WO2019022234A1 - Agent thérapeutique ou agent prophylactique contre des maladies inflammatoires de l'intestin - Google Patents

Agent thérapeutique ou agent prophylactique contre des maladies inflammatoires de l'intestin Download PDF

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WO2019022234A1
WO2019022234A1 PCT/JP2018/028276 JP2018028276W WO2019022234A1 WO 2019022234 A1 WO2019022234 A1 WO 2019022234A1 JP 2018028276 W JP2018028276 W JP 2018028276W WO 2019022234 A1 WO2019022234 A1 WO 2019022234A1
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compound
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mmol
trifluoromethoxy
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新之助 林
マーシャル バレット
慎也 横坂
和也 大角
拓実 青木
目黒　裕之
戒能　美枝
こずえ 高垣
雄大 高橋
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東レ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic or prophylactic agent for inflammatory bowel disease.
  • Inflammatory bowel disease is a generic term for diseases that cause chronic inflammation or ulceration in the mucosa of the large and small intestines, and mainly includes ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease that shows nonspecific chronic inflammation that is more diffuse than the rectum and continuously affects the large intestine mucosa, and Crohn's disease is inflammation, deep ulcers and perforations in various parts of the digestive tract. It is a disease that exhibits full-thickness symptoms. Although the cause is unknown for all, various causes such as infection, environmental factors, psychosomatic problems, genetic or immune abnormalities are assumed, and it is generally considered that this is a multifactorial disease caused by complex entanglement. (Non-patent document 1).
  • Non-Patent Document 2 the treatment of Crohn's disease centers on nutrition therapy, drug therapy or surgery.
  • Non-patent document 3 With regard to drug therapy for Crohn's disease, it has been reported that 5-aminosalicylic acid preparations are used as a basis, and corticosteroids, immunosuppressants (Non-patent document 3), anti-TNF- ⁇ antibodies, etc. are used according to the symptoms. (Non-patent document 4).
  • Th17 cells which is one of a subset of helper T cells, and inflammatory cytokines produced by it. It is reported that certain IL-17 plays an important role in the onset and progress of inflammatory bowel disease (Non-patent Document 5).
  • ROR ⁇ nuclear receptor retinoid-related orphan receptor ⁇
  • ROR ⁇ nuclear receptor retinoid-related orphan receptor ⁇
  • suppression of ROR ⁇ expression or function suppresses the differentiation and activation of Th17 cells and the production of IL-17
  • lymphocytes from ROR ⁇ knockout mice are It has been reported that the transferred RAG deficient mouse alleviates the symptoms of colitis (Non-patent Document 7).
  • binding between ROR ⁇ and a coactivator is necessary (Non-patent Document 8).
  • N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has hitherto been described.
  • Non-patent Document 9 4-Methylthiazol-2-yl) acetamide
  • Non-patent Document 9 6- (2-Chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl) iso
  • Substituted azole derivatives such as oxazol-3-yl) -5-oxohexanoic acid
  • Patent Document 1 N- (5- (2-chlorobenzoyl) -4- (3-chlorophenyl) thiazol-2-yl
  • Sulfonylbenzene derivatives such as 2- (4- (ethylsulfonyl) phenyl) acetamide have been reported (Patent Document 2).
  • Patent Document 1 and Patent Document 2 do not disclose compounds having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide.
  • Patent Document 3 does not show any specific efficacy data of the disclosed compound for inflammatory bowel disease
  • Patent Document 4 discloses or suggests the action of the disclosed compound for ROR ⁇ . Not.
  • this invention aims at providing the therapeutic agent or preventive agent of inflammatory bowel disease which has ROR (gamma) antagonist activity.
  • the present invention provides an agent for treating or preventing inflammatory bowel disease, which comprises a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 represents an alkyloxy group having 1 to 3 carbon atoms (wherein 1 to 3 arbitrary hydrogen atoms in the alkyloxy group may be substituted with a halogen atom)
  • R 2 represents R 2.
  • R 3 is a hydrogen atom, a halogen atom or a hydroxyl group
  • R 4 is a hydrogen atom or a halogen atom
  • R 5 is a hydrogen atom
  • -OR 7, -SR 7, -S ( O) 2 -R 7
  • R 6 represents an alkyl group having 1 to 5 carbon atoms
  • R 7 is an alkyl group (the alkyl group of which a hydrogen atom or a C 1-3, 1-3
  • R 8 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an acyl group having 2 to 4 carbon atoms, or 1 to 3 carbon atoms).
  • R 1 is an alkyloxy group having 1 to 3 carbon atoms (in the alkyloxy group, 1 to 3 arbitrary hydrogen atoms are a fluorine atom or a chlorine atom)
  • R 2 is a fluorine atom or a chlorine atom
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom or a hydroxyl group
  • R 4 is a hydrogen atom or a fluorine atom.
  • An alkyl group having 1 to 3 carbon atoms in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) or a heteroaryl group (the heteroaryl group is And any hydrogen atom may be substituted with a methyl group).
  • R 6 is an alkyl group having 1 to 3 carbon atoms
  • R 7 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms are fluorine atoms) Or a chlorine atom which may be substituted) is preferable.
  • R 1 is a methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom).
  • R 2 is a fluorine atom or a chlorine atom
  • R 3 is a hydrogen atom, a fluorine atom or a hydroxyl group
  • R 4 is a hydrogen atom or a fluorine atom
  • n is an integer of 0 to 4
  • R 5 is a hydrogen atom, -OR 7 , -N (R 7 ) R 8 , an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms are substituted with a fluorine atom) Or a 5-membered ring heteroaryl group (in the 5-membered ring heteroaryl group, any hydrogen atom may be substituted with a methyl group), and R 6 is a methyl group or R 7 is a hydrogen atom or
  • R 1 is a trifluoromethoxy group
  • R 2 is a chlorine atom
  • R 3 is a hydrogen atom
  • R 4 is A hydrogen atom
  • n is an integer of 0 to 3
  • R 5 is a methyl group, a trifluoromethyl group,- N (R 7 ) R 8 , imidazolyl group, triazolyl group or tetrazolyl group (in the imidazolyl group, triazolyl group or tetrazolyl group, any hydrogen atom may be substituted with a methyl group)
  • R 7 is R 8 is more preferably a hydrogen atom, a methyl group, an acetyl group, a propionyl group, a methylsulfonyl group or an ethylsulfonyl group.
  • the invention relates to a method of treating or preventing inflammatory bowel disease, the cyclic amine derivative represented by the above general formula (I) in a subject in need of treating or preventing inflammatory bowel disease Or providing a method comprising the step of administering a pharmacologically acceptable salt thereof.
  • a method of treating or preventing inflammatory bowel disease the cyclic amine derivative represented by the above general formula (I) in a subject in need of treating or preventing inflammatory bowel disease
  • providing a method comprising the step of administering a pharmacologically acceptable salt thereof.
  • the above-mentioned preferred embodiments relating to the cyclic amine derivative represented by the general formula (I) also apply to this embodiment.
  • the present invention provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use in a method of treating or preventing inflammatory bowel disease I will provide a.
  • a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use in a method of treating or preventing inflammatory bowel disease I will provide a.
  • the above-mentioned preferred embodiments relating to the cyclic amine derivative represented by the general formula (I) also apply to this embodiment.
  • the present invention provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for inflammatory bowel disease
  • a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for producing a therapeutic or prophylactic agent for inflammatory bowel disease
  • the therapeutic agent or preventive agent for inflammatory bowel disease of the present invention can effectively suppress the function of ROR ⁇ and significantly improve the symptoms of inflammatory bowel disease.
  • FIG. 16 shows the inhibitory effect of the compound of Example 29 on the increase in gross injury score in a TNBS-induced rat colitis model.
  • FIG. 16 shows the inhibitory effect of the compound of Example 57 on the increase in gross injury score in a TNBS-induced rat colitis model.
  • the therapeutic agent or preventive agent for inflammatory bowel disease of the present invention is characterized by containing a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 represents an alkyloxy group having 1 to 3 carbon atoms (wherein 1 to 3 arbitrary hydrogen atoms in the alkyloxy group may be substituted with a halogen atom), and R 2 represents R 2.
  • R 3 is a hydrogen atom, a halogen atom or a hydroxyl group
  • R 4 is a hydrogen atom or a halogen atom
  • R 5 is a hydrogen atom
  • -OR 7, -SR 7, -S ( O) 2 -R 7
  • R 6 represents an alkyl group having 1 to 5 carbon atoms
  • R 7 is an alkyl group (the alkyl group of which a hydrogen atom or a C 1-3, 1-3
  • R 8 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an acyl group having 2 to 4 carbon atoms, or 1 to 3 carbon atoms).
  • C1-C3 alkyl group means a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • alkyl group having 1 to 5 carbon atoms means a linear or branched saturated hydrocarbon group having 1 to 5 carbon atoms or 3 to 5 carbon atoms, and examples thereof include a methyl group, Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group or tert-pentyl group can be mentioned.
  • C1-C3 alkyloxy group means a methoxy group, an ethoxy group, a propyloxy group or an isopropyloxy group.
  • C4 to C4 acyl group means an acetyl group, a propionyl group, a butanoyl group or a 2-methylpropanoyl group.
  • C1-C3 alkylsulfonyl group means a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group or an isopropylsulfonyl group.
  • Heteroaryl group means a heterocyclic aromatic group containing 1 to 4 hetero atoms arbitrarily selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, such as thienyl group, pyrrolyl group And furyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
  • the “5-membered ring heteroaryl group” is a heterocyclic aromatic ring containing 5 to 4 ring atoms, containing 1 to 4 heteroatoms optionally selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom.
  • Group group, and examples thereof include thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group or tetrazolyl group.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the alkyl group having 1 to 3 carbon atoms (in the alkyl group, any one to 3 hydrogen atoms may be substituted with a halogen atom)” means the above-mentioned alkyl group having 1 to 3 carbon atoms 1 to 3 optional hydrogen atoms each independently represent a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a fluoromethyl group.
  • a difluoromethyl group a trifluoromethyl group, a 2-fluoroethyl group, a trifluoroethyl group, a trichloromethyl group or a trichloroethyl group.
  • the alkyl group having 1 to 3 carbon atoms (in the alkyl group, any one to 3 hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)” means the above-mentioned 1 to 3 carbon atoms 1 to 3 optional hydrogen atoms of the alkyl group in the above alkyl groups each independently represent a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methyl group, an ethyl group, a propyl group and an isopropyl group. And fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, trichloromethyl group or trichloroethyl group.
  • the alkyl group having 1 to 3 carbon atoms (in the alkyl group, any one to 3 hydrogen atoms may be substituted with a fluorine atom)” means the above-mentioned alkyl group having 1 to 3 carbon atoms 1 to 3 optional hydrogen atoms may be substituted with a fluorine atom, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a fluoromethyl group, a difluoromethyl group and a trifluoro group. A methyl group, a 2-fluoroethyl group or a trifluoroethyl group can be mentioned.
  • the “C1-C3 alkyloxy group (in the alkyloxy group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)” means the above-mentioned C1-C3 alkyl 1 to 3 optional hydrogen atoms of the alkyloxy group each independently represent a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methoxy group, an ethoxy group, a propyloxy group and an isopropyloxy group. And fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, trifluoroethoxy, trichloromethoxy or trichloroethoxy.
  • C1-C3 alkyloxy group (in the alkyloxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)" means that the above-mentioned carbon number 1 1 to 3 optional hydrogen atoms of the alkyloxy group of to 3 each independently represent a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methoxy group, an ethoxy group and a propyloxy group. And isopropyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, trifluoroethoxy, trichloromethoxy and trichloroethoxy.
  • methoxy group (the methoxy group may have 1 to 3 optional hydrogen atoms optionally substituted with a fluorine atom)" means a methoxy group, a fluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group.
  • heteroaryl group in the heteroaryl group, any hydrogen atom may be substituted with an alkyl group of 1 to 3 carbon atoms
  • any hydrogen atom may be substituted with an alkyl group of 1 to 3 carbon atoms
  • optional hydrogen atoms each independently represent the group which may be substituted by the above-mentioned alkyl group having 1 to 3 carbon atoms, and examples thereof include a thienyl group, a pyrrolyl group, a furyl group and a thiazolyl group.
  • heteroaryl group in the heteroaryl group, any hydrogen atom may be substituted with a methyl group
  • the hydrogen atoms each independently represent a group which may be substituted with a methyl group.
  • the “5-membered ring heteroaryl group in the 5-membered ring heteroaryl group, any hydrogen atom may be substituted with a methyl group)” means one or more of the above-mentioned 5-membered ring heteroaryl groups (for example, 1 to 4 optional hydrogen atoms each independently represent a group which may be substituted with a methyl group, and examples thereof include a thienyl group, a pyrrolyl group, a furyl group, a thiazolyl group, an imidazolyl group and an oxazolyl group.
  • R 1 is an alkyloxy group having 1 to 3 carbon atoms (1 to 3 optional hydrogen atoms of the alkyloxy group are each independently a fluorine atom or It is preferable that it may be substituted by a chlorine atom), and a methoxy group (one to three optional hydrogen atoms of the methoxy group may be independently substituted by a fluorine atom). And the trifluoromethoxy group is more preferable.
  • R 2 is preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • R 3 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a hydroxyl group, more preferably a hydrogen atom, a fluorine atom or a hydroxyl group, and still more preferably a hydrogen atom.
  • R 4 is preferably a hydrogen atom, a fluorine atom or a chlorine atom, more preferably a hydrogen atom or a fluorine atom, and still more preferably a hydrogen atom.
  • N is preferably an integer of 0 to 4, and more preferably an integer of 0 to 3.
  • (1 to 3 optional hydrogen atoms of the alkyl group may be each independently substituted with a fluorine atom) or a 5-membered ring heteroaryl group (one or more of the 5-membered ring heteroaryl group
  • Arbitrary hydrogen atoms may be each independently substituted with a methyl group
  • the hydrogen atoms may be each independently substituted with a methyl group).
  • R 6 is preferably an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group or an ethyl group.
  • R 7 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (1 to 3 optional hydrogen atoms of the alkyl group may be each independently substituted with a fluorine atom or a chlorine atom) It is preferable that it is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (1 to 3 optional hydrogen atoms of the alkyl group may be each independently substituted with a fluorine atom).
  • a hydrogen atom, a methyl group or an ethyl group is more preferable.
  • R 8 is more preferably a hydrogen atom, a methyl group, an acyl group having 2 to 4 carbon atoms or an alkylsulfonyl group having 1 to 3 carbon atoms, and a hydrogen atom, a methyl group, an acetyl group, a propionyl group, a methylsulfonyl group Or an ethylsulfonyl group is more preferred.
  • the compounds described in Tables 1-1 to 1-3 also include their pharmacologically acceptable salts.
  • the cyclic amine derivative represented by the above general formula (I) may have a conformational isomer, a rotational isomer, a tautomer, an optical isomer, a diastereomer, etc., but only a single isomer. It also includes racemic and diastereomeric mixtures.
  • the cyclic amine derivative represented by the above general formula (I) may be labeled with one or more isotopes, and the isotopes to be labeled include, for example, 2 H, 3 H, 13 C, 14 C , 15 N, 15 O, 18 O and / or 125 I.
  • Examples of the “pharmaceutically acceptable salt” of the cyclic amine derivative represented by the above general formula (I) include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid Salt of
  • Examples of salts with inorganic bases include alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts, aluminum salts or zinc salts, and salts with organic bases
  • Examples of the salt include salts with organic amines such as triethylamine, ethanolamine, morpholine, piperidine or dicyclohexylamine, and salts with basic amino acids such as arginine or lysine.
  • salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides or phosphates
  • salts with organic acids include, for example, oxalic acid. Salt, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbic acid Salt, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or cinnamate An acid salt etc. are mentioned.
  • the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof may be an anhydride or may form a solvate such as a hydrate. .
  • a solvate a pharmacologically acceptable solvate is preferable.
  • the pharmacologically acceptable solvate may be either hydrate or non-hydrate, but hydrate is preferred.
  • the solvent constituting the solvate include alcohol solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO) or water.
  • cyclic amine derivative (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent. Starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.
  • the cyclic amine derivative (I) and the intermediates and starting materials used for its preparation can be isolated and purified by known means.
  • Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
  • each isomer can be obtained as a single compound by a known method.
  • Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.
  • a protective group may be introduced to these groups, and after the reaction, the protective group is optionally deprotected.
  • the target compound can be obtained.
  • an alkylcarbonyl group having 2 to 6 carbon atoms eg, acetyl group
  • benzoyl group an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group
  • an aralkyl group having 7 to 10 carbon atoms eg, benzyl group
  • a phthaloyl group for example, an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group) or a phthaloyl group.
  • an alkylcarbonyl group having 2 to 6 carbon atoms eg,
  • Examples of the protecting group for the carboxyl group include, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).
  • the deprotection of the protective group is carried out according to known methods (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis”; Wiley-Interscience) or a modification thereof although it varies depending on the kind of protective group. be able to.
  • the cyclic amine derivative (I) is, for example, as shown in Scheme 1, a coupling reaction (step 1) of a boronic acid derivative (II) with an aryl halide derivative (III) in the presence of a metal catalyst and a base
  • a coupling reaction step 1 of a boronic acid derivative (II) with an aryl halide derivative (III) in the presence of a metal catalyst and a base
  • the condensation reaction of biphenylamine derivative (IV) obtained in the first step with the pipecolic acid derivative (V) in the presence of a condensing agent and a base step 2
  • the second step in the presence of an acid Deprotection reaction of the obtained N-tert-butoxycarbonylpipecolic acid amide derivative (VI) (step 3), followed by pipecolic acid amide derivative (VII) obtained in the third step in the presence of a base and an organic compound
  • the cyclic amine derivative (I) can also be obtained by condensation reaction of the pipecolic acid amide derivative (VII) with the organic acid ester derivative (IX). Moreover, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VII) and organic acid chloride derivative (X) in the presence of a base. In addition, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VII) and organic acid derivative (XI) in the presence of a condensing agent and a base. Moreover, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VII) and trimethylsilyl isocyanate in the presence of a base.
  • cyclic amine derivative (I) contains, for example, an amino group
  • the amino group is converted to an amide group, a sulfonamide group, etc. or an N-alkyl compound by a condensation reaction or a reductive amination reaction, etc. May be Moreover, when it contains a sulfide group, the said sulfide group may be converted into a sulfonyl group by oxidation reaction.
  • an ester group is contained, the ester group may be converted to a carboxyl group by a hydrolysis reaction.
  • Q represents a halogen atom
  • R 1 to R 4 and X are as defined above.
  • the amount of the halogenated aryl derivative (III) used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 0.7 to 3 equivalents, to the boronic acid derivative (II).
  • Examples of the metal catalyst used for the coupling reaction include 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) dichloromethane adduct, palladium (II) chloride, bis (dibenzylideneacetone) palladium (0), Although tetrakistriphenyl phosphine palladium (0) or dichloro bis triphenyl phosphine palladium (0) is mentioned, 1,1'-bis (diphenyl phosphino) ferrocene dichloro palladium (II) dichloromethane adduct is preferred.
  • the amount of the metal catalyst used for the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, to the boronic acid derivative (II).
  • a base used for the coupling reaction for example, organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium carbonate or potassium carbonate, lithium amides such as lithium hexamethyl disilazide or lithium diisopropylamide, tert-butyloxy sodium Or a metal alkoxide such as tert-butyloxy potassium or a mixture thereof, but an inorganic base such as sodium carbonate or potassium carbonate is preferred.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium carbonate or potassium carbonate
  • lithium amides such as lithium hexamethyl disilazide or lithium diisopropylamide
  • tert-butyloxy sodium Or a metal alkoxide such as tert-butyloxy potassium or a mixture thereof
  • an inorganic base such as sodium carbonate or potassium carbonate is preferred.
  • the amount of the base used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the boronic acid derivative (II).
  • the reaction solvent used for the coupling reaction is appropriately selected according to the type of reagent used, etc., and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or Ether solvents such as dimethoxyethane, nitrile solvents such as acetonitrile or propionitrile, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, water or mixed solvents thereof However, mixed solvents of nitrile solvents such as acetonitrile or propionitrile with water are preferred.
  • the reaction temperature of the coupling reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.
  • the reaction time of the coupling reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of the reaction of the boronic acid derivative (II) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.
  • the boronic acid derivative (II) and the halogenated aryl derivative (III) used for the coupling reaction can be purchased or can be prepared by known methods.
  • Step 2 The amount of pipecolic acid derivative (V) used for the condensation reaction is preferably 0.1 to 10 equivalents, and more preferably 0.5 to 3 equivalents with respect to biphenylamine derivative (IV).
  • Examples of the condensing agent used for the condensation reaction include N, N′-dicyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, N, N′-carbodiimidazole, ⁇ [(1- Cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate (hereinafter, COMU), O- (7-azabenzotriazol-1-yl) -1, 1,3,3-Tetramethyluronium hexafluorophosphate (hereinafter HATU) or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (
  • COMU O- (7-azabenzotriazol-1-yl) -1, 1,3,3-Te
  • the amount of the condensing agent used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, with respect to the biphenylamine derivative (IV).
  • Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide
  • the amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the biphenylamine derivative (IV).
  • the biphenylamine derivative (IV) used for the condensation reaction may be a free form or a salt such as hydrochloride.
  • the reaction solvent used for the condensation reaction is appropriately selected according to the type of the reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, nitrile solvents such as acetonitrile or propionitrile, etc. may be mentioned.
  • Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.
  • the reaction temperature of the condensation reaction is preferably 0 to 200 ° C., and more preferably 20 to 100 ° C.
  • the reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 100 hours.
  • the concentration at the start of the reaction of the biphenylamine derivative (IV) used for the condensation reaction is preferably 1 mmol / L to 1 mol / L.
  • the pipecolic acid derivative (V) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Examples of the acid used for the deprotection reaction include hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, with hydrochloric acid or trifluoroacetic acid being preferred.
  • the amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-tert-butoxycarbonylpipecolic acid amide derivative (VI).
  • the reaction solvent used for the deprotection reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4- Ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, aprotic such as DMF or DMSO Although polar solvents or mixed solvents thereof may be mentioned, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferable.
  • the reaction temperature of the deprotection reaction is preferably ⁇ 78 ° C. to 200 ° C., and more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 50 hours.
  • the concentration of the N-tert-butoxycarbonylpipecolic acid amide derivative (VI) used for the deprotection reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • the amount of the organic acid anhydride derivative (VIII), the organic acid ester derivative (IX), the organic acid chloride derivative (X), the organic acid derivative (XI) or trimethylsilyl isocyanate used for the condensation reaction is the pipecolic acid amide derivative (VII) Is preferably 1 to 200 equivalents, more preferably 1 to 80 equivalents.
  • condensing agent used for the condensation reaction for example, N, N′-dicyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, N, N′-carbodiimidazole, COMU, HATU or HBTU Of these, HATU or HBTU is preferred.
  • the amount of the condensing agent used for the condensation reaction is preferably 0 to 10 equivalents, more preferably 0 to 3 equivalents, relative to the pipecolic acid amide derivative (VII).
  • Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide
  • the amount of the base used for the condensation reaction is preferably 0 to 10 equivalents, more preferably 0 to 5 equivalents based on the pipecolic acid amide derivative (VII).
  • the pipecolic acid amide derivative (VII) used for the condensation reaction may be a free form or a salt such as hydrochloride.
  • the reaction solvent used for the condensation reaction is appropriately selected according to the type of the reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, nitrile solvents such as acetonitrile or propionitrile, etc. may be mentioned.
  • Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.
  • the reaction temperature of the condensation reaction is preferably -78 ° C to 200 ° C, and more preferably -20 ° C to 100 ° C.
  • the reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 100 hours.
  • the concentration of the pipecolic acid amide derivative (VII) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • Organic acid anhydride derivative (VIII), organic acid ester derivative (IX), organic acid chloride derivative (X), organic acid derivative (XI) and trimethylsilyl isocyanate used for condensation reaction can be purchased or known It can manufacture by a method or the method according to it.
  • the “ROR ⁇ antagonist” means a compound having the function of suppressing the function of ROR ⁇ to abolish or attenuate its activity.
  • ulcerative colitis refers to a general term for diseases that cause chronic inflammation or ulceration in the mucosa of the large and small intestines, and mainly includes ulcerative colitis and Crohn's disease. Ulcerative colitis presents with bloody stools, mucous bloody stools, diarrhea or bloody diarrhea. In mild cases, bloody stools may be small and not accompanied by diarrhea, but in more severe cases, bloody diarrhea will result. Other symptoms may include abdominal pain, fever, loss of appetite, weight loss or anemia. Crohn's disease includes abdominal pain, diarrhea, weight loss, fever, or anal lesions. Intestinal obstruction, intestinal perforation or major hemorrhage may develop and may require surgery.
  • Complications include lupus erythematosus, anemia, hypoproteinemia, ankylosing spondylitis, buccal aphthitis, erythema nodosa, pyoderma gangrenosum, ulceris or growth disorder and the like.
  • Cyclic amine derivative (I) or a pharmacologically acceptable salt thereof which is an active ingredient of the therapeutic or preventive agent for inflammatory bowel disease of the present invention, inhibits the binding of ROR ⁇ to a coactivator. It is characterized by suppressing the function of ROR ⁇ . Since ROR ⁇ is involved in the development of inflammatory bowel disease and disease progression, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof suppresses inflammatory bowel disease by suppressing the function of ROR ⁇ . It can improve, cure or prevent.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof has ROR ⁇ antagonist activity which inhibits the binding of ROR ⁇ to a coactivator.
  • a method of evaluating the binding of ROR ⁇ to an agonist eg, cholesterol
  • a ligand binding domain of ROR ⁇ e.g., cholesterol
  • a coacti Methods for assessing binding to beta can be mentioned (WO 2012/064744, WO 2013/018695).
  • the transcriptional activity inhibitory action of ROR ⁇ can be evaluated using various reporter gene assays (WO 2012/158784, WO 2012/064744, WO 2013/018695).
  • cyclic amine derivative (I) or a pharmacologically acceptable salt thereof suppresses the function of ROR ⁇ can produce IL-17 or Th17 using lymphocyte cells from various organs such as spleen or peripheral blood. Cell differentiation can be evaluated as an indicator.
  • a method using IL-17 production as an index for example, a method of measuring IL-17 production by IL-23 stimulation using mouse splenocytes can be mentioned (The Journal of Biological Chemistry, 2003, 278) , No. 3, p. 1910-1914).
  • Th17 cell differentiation for example, various cytokines (eg, IL-1 ⁇ , IL-6, IL-23 and / or TGF are used, using CD4 positive naive T cells derived from mouse splenocytes or human PBMC). Stimulate with - ⁇ ) and various antibodies (eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN- ⁇ antibody and / or anti-IL-2 antibody) to differentiate to Th17 and produce IL-17 The method includes measuring the amount or the proportion of IL-17 positive cells etc. (WO 2012/158784, WO 2013/018695).
  • cytokines eg, IL-1 ⁇ , IL-6, IL-23 and / or TGF
  • CD4 positive naive T cells derived from mouse splenocytes or human PBMC.
  • various antibodies eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN- ⁇ antibody and / or anti-IL-2 antibody
  • a pathological model for example, TNBS-induced colitis model (Europian Journal of Pharmacology, 2001, 431, p. 103-110), dextran sulfate sodium-induced colitis model (Laboratory Investigation, 1993, 69, p. .238-249), CD4-positive lymphocyte transfer colitis model (Gastroenterology, 2009, 136, p257-267), oxazolone-induced colitis model (Journal of Experimental Medicine, 1998, 188, p. 1929). -1939) or interleukin-10 deficient mice (Nature Genetics, 2008, 40, 1118-). 125) can be mentioned.
  • the efficacy of the cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof for treating or preventing inflammatory bowel disease can be determined, for example, by using the above-mentioned in vitro test, for example, the ligand binding domain of ROR ⁇ and the coactivator. It is possible to evaluate the decrease in the amount of binding to E. coli or the decrease in the amount of IL-17 produced, which is an indicator of the function of ROR ⁇ , as an indicator. In addition, the efficacy for the treatment or prevention of inflammatory bowel disease should be evaluated, for example, using the TNBS-induced colitis model described above as a marker for the reduction of the gross injury score which is a characteristic indicator of inflammatory bowel disease. Can.
  • the cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof is administered to mammals (eg, mice, rats, hamsters, rabbits, dogs, cats, monkeys, cattle, sheep or humans), particularly humans. When used, it can be used as a therapeutic or preventive agent for useful inflammatory bowel disease.
  • the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is Salts, or pharmacologically acceptable carriers such as excipients, stabilizers, preservatives, buffers, solubilizers, solubilizers, emulsifiers, additives such as emulsifiers or diluents, etc. It can be mixed and administered orally or parenterally.
  • the above-mentioned therapeutic agent or preventive agent for inflammatory bowel disease can be produced by a usual method using a carrier for these drugs as appropriate.
  • the administration form of the above-mentioned therapeutic agent or preventive agent for inflammatory bowel disease may be, for example, tablets, capsules, granules, oral preparations such as powders or syrups, inhalants, noninjectives, injections, suppositories or liquids, etc.
  • An ointment, a cream or a patch for oral administration or topical administration may be mentioned. Also, it may be a known sustained release preparation.
  • the therapeutic or preventive agent for the above-mentioned inflammatory bowel disease preferably contains 0.00001 to 90% by weight of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, preferably 0.01 to 70%. It is more preferable to contain%.
  • the dose is appropriately selected according to the patient's condition, age and body weight, and administration method, but as an active ingredient amount for adults, 0.1 ⁇ g to 1 g per day for injections and 1 for oral preparations 1 ⁇ g to 10 g per day, 1 ⁇ g to 10 g per day for patches, 1 ⁇ g to 10 g per day for ointments, 1 ⁇ g to 10 g per day for creams, each once or several times It can be divided and administered.
  • Examples of pharmacologically acceptable carriers or diluents for the above-mentioned therapeutic or preventive agent for inflammatory bowel disease include binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth, etc.), excipients, etc.
  • binders saclatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth, etc.
  • excipients etc.
  • the agents sacgar, lactose, corn starch, calcium phosphate, sorbitol or glycine etc.
  • lubricants magnesium stearate, polyethylene glycol, talc or silica etc.
  • the above-mentioned therapeutic agent or preventive agent for inflammatory bowel disease may be used in combination with or in combination with other agents in an appropriate amount in order to supplement or enhance its therapeutic or preventive effect or to reduce its dose.
  • the compounds used for the synthesis of the compounds of Reference Examples and Examples were commercially available compounds that were not described in the synthesis method.
  • the “room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for yield, volume% for solvents used in column chromatography and high performance liquid chromatography, and weight% unless otherwise specified.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 nuclear magnetic resonance apparatus (Nippon Electron Ltd.) or a JNM-ECS400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.).
  • Silica gel used silica gel 60 (Merck), amine silica gel used amine silica gel DM 1020 (Fuji Silysia Chemical Ltd.), and chromatography used YFLC W-prep 2 XY (Yamazen Co., Ltd.).
  • Example 1 Synthesis of 1-Acetyl-N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) piperidine-2-carboxamide: Triethylamine (0.0367 mL, 0.263 mmol) and acetic anhydride (0.0182 mL, 0.193 mmol) in dichloromethane (3.0 mL) solution of the compound of Reference Example 3 (0.0700 g, 0.176 mmol) at 0 ° C. In addition, the mixture was heated to room temperature and stirred for 1 hour. Distilled water was added to the reaction solution, and extracted with chloroform.
  • Example 2 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2,2,2-trifluoroacetyl) piperidine Synthesis of 2-carboxamide: N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] in the same manner as in Example 1 except for using trifluoroacetic anhydride instead of acetic anhydride 4-yl) -1- (2,2,2-trifluoroacetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 2) (0.0500 g, 0.101 mmol, 99.0%) as a white solid Got as.
  • Example 4 Synthesis of N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2-methoxyacetyl) piperidine-2-carboxamide : A solution of the compound of Reference Example 3 (0.0300 g, 0.0752 mmol) in DMF (0.5 mL) in a solution of 2-methoxyacetic acid (0.00693 ml, 0.0903 mmol) in DMF (0.5 mL), HATU (0. 0343 g (0.0902 mmol) and diisopropylethylamine (0.0197 mL, 0.113 mmol) were added at room temperature and stirred at the same temperature for 3 hours.
  • Example 5 Synthesis of N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2-hydroxyacetyl) piperidine-2-carboxamide : N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl]-was carried out according to the same procedure as in Example 4 except that glycolic acid was used instead of 2-methoxyacetic acid. 4-yl) -1- (2-hydroxyacetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 5) (0.0114 g, 0.0250 mmol, 33.2%) was obtained as a white solid.
  • Example 6 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (dimethylamino) acetyl) piperidine-2- Carboxamide Synthesis: The procedure is as in Example 4 except that N, N-dimethylglycine hydrochloride is used instead of 2-methoxyacetic acid, and N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1 is obtained by the same procedure as in Example 4.
  • Example 7 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2,2-difluoroacetyl) piperidine-2-carboxamide Composition of: N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl]-was carried out according to the same procedure as in Example 4 except for using difluoroacetic acid instead of 2-methoxyacetic acid.
  • Example 8 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (trifluoromethoxy) acetyl) piperidine-2 -Synthesis of carboxamide: The procedure is as in Example 4 except that 2-trifluoromethoxyacetic acid is used instead of 2-methoxyacetic acid, and N- (2-chloro-2 '-(trifluoromethoxy)-[1,1' -Biphenyl] -4-yl) -1- (2- (trifluoromethoxy) acetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 8) (0.00890 g, 0.0170 mmol, 16.9%) Obtained as a white solid.
  • Reference Example 5 Synthesis of 1- (2-aminoacetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) piperidine-2-carboxamide : To a solution of the compound of Reference Example 4 (0.115 g, 0.207 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.112 mL, 1.45 mmol) at room temperature, and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, aqueous potassium carbonate solution was added to neutralize, and then extracted with chloroform.
  • Example 9 Synthesis of 1- (2-acetamidoacetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) piperidine-2-carboxamide : According to the same procedure as in Example 3 except for using the compound of Reference Example 5 in place of the compound of Reference Example 3 and acetyl chloride instead of propionyl chloride, 1- (2-acetamidoacetyl) -N- ( 2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 9) (0.0274 g, 0.0550 mmol, 80) .9%) was obtained as a white solid.
  • Example 10 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (methylsulfonamido) acetyl) piperidine-2 -Synthesis of carboxamide: N- (2-chloro-2 ′-(N- (2-chloro-2 ′-()) by the same procedure as in Example 3 except for using the compound of Reference Example 5 in place of the compound of Reference Example 3 and methanesulfonyl chloride in place of Trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (methylsulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 10) (0.0202 g, 0.0378 mmol, 79.2%) were obtained as a white solid.
  • Example 12 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-methylacetamido) acetyl) piperidine
  • 2-carboxamide N- (2-chloro-2 '-(tri) by the same procedure as in Example 3 except for using the compound of Example 11 in place of the compound of Reference Example 3 and acetyl chloride in place of propionyl chloride Fluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-methylacetamido) acetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 12) (0.0261 g, 0.0510 mmol, 95.8%) were obtained as a white solid.
  • Example 13 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfonamido) acetyl) Synthesis of piperidine-2-carboxamide: N- (2-chloro-2 ′-(N- (2-chloro-2 ′-()) by a procedure similar to that of Example 3 except that the compound of Example 11 is used instead of the compound of Reference Example 3 and methanesulfonyl chloride is used instead of propionyl chloride.
  • Example 14 Synthesis of N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (ethylsulfonyl) piperidine-2-carboxamide: N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4 by the same procedure as in Example 3 except for using ethanesulfonyl chloride instead of propionyl chloride -Yl) -1- (ethylsulfonyl) piperidine-2-carboxamide (hereinafter compound of Example 14) (0.0660 g, 0.134 mmol, 99.3%) was obtained as a white solid.
  • Example 15 Synthesis of N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (methylsulfonyl) piperidine-2-carboxamide: N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4 by the same procedure as in Example 3 except that methanesulfonyl chloride is used instead of propionyl chloride. -Yl) -1- (methylsulfonyl) piperidine-2-carboxamide (hereinafter, the compound of Example 15) (0.0800 g, 0.168 mmol, 66.9%) was obtained as a white solid.
  • Example 16 Synthesis of N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1-formylpiperidine-2-carboxamide: Ethyl formate (0.567 mL, 7.02 mmol) is added to a solution of the compound of Reference Example 3 (0.0400 g, 0.100 mmol) in dichloromethane (1.0 mL) at 0 ° C., and the temperature is raised to 90 ° C. for 18 hours It stirred.
  • N 2 - (2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-1,2-dicarboxamide Trimethylsilyl isocyanate (0.0333 mL, 0.251 mmol) and triethylamine (0.0349 mL, 0.251 mmol) were added to a solution of the compound of Reference Example 3 (0. 100 g, 0.251 mmol) in dichloromethane (3.0 mL) at 0 ° C. The mixture was stirred for 72 hours after the temperature was raised to room temperature. Methanol was added to the reaction solution and concentrated under reduced pressure.
  • Example 19 Synthesis of methyl 2-((2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) carbamoyl) piperidine-1-carboxylate: 2-((2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] by the same procedure as in Example 3 except for using methyl chloroformate instead of propionyl chloride Methyl 4-yl) carbamoyl) piperidine-1-carboxylate (hereinafter, the compound of Example 19) (0.0316 g, 0.0692 mmol, 92.0%) was obtained as a white solid.
  • Reference Example 7 (R) -2-((2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of: The compound of Reference Example 1 (1.05 g, 3) was added to a solution of (R)-(+)-1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.840 g, 3.66 mmol) in DMF (18 mL).
  • the retention time of the obtained compound of Example 20 was 32.8 minutes, and the optical purity at that time was 99.0% ee.
  • the analysis conditions using a chiral column are as follows. Measuring equipment; Shimadzu Corporation High-performance liquid chromatograph LC-2010CHT Column; Daicel Chemical Industries, Ltd.
  • Example 21 (R) -N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (methylsulfonyl) piperidine-2-carboxamide Composition of: (R) -N- (2-chloro-) by the same procedure as in Example 3 except for using the compound of Reference Example 8 in place of the compound of Reference Example 3 and methanesulfonyl chloride instead of propionyl chloride.
  • the retention time of the obtained compound of Example 23 was 33.6 minutes, and the optical purity at that time was 95.0% ee.
  • the analysis conditions using a chiral column are as follows. Measuring equipment; Shimadzu Corporation High-performance liquid chromatograph LC-2010CHT Column; Daicel Chemical Industries, Ltd.
  • reaction solution is filtered and the solid collected by filtration is washed with ethyl acetate and then dried, and (2R, 4S) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl]- 4-yl) -4-hydroxypiperidine-2-carboxamide hydrochloride (hereinafter, the compound of Reference Example 12) (0.0409 g, 0.0908 mmol, 93.3%) was obtained as a white solid.
  • Example 24 (2R, 4S) -1-Acetyl-N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -4-hydroxypiperidine- Synthesis of 2-carboxamide: (2R, 4S) -1-Acetyl-N--A by the procedure of Example 3 except for using the compound of Reference Example 12 in place of the compound of Reference Example 3 and acetyl chloride instead of propionyl chloride (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -4-hydroxypiperidine-2-carboxamide (hereinafter, the compound of Example 24) (0.0166 g, 0.0363 mmol, 91.1%) were obtained as a white solid.
  • Example 25 (2R, 4R) -1-Acetyl-N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -4-fluoropiperidine- Synthesis of 2-carboxamide: (2R, 4R) -1-Acetyl-N--A by the same procedure as in Example 3 except for using the compound of Reference Example 14 in place of the compound of Reference Example 3 and acetyl chloride instead of propionyl chloride (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -4-fluoropiperidine-2-carboxamide (compound of Example 25 below) (0.0108 g, 0.0235 mmol, 62.8%) were obtained as a white solid.
  • reaction solution is concentrated under reduced pressure, and the residue is dissolved in dichloromethane (0.8 mL), and then triethylamine (0.00135 mL, 0.0970 mmol) and acetyl chloride (0.00359 mL, 0.0504 mmol) are added at 0 ° C., and the same temperature is added. The mixture was stirred for 1 hour. Methanol was added to the reaction solution and concentrated under reduced pressure.
  • Example 28 (R) -N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -4,4-difluoro-1- (methylsulfonyl) ) Synthesis of piperidine-2-carboxamide: (R) -N- (2-chloro-) according to the procedure of Example 27 except using the compound of Reference Example 18 in place of the compound of Reference Example 16, and using methanesulfonyl chloride instead of acetyl chloride.
  • Example 29 (R) -N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfone) Synthesis of Amid) acetyl) piperidine-2-carboxamide: A solution of the compound of Reference Example 8 (0.184 g, 0.462 mmol) in DMF (1.0 mL) in a solution of the compound of Reference Example 20 (0.0850 g, 0.508 mmol) in DMF (2.0 mL), HATU (0 193 g (0.508 mmol) and diisopropylethylamine (0.121 mL, 0.693 mmol) were added at room temperature and stirred at the same temperature for 18 hours.
  • the retention time of the obtained compound of Example 29 was 34.5 minutes, and the optical purity at that time was 98.2% ee.
  • the analysis conditions using a chiral column are as follows. Measuring equipment; Shimadzu Corporation High-performance liquid chromatograph LC-2010CHT Column; Daicel Chemical Industries, Ltd.
  • Example 30 1- (3-Aminopropanoyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide Synthesis: Using the compound of Reference Example 21 instead of the compound of Reference Example 4 and using the same procedure as Reference Example 5 except the above, 1- (3-aminopropanoyl) -N- (2-chloro-2 '-( Trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 30) (0.155 g, 0.329 mmol, 65.6%) as a white solid Obtained.
  • Example 31 1- (3-acetamidopropanoyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) piperidine-2-carboxamide Synthesis: The procedure of Example 3 is repeated except that the compound of Example 30 is used instead of the compound of Reference Example 3 and acetyl chloride is used instead of propionyl chloride, and 1- (3-acetamidopropanoyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 31) (0.0218 g, 0.0420 mmol, 99.1%) was obtained as a white solid.
  • Example 32 N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (3- (methylsulfonamido) propanoyl) piperidine-2 -Synthesis of carboxamide: N- (2-chloro-2 ′-(N- (2-chloro-2 ′-()) by a procedure similar to that of Example 3 except that the compound of Example 30 is used instead of the compound of Reference Example 3, and methanesulfonyl chloride is used instead of propionyl chloride.
  • Trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (3- (methylsulfonamido) propanoyl) piperidine-2-carboxamide (hereinafter, the compound of Example 32) (0.0224 g, 0.0409 mmol, 96.1%) was obtained as a white solid.
  • Example 33 N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (3- (dimethylamino) propanoyl) piperidine-2- Carboxamide Synthesis: N- (2-Chloro-2 '-(trifluoromethoxy)-[N-], following the procedure as in Example 4 but using 3- (dimethylamino) propanoic acid hydrochloride instead of 2-methoxyacetic acid 1,1′-biphenyl] -4-yl) -1- (3- (dimethylamino) propanoyl) piperidine-2-carboxamide (hereinafter, the compound of Example 33) (0.0274 g, 0.0550 mmol, 73.2) %) As a white solid.
  • Example 35 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (N-methylacetamido) propanoyl) piperidine Synthesis of 2-carboxamide: N- (2-chloro-2 '-(tri) by the same procedure as in Example 3 except for using the compound of Example 34 in place of the compound of Reference Example 3 and acetyl chloride instead of propionyl chloride Fluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (N-methylacetamido) propanoyl) piperidine-2-carboxamide (hereinafter compound of Example 35) (0.0316 g, 0.0601 mmol, 74.5%) were obtained as a white solid.
  • Example 36 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (N-methylmethylsulfonamido) propanoyl) Synthesis of piperidine-2-carboxamide: N- (2-chloro-2 ′-(N- (2-chloro-2 ′-()) by a procedure similar to that of Example 3 except that the compound of Example 34 is used instead of the compound of Reference Example 3, and methanesulfonyl chloride is used instead of propionyl chloride.
  • Example 37 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-ethylmethylsulfonamido) acetyl) Synthesis of piperidine-2-carboxamide: N- (2-chloro-2 ′-(N- (2-chloro-2 ′-()) by a procedure similar to Trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-ethylmethylsulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 37) (0 0.015 g (0.0311 mmol, 78.1%) was obtained as a white solid.
  • Example 39 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (methylthio) propanoyl) piperidine-2-carboxamide Composition of: The procedure is as in Example 4 except that 3- (methylthio) propanoic acid is used instead of 2-methoxyacetic acid, and N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1 is obtained by the same procedure as Example 4.
  • Example 40 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (methylsulfonyl) propanoyl) piperidine-2- Carboxamide Synthesis: To a solution of the compound of Example 39 (0.0480 g, 0.0958 mmol) in dichloromethane (1.0 mL) was added 3-chloroperbenzoic acid (0.0496 g, 0.287 mmol) at 0 ° C., and the temperature was raised to room temperature Stir for 17 hours. To the reaction mixture were added saturated aqueous sodium thiosulfate solution and saturated sodium bicarbonate, and the mixture was extracted with chloroform.
  • Example 41 (R) -N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3- (methylamino) propanoyl) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 25 instead of the compound of Reference Example 4, and otherwise the procedure of Reference Example 5 is repeated, (R) -N- (2-chloro-2 '-(trifluoromethoxy)-[ 1,1′-biphenyl] -4-yl) -1- (3- (methylamino) propanoyl) piperidine-2-carboxamide (hereinafter, the compound of Example 41) (0.748 g, 0.155 mmol, 77.1) %) As a white solid.
  • Example 42 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3-hydroxypropanoyl) piperidine-2-carboxamide Synthesis: N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-) by the same procedure as in Example 4 except for using 3-hydroxypropanoic acid instead of 2-methoxyacetic acid Biphenyl] -4-yl) -1- (3-hydroxypropanoyl) piperidine-2-carboxamide (hereinafter, the compound of Example 42) (0.212 g, 0.450 mmol, 59.9%) was obtained as a white solid.
  • Example 43 3- (2-((2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -3-oxo Synthesis of methyl propanoate: 3- (2-((2-chloro-2 '-(trifluoromethoxy)) by the same procedure as in Example 3 except for using methyl 3-chloro-3-oxopropanoate instead of propionyl chloride -[1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) methyl 3-oxopropanoate (hereinafter, the compound of Example 43) (0.0500 g, 0.100 mmol, 80.0) %) As a white solid.
  • Example 44 4- (2-((2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -4-oxobutane Synthesis of methyl acid: 4- (2-((2-chloro-2 '-(trifluoromethoxy)-) by the same procedure as in Example 3 except for using methyl 4-chloro-4-oxobutanoate instead of propionyl chloride [1,1′-Biphenyl] -4-yl) carbamoyl) piperidin-1-yl) methyl 4-oxobutanoate (hereinafter, the compound of Example 44) (0.0390 g, 0.0760 mmol, quantitative) as white Obtained as a solid.
  • Example 45 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3-methoxypropanoyl) piperidine-2-carboxamide Synthesis: Using the same procedure as Reference Example 2 except for using 1- (3-methoxypropanoyl) piperidine-2-carboxylic acid instead of 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid, N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (3-methoxypropanoyl) piperidine-2-carboxamide (a compound of Example 45 below) ) (0.0467 g, 0.0963 mmol, 50.6%) was obtained as a white solid.
  • Example 47 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (1-methyl-1H-imidazole-4-carbonyl) Synthesis of piperidine-2-carboxamide: N- (2-chloro-2 ′-(trifluoromethoxy) is carried out according to the same procedure as in Example 4 except for using 1-methyl-1H-imidazole-4-carboxylic acid instead of 2-methoxyacetic acid -[1,1'-biphenyl] -4-yl) -1- (1-methyl-1H-imidazole-4-carbonyl) piperidine-2-carboxamide (hereinafter, the compound of Example 47) (0.0369 g, 0 .0728 mmol, 96.9%) were obtained as a white solid.
  • Example 48 N- (2-Chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (1H-pyrazole-4-carbonyl) piperidine-2- Carboxamide Synthesis: The procedure is as in Example 4, but using 1H-pyrazole-4-carboxylic acid instead of 2-methoxyacetic acid, to obtain N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1 1′-biphenyl] -4-yl) -1- (1H-pyrazole-4-carbonyl) piperidine-2-carboxamide (hereinafter compound of Example 48) (0.0163 g, 0.0331 mmol, 44.0%) Was obtained as a white solid.
  • Reference Example 26 Synthesis of methyl 1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxylate: A compound of Reference Example 20 is used instead of 2-methoxyacetic acid, methyl piperidine-2-carboxylate hydrochloride is used instead of the compound of Reference Example 3, and the procedure is the same as that of Example 4 except that 1- ( Methyl 2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxylate (hereinafter, the compound of Reference Example 26) (0.934 g, 3.19 mmol, 82.0) was obtained as a white solid.
  • Reference Example 27 Synthesis of 1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxylic acid: To a solution of the compound of Reference Example 26 (0.933 g, 3.19 mmol) in methanol (10.0 mL) was added 1 M aqueous sodium hydroxide solution (3.83 mL, 3.83 mmol) at 0 ° C., and the temperature was raised to room temperature 17 Stir for hours. The reaction solution was added with 1 M hydrochloric acid and extracted with chloroform.
  • Reference Example 28 Synthesis of N- (4-bromo-3-chlorophenyl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxamide: The compound of Reference Example 27 is used in place of 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid, 4-bromo-3-chloroaniline is used in place of the compound of Reference Example 1, and Reference Example 2 is otherwise obtained. N- (4-Bromo-3-chlorophenyl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxamide (hereinafter referred to as the compound of Reference Example 28) (0.
  • Example 49 N- (2-Chloro-2′-isopropoxy- [1,1′-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2 -Synthesis of carboxamide: Procedure similar to Reference Example 1 except for using 2-isopropoxyphenylboronic acid instead of 2-trifluoromethoxyphenylboronic acid and the compound of Reference Example 28 instead of 4-bromo-3-chloroaniline N- (2-chloro-2′-isopropoxy- [1,1′-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxamide Thereafter, the compound of Example 49 (0.0253 g, 0.0485 mmol, 75.3%) was obtained as a white solid.
  • Example 50 N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (2- (1-methyl-1H-imidazole-2) Synthesis of (yl) acetyl) piperidine-2-carboxamide: The procedure was as in Example 4 except that 2- (1-methyl-1H-imidazol-2-yl) acetic acid was used instead of 2-methoxyacetic acid, and the procedure was as in Example 4 to obtain N- (2-chloro-2 ′-( Trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (1-methyl-1H-imidazol-2-yl) acetyl) piperidine-2-carboxamide (Example 50 below) (0.0341 g, 0.0654 mmol, 87.0%) were obtained as a white solid.
  • Reference Example 29 Synthesis of N- (4-bromo-3-fluorophenyl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxamide: The compound of Reference Example 27 is used in place of 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid, 4-bromo-3-fluoroaniline is used in place of the compound of Reference Example 1, and Reference Example 2 is otherwise obtained.
  • Example 51 N- (2-Fluoro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfonamido) acetyl) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 29 instead of 4-bromo-3-chloroaniline and following the same procedure as Reference Example 1 except for N- (2-fluoro-2 '-(trifluoromethoxy)-[1 , 1′-biphenyl] -4-yl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, the compound of Example 51) (0.0132 g, 0.0248 mmol, 44.7%) was obtained as a white solid.
  • Example 52 1- (2- (1H-imidazol-1-yl) acetyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl ) Synthesis of piperidine-2-carboxamide: A procedure similar to that of Example 4 except that 1-imidazoleacetic acid is used instead of 2-methoxyacetic acid, to give 1- (2- (1H-imidazol-1-yl) acetyl) -N- (2-chloro) -2 '-(Trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 52) (0.0189 g, 0.0373 mmol, 49.6% ) As a white solid.
  • Example 53 (2- (1H-tetrazol-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl ) Synthesis of piperidine-2-carboxamide: The procedure is as in Example 4, except that 1H-tetrazole-1-acetic acid is used instead of 2-methoxyacetic acid, to obtain 1- (2- (1H-tetrazol-1-yl) acetyl) -N- ( 2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 53) (0.0244 g, 0.0479 mmol, 38 .2%) was obtained as a white solid.
  • Example 54 1- (2- (furan-2-yl) acetyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine Synthesis of -2-carboxamide: A procedure similar to that of Example 4 except that 2-furanacetic acid is used instead of 2-methoxyacetic acid, to give 1- (2- (furan-2-yl) acetyl) -N- (2-chloro-2 '-(Trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 54) (0.0605 g, 0.119 mmol, 95.2%) Obtained as a white amorphous.
  • Example 55 (2- (3,5-Dimethyl-1H-pyrazol-1-yl) acetyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'- Synthesis of biphenyl] -4-yl) piperidine-2-carboxamide: The procedure is as in Example 4 except that 3,5-dimethyl-1H-pyrazole-1-acetic acid is used instead of 2-methoxyacetic acid, and 1- (2- (3,5-dimethyl-1H-) Pyrazol-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter referred to as Example 55) Compound (0.0579 g, 0.108 mmol, 86.3%) was obtained as a white amorphous.
  • Example 56 (2- (3-Methylisoxazol-5-yl) acetyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4 Synthesis of (yl) piperidine-2-carboxamide: 1- (2- (3-Methylisoxazol-5-yl) acetyl) in the same manner as in Example 4 except for using 3-methyl-5-isoxazole acetic acid instead of 2-methoxyacetic acid -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 56) (0.0652 g, 0 .125 mmol, 99.6%) were obtained as a white amorphous.
  • the retention time of the obtained compound of Example 57 was 55.3 minutes, and the optical purity at that time was 99.4% ee.
  • Example 58 (R) -1- (3- (1H-tetrazol-1-yl) propanoyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] Synthesis of 4-yl) piperidine-2-carboxamide: Using 3- (tetrazol-1-yl) propionic acid instead of 2-methoxyacetic acid, using the compound of Reference Example 8 instead of the compound of Reference Example 3, and using the same procedure as Example 4 except that ( R) -1- (3- (1H-tetrazol-1-yl) propanoyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine -2-carboxamide (hereinafter, the compound of Example 58) (0.117 g, 0.224 mmol, 89.1%) was obtained as a white amorphous.
  • Example 59 (R) -1- (3- (1H-Imidazol-1-yl) propanoyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] Synthesis of 4-yl) piperidine-2-carboxamide: Using 3- (imidazol-1-yl) propionic acid instead of 2-methoxyacetic acid, using the compound of Reference Example 8 instead of the compound of Reference Example 3, and using the same procedure as Example 4 except that R) -1- (3- (1H-imidazol-1-yl) propanoyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) piperidine -2-carboxamide (hereinafter, the compound of Example 59) (0.0799 g, 0.153 mmol, 60.9%) was obtained as a white amorphous.
  • Example 60 (R) -1- (3- (3-Methyl-1H-pyrazol-1-yl) propanoyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1 Synthesis of '-biphenyl] -4-yl) piperidine-2-carboxamide: Using 3- (3-methyl-pyrazol-1-yl) propionic acid instead of 2-methoxyacetic acid, using the compound of Reference Example 8 instead of the compound of Reference Example 3 and using the same method as Example 4 except the above.
  • Example 61 (R) -1- (2- (1H-Pyrazole-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1,1′-biphenyl] Synthesis of 4-yl) piperidine-2-carboxamide: Using 2- (1H-pyrazol-1-yl) acetic acid instead of 2-methoxyacetic acid, using the compound of Reference Example 8 instead of the compound of Reference Example 3, and following the same procedure as Example 4 (R) -1- (2- (1H-pyrazol-1-yl) acetyl) -N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) Piperidine-2-carboxamide (hereinafter, the compound of Example 61) (0.0623 g, 0.123 mmol, 98.0%) was obtained as a white solid.
  • Example 63 (R) -1- (2- (1H-1,2,4-triazol-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1 Synthesis of 1,1′-biphenyl] -4-yl) piperidine-2-carboxamide: Sodium 2- (1H-1,2,4-triazol-1-yl) acetate instead of 2-methoxyacetic acid, the compound of Reference Example 8 instead of the compound of Reference Example 3, and the other examples A procedure similar to 4 gives (R) -1- (2- (1H-1,2,4-triazol-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)- [1,1′-Biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of Example 63) (0.0587 g, 0.116 mmol, 92.2%) was obtained as a white solid.
  • Example 64 (R) -1- (2- (1H-1,2,3-Triazol-1-yl) acetyl) -N- (2-chloro-2 ′-(trifluoromethoxy)-[1 Synthesis of 1,1′-biphenyl] -4-yl) piperidine-2-carboxamide: Instead of 2-methoxyacetic acid, 2- (1H-1,2,3-triazol-1-yl) acetic acid is used, and instead of the compound of Reference Example 3, the compound of Reference Example 8 is used, and Example 4 is otherwise obtained.
  • Reference Example 31 Synthesis of sodium 2- (5-methyl-1,3,4-oxadiazol-2-yl) acetate: To a solution of the compound of Reference Example 30 (0.0900 g, 0.529 mmol) in tetrahydrofuran (1.0 mL), 1 M aqueous sodium hydroxide solution (1.06 mL, 1.06 mmol) and ethanol (1.0 mL) are added at room temperature, The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude sodium 2- (5-methyl-1,3,4-oxadiazol-2-yl) acetate (hereinafter, the compound of Reference Example 31) (0.0835 g) as a white solid.
  • Example 68 (R) -N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (3- (dimethylamino) propanoyl) Synthesis of piperidine-2-carboxamide: Using the same procedure as in Example 4 except for using 3- (dimethylamino) propanoic acid hydrochloride instead of 2-methoxyacetic acid and the compound of Reference Example 8 instead of the compound of Reference Example 3 (R ) -N- (2-Chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl] -4-yl) -1- (3- (dimethylamino) propanoyl) piperidine-2-carboxamide (infra) Compound of Example 68 (0.0826 g, 0.166 mmol, 66.2%) was obtained as a white amorphous.
  • ROR ⁇ -coactivator binding inhibitory action Time-resolved fluorescence energy transfer (TR-) of the inhibitory effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on the binding of the ligand binding domain of ROR ⁇ (hereinafter referred to as ROR ⁇ -LBD) to the coactivator was evaluated using the LanthaScreen using FRET) TM TR-FRET Retinoid- Related Orphan Receptor (ROR) gamma Coactivator Assay kit (invitrogen, Inc.).
  • TR- Time-resolved fluorescence energy transfer
  • test compound was dissolved in DMSO and then diluted with a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitogen) to a final DMSO concentration of 1%.
  • a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D invitogen
  • To each well of a 384 well black plate (Corning), 4 nmol / L GST-fused ROR ⁇ -LBD (invitogen) diluted with the above buffer and a test compound were added.
  • a test compound-free and GST-fused ROR ⁇ -LBD-free (background), and a test compound-free and GST-fused ROR ⁇ -LBD-added (control) wells were provided.
  • ROR ⁇ -coactivator binding inhibition rate (1 ⁇ ((Fold change upon addition of test compound) ⁇ (Fold change)) / ((Fold change) ⁇ (Fold change) )) ⁇ 100 ⁇
  • the ROR ⁇ -coactivator binding inhibition rate (%) at 33 ⁇ mol / L of the test compound is shown in Table 2-1 and Table 2-2.
  • Example 72 Inhibitory effect on IL-17 production in mouse splenocytes: The suppression effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on IL-23 production by IL-23 stimulation using mouse splenocytes is shown in The Journal of Biological Chemistry, 2003, vol. 278. , No. 3, p. The method described in 1910-1914 was partially modified and evaluated.
  • a single cell suspension was prepared from the spleen of a C57BL / 6J mouse (male, 7-23 weeks old) (Charles River Japan, Inc.), and splenocytes were prepared using Histopaque-1083 (Sigma).
  • the culture medium is RPMI 1640 medium (Gibco), 10% FBS (Gibco), 50 U / mL penicillin, 50 ⁇ g / mL streptomycin (Gibco), 50 ⁇ mol / L 2-mercaptoethanol (Gibco) and 100 U / mL human IL- 2 (Cell Science Research Institute, Inc.) was added and used.
  • the test compound was dissolved in DMSO and then diluted to a final concentration of 0.1% in culture medium.
  • Splenocytes (3 ⁇ 10 5 cells / well) prepared in culture medium are seeded in wells of a 96 well flat bottom plate (Corning Co.), and a test compound and 10 ng / mL of human IL-23 (R & D systems) are added.
  • the cells were cultured at 37 ° C. and 5% CO 2 for 3 days.
  • a human IL-23 non-added and a test compound non-added, and a human IL-23 added and test compound non-added well were provided. After completion of the culture, the culture supernatant was collected, and the amount of IL-17 produced in the supernatant was quantified by ELISA (R & D systems).
  • IL-17 production suppression rate (%) (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) )) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) ⁇ 100 ⁇
  • IL-17 production suppression rate (%) (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) ))) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) ⁇ 100 ⁇
  • Formula 2 (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) ))) / ((The
  • the inhibition ratio (%) of IL-17 production at 5 ⁇ mol / L of the test compound is shown in Table 3-1 and Table 3-2.
  • Example 73 Inhibitory effect of inflammatory bowel disease by TNBS-induced rat colitis model: Cyclic amine derivative (I) or its pharmacologically acceptable substance in inflammatory bowel disease, using as a marker of colitis the large intestine injury induced by administering Trinitrobenzene slonic acid (TNBS) solution intrarectally to Wistar rats The effect of salt was evaluated.
  • the inflammatory bowel disease model of rat by TNBS was prepared by partially modifying the method of Bobin-Dubigeon et al. (Europian Journal of Pharmacology, Volume 431, p. 103-110).
  • the test compound (the compound of Example 29 and the compound of Example 57) was suspended at 6 mg / mL in 0.5 w / v% methylcellulose (Kanto Chemical Co., Ltd .; 0.5% MC) using a rattan mortar. It was prepared at use as a solution.
  • the test compound was orally administered at a dose of 30 mg / kg (5 mL / kg) in the evening on Day-1 and 1 hour before the rectal administration of TNBS on Day 0.
  • the group to which the compound of Example 29 was administered was taken as the compound administration group of Example 29 and the group to which the compound of Example 57 was administered was taken as the compound administration group of Example 57.
  • the solvent administration group was orally administered 0.5% MC solution (solvent of each test compound) at a volume of 5 mL / kg.
  • TNBS was prepared on Day 0 using a feeding tube under anesthesia with pentobarbital sodium solution (Nembutal Injection, Dainippon Pharmaceutical Co., Ltd.), using a TNBS solution (Wako Pure Chemical Industries, Ltd .; 30 v / v% ethanol solution) ) was administered rectally at a dose of 20 mg / head. After administration of the TNBS solution, the animals were allowed to stand for 1 hour, and then returned to the breeding cages to resume feeding.
  • test compound was orally administered at a dose of 30 mg / kg twice a day from Day 1 to Day 4.
  • vehicle administration group was orally administered 0.5% MC solution at a volume of 5 mL / kg twice a day.
  • the abdomen was opened under isoflurane anesthesia on Day 5 and the abdominal aorta was cut off and exsanguinated, then the large intestine was lifted from the anal side, the adhesion state between the large intestine and the surrounding tissue was observed, and the adhesion state is described in Table 4 Scored according to criteria.
  • the large intestine was removed, and the large intestine was cut at a length of 10 cm from the anal side. After longitudinal dissection of the excised colon, stool status was observed and scored according to the criteria described in Table 5.
  • FIG. 1 and FIG. 2 The results are shown in FIG. 1 and FIG.
  • the “compound of Example 29” in FIG. 1 indicates the compound administration group of Example 29, and the “compound of Example 57” in FIG. 2 indicates the compound administration group of Example 57.
  • * Indicates statistical significance when compared with the vehicle administration group (Wilcoxon test) if the risk factor is less than 5%.
  • Rectal administration of TNBS showed a gross injury score of 6.0 ⁇ 0.66 in the vehicle administration group.
  • This macroscopic injury score was statistically significantly suppressed by the administration of the compound of Example 29 or the compound of Example 57 (the macroscopic injury score of the compound administration group of Example 29: 4.0 ⁇ 0 Macroscopic injury score of the compound administration group of Example 50, 50. 50, 3.6 ⁇ 0.63).
  • the cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof has excellent ROR ⁇ antagonist activity, it can be used as a therapeutic agent or prophylactic agent for inflammatory bowel disease by suppressing the function of ROR ⁇ it can.

Abstract

Le but de la présente invention est de fournir un agent thérapeutique ou un agent prophylactique destiné à une maladie inflammatoire de l'intestin, qui présent une activité antagoniste contre le récepteur γ orphelin associé aux rétinoïdes (RORγ). Afin d'atteindre cet objectif, la présente invention concerne un agent thérapeutique ou un agent prophylactique contre une maladie inflammatoire de l'intestin qui contient, en tant que principe actif, un dérivé d'amine cyclique représenté par le composé indiqué ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2018/028276 2017-07-27 2018-07-27 Agent thérapeutique ou agent prophylactique contre des maladies inflammatoires de l'intestin WO2019022234A1 (fr)

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Citations (5)

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JP2015514794A (ja) * 2012-04-27 2015-05-21 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ 新規化合物
WO2015103507A1 (fr) * 2014-01-06 2015-07-09 Bristol-Myers Squibb Company Composés cyclohéxyle sulfone servant de modulateurs de rorϒ
WO2015103508A1 (fr) * 2014-01-06 2015-07-09 Bristol-Myers Squibb Company Composés sulfone carbocyclique servant de modulateurs de rorγ
JP2015521193A (ja) * 2012-05-31 2015-07-27 フェネックス ファーマシューティカルス アーゲー オーファン核内受容体ＲＯＲγの調整剤としてのカルボキサミドまたはスルホンアミド置換されたチアゾールおよび関連する誘導体
WO2017131156A1 (fr) * 2016-01-29 2017-08-03 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée

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JP2015514794A (ja) * 2012-04-27 2015-05-21 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ 新規化合物
JP2015521193A (ja) * 2012-05-31 2015-07-27 フェネックス ファーマシューティカルス アーゲー オーファン核内受容体ＲＯＲγの調整剤としてのカルボキサミドまたはスルホンアミド置換されたチアゾールおよび関連する誘導体
WO2015103507A1 (fr) * 2014-01-06 2015-07-09 Bristol-Myers Squibb Company Composés cyclohéxyle sulfone servant de modulateurs de rorϒ
WO2015103508A1 (fr) * 2014-01-06 2015-07-09 Bristol-Myers Squibb Company Composés sulfone carbocyclique servant de modulateurs de rorγ
WO2017131156A1 (fr) * 2016-01-29 2017-08-03 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique associée

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FAUBER, B. P. ET AL.: "Discovery of 1-{4-[3-Fluoro-4((3S, 6R)-3-methyl-1, 1-dioxo-6-phenyl-[1, 2]thiazinan-2- ylmethyl)-phenyl]-piperazin-1-yl}-ethanone(GNE-3500): a potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C (RORc or RORy) Inverse Agonist", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 13, 23 June 2015 (2015-06-23), pages 5308 - 5322, XP055519638 *

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