1-オン
2-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]-5-vinyl-isoindolin-1-one
実施例19(19a)の5-ブロモ-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン(183 mg, 0.35 mmol)を1,4-ジオキサン(4 mL)と水(2 mL)の混合溶媒に溶解し、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン(108 mg, 0.7 mmol)、リン酸カリウム(223 mg, 1.1 mmol)及びテトラキス（トリフェニルホスフィン）パラジウム(0)(40 mg, 0.035 mmol)を加え、110℃にて3時間攪拌した。
反応溶液を室温に冷却し、酢酸エチルで3回抽出した後、有機層を硫酸マグネシウムで乾燥、濾過し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒：ヘキサン/酢酸エチル＝1/1-0/1、酢酸エチル/メタノール＝4/1(V/V)]で精製し、標記化合物137 mg（収率：83%）を白色固体として得た。 (19b)
2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] -5-vinyl-isoindoline-1-one
2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] -5-vinyl-isoindolin-1-one
5-bromo-2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] iso of Example 19 (19a) Indoline-1-one (183 mg, 0.35 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL) to give 4,4,5,5-tetramethyl-2-vinyl- Add 1,3,2-dioxaborolane (108 mg, 0.7 mmol), potassium phosphate (223 mg, 1.1 mmol) and tetrakis (triphenylphosphine) palladium (0) (40 mg, 0.035 mmol), and add at 110 ° C. Stir for 3 hours.
The reaction solution was cooled to room temperature and extracted three times with ethyl acetate, then the organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 1-0 / 1, ethyl acetate / methanol = 4/1 (V / V)] to give the title compound 137 mg (yield: 83) %) As a white solid.
（19c）
5-(ヒドロキシメチル)-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン
5-(hydroxymethyl)-2-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]isoindolin-1-one
実施例19(19b)の2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]-5-ビニル-イソインドリン-1-オン(137 mg, 0.29 mmol)をテトラヒドロフラン(3 mL)、水(1 mL)の混合溶媒に溶解し、過ヨウ素酸ナトリウム(186 mg, 0.87 mmol)及び2.5 %四酸化オスミウムtert-ブタノール溶液(89 mg, 0.0087 mmol)を0℃で加え3時間攪拌した。
反応溶液をチオ硫酸ナトリウム水溶液でクエンチし、酢酸エチルで3回抽出し、有機層を硫酸マグネシウムで乾燥した後、濾過、濃縮して得られた残渣をメタノール(4 mL)に溶解し、水素化ホウ素ナトリウム(78 mg, 0.21 mmol)を0℃にて加え、30分間攪拌した。
反応溶液に水を加えた後、酢酸エチルで3回抽出し、有機層を硫酸マグネシウムで乾燥した。濾過、濃縮した後、シリカゲルカラムクロマトグラフィーで精製し、標記化合物91.4 mg（収率：94％）を白色固体として得た。 (19c)
5- (hydroxymethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindoline-1- on
5- (hydroxymethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindolin-1-one
Example 19 (19b) 2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] -5-vinyl- Dissolve isoindolin-1-one (137 mg, 0.29 mmol) in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), and add sodium periodate (186 mg, 0.87 mmol) and 2.5% osmium tetraoxide tert -A butanol solution (89 mg, 0.0087 mmol) was added at 0 ° C and stirred for 3 hours.
The reaction solution is quenched with aqueous sodium thiosulfate solution, extracted three times with ethyl acetate, the organic layer is dried over magnesium sulfate, filtered and concentrated, and the obtained residue is dissolved in methanol (4 mL) and hydrogenated Sodium boron (78 mg, 0.21 mmol) was added at 0 ° C. and stirred for 30 minutes.
Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain 91.4 mg (yield: 94%) of the title compound as a white solid.
（19d）
5-(アゼチジン-1-イルメチル)-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン
5-(azetidin-1-ylmethyl)-2-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]isoindolin-1-one
実施例19(19c)の5-(ヒドロキシメチル)-2-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]イソインドリン-1-オン(92 mg, 0.19 mmol)をジクロロメタン(5 mL)に溶解し、四臭化炭素(128 mg, 0.39 mmol)およびトリフェニルホスフィン(101 mg, 0.39 mmol)を0℃で加え、室温にて1時間攪拌した後、反応溶液にアゼチジン(55 mg, 0.96 mmol)を室温で加え、室温にて22時間攪拌した。
反応溶液を濃縮し、NHシリカゲルカラムクロマトグラフィーで精製し、標記化合物36.8 mg （収率：37％）を白色固体として得た。 (19d)
5- (Azetidin-1-ylmethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindoline -1- on
5- (azetidin-1-ylmethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] isoindolin-1 -one
Example 19 (19c) 5- (hydroxymethyl) -2- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] Dissolve cyclohexyl] isoindoline-1-one (92 mg, 0.19 mmol) in dichloromethane (5 mL), carbon tetrabromide (128 mg, 0.39 mmol) and triphenylphosphine (101 mg, 0.39 mmol) at 0 ° C. After stirring for 1 hour at room temperature, azetidine (55 mg, 0.96 mmol) was added to the reaction solution at room temperature and stirred for 22 hours at room temperature.
The reaction solution was concentrated and purified by NH silica gel column chromatography to obtain 36.8 mg (yield: 37%) of the title compound as a white solid.
（実施例20）
1-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピラゾール-4-カルボキサミド
1-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]pyrazole-4-carboxamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.1 g, 0.29 mmol)をジクロロメタン(0.6 mL)に溶解し、1-メチル-1H-ピラゾール-4-カルボン酸(Combi-blocks カタログコード：HC-3334) (0.0434 g, 0.34 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(0.165 g, 0.86 mmol)、ジメチルアミノピリジン(0.0526 g, 0.43 mmol)を加え、室温にて4時間攪拌した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-9/1(V/V)］にて精製し、標記化合物90 mg（収率：69％）を淡黄色固体として得た。 Example 20
1-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] pyrazole-4-carboxamide
1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] pyrazole-4-carboxamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.1 g, 0.29 mmol) of Example 1 (1d) Is dissolved in dichloromethane (0.6 mL), 1-methyl-1H-pyrazole-4-carboxylic acid (Combi-blocks catalog code: HC-3334) (0.0434 g, 0.34 mmol), 1-ethyl-3- (3-) Dimethylaminopropyl) carbodiimide hydrochloride (0.165 g, 0.86 mmol) and dimethylaminopyridine (0.0526 g, 0.43 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-9 / 1 (V / V)] to give 90 mg of the title compound (Yield: 69%) was obtained as a pale yellow solid.
（実施例21）
(2S,5R)-5-(ジメチルアミノ)-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]テトラヒドロピラン-2-カルボキシサミド
（21a）
tert-ブチル N-[(3R,6S)-6-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]テトラヒドロピラン-3-イル]カルバメート
tert-butyl N-[(3R,6S)-6-[[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamoyl]tetrahydropyran-3-yl]carbamate
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.15 g, 0.43 mmol)をジクロロメタン(0.9 mL)に溶解し、(2S,5R)-5-(tert-ブトキシカルボニルアミノ)テトラヒドロピラン-2-カルボン酸(CAS Registry Number:603130-13-8, Journal of Medicinal Chemistry 2013, 56, 7396-7415) (0.127 g, 0.52 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(0.248 g, 1.3 mmol)、ジメチルアミノピリジン(0.0789 g, 0.65 mmol)を加えて室温にて4時間攪拌した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣に酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物260 mg（収率：定量的）を淡黄色固体として得た。 (Example 21)
(2S, 5R) -5- (Dimethylamino) -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl ] Phenyl] tetrahydropyran-2-carboxamide (21a)
tert-Butyl N-[(3R, 6S) -6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl ] Phenyl] carbamoyl] tetrahydropyran-3-yl] carbamate
tert-Butyl N-[(3R, 6S) -6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl ] carbamoyl] tetrahydropyran-3-yl] carbamate
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.15 g, 0.43 mmol) of Example 1 (1d) Is dissolved in dichloromethane (0.9 mL), (2S, 5R) -5- (tert-butoxycarbonylamino) tetrahydropyran-2-carboxylic acid (CAS Registry Number: 603130-13-8, Journal of Medicinal Chemistry 2013, 56 , 7396-7415) (0.127 g, 0.52 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.248 g, 1.3 mmol) and dimethylaminopyridine (0.0789 g, 0.65 mmol) are added. Stir at room temperature for 4 hours.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 260 mg (yield: quantitative) of the title compound as a pale yellow solid.
（21b）
(2S,5R)-5-アミノ-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]テトラヒドロピラン-2-カルボキサミド
(2S,5R)-5-amino-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]tetrahydropyran-2-carboxamide
実施例21(21a)のtert-ブチル N-[(3R,6S)-6-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]テトラヒドロピラン-3-イル]カルバメート(0.26 g, 0.45 mmol)をジクロロメタン(1.8 mL)に溶解し、トリフルオロ酢酸(1 mL)を加えて室温にて2時間攪拌後、終夜放置した。
減圧下にて溶媒を留去して得られた残渣に飽和重曹水を加え、クロロホルムにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-19/1(V/V)］にて精製し、標記化合物146 mg（収率：68％）を白色固体として得た。 (21b)
(2S, 5R) -5-amino-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] Tetrahydropyran-2-carboxamide
(2S, 5R) -5-amino-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] tetrahydropyran- 2-carboxamide
Tert-Butyl N-[(3R, 6S) -6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2 of Example 21 (21a) Dissolve 4-triazol-3-yl] phenyl] carbamoyl] tetrahydropyran-3-yl] carbamate (0.26 g, 0.45 mmol) in dichloromethane (1.8 mL) and add trifluoroacetic acid (1 mL) at room temperature After stirring for 2 hours, it was left overnight.
Saturated aqueous sodium bicarbonate was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-19 / 1 (V / V)] to give the title compound 146 mg (yield: 68%) was obtained as a white solid.
（21c）
(2S,5R)-5-(ジメチルアミノ)-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]テトラヒドロピラン-2-カルボキシサミド
(2S,5R)-5-(dimethylamino)-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]tetrahydropyran-2-carboxamide
実施例21(21b)の(2S,5R)-5-アミノ-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]テトラヒドロピラン-2-カルボキサミド(0.14 g, 0.29 mmol)をジクロロメタン(0.6 mL)に溶解し、ホルムアルデヒド液(37%) (0.087 mL, 1.2 mmol)を加えて、室温にて5分間攪拌した後、反応混合物にナトリウムトリアセトキシボロヒドリド(95%) (0.38 g, 1.8 mmol)を加えて、室温にて1時間攪拌した。
反応混合物に飽和重曹水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣に酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物86 mg（収率：58％）を淡黄色固体として得た。 (21c)
(2S, 5R) -5- (Dimethylamino) -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl ] Phenyl] tetrahydropyran-2-carboxamide
(2S, 5R) -5- (dimethylamino) -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] tetrahydropyran-2-carboxamide
Example 21 (21 b) (2S, 5R) -5-Amino-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole of -3-yl] phenyl] tetrahydropyran-2-carboxamide (0.14 g, 0.29 mmol) is dissolved in dichloromethane (0.6 mL), formaldehyde solution (37%) (0.087 mL, 1.2 mmol) is added, and the mixture is allowed to stand at room temperature. After stirring for 5 minutes, sodium triacetoxyborohydride (95%) (0.38 g, 1.8 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour.
Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 86 mg (yield: 58%) of the title compound as a pale yellow solid.
（実施例22）
4-[(3-フルオロアゼチジン-1-イル)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
（22a）
メチル 4-[(3-フルオロアゼチジン-1-イル)メチル]ベンゾエート
methyl 4-[(3-fluoroazetidin-1-yl)methyl]benzoate
テレフタルアルデヒド酸メチル(東京化成工業: カタログ番号: T0012) (0.5 g, 3 mmol)をジクロロメタン(6.1 mL)に溶解し、3-フルオロアゼチジン塩酸塩(PharmaBlock カタログコード: PB00233) (0.374 g, 3.4 mmol)およびトリエチルアミン(0.47 mL, 3.4 mmol)を加え、室温にて3時間攪拌した後、ナトリウムトリアセトキシボロヒドリド(95%) (1.94 g, 9.1 mmol)を加えて、室温にて放置した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝9/1-3/1(V/V)］にて精製し、標記化合物486 mg（収率：71%）を無色油状物として得た。 (Example 22)
4-[(3-Fluoroazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide (22a)
Methyl 4-[(3-Fluoroazetidin-1-yl) methyl] benzoate
methyl 4-[(3-fluoroazetidin-1-yl) methyl] benzoate
Methyl terephthalaldehyde (Tokyo Chemical Industry: catalog number: T0012) (0.5 g, 3 mmol) is dissolved in dichloromethane (6.1 mL) and 3-fluoroazetidine hydrochloride (PharmaBlock catalog code: PB00233) (0.374 g, 3.4) After adding mmol) and triethylamine (0.47 mL, 3.4 mmol) and stirring at room temperature for 3 hours, sodium triacetoxyborohydride (95%) (1.94 g, 9.1 mmol) was added and left at room temperature.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 9 / 1-3 / 1 (V / V)] to give the title compound 486 mg (yield: 71%) was obtained as a colorless oil.
（22b）
4-[(3-フルオロアゼチジン-1-イル)メチル]安息香酸
4-[(3-fluoroazetidin-1-yl)methyl]benzoic acid
実施例22(22a)のメチル 4-[(3-フルオロアゼチジン-1-イル)メチル]ベンゾエート(0.29 g, 1.3 mmol)をテトラヒドロフラン(1.3 mL)およびメタノール(1.3 mL)の混合溶媒に溶解し、水酸化ナトリウム (0.26 g, 6.5 mmol)水(1.5 mL)溶液を加えて、室温にて5時間攪拌した。
減圧下にて溶媒を留去して、1N塩酸を加えて酸性とした後、1N水酸化ナトリウム水溶液にてpH7に調整し、ジクロロメタンで洗浄した。水層を減圧下にて濃縮し、得られた残渣にジクロロメタンを加え不溶物を濾過した。濾液を減圧下にて濃縮し、標記化合物140 mg （収率：52%）を無色固体として得た。 (22b)
4-[(3-Fluoroazetidin-1-yl) methyl] benzoic acid
4-[(3-fluoroazetidin-1-yl) methyl] benzoic acid
The methyl 4-[(3-fluoroazetidin-1-yl) methyl] benzoate (0.29 g, 1.3 mmol) of Example 22 (22a) was dissolved in a mixed solvent of tetrahydrofuran (1.3 mL) and methanol (1.3 mL) A solution of sodium hydroxide (0.26 g, 6.5 mmol) in water (1.5 mL) was added, and the mixture was stirred at room temperature for 5 hours.
The solvent was distilled off under reduced pressure, and the residue was acidified by adding 1N hydrochloric acid, adjusted to pH 7 with 1N aqueous sodium hydroxide solution, and washed with dichloromethane. The aqueous layer was concentrated under reduced pressure, dichloromethane was added to the obtained residue, and insolubles were filtered. The filtrate was concentrated under reduced pressure to give 140 mg (yield: 52%) of the title compound as a colorless solid.
（22c）
4-[(3-フルオロアゼチジン-1-イル)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(3-fluoroazetidin-1-yl)methyl]-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.1 g, 0.29 mmol)をジクロロメタン(0.6 mL)に溶解し、実施例22(22b)の4-[(3-フルオロアゼチジン-1-イル)メチル]安息香酸(0.072 g, 0.34 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(0.17 g, 0.87 mmol)、ジメチルアミノピリジン(0.053 g, 0.43 mmol)を加えて室温にて2間攪拌した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-9/1(V/V)］にて精製後、酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物88.5 mg（収率：57%）を淡黄色固体として得た。 (22c)
4-[(3-Fluoroazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide
4-[(3-fluoroazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl [phenyl] benzamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.1 g, 0.29 mmol) of Example 1 (1d) Was dissolved in dichloromethane (0.6 mL), 4-[(3-fluoroazetidin-1-yl) methyl] benzoic acid (0.072 g, 0.34 mmol) of Example 22 (22b), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (0.17 g, 0.87 mmol) and dimethylaminopyridine (0.053 g, 0.43 mmol) were added and stirred at room temperature for 2 minutes.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-9 / 1 (V / V)], and then ethyl acetate is added. The precipitated solid was collected by filtration and dried to give 88.5 mg (yield: 57%) of the title compound as a pale yellow solid.
（実施例23）
4-[(3-ヒドロキシアゼチジン-1-イル)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
（23a）
4-ホルミル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-formyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.3 g, 0.86 mmol)のジクロロメタン(1.7 mL)溶液に、テレフタルアルデヒド酸(東京化成工業 カタログ番号: T0011) (0.16 g, 1.0 mmol)、ジメチルアミノピリジン(0.16 g, 1.3 mmol)および1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(0.5 g, 2.6 mmol)を加えて室温にて4時間攪拌した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣に酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物260 mg（収率：62%）を淡黄色固体として得た。 (Example 23)
4-[(3-hydroxyazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide (23a)
4-formyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] benzamide
4-formyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] benzamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.3 g, 0.86 mmol) of Example 1 (1 d) Terephthalaldehyde acid (Tokyo Chemical Industry Co., Ltd. catalog number: T0011) (0.16 g, 1.0 mmol), dimethylaminopyridine (0.16 g, 1.3 mmol) and 1-ethyl-3- (3-dimethyl) in a dichloromethane (1.7 mL) solution of Aminopropyl) carbodiimide hydrochloride (0.5 g, 2.6 mmol) was added and stirred at room temperature for 4 hours.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 260 mg (yield: 62%) of the title compound as a pale yellow solid.
（23b）
4-[(3-ヒドロキシアゼチジン-1-イル)メチル]-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(3-hydroxyazetidin-1-yl)methyl]-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]benzamide
実施例23(23a)の4-ホルミル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.05 g, 0.1 mmol)をジクロロメタン(0.2 mL)に溶解し、3-ヒドロキシアゼチジン塩酸塩(東京化成工業: カタログ番号: H1264) (0.011 g, 0.1 mmol)およびトリエチルアミン (0.012 g, 0.12 mmol)を加えて、室温にて30分間攪拌後、ナトリウムトリアセトキシボロヒドリド(95%) (0.066 g, 0.31 mmol)を加えて、室温で30分間攪拌後、一晩放置した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣に酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物28 mg （収率：50%）を無色固体として得た。 (23b)
4-[(3-hydroxyazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl] phenyl] benzamide
4-[(3-hydroxyazetidin-1-yl) methyl] -N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl [phenyl] benzamide
Example 23 (23a) 4-formyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl of Dissolving benzamide (0.05 g, 0.1 mmol) in dichloromethane (0.2 mL), 3-hydroxyazetidine hydrochloride (Tokyo Chemical Industry: catalog number: H1264) (0.011 g, 0.1 mmol) and triethylamine (0.012 g, 0.12) After adding mmol) and stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (95%) (0.066 g, 0.31 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and left overnight.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and then dried to obtain 28 mg (yield: 50%) of the title compound as a colorless solid.
（実施例24）
N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]-1,2,3,4-テトラヒドロイソキノリン-6-カルボキサミド
（24a）
2-tert-ブトキシカルボニル-3,4-ジヒドロ-1H-イソキノリン-6-カルボン酸
2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid
N-tert-ブチルカルボニル-メチル-1,2,3,4-テトラヒドロイソキノリン-6-カルボキシレート(Allweys カタログコード: 21161) (1.5 g, 5.1 mmol)のメタノール(10 mL)およびテトラヒドロフラン(10 mL)溶液に1N水酸化ナトリウム水溶液(7.7 mL)を加えて80℃で2時間攪拌した。
減圧下にて溶媒を留去して得られた固体を、水(3ml)に溶解させ、氷冷下にて、1N塩酸水溶液を加えて約pH=4にして析出した固体を濾取後、ジエチルエーテルを加え、溶媒を減圧下で留去後に乾燥し、標記化合物1.41 g（収率：98%）を無色固体として得た。 (Example 24)
N- [4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] -1,2,3,4-tetrahydro Isoquinoline-6-carboxamide (24a)
2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid
2-tert-butylcarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid
N-tert-Butylcarbonyl-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Allweys catalog code: 21161) (1.5 g, 5.1 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) To the solution was added 1N aqueous sodium hydroxide solution (7.7 mL), and the mixture was stirred at 80 ° C. for 2 hours.
The solid obtained by distilling off the solvent under reduced pressure is dissolved in water (3 ml), 1N hydrochloric acid aqueous solution is added under ice cooling to adjust to about pH = 4, and the precipitated solid is filtered off, Diethyl ether was added and the solvent was evaporated under reduced pressure and then dried to obtain 1.41 g (yield: 98%) of the title compound as a colorless solid.
（24b）
tert-ブチル 6-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]-3,4-ジヒドロ-1H-イソキノリン-2-カルボキシレート
tert-butyl 6-[[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(0.15 g, 0.43 mmol)および実施例24(24a)の2-tert-ブトキシカルボニル-3,4-ジヒドロ-1H-イソキノリン-6-カルボン酸(0.14 g, 0.52 mmol)の脱水N,N-ジメチルホルムアミド(1 mL)溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(0.18 g, 0.65 mmol)を加え室温にて4時間攪拌後、50℃にて6時間攪拌した。
反応液に飽和食塩水を加え、析出した固体を濾取し、標記化合物205 mg（収率：78%）を無色固体として得た。 (24b)
tert-Butyl 6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] carbamoyl] -3,4 -Dihydro-1H-isoquinoline-2-carboxylate
tert-butyl 6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] carbamoyl] -3,4-dihydro -1H-isoquinoline-2-carboxylate
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (0.15 g, 0.43 mmol) of Example 1 (1d) And a solution of 2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (0.14 g, 0.52 mmol) of Example 24 (24a) in dehydrated N, N-dimethylformamide (1 mL) Add 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (0.18 g, 0.65 mmol) and stir at room temperature for 4 hours at 50 ° C. Stir for 6 hours.
To the reaction mixture was added saturated brine, and the precipitated solid was collected by filtration to give 205 mg (yield: 78%) of the title compound as a colorless solid.
（24c）
N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]-1,2,3,4-テトラヒドロイソキノリン-6-カルボキサミド
N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide
実施例24(24b)のtert-ブチル 6-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]-3,4-ジヒドロ-1H-イソキノリン-2-カルボキシレート(0.2 g, 0.33 mmol)のジクロロメタン(1.6 mL)溶液にトリフルオロ酢酸(0.5 mL)を加えて室温にて2時間攪拌後、終夜放置した。
減圧下にて溶媒を留去して得られた残渣に飽和重曹水を加え、ジクロロメタンにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-19/1(V/V)］にて精製し、標記化合物85 mg（収率：51%）を無色固体として得た。 (24c)
N- [4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] -1,2,3,4-tetrahydro Isoquinoline-6-carboxamide
N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] -1,2,3,4-tetrahydroisoquinoline-6 -carboxamide
Example 24 tert-butyl 6-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl of Example 24 (24b) After adding trifluoroacetic acid (0.5 mL) to a solution of carbamoyl] -3,4-dihydro-1H-isoquinoline-2-carboxylate (0.2 g, 0.33 mmol) in dichloromethane (1.6 mL) and stirring at room temperature for 2 hours , Left overnight.
Saturated aqueous sodium bicarbonate was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-19 / 1 (V / V)], and the title compound 85 is obtained. mg (yield: 51%) was obtained as a colorless solid.
（実施例25）
2-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]-3,4-ジヒドロ-1H-イソキノリン-6-カルボキサミド
2-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]-3,4-dihydro-1H-isoquinoline-6-carboxamide
実施例24(24c)のN-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]-1,2,3,4-テトラヒドロイソキノリン-6-カルボキサミド(0.065 g, 0.13 mmol)のジクロロメタン(0.3 mL)溶液にホルムアルデヒド液(37%) (0.019 mL, 0.26 mmol)を加えて、室温にて5分間攪拌した後、ナトリウムトリアセトキシボロヒドリド(95%) (0.081 g, 0.38 mmol)を加えて、室温にて1間攪拌後に終夜放置した。
反応混合物をジクロロメタンで希釈し、飽和重曹水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-9/1(V/V)］にて精製後、酢酸エチルを加えて析出した固体を濾取後に乾燥して、標記化合物45 mg （収率：67%）を無色固体として得た。 (Example 25)
2-Methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] -3,4-dihydro -1H-isoquinoline-6-carboxamide
2-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl-3,4-dihydro-1H -isoquinoline-6-carboxamide
N- [4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] -1 of Example 24 (24c) Formaldehyde solution (37%) (0.019 mL, 0.26 mmol) is added to a solution of 2,3,4-tetrahydroisoquinoline-6-carboxamide (0.065 g, 0.13 mmol) in dichloromethane (0.3 mL) and stirred at room temperature for 5 minutes After that, sodium triacetoxyborohydride (95%) (0.081 g, 0.38 mmol) was added, and left to stand overnight after stirring at room temperature for 1 hour.
The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-9 / 1 (V / V)], and then ethyl acetate is added. The precipitated solid was collected by filtration and dried to give 45 mg (yield: 67%) of the title compound as a colorless solid.
（実施例26）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-フルオロフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-[(3-fluorophenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.15 g, 0.41 mmol)をアセトニトリル (5 mL)に懸濁し3-フルオロフェノール(東京化成工業 カタログ番号: F0159) (0.055 g, 0.49 mmol)、シアノメチレントリブチルホスホラン(0.15 g, 0.62 mmol)を加え90℃にて6時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/9(V/V)］にて精製し、標記化合物17 mg（収率：9%）を無色固体として得た。 (Example 26)
4-[(Dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5-[(3-fluorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( Suspend 0.15 g (0.41 mmol) in acetonitrile (5 mL) and add 3-fluorophenol (Tokyo Chemical Industry Catalog No .: F0159) (0.055 g, 0.49 mmol) and cyanomethylenetributylphosphorane (0.15 g, 0.62 mmol) Stir at 90 ° C. for 6 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 9 (V / V)] to give the title compound 17 mg (yield: 9%) was obtained as a colorless solid.
（実施例27）
N-[4-[5-[(3-シアノフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]-4-[(ジメチルアミノ)メチル]ベンズアミド
N-[4-[5-[(3-cyanophenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]-4-[(dimethylamino)methyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.15 g, 0.41 mmol)を1,4-ジオキサン(3 mL)に溶解しシアノメチレントリブチルホスホラン(0.22 mL, 0.82 mmol)、3-シアノフェノール(東京化成工業 カタログ番号: C1583) (0.098 g, 0.82 mmol)を加え110℃にて4時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/0-7/3(V/V)］にて精製し、標記化合物85 mg（収率44%）を無色固体として得た。 (Example 27)
N- [4- [5-[(3-cyanophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl] benzamide
N- [4- [5-[(3-cyanophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl] benzamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( Dissolve 0.15 g (0.41 mmol) in 1,4-dioxane (3 mL) and add cyanomethylenetributylphosphorane (0.22 mL, 0.82 mmol), 3-cyanophenol (Tokyo Kasei Kogyo catalog number: C1583) (0.098 g, 0.82 The mixture was added with mmol) and stirred at 110 ° C. for 4 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1 / 0-7 / 3 (V / V)], and the title compound 85 is obtained. mg (yield 44%) was obtained as a colorless solid.
（実施例28）
N-[4-[5-[(3-クロロ-4-フルオロ-フェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]-4-[(ジメチルアミノ)メチル]ベンズアミド
N-[4-[5-[(3-chloro-4-fluoro-phenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]-4-[(dimethylamino)methyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(0.15 g, 0.41 mmol)を1,4-ジオキサン(3 mL)に懸濁しシアノメチレントリブチルホスホラン(0.32 mL, 1.2 mmol)、3-クロロ-4-フルオロフェノール(東京化成工業 カタログ番号: C1121) (0.18 g, 1.2 mmol)を加え110℃にて4時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/9(V/V)］にて精製し、標記化合物95 mg（収率47%）を無色固体として得た。 (Example 28)
N- [4- [5-[(3-Chloro-4-fluoro-phenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl ] Benzamide
N- [4- [5-[(3-chloro-4-fluoro-phenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl] benzamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 0.15 g (0.41 mmol) was suspended in 1,4-dioxane (3 mL) and cyanomethylene tributylphosphorane (0.32 mL, 1.2 mmol), 3-chloro-4-fluorophenol (Tokyo Kasei Kogyo catalog number: C1121) ( 0.18 g (1.2 mmol) was added and stirred at 110 ° C. for 4 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 9 (V / V)] to give the title compound 95 mg (yield 47%) was obtained as a colorless solid.
（実施例29）
N-[4-[5-[(3-クロロ-2-フルオロ-フェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]-4-[(ジメチルアミノ)メチル]ベンズアミド
N-[4-[5-[(3-chloro-2-fluoro-phenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]-4-[(dimethylamino)methyl]benzamide
実施例2(2e)の4-[(ジメチルアミノ)メチル]-N-[4-[5-(ヒドロキシメチル)-4-メチル-1,2,4-トリアゾール-3-イル]フェニル]ベンズアミド(100 mg, 0.27 mmol)を1,4-ジオキサン(3 mL)に懸濁しシアノメチレントリブチルホスホラン(0.22 mL, 0.82 mmol)、3-クロロ-2-フルオロフェノール(Matrixカタログコード: 002111) (0.12 g, 0.82 mmol)を加え110℃にて14時間撹拌した。
減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/ジクロロメタン＝0/1-1/9(V/V)］にて精製し、標記化合物78 mg（収率58%）を淡黄色固体として得た。 (Example 29)
N- [4- [5-[(3-chloro-2-fluoro-phenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl ] Benzamide
N- [4- [5-[(3-chloro-2-fluoro-phenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl] -4-[(dimethylamino) methyl] benzamide
Example 2 (2e) 4-[(dimethylamino) methyl] -N- [4- [5- (hydroxymethyl) -4-methyl-1,2,4-triazol-3-yl] phenyl] benzamide ( 100 mg (0.27 mmol) was suspended in 1,4-dioxane (3 mL) and cyanomethylenetributylphosphorane (0.22 mL, 0.82 mmol), 3-chloro-2-fluorophenol (Matrix catalog code: 002111) (0.12 g) , 0.82 mmol) and stirred at 110 ° C. for 14 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / dichloromethane = 0 / 1-1 / 9 (V / V)] to give the title compound 78 mg (yield 58%) was obtained as a pale yellow solid.
（実施例30）
4-フルオロ-1-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-4-カルボキサミド
4-fluoro-1-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]piperidine-4-carboxamide
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(50 mg, 0.14 mmol)および4-フルオロ-1-メチル-ピペリジン-4-カルボン酸 塩酸塩(ZERENEX カタログコード: ZXH001982) (34 mg, 0.17 mmol)の脱水N,N-ジメチルホルムアミド(1 mL)溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(60 mg, 0.22 mmol)を加え室温にて24時間攪拌した。
反応液に炭酸カリウム水溶液を加え、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/19(V/V)］にて精製し、標記化合物45 mg（収率：64%）を薄黄色固体として得た。 (Example 30)
4-Fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine- 4-carboxamide
4-fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-4- carboxamide
4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (50 mg, 0.14 mmol) of Example 1 (1d) And 4-fluoro-1-methyl-piperidine-4-carboxylic acid hydrochloride (ZERENEX catalog code: ZXH001982) (34 mg, 0.17 mmol) in a solution of dehydrated N, N-dimethylformamide (1 mL) 4- (4, 6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (60 mg, 0.22 mmol) was added and stirred at room temperature for 24 hours.
To the reaction mixture was added aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 19 (V / V)] to give the title compound 45 mg (yield: 64%) were obtained as a pale yellow solid.
（実施例31）
4-(アゼチジン-1-イルメチル)-2-フルオロ-N-[6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]-3-ピリジル]ベンズアミド
（31a）
tert-ブチル N-[6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]-3-ピリジル]カルバメート
tert-butyl 
N-[6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-pyridyl]carbamate
実施例8(8b)のtert-ブチル N-[6-(メチルカルバモチオイル)-3-ピリジル]カルバメート(1.7 g, 6.4 mmol)をテトラヒドロフラン(40 mL)に溶解しヨウ化メチル(4.0 mL, 64 mmol)、炭酸カリウム(0.88 g, 6.4 mmol)を加え室温にて5時間撹拌した。
不溶物を濾過で取り除き母液を濃縮した。残渣を1,4-ジオキサン(20 mL)に溶解し、実施例13(13b)の2-(3-イソプロピルフェノキシ)アセトヒドラジド(1.5 g, 7.0 mmol)を加え100℃にて6時間撹拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝4/1-0/1(V/V)］にて精製し、標記化合物360mg（収率13%）を淡黄色固体として得た。 (Example 31)
4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide (31a)
tert-Butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridyl] carbamate
tert-butyl
N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3-pyridine] carbamate
Example 8 (8b) tert-butyl N- [6- (methylcarbamothiol) -3-pyridyl] carbamate (1.7 g, 6.4 mmol) was dissolved in tetrahydrofuran (40 mL) and methyl iodide (4.0 mL, 64 mmol) and potassium carbonate (0.88 g, 6.4 mmol) were added and stirred at room temperature for 5 hours.
The insolubles were removed by filtration and the mother liquor was concentrated. The residue was dissolved in 1,4-dioxane (20 mL), 2- (3-isopropylphenoxy) acetohydrazide (1.5 g, 7.0 mmol) of Example 13 (13b) was added, and the mixture was stirred at 100 ° C. for 6 hours.
After the reaction temperature is returned to room temperature, the solvent is distilled off under reduced pressure, and the residue thus obtained is subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 4 / 1-0 / 1 (V / V) The product was purified by the above-mentioned formula to give 360 mg (yield 13%) of the title compound as a pale yellow solid.
（31b）
6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]ピリジン-3-アミン
6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]pyridin-3-amine
実施例31(31a)のtert-ブチル N-[6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]-3-ピリジル]カルバメート(0.36 g, 0.85 mmol)をジクロロメタン(4.5 mL)に溶解し、トリフルオロ酢酸(0.5 mL)を加え室温にて3時間撹拌した。
反応混合物を飽和重曹水で中和しジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/20(V/V)］にて精製し、標記化合物120 mg（収率44%）を淡黄色固体として得た。 (31b)
6- [5-[(3-Isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] pyridin-3-amine
6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] pyridine-3-amine
Example 31 tert-Butyl N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] carbamate of Example 31 (31a) (0.36 g, 0.85 mmol) was dissolved in dichloromethane (4.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours.
The reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 20 (V / V)] to give the title compound 120 mg (yield 44%) was obtained as a pale yellow solid.
（31c）
4-(アゼチジン-1-イルメチル)-2-フルオロ-N-[6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]-3-ピリジル]ベンズアミド
4-(azetidin-1-ylmethyl)-2-fluoro-N-[6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-pyridyl]benzamide
メチル 4-(ブロモメチル)-2-フルオロベンゾエート(CAS Registry Number: 85070-57-1, WO2014144380) (1.48 g, 6 mmol)のテトラヒドロフラン(30 mL)溶液にアゼチジン(1.71 g, 30 mmol)を0℃で加え3時間攪拌した。
減圧下で濃縮し残渣をNHシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ヘキサン＝1/20-1/2(V/V)］で精製し、メチル 4-(アゼチジン-1-イルメチル)-2-フルオロ-ベンゾエート1.34 gを粗生成物として得た。
この粗生成物1.3 gのメタノール(20 mL)溶液に2N水酸化ナトリウム水溶液(3 mL)を室温で加え20時間攪拌した。
反応溶液に1N塩酸(6 mL)を室温で加え、濃縮、乾燥し4-(アゼチジン-1-イルメチル)-2-フルオロ-安息香酸1.6 gを粗生成物として得た。
この粗生成物0.12 gをジクロロメタン(5 mL)に懸濁しチオニルクロリド (0.074 g, 0.62 mmol)、N,N-ジメチルホルムアミド(0.1 mL)を加え室温にて6時間撹拌した。
反応液を濃縮しトルエンで2回共沸した。ピリジン(3 mL)、ジクロロメタン (3 mL)に溶解し、実施例31(31b)の6-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]ピリジン-3-アミン(0.1 g, 0.31 mmol)を加え室温にて終夜放置した。
反応液に水を加え、ジクロロメタンにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/9(V/V)］にて精製し、標記化合物106 mg（収率：67%）を白色固体として得た。 (31c)
4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3 -Pyridyl] benzamide
4- (azetidin-1-ylmethyl) -2-fluoro-N- [6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] -3- pyridyl] benzamide
Azetidine (1.71 g, 30 mmol) in tetrahydrofuran (30 mL) solution of methyl 4- (bromomethyl) -2-fluorobenzoate (CAS Registry Number: 85070-57-1, WO2014144380) (1.48 g, 6 mmol) at 0 ° C And stirred for 3 hours.
After concentration under reduced pressure, the residue is purified by NH silica gel column chromatography [eluent: ethyl acetate / hexane = 1 / 20-1 / 2 (V / V)] and methyl 4- (azetidin-1-ylmethyl) -2 1.34 g of -Fluoro-benzoate are obtained as a crude product.
To a solution of 1.3 g of this crude product in methanol (20 mL) was added 2N aqueous sodium hydroxide solution (3 mL) at room temperature and stirred for 20 hours.
To the reaction solution was added 1N hydrochloric acid (6 mL) at room temperature, concentrated and dried to give 1.6 g of 4- (azetidin-1-ylmethyl) -2-fluoro-benzoic acid as a crude product.
0.12 g of this crude product was suspended in dichloromethane (5 mL), thionyl chloride (0.074 g, 0.62 mmol) and N, N-dimethylformamide (0.1 mL) were added, and the mixture was stirred at room temperature for 6 hours.
The reaction solution was concentrated and azeotroped twice with toluene. The compound was dissolved in pyridine (3 mL), dichloromethane (3 mL), 6- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazole-3 of Example 31 (31 b). -Yl] pyridin-3-amine (0.1 g, 0.31 mmol) was added and left at room temperature overnight.
Water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 9 (V / V)] to give the title compound 106 mg (yield: 67%) were obtained as a white solid.
（実施例32）
6-[(ジメチルアミノ)メチル]-N-[トランス-4-[5-[(3-イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキシル]ピリジン-3-カルボキサミド
6-[(dimethylamino)methyl]-N-[trans-4-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]cyclohexyl]pyridine-3-carboxamide
実施例17(17b)のトランス-4-[5-[(3イソプロピルフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]シクロヘキサンアミン(50 mg, 0.15 mmol)のジクロロメタン(2 mL)溶液に6-[(ジメチルアミノ)メチル]ピリジン-3-カルボン酸 二塩酸塩(ENAMINE カタログコード: BBV-42875569) (58 mg, 0.23 mmol)、N,N-ジイソプロピルエチルアミン(0.13 mL, 0.76 mmol)、及びN,N,N’,N’-テトラメチル-O-(ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート87 mg, 0.23 mmol)を室温で加え3時間攪拌した。
反応溶液を直接NHシリカゲルカラムクロマトグラフィー[溶出溶媒：メタノール/酢酸エチル＝0/1-3/7 (V/V)]で精製し、標記化合物52.6 mg（収率70%）を淡黄色固体として得た。 (Example 32)
6-[(Dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine- 3-carboxamide
6-[(dimethylamino) methyl] -N- [trans-4- [5-[(3-isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexyl] pyridine-3- carboxamide
Dichloromethane of trans-4- [5-[(3 isopropylphenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] cyclohexanamine (50 mg, 0.15 mmol) of Example 17 (17b) 6-[(Dimethylamino) methyl] pyridine-3-carboxylic acid dihydrochloride (ENAMINE catalog code: BBV-42875569) (58 mg, 0.23 mmol), N, N-diisopropylethylamine (0.13 mL) in solution (2 mL) , 0.76 mmol), and N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium hexafluorophosphate 87 mg, 0.23 mmol) were added at room temperature and stirred for 3 hours.
The reaction solution is directly purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-3 / 7 (V / V)] to give 52.6 mg (yield 70%) of the title compound as a pale yellow solid Obtained.
（実施例33）
3-フルオロ-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-3-カルボキサミド
（33a）
tert-ブチル 3-フルオロ-3-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]ピペリジン-1-カルボキシレート
tert-butyl 3-fluoro-3-[[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamoyl]piperidine-1-carboxylate (Example 33)
3-Fluoro-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine-3-carboxamide ( 33a)
tert-Butyl 3-fluoro-3-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] carbamoyl] Piperidine-1-carboxylate
tert-butyl 3-fluoro-3-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] carbamoyl] piperidine- 1-carboxylate
実施例1(1d)の4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]アニリン(200 mg, 0.57 mmol)および1-tert-ブトキシカルボニル-3-フルオロピペリジン-3-カルボン酸(Accelachem カタログコード: SY014959) (156 mg, 0.63 mmol)を脱水N,N-ジメチルホルムアミド(3 mL)に溶解し、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(238 mg, 0.86 mmol)を加え、室温にて24時間撹拌した。
反応混合物に炭酸カリウム水溶液を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝1/99-15/85(V/V)］にて精製し、標記化合物287 mg（収率：87%）を黄色固体として得た。 4- [4-Methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] aniline (200 mg, 0.57 mmol) of Example 1 (1d) And 1-tert-butoxycarbonyl-3-fluoropiperidine-3-carboxylic acid (Accelachem catalog code: SY014959) (156 mg, 0.63 mmol) is dissolved in dehydrated N, N-dimethylformamide (3 mL), 4- ( 4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (238 mg, 0.86 mmol) was added and stirred at room temperature for 24 hours.
To the reaction mixture was added aqueous potassium carbonate solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 1 / 99-15 / 85 (V / V)] to give the title compound 287 mg (yield: 87%) were obtained as a yellow solid.
（33b）
3-フルオロ-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-3-カルボキサミド
3-fluoro-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]piperidine-3-carboxamide
実施例33(33a)のtert-ブチル 3-フルオロ-3-[[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]カルバモイル]ピペリジン-1-カルボキシレート(280 mg, 0.48 mmol)をジクロロメタン(6 mL)に溶解し、トリフルオロ酢酸(2 mL)を加え、室温にて1時間撹拌した。
反応混合物を減圧下で濃縮後、炭酸カリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた固体を、ジエチルエーテルでトリチュレーションし、標記化合物180 mg(収率：78%)を薄黄色固体として得た。 (33b)
3-Fluoro-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine-3-carboxamide
3-fluoro-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-3-carboxamide
Example 33 tert-butyl 3-fluoro-3-[[4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3 according to Example 33 (33a) -Yl] phenyl] carbamoyl] piperidine-1-carboxylate (280 mg, 0.48 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was concentrated under reduced pressure, aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was triturated with diethyl ether to give 180 mg (yield: 78%) of the title compound as a pale yellow solid.
（実施例34）
3-フルオロ-1-メチル-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-3-カルボキサミド
3-fluoro-1-methyl-N-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]piperidine-3-carboxamide
実施例33(33b)の3-フルオロ-N-[4-[4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル]フェニル]ピペリジン-3-カルボキサミド(80 mg, 0.17 mmol)のジクロロメタン(3 mL)溶液にホルムアルデヒド液(37%) (0.12 mL, 1.7 mmol)を加えて、室温にて5分間攪拌した後、反応混合物に、ナトリウムトリアセトキシボロヒドリド(95%) (71 mg, 0.34 mmol)を加えて、室温にて1時間攪拌した。
反応混合物に炭酸カリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣を、NHシリカゲルカラムクロマトグラフィー［溶出溶媒：メタノール/酢酸エチル＝0/1-1/19(V/V)］にて精製し、標記化合物42 mg（収率：51%）を薄黄色固体として得た。 (Example 34)
3-Fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl] piperidine- 3-carboxamide
3-fluoro-1-methyl-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] piperidine-3- carboxamide
Example 33 (33b) 3-Fluoro-N- [4- [4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl] phenyl of Formaldehyde solution (37%) (0.12 mL, 1.7 mmol) is added to a solution of piperidine-3-carboxamide (80 mg, 0.17 mmol) in dichloromethane (3 mL), and after stirring for 5 minutes at room temperature, Then, sodium triacetoxyborohydride (95%) (71 mg, 0.34 mmol) was added and stirred at room temperature for 1 hour.
To the reaction mixture was added aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by NH silica gel column chromatography [eluent: methanol / ethyl acetate = 0 / 1-1 / 19 (V / V)] to give the title compound 42 mg (yield: 51%) were obtained as a pale yellow solid.
（実施例35）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]イソキサゾール-5-イル]フェニル]ベンズアミド
（35a）
3-[(3-イソプロピルフェノキシ)メチル]-5-(4-ニトロフェニル)イソキサゾール
3-[(3-isopropylphenoxy)methyl]-5-(4-nitrophenyl)isoxazole
メチル 5-(4-ニトロフェニル)イソキサゾール-3-カルボキシレート(CAS Registry Number: 487034-01-5, Organic Letters, 2006, 8, 713-716) (300 mg, 1.2 mmol)をエタノールに溶解し、水素化ホウ素ナトリウム(92 mg, 2.4 mmol)を室温で加え、50℃にて2時間攪拌した。
反応温度を室温に戻した後、減圧下にて溶媒を留去し、酢酸エチル及び水を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた固体を濾取、エーテルで洗浄、乾燥し、[5-(4-ニトロフェニル)イソキサゾール-3-イル]メタノール200 mgを粗生成物として得た。
この粗生成物420 mgをジクロロメタンに溶解し、トリエチルアミン(230 mg, 2.3 mmol)及びメシルクロリド(230 mg, 2.1 mmol)を0℃にて加え、10分間攪拌した。
ジクロロメタンで希釈し、有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣をアセトニトリルに溶解し、炭酸セシウム(1.2 g, 3.8 mmol)、3-イソプロピルフェノール(200 mg, 1.5 mmol)を加え、50℃にて12時間攪拌した。
酢酸エチルで希釈し、有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝20/1-9/1(V/V)］にて精製し、標記化合物420 mg （収率：49%）を黄色固体として得た。 (Example 35)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] phenyl] benzamide (35a)
3-[(3-Isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole
3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole
Dissolve methyl 5- (4-nitrophenyl) isoxazole-3-carboxylate (CAS Registry Number: 487034-01-5, Organic Letters, 2006, 8, 713-716) (300 mg, 1.2 mmol) in ethanol, Sodium borohydride (92 mg, 2.4 mmol) was added at room temperature and stirred at 50 ° C. for 2 hours.
After the reaction temperature was returned to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate and water were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solid obtained by evaporation of the solvent under reduced pressure was collected by filtration, washed with ether and dried to give 200 mg of [5- (4-nitrophenyl) isoxazol-3-yl] methanol as a crude product .
420 mg of this crude product was dissolved in dichloromethane, triethylamine (230 mg, 2.3 mmol) and mesyl chloride (230 mg, 2.1 mmol) were added at 0 ° C. and stirred for 10 minutes.
The mixture was diluted with dichloromethane, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is dissolved in acetonitrile, cesium carbonate (1.2 g, 3.8 mmol) and 3-isopropylphenol (200 mg, 1.5 mmol) are added, and the mixture is kept at 50 ° C for 12 hours. It stirred.
The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 20 / 1-9 / 1 (V / V)] to give the title compound 420 mg (Yield: 49%) was obtained as a yellow solid.
（35b）
4-[3-[(3-イソプロピルフェノキシ)メチル]イソキサゾール-5-イル]アニリン
4-[3-[(3-isopropylphenoxy)methyl]isoxazol-5-yl]aniline
実施例35(35a)の3-[(3-イソプロピルフェノキシ)メチル]-5-(4-ニトロフェニル)イソキサゾール(200 mg, 0.59 mmol)をエタノール(5 mL)及びジオキサン(5 mL)の混合溶媒に溶解し、塩化アンモニウム(160 mg, 3.5 mmol)、鉄粉(325 mg, 5.9 mmol)および水(3 mL)を加え、80℃にて1.5時間攪拌した。
反応温度を室温に戻した後、酢酸エチル及び水を加え、不溶物をセライト濾過によって除去した。濾液を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、標記化合物190 mg（収率：定量的）を黄色固体として得た。 (35b)
4- [3-[(3-Isopropylphenoxy) methyl] isoxazol-5-yl] aniline
4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] aniline
A mixed solvent of 3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) isoxazole (200 mg, 0.59 mmol) of Example 35 (35a) in ethanol (5 mL) and dioxane (5 mL) The reaction mixture was dissolved in ammonium chloride (160 mg, 3.5 mmol), iron powder (325 mg, 5.9 mmol) and water (3 mL), and the mixture was stirred at 80.degree. C. for 1.5 hours.
After the reaction temperature was returned to room temperature, ethyl acetate and water were added, and the insolubles were removed by celite filtration. The filtrate was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 190 mg (yield: quantitative) of the title compound as a yellow solid.
（35c）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]イソキサゾール-5-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[3-[(3-isopropylphenoxy)methyl]isoxazol-5-yl]phenyl]benzamide
実施例35(35b)の4-[3-[(3-イソプロピルフェノキシ)メチル]イソキサゾール-5-イル]アニリン(190 mg, 0.62 mmol)を脱水N,N-ジメチルホルムアミドに溶解し、4-ジメチルアミノメチル-安息香酸 塩酸塩(160 mg, 0.74 mmol)、N-メチルモルホリン(93 mg, 0.93 mmol)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(260 mg, 0.93 mmol)を加え室温にて2日間撹拌した。
反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、標記化合物19 mg（収率：6.5％）を白色固体として得た。 (35c)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] phenyl] benzamide
Example 35 (35b) 4- [3-[(3-isopropylphenoxy) methyl] isoxazol-5-yl] aniline (190 mg, 0.62 mmol) is dissolved in dehydrated N, N-dimethylformamide, Aminomethyl-benzoic acid hydrochloride (160 mg, 0.74 mmol), N-methylmorpholine (93 mg, 0.93 mmol), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4 -Methylmorpholinium chloride (260 mg, 0.93 mmol) was added and stirred at room temperature for 2 days.
The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 19 mg (yield: 6.5%) of the title compound as a white solid.
（実施例36）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]-1H-ピラゾール-5-イル]フェニル]ベンズアミド
（36a）
エチル 5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール-3-カルボキシレート
ethyl 5-(4-nitrophenyl)-1-tetrahydropyran-2-yl-pyrazole-3-carboxylate
エチル 5-(4-ニトロフェニル)-1H-ピラゾール-3-カルボキシレート(CAS Registry Number: 189083-63-4, Bioorganic and Medicinal Chemistry Letters, 2013, 23, 4177-4184) (1.2 g, 4.7 mmol)をテトラヒドロフランに溶解し、3,4-ジヒドロ-2H-ピラン(600 mg, 6 mmol)、p-トルエンスルホン酸(触媒量)を加え、室温にて48時間攪拌した。
酢酸エチルで希釈し、有機層を重曹水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-85/15(V/V)］にて精製し、標記化合物1.26 g（収率：78%）を黄色固体として得た。 (Example 36)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1H-pyrazol-5-yl] phenyl] benzamide (36a)
Ethyl 5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole-3-carboxylate
ethyl 5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole-3-carboxylate
Ethyl 5- (4-nitrophenyl) -1H-pyrazole-3-carboxylate (CAS Registry Number: 189083-63-4, Bioorganic and Medicinal Chemistry Letters, 2013, 23, 4177-4184) (1.2 g, 4.7 mmol) Was dissolved in tetrahydrofuran, 3,4-dihydro-2H-pyran (600 mg, 6 mmol) and p-toluenesulfonic acid (catalytic amount) were added, and the mixture was stirred at room temperature for 48 hours.
The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-85 / 15 (V / V)] to give the title compound 1.26 g (Yield: 78%) was obtained as a yellow solid.
（36b）
[5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール-3-イル]メタノール
[5-(4-nitrophenyl)-1-tetrahydropyran-2-yl-pyrazol-3-yl]methanol
テトラヒドロフランに水素化アルミニウムリチウム(2.5 M溶液, 2.2 mL)を加え、0℃に冷却し、実施例36(36a)のエチル 5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール-3-カルボキシレート(1.3 g, 3.65 mmol)を加え、氷冷下20分間攪拌した。
反応溶液に硫酸ナトリウム水溶液を加え、セライト濾過した。濾液を減圧下にて濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝1/1(V/V)］にて精製し、標記化合物380 mg（収率：34%）を黄色固体として得た。 (36b)
[5- (4-Nitrophenyl) -1-tetrahydropyran-2-yl-pyrazol-3-yl] methanol
[5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazol-3-yl] methanol
Lithium aluminum hydride (2.5 M solution, 2.2 mL) was added to tetrahydrofuran, cooled to 0 ° C., and ethyl 5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole of Example 36 (36a) Add -3-carboxylate (1.3 g, 3.65 mmol) and stir for 20 minutes under ice cooling.
An aqueous solution of sodium sulfate was added to the reaction solution, and the mixture was filtered through celite. The filtrate is concentrated under reduced pressure and the residue thus obtained is purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 1/1 (V / V)] to give the title compound 380 mg (yield: 34) %) As a yellow solid.
（36c）
3-[(3-イソプロピルフェノキシ)メチル]-5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール
3-[(3-isopropylphenoxy)methyl]-5-(4-nitrophenyl)-1-tetrahydropyran-2-yl-pyrazole
実施例36(36b)の[5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール-3-イル]メタノール(380 mg, 1.3 mmol)をジクロロメタンに溶解し、トリエチルアミン(190 mg, 1.9 mmol)及びメシルクロリド(171 mg, 1.5 mmol)を加え、室温にて10分間攪拌した。
ジクロロメタンで希釈し、有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣をアセトニトリルに溶解し、3-イソプロピルフェノール(0.17 mL, 1.2 mmol)及び炭酸セシウム(1 g, 3.1 mmol)を加え、室温にて12時間攪拌した。
酢酸エチルで希釈し、有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、標記化合物530 mg（収率：定量的）を黄色固体として得た。 (36c)
3-[(3-Isopropylphenoxy) methyl] -5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole
3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole
Example 36 (36b) of [5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazol-3-yl] methanol (380 mg, 1.3 mmol) is dissolved in dichloromethane and triethylamine (190 mg) , 1.9 mmol) and mesyl chloride (171 mg, 1.5 mmol) were added and stirred at room temperature for 10 minutes.
The mixture was diluted with dichloromethane, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is dissolved in acetonitrile, 3-isopropylphenol (0.17 mL, 1.2 mmol) and cesium carbonate (1 g, 3.1 mmol) are added, and the mixture is stirred at room temperature for 12 hours did.
The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 530 mg (yield: quantitative) of the title compound as a yellow solid.
（36d）
4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-2-テトラヒドロピラン-2-イル-ピラゾール-3-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[5-[(3-isopropylphenoxy)methyl]-2-tetrahydropyran-2-yl-pyrazol-3-yl]phenyl]benzamide
実施例36(36c)の3-[(3-イソプロピルフェノキシ)メチル]-5-(4-ニトロフェニル)-1-テトラヒドロピラン-2-イル-ピラゾール(530 mg, 1.3 mmol)をエタノール(8 mL)及びジオキサン(8 mL)の混合溶媒に溶解し、塩化アンモニウム(340 mg, 7.5 mmol)、鉄粉(700 mg, 12 mmol)および水(6.4 mL)を加え、80℃にて30分間攪拌した。
反応温度を室温に戻した後、酢酸エチルを加え、不溶物をセライト濾過によって除去した。濾液を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し、残渣をエタノールに溶解し、4-ジメチルアミノメチル安息香酸 塩酸塩(390 mg, 1.8 mmol)、N-メチルモルホリン(182 mg, 1.8 mmol)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(621 mg, 2.3 mmol)を加え室温にて2時間撹拌した。
反応混合物を水に注ぎ、反応混合物を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝1/0-20/1(V/V)］にて精製し、標記化合物415 mg（収率：56%）を黄色固体として得た。 (36d)
4-[(Dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -2-tetrahydropyran-2-yl-pyrazol-3-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -2-tetrahydropyran-2-yl-pyrazol-3-yl] benzamide
Example 36 (36c) 3-[(3-isopropylphenoxy) methyl] -5- (4-nitrophenyl) -1-tetrahydropyran-2-yl-pyrazole (530 mg, 1.3 mmol) in ethanol (8 mL) In a mixed solvent of) and dioxane (8 mL), ammonium chloride (340 mg, 7.5 mmol), iron powder (700 mg, 12 mmol) and water (6.4 mL) were added, and the mixture was stirred at 80 ° C for 30 minutes .
After the reaction temperature was returned to room temperature, ethyl acetate was added, and the insolubles were removed by celite filtration. The filtrate was washed with water, brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, the residue is dissolved in ethanol, 4-dimethylaminomethylbenzoic acid hydrochloride (390 mg, 1.8 mmol), N-methylmorpholine (182 mg, 1.8 mmol), 4- (4) 6,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (621 mg, 2.3 mmol) was added and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was poured into water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 1 / 0-20 / 1 (V / V)] to give 415 mg of the title compound ( Yield: 56%) was obtained as a yellow solid.
（36e）
4-[(ジメチルアミノ)メチル]-N-[4-[3-[(3-イソプロピルフェノキシ)メチル]-1H-ピラゾール-5-イル]フェニル]ベンズアミド
4-[(dimethylamino)methyl]-N-[4-[3-[(3-isopropylphenoxy)methyl]-1H-pyrazol-5-yl]phenyl]benzamide
実施例36(36d)の4-[(ジメチルアミノ)メチル]-N-[4-[5-[(3-イソプロピルフェノキシ)メチル]-2-テトラヒドロピラン-2-イル-ピラゾール-3-イル]フェニル]ベンズアミド(465 mg, 0.84 mmol)をメタノール(30 mL)に溶解し、4N塩酸-ジオキサン(8 mL)を加え、室温にて30分間攪拌した。
減圧下にて溶媒を留去し、水を加え、1N水酸化ナトリウム水溶液にて塩基性とした後、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、標記化合物300 mg（収率：77%）を黄色固体として得た。 (36e)
4-[(Dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1H-pyrazol-5-yl] phenyl] benzamide
4-[(dimethylamino) methyl] -N- [4- [3-[(3-isopropylphenoxy) methyl] -1H-pyrazol-5-yl] phenyl] benzamide
Example 36 (36d) of 4-[(dimethylamino) methyl] -N- [4- [5-[(3-isopropylphenoxy) methyl] -2-tetrahydropyran-2-yl-pyrazol-3-yl] Phenyl] benzamide (465 mg, 0.84 mmol) was dissolved in methanol (30 mL), 4N hydrochloric acid-dioxane (8 mL) was added, and the mixture was stirred at room temperature for 30 minutes.
The solvent was evaporated under reduced pressure, water was added, and the reaction mixture was basified with 1N aqueous sodium hydroxide solution, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate to give 300 mg (yield: 77%) of the title compound as a yellow solid.
　以下に、実施例に記載の化合物の構造式とその物理化学的データをまとめた。 The structural formulas of the compounds described in the examples and their physicochemical data are summarized below.
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
  
 
Figure JPOXMLDOC01-appb-T000064
  
 

Claims (22)

  1. 　一般式(1)の化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     [式中の記号は以下に定義される。
    A1、A2、A3：それぞれ独立して、-CH=、又は、-N=
    E：-CH2-、又は、-O-
    G：硫黄原子、窒素原子、又は、酸素原子を有していてもよい5員芳香族複素環（当該環は2つ以上の結合手を有する）
    但し、以下の5員芳香族複素環（左右の向きも記載のとおり）は除く。
    Figure JPOXMLDOC01-appb-C000002
     X：以下から選択されるいずれかの環（当該環は2つ以上の結合手を有し、2つの環が縮環した場合や、架橋した場合も含む）
    Figure JPOXMLDOC01-appb-C000003
     　A4、A5：それぞれ独立して、-CH=、又は、-N=
    　A6：-CH2-、-O-、又は、-NH-
    　ｍは、0、1、又は、2
    Y：
    置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
    置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいフェニル基、
    置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基、
    置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基（架橋構造を有する場合がある）、又は、
    置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基（架橋構造を有する場合がある）
    なお、Yは連結するアミド部分と一緒になってラクタムを形成する場合がある。すなわち、以下の左に示す鎖状アミドの部分構造が、以下の右に示す環状アミドの部分構造になる場合がある。
    Figure JPOXMLDOC01-appb-C000004
     置換基群Y1：
    水酸基、
    アミノ基、
    ニトロ基、
    シアノ基、
    ハロゲン原子、
    置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルキル基、
    置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC3-C8シクロアルキル基、
    置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよいC1-C6アルコキシ基、
    置換基群Y2から選択される同一または異なる1-2の基で置換されていてもよいアミノC1-C6アルキル基、
    置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基、
    置換基群Y2から選択される同一または異なる1-3の基で置換されていてもよい5-6員芳香族複素環基
    置換基群Y2：
    水酸基、
    ハロゲン原子、
    C1-C6アルキル基、
    C1-C6アルコキシ基、
    置換基群Y3から選択される同一または異なる1-2の基で置換されていてもよいアミノ基、
    置換基群Y3から選択される同一または異なる1-3の基で置換されていてもよい4-7員飽和複素環基 
    置換基群Y3：
    水酸基、
    ハロゲン原子、
    C1-C6アルキル基、
    C1-C6アルコキシ基
    R1、R2：それぞれ独立して、水素原子、シアノ基、ハロゲン原子、C1-C6アルキル基、C1-C6アルコキシ基、C3-C8シクロアルキル基、C3-C8シクロアルコキシ基、ハロC1-C6アルキル基、ハロC1-C6アルコキシ基、フェニル基、5-6員芳香族複素環基、C1-C6アルキルカルボニル基、C1-C6アルコキシカルボニル基、C3-C8シクロアルキルカルボニル基、C3-C8シクロアルコキシカルボニル基、ハロC1-C6アルキルカルボニル基、ハロC1-C6アルコキシカルボニル基、フェニルカルボニル基、又は、フェノキシカルボニル基
    R3：水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、又は、C3-C8シクロアルキル基
    R4：水素原子、ハロゲン原子、又は、C1-C6アルキル基
    R5a、R5b、R5c、R5d：それぞれ独立して水素原子、又は、C1-C6アルキル基
    n1、n2、n3：それぞれ独立して、0、1、又は、2]     The compound of General formula (1) or its pharmacologically acceptable salt.
    Figure JPOXMLDOC01-appb-C000001
     [The symbols in the formula are defined below.
    A 1 , A 2 and A 3 : each independently, -CH = or -N =
    E: -CH 2- or -O-
    G: 5-membered aromatic heterocycle which may have a sulfur atom, nitrogen atom or oxygen atom (the ring has two or more bonds)
    However, the following five-membered aromatic heterocycle (the direction of right and left is also as described) is excluded.
    Figure JPOXMLDOC01-appb-C000002
     X: any ring selected from the following (including the case where the ring has two or more bonds and two rings are fused or bridged)
    Figure JPOXMLDOC01-appb-C000003
     A 4 and A 5 : each independently, -CH = or -N =
    A 6 : -CH 2- , -O-, or -NH-
    m is 0, 1 or 2
    Y:
    C1-C6 alkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
    A phenyl group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
    5-6 membered aromatic heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 1 ;
    A C3-C8 cycloalkyl group (which may have a crosslinked structure) optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 1 or
    4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent group Y 1 (may have a crosslinked structure)
    In addition, Y may form a lactam together with the linked amide moiety. That is, the partial structure of the linear amide shown on the left below may be the partial structure of the cyclic amide shown on the right below.
    Figure JPOXMLDOC01-appb-C000004
     Substituent group Y 1 :
    Hydroxyl group,
    Amino group,
    Nitro group,
    Cyano group,
    Halogen atom,
    A C1-C6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
    A C3-C8 cycloalkyl group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
    C1-C6 alkoxy group optionally substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
    An amino C1-C6 alkyl group which may be substituted with the same or different 1-2 groups selected from Substituent Group Y 2 ;
    4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 2 ;
    Identical are selected from substituent group Y 2 or 5-6 membered aromatic may be substituted with a different 1-3 heterocyclic group substituent group Y 2:
    Hydroxyl group,
    Halogen atom,
    C1-C6 alkyl group,
    C1-C6 alkoxy group,
    An amino group which may be substituted with the same or different 1 to 2 groups selected from Substituent Group Y 3 ;
    4-7 membered saturated heterocyclic group which may be substituted by the same or different 1 to 3 groups selected from Substituent Group Y 3
    Substituent group Y 3 :
    Hydroxyl group,
    Halogen atom,
    C1-C6 alkyl group,
    C1-C6 alkoxy group
    R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a halo C1-C6 Alkyl group, halo C1-C6 alkoxy group, phenyl group, 5-6 membered aromatic heterocyclic group, C1-C6 alkyl carbonyl group, C1-C6 alkoxy carbonyl group, C3-C8 cycloalkyl carbonyl group, C3-C8 cyclo alkoxy A carbonyl group, a halo C1-C6 alkylcarbonyl group, a halo C1-C6 alkoxycarbonyl group, a phenylcarbonyl group, or a phenoxycarbonyl group
    R 3 : hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
    R 4 : hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
    R 5a , R 5b , R 5c and R 5d each independently represents a hydrogen atom or a C1-C6 alkyl group
    n 1 , n 2 , n 3 : each independently, 0, 1 or 2]
  2. A1、A2、及び、A3のいずれもが同一であり、-CH=； 又は、いずれか１個が-N=である請求項1に記載の一般式(1)の化合物又はその薬理上許容される塩。 The compound of the general formula (1) or the pharmacology thereof according to claim 1, wherein all of A 1 , A 2 and A 3 are the same and -CH =; Top acceptable salt.
  3. Eが、-O-であり、n1が0であり、n2が、1である請求項1又は2に記載の一般式(1)の化合物又はその薬理上許容される塩。 The compound of the general formula (1) or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein E is -O-, n 1 is 0, and n 2 is 1.
  4. Gが、以下から選択されるいずれかである、請求項1-3のいずれかに記載の化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000005
         The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein G is any one selected from the following.
    Figure JPOXMLDOC01-appb-C000005
  5. Xが、以下から選択されるいずれかである、請求項1-4のいずれかに記載の化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000006
         The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein X is any one selected from the following.
    Figure JPOXMLDOC01-appb-C000006
  6. n3が、0である、請求項1-5のいずれかに記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein n 3 is 0.
  7. Yが、以下から選択されるいずれかの基（なお、Yは、置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい。置換基群Y1は、請求項1で定義のとおり。）である、請求項1-6のいずれかに記載の化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000007
         Y is any group (Note selected from the following, Y may be substituted with same or different 1-3 groups selected from Substituent Group Y 1. Substituent group Y 1 is The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 6, which is as defined in claim 1.
    Figure JPOXMLDOC01-appb-C000007
  8. 　一般式(1a)の化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000008
     [式中の記号は以下に定義される。
    A1、A2、及び、A3：いずれもが同一であり、-CH=； 又は、いずれか１個が-N=である
    G：以下から選択されるいずれかの5員芳香族複素環
    Figure JPOXMLDOC01-appb-C000009
     X：以下から選択されるいずれかの環
    Figure JPOXMLDOC01-appb-C000010
     Y：以下から選択されるいずれかの基（なお、Yは、置換基群Y1から選択される同一または異なる1-3の基で置換されていてもよい。置換基群Y1は、請求項1で定義のとおり。）
    Figure JPOXMLDOC01-appb-C000011
     R1、R2：それぞれ独立して、水素原子、シアノ基、ハロゲン原子、C1-C6アルキル基、C1-C6アルコキシ基、ハロC1-C6アルキル基、又は、ハロC1-C6アルコキシ基、
    R3：水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、又は、C3-C8シクロアルキル基
    R4：水素原子、ハロゲン原子、又は、C1-C6アルキル基
    R5c、R5d：それぞれ独立して水素原子、又は、C1-C6アルキル基]     The compound of General formula (1a) or its pharmacologically acceptable salt.
    Figure JPOXMLDOC01-appb-C000008
     [The symbols in the formula are defined below.
    A 1 , A 2 and A 3 : all are the same, -CH =; or any one is -N =
    G: any 5-membered aromatic heterocycle selected from the following:
    Figure JPOXMLDOC01-appb-C000009
     X: any ring selected from the following
    Figure JPOXMLDOC01-appb-C000010
     Y:. Either group selected from the following (Note, Y may be substituted with same or different 1-3 groups selected from substituent group Y 1 substituent group Y 1 is claimed As defined in Section 1.)
    Figure JPOXMLDOC01-appb-C000011
     R 1 and R 2 each independently represents a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halo C1-C6 alkyl group, or a halo C1-C6 alkoxy group,
    R 3 : hydrogen atom, C 1 -C 6 alkyl group, halo C 1 -C 6 alkyl group, or C 3 -C 8 cycloalkyl group
    R 4 : hydrogen atom, halogen atom, or C 1 -C 6 alkyl group
    R5c and R5d : each independently a hydrogen atom or a C1-C6 alkyl group]
  9. 以下から選択されるいずれかの化合物又はその薬理上許容される塩。
    4-[(ジメチルアミノ)メチル]-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]-1,2,3,4-テトラヒドロイソキノリン-6-カルボキサミド
    4-フルオロ-1-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ピペリジン-4-カルボキサミド
    4-シアノ-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    N-(4-[5-[(3-クロロフェノキシ)メチル]-4-メチル-1,2,4-トリアゾール-3-イル]フェニル)-4-[(ジメチルアミノ)メチル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[トランス-4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-41,2,4-トリアゾール-3-イル)シクロヘキシル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[6-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ピリジン-3-イル]ベンズアミド
    (2S,5R)-5-(ジメチルアミノ)-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]テトラハイドロ-2H-ピラン-2-カルボキサミド
    4-[(3-フルオロアゼチジン-1-イル)メチル]-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[トランス-4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)シクロヘキシル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-({[4-(トリフルオロメチル)ピリジン-2-イル]オキシ)メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
    4-(アゼチジン-1-イルメチル)-2-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ベンズアミド
    3-フルオロ-1-メチル-N-[4-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)フェニル]ピペリジン-3-カルボキサミド
    4-[(ジメチルアミノ)メチル]-N-{4-[4-メチル-5-([[6-メチル-4-(トリフルオロメチル)ピリジン-2-イル]オキシ]メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[4-(4-[[3-(プロパン-2-イル)フェノキシ]メチル]-イミダゾール-1-イル)フェニル]ベンズアミド
    4-[(ジメチルアミノ)メチル]-N-[4-[4-メチル-5-({[4-(プロパン-2-イル)ピリジン-2-イル]オキシ]メチル)-1,2,4-トリアゾール-3-イル]フェニル}ベンズアミド
    4-(アゼチジン-1-イルメチル)-2-フルオロ-N-[6-(4-メチル-5-[[3-(トリフルオロメチル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ピリジン-3-イル]ベンズアミド
    N-[4-[(ジメチルアミノ)メチル]フェニル]-4-(4-メチル-5-[[3-(プロパン-2-イル)フェノキシ]メチル]-1,2,4-トリアゾール-3-イル)ベンズアミド     Any compound selected from the following or a pharmacologically acceptable salt thereof.
    4-[(Dimethylamino) methyl] -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] Benzamide
    2-Methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] -1,2,3 , 4-Tetrahydroisoquinoline-6-carboxamide
    4-Fluoro-1-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] piperidine- 4-carboxamide
    4-Cyano-2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] benzamide
    4-[(Dimethylamino) methyl] -2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) phenyl] benzamide
    4-[(Dimethylamino) methyl] -N- [4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazol-3-yl) Phenyl] benzamide
    N- (4- [5-[(3-chlorophenoxy) methyl] -4-methyl-1,2,4-triazol-3-yl] phenyl) -4-[(dimethylamino) methyl] benzamide
    4-[(Dimethylamino) methyl] -N- [trans-4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -41,2,4-triazol-3-yl) Cyclohexyl] benzamide
    4-[(Dimethylamino) methyl] -N- [6- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) pyridine- 3-yl] benzamide
    (2S, 5R) -5- (Dimethylamino) -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl ) Phenyl] Tetrahydro-2H-pyran-2-carboxamide
    4-[(3-Fluoroazetidin-1-yl) methyl] -N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole -3-yl) phenyl] benzamide
    4-[(Dimethylamino) methyl] -N- [trans-4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazole-3-) I) cyclohexyl] benzamide
    4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-({[4- (trifluoromethyl) pyridin-2-yl] oxy) methyl) -1,2,4-triazole -3-yl] phenyl} benzamide
    4- (Azetidin-1-ylmethyl) -2-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) phenyl] benzamide
    3-Fluoro-1-methyl-N- [4- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazol-3-yl) phenyl] piperidine- 3-carboxamide
    4-[(Dimethylamino) methyl] -N- {4- [4-methyl-5-([[6-methyl-4- (trifluoromethyl) pyridin-2-yl] oxy] methyl) -1,2 , 4-Triazol-3-yl] phenyl} benzamide
    4-[(Dimethylamino) methyl] -N- [4- (4-[[3- (propan-2-yl) phenoxy] methyl] -imidazol-1-yl) phenyl] benzamide
    4-[(Dimethylamino) methyl] -N- [4- [4-methyl-5-({[4- (propan-2-yl) pyridin-2-yl] oxy] methyl) -1,2,4 -Triazol-3-yl] phenyl} benzamide
    4- (Azetidin-1-ylmethyl) -2-fluoro-N- [6- (4-methyl-5-[[3- (trifluoromethyl) phenoxy] methyl] -1,2,4-triazole-3- Yl) pyridin-3-yl] benzamide
    N- [4-[(Dimethylamino) methyl] phenyl] -4- (4-methyl-5-[[3- (propan-2-yl) phenoxy] methyl] -1,2,4-triazole-3- I) benzamide
  10. IL10を増加させるための請求項1-9のいずれかに記載の化合物又はその薬理上許容される塩。 The compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof for increasing IL10.
  11. 請求項1-9のいずれかに記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof as an active ingredient.
  12. 炎症性疾患の予防及び/又は治療用である、請求項11に記載の医薬組成物。 The pharmaceutical composition according to claim 11, which is for the prevention and / or treatment of an inflammatory disease.
  13. 炎症性疾患が、末梢性炎症性疾患である、請求項12に記載の医薬組成物。 The pharmaceutical composition according to claim 12, wherein the inflammatory disease is a peripheral inflammatory disease.
  14. 炎症性疾患が、中枢性炎症性疾患である、請求項12に記載の医薬組成物。 The pharmaceutical composition according to claim 12, wherein the inflammatory disease is a central inflammatory disease.
  15. 末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、強皮症、気管支喘息、喘息性気管支炎、びまん性間質性肺炎、慢性閉塞性肺疾患、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、急性肝炎、慢性肝炎、劇症肝炎、自己免疫性肝炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、アルコール性肝炎、非アルコール性脂肪性肝炎、肝硬変、末梢神経炎、強直性脊椎炎、湿疹（急性・亜急性・慢性）、接触皮膚炎、日光（紫外線）皮膚炎、放射線皮膚炎、アトピー皮膚炎、脂漏性皮膚炎、尋常性乾癬、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、扁平苔癬、紅斑症、酒さ、蕁麻疹、円形脱毛症、天疱瘡群、紅皮症、尋常性ざ瘡、褥瘡、創傷、熱傷、結膜炎，角膜炎，強膜炎，急性・慢性中耳炎、通年性アレルギー性鼻炎、花粉症、副鼻腔炎、喉頭炎、食道炎、難治性口内炎及、舌炎、急性・慢性唾液腺炎、口角炎、口唇炎、ベーチェット病、多発性硬化症、I型糖尿病、II型糖尿病、アテローム性動脈硬化症、膵炎、及び、慢性心不全からなる群より選択されるいずれかである、請求項13に記載の医薬組成物。 Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia, chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, celiac disease,痔 瘻, radiation enteritis, acute hepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, cirrhosis, peripheral neuritis , Ankylosing spondylitis, eczema (acute, subacute, chronic), contact dermatitis, sun (ultraviolet) dermatitis, radiation dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis, Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, urticaria, alopecia areata, pemphigus, erythema, acne vulgaris, acne, wounds, burns, conjunctivitis, keratitis , Scleritis, acute / chronic otitis media, perennial allergic Inflammation, hay fever, sinusitis, laryngitis, esophagitis, intractable stomatitis, intractable glossitis, acute / chronic sialadenitis, canker sores, lipitis, Behcet's disease, multiple sclerosis, type I diabetes, type II diabetes The pharmaceutical composition according to claim 13, which is any one selected from the group consisting of atherosclerosis, pancreatitis and chronic heart failure.
  16. 末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、気管支喘息、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、急性肝炎、自己免疫性肝炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、アルコール性肝炎、非アルコール性脂肪性肝炎、強直性脊椎炎、接触皮膚炎、日光（紫外線）皮膚炎、アトピー皮膚炎、脂漏性皮膚炎、尋常性乾癬、関節症性乾癬、乾癬性紅皮症、膿疱性乾癬、扁平苔癬、紅斑症、酒さ、円形脱毛症、天疱瘡群、紅皮症、尋常性ざ瘡、褥瘡、創傷、熱傷、副鼻腔炎、喉頭炎、食道炎、難治性口内炎、舌炎、急性・慢性唾液腺炎、口角炎、及び、口唇炎及びベーチェット病からなる群より選択されるいずれかである、請求項13に記載の医薬組成物。 Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, acute hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary Sclerosing cholangitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spondylitis, contact dermatitis, sun (ultraviolet) dermatitis, atopic dermatitis, seborrhoeic dermatitis, psoriasis vulgaris, arthritic psoriasis Psoriatic erythroderma, pustular psoriasis, lichen planus, erythema, rosacea, rosacea, alopecia areata, pemphigus, erythema, acne vulgaris, acne, wounds, burns, sinusitis, laryngitis The pharmaceutical composition according to claim 13, which is any one selected from the group consisting of esophagitis, intractable stomatitis, glossitis, acute / chronic sialadenitis, cankerulitis, and lipitis and Behcet's disease.
  17. 末梢性炎症性疾患が、関節リウマチ、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、セリアック病、痔瘻、放射線性腸炎、自己免疫性肝炎、アルコール性肝炎、非アルコール性脂肪性肝炎、強直性脊椎炎、創傷、難治性口内炎、舌炎、及び、ベーチェット病からなる群より選択されるいずれかである、請求項13に記載の医薬組成物。 Peripheral inflammatory diseases include rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, celiac disease, epilepsy, radiation enteritis, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, ankylosing spine The pharmaceutical composition according to claim 13, which is any one selected from the group consisting of inflammation, wound, intractable stomatitis, glossitis and Behcet's disease.
  18. 中枢性炎症性疾患が、
    アルツハイマー病、パーキンソン病、レビー小体型認知症、多系統萎縮症、ピック病、進行性核上性麻痺、大脳皮質基底核変性症、前頭側頭葉変性症、ハンチントン病、筋萎縮性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、脊髄小脳変性症、多発性硬化症、クロイツフェルト・ヤコブ病、致死性家族性不眠症、ゲルストマン・ストロイスラー・シャインカー症候群、ダウン症侯群、ニーマン－ピック病、脳アミロイド血管症、HIV脳症、インフルエンザ脳症、肝性脳症、進行性多巣性白質脳症、抗NMDA受容体抗体脳炎、脳血管障害、外傷性脳損傷、脊髄損傷、低酸素脳症、てんかん、視神経炎、先天性代謝性脳疾患、ウェルニッケ脳症、自閉スペクトラム障害、注意欠如・多動性障害、チック障害、統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害、心的外傷およびストレス因関連障害、摂食障害、概日リズム睡眠・覚醒障害、ナルコレプシー、物質関連障害（アルコール依存、薬物依存）、衝動制御障害、せん妄、パーソナリティ障害、レット症候群
    からなる群より選択されるいずれかである、請求項14に記載の医薬組成物。     Central inflammatory disease,
    Alzheimer's disease, Parkinson's disease, Lewy body type dementia, multiple system atrophy, Pick's disease, progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, frontotemporal lobar degeneration, Huntington's disease, amyotrophic lateral sclerosis Disease, bulbar and spinal muscular atrophy, spinal muscular atrophy, spinocerebellar degeneration, multiple sclerosis, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann Stroisler Shinker syndrome, Down syndrome group , Niemann-Pick disease, cerebral amyloid angiopathy, HIV encephalopathy, influenza encephalopathy, hepatic encephalopathy, progressive multifocal leukoencephalopathy, anti-NMDA receptor antibody encephalitis, cerebrovascular disorder, traumatic brain injury, spinal cord injury, hypoxia Encephalopathy, epilepsy, optic neuritis, congenital metabolic brain disease, Wernicke's encephalopathy, autism spectrum disorder, attention deficit / hyperactivity disorder, tic disorder, schizophrenia, bipolar disorder, major depressive disorder Harm (treatment-resistant depression, postpartum depression), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, obsessive compulsive disorder, trauma and stress related disorder Eating disorder, circadian rhythm sleep and wake disorder, narcolepsy, substance related disorder (alcoholic and drug dependent), impulse control disorder, delirium, personality disorder, Rett syndrome, any one selected from the group consisting of The pharmaceutical composition according to Item 14.
  19. 中枢性炎症性疾患が、
    アルツハイマー病、パーキンソン病、レビー小体型認知症、多系統萎縮症、ピック病、進行性核上性麻痺、大脳皮質基底核変性症、前頭側頭葉変性症、ハンチントン病、筋萎縮性側索硬化症、球脊髄性筋萎縮症、脊髄性筋萎縮症、脊髄小脳変性症、多発性硬化症、クロイツフェルト・ヤコブ病、統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害、心的外傷およびストレス因関連障害、摂食障害、概日リズム睡眠・覚醒障害、ナルコレプシー、物質関連障害（アルコール依存、薬物依存）、衝動制御障害、せん妄、パーソナリティ障害、レット症候群
    からなる群より選択されるいずれかである、請求項14に記載の医薬組成物。     Central inflammatory disease,
    Alzheimer's disease, Parkinson's disease, Lewy body type dementia, multiple system atrophy, Pick's disease, progressive supranuclear palsy, cerebral cortex basal ganglia degeneration, frontotemporal lobar degeneration, Huntington's disease, amyotrophic lateral sclerosis Disorders, spinal muscular atrophy, spinal muscular atrophy, spinocerebellar degeneration, multiple sclerosis, Creutzfeldt-Jakob disease, schizophrenia, bipolar disorder, major depressive disorder Postpartum depression), persistent depressive disorder (thymic disorder), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, obsessive compulsive disorder, trauma and stress related disorder, eating disorder, circadian The rhythm sleep-wake disorder, narcolepsy, substance-related disorder (alcohol dependence, drug dependence), impulse control disorder, delirium, personality disorder, Rett syndrome, any one selected from the group consisting of The pharmaceutical compositions of the mounting.
  20. 中枢性炎症性疾患が、
    統合失調症、双極性障害、大うつ病性障害（治療抵抗性うつ、産後うつ）、持続性抑うつ障害（気分変調症）、月経前不快気分障害、不安障害、限局性恐怖症、パニック障害、強迫性障害
    からなる群より選択されるいずれかである、請求項14に記載の医薬組成物。     Central inflammatory disease,
    Schizophrenia, bipolar disorder, major depressive disorder (treatment resistant depression, postpartum depression), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, anxiety disorder, focal phobia, panic disorder, The pharmaceutical composition according to claim 14, which is any one selected from the group consisting of obsessive compulsive disorder.
  21. 炎症性疾患の治療における使用のための請求項1-9のいずれかに記載の化合物又はその薬理上許容される塩。 A compound according to any of claims 1-9 or a pharmacologically acceptable salt thereof for use in the treatment of inflammatory diseases.
  22. 請求項11に記載の医薬組成物の有効量を投与する炎症性疾患の予防及び/又は治療方法。 A method for preventing and / or treating inflammatory diseases, which comprises administering an effective amount of the pharmaceutical composition according to claim 11.
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US11851440B2 (en) 2017-08-09 2023-12-26 Denali Therapeutics Inc. Modulators of eukaryotic initiation factor 2B, compositions and methods
JP2020532506A (en) * 2017-09-01 2020-11-12 デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． Compounds, compositions, and methods
JP7382308B2 (en) 2017-09-01 2023-11-16 デナリ セラピューティクス インコーポレイテッド Compounds, compositions and methods
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