WO2018235813A1 - Dérivé d'imidazole et médicament comprenant celui-ci - Google Patents

Dérivé d'imidazole et médicament comprenant celui-ci Download PDF

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WO2018235813A1
WO2018235813A1 PCT/JP2018/023286 JP2018023286W WO2018235813A1 WO 2018235813 A1 WO2018235813 A1 WO 2018235813A1 JP 2018023286 W JP2018023286 W JP 2018023286W WO 2018235813 A1 WO2018235813 A1 WO 2018235813A1
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Prior art keywords
methyl
group
trifluoromethyl
imidazole
tert
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PCT/JP2018/023286
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English (en)
Japanese (ja)
Inventor
興 久村
広太 村▲崎▼
佑太 藤原
政人 市來
優樹 佐藤
加藤　幹也
大護 上村
Original Assignee
Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
科研製薬株式会社
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Publication of WO2018235813A1 publication Critical patent/WO2018235813A1/fr

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Definitions

  • the present invention comprises a novel imidazole derivative having an inhibitory action on retinoic acid receptor-related orphan receptor ⁇ t (retinoic acid receptor-related orphan receptor- ⁇ t: ROR ⁇ t) or a salt thereof, and the imidazole derivative or a salt thereof as an active ingredient It relates to medicine.
  • ROR retinoic acid receptor-related orphan receptor
  • ROR ⁇ t is an isoform of ROR ⁇ and is mainly expressed in cells of the immune system. In recent years, it has been revealed that ROR ⁇ t functions as an important regulator of Th17 cell differentiation (Non-patent Document 1).
  • Non-patent Document 2 Regarding the importance of ROR ⁇ t in differentiation of Th17 cells and involvement in disease of Th17 cells, suppression of differentiation to Th17 cells and IL-17 production in T cells of ROR ⁇ t knockout mice, pathogenesis model of multiple sclerosis It is shown by the suppression of the pathological condition of Experimental Autoimmune encephalomyelitis (Non-patent Document 2).
  • Th17 cells are one of the helper T cell subsets that produce inflammatory cytokines such as IL-17A, IL-17F, IL-21 and IL-22.
  • Inflammatory cytokines such as Th17 cells or IL-17A and IL-17F include various species including psoriasis, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), rheumatoid arthritis, systemic lupus erythematosus, etc. Its relevance has been shown in autoimmune diseases and allergic diseases (Non-patent Document 3). Therefore, drugs that inhibit the action of ROR ⁇ t inhibit differentiation and activation of Th17 cells, and exert therapeutic or prophylactic effects in various diseases involving inflammatory cytokines such as Th17 cells or IL-17A or IL-17F. It is expected.
  • Patent Document 1 compounds represented by the following formulas are known as ROR ⁇ t inhibitors (Patent Documents 1 to 6).
  • Patent Document 1 In the formula, X represents an oxygen atom or a nitrogen atom substituted by R a .
  • X represents an oxygen atom or a nitrogen atom substituted by R a .
  • Patent Document 2 (Wherein R 3 is a 6- to 10-membered 1 or 2 aromatic ring, or a 5 to 14-membered 1, 2 or 3 cyclic heteroaromatic ring, any of N, O or S Contains 1 to 5 heteroatoms (see the relevant literature for details).
  • Patent Document 3 (Wherein, X, Y and Z each represent a nitrogen atom or a carbon atom substituted with R e . For details, refer to the relevant literature.)
  • Patent Document 5 (Wherein, R 3 represents ⁇ , F, Cl, CH 3 or CF 3. Refer to the relevant literature for details.)
  • Patent Document 6 (Patent Document 6)
  • Patent Document 7 a compound represented by the following formula is known to inhibit blood coagulation factor Xa and / or factor VIIa (Patent Document 7), but there is no specific disclosure of the compound of the present invention, The pharmacological action is different from the present invention.
  • Patent Document 7 (Wherein, R 2 represents a direct bond or-(C 1 -C 4) -alkylene. For details, refer to the relevant literature.)
  • An object of the present invention is to provide a novel compound or a salt thereof which has ROR ⁇ t inhibitory activity and is useful as a preventive or therapeutic agent for autoimmune diseases, allergic diseases and the like.
  • Another object of the present invention is to provide a medicament useful for preventing or treating autoimmune diseases, allergic diseases and the like, which comprises the above-mentioned novel compound or a salt thereof as an active ingredient.
  • the inventors of the present invention conducted intensive studies to solve the above problems, and as a result, they found that the imidazole derivative represented by the following general formula (I) had excellent ROR ⁇ t inhibitory action, and based on this finding, the present invention Completed.
  • the present invention will be described in detail.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is generically referred to as "the imidazole derivative of the present invention”.
  • R 1 is a halogen atom, a C 1 to C 6 alkyl group which may be substituted by a C 1 to C 6 alkoxy group, a C 1 to C 6 haloalkyl group, a C 3 to C which may be substituted by Ra 6 cycloalkyl groups (wherein, R a represents a C 1 to C 6 alkyl group, a C 1 to C 6 alkyl group substituted with a C 1 to C 6 alkoxy group, a C 1 to C 6 haloalkyl group), 4 to 6 optionally substituted by a C 3 to C 6 cycloalkenyl group, a 4 to 6-membered heterocycloalkyl group optionally substituted by a C 1 to C 6 alkyl group, or a C 1 to C 3 alkylene group Membered heterocycloalkyl group, R 2 is a halogen atom or a C 1 to
  • R 1 is a C 1 to C 6 alkyl group
  • R 2 is a C 1 to C 6 alkyl group
  • R 3 and R 4 are each independently a hydrogen atom or Hydroxymethyl group
  • R 5 is a C 1 to C 6 alkyl group
  • R 8 is a C 1 to C 6 haloalkyl group
  • X is an oxygen atom
  • ring A and ring B are each independently phenyl Or a compound according to (1) which is pyridyl or a pharmaceutically acceptable salt thereof.
  • R 5 is a methyl group or an ethyl group.
  • R 7 is a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, cyclopropyl (hydroxy) methyl group, 2,2-difluoro-1-hydroxyethyl group or 2 Or a compound according to any one of (1) to (10), which is a 2,2-trifluoro-1-hydroxyethyl group, or a pharmaceutically acceptable salt thereof.
  • a medicament comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  • the medicament according to (17), wherein the inflammatory cytokine is IL-17A and / or IL-17F.
  • a method for preventing and / or treating a disease involving Th17 cells in a mammal including human which is effective for treating and / or preventing the compound according to (1) or the pharmaceutically acceptable salt thereof Administering the amount to a mammal in need of treatment or prevention.
  • the imidazole derivative of the present invention or a salt thereof has excellent ROR ⁇ t inhibitory activity and suppresses differentiation and / or activation of Th17 cells to produce inflammatory cytokines such as IL-17A and / or IL-17F. Can be suppressed.
  • a medicament containing the imidazole derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is, for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), multiple sclerosis And various autoimmune diseases such as systemic lupus erythematosus, ankylosing spondylitis, uveitis and allergic diseases (asthma, atopic dermatitis, chronic obstructive pulmonary disease etc.), Th17 cells or IL-17A or IL-17F And the like, and is useful as an active ingredient of a medicine for the prevention and / or treatment of diseases involving inflammatory cytokines such as Furthermore, the imidazole derivative of the present invention or a salt thereof has excellent properties in solubility, safety, pharmacokinetics and the like.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “C 1 to C 6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -Butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-pentan-3-yl, tert-pentyl, 3-methylbutyl (isopentyl), neopentyl, n- A hexyl group etc. are mentioned.
  • the “C 1 to C 3 alkylene group” represents an alkylene group having 1 to 3 carbon atoms, and specific examples include methylene, 1,2-ethylene, 1,3-propylene and the like.
  • the “C 1 to C 6 haloalkyl group” means a group in which one or more halogen atoms may be substituted on the C 1 to C 6 alkyl group, and specific examples thereof include Trifluoromethyl group, difluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, trichloromethyl group, 3-chloropropyl group, 1,1,1-trifluoropropan-2-yl group, 2,2-difluoropropyl group, 4-bromobutyl group, 1,1,1,3,3,3-hexafluoropropan-2-yl group and the like.
  • C 1 -C 6 hydroxyalkyl group means a group in which a hydroxy group can be substituted at any position at which a C 1 -C 6 alkyl group can be substituted, and specific examples thereof include a hydroxymethyl group, 1- Hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 4-hydroxybutyl group, etc. Can be mentioned.
  • the “C 1 to C 6 alkoxy group” represents an alkoxy group in which the alkyl moiety is the same as the above C 1 to C 6 alkyl group, and specific examples thereof include a methoxy group, an ethoxy group, n-propoxy group, isopropoxy Group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group, n-hexyloxy group etc.
  • the “C 1 to C 6 haloalkoxy group” means a group in which one or more halogen atoms may be substituted on the C 1 to C 6 alkoxy group at any position capable of being substituted, and specific examples thereof include Trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy and the like Be
  • C 3 -C 6 cycloalkyl represents a monocyclic cycloalkyl having 3 to 6 carbon atoms, and specifically means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the “C 3 -C 6 cycloalkenyl group” represents a cyclic alkenyl group having one or two double bonds and a group consisting of 3 to 6 carbon atoms. Specific examples thereof include cyclopropenyl group having a bonding position at any carbon atom, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and the like.
  • hydroxydi C 1 -C 6 alkylsilyl group represents a group in which a hydroxyl group and two of the above C 1 -C 6 alkyl groups are bonded to a silyl group. Specific examples include hydroxydimethylsilyl group, hydroxydiethylsilyl group and the like.
  • the “6- to 10-membered aryl group” represents a monocyclic or bicyclic aromatic carbocyclic ring, and specifically means phenyl, 1-naphthyl or 2-naphthyl.
  • 5- to 10-membered heteroaryl refers to a 5- to 10-membered monocyclic or bicyclic group having at least one hetero atom selected from nitrogen atom, oxygen atom and sulfur atom in a ring constituting atom
  • specific examples thereof include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzoimidazolyl, indazolyl, benzo Examples include oxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, triazolyl, oxazolyl
  • the “4- to 6-membered heterocycloalkyl group” represents a 4- to 6-membered saturated monocyclic ring containing at least one hetero atom selected from a nitrogen atom and an oxygen atom.
  • Specific examples generally include oxetanyl having a bonding position at any possible carbon atom or nitrogen atom, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like.
  • any hydrogen atom may be replaced by a deuterium atom among one or two or more hydrogen atoms present in a substituent such as an alkyl group or an alkoxy group.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) is not particularly limited as long as it is pharmaceutically acceptable.
  • salts with organic acids, salts with inorganic acids, and salts with inorganic acids examples include salts with amino acids.
  • salts with organic acids are formate, acetate, tartrate, fumaric acid, maleate, succinate, lactate, citric acid, malate, ascorbate, oxalate, glycolic acid Salt, phenyl acetate, benzoate, methane sulfonate, benzene sulfonate and the like can be mentioned.
  • salts with inorganic acids include hydrochloride, hydrobromide, phosphate, sulfamate, nitrate, sulfate and the like.
  • salts with amino acids aspartate, glutamate and the like can be mentioned.
  • R 1 is preferably a C 1 -C 6 alkyl group, more preferably a tert-butyl group.
  • R 2 is preferably a C 1 to C 6 alkyl group, more preferably a methyl group or an ethyl group, and a methyl group is even more preferable.
  • R 3 and R 4 preferably, R 3 and R 4 are both hydrogen atoms, or one of R 3 and R 4 is a hydrogen atom, and the other is a C 1 to C 6 hydroxyalkyl group, more preferably And R 3 and R 4 are both hydrogen atoms, or one of R 3 and R 4 is a hydrogen atom and the other is a hydroxymethyl group.
  • R 5 is preferably a C 1 to C 6 alkyl group, more preferably a methyl group or an ethyl group.
  • R 6 is preferably a hydrogen atom.
  • R 7 is preferably a hydrogen atom, a halogen atom, C 1 ⁇ C 6 haloalkyl group or C 3 ⁇ C 6 cycloalkyl group optionally substituted C 1 ⁇ C 6 hydroxyalkyl group, C 1 ⁇ C 6 an alkoxy group or C 1 ⁇ C 6 haloalkoxy group, more preferably, at C 1 ⁇ C 6 haloalkyl group or C 3 ⁇ C 6 may be substituted with a cycloalkyl group C 1 ⁇ C 6 hydroxyalkyl group More preferably, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, cyclopropyl (hydroxy) methyl group, 2,2-difluoro-1-hydroxyethyl group, 2,2,2-triyl group. It is a
  • R 8 is preferably a halogen atom or a C 1 -C 6 haloalkyl group, more preferably a trifluoromethyl group.
  • X is preferably an oxygen atom or NH, more preferably an oxygen atom.
  • Ring A is preferably phenyl or pyridyl, more preferably phenyl.
  • Ring B is preferably thiazolyl, phenyl or pyridyl, more preferably phenyl or pyridyl.
  • the substitution position of the substituents R 7 and R 8 is Is preferred.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, ring A, rings B and n in the general formula (I) are preferable.
  • R 1 is a C 1 to C 6 alkyl group and R 2 is a C 1 to C 6 alkyl group, R 1 is a tert-butyl group, and R 2 is a methyl group or ethyl Those which are groups are more preferred.
  • R 5 is a C 1 -C 6 alkyl group and X is an oxygen atom are preferred, and those in which R 5 is a methyl group or an ethyl group and X is an oxygen atom are more preferred.
  • R 5 is a methyl group or an ethyl group
  • R 6 is a hydrogen atom
  • X is an oxygen atom
  • ring B is phenyl or pyridyl
  • the substitution position is Is preferred.
  • R 3 and R 4 are both hydrogen atoms, R 5 is a methyl group or an ethyl group, R 6 is a hydrogen atom, X is an oxygen atom, ring B is phenyl or pyridyl, and substitution the position is, Is preferred.
  • R 3 and R 4 is a hydrogen atom, the other is a hydroxymethyl group, R 5 is a methyl group or an ethyl group, R 6 is a hydrogen atom, X is an oxygen atom, and ring B is phenyl Or pyridyl and the substitution position is Is preferred.
  • Ring A is phenyl
  • R 7 is C 1 ⁇ C 6 haloalkyl group or C 3 ⁇ C 6 may be substituted with a cycloalkyl group C 1 ⁇ C 6 hydroxyalkyl group
  • R 8 is a halogen atom or It is a C 1 -C 6 haloalkyl group and n is preferably 0, and R 7 is preferably a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, cyclopropyl (hydroxy) methyl group, 2,2- It is more preferable that it is a difluoro-1-hydroxyethyl group or a 2,2,2-trifluoro-1-hydroxyethyl group, R 8 is a trifluoromethyl group and n is 0.
  • R 1 is a C 1 -C 6 alkyl group
  • R 2 is a C 1 -C 6 alkyl group
  • R 3 and R 4 are both hydrogen atoms, or one of R 3 and R 4 is a hydrogen atom, and the other is a C 1 to C 6 hydroxyalkyl group
  • R 5 is a C 1 -C 6 alkyl group
  • R 6 is a hydrogen atom
  • R 7 is located in C 1 ⁇ C 6 haloalkyl group or C 3 ⁇ C 6 may be substituted with a cycloalkyl group C 1 ⁇ C 6 hydroxyalkyl group
  • R 8 is a C 1 -C 6 haloalkyl group
  • X is an oxygen atom
  • Ring A is phenyl or pyridyl
  • Ring B is thiazolyl, phenyl or pyridyl, The compound wherein n is 0.
  • the compounds represented by the general formula (I) can be produced by various methods, and can be produced, for example, by the methods shown in the following reaction formula-1 (steps 1-1 to 1-4).
  • Step 1-1 is a step of reacting the compound represented by General Formula (II) with the compound represented by General Formula (III) to produce a compound represented by General Formula (IV).
  • the compound represented by (IV) is reacted with a compound represented by the general formula (II) and a compound represented by the general formula (III) in the presence of an acid using a radical initiator.
  • Radical initiators include, but are not limited to, combinations of metal salts such as silver (I) nitrate or iron (II) sulfate heptahydrate with oxidizing agents such as ammonium peroxodisulfate, hydrogen peroxide or benzoyl peroxide I will not.
  • the acid to be used examples include formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, and toluene-4-sulfonic acid.
  • a solvent may be used, and the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and methanol, diethyl ether, dichloromethane, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane And cyclopentyl methyl ether, water, a mixed solvent thereof and the like.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 150 ° C.
  • the reaction time is not particularly limited, and is preferably 10 minutes to 1 hour.
  • the compound represented by general formula (VI) is produced by reacting the compound represented by general formula (IV) with the compound represented by general formula (V) in the presence of a base in a solvent Can be manufactured.
  • a base to be used, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium Hexamethyldisilazane or inorganic base such as sodium hydride or trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicy
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and N, N-dimethylformamide, N, N-dimethylacetamide, N, N'-dimethylpropyleneurea, dimethylsulfoxide, N-methylpyrrolidone, acetone , Acetonitrile, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, pyridine, dichloromethane, chloroform, or a mixed solvent thereof, and the like.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 150 ° C.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • the compound represented by general formula (VII) can be produced by hydrolyzing the compound represented by general formula (VI) in a solvent in the presence of a base.
  • the base to be used include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the base may be used as an aqueous solution.
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and the like can be mentioned.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 90 ° C.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • Step 1-4 is a step of reacting the compound represented by General Formula (VII) with the compound represented by General Formula (VIII) to produce a compound represented by General Formula (I). Specifically, carrying out a condensation reaction using a condensing agent, in the presence or absence of a base, in a solvent and the compound represented by General Formula (VII) and the compound represented by General Formula (VIII) The compound represented by general formula (I) can be manufactured by this.
  • DBU 1,8-diazabicyclo [5.4 .0] -7-Undecene
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; ethers such as tetrahydrofuran; N, N-dimethylformamide, N, N -Amides such as dimethylacetamide; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as toluene; and mixed solvents of these.
  • reaction reagents such as 1-hydroxybenzotriazole (HOBt) may be added.
  • the reaction temperature is not particularly limited, and is preferably 0 ° C. to 80 ° C., for example.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • the compound represented by the general formula (VII) may be reacted with a compound represented by the general formula (VIII) after being derivatized into a reaction intermediate using an activating agent for a carboxyl group in a solvent.
  • the compounds represented by the general formula (I) can be produced.
  • the activating agent for the carboxyl group include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosgene, triphosgene, 1,1'-carbonyldiimidazole, ethyl chlorocarbonate and the like.
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, nitrobenzene and xylene; halogenated hydrocarbon solvents such as chloroform and dichloromethane; ethers such as tetrahydrofuran And ketones such as acetone and methyl ethyl ketone; nitrile solvents such as acetonitrile and propionitrile; and mixed solvents thereof. If necessary, a catalytic amount of an amide such as N, N-dimethylformamide may be added.
  • the reaction temperature is not particularly limited, and is preferably 0 ° C. to 80 ° C., for example.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • the compounds represented by General Formula (VI) in Reaction Formula-1 can also be produced by the following Reaction Formula-2 (Steps 2-1 to 2-4).
  • Reaction formula-2> [Wherein, the ring A, n, R 1 , R 2 , R 7 , R 8 and R 9 are as defined in the general formula (I) above; R 10 is a methyl group, an ethyl group, a t-butyl group or It is a benzyl group, and m represents 0-2.
  • the compound represented by the general formula (XIV) may be in any form of (E) form, (Z) form or a mixture thereof. ]
  • step 2-1 the compound represented by general formula (IX) is reacted with the compound represented by general formula (X) by the same method as the method described in step 1-4 of Reaction formula-1
  • the compound represented by the general formula (XI) can be produced.
  • the compound represented by general formula (XII) can be produced by oxidation reaction of the compound represented by general formula (XI) in a solvent.
  • oxidation reaction various oxidation reactions widely known to those skilled in the art can be applied, and oxidation of metal such as chromium, manganese or ruthenium by a hypervalent iodine compound such as desmartin periodinane can be applied.
  • Oxidation with dimethyl sulfoxide and acid chloride, acid anhydride or carbodiimide, etc. such as swan oxidation reaction, or by halogen type oxidizing agent (a catalyst such as TEMPO may be added) Reaction etc.
  • a catalyst such as TEMPO may be added
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; ethers such as tetrahydrofuran; N, N-dimethylformamide, N, N -Amides such as dimethylacetamide; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as toluene; and mixed solvents of these.
  • the reaction temperature is not particularly limited, and for example, -78 ° C to 80 ° C is preferable.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • step 2-3 the compound represented by general formula (XIV) is produced by heating the compound represented by general formula (XII) and the compound represented by general formula (XIII) in a solvent Can.
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and includes benzene, toluene, chlorobenzene, xylene, pyridine, a mixed solvent thereof, and the like. If necessary, an acid such as toluene-4-sulfonic acid may be added.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 150 ° C.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • the compound represented by formula (VI) can be produced by heating the compound represented by formula (XIV) in a solvent in the presence of an acid or a salt.
  • the acid to be used include hydrogen chloride, sulfuric acid, trifluoromethanesulfonic acid, polyphosphoric acid and the like
  • the salt include ammonium sulfate and the like.
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and 1,1,1,3,3,3-hexamethyldisilazane, benzene, toluene, chlorobenzene, xylene, pyridine, or a mixed solvent thereof Etc.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 150 ° C.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • the compound represented by the general formula (XIV) which can be produced in Step 2-3 may be carried out continuously with Step 2-4 without isolation.
  • Reaction Formula-1 The compounds represented by General Formula (VI) in Reaction Formula-1 can also be produced by the following Reaction Formula-3 (Step 3-1 to Step 3-2).
  • Reaction formula 3> [Wherein, the ring A, n, R 1 , R 2 , R 7 , R 8 and R 9 are as defined in the general formula (I) above; R 10 is a methyl group, an ethyl group, a t-butyl group or It is a benzyl group, and Z represents a halogen atom. ]
  • Step 3-1 a compound represented by general formula (XV) is produced from a compound represented by general formula (II) by a method similar to the method described in step 1-2 of Reaction formula-1 be able to.
  • Step 3-2 is a step of producing a compound in which R 1 is a halogen atom among the compounds represented by General Formula (VI) from the compound represented by General Formula (XV). Specifically, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) in a compound represented by the general formula (XV) and a solvent The compound can be converted to a compound represented by the general formula (VI) by the action of N-chlorosuccinimide or N-bromosuccinimide or the like.
  • the solvent is not particularly limited as long as it does not significantly inhibit the reaction, and aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; diethyl ether And ethers such as tetrahydrofuran and 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile and propionitrile .
  • the reaction temperature is not particularly limited, and the reaction is usually performed at room temperature to 150 ° C.
  • the reaction time is not particularly limited, and is preferably 1 hour to 24 hours.
  • these compounds may be subjected to general reactions for those skilled in the art such as condensation reaction, addition reaction, oxidation reaction, reduction reaction, substitution reaction, coupling reaction, halogenation reaction, dehydration reaction or hydrolysis. Alternatively, they can be converted into other compounds by combining these reactions as appropriate.
  • the compound represented by the general formula (I) produced by the method described above is isolated and purified as a free compound, a salt thereof, various solvates such as a hydrate or ethanolate thereof or a crystal polymorph.
  • the pharmaceutically acceptable salts of the compounds of the present invention can be prepared by conventional salt formation reactions. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization, various chromatography and the like.
  • optically active substances can be obtained as stereochemically pure isomers by selecting appropriate starting compounds or from racemates by conventional optical resolution. For example, when a racemate is optically resolved using a chiral column, methods known to those skilled in the art (for example, “Separation of optical isomers” (Quarterly Chemical Review No.
  • a medicament containing the imidazole derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is also useful as a drug based on this action.
  • the medicament of the present invention containing the imidazole derivative of the present invention as an active ingredient can suppress differentiation into Th17 cells and activation of Th17 cells by ROR ⁇ t inhibitory activity, It is useful for the prevention and / or treatment of various diseases in which Th17 cells are involved or various diseases in which inflammatory cytokines such as IL-17A and IL-17F are involved.
  • Such diseases include, for example, psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, scleroderma, uveitis, asthma, tonicity Spondylitis, systemic lupus erythematosus, atopic dermatitis, chronic obstructive pulmonary disease, type I diabetes, alopecia areata, glomerulonephritis, neuromyelitis optica, Sjögren's syndrome, celiac disease, dry eye and graft versus host disease etc
  • psoriasis psoriatic arthritis
  • rheumatoid arthritis inflammatory bowel disease (such as Crohn's disease and ulcerative colitis)
  • multiple sclerosis such as Crohn's disease and ulcerative colitis
  • scleroderma uveitis
  • asthma tonicity Spondylitis
  • the medicament of the present invention is preferably psoriatic, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, scleroderma, uveitis, asthma, ankylosing spondylitis It can be used as a preventive or therapeutic agent for systemic lupus erythematosus, atopic dermatitis and chronic obstructive pulmonary disease.
  • the medicament containing the imidazole derivative of the present invention can be administered systemically or locally.
  • the administration route is also not particularly limited, and oral administration or parenteral administration, for example, transdermal, nasal, respiratory, pulmonary, eye drops, intravenous injection, subcutaneous injection, rectal administration, etc. it can.
  • the dosage form can be appropriately selected depending on the administration route, for example, tablet, troche, sublingual tablet, sugar-coated tablet, capsule tablet, pill, powder, granule, solution, emulsion, cream, ointment Agents, lotions, jellies, suspensions, syrups, eye drops, nasal drops, inhalants, suppositories, injections and the like.
  • the medicament containing the imidazole derivative of the present invention is a pharmaceutically acceptable carrier, that is, an excipient, and further, if necessary, a binder, a disintegrant, a coating agent, a lubricant, a preservative, a wetting agent.
  • a pharmaceutically acceptable carrier that is, an excipient, and further, if necessary, a binder, a disintegrant, a coating agent, a lubricant, a preservative, a wetting agent.
  • Various commonly used additives such as additives, emulsifiers, stabilizers, preservatives, colorants, sweeteners, solubilizers and the like may be suitably contained, and can be prepared according to a conventional method in the art .
  • the dose of the medicament containing the imidazole derivative of the present invention may be appropriately determined according to the conditions such as administration subject, administration route, symptoms, etc.
  • the present compound which is an active ingredient Is usually in the range of about 0.01 to 1000 mg, preferably 0.1 to 500 mg, and is preferably administered one to three times a day.
  • HATU O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate tert: tertiary (third grade)
  • n normal
  • Example 1 2- (tert-Butyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-1) Preparation (1) Silver nitrate (I) (2.63 g, 15.5 mmol) in a 10% sulfuric acid solution (240 mL) of pivalic acid (7.95 g, 77.8 mmol), 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester (4.00 g, 25.9 mmol) was added, and an aqueous solution of ammonium peroxodisulfate (17.8 g, 77.8 mmol) (240 mL) was added dropwise at 80 ° C.
  • Example 2 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-
  • carboxamide (I-2) (5- (ethylsulfonyl) pyridin-2-yl) synthesized by the method described in Reference Example 1 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • Compound (I-2) was obtained in the same manner as in Example 1 using methaneamine hydrochloride.
  • Example 3 2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-
  • 4-carboxamide (I-3) 2-amino-2- (4- (ethyl) synthesized by the method described in Reference Example 2 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • Compound (I-3) was obtained in the same manner as in Example 1 using sulfonyl) phenyl) ethanol hydrochloride.
  • Example 4 Preparation of 2- (tert-Butyl) -1- (2-chlorobenzyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1H-imidazole-4-carboxamide (I-4)
  • Example 1 Compound (I-4) was produced in the same manner as in Example 1 except that 1- (bromomethyl) -2-chlorobenzene was used instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in (2). Obtained.
  • Example 5 2- (tert-Butyl) -1- (2-chlorobenzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide ( Preparation of I-5) Using 1- (bromomethyl) -2-chlorobenzene in place of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2), and Ex. 1 (4).
  • Example 6 Preparation of 2- (tert-Butyl) -1- (2,4-dichlorobenzyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1H-imidazole-4-carboxamide (I-6) In the same manner as in Example 1 except that 1- (bromomethyl) -2,4-dichlorobenzene was used instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2), I-6).
  • Example 7 2- (tert-Butyl) -1- (2,4-dichlorobenzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4- Preparation of carboxamide (I-7) Using 1- (bromomethyl) -2,4-dichlorobenzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2), and The 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described in Reference Example 2 is used instead of 4- (methylsulfonyl) benzylamine in Example 1 (4). Compound (I-7) was obtained in the same manner as in Example 1.
  • Example 8 2- (tert-Butyl) -1- (2,4-dichlorobenzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide ( Preparation of I-8) Using 1- (bromomethyl) -2,4-dichlorobenzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2), Example Example 1 was repeated using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1 in place of 4- (methylsulfonyl) benzylamine in 1 (4). Compound (I-8) was obtained in the same manner.
  • Example 9 2- (tert-Butyl) -1- (2-chloro-6- (trifluoromethyl) benzyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1H-imidazole-4-carboxamide (I Preparation of -9) Using 2- (bromomethyl) -1-chloro-3- (trifluoromethyl) benzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) Compound (I-9) was obtained in the same manner as in Example 1.
  • Example 10 2- (tert-Butyl) -1- (2-chloro-6- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-
  • imidazole-4-carboxamide (I-10) 2- (bromomethyl) -1-chloro-3- (instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2)
  • Compound (I-10) was obtained in the same manner as in Example 1 using (I) methaneamine hydrochloride.
  • Example 11 2- (tert-Butyl) -1- (2-chloro-6- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-
  • I-11 2- (bromomethyl) -1-chloro-3 in place of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1
  • Compound (I-11) was obtained in the same manner as in Example 1 using (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 12 2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1H-imidazole-4-carboxamide (I Production of -12) Using 1- (bromomethyl) -4-chloro-2- (trifluoromethyl) benzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) Compound (I-12) was obtained in the same manner as in Example 1.
  • Example 13 2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-
  • imidazole-4-carboxamide (I-13) 1- (bromomethyl) -4-chloro-2- (l) instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2)
  • Compound (I-13) was obtained in the same manner as in Example 1 using (I) methaneamine hydrochloride.
  • Example 14 2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-
  • 1H-imidazole-4-carboxamide I-14
  • Compound (I-14) was obtained in the same manner as in Example 1 using (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 15 (S) -2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -N- (1- (4-ethylsulfonyl) phenyl) -2-hydroxyethyl) -5
  • 2-methyl-1H-imidazole-4-carboxamide I-15
  • 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) 1- (bromomethyl) -4- Using chloro-2- (trifluoromethyl) benzene and substituting (S) -2-amino-2- (4- (ethylsulfonyl) instead of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • Compound (I-15) was obtained in the same manner as in Example 1 using (phenyl) ethanol hydrochloride.
  • Example 16 (R) -2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -N- (1- (4-ethylsulfonyl) phenyl) -2-hydroxyethyl) -5
  • 2-Methyl-1H-imidazole-4-carboxamide I-16
  • 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) 1- (bromomethyl) -4- Using chloro-2- (trifluoromethyl) benzene and substituting for (R) -2-amino-2- (4- (ethylsulfonyl) in place of 4- (methylsulfonyl) benzylamine in Example 1 (4).
  • Compound (I-16) was obtained in the same manner as in Example 1 using (phenyl) ethanol hydrochloride.
  • Example 17 2- (tert-Butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -5-methyl-1- (2- (trifluoromethyl) benzyl)- Preparation of 1H-imidazole-4-carboxamide (I-17) 2-amino-2- (Synthetic Example 3) described in Reference Example 3 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4) Compound (I-17) was obtained in the same manner as in Example 1 using 5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride.
  • Example 18 2- (tert-Butyl) -5-methyl-N- (4- (methylsulfonyl) benzyl) -1- (2- (trifluoromethoxy) benzyl) -1H-imidazole-4-carboxamide (I-18) Preparation A method similar to Example 1 using 1- (bromomethyl) -2- (trifluoromethoxy) benzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) The compound (I-18) was obtained by
  • Example 19 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (2- (trifluoromethoxy) benzyl) -1H-imidazole-4- Preparation of carboxamide (I-19) Using 1- (bromomethyl) -2- (trifluoromethoxy) benzene instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2) In addition, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1 is used instead of 4- (methylsulfonyl) benzylamine in Example 1 (4). Compound (I-19) was obtained in the same manner as in Example 1.
  • Example 20 2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (2- (trifluoromethoxy) benzyl) -1H-imidazole-
  • 4-carboxamide (I-20) 1- (bromomethyl) -2- (trifluoromethoxy) benzene was substituted for 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2).
  • Example 21 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-2- (tert-pentyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4- Preparation of carboxamide (I-21) Instead of pivalic acid in Example 1 (1), 2,2-dimethylbutyric acid was used, and in Example 1 (4), 4- (methylsulfonyl) benzylamine was used. A compound (I-21) was obtained in the same manner as in Example 1 using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1 instead.
  • Example 22 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (tert-pentyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole- Preparation of 4-carboxamide (I-22) Instead of pivalic acid in Example 1 (1), 2,2-dimethylbutyric acid was used and 4- (methylsulfonyl) benzyl in Example 1 (4) Compound (I-22) was prepared by the same method as Example 1, using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described in Reference Example 2 instead of amine. I got
  • Example 23 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-1H-
  • imidazole-4-carboxamide (I-23) 1- (bromomethyl) -3-methoxy-2- (l) instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2)
  • Compound (I-23) was obtained in the same manner as in Example 1 using (I) methaneamine hydrochloride.
  • Example 24 2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-
  • 1H-imidazole-4-carboxamide I-24
  • Compound (I-24) was obtained in the same manner as in Example 1 using (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 25 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-2- (1-methylcyclopentyl) Preparation of -1H-imidazole-4-carboxamide (I-25)
  • Example 1 (1) using 1-methylcyclopentane-1-carboxylic acid instead of pivalic acid, 1 in Example 1 (2) In place of-(bromomethyl) -2- (trifluoromethyl) benzene, 1- (bromomethyl) -3-methoxy-2- (trifluoromethyl) benzene is used, and 4- (4) in Example 1 (4) 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described in Reference Example 2 in place of methylsulfonyl) benzylamine Compound (I-25) was obtained
  • Example 26 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-2- (1-methylcyclopentyl) -1H -Imidazole-4-carboxamide (I-26) Using 1-methylcyclopentane-1-carboxylic acid instead of pivalic acid in Example 1 (1), using 1- (Example 1 (2)) Instead of bromomethyl) -2- (trifluoromethyl) benzene, 1- (bromomethyl) -3-methoxy-2- (trifluoromethyl) benzene is used, and 4- (methylsulfonyl) in Example 1 (4) is used.
  • Example 27 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (1-methoxy-2-methylpropan-2-yl) -5-methyl-1- (2- (trifluoromethyl) Preparation of (Benzyl) -1H-imidazole-4-carboxamide (I-27) (1) Ethyl 2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylate in Example 1 (2) Example 1 (2) using 2- (1-methoxy-2-methylpropan-2-yl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester obtained in Reference Example 4 in place of In a manner similar to this, ethyl 2- (1-methoxy-2-methylpropan-2-yl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylate To give the ester.
  • Example 28 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- (1-methoxy-2-methylpropan-2-yl) -5-methyl-1- (2- (trifluoro) Preparation of (Methyl) benzyl) -1H-imidazole-4-carboxamide (I-28) 2- (tert-Butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl in Example 1 (4) 2- (1-Methoxy-2-methylpropan-2-yl) -5-methyl-1- (2- (2- (1-methoxy-2-methylpropan-2-yl)) obtained in Example 27 (2) instead of 1) H-imidazole-4-carboxylic acid 2-amino-2- (4) synthesized by the method described in Reference Example 2 using trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid and substituting for 4- (methylsulfonyl
  • Example 29 2- (tert-Butyl) -1- (3,4-dimethoxy-2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl- Preparation of 1H-imidazole-4-carboxamide (I-29) The compound was synthesized by the method described in Reference Example 5 instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2).
  • Example 30 (S) -2- (tert-Butyl) -1- (3,4-dimethoxy-2- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl
  • -5-methyl-1H-imidazole-4-carboxamide (I-30) Described in Reference Example 5 in place of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2)
  • the compound (I-30) was obtained in the same manner as in Example 1 using -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 31 2- (tert-Butyl) -N-((5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-
  • imidazole-4-carboxamide (I-31) (5- (ethylsulfonyl) -3 synthesized by the method described in Reference Example 6 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • Compound (I-31) was obtained in the same manner as in Example 1 using -fluoropyridin-2-yl) methanamine hydrochloride.
  • Example 32 2- (tert-butyl) -N-((5-((cyclobutylmethyl) sulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-
  • imidazole-4-carboxamide (I-32) Synthesized by the method described in Reference Example 7 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4) (5-((Cyclobutylmethyl) The compound (I-32) was obtained in the same manner as in Example 1 using sulfonyl) pyridin-2-yl) methanamine hydrochloride.
  • Example 33 2- (tert-Butyl) -N-((5- (ethylsulfonyl) thiophen-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-
  • Example 1 was repeated using (5- (ethylsulfonyl) thiophen-2-yl) methanamine hydrochloride in place of 4- (methylsulfonyl) benzylamine in Example 1 (4).
  • Compound (I-33) was obtained in the same manner.
  • Example 34 2- (tert-Butyl) -1- (4-chloro-2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -5-methyl-1H-
  • imidazole-4-carboxamide (I-34) 1- (bromomethyl) -4-chloro-2- (l) instead of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1 (2)
  • Compound (I-34) was obtained in the same manner as in Example 1 using (I) methaneamine hydrochloride.
  • Example 35 2- (tert-Butyl) -5-methyl-N-((5-((oxetan-3-ylmethyl) sulfonyl) pyridin-2-yl) methyl) -1- (2- (trifluoromethyl) benzyl)- Preparation of 1H-imidazole-4-carboxamide (I-35)
  • the compound was synthesized by the method described in Reference Example 9 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • (5-((oxetane- Compound (I-35) was obtained in the same manner as in Example 1 by using 3-ylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride.
  • Example 36 2- (tert-Butyl) -N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-
  • carboxamide (I-36) (5- (ethylsulfonyl) thiazol-2-yl) synthesized by the method described in Reference Example 8 in place of 4- (methylsulfonyl) benzylamine in Example 1 (4)
  • Compound (I-36) was obtained in the same manner as in Example 1 by using methanamine hydrochloride.
  • Example 37 3-((2- (tert-Butyl) -4-(((5- (ethylsulfonyl) pyridin-2-yl) methyl) carbamoyl) -5-methyl-1H-imidazol-1-yl) methyl) -2
  • 2- (trifluoromethyl) benzoic acid methyl ester (I-37) (1)
  • Methanol (10 mL), tetrahydrofuran (10 mL) and 1 mol / L sodium hydroxide (10 mL, 10 mmol) were added to ethyl ester (1.0 g, 4.8 mmol) and stirred at room temperature for 15 hours.
  • Example 38 3-((2- (tert-Butyl) -4-((1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) carbamoyl) -5-methyl-1H-imidazol-1-yl) methyl)
  • 2- (trifluoromethyl) benzoic acid methyl ester (I-38) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl in Example 1 (4)
  • Example 39 3-((2- (tert-Butyl) -4-(((5- (ethylsulfonyl) thiazol-2-yl) methyl) carbamoyl) -5-methyl-1H-imidazol-1-yl) methyl) -2
  • Example 1 2- (tert-butyl) -1- (3- (methoxycarbonyl) -2- (trifluoromethyl) benzyl) -5 obtained in Example 37 (4) instead of 1H-imidazole-4-carboxylic acid (5- (ethylsulfonyl) thiazole synthesized by the method described in Reference Example 8 using -methyl-1H-imidazole-4-carboxylic acid and replacing 4- (methylsulfonyl)
  • Example 40 2- (tert-Butyl) -1- (3- (difluoromethoxy) -2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl
  • I-40 1- (bromomethyl) -3 in place of 1- (bromomethyl) -2- (trifluoromethyl) benzene in Example 1
  • 2- (tert-butyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl in the same manner as in Example 1 (2) using -methoxy-2- (trifluoromethyl) benzene ) 5-Methyl-1H-imidazole-4-carboxylic acid ethyl ester was obtained.
  • reaction solution is filtered, and the solvent is evaporated under reduced pressure, and then ammonium sulfate (6.2 mg, 0.047 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (1.8 mL) are added, and the temperature is 135 ° C.
  • ammonium sulfate 6.2 mg, 0.047 mmol
  • 1,1,1,3,3,3-hexamethyldisilazane 1.8 mL
  • the mixture was stirred for 15 hours.
  • the solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with brine and dried over anhydrous sodium sulfate.
  • Example 42 (R) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1-((3- (trifluoromethyl) thiophene) Preparation of 2-yl) methyl) -1H-imidazole-4-carboxamide (I-42)
  • Compound (I-42) was obtained in the same manner as in Example 41, using (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in place of the salt.
  • Example 43 2- (tert-Butyl) -N- (4- (ethylsulfonyl) benzyl) -5-methyl-1-((4- (trifluoromethyl) pyridin-3-yl) methyl) -1H-imidazole-4-
  • carboxamide (I-43) (4- (trifluoromethyl) pyridin-3-yl) methanamine instead of (3- (trifluoromethyl) thiophen-2-yl) methanamine in Example 41
  • (4- (ethylsulfonyl) phenyl) methanamine is used instead of (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 41 (5), using the hydrochloride salt.
  • Compound (I-43) was obtained in the same manner as in Example 41 using a hydrochloride salt.
  • Example 44 2- (tert-Butyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1-((2- (trifluoromethyl) cyclohexyl) Preparation of methyl) -1H-imidazole-4-carboxamide (I-44) The compound obtained in Reference Example 12 in place of (3- (trifluoromethyl) thiophen-2-yl) methanamine in Example 41 (3).
  • Example 41 Using (2- (trifluoromethyl) cyclohexyl) methanamine and substituting for (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 41 (5).
  • Compound (I-44) was prepared by the same method as in Example 41 using (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride as It was.
  • Example 45 2- (tert-Butyl) -N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1-((2- (trifluoromethyl) cyclohexyl) Preparation of methyl) -1H-imidazole-4-carboxamide (I-45)
  • Example 41 (3) obtained in Reference Example 12 in place of (3- (trifluoromethyl) thiophen-2-yl) methanamine
  • Compound (I-45) was obtained in the same manner as in Example 41 using (2- (trifluoromethyl) cyclohexyl) methanamine.
  • Example 46 2- (tert-Butyl) -N-((5-ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (4-hydroxypiperidin-1-yl) -2- (trifluoromethyl) benzyl Preparation of (5) 5-methyl-1H-imidazole-4-carboxamide (I-46) (1) Reference was made in place of (3- (trifluoromethyl) thiophen-2-yl) methanamine in Example 41 (3).
  • Example 47 2- (tert-Butyl) -N-((5-ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (3-hydroxyazetidin-1-yl) -2- (trifluoromethyl) Preparation of benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-47) (1) Instead of (3- (trifluoromethyl) thiophen-2-yl) methanamine in Example 41 (3), Using 1- (3- (aminomethyl) -2- (trifluoromethyl) phenyl) azetidin-3-ol synthesized by the method described in Reference Example 14, and in the same manner as in Example 41 (3), 2- (tert-Butyl) -1- (3- (3-hydroxyazetidin-1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester It was obtained
  • Example 48 (R) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (3-hydroxyazetidin-1-yl)- Preparation of 2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-48) 2- (tert-butyl) -5-methyl-1- in Example 1 (4) The 2- (tert-butyl) -1- (3- (3-hydroxyazetic) obtained in Example 47 (2) instead of (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid In addition to 4- (methylsulfonyl) benzylamine, (R)-(Gin-1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid is used. 2-a
  • Example 49 (S) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (3-hydroxyazetidin-1-yl)- Preparation of 2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-49) 2- (tert-butyl) -5-methyl-1- in Example 1 (4) The 2- (tert-butyl) -1- (3- (3-hydroxyazetic) obtained in Example 47 (2) instead of (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid In addition to 4- (methylsulfonyl) benzylamine, (S)-(Gin-1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid is used. 2-a
  • Example 50 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (4-hydroxypiperidin-1-yl) -2 Preparation of-(Trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-50) 2- (tert-butyl) -1- (3- (4-hydroxypiperidine) obtained in Example 46 (2) instead of 2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid 1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (R) -2- amino- Compound (I-50) was obtained in the same manner as in Example 1 (4) using 2- (4- (ethyls
  • Example 51 (S) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (4-hydroxypiperidin-1-yl) -2 Preparation of-(Trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-51) 2- (tert-butyl) -1- (3- (4-hydroxypiperidine) obtained in Example 46 (2) instead of 2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid 1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (S) -2- amino- Compound (I-51) was obtained in the same manner as in Example 1 (4) using 2- (4- (ethyls
  • Example 52 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4-fluoro-5- (hydroxymethyl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-52) Instead of (3- (trifluoromethyl) thiophen-2-yl) methanamine in Example 41 (3) Then, using (5- (aminomethyl) -2-fluoro-4- (trifluoromethyl) phenyl) methanol synthesized by the method described in Reference Example 15, and using (S) in Example 41 (5) Instead of -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride, (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol
  • the organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is dissolved in N, N-dimethylformamide (20 mL), potassium carbonate (1.38 g, 10.0 mmol) and iodomethane (0.623 mL, 10.0 mmol) are added, and the temperature is 70 ° C. The mixture was stirred for 1 hour. Water was added to the reaction solution, extraction was performed with diethyl ether, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 53 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4-fluoro-3- (hydroxymethyl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-53)
  • N-pivaloyl-L-threonine benzyl ester was obtained in the same manner as in Example 41 (1) using a hydrochloride salt.
  • Example 41 (2) with N-pivaloyl-L-threonine benzyl ester obtained in the above (1) instead of N-pivaloyl-L-threonine methyl ester in Example 41 (2) In a similar manner, (S) -3-oxo-2-pivalamidobutanoic acid benzyl ester was obtained.
  • Example 54 2- (tert-Butyl) -N- (4- (ethylsulfonyl) benzyl) -1- (4-fluoro-3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-1H- Preparation of Imidazole-4-carboxamide (I-54) 2- (tert-Butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4 in Example 1 (4) 2- (tert-Butyl) -1- (4-fluoro-3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-obtained in Example 53 (5) instead of -carboxylic acid Carried out using methyl-1H-imidazole-4-carboxylic acid and using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride in place of 4- (methylsulfonyl) benzylamine
  • Example 55 1- (3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H- Preparation of imidazole-4-carboxamide (I-55) (1)
  • Example 41 Using the synthesized (3-bromo-2- (trifluoromethyl) phenyl) methanamine, 1- (3-bromo-2- (trifluoromethyl) benzyl)-in the same manner as in Example 41 (3).
  • 2- (tert-Butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester was obtained.
  • Example 1 (4) In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3). Performed using 1- (3-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester obtained in (3) In the same manner as in Example 1 (3), 1- (3-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid was obtained. Obtained.
  • Example 56 (S) -1- (3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • 5-methyl-1H-imidazole-4-carboxamide (I-56) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1
  • 1- 3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl obtained in Example 55 (4) instead of 1H-imidazole-4-carboxylic acid Using (1H) -imidazole-4-carboxylic acid and (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride instead of 4- (methylsulfonyl)
  • Example 58 (R) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (1- (hydroxyimino) ethyl) -2- Preparation of (Trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-58) (R) -1- (3-acetyl-2- (trifluoromethyl) obtained in Example 57 ) Benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-57) ( Hydroxylamine hydrochloride (14.3 mg, 0.206 mmol) was added to 10.0 mg (0.0168 mmol) and sodium acetate (16.6 mg, 0.206 m
  • Example 60 2- (tert-Butyl) -5-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-
  • Example 41 (using 2-oxotrifluoromethyl) benzylamine, using 2-oxo-2-pivalamidopentanoic acid methyl ester instead of (3- (trifluoromethyl) thiophen-2-yl) methanamine 2- (tert-Butyl) -5-ethyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid methyl ester in the same manner as 3)
  • reaction solution is filtered, and the solvent is evaporated under reduced pressure, and then ammonium sulfate (14.0 mg, 0.106 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (4.1 mL) are added, and the temperature is 130 ° C.
  • ammonium sulfate (14.0 mg, 0.106 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (4.1 mL) are added, and the temperature is 130 ° C.
  • the mixture was stirred for 16 hours.
  • the solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure.
  • Example 62 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (1-methylcyclopentyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole
  • -4-carboxamide (I-62) In the same manner as in Example 61, 1-methylcyclopentanecarboxylic acid was used instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1). Compound (I-62) was obtained.
  • Example 63 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-2- (1-methylcyclopentyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4 -Preparation of 2-carboxamide (I-63)
  • 1-methylcyclopentanecarboxylic acid is used instead of 2-ethoxy-2-methylpropionic acid, and 2 in Example 61 (5)
  • Compound (I-63) was obtained in the same manner as in Example 61.
  • Example 64 N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -5-methyl-2- (1-methylcyclopentyl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4 -Preparation of 2-carboxamide (I-64)
  • 1-methylcyclopentanecarboxylic acid is used instead of 2-ethoxy-2-methylpropionic acid, and 2 in Example 61 (5)
  • (5- (ethylsulfonyl) thiazol-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 8 is used instead of -amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Compound (I-64) was obtained in the same manner as in Example 61.
  • Example 65 1- (4-Chloro-2- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- (1-methoxy-2-methylpropane- Preparation of 2-yl) -5-methyl-1H-imidazole-4-carboxamide (I-65) 3-methoxy-2,2 instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) With dimethylpropanoic acid and (4-chloro-2- (trifluoromethyl) phenyl) methanamine in place of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) Compound (I-65) was obtained in the same manner as in Example 61.
  • Example 66 1- (4-Chloro-2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -2- (1-methoxy-2-methylpropane-2-) Preparation of (I) -5-methyl-1H-imidazole-4-carboxamide (I-66) 3-methoxy-2,2-dimethyl instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Using (4-chloro-2- (trifluoromethyl) phenyl) methanamine instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) using propanoic acid, Example 61 The compound was synthesized by the method described in Reference Example 1 in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in (5) Compound (I-66) was obtained in the same manner as in Example
  • Example 67 1- (4-Chloro-2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -2- (1-methoxy-2-methylpropane-2-) Preparation of yl) -5-methyl-1H-imidazole-4-carboxamide (I-67) 3-methoxy-2,2-dimethyl in place of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Using (4-chloro-2- (trifluoromethyl) phenyl) methanamine instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) using propanoic acid, Example 61 The compound was synthesized by the method described in Reference Example 8 in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in (5) The compound (I-67) was obtained in the same manner as in
  • Example 68 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -2- (1-methoxy-2-methylpropane- Preparation of 2-yl) -5-methyl-1H-imidazole-4-carboxamide (I-68) 3-methoxy-2,2 instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Using (-methoxy-2- (trifluoromethyl) phenyl) methylamine instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) Compound (I-68) was obtained in the same manner as in Example 61.
  • Example 69 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -2- (1-methoxy-2-methylpropane-2-) Preparation of yl) -5-methyl-1H-imidazole-4-carboxamide (I-69) 3-methoxy-2,2-dimethyl in place of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Using (3-methoxy-2- (trifluoromethyl) phenyl) methylamine instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) using propanoic acid, and using Example The compound was synthesized by the method described in Reference Example 1 in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in 61 (5) The compound (I-69) was obtained in the same manner
  • Example 70 N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -2- (1-methoxy-2-methylpropane-2-) (I) Preparation of -5-methyl-1H-imidazole-4-carboxamide (I-70) 3-methoxy-2,2-dimethyl instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Using (3-methoxy-2- (trifluoromethyl) phenyl) methylamine instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3) using propanoic acid, and using Example The compound was synthesized by the method described in Reference Example 8 in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in 61 (5). Compound (I-70) was obtained in the same manner as in
  • Example 71 (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-2- (1 Preparation of (Methylcyclobutyl) -1H-imidazole-4-carboxamide (I-71) In Example 61 (1), 1-methylcyclobutane-1-carboxylic acid was used instead of 2-ethoxy-2-methylpropionic acid.
  • Example 61 instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3), (3-methoxy-2- (trifluoromethyl) phenyl) methylamine is used, and Example 61 (5) is used. Instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Compound (I-71) was obtained in the same manner as in Example 61 using fonyl) phenyl) ethanol hydrochloride.
  • Example 72 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-2- (1-methylcyclobutyl)- Preparation of 1H-imidazole-4-carboxamide (I-72)
  • -2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride it was synthesized by the method described in Reference Example 1 (5- (ethylsulfonyl) pyri Compound (I-72) was obtained in
  • Example 73 (S) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3-methoxy-2- (trifluoromethyl) benzyl) -5-methyl-2- (1 Preparation of (Methylcyclobutyl) -1H-imidazole-4-carboxamide (I-73) In Example 61 (1), 1-methylcyclobutane-1-carboxylic acid was used instead of 2-ethoxy-2-methylpropionic acid.
  • Example 61 instead of (2- (trifluoromethyl) phenyl) methanamine in Example 61 (3), (3-methoxy-2- (trifluoromethyl) phenyl) methylamine is used, and Example 61 (5) is used. Instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Compound (I-73) was obtained in the same manner as in Example 61 using fonyl) phenyl) ethanol hydrochloride.
  • Example 74 N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (3-methyltetrahydrofuran-3-yl) -1- (2- (trifluoro) Preparation of (Methyl) benzyl) -1H-imidazole-4-carboxamide (I-74) Using 3-methyltetrahydrofuran-3-carboxylic acid instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Also, in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 61 (5), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl Compound (I-74) was obtained in the same manner as in Example 61 using ethanol hydrochloride.
  • Example 75 N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (3-methyltetrahydrofuran-3-yl) -1- (2- (trifluoro) Preparation of (Methyl) benzyl) -1H-imidazole-4-carboxamide (I-75) Using 3-methyltetrahydrofuran-3-carboxylic acid instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Also, in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 61 (5), (S) -2-amino-2- (4- (ethylsulfonyl) phenyl Compound (I-75) was obtained in the same manner as in Example 61 using ethanol hydrochloride.
  • Example 76 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-2- (3-methyltetrahydrofuran-3-yl) -1- (2- (trifluoromethyl) benzyl) -1H
  • 3-imidazole-4-carboxamide I-76
  • 3-methyltetrahydrofuran-3-carboxylic acid is used in place of 2-ethoxy-2-methylpropionic acid
  • Example 61 (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 1 instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in (5)
  • Compound (I-76) was obtained in the same manner as in Example 61 using a hydrochloride salt.
  • Example 77 N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (2-methyltetrahydrofuran-2-yl) -1- (2- (trifluoro) Preparation of (Methyl) benzyl) -1H-imidazole-4-carboxamide (I-77) Using 2-methyltetrahydrofuran-2-carboxylic acid instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Also, in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 61 (5), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl Compound (I-77) was obtained in the same manner as in Example 61 using ethanol hydrochloride.
  • Example 78 N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (2-methyltetrahydrofuran-2-yl) -1- (2- (trifluoro) Preparation of (Methyl) benzyl) -1H-imidazole-4-carboxamide (I-78) Using 2-methyltetrahydrofuran-2-carboxylic acid instead of 2-ethoxy-2-methylpropionic acid in Example 61 (1) Also, in place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 61 (5), (S) -2-amino-2- (4- (ethylsulfonyl) phenyl Compound (I-78) was obtained in the same manner as in Example 61 using ethanol hydrochloride.
  • Example 79 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-2- (2-methyltetrahydrofuran-2-yl) -1- (2- (trifluoromethyl) benzyl) -1H -Imidazole-4-carboxamide (I-79)
  • 2-methyltetrahydrofuran-2-carboxylic acid is used in place of 2-ethoxy-2-methylpropionic acid
  • Example 61 (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 1 instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in (5)
  • Compound (I-79) was obtained in the same manner as in Example 61 using a hydrochloride salt.
  • Example 80 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-2- (1,1,1-trifluoro-2-methylpropan-2-yl) -1- (2- Preparation of (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-80) (1) 2- (tert-butyl) -5-methyl-1H-imidazole-4 in Example 1 (2) 5-methyl-2- (1,1,1-trifluoro-2-methylpropan-2-yl) -1H-imidazole-4 synthesized by the method described in Reference Example 19 in place of -carboxylic acid ethyl ester 5-methyl-2- (1,1,1-trifluoro-2-methylpropan-2-yl) -1- (in the same manner as in Example 1 (2)) using -carboxylic acid ethyl ester 2- (trifluoromethyl) Njiru) was obtained -1H-
  • Example 81 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -2- (1- (trifluoromethyl) cyclopropyl)- Preparation of 1H-imidazole-4-carboxamide (I-81) (1) Instead of 2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (2) , 5-methyl-2- (1- (trifluoromethyl) cyclopropyl) -1H-imidazole-4-carboxylic acid ethyl ester synthesized by the method described in Reference Example 20, in the same manner as Example 1 (2) 5-methyl-1- (2- (trifluoromethyl) benzyl) -2- (1- (trifluoromethyl) cyclopropyl) -1H-imidazole-4-carbo by the method of To obtain an
  • Example 82 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-2- (piperidin-1-yl) -1- (2- (trifluoromethyl) benzyl) -1H-
  • imidazole-4-carboxamide I-82
  • 4-Methyl-5-imidazolecarboxylic acid ethyl ester (2.00 g, 13.0 mmol) in N, N-dimethylformamide (32 mL), potassium carbonate (3.59) g, 25.9 mmol) and 1- (bromomethyl) -2- (trifluoromethyl) benzene (3.72 g, 15.6 mmol) were added and stirred at room temperature for 1.5 hours.
  • Example 1 In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3).
  • Example 1 using 5-methyl-2- (piperidin-1-yl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester obtained in (3)
  • 5-methyl-2- (piperidin-1-yl) -1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid was obtained in the same manner as (3).
  • Example 83 2-Cyclopentyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide ( Preparation of I-83) (1) 2-Bromo-5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester obtained in Example 82 (2) (600 mg, 1.53 mmol), cyclopenten-1-yl-boronic acid (343 mg, 3.07 mmol), potassium carbonate (424 mg, 3.07 mmol) and tetrakistriphenylphosphine palladium (0) (0.109 mg, 0.0943 mmol) 1,4-dioxane (12.0 mL) and water (2.4 mL) were added, and the mixture was stirred at 100 ° C.
  • Example 2 In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3)
  • Example 2- Cyclopentyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester obtained in (2) above was used to give Example 1 (3
  • 2-cyclopentyl-5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid was obtained.
  • Example 84 2- (Cyclohex-1-en-1-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (2- (trifluoromethyl) benzyl Preparation of (-1) -H-imidazole-4-carboxamide (I-84) (1) Using cyclohexen-1-yl-boronic acid instead of cyclopenten-1-yl-boronic acid in Example 83 (1) In the same manner as in Example 83 (1), 2- (cyclohex-1-en-1-yl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4- Carboxylic acid ethyl ester was obtained.
  • Example 2 In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3).
  • Example 2- (Cyclohex-1-en-1-yl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester obtained in (1) above 2- (Cyclohex-1-en-1-yl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole in the same manner as in Example 1 (3) using -4-carboxylic acid was obtained.
  • 3-oxa-8-azabicyclo [3.2.1 in Example 85 (1) In the same manner as in Example 85 (1), using 8-azabicyclo [3.2.1] octan-8-yl benzoate synthesized by the method described in Reference Example 22 instead of octane-8-yl benzoate.
  • Example 88 1-((1,1'-biphenyl) -4-ylmethyl) -2-bromo-5-methyl-N-((1- (methylsulfonyl) piperidin-4-yl) methyl) -1H-imidazole-4-
  • carboxamide I-88
  • 5-Methyl-1H-imidazole-4-carboxylic acid ethyl ester 800 mg, 5.19 mmol
  • N, N-dimethylformamide (17 mL) solution of potassium carbonate (1.08) g, 7.81 mmol) and 4-bromomethylbiphenyl (1.54 g, 6.23 mmol) were added and stirred at room temperature for 6 hours.
  • N, N-dimethylformamide of 1-((1,1'-biphenyl) -4-ylmethyl) -2-bromo-5-methyl-1H-imidazole-4-carboxylic acid (15.0 mg, 0.0404 mmol)
  • (1- (Methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (11.1 mg, 0.0485 mmol)
  • N, N-diisopropylethylamine (15.7 mg) synthesized by the method described in Reference Example 23 in a solution (1.0 mL) , 0.121 mmol) and HATU (23.0 mg, 0.0606 mmol) were sequentially added, and stirred at room temperature for 3 hours.
  • Example 89 1-((1,1'-biphenyl) -4-ylmethyl) -2-chloro-5-methyl-N-((1- (methylsulfonyl) piperidin-4-yl) methyl) -1H-imidazole-4- Preparation of carboxamide (I-89)
  • N-chlorosuccinimide was used instead of N-bromosuccinimide in (2) to give compound (I-89).
  • Example 90 1-((1,1'-biphenyl) -4-ylmethyl) -2-cyclopropyl-5-methyl-N-((1- (methylsulfonyl) piperidin-4-yl) methyl) -1H-imidazole-4
  • -carboxamide I-90
  • (1) 1-((1,1'-biphenyl) -4-ylmethyl) -2-bromo-5-methyl- synthesized by the method described in Example 88
  • N, N-dimethyl of 1-((1,1'-biphenyl) -4-ylmethyl) -2-cyclopropyl-5-methyl-1H-imidazole-4-carboxylic acid (15.0 mg, 0.0451 mmol)
  • (1- (Methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (12.4 mg, 0.0542 mmol) synthesized by the method described in Reference Example 23 in formamide (0.50 mL) solution, N, N-diisopropylethylamine (17.5) mg, 0.135 mmol) and HATU (25.7 mg, 0.0677 mmol) were sequentially added, and stirred at room temperature for 5 hours.
  • Example 91 1-((1,1'-biphenyl) -4-ylmethyl) -2-cyclopropyl-5-methyl-N- (4-sulfamoylbenzyl) -1H-imidazole-4-carboxamide (I-91) Preparation In the same manner as in Example 90, homosulfamine hydrochloride was used instead of (1- (methylsulfonyl) piperidin-4-yl) methanamine hydrochloride of (3) to give compound (I-91). .
  • Example 92 1-((1,1′-biphenyl) -4-ylmethyl) -2,5-dimethyl-N-((1- (methylsulfonyl) piperidin-4-yl) methyl) -1H-imidazole-4-carboxamide ( Preparation of I-92) 1-((1,1'-biphenyl) -4-ylmethyl) -2-bromo-5-methyl-N-((1- (methylsulfonyl) piperidin-4-yl) methyl)- 1 mol / L dimethylzinc n-hexane solution (82 ⁇ L, 0.082 mmol) and [1,1 ′ in a solution of 1 H-imidazole-4-carboxamide (30.0 mg, 0.0550 mmol) in 1,4-dioxane (0.55 mL) -Bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane
  • Example 93 2- (tert-Butyl) -5-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) Preparation of -1H-imidazole-4-carboxamide (I-93) (1) In place of (S) -3-oxo-2-pivalamidobutanoic acid methyl ester in Example 41 (3), Reference Example 18 was used.
  • reaction solution is filtered, and the solvent is evaporated under reduced pressure, and then ammonium sulfate (11.3 mg, 0.0858 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (3.3 mL) are added, and the temperature is 130 ° C.
  • ammonium sulfate (11.3 mg, 0.0858 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (3.3 mL) are added, and the temperature is 130 ° C.
  • the mixture was stirred for 17 hours. After evaporating the solvent under reduced pressure, water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate.
  • reaction mixture was stirred at the same temperature for 30 minutes, and then added dropwise to a solution of sodium borohydride (75.9 mg, 2.01 mmol) in methanol (5.0 mL) at the same temperature. After stirring for 30 minutes at 0 ° C., 5 mol / L hydrochloric acid was added until the pH reached 5, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
  • sodium borohydride 75.9 mg, 2.01 mmol
  • methanol 5.0 mL
  • Example 97 (S) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-2
  • I-97 (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) in Example 96 (7)
  • Compound (I-97) was obtained in the same manner as in Example 96, using (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in place of ethanol hydrochloride.
  • Example 98 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-2- (1-methylcyclo) Preparation of (butyl) -1H-imidazole-4-carboxamide (I-98) Instead of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 96 (7) The compound (I-98) was obtained in the same manner as in Example 96 using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1.
  • Example 99 N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -2- (1- (methoxymethyl) Preparation of Cyclopentyl) -5-methyl-1H-imidazole-4-carboxamide (I-99) Synthesized by the method described in Reference Example 2 using 1-carboxylic acid instead of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 96 (7) Compound (I-99) was obtained in the same manner as in Example 96 using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 100 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -2- (1- (methoxymethyl) cyclopentyl) Preparation of -5-methyl-1H-imidazole-4-carboxamide (I-100) 1- (methoxymethyl) cyclopentane-1- 1 in place of 1-methylcyclobutane-1-carboxylic acid in Example 96 (1) It was synthesized by the method described in Reference Example 1 using a carboxylic acid and substituting for (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 96 (7). Compound (I-100) was obtained in the same manner as in Example 96 using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride.
  • Example 101 N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-2
  • Preparation of-(2-methyltetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (I-101) 2-methyltetrahydrofuran instead of 1-methylcyclobutane-1-carboxylic acid in Example 96
  • Compound (I-101) was obtained in the same manner as in Example 96 using -2-carboxylic acid.
  • Example 102 N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-2
  • Preparation of-(2-methyltetrahydrofuran-2-yl) -1H-imidazole-4-carboxamide (I-102) 2-methyltetrahydrofuran instead of 1-methylcyclobutane-1-carboxylic acid in Example 96
  • (S) -2-amino instead of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 96 (7).
  • the compound (I-102) was obtained in the same manner as in Example 96 using -2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 103 N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-2- (2-methyltetrahydrofuran
  • 2--2-yl) -1H-imidazole-4-carboxamide (I-103) 2-methyltetrahydrofuran-2-carboxylic acid in place of 1-methylcyclobutane-1-carboxylic acid in Example 96
  • the compound was synthesized by the method described in Reference Example 1 in place of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in Example 96 (7).
  • Compound (I-103) was obtained in the same manner as in Example 96 using (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride.
  • Example 105 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -5
  • 2-Methyl-1H-imidazole-4-carboxamide (I-105) Described in Reference Example 1 in place of (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 104 (3)
  • Compound (I-105) was obtained in the same manner as in Example 104 using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method of
  • Example 106 2- (tert-Butyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (1-hydroxyethyl) -2- (trifluoro) Preparation of methyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-106)
  • (I-106) In place of (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 104 (3)
  • Compound (I-106) was obtained in the same manner as in Example 104 using (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 107 2- (tert-Butyl) -N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (1-hydroxyethyl) -2- (trifluoro) Preparation of methyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-107) Instead of (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 104 (3) Compound (I-107) was obtained in the same manner as in Example 104 using (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride.
  • Example 108 2- (tert-Butyl) -1- (3- (1-hydroxy-2-methylpropyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine) Preparation of 2-yl) methyl) -1H-imidazole-4-carboxamide (I-108) (1) 1- (3-bromo-2- (trifluoromethyl) synthesized by the method described in Example 55 (1) )) Benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester (1.75 g, 4.05 mmol) in methanol (15.0 mL), tetrahydrofuran (15.0 mL) and 1 mol / L Aqueous sodium hydroxide solution (15.0 mL, 15.0 mmol) was added and stirred at 70 ° C.
  • Example 109 2- (tert-Butyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (1-hydroxy-2-methylpropyl) -2
  • Preparation of-(trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-109) (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 108 (6)
  • the compound (I-109) was obtained in the same manner as in Example 108 by using (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride in place of the salt.
  • Example 110 2- (tert-Butyl) -1- (3- (1-hydroxy-3-methylbutyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2)
  • Preparation of (yl) methyl) -1H-imidazole-4-carboxamide (I-110) A 2 mol / L isobutylmagnesium chloride tetrahydrofuran solution instead of the 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution in Example 108 (4) By using it, compound (I-110) was obtained in the same manner as in Example 108.
  • 2-methyl-1H-imidazole-4-carboxamide (I-111) In Example 108 (4), a 0.97 mol / L solution of ethylmagnesium bromide in tetrahydrofuran was used instead of the 2 mol / L solution of isopropylmagnesium chloride in tetrahydrofuran, , (5- (ethylsulfonyl) pyridin-2-yl) synthesized by the method described in Reference Example 1 in place of (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 108 (6).
  • Compound (I-111) was obtained in the same manner as in Example
  • Example 113 2- (tert-Butyl) -1- (3- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of -5-methyl-1H-imidazole-4-carboxamide (I-113)
  • Compound (I-113) was obtained in the same manner as in Example 112, using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described.
  • Example 114 2- (tert-Butyl) -1- (3- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) Preparation of -2-Hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-114)
  • Compound (I-114) was obtained in the same manner as in Example 112, using (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride instead.
  • Example 115 2- (tert-Butyl) -1- (3- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) Preparation of ethyl) -5-methyl-1H-imidazole-4-carboxamide (I-115)
  • the compound (I-115) was obtained in the same manner as in Example 112 using 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described in 25.
  • Example 116 2- (tert-Butyl) -1- (3- (cyclobutyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl)
  • (Methyl) -1H-imidazole-4-carboxamide (I-116) instead of the 0.5 mol / L cyclopropylmagnesium bromide tetrahydrofuran solution in Example 112 (2) Compound (I-116) was obtained in the same manner as in Example 112 using a mol / L cyclobutylmagnesium bromide diethyl ether solution.
  • Example 117 2- (tert-Butyl) -1- (3- (cyclopentyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl)
  • (Methyl) -1H-imidazole-4-carboxamide (I-117) In place of the 0.5 mol / L cyclopropyl magnesium bromide tetrahydrofuran solution in Example 112 (2), a 2.0 mol / L cyclopentyl magnesium bromide diethyl ether solution The compound (I-117) was obtained in the same manner as in Example 112, using it.
  • Example 118 2- (tert-Butyl) -1- (3- (1-hydroxy-2,2-dimethylpropyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) Preparation of pyridin-2-yl) methyl) -1H-imidazole-4-carboxamide (I-118) 0.97 mol / L tert- instead of the 0.5 mol / L cyclopropylmagnesium bromide tetrahydrofuran solution in Example 112 (2) Compound (I-118) was obtained in the same manner as in Example 112 using a butylmagnesium chloride tetrahydrofuran solution.
  • Example 120 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (3- (2,2,2-trifluoro-1-hydroxyethyl) Preparation of (2-) (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-120) (1) 2- (tert-Butyl) -5-methyl-1- (3- (2,2,2-trifluoro-1-hydroxy) in the same manner as in Example 119 (1) using methyl) trimethylsilane Ethyl) -2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid was obtained.
  • Example 121 2- (tert-Butyl) -N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (3- (2,2,2-tri) Preparation of fluoro-1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-121) 2- (tert-butyl) -5-5 in Example 1 (4) 2- (tert-butyl) -5-methyl-1- obtained in Example 120 (1) instead of methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Using (3- (2,2,2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid, 4- (methylsulfonyl) benzylamine Generation of In the
  • Example 122 2- (tert-Butyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1- (3- (2,2,2-tri) Preparation of fluoro-1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-122) 2- (tert-butyl) -5-5 in Example 1 (4) 2- (tert-butyl) -5-methyl-1- obtained in Example 120 (1) instead of methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Using (3- (2,2,2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid, 4- (methylsulfonyl) benzylamine Generation of In the
  • Example 128 2- (tert-Butyl) -1- (3- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl)
  • 1-H-imidazole-4-carboxamide (I-128) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H- in Example 1 (4)
  • Triethylamine (15.8 mL, 113 mmol) was added at ⁇ 78 ° C., and the mixture was stirred for 30 minutes at the same temperature, then warmed to room temperature and stirred for 1 hour.
  • Water was added to the reaction solution, extraction was performed with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate) to give 2-((tert-butyldimethylsilyl) oxy) acetaldehyde (yield 3.43 g, 76% yield) Got).
  • the solution was added dropwise and stirred at the same temperature for 2 hours, and then warmed to room temperature and stirred for 1 hour.
  • Water was added to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 130 2- (tert-Butyl) -1- (3- (hydroxymethyl-d2) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) Preparation of methyl) -1H-imidazole-4-carboxamide (I-130) (1) 2- (tert-butyl) -1- (3-formyl-2-) synthesized by the method described in Example 112 (1) (Trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester in tert-butanol (5.2 mL), tetrahydrofuran (5.2 mL) and water (1.7 mL), 2-methyl-2-butene (0.444 mL, 4.18 mmol), sodium dihydrogen phosphate dihydrate (244 mg, 1.57 mmol) and sodium chlorite (142 mg, 1.57 mmol) were sequentially added,
  • reaction solution was added dropwise to a solution of sodium borohydride (17 mg, 0.41 mmol) in tetrahydrofuran (1 mL) at 0 ° C., and stirred at the same temperature for 30 minutes.
  • tetrahydrofuran 1 mL
  • saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 1 (4) In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3). Performed using 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester obtained in (3) In the same manner as in Example 1 (3), 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid was obtained. Obtained.
  • Example 132 (R) -1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • I-132 5-methyl-1H-imidazole-4-carboxamide
  • 2- tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1
  • 1- 4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5- (5) obtained in Example 131 (4) instead of 1H-imidazole-4-carboxylic acid (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride using methyl-1H-imidazole-4-carboxylic acid and substituting 4- (methylsulfony
  • Example 133 1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-
  • imidazole-4-carboxamide I-133
  • 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4 in Example 1
  • Example 1 4-
  • Example 134 2- (tert-Butyl) -N-((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (1-hydroxyethyl) -2- (trifluoro) Preparation of methyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-134) 1- (3-acetyl-2- (trifluoromethyl) benzyl) -2- in Example 104 (1) (S) -1- (4-acetyl-2- (trifluoromethyl) benzyl) obtained in Example 131 instead of (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4
  • Example 135 2- (tert-Butyl) -N-((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (1-hydroxyethyl) -2- (trifluoro) Preparation of (Methyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-135) 1- (3-acetyl-2- (trifluoromethyl) benzyl) -2- in Example 104 (1) (R) -1- (4-acetyl-2- (trifluoromethyl) benzyl) obtained in Example 132 instead of (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imid
  • Example 136 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -5
  • I-136 1- (3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl)-in
  • Example 104 (1) 1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N obtained in Example 133 instead of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester The same method as in Example 104 (1) using-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide
  • Example 138 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (1- (hydroxyimino) ethyl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-138)
  • S -1- (4-acetyl-2- (trifluoromethyl) benzyl) in Example 137 -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-131)
  • R -1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethyl
  • Example 139 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (1- (hydroxyimino) ethyl) -2- (trifluoromethyl) benzyl) Preparation of -5-methyl-1H-imidazole-4-carboxamide (I-139) (S) -1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-) in Example 137 Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-131) instead of being obtained in Example 133 1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulf
  • Example 142 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (1-methoxyimino) ethyl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-142) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (Example 140) obtained in Example 132 in place of tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) (R) -1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (
  • Example 143 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (1-((2-hydroxyethoxy) imino) ethyl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-143) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2 obtained in Example 133 -(Tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) (17 mg, 0.029 mmol), To a solution of acetic acid (3.4 ⁇ L, 0.059 mmol) in methanol (0.4 mL), 2-aminooxyethanol (5.9 ⁇ L,
  • Example 146 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (2-hydroxypropan-2-yl) -2- (trifluoromethyl) Preparation of benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-146) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-) obtained in Example 133 Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) (15 mg, 0.027 mmol) in tetrahydrofuran (0.3 mL) 0.92 mol / L methylmagnesium bromide tetrahydrofuran solution (150 ⁇ L, 0.14 mmol) was added to the solution
  • Example 148 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (2-hydroxypropan-2-yl) -2 Preparation of-(trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-148) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2 in Example 146 Obtained in Example 132 in place of-(tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) (R) -1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsul
  • Example 149 2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-((6- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine
  • (3-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-149) (1) (3- (trifluoromethyl) thiophen-2-yl in Example 41 (3) ) (2- (tert-Butyl) -5-methyl-1 in the same manner as in Example 41 (3), using (4- (trifluoromethyl) pyridin-3-yl) methanamine instead of methanamine -((4- (Trifluoromethyl) pyridin-3-yl) methyl) -1H-imidazole-4-carboxylic acid methyl ester was obtained.
  • Example 104 1- (3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester in Example 104 (1)
  • — (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide the title compound (I-149) was obtained in the same manner as in Example 104 (1).
  • the title compound (I-149) was obtained in the same manner as in Example 104 (1).
  • Example 150 2- (tert-Butyl) -N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -1-((6- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine-3
  • 2- (tert-butyl) -5-methyl-1- in Example 1 (4)
  • 4- (methylsulfonyl) benzylamine instead of 4- (methylsulfonyl) benzylamine instead of 4- (methylsulfonyl) benzylamine instead of 4- (methylsulfonyl) benzylamine instead of 4- (methylsulfonyl) benzylamine instead of 4- (methylsulfonyl) benzy
  • Example 104 (2) 1- (3-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester in Example 104 (1) Instead of 1-((6-acetyl-4- (trifluoromethyl) pyridin-3-yl) methyl) -2- (tert-butyl) -N-((5- ( The title compound (I-150) was obtained in the same manner as in Example 104 (1) using ethylsulfonyl) thiazol-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide.
  • Example 152 2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-((6- (1- (methoxyimino) ethyl) -4- (trifluoro Preparation of methyl) pyridin-3-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-152) 1- (4-acetyl-2- (trifluoromethyl) benzyl) in Example 140 Example instead of -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) 1-((6-acetyl-4- (trifluoromethyl) pyridin-3-yl) methyl) -2- (tert-butyl) -N- (1- (4
  • Example 154 (R) -1- (3- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of (2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-154) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (3- (1H-pyrazol-4-yl) -2- (trifluoro) obtained in Example 153 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (R) -2-amino-
  • Example 155 (S) -1- (3- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of (2-Hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-155) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (3- (1H-pyrazol-4-yl) -2- (trifluoro) obtained in Example 153 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (S) -2-
  • Example 156 1- (3- (1H-Pyrazol-3-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl
  • I-156 5-methyl-1H-imidazole-4-carboxamide
  • Example 55 3- (3-bromo-2- (trifluoromethyl) benzyl)-obtained in Example 55
  • 2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester (86 mg, 0.20 mmol) in dioxane (1.6 mL)
  • tetrakistriphenylphosphine palladium (0) (12 mg, 0.010 mmol
  • cesium carbonate 98 mg, 0.30 mmol
  • Example 157 (R) -1- (3- (1H-pyrazol-3-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of (2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-157) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (3- (1H-pyrazol-3-yl) -2- (trifluoro) obtained in Example 156 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (R) -2-amino-
  • Example 158 (S) -1- (3- (1H-pyrazol-3-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of (2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-158) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (3- (1H-pyrazol-3-yl) -2- (trifluoro) obtained in Example 156 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (S) -2-amino-
  • Example 159 1- (3- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2 Preparation of (yl) methyl) -1H-imidazole-4-carboxamide (I-159) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl)) in Example 1 (4) 1- (3- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) obtained in Example 153 (2) instead of benzyl) -1H-imidazole-4-carboxylic acid (5- (methylsulfonyl) pyridin-2-yl) methane instead of 4- (methylsulfonyl) benzylamine using-(tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid Compound (I
  • Example 160 (R) -1- (3- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (2-hydroxy-1- (4- (4- Preparation of methylsulfonyl) phenyl) ethyl) -5-methyl-1H-imidazole-4-carboxamide (I-160) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (3- (1H-pyrazol-4-yl) -2- (trifluoro) obtained in Example 153 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and using the method described in Reference Example 27 in place of 4- (methylsulfonyl) benzylamine Synthesized
  • Example 162 (R) -2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (3- (hydroxymethyl) pyrrolidin-1-yl)- Preparation of 2- (Trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-162) (S) -3-((benzyloxy) methyl) pyrrolidine in Example 161 (1) Compound (I-162) was obtained in the same manner as in Example 161, using (R) -3-((benzyloxy) methyl) pyrrolidine synthesized by the method described in Reference Example 29 in place of
  • Example 163 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (3- (6-hydroxy-2-azaspiro [3.3] heptane-2-yl Preparation of (2-) (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-163) (1) (S) -3- (benzyl) in Example 161 (1)
  • Example 161 (1) was prepared using 6-((tert-butyldimethylsilyl) oxy) -2-azaspiro [3.3] heptane synthesized by the method described in Reference Example 30 in place of oxy) methyl) pyrrolidine.
  • Example 164 (R) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (6-hydroxy-2-azaspiro [3.3] Preparation of heptan-2-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-164) 2- (tert-butyl) in Example 1 (4) 2- (tert-butyl) -1-l obtained in Example 163 (3) instead of) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid (3- (6-hydroxy-2-azaspiro [3.3] heptan-2-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid and 4- (methylsulfo Compound (
  • Example 165 (S) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (3- (6-hydroxy-2-azaspiro [3.3] Preparation of heptan-2-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-165) 2- (tert-butyl) in Example 1 (4) 2- (tert-butyl) -1-l obtained in Example 163 (3) instead of) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid (3- (6-hydroxy-2-azaspiro [3.3] heptan-2-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid and 4- (methylsulfo Compound (
  • Example 166 1- (3-Amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H- Preparation of imidazole-4-carboxamide (I-166) (1) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl)-obtained in Example 55 (1) To a solution of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester (433 mg, 1.00 mmol) in dioxane (5 mL), tert-butyl carbamate (176 mg, 1.50 mmol), tris (dibenzylideneacetone) di Add palladium (0) (92 mg, 0.10 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (116
  • Example 1 (2) In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3). Performed using 1- (3-amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester obtained in (1) In the same manner as in Example 1 (3), 1- (3-amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid was obtained. Obtained.
  • Example 167 (R) -1- (3-Amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • I-167 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1 (4)
  • Example 166 instead of 1H-imidazole-4-carboxylic acid Using (1H) -imidazole-4-carboxylic acid and (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride instead of 4- (methylsulfonyl)
  • Example 168 (S) -1- (3-Amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • 5-methyl-1H-imidazole-4-carboxamide (I-168) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1
  • Example (4) 1- (3-Amino-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl obtained in Example 166 (2) instead of 1H-imidazole-4-carboxylic acid Using (1H) -imidazole-4-carboxylic acid and (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride instead of 4- (methylsulfonyl
  • imidazole-4-carboxamide I-169
  • Zinc cyanide (II) (35.2 mg, 0.300 mmol), powder, in a solution of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester (217 mg, 0.500 mmol) in N, N-dimethylacetamide (2 mL)
  • Zinc (42.5 mg, 0.650 mmol) and (1,1′-bis (diphenylphosphino) ferrocene) palladium (II) dichloride dichloromethane adduct
  • Example 1 (2) In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3). Performed using 2- (tert-butyl) -1- (3-cyano-2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester obtained in (1) Using a method similar to Example 1 (3), 2- (tert-butyl) -1- (3-cyano-2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid Obtained.
  • Example 170 (S) -2- (tert-Butyl) -1- (3-cyano-2- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • I-170 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1
  • Example 171 (R) -2- (tert-Butyl) -1- (3-cyano-2- (trifluoromethyl) benzyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)-
  • I-171 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1
  • Example 172 1- (4- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2 Preparation of (-yl) methyl) -1H-imidazole-4-carboxamide (I-172) (1) 1- (4-bromo-2- (trifluoromethyl) benzyl)-obtained in Example 131 (1) 2- (tert-Butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester (151 mg, 0.338 mmol), tetrakistriphenylphosphine palladium (0) (39.8 mg, 34.4 ⁇ mol), 4- (4) , 4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl este
  • Example 173 (R) -1- (4- (1H-pyrazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of (2-Hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-173) 2- (tert-butyl) -5-methyl-1- (2) in Example 1 (4) 1- (4- (1H-pyrazol-4-yl) -2- (trifluoro) obtained in Example 172 (2) instead of-(trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and, instead of 4- (methylsulfonyl) benzylamine, (R) -2-
  • Example 175 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (hydroxymethyl) -2- (trifluoromethyl) benzyl) -5-methyl
  • 1-H-imidazole-4-carboxamide I-175
  • Example 55 2-
  • Butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester instead of tributyl (1-ethoxyvinyl) tin, tributylstannylmethanol was used.
  • Example 178 2- (tert-Butyl) -1- (4- (1-hydroxyethyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) Preparation of methyl) -1H-imidazole-4-carboxamide (I-178) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl)-in Example 112 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) obtained in Example 131 (1) instead of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester 0.5 mol / L cyclopropylmagnesium bromide tetrahydrofuran in Example 112 (2)) using 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester In the same manner as in Example 11
  • Preparation of -5-methyl-1H-imidazole-4-carboxamide (I-179) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) in Example 112
  • 1- (4-Bromo-2- (trifluoromethyl) benzyl) -2- (tert) obtained in Example 131 (1) instead of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester -Butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester and using 0.5 mol / L cyclopropylmagnesium bromide in Example 112 (2).
  • Example 112 A 0.98 mol / L methylmagnesium bromide tetrahydrofuran solution is used instead of the drofuran solution, and Reference Example 25 is used instead of (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 112 (4).
  • the compound (I-179) was obtained in the same manner as in Example 112, using 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described above.
  • Example 180 2- (tert-Butyl) -1- (4- (1-hydroxypropyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) Preparation of methyl) -1H-imidazole-4-carboxamide (I-180) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl)-in Example 112 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) obtained in Example 131 (1) instead of 5-methyl-1H-imidazole-4-carboxylic acid methyl ester 0.5 mol / L cyclopropylmagnesium bromide tetrahydrofuran in Example 112 (2)) using 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester A compound (I-180) was obtained
  • Example 181 2- (tert-Butyl) -1- (4- (1-hydroxy-2-methylpropyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine) Preparation of 2-yl) methyl) -1H-imidazole-4-carboxamide (I-181) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert) in Example 112 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- obtained in Example 131 (1) instead of -butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester Using (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester and using 0.5 mol / L cyclopropylmagnesium bromide in Example 112 (2) Compound (I-181) was obtained
  • Example 182 2- (tert-Butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N-((R) -2-hydroxy-1- (4- (methyl) Preparation of sulfonyl) phenyl) ethyl) -5-methyl-1H-imidazole-4-carboxamide (I-182) (1) (3- (trifluoromethyl) thiophen-2-yl) in Example 41 (3) In the same manner as in Example 41 (3), using (4-bromo-2- (trifluoromethyl) phenyl) methanamine instead of methanamine, 1- (4-bromo-2- (trifluoromethyl) Benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester was obtained.
  • Example 112 (2) 1- (3-Bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester in Example 112 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester obtained in the above (1) instead of 2- (tert-butyl) -1- (4-formyl-2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4 in the same manner as in Example 112 (1) using -Carboxylic acid methyl ester was obtained.
  • Example 183 2- (tert-Butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2-) Preparation of (I) methyl) -1H-imidazole-4-carboxamide (I-183) 2- (tert-Butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl in Example 1 (4) 2- (tert-Butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoro) obtained in Example 182 (4) instead of 1) 1H-imidazole-4-carboxylic acid (Methyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid, and (5- (methylsulfonyl) pyridine instead of 4- (methylsulfonyl) benzylamine Compound (
  • Example 184 2- (tert-Butyl) -1- (4- (cyclobutyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) Preparation of (Methyl) -1H-imidazole-4-carboxamide (I-184) 1- (3-Bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) in Example 112 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-) obtained in Example 131 (1) instead of -5-methyl-1H-imidazole-4-carboxylic acid methyl ester Butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester and using 0.5 mol / L cyclopropylmagnesium bromide tetramer in Example 112 (2)
  • a compound (I-184) was obtained in the same manner as in Example 112 using a 2 mol / L cyclobutylmagnesium bromide diethyl ether solution synthesized by the method described in Reference Example 26 instead of the hydrofuran solution.
  • Example 185 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (4- (2,2,2-trifluoro-1-hydroxyethyl) Preparation of (2-) (Trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-185) (1) 2- (tert-butyl) -5-methyl-1 in Example 1 (3) 1- (4-bromo-2- (trifluoromethyl) benzyl obtained in Example 131 (1) instead of-(2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester 1- (4-Bromo-2- (2-bromo-t-butyl) -5-methyl-1H-imidazole-4-carboxylic acid ethyl ester in the same manner as in Example 1 (3). Trifluoromethyl) Benzyl)
  • Example 108 (2) Instead of 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid in Example 108 (2) Using the 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid obtained in (1) above; In the same manner as in Example 108 (2), 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid The tert-butyl ester was obtained.
  • Example 186 1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H- Preparation of imidazole-4-carboxamide (I-186) (1) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-5 in Example 55 (2) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) obtained in Example 182 (1) instead of methyl-1H-imidazole-4-carboxylic acid methyl ester 2- (tert-butyl) -1- (4- (1-ethoxyvinyl) in the same manner as in Example 55 (2) using -5-methyl-1H-imidazole-4-carboxylic acid methyl ester -2- (trif Oromechiru) benz
  • Example 1 (3) In place of 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid ethyl ester in Example 1 (3). Performed using 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester obtained in (2) In the same manner as in Example 1 (3), 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid was obtained Obtained.
  • Example 187 2- (tert-Butyl) -1- (4- (1-hydroxyethyl-1-d) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine) Preparation of 2-yl) methyl) -1H-imidazole-4-carboxamide (I-187) 1- (3-acetyl-2- (trifluoromethyl) benzyl) -2- (tert) in Example 104 (1) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-) obtained in Example 186 instead of -butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester Butyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-imidazole-4-carboxamide (I-186) and using borohydride Compound (
  • Example 188 2- (tert-Butyl) -1- (4- (2-hydroxypropan-2-yl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine) Preparation of 2-yl) methyl) -1H-imidazole-4-carboxamide (I-188) 1- (4-acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) in Example 146 1- (4) obtained in Example 186 instead of -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-133) -Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl
  • Example 189 (R) -1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl)- Preparation of 5-methyl-1H-imidazole-4-carboxamide (I-189) 2- (tert-butyl) -5-methyl-1- (2- (trifluoromethyl) benzyl) in Example 1 (4) 1- (4-Acetyl-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl obtained in Example 186 (3) instead of 1H-imidazole-4-carboxylic acid The (R) -2-amino-2- (4- (4- (4- (4- (methylamino))) synthesized by the method described in Reference Example 27 using 1H-imidazole-4-carboxylic acid and replacing 4- (methylsulfonyl) benz
  • Example 190 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (4-morpholino-2- (trifluoromethyl) benzyl) -1H-
  • I-190 (1) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) -5-5 in Example 161 (1)
  • Example 161 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl)-obtained in Example 182 (1) instead of methyl-1H-imidazole-4-carboxylic acid methyl ester
  • Example 161 (1) using 5-methyl-1H-imidazole-4-carboxylic acid methyl ester and using morpholine instead of (S) -3-((benzyloxy) methyl) pyrrolidine In a similar manner,
  • Example 191 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-methyl-1- (4- (2-oxopyrrolidin-1-yl) -2- ( Preparation of trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (I-191) (1) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2 in Example 161 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) obtained in Example 182 (1) instead of-(tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester Pyrrolidine-2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester is used instead of (S) -3-((benzyloxy) methyl) pyrrolidine 2- (tert-
  • Example 192 (S) -2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (3-hydroxypyrrolidin-1-yl) -2- ( Preparation of trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-192) (1) 1- (3-bromo-2- (trifluoromethyl) in Example 161 (1) 1- (4-bromo-2- (trifluoro) obtained in Example 182 (1) instead of benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester Methyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester, using (S) instead of (S) -3-((benzyloxy) methyl) pyr
  • Example 193 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (4-hydroxypiperidin-1-yl) -2- (trifluoromethyl) Preparation of benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-193) (1) 1- (3-bromo-2- (trifluoromethyl) benzyl) -2 in Example 161 (1) 1- (4-bromo-2- (trifluoromethyl) benzyl) obtained in Example 182 (1) instead of-(tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester was used instead of (S) -3-((benzyloxy) methyl) pyrrolidine in Reference Example 31 Using the synthesized 4-
  • Example 196 2- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1- (4- (3-hydroxyazetidin-1-yl) -2- (trifluoromethyl) )) Benzyl) Preparation of 5-methyl-1H-imidazole-4-carboxamide (I-196) (1) 1- (3-bromo-2- (trifluoromethyl) benzyl)-in Example 161 (1) 1- (4-bromo-2- (trifluoromethyl) synthesized by the method described in Example 182 (1) instead of methyl 2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylate ) (Benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester and using (S) -3-((benzyloxy) in Example 161 (1) Me 2- (tert-buty
  • Example 197 (R) -2- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (3-hydroxyazetidin-1-yl)- Preparation of 2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-197) 2- (tert-butyl) -5-methyl-1- in Example 1 (4) The 2- (tert-butyl) -1- (4- (3-hydroxyazetic) obtained in Example 196 (2) instead of (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid In addition to 4- (methylsulfonyl) benzylamine, (R)-(Gin-1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid is used. 2-
  • Example 198 (S) -2- (tert-Butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1- (4- (3-hydroxyazetidin-1-yl)- Preparation of 2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxamide (I-198) 2- (tert-butyl) -5-methyl-1- in Example 1 (4) The 2- (tert-butyl) -1- (4- (3-hydroxyazetic) obtained in Example 196 (2) instead of (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid In addition to 4- (methylsulfonyl) benzylamine, (S)-(Gin-1-yl) -2- (trifluoromethyl) benzyl) -5-methyl-1H-imidazole-4-carboxylic acid is used. 2-
  • Example 199 1- (4- (1H-1,2,3-Triazol-4-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N-((5- (ethylsulfonyl) pyridine) Preparation of (2-yl) methyl) -5-methyl-1H-imidazole-4-carboxamide (I-199) (1) 1- (4-bromo-2) synthesized by the method described in Example 182 (1) -(Trifluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid methyl ester (120 mg, 0.28 mmol), triethylamine (2 mL), trimethylsilylacetylene (41) mg, 0.42 mmol), copper (I) iodide (11 mg, 0.056 mmol) and tetrakistriphenylphosphine palladium (0) (32 mg,
  • reaction solution was filtered through celite and washed with ethyl acetate. Water was added to the filtrate and extracted with ethyl acetate. The organic layer is washed with saturated brine, and the solvent is evaporated under reduced pressure.
  • Example 200 2- (tert-Butyl) -1- (4- (isoxazol-4-yl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2-) Preparation of (I) methyl) -1H-imidazole-4-carboxamide (I-200) (1) 2- (tert-butyl) -5-methyl-1- (2- (trifluoro) in Example 1 (4) 1- (4-bromo-2- (trifluoromethyl) benzyl) -2- (tert-butyl) obtained in Example 185 (1) instead of methyl) benzyl) -1H-imidazole-4-carboxylic acid -5-methyl-1H-imidazole-4-carboxylic acid, and (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride instead of 4- (methylsulfonyl) benzylamine In the same
  • Example 201 2- (tert-Butyl) -1- (4- (cyclopropanecarbonyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl
  • 2- (tert-Butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoro) obtained in Example 183 Methyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-imidazole-4-carboxamide (I-183) (10 mg, 0.017 mmol) in dichloromethane (236 ⁇ L) and Dess-Martin periodinane (36 mg, 0.085 mmol) were added and stirred at room temperature for 7 and a half hours.
  • Example 202 2- (tert-Butyl) -1- (3- (cyclopropanecarbonyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl
  • 1-H-imidazole-4-carboxamide I-202
  • Example 205 (S) -1- (4- (1,2,4-oxadiazol-3-yl) -2- (trifluoromethyl) benzyl) -2- (tert-butyl) -N- (1- (4-) Preparation of-(ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-methyl-1H-imidazole-4-carboxamide (I-205) (1) 2- (tert-butyl) in Example 1 (4) 1- (4-bromo-2- (tri) obtained in Example 185 (1) instead of -5-methyl-1- (2- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxylic acid Fluoromethyl) benzyl) -2- (tert-butyl) -5-methyl-1H-imidazole-4-carboxylic acid and (S) -2-amino instead of 4- (methylsulfonyl) benzylamine -2- (4- (eth
  • Example 206 2- (tert-Butyl) -1- (3- (1-hydroxycyclopropyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) ) Methyl) -1H-imidazole-4-carboxamide (I-206-A) and 2- (tert-butyl) -5-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl)-
  • I-206-B 2- (tert-butyl) in Example 1 (4)
  • Example 213 2- (tert-Butyl) -1- (3- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N-((R) -2-hydroxy-1- (4- (methyl) Preparation of sulfonyl) phenyl) ethyl) -5-methyl-1H-imidazole-4-carboxamide and separation of its diastereomer (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride in Example 112 (4) Obtained in the same manner as in Example 112, using (R) -2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride synthesized by the method described in Reference Example 27 in place of the salt 2- (tert-Butyl) -1- (3- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -N-((R)
  • Example 214 2- (tert-Butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl) -5-methyl-N-((5- (methylsulfonyl) pyridine-2-) Optical resolution of (I) methyl) -1H-imidazole-4-carboxamide (I-183) 2- (tert-butyl) -1- (4- (cyclopropyl (hydroxy) methyl) -2- (trifluoromethyl) benzyl ) -5-Methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-imidazole-4-carboxamide (I-183) (60 mg) in 2-propanol (2 mL) and Dissolve in a mixed solution of n-hexane (2 mL) and recycle by preparative HPLC (column: CHIRALPAK IA 2 cmx 25 cm,
  • Test Example 1 ROR ⁇ t Inhibitory Action Evaluation The ROR ⁇ t inhibitory action of the test compound was evaluated using the following reporter gene assay.
  • Jurkat cells used for the assay were cultured in RPMI 1640 medium containing 10 (v / v)% of fetal bovine serum. On the day of the test, Jurkat cells are collected by centrifugation (1000 rpm, 5 minutes) and suspended in PBS (phosphate buffered saline) containing 0.5 (w / v)% of bovine serum albumin (Sigma Aldrich). did.
  • the cells were recovered by centrifugation again, and 100 ⁇ L of Cell Line Nucleofector Solution V (Amaxa Cell Line Nucleofector kit V, Lonza) was added to 3 ⁇ 10 6 cells and suspended.
  • 100 ⁇ L of this cell suspension 2 ⁇ g of a vector (TrueClone Full-Length cDNA Clones, Origene) in which the sequence of ROR ⁇ t was inserted downstream of the CMV promoter, and pOR4.15 (Promega) for ROR response element of human IL-17 3 ⁇ g of the reporter vector inserted upstream of the luciferase gene of (iii) was added, and gene transfer was carried out under the condition of X-005 with an electroporation apparatus (Nucleofector, Lonza).
  • RPMI 1640 medium containing 10 (v / v)% fetal bovine serum for 5 hours, and then collected by centrifugation to obtain assay medium (10 (v / v)% fetal bovine serum , Suspended in RPMI 1640 containing 10 mM HEPES and 1 mM sodium pyruvate, no phenol red medium (Life Technologies), and 1 ⁇ 10 5 cells / 50 ⁇ L / well in 96-well plates (B & W IsoPlate-96 TC) , Perkin Elmer, Inc.). The test compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted in assay medium and added to the cells on the day of the test.
  • DMSO dimethyl sulfoxide
  • test compound was added at 20 ⁇ L / well, and the final DMSO concentration was 0.1 (v / v)%. After addition of the test compound, the cells were cultured overnight in an incubator. Add 10 ⁇ l of stimulation solution (final concentration 50 ng / mL phorbol-12-myristate-13-acetate (Sigma Aldrich) and final concentration 1 ⁇ M ionomycin (Sigma Aldrich)) in the incubator for 7 hours Incubated for 20 minutes.
  • stimulation solution final concentration 50 ng / mL phorbol-12-myristate-13-acetate (Sigma Aldrich) and final concentration 1 ⁇ M ionomycin (Sigma Aldrich)
  • Cell viability was measured using the fluorescence method by CellTiter-Fluor cell viability assay (Promega). 20 ⁇ L of CellTiter-Fluor reagent was added to a 96-well plate and incubated in an incubator for 40 minutes. Using a microplate reader, the fluorescence at 495 nm was measured using an excitation wavelength of 340 nm. The viable cell rate after the test compound treatment was treated with only 0.1 (v / v)% of DMSO, and expressed as% of control, where the measured value of the cells to which the stimulation solution was added was 100%.
  • ROR ⁇ t activity was measured using luciferase activity as an index using Bright-Glo Luciferase Assay System (Promega). After measurement of cell viability, 100 ⁇ L of Bright-Glo reagent was added and incubated for 3 minutes at room temperature. The amount of luminescence was measured using a microplate reader. In wells treated with only 0.1 (v / v)% DMSO and treated with 100%, 0.1 (v / v)% DMSO only, and with no luminescence solution in wells to which stimulation solution was added The luciferase activity after the test compound treatment was expressed as% of control, assuming that the amount of luminescence was 0%. The IC 50 value of the test compound was calculated from the linear expression of a straight line passing two points sandwiching 50% of control.
  • Tables 29 and 30 show the results of ROR ⁇ t inhibition evaluation.
  • Compounds with IC 50 values less than 300 nM are designated by the letter “A”
  • compounds having an IC 50 value of less than 300 nM or 900 nM is represented by the letter "B”.
  • the imidazole derivative of the present invention has excellent ROR ⁇ t inhibitory activity, and has rheumatoid arthritis, psoriasis, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), multiple sclerosis, systemic lupus erythematosus, ankylosing spine It is useful as an active ingredient of a medicine for preventing and / or treating various autoimmune diseases such as inflammation and uveitis and allergic diseases (asthma, atopic dermatitis, chronic obstructive pulmonary disease and the like).

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Abstract

La présente invention concerne un composé représenté par la formule, qui a un effet inhibiteur de RORγt et qui est utile en tant qu'agent prophylactique ou thérapeutique pour des maladies auto-immunes, des maladies allergiques, etc, ou un sel de celui-ci.
PCT/JP2018/023286 2017-06-21 2018-06-19 Dérivé d'imidazole et médicament comprenant celui-ci WO2018235813A1 (fr)

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028896A1 (fr) * 1993-06-10 1994-12-22 The Du Pont Merck Pharmaceutical Company Imidazoles substitues en position 5, antagonistes de l'angiotensine ii
WO2013079223A1 (fr) * 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolocarboxamides en tant que modulateurs de l'activité d'un récepteur orphelin gamma (rorϒ, nr1f3) apparenté au récepteur nucléaire orphelin rar et destinés au traitement de maladies inflammatoires chroniques et auto-immunes
WO2013178362A1 (fr) * 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Thiazoles substitués par carboxamide ou sulfonamide et dérivés apparentés en tant que modulateurs du récepteur nucléaire orphelin ror[gamma]
WO2014023367A1 (fr) * 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Hétérocycles à 5 chaînons contenant de l'azote substitués par carboxamide ou sulfonamide en tant que modulateurs pour le récepteur nucléaire orphelin ror gamma
WO2014200075A1 (fr) * 2013-06-12 2014-12-18 科研製薬株式会社 Dérivé de 4-alcynylimidazole et médicament le comprenant en tant que principe actif
WO2015017335A1 (fr) * 2013-07-30 2015-02-05 Boehringer Ingelheim International Gmbh Composés d'azaindole à titre de modulateurs de rorc
WO2015035278A1 (fr) * 2013-09-09 2015-03-12 Bristol-Myers Squibb Company Modulateurs de rorγ
WO2015095788A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Benzoxazine carbamates de 2-acylamidométhyle et de sulfonylamidométhyle pour l'inhibition de l'activité du rorgamma et le traitement d'une maladie
WO2015116904A1 (fr) * 2014-02-03 2015-08-06 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2016061160A1 (fr) * 2014-10-14 2016-04-21 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2016193461A1 (fr) * 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2017044410A1 (fr) * 2015-09-09 2017-03-16 Eli Lilly And Company Composés utiles pour l'inhibition du ror-gamma-t

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028896A1 (fr) * 1993-06-10 1994-12-22 The Du Pont Merck Pharmaceutical Company Imidazoles substitues en position 5, antagonistes de l'angiotensine ii
WO2013079223A1 (fr) * 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolocarboxamides en tant que modulateurs de l'activité d'un récepteur orphelin gamma (rorϒ, nr1f3) apparenté au récepteur nucléaire orphelin rar et destinés au traitement de maladies inflammatoires chroniques et auto-immunes
WO2013178362A1 (fr) * 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Thiazoles substitués par carboxamide ou sulfonamide et dérivés apparentés en tant que modulateurs du récepteur nucléaire orphelin ror[gamma]
WO2014023367A1 (fr) * 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Hétérocycles à 5 chaînons contenant de l'azote substitués par carboxamide ou sulfonamide en tant que modulateurs pour le récepteur nucléaire orphelin ror gamma
WO2014200075A1 (fr) * 2013-06-12 2014-12-18 科研製薬株式会社 Dérivé de 4-alcynylimidazole et médicament le comprenant en tant que principe actif
WO2015017335A1 (fr) * 2013-07-30 2015-02-05 Boehringer Ingelheim International Gmbh Composés d'azaindole à titre de modulateurs de rorc
WO2015035278A1 (fr) * 2013-09-09 2015-03-12 Bristol-Myers Squibb Company Modulateurs de rorγ
WO2015095788A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Benzoxazine carbamates de 2-acylamidométhyle et de sulfonylamidométhyle pour l'inhibition de l'activité du rorgamma et le traitement d'une maladie
WO2015116904A1 (fr) * 2014-02-03 2015-08-06 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2016061160A1 (fr) * 2014-10-14 2016-04-21 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2016193461A1 (fr) * 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2017044410A1 (fr) * 2015-09-09 2017-03-16 Eli Lilly And Company Composés utiles pour l'inhibition du ror-gamma-t

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