Entitled cyclic amine derivatives and pharmaceutical use
Technical field
[0001]
　The present invention relates to cyclic amine derivatives and their pharmaceutical use.
Background technique
[0002]
　Autoimmune disease is a general term for diseases in which excessive immune response leading to symptoms to attack normal cells and tissues of the self, such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, include uveitis or polymyalgia rheumatica syndrome.
[0003]
　Allergic diseases are diseases resulting from the immune reaction occurs over a specific antigen, such as allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic sex gastroenteritis, bronchial asthma, childhood asthma, or food allergy.
[0004]
　Although the onset and progression of autoimmune diseases and allergic diseases have various mechanisms are proposed, as one is the Th17 cells and inflammatory cytokines which it is produced, which is one of a subset of helper T cells IL-17 is known to play an important role in the onset and progression of autoimmune diseases and allergic diseases (non-Patent documents 1 and 2).
[0005]
　IL-17 fibroblast, epithelial cells, vascular endothelial cells, acts on various cells such as macrophages, involved in the migration of inflammatory cytokines, chemokines, metalloproteinases and other inflammatory inducing mediators and neutrophils ing. Therefore, a strong anti-inflammatory action if it is possible to suppress the production or function of IL-17 is believed to be exerted, clinical trials carried out in the anti-IL-17 antibody and indications of various autoimmune diseases It is.
[0006]
　Recently, a retinoid-related orphan receptor is a nuclear receptor gamma (hereinafter, ROR) becomes the clear that functions as an essential transcription factor for expression of Th17 cells differentiation proliferation and IL-17 (Non-patent Document 3), by inhibiting the expression or function of ROR, production of Th17 cells differentiation and activation, as well as IL-17 has been shown to be inhibited (non-Patent Document 4).
[0007]
　Autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus, etc.) in patients or allergic diseases (allergic dermatitis) patients, ROR expression in peripheral blood mononuclear cells or skin tissue compared to healthy persons It has been reported to exhibit high values ​​(non-Patent documents 5-7). In knockout mice ROR, the pathology of mouse experimental autoimmune encephalomyelitis model is suppressed and an animal model of multiple sclerosis, allergic diseases such as symptoms and asthma autoimmune diseases colitis etc. symptoms have been reported to be inhibited (non-Patent documents 3, 8 and 9).
[0008]
　Furthermore, in order RORγ to function as a transcription factor, it has been suggested that it is necessary to bond the RORγ and coactivators (Non-Patent Document 10). Therefore, ROR antagonist is a compound that inhibits the binding of ROR and coactivators are expected to be useful as a therapeutic or preventive agent for autoimmune diseases or allergic diseases.
[0009]
　On the other hand, the RORγ antagonists, ever N- (5- (N- (4- (1,1,1,3,3,3- hexafluoro-2-hydroxy-2-yl) phenyl) sulfamoyl) 4-methylthiazol-2-yl) acetamide (non-Patent Document 11) and 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentyl-cyclobutyl) iso oxazol-3-yl) -5-oxo-hexanoic acid-substituted azole derivatives, including (Patent Document 1) and, N-(5-(2-chlorobenzoyl) -4- (3-chlorophenyl) thiazol-2-yl ) -2- Although (4- (ethylsulfonyl) phenyl) sulfonyl benzene derivatives such as acetamide (Patent Document 2) have been reported, a 1-substituted piperidine-2 Those having a cyclic amine structure, such as Rubokisamido is not disclosed.
[0010]
　The compound having a cyclic amine structure, such as a 1-substituted piperidine-2-carboxamide, as a cannabinoid type 2 receptor agonist, (S) -1- (2- (3,3- difluoro-1-yl) acetyl)-N-(1-ethyl-5-phenyl--1H-1,2,4-triazol-3-yl) piperidine-2-carboxamide and the like have been reported (Patent Document 3), acyl-coenzyme A: diacylglycerol as converting enzyme 1 inhibitors have been reported (R)-N-(5-benzyl-4-phenyl-2-yl) -1- (2-cyclopentyl-acetyl) piperidine-2-carboxamide or the like (Patent Document 4), it is not disclosed or suggested about the effect on RORγ of these compounds.
[0011]
　As the therapeutic agent or prophylactic agent for multiple sclerosis, as positive allosteric modulators of metabotropic glutamate receptors, (S) - (3- (5- (4- fluorobenzyl) -l diazole-3-yl) piperidin-1-yl) (4-fluorophenyl) but methanone like have been reported (Patent Document 5), specific efficacy data at all for multiple sclerosis of these compounds shows not not been, its usefulness is not show any. In addition, the said patent document 5, not been disclosed or suggested for effects on RORγ of these compounds, it is not disclosed to have a 1-substituted piperidine-2-carboxamide structure.
CITATION
Patent Document
[0012]
Patent Document 1: JP 2012-236822 Patent
Patent Document 2: WO 2012/027965 Patent
Patent Document 3: WO 2010/096371
Patent Document 4: WO 2010/007046 Patent
Patent Document 5: WO 2006/129199 No.
Non-Patent Document
[0013]
Non-Patent Document 1: Chen et al., International Immunopharmacology, 2011 years, Vol. 11, p. 536-542
Non-Patent Document 2: Hofmann et al, Current Opinion in Allergy and Clinical Immunology , 2016 years, Vol. 16, p. 451-457
Non-Patent Document 3: Ivanov et al., Cell, 2006 year, the 126 Volume, p. 1121-1133
Non-Patent Document 4: Jetten, Nuclear Receptor Signaling, 2009 years, Vol. 7, e003
Non-Patent Document 5: Hamzaoui et al., Medical Science Monitor, 2011 years, Vol. 17, p. CR227-234
Non-Patent Document 6: Ma et al., Journal of the European Academy of Dermatology and Venereology, 2014 years, Vol. 28, p. 1079-1086
Non-Patent Document 7: Zhao et al., British Journal of Dermatology, 2009 years, the first Vol. 161, p. 1301-1306
Non-Patent Document 8: Leppkes et al., Gastroenterology, 2009 year, the first 136 Volume, p. 257-267
Non-Patent Document 9: Jetten et al., The Journal of Immunology, 2007 year, the first 178 Volume, p. 3208-3218
Non-Patent Document 10: Li et al., Molecular Endocrinology, 2010 years, Vol. 24, p. 923-929
Non-Patent Document 11: Burris et al., Nature, 2011 year, # 472, Volume, p. 491-494
Summary of the Invention
Problems that the Invention is to Solve
[0014]
　In fact the treatment of autoimmune diseases and allergic diseases, steroids or immunosuppressive agent acting for the entire immune system has been used as oral medicine, sufficient because of concerns about severe side effects such as infectious diseases the stop forced case the administration before the drug effect is found is there are many clinically at present. Therefore, development of new pharmaceutical molecules that play an important role in the onset and progression mechanisms of autoimmune diseases or allergic diseases targeting is desired.
[0015]
　Accordingly, the present invention aims at providing a novel compound having a RORγ antagonist activity. The present invention aims at providing a therapeutic agent or prophylactic agent for autoimmune diseases or allergic diseases based on the functional inhibition of RORγ by RORγ antagonist activity.
Means for Solving the Problems
[0016]
　The present inventors have result of intensive studies to solve the above problems, it found a novel cyclic amine derivative having a RORγ antagonist activity, thereby completing the present invention.
[0017]
　That is, the present invention provides a cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the following general formula (I).
[Chemical formula 1]

wherein, R 1 represents a 1 to 3 optional hydrogen atom an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, R 2 is a halogen atom represents, R 3 is a hydrogen atom, a halogen atom or a hydroxyl group, R 4 represents a hydrogen atom or a halogen atom, X is, -C (= O) - (CH 2 ) n -R 5 or -S ( = O) 2 -R 6 represent, n is 0 to an integer of 5, R 5 is a hydrogen atom, -OR 7 , -SR 7 , -S (= O) 2 -R 7 , -C ( = O) -OR 7 , -N (R 7 ) R 8 , 1 - 3 or any alkyl group or any of the hydrogen atoms of the hydrogen atom to 1 carbon atoms which may be substituted by a halogen atom 3 carbon It represents a number 1-3 heteroaryl group optionally substituted with an alkyl group, R 6Represents an alkyl group having 1 to 5 carbon atoms, R 7 represents a hydrogen atom or 1 to 3 optional hydrogen atom is an alkyl group of 1-3 1 carbon atoms which may be substituted with a halogen atom, R 8 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkylsulfonyl group of an acyl group or a C 1-3 having 2 to 4 carbon atoms. ]
[0018]
　In cyclic amine derivative represented by the above general formula (I), R 1 is 1 to 3 optional hydrogen atom a fluorine atom or an alkyl group of chlorine to 1 carbon atoms which may be substituted with atoms 3 and a, 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, a fluorine atom or a chlorine atom, R 5 is a hydrogen atom, -OR 7 , -SR 7 , -S (= O) 2 -R 7 , -C (= O) -OR 7 , -N (R 7 ) R 8 , 1 ~ 3 one arbitrary hydrogen atom is a fluorine atom or which may have been good having 1 to 3 carbon atoms substituted by a chlorine atom alkyl group or any hydrogen atom is optionally a heteroaryl group optionally substituted with a methyl group, R 6 is a carbon number 1 an alkyl group of ~ 3, R 7 is a hydrogen atom or 1 to 3 It is preferred optional hydrogen atom is an alkyl group having a fluorine atom or carbon atoms 1 be substituted by a chlorine atom 1-3.
[0019]
　In this case, the expected higher RORγ antagonist activity.
[0020]
　Further, the cyclic amine derivative represented by the above general formula (I), R 1 is 1 to 3 optional hydrogen atoms may methoxy group optionally substituted by a fluorine atom, R 2 is fluorine an 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 ~ 4, R 5 is a hydrogen atom , -OR 7 , -N (R 7 ) R 8 , the 1 to 3 6 is methyl group or ethyl group, R 7 is a hydrogen atom or a 1-3 arbitrary hydrogen atoms are substituted by fluorine atoms and is also an alkyl group having a carbon number of 1 ~ 3, R 8 is water Atom, a methyl group, more preferably an alkylsulfonyl group having an acyl group or a C 1-3 having 2 to 4 carbon atoms.
[0021]
　In this case, the expected higher RORγ antagonist activity can be expected excellent therapeutic or prophylactic effect in addition allergic diseases such as autoimmune diseases or allergic dermatitis, such as multiple sclerosis or psoriasis.
[0022]
　Further, the cyclic amine derivative represented by the above general formula (I), R 1 is trifluoromethoxy, R 2 is chlorine atom, R 3 is hydrogen atom, R 4 is is a hydrogen atom, X is, -C (= O) - (CH 2 ) n -R 5 is, n is an integer of 0 ~ 3, R 5 is a methyl group, a trifluoromethyl group, - N (R 7 ) R 8 , or any hydrogen atoms may be substituted with a methyl group, an imidazolyl group, a triazolyl group or a tetrazolyl radical, R 7 is a hydrogen atom, a methyl group or an ethyl group, R 8 represents a hydrogen atom, a methyl group, an acetyl group, a propionyl group, more preferably a methylsulfonyl group or an ethylsulfonyl group.
[0023]
　In this case, the expected higher RORγ antagonist activity can be expected excellent therapeutic or prophylactic effect in addition allergic diseases such as autoimmune diseases or allergic dermatitis, such as multiple sclerosis or psoriasis.
[0024]
　The present invention contains a cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I) as an active ingredient, a pharmaceutical and RORγ antagonists.
[0025]
　Aforementioned medicament is preferably a therapeutic or preventive agent for autoimmune diseases or allergic diseases, as a therapeutic agent or prophylactic agent of the above-mentioned autoimmune diseases, multiple sclerosis or psoriasis therapeutic agent or prophylactic agent more preferably, the therapeutic agent or prophylactic agent of the above-mentioned allergic diseases, more preferably a therapeutic agent or prophylactic agent for allergic dermatitis, as a therapeutic agent or prophylactic agent for allergic dermatitis , and more preferably a therapeutic agent or preventive agent for contact dermatitis or atopic dermatitis.
Effect of the invention
[0026]
　Cyclic amine derivative or a pharmacologically acceptable salt thereof of the present invention is utilized, since it has a ROR antagonist activity, could effectively inhibit the function of ROR, as a therapeutic or preventive agent for autoimmune diseases or allergic diseases it can.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027]
FIG. 1 is a diagram showing the inhibitory effect of the compound of Example 20 with respect to increase in neuronal symptom score in the mouse experimental autoimmune encephalomyelitis model.
Is a diagram showing the inhibitory effect of the compound of Example 29 for [2] increased neurological symptom score in the mouse experimental autoimmune encephalomyelitis model.
3 is a diagram showing the inhibitory effect of the compound of Example 57 with respect to increase in neuronal symptom score in the mouse experimental autoimmune encephalomyelitis model.
Is a diagram showing the inhibitory effect of the compound of [4] Imiquimod induces Example 20 for ear thickness increase in the mouse model of psoriasis.
Is a diagram showing the inhibitory effect of the compound of Example 29 for the ear thickness increase in [5] imiquimod induced mouse model of psoriasis.
Is a diagram showing the inhibitory effect of the compound of Example 57 for the ear thickness increase in [6] Imiquimod induced mouse model of psoriasis.
7 is a diagram showing the inhibitory effect of the compound of Example 20 with respect to the increase in the ear swelling rate in dinitrofluorobenzene-induced mouse allergic dermatitis model.
8 is a diagram showing the inhibitory effect of the compound of Example 29 with respect to the increase in the ear swelling rate in dinitrofluorobenzene-induced mouse allergic dermatitis model.
9 is a diagram showing the inhibitory effect of the compound of Example 57 with respect to the increase in the ear swelling rate in dinitrofluorobenzene-induced mouse allergic dermatitis model.
Is a diagram showing the inhibitory effect of the compound of [10] oxazolone-induced mice atopic Example 20 with respect to the increase in the ear thickness at dermatitis model.
Is a diagram showing the inhibitory effect of the compound of [11] oxazolone-induced mice atopic Example 29 with respect to the increase in the ear thickness at dermatitis model.
It is a diagram showing the inhibitory effect of the compound of Example 57 for the ear thickness increase in [12] oxazolone-induced mice atopic dermatitis model.
DESCRIPTION OF THE INVENTION
[0028]
　Cyclic amine derivative of the present invention is characterized in that represented by the following general formula (I).
[Formula 2]

wherein, R 1 represents 1-3 optional hydrogen atom an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, R 2 is a halogen atom represents, R 3 is a hydrogen atom, a halogen atom or a hydroxyl group, R 4 represents a hydrogen atom or a halogen atom, X is, -C (= O) - (CH 2 ) n -R 5 or -S ( = O) 2 -R 6 represent, n is 0 to an integer of 5, R 5 is a hydrogen atom, -OR 7 , -SR 7 , -S (= O) 2 -R 7 , -C ( = O) -OR 7 , -N (R 7 ) R 8 , 1 - 3 or any alkyl group or any of the hydrogen atoms of the hydrogen atom to 1 carbon atoms which may be substituted by a halogen atom 3 carbon It represents a number 1-3 heteroaryl group optionally substituted with an alkyl group, R 6Represents an alkyl group having 1 to 5 carbon atoms, R 7 represents a hydrogen atom or 1 to 3 optional hydrogen atom is an alkyl group of 1-3 1 carbon atoms which may be substituted with a halogen atom, R 8 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkylsulfonyl group of an acyl group or a C 1-3 having 2 to 4 carbon atoms. ]
[0029]
　The following terms used herein, unless otherwise specified, are as defined below.
[0030]
　"Alkyl group having 1 to 3 carbon atoms" means a methyl group, an ethyl group, a propyl group or an isopropyl group.
[0031]
　The "alkyl group having 1 to 5 carbon atoms" means a straight or branched chain saturated hydrocarbon radicals having 3-5 carbon atoms having 1-5 carbon atoms, such as methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, isopentyl group, neopentyl group or tert- pentyl.
[0032]
　"Alkyl group having 1 to 3 carbon atoms" refers to a methoxy group, an ethoxy group, a propyl group or an isopropyl group.
[0033]
　"Acyl group having 2 to 4 carbon atoms" means an acetyl group, a propionyl group, butanoyl group, or a 2-methylpropanoyl group.
[0034]
　"Alkylsulfonyl group having 1 to 3 carbon atoms" means a methyl group, an ethylsulfonyl group, propylsulfonyl group or isopropylsulfonyl group.
[0035]
　"Heteroaryl group" means a nitrogen atom, an oxygen atom and a heterocyclic aromatic group containing 1 to 4 hetero atoms optionally selected from the group consisting of sulfur atoms, for example, a thienyl group, a pyrrolyl group , furyl group, a thiazolyl group, an imidazolyl group, an oxazolyl group, a pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group or a triazinyl group.
[0036]
　The "5-membered heteroaryl group", the nitrogen atom, an oxygen atom and 1 to 4 hetero atoms optionally selected from the group consisting of sulfur atom, the heterocyclic aromatic ring constituting atoms is five means a family group, for example, a thienyl group, a pyrrolyl group, a furyl group, a thiazolyl group, an imidazolyl group, an oxazolyl group, a pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group, and oxadiazolyl or tetrazolyl group.
[0037]
　"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0038]
　The "1 to 3 optional hydrogen atom is an alkyl group having 1 to carbon atoms which may be substituted with a halogen atom 3", the alkyl group having a carbon number of 1 to 3 above 1-3 any of hydrogen atoms are each independently substituted with a halogen atom of the means which may group include a methyl group, an ethyl group, a propyl group, an isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, and a trichloromethyl group or trichloroethyl group.
[0039]
　The "1 to 3 optional hydrogen atom an alkyl group having a fluorine atom or a chlorine atom and 1 carbon atoms which may be substituted with 3 ', 1 to 3 alkyl groups having 1 to 3 carbon atoms of the any hydrogen atoms are each independently means a fluorine atom or a chlorine atom in an optionally substituted group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, fluoromethyl group, difluoromethyl group , trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, and a trichloromethyl group or trichloroethyl group.
[0040]
　The "1 to 3 optional hydrogen atom alkyl group having 1 carbon atoms which may be 3-substituted by a fluorine atom", the alkyl group having a carbon number of 1 to 3 above 1-3 any of hydrogen atom, means a group which may be substituted by a fluorine atom, for example, a methyl group, an ethyl group, a propyl group, an carbamoyl) piperidin-1-yl ) -3-oxopropyl) (methyl) carbamic acid tert- butyl:
Formula

　68] 2-methoxy instead 3 of acetic acid - (a (tert- butoxycarbonyl) (methyl) amino) propanoic acid, reference example 3 It used instead of the compound of reference example 8 compound, the same procedure otherwise as in example 4, (R) - (3- (2 - ((2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -3-oxopropyl) (methyl) carbamic acid tert- butyl (hereinafter, the compound of reference example 25) (0.117 g, 0.201m ol, was obtained 91.5%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.35 (s, 9H), 1.30-1.77 (M5H,), 2.37-2.80 (m, 3H), 2.93 ( s, 3H), 3.18-3.30 (m , 2H) 3.84 (d, J = 13.7Hz, 1H), 3.95-4.03 (m, 1H), 5.38-5 .42 (m, 1H), 7.20 (d, J = 8.3Hz, 1H), 7.31-7.46 (m, 4H), 7.66-7.72 (m, 1H), 7 .90-7.92 (m, 1H), 9.10 (br, 1H).
MS-ESI: M / Z = 584 (M Tasu H) Tasu .
[0199]
(Example 41) (R)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3- (methylamino) propanoyl) piperidine-2-carboxamide:
Formula 69]

　with a compound of reference example 25 instead of the compound of reference example 4, otherwise the same procedure as in reference example 5, (R) -N- (2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3- (methylamino) propanoyl) piperidine-2-carboxamide (hereinafter, the compound of example 41) (0.748g, 0.155mmol, 77.1%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.46-1.83 (m, 5H), 2.47 (s, 3H), 2.40-2.48 (m, IH), 2.75 -2.83 (m, 1H), 2.94-2.99 (m, 2H), 3.16 (td, J = 13.1,2.6Hz, 1H), 3.88 (d, J = 13.1Hz, 1H), 5.41 (d , J = 5.4Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 7.30-7.81 (m, 6H), 8.80 (br, 1H).
MS-ESI: M / Z = 484 (M Tasu H) Tasu .
[0200]
(Example 42) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3-hydroxy-propanoyl) piperidine-2-carboxamide synthesis:
[of 70]

　using 3-hydroxypropanoic acid instead of 2-methoxyacetic acid, the same procedure otherwise as in example 4, N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3-hydroxy-propanoyl) piperidine-2-carboxamide (hereinafter, the compound of example 42) (0.212 g, 0.450 mmol, 59.9% ) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.50-1.92 (m, 4H), 2.35 (d, J = 14.1 Hz, IH), 2.64-2.80 (m, 2H), 3.06 (t, J = 6.3Hz, 1H), 3.19 (td, J = 13.2,2.4Hz, 1H), 3.83 (d, J = 14.1Hz, 1H ), 3.98 (q, J = 5.4Hz, 2H), 5.34 (d, J = 5.4Hz, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.30 -7.44 (m, 6H), 7.70-7.90 (brm, 1H), 8.39 (br, 1H).
MS-ESI: M / Z = 471 (M Tasu H) Tasu .
[0201]
(Example 43) 3- (2 - ((2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -3-oxo synthesis of methyl propanoic acid:
Formula 71]

　using propionyl chloride 3-chloro-3-oxo-propanoate in place of chloride, by the same procedure otherwise as in example 3, 3- (2 - ((2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -3-oxo-propanoate (hereinafter, the compound of example 43) (0 .0500g, 0.100mmol, to obtain 80.0%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.50-1.80 (m, 5H), 2.57-2.62 (m, IH), 3.16-3.25 (m, IH) , 3.57 (d, J = 17.2Hz , 1H), 3.59-3.65 (m, 1H), 3.84 (s, 3H), 3.85 (d, J = 17.2Hz, 2H), 5.49 (s, 1H ), 7.22 (d, J = 8.2Hz, 1H), 7.30-7.37 (m, 3H), 7.40-7.44 (m, 1H), 7.92-7.95 (m, 1H ), 8.87 (br, 1H).
MS-ESI: M / Z = 499 (M Tasu H) Tasu .
[0202]
(Example 44) 4- (2 - ((2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -4-oxobutanoic synthesis of methyl:
Formula 72]

　using 4-chloro-4-methyl-oxobutanoic acid instead of propionyl chloride, the same procedure otherwise as in example 3, 4- (2 - ((2-chloro - 2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -4-methyl-oxobutanoic acid (hereinafter, the compound of example 44) (0.0390g, 0.0760Mmol, quantitative) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.52-1.60 (m, 5H), 2.42-2.60 (m, 2H), 2.62-2.70 (m, IH) , 2.88-2.96 (m, 1H), 2.99-3.08 (m, 1H), 3.22 (d, J = 14.6Hz, 1H), 3.74 (s, 3H) , 3.97 (d, J = 14.6Hz , 1H), 5.46 (d, J = 5.4Hz, 1H), 7.21 (d, J = 8.3Hz, 1H), 7.28- 7.44 (m, 6H), 8.49 (br, 1H).
MS-ESI: M / Z = 513 (M Tasu H) Tasu .
[0203]
(Example 45) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3-methoxy-propanoyl) piperidine-2-carboxamide synthesis:
[of

　73] 1- (tert-butoxycarbonyl) instead of piperidine-2-carboxylic acid using 1- (3-methoxy-propanoyl) piperidine-2-carboxylic acid, the same manner as in example 2 except that the procedure, N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3-methoxy-propanoyl) piperidine-2-carboxamide (hereinafter to give compound) (0.0467G example 45, 0.0963Mmol, 50.6%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.46-1.87 (m, 5H), 2.39 (d, J = 13.9 Hz, IH), 2.64 (dt, J = 15. 0,5.7Hz, 1H), 2.85-2.92 (m , 1H), 3.14 (td, J = 13.1,2.3Hz, 1H), 3.38 (s, 3H), 3.67-3.78 (m, 1H), 3.81-3.86 (m, 1H), 3.92 (d, J = 13.9Hz, 1H), 5.40 (d, J = 4 .9Hz, 1H), 7.21 (d , J = 8.3Hz, 1H), 7.29-7.80 (m, 6H), 8.46 (s, 1H).
-MS ESI: m / z = 483 (M-H) - .
[0204]
(Example 46) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (1-methyl -1H- pyrazole-4-carbonyl) piperidine-2-carboxamide:
Formula

　74] using 1-methyl -1H- pyrazole-4-carboxylic acid instead of 2-methoxyacetic acid, the same procedure otherwise as in example 4, N-( 2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (1-methyl -1H- pyrazole-4-carbonyl) piperidine-2-carboxamide (hereinafter, compound) (0.0314G example 46, 0.0619mmol, 82.4%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.62-1.71 (m, 2H), 1.78-1.87 (m, 2H), 1.99-2.11 (m, IH) , 2.37 (d, J = 12.9Hz , 1H), 3.08-3.21 (m, 1H), 3.96 (s, 3H), 4.13-4.23 (m, 1H) , 5.18-5.20 (m, 1H), 7.22 (d, J = 8.3Hz, 1H), 7.27-7.90 (m, 6H), 7.70 (s, 1H) , 7.81 (s, 1H), 9.18 (br, 1H).
MS-ESI: M / Z = 507 (M Tasu H) Tasu .
[0205]
(Example 47) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (1-methyl -1H- imidazole-4-carbonyl) piperidine-2-carboxamide:
Formula

　75] using 1-methyl -1H- imidazole-4-carboxylic acid instead of 2-methoxyacetic acid, the same procedure otherwise as in example 4, N-( 2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (1-methyl -1H- imidazole-4-carbonyl) piperidine-2-carboxamide (hereinafter, compound) (0.0369G example 47, 0.0728mmol, 96.9%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.45-1.83 (m, 4H), 2.15-2.32 (m, 2H), 2.75-2.87 (m, IH) , 3.79 (s, 3H), 4.55-4.65 (m, 1H), 5.31-5.37 (m, 1H), 7.21 (d, J = 8.3Hz, 1H) , 7.31-7.63 (m, 7H), 7.75-7.90 (m, 1H), 11.47 (br, 1H).
MS-ESI: M / Z = 507 (M Tasu H) Tasu .
[0206]
(Example 48) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl)-1-(1H-pyrazol-4-carbonyl) piperidine-2 synthesis of carboxamide:
[of

　76] using 1H- pyrazole-4-carboxylic acid instead of 2-methoxyacetic acid, the same procedure otherwise as in example 4, N-(2-chloro-2 '- ( trifluoromethoxy) - [1,1'-biphenyl] -4-yl)-1-(1H-pyrazol-4-carbonyl) piperidine-2-carboxamide (hereinafter, the compound of example 48) (0.0163g, 0 .0331Mmol, to obtain 44.0%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.45-1.90 (m, 4H), 1.95-2.17 (m, IH), 2.33-2.43 (m, IH) , 3.15-3.26 (m, 1H), 4.09-4.21 (m, 1H), 5.20-5.27 (m, 1H), 7.22 (d, J = 8. 5Hz, 1H), 7.28-7.52 (m , 5H), 7.70-8.00 (m, 3H), 9.16 (br, 1H), 10.79 (br, 1H).
MS-ESI: M / Z = 493 (M Tasu H) Tasu .
[0207]
(Reference Example 26) Synthesis of 1 (2- (N-methyl sulfonamido) acetyl) piperidine-2-carboxylic acid methyl:
[of

　77] the compound of Reference Example 20 instead of 2-methoxyacetic acid, Example using 3 piperidine-2-carboxylate hydrochloride in place of compound, by the same procedure otherwise as in example 4, 1- (2- (N- methyl sulfonamide) acetyl) piperidine-2 carboxylate (hereinafter, reference example compounds of 26) (0.934g, 3.19mmol, 82.0 ) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.24-1.76 (m, 5H), 2.25-2.32 (m, IH), 2.99 (s, 3H), 3.00 (s, 3H), 3.25 ( td, J = 13.0,3.2Hz, 1H), 3.58-3.64 (m, 1H), 3.75 (d, J = 4.6Hz, 3H), 4.11 (d, J = 17.1Hz, 1H), 4.30 (d, J = 17.1Hz, 1H), 5.25 (d, J = 5.6Hz, 1H).
MS-ESI: M / Z = 293 (M Tasu H) Tasu .
[0208]
(Reference Example 27) Synthesis of 1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxylic acid:
[Chem 78]

　the compound of Reference Example 26 (0.933 g, 3.19 mmol) in methanol ( to 10.0 mL) solution, 1M aqueous sodium hydroxide (3.83 mL, 3.83 mmol) was added at 0 ° C., and stirred After heating 17 hours at room temperature. 1M hydrochloric acid was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, the crude 1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxylic acid (hereinafter to give the compound of reference example 27) and (0.812 g) as a white solid. Compound of Reference Example 27 was used as such for the next reaction.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.18-1.75 (m, 5H), 2.30 (d, J = 13.1 Hz, IH), 2.98 (s, 3H), 2 .99 (s, 3H), 3.24 (t, J = 12.0Hz, 1H), 3.63 (d, J = 13.1Hz, 1H), 4.13 (d, J = 17.2Hz, 1H), 4.27 (d, J = 17.2Hz, 1H), 5.24 (d, J = 4.1Hz, 1H).
MS-ESI: M / Z = 279 (M Tasu H) Tasu .
[0209]
(Reference Example 28) N-(4-bromo-3-chlorophenyl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide:
[Chem

　79] 1-(tert-butoxy the compound of reference example 27 in place of the carbonyl) piperidine-2-carboxylic acid with 4-bromo-3-chloroaniline instead of the compound of reference example 1, otherwise the same procedure as in reference example 2, N-(4-bromo-3-chlorophenyl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, the compound of reference example 28) (0.296 g, 0.634 mmol, 58.8%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.49-1.85 (m, 5H), 2.34 (d, J = 12.8 Hz, IH), 3.03 (s, 3H), 3 .03 (s, 3H), 3.20 (t, J = 12.8Hz, 1H), 3.71 (d, J = 12.8Hz, 1H), 4.12 (d, J = 16.7Hz, 1H), 4.23 (d, J = 16.7Hz, 1H), 5.22 (d, J = 4.9Hz, 1H), 7.20-7.24 (m, 1H), 7.50 ( dd, J = 8.5,2.0Hz, 1H) , 7.84 (t, J = 2.3Hz, 1H), 8.20 (br, 1H).
MS-ESI: M / Z = 467 (M Tasu H) Tasu .
[0210]
(Example 49) N-(2-chloro-2'-isopropoxy - [1,1'-biphenyl] -4-yl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine -2 - synthesis of carboxamide:
[Formula 80]

　2- 2-isopropoxyphenyl boronic acid in place of trifluoromethoxyphenyl boronic acid, using the compound of reference example 28 instead of 4-bromo-3-chloroaniline, it the same procedure as in reference example 1 except, N-(2-chloro-2'-isopropoxy - [1,1'-biphenyl] -4-yl) -1- (2- (N- methyl sulfonamide ) acetyl) piperidine-2-carboxamide (hereinafter, to give compound) (0.0253G example 49, 0.0485Mmol, 75.3%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.20 (d, J = 6.0 Hz, 6H), 1.50-1.88 (m, 5H), 2.31-2.39 (m, 1H), 3.05 (s, 3H ), 3.05 (s, 3H), 3.21-3.28 (m, 1H), 3.69-3.74 (m, 1H), 4.19 (d, J = 16.8Hz, 1H ), 4.25 (d, J = 16.8Hz, 1H), 4.41 (t, J = 6.0Hz, 1H), 5.23-5.26 ( m, 1H), 6.95-7.00 (m , 2H), 7.17 (dd, J = 7.4,2.0Hz, 1H), 7.22-7.37 (m, 3H), 7.76 (d, J = 2.0Hz, 1H), 8.11 (s, 1H).
MS-ESI: M / Z = 523 (M Tasu H) Tasu .
[0211]
(Example 50) N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (2- (1-methyl -1H- imidazol-2 - yl) acetyl) piperidine-2 synthesis of carboxamide:
[Formula

　81] 2 instead of the methoxy-acetic acid 2- (using 1-methyl -1H- imidazol-2-yl) acetic acid, otherwise example 4 the same procedure as, N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (2- (1-methyl -1H- imidazole - 2-yl) acetyl) piperidine-2-carboxamide (hereinafter, to give compound) (0.0341G example 50, 0.0654Mmol, 87.0%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.49-1.80 (m, 5H), 2.67-2.74 (m, IH), 3.20-3.27 (m, IH) , 3.54-3.62 (m, 1H), 3.63 (s, 3H), 3.73 (d, J = 15.9Hz, 1H), 4.05 (d, J = 15.9Hz, 1H), 5.59-5.63 (m, 1H ), 6.89-6.98 (m, 2H), 7.20-7.29 (m, 1H), 7.32-7.37 ( m, 3H), 7.39-7.45 (m , 1H), 7.71-7.99 (m, 2H), 10.64 (br, 1H).
MS-ESI: M / Z = 521 (M Tasu H) Tasu .
[0212]
(Reference Example 29) N-(4-bromo-3-fluorophenyl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide:
[Chem

　82] 1-(tert butoxycarbonyl) piperidine compound of reference example 27 in place of the 2-carboxylic acid with 4-bromo-3-fluoroaniline instead of the compound of reference example 1, otherwise the same procedure as reference example 2 , N-(4-bromo-3-fluorophenyl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, reference example compounds of 29) (0.0253g, 0. 0562Mmol, to obtain 52.1%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.48-1.83 (m, 5H), 2.31-2.39 (m, IH), 3.03 (s, 3H), 3.03 (s, 3H), 3.16-3.23 ( m, 1H), 3.68-3.75 (m, 1H), 4.10 (d, J = 16.6Hz, 1H), 4.24 (d, J = 16.6Hz, 1H ), 5.21-5.24 (m, 1H), 7.06 (dd, J = 9.0,2.0Hz, 1H), 7.43 (t, J = 8.2Hz, 1H), 7.63 (dd, J = 10.5,2.4Hz, 1H), 8.24 (br, 1H).
MS-ESI: M / Z = 451 (M Tasu H) Tasu .
[0213]
(Example 51) N-(2-fluoro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide:
[formula 83]

　4-bromo-3 instead of chloroaniline using the compound of reference example 29, otherwise the same procedure as in reference example 1, N-(2-fluoro -2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl)-1-(2-(N-methyl sulfonamido) acetyl) piperidine-2-carboxamide (hereinafter, example 51 of the compound) (0.0132g, 0.0248mmol, to obtain 44.7%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.45-1.90 (m, 5H), 2.33-2.41 (m, IH), 3.05 (s, 6H), 3.20 -3.29 (m, 1H), 3.69-3.76 (m, 1H), 4.17 (d, J = 16.8Hz, 1H), 4.25 (d, J = 16.8Hz, 1H), 5.23-5.27 (m, 1H ), 7.20-7.44 (m, 6H), 7.62 (dd, J = 11.7,2.0Hz, 1H), 8. 24 (br, 1H).
[0214]
(Example 52) 1-(2-(1H-imidazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl ) piperidine-2-carboxamide:
Formula

　84] with 2-methoxy-1-imidazole acetic acid instead of acetic acid, by the same procedure otherwise as in example 4, 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) (0.0189g, 0.0373mmol, 49.6%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.44-2.05 (m, 5H), 2.23-2.31 (m, IH), 3.37-3.47 (m, IH) , 3.67-3.74 (m, 1H), 4.86 (d, J = 16.6Hz, 1H), 4.91 (d, J = 16.6Hz, 1H), 5.16-5. 22 (m, 1H), 6.97 (s, 1H), 7.13 (s, 1H), 7.20 (d, J = 8.3Hz, 1H), 7.29-7.37 (m, 4H), 7.40-7.45 (m, 1H ), 7.53 (s, 1H), 7.70-7.87 (m, 1H), 8.41 (br, 1H).
MS-ESI: M / Z = 507 (M Tasu H) Tasu .
[0215]
(Example 53) 1-(2-(1H-tetrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl ) piperidine-2-carboxamide:
Formula

　85] with 2-methoxy-1H- tetrazol-1-acetic acid in place of acetic acid, by the same procedure otherwise as in example 4, 1- (2- (1H - tetrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, example 53 of the compound) (0.0244g, 0.0479mmol, to obtain a 38.2%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.59-2.02 (m, 5H), 2.29-2.32 (m, IH), 3.49-3.57 (m, IH) , 3.73-3.77 (m, 1H), 5.18-5.19 (m, 1H), 5.40 (d, J = 16.8Hz, 1H), 5.48 (d, J = 16.8Hz, 1H), 7.21-7.46 (m , 6H), 7.81 (br, 1H), 8.02 (s, 1H), 8.86 (s, 1H).
MS-ESI: M / Z = 509 (M Tasu H) Tasu .
[0216]
(Example 54) 1- (2- (furan-2-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine -2-carboxamide:
[formula

　86] with 2-methoxy-2-furan acetic acid instead of acetic acid, by the same procedure otherwise as in example 4, 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) (0.0605G , 0.119 mmol, was obtained 95.2%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.41-1.95 (m, 5H), 2.33-2.38 (m, IH), 3.08-3.16 (m, IH) , 3.85-3.97 (m, 3H), 5.34-5.36 (m, 1H), 6.22-6.23 (m, 1H), 6.35-6.37 (m, 1H), 7.19-7.44 (m, 8H ), 8.33 (br, 1H).
MS-ESI: M / Z = 505 (M-H) - .
[0217]
(Example 55) 1- (2- (3,5-dimethyl -1H- pyrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'- synthesis of biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　87] 2 instead of the methoxy-acetic acid with 3,5-dimethyl -1H- pyrazole-1-acetic acid, otherwise example 4 by the same procedure, 1- (2- (3,5-dimethyl -1H- pyrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'- biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, compound) (0.0579G example 55, 0.108 mmol, was obtained 86.3%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.46-1.66 (m, 2H), 1.74-1.79 (m, 3H), 2.08 (s, 3H), 2.27 (s, 3H), 2.47-2.50 ( m, 1H), 3.11-3.19 (m, 1H), 3.69-3.74 (m, 1H), 4.83 (d , J = 15.2Hz, 1H), 4.96 (d, J = 15.2Hz, 1H), 5.35-5.36 (m, 1H), 5.89 (s, 1H), 7.21 -7.45 (m, 7H), 8.86 (br, 1H).
MS-ESI: M / Z = 535 (M Tasu H) Tasu .
[0218]
(Example 56) 1- (2- (3-methylisoxazol-5-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4 - yl) piperidine-2-carboxamide:
Formula 88]

　with 2-methoxy-3-methyl-5-isoxazole acetic acid instead of acetic acid, by the same procedure otherwise as in example 4, 1- ( 2- (3-methylisoxazol-5-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 56) (0.0652g, 0.125mmol, 99.6 %) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.47-1.96 (m, 5H), 2.29 (s, 3H), 2.33-2.39 (m, IH), 3.21 -3.28 (m, 1H), 3.82-3.87 (m, 1H), 3.95 (d, J = 16.1Hz, 1H), 4.01 (d, J = 16.1Hz, 1H), 5.32-5.33 (m, 1H ), 6.08 (s, 1H), 7.21-7.45 (m, 7H), 8.27 (br, 1H).
MS-ESI: M / Z = 520 (M-H) - .
[0219]
(Example 57) (R) -1- (2-(1H-tetrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] synthesis of 4-yl) piperidine-2-carboxamide:
[Chem

　89] 1H-tetrazole-1-acetic acid (1.67 g, in DMF (30 mL) solution of 13.04Mmol), the compound of reference example 8 (4.00 g added DMF (10 mL) solution of 10.03mmol), HATU (4.96g, 13.04mmol ) and diisopropylethylamine (2.63mL, 15.04mmol) was stirred at room temperature for 17 hours at the same temperature. Distilled water was added to the reaction solution, extracted with toluene, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (amine silica gel, n- hexane / ethyl acetate = 40/60 ~ 0/100 ), (R) -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 57) (3.87 g, 7.60 mmol to obtain 75.9%) as a white amorphous. Was analyzed by chiral column, retention time of the compound obtained in Example 57 is 55.3 minutes, optical purity at that time was ee 99.4%. Analysis conditions using a chiral column is as follows.
Measurement instrument; Shimadzu Corporation high performance liquid chromatograph LC-2010CHT
column; Daicel Chemical Industries, Ltd. CHIRALCEL OD-RH 0.46cmφ × 15cm diameter 5μm
Column temperature; 40 ° C.
Mobile phase; (A solution) distilled water, (B liquid) acetonitrile
mobile phase composition; a solution: B solution = 60: 40 (0-75 min).
流速；０．５ｍＬ／分
検出；ＵＶ（２１０ｎｍ）
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．６２－２．００（ｍ，５Ｈ），２．２７－２．３１（ｍ，１Ｈ），３．５２－３．５８（ｍ，１Ｈ），３．７３－３．７６（ｍ，１Ｈ），５．１８－５．１９（ｍ，１Ｈ），５．４０（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），５．４８（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），７．２１－７．４５（ｍ，６Ｈ），７．８１（ｂｒ，１Ｈ），８．１５（ｓ，１Ｈ），８．８６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５０９（Ｍ＋Ｈ）＋．
[0220]
(Example 58) (R) -1- (3- (1H-tetrazol-1-yl) propanoyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] 4-yl) piperidine-2-carboxamide synthesis of:
Formula 90]

　2-methoxy acetic acid instead of 3- (tetrazol-1-yl) propionic acid, compound of reference example 8 instead of the compound of reference example 3 using, by the same procedure otherwise as in example 4, (R) -1- (3- (1H-tetrazol-1-yl) propanoyl)-N-(2-chloro-2 '- (trifluoro methoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, to give compound) (0.117 g of example 58, 0.224 mmol, 89.1%) as a white amorphous .
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.43-1.97 (m, 5H), 2.25-2.29 (m, IH), 3.04-3.19 (m, 2H) , 3.25 (td, J = 13.0,2.7Hz , 1H) 3.70-3.74 (m, 1H), 4.79-4.92 (m, 2H), 5.18-5 .19 (m, 1H), 7.22-7.44 (m, 6H), 7.79 (br, 1H), 8.13 (br, 1H), 8.84 (s, 1H).
MS-ESI: M / Z = 521 (M-H) - .
[0221]
(Example 59) (R) -1- (3- (1H-imidazol-1-yl) propanoyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] 4-yl) piperidine-2-carboxamide synthesis of:
Formula 91]

　2-methoxy acetic acid instead of 3- (imidazol-1-yl) propionic acid, compound of reference example 8 instead of the compound of reference example 3 using, by the same procedure otherwise as in example 4, (R) -1- (3- (1H-imidazol-1-yl) propanoyl)-N-(2-chloro-2 '- (trifluoro methoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, compound) (0.0796G example 59, 0.153 mmol, was obtained 60.9%) as a white amorphous .
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.37-1.99 (m, 5H), 2.26-2.29 (m, IH), 2.87-2.91 (m, 2H) , 3.17 (td, J = 13.3,2.7Hz , 1H) 3.67-3.71 (m, 1H), 4.34-4.47 (m, 2H), 5.24-5 .25 (m, 1H), 6.99 (s, 1H), 7.06 (s, 1H), 7.21-7.45 (m, 6H), 7.58 (br, 1H), 7. 71-7.82 (m, 1H), 8.33 (br, 1H).
MS-ESI: M / Z = 521 (M Tasu H) Tasu .
[0222]
(Example 60) (R) -1- (3- (3- methyl -1H- pyrazol-1-yl) propanoyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1 '- biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　92] 2-methoxy instead of 3- (3-methyl acetate - pyrazol-1-yl) propionic acid, compound of reference example 3 using instead to the compound of reference example 8, by the same procedure otherwise as in example 4, (R) -1- (3- (3- methyl -1H- pyrazol-1-yl) propanoyl) -N - (2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 60) (0.135 g, 0.252 mmol , white quantitative) amorpha It was obtained as a nest.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.37-1.89 (m, 5H), 2.12 (s, 3H), 2.35-2.38 (m, IH), 2.85 -3.12 (m, 3H), 3.67-3.70 (m, 1H), 4.38-4.44 (m, 1H), 4.51-4.58 (m, 1H), 5 .30-5.32 (m, 1H), 5.96-5.97 (m, 1H), 7.19-7.45 (m, 8H), 8.59 (br, 1H).
MS-ESI: M / Z = 535 (M Tasu H) Tasu .
[0223]
(Example 61) (R) -1- (2-(1H-pyrazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] 4-yl) piperidine-2-carboxamide synthesis of:
Formula

　93] 2-methoxy acetic acid instead of 2- (1H-pyrazol-1-yl) acetic acid instead of reference example 8 of the compound of reference example 3 using the compounds, according to the same procedure otherwise as in example 4, (R) -1- (2-(1H-pyrazol-1-yl) acetyl)-N-(2-chloro-2 '- (tri the resulting [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 61) and (0.0623g, 0.123mmol, 98.0%) as a white solid - fluoromethoxy) It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.46-1.74 (m, 5H), 2.52-2.55 (m, IH), 3.04-3.12 (m, IH) , 3.65-3.69 (m, 1H), 5.01 (d, J = 14.5Hz, 1H), 5.22 (d, J = 14.5Hz, 1H), 5.43-5. 44 (m, 1H), 6.39 (dd, J = 2.3,2.0Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 7.32-7.37 (m , 3H), 7.41-7.45 (m, 1H), 7.52-7.61 (m, 1H), 7.53 (d, J = 2.3Hz, 1H), 7.58 (d , J = 2.0Hz, 1H), 7.80-7.87 (brm, 1H), 9.02 (s, 1H).
MS-ESI: M / Z = 507 (M Tasu H) Tasu .
[0224]
(Example 62) (R) -1- (2- (4H-1,2,4- triazol-4-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1 , 1'-biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　94] 2-methoxy 2- (4H-1,2,4-triazol-4-yl instead of acetic acid) acetic acid, using the compound of reference example 8 instead of the compound of reference example 3, the same procedure otherwise as in example 4, (R) -1- (2- (4H-1,2,4- triazol -4 - yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 62) ( 0.0575g, 0.113mmol, and 90.3%) as a white solid It is obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.55-1.90 (m, 5H), 2.29-2.32 (m, IH), 3.57-3.71 (m, 2H) , 4.93 (d, J = 16.8Hz , 1H), 5.02 (d, J = 16.8Hz, 1H), 5.22-5.23 (m, 1H), 7.19 (d, J = 8.2Hz, 1H), 7.28-7.37 (m, 4H), 7.40-7.45 (m, 1H), 7.81 (s, 1H), 8.21 (s, 2H), 8.84 (s, 1H ).
-MS ESI: m / z = 508 (M + H) + .
[0225]
(Example 63) (R) -1- (2- (1H-1,2,4- triazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1 , 1'synthesis of biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　95] 2-methoxy 2- (IH-1,2,4-triazol-1-yl) sodium acetate in place of acetic acid , using the compound of reference example 8 instead of the compound of reference example 3, the same procedure otherwise as in example 4, (R) -1- (2- (1H-1,2,4- triazole - 1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 63) (0.0587g, 0.116mmol, 92.2%) a white It was obtained as a color solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.54-1.70 (m, 2H), 1.77-1.90 (m, 3H), 2.38-2.41 (m, IH) , 3.31-3.39 (m, 1H), 3.74-3.78 (m, 1H), 5.13 (d, J = 15.4Hz, 1H), 5.22 (d, J = 15.4Hz, 1H), 5.29 (d , J = 5.0Hz, 1H), 7.23 (d, J = 8.2Hz, 1H), 7.30-7.37 (m, 4H), 7.41-7.45 (m, 1H), 7.79 (brs, 1H), 8.02 (s, 1H), 8.26 (s, 1H), 8.39 (s, 1H).
-MS ESI: m / z = 508 (M + H) + .
[0226]
(Example 64) (R) -1- (2- (1H-1,2,3- triazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1 , 1'-biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　96] 2-methoxy 2- (IH-1,2,3-triazol-1-yl instead of acetic acid) acetic acid, using the compound of reference example 8 instead of the compound of reference example 3, the same procedure otherwise as in example 4, (R) -1- (2- (1H-1,2,3- triazole -1 - yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 64) ( 0.0619g, 0.122mmol, and 97.2%) as a white solid It is obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.51-1.70 (m, 2H), 1.76-1.88 (m, 3H), 2.39-2.42 (m, IH) , 3.32-3.39 (m, 1H), 3.74-3.78 (m, 1H), 5.30-5.31 (m, 1H), 5.34 (d, J = 15. 4Hz, 1H), 5.41 (d , J = 15.4Hz, 1H), 7.23 (d, J = 8.6Hz, 1H), 7.30-7.37 (m, 3H), 7. 41-7.45 (m, 1H), 7.52 (brs, 1H), 7.76 (d, J = 0.9Hz, 1H), 7.82 (d, J = 0.9Hz, 1H), 7.91 (brs, 1H), 8.43 (s, 1H).
-MS ESI: m / z = 508 (M + H) + .
[0227]
(Example 65) (R) -1- (2-(1H-imidazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] 4-yl) piperidin-2-synthesis of carboxamide:
[Formula 97]

　1-imidazole acetic acid instead of 2-methoxyacetic acid, using the compound of reference example 8 instead of the compound of reference example 3, except the the same procedure as in example 4, (R) -1- (2- (1H- imidazol-1-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1 '- biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, to give the compound of example 65) (0.635 g, 1.25 mmol, 63.5%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.44-2.05 (m, 5H), 2.23-2.31 (m, IH), 3.37-3.47 (m, IH) , 3.67-3.74 (m, 1H), 4.86 (d, J = 16.6Hz, 1H), 4.91 (d, J = 16.6Hz, 1H), 5.16-5. 22 (m, 1H), 6.97 (s, 1H), 7.13 (s, 1H), 7.20 (d, J = 8.3Hz, 1H), 7.29-7.37 (m, 4H), 7.40-7.45 (m, 1H ), 7.53 (s, 1H), 7.70-7.87 (m, 1H), 8.41 (brs, 1H).
MS-ESI: M / Z = 507 (M Tasu H) Tasu .
[0228]
(Example 66) (R) -1- (2- (2H-1,2,3- triazol-2-yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1 , 1'-biphenyl] -4-yl) piperidine-2-carboxamide:
[formula

　98] 2-methoxy 2- (2H-1,2,3-triazol-2-yl instead of acetic acid) acetic acid, using the compound of reference example 8 instead of the compound of reference example 3, the same procedure otherwise as in example 4, (R) -1- (2- (2H-1,2,3- triazole -2 - yl) acetyl)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide (hereinafter, the compound of example 66) ( 0.0321g, 0.0632mmol, white 50.4%) amorphadiene It was obtained as a fastest.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.47-1.65 (m, 2H), 1.68-1.77 (m, 3H), 2.49-2.52 (m, IH) , 2.98-3.06 (m, 1H), 3.55-3.58 (m, 1H), 5.33 (d, J = 15.0Hz, 1H), 5.42 (d, J = 5.0Hz, 1H), 5.57 (d , J = 15.0Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 7.32-7.37 (m, 3H), 7.41-7.46 (m, 1H), 7.42-7.88 (brm, 2H), 7.73 (s, 2H), 8.63 (s, 1H).
-MS ESI: m / z = 530 (M + Na) + .
[0229]
Synthesis of (Reference Example 30) 2- (5-methyl-1,3,4-oxadiazol-2-yl) ethyl acetate:
[Chem

　99] 2- (1H-tetrazol-5-yl) ethyl acetate (0 .500G, in dichloroethane (6.4 mL) solution of 3.20 mmol), acetic anhydride (0.393mL, 4.16mmol) at room temperature and stirred After heating 11 hours 100 ° C.. Of 1M aqueous sodium hydroxide was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate = 70 / 30-40 / 60) to give 2- (5-methyl-1,3,4-oxadiazol-2-yl) ethyl acetate (hereinafter, reference compound of example 30) (0.0908g, 0.534mmol, 16.7 %) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.29 (t, J = 7.2 Hz, 3H), 2.55 (s, 3H), 3.92 (s, 2H), 4.23 (q , J = 7.2Hz, 2H).
MS-ESI: M / Z = 171 (M Tasu H) Tasu .
[0230]
(Reference Example 31) 2- (5-methyl-1,3,4-oxadiazol-2-yl) Synthesis of sodium acetate:
Formula 100]

　the compound of Reference Example 30 (0.0900g, 0.529mmol) in tetrahydrofuran (1.0 mL) solution, 1M aqueous sodium hydroxide (1.06 mL, 1.06 mmol) and ethanol (1.0 mL) was added at room temperature and stirred for 2 hours at the same temperature. The reaction mixture was concentrated under reduced pressure to give crude 2- (5-methyl-1,3,4-oxadiazol-2-yl) sodium acetate (hereinafter, compound of Reference Example 31) and (0.0835G) as a white solid It was. Compound of Reference Example 31 was used as such for the next reaction.
1 H-NMR (400 MHz, DMSO-D 6 ) [delta]: 2.41 (s, 3H), 3.38 (s, 2H).
MS-ESI: M / Z = 143 (M Tasu H) Tasu .
[0231]
(Example 67) (R)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (2- (5-methyl-1 , 3,4-oxadiazol-2-yl) acetyl) piperidine-2-carboxamide:
[Chem 101]

　2-methoxy compound of reference example 31 in place of acetic acid, reference instead of the compound of reference example 3 using the compound of example 8, by the same procedure otherwise as in example 4, (R)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4 - yl) -1- (2- (5-methyl-1,3,4-oxadiazol-2-yl) acetyl) piperidine-2-carboxamide (hereinafter, the compound of example 67) (0.0524g, 0 .0910Mmol, 90.8%) as a white amorphous It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.50-1.66 (m, 3H), 1.74-1.77 (m, 2H), 2.57 (s, 3H), 2.62 -2.65 (m, 1H), 3.27-3.34 (m, 1H), 3.61-3.64 (m, 1H), 3.94 (d, J = 17.4Hz, 1H) , 4.21 (d, J = 17.4Hz , 1H), 5.54-5.55 (m, 1H), 7.25-7.27 (m, 1H), 7.33-7.36 ( m, 3H), 7.40-7.44 (m , 1H), 7.77 (brs, 1H), 8.18 (brs, 1H), 9.38 (s, 1H).
-MS ESI: m / z = 545 (M + Na) + .
[0232]
(Example 68) (R)-N-(2-chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3- (dimethylamino) propanoyl) piperidine-2-carboxamide:
[Chem 102]

　2-methoxy 3- (dimethylamino) propanoic acid hydrochloride in place of acetic acid, using the compound of reference example 8 instead of the compound of reference example 3, except that by the same procedure as in example 4, (R) -N- (2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) -1- (3- ( dimethylamino) propanoyl) piperidine-2-carboxamide (hereinafter, compound) (0.0826G example 68, 0.166 mmol, was obtained 66.2%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.46-1.83 (m, 5H), 2.26 (s, 0.6H), 2.28 (s, 5.4H), 2.40 -2.44 (m, 1H), 2.55-2.62 (m, 1H), 2.65-2.81 (m, 3H), 2.99-3.05 (m, 0.1H) , 3.13-3.20 (m, 0.9H), 3.88-3.91 (m, 0.9H), 4.69 (d, J = 5.0Hz, 0.1H), 4. 73-4.76 (m, 0.1H), 5.43 (d, J = 5.0Hz, 0.9H), 7.21 (d, J = 8.6Hz, 1H), 7.31-7 .86 (m, 6H), 8.76 (br, 0.9H), 9.33 (br, 0.1H).
MS-ESI: M / Z = 498 (M Tasu H) Tasu .
[0233]
(Example 69) (R) -5- (2 - ((2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) synthesis of 5-oxo-pentanoic acid methyl:
[chemical Formula 103]

　in place of propionyl chloride 4- (chloroformyl) butyrate, using the compound of reference example 8 instead of the compound of reference example 3, the implementation otherwise the same procedure as example 3, (R) -5- (2 - ((2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidine -1 - yl) -5-oxo pentanoic acid methyl (hereinafter, to give compound) (0.130 g of example 69, 0.247 mmol, 98.4%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.44-1.79 (m, 4H), 1.84-1.95 (m, IH), 1.96-2.13 (m, 2H) , 2.35 (d, J = 13.7Hz , 1H), 2.40-2.62 (m, 4H), 2.63-2.70 (m, 0.1H), 3.14-3. 21 (m, 0.9H), 3.68 (s, 2.7H), 3.69 (s, 0.3H), 3.84-3.88 (m, 0.9H), 4.66- 4.69 (m, 0.2H), 5.34 (d, J = 5.0Hz, 0.9H), 7.20 (d, J = 8.2Hz, 1H), 7.29-7.94 (m, 6H), 8.68 ( s, 0.9H), 8.90 (s, 0.1H).
[0234]
(Example 70) (R) -5- (2 - ((2- chloro-2 '- (trifluoromethoxy) - [1,1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) synthesis of 5-oxo-pentanoic acid:
Formula 104]

　the compound of example 69 (0.130 g, 0.247 mmol) in methanol (2.5 mL) was added aqueous 1M sodium hydroxide (2.47 mL, 2.47 mmol ) and added tetrahydrofuran (2.5 mL) at 0 ° C., and stirred for 5 hours after raising the temperature to room temperature. 1M hydrochloric acid was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol = 98/2 ~ 90/10 ), (R) -5- (2 - ((2- chloro-2 '- (trifluoromethoxy) - [1 , 1'-biphenyl] -4-yl) carbamoyl) piperidin-1-yl) -5-oxopentanoic acid (hereinafter, the compound of example 70) (0.0592g, 0.115mmol, 46.7 %) as a white It was obtained as an amorphous.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.49-1.79 (m, 4H), 1.84-1.94 (m, IH), 2.00-2.10 (m, 2H) , 2.32 (d, J = 13.6Hz , 1H), 2.44-2.63 (m, 4H), 3.20 (td, J = 13.3,2.6Hz, 1H), 3. 81-3.87 (m, 1H), 5.30 (d, J = 4.5Hz, 1H), 7.20 (d, J = 8.6Hz, 1H), 7.29-7.36 (m , 3H), 7.40-7.45 (m, 2H), 7.75-7.88 (m, 1H), 8.62 (s, 1H).
-MS ESI: m / z = 535 (M + Na) +．
[0235]
(Example 71) RORγ- coactivator binding inhibitory
　activity: Ligand binding domain of ROR (hereinafter, ROR-LBD) on the binding of a coactivator, are cyclic amine derivative (I) or a pharmaceutically acceptable the inhibitory action of salts, time-resolved fluorescence energy transfer LanthaScreen of (TR-FRET) invitrogen, Inc. using TM　was evaluated using the TR-FRET retinoid-Related Orphan Receptor (ROR) gamma Coactivator Assay kit.
[0236]
　After test compound dissolved in DMSO, DMSO final concentration was used diluted to 1% 5 mmol / L DTT containing TR-FRET Coregulator Buffer D (invitogen Inc.). To each well of a 384 well black plate (Corning Inc.), was added the buffer in diluted 4 nmol / L GST-fusion ROR-LBD (Invitogen Corp.) and the test compound. Incidentally, the test compound non-addition and GST fusion ROR-LBD not added (background), and, provided the wells of the test compound non-addition and GST fusion ROR-LBD added (control). Was then added and Flurescein labeled TRAP220 / DRIP-2 of 150 nmol / L diluted in the buffer (Invitogen Corp.), 32nmol / L of terbium-labeled anti-GST antibody (Invitogen Corp.) to each well. Plates were incubated for 16-24 hours at room temperature, the fluorescence of 495nm and 520nm when excited at 320nm for each well was measured to calculate the Ratio (the fluorescence value of the fluorescence value / 495nm of 520nm).
[0237]
　Test compounds upon addition Fold change (Ratio of Ratio / background when test compound added), (Ratio controls Ratio / background) Fold change of control, and, the Fold change (Background Background Ratio / back after calculating the ratio) of ground, ROR-LBD and binding inhibition rate of the coactivators (hereinafter, it was calculated RORγ- coactivator binding inhibition rate) (%) of the following formula 1.

　RORγ- coactivator binding inhibition rate (%) = (1 - ((test compound upon addition Fold change) - (background Fold change)) / ((Fold change of control) - (Fold background change) )) × 100 ··· formula 1
[0238]
　RORγ- coactivator binding inhibition rate in test compound 33 mol / L of (%) are shown in Table 2-1 and 2-2.
[0239]
[table 2-1]

[0240]
[Table 2-2]

[0241]
　From this result, a cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically was revealed to significantly inhibit the binding of ROR-LBD and coactivator.
[0242]
(Example 72) IL-17 production inhibitory activity in mouse splenocytes:
　using mouse splenocytes, cyclic amine derivatives for the IL-17 production by IL-23 stimulation (I) or a pharmacologically acceptable salt thereof an inhibitory effect, the Journal of Biological Chemistry, 2003 year, the first 278 Vol., No. 3, p. It was evaluated in partially modified the method described in 1910-1914.
[0243]
　C57BL / 6J mice (male, 7-23 weeks old) were prepared single cell suspensions from the spleens of (Charles River, Japan) were prepared splenocytes using Histopaque-1083 a (Sigma). Culture medium RPMI1640 medium (Gibco, Inc.) in 10% FBS (Gibco, Inc.), 50 U / mL penicillin · 50 [mu] g / mL streptomycin (Gibco Co.), 50 [mu] mol / L 2-mercaptoethanol (Gibco Co.) and 100 U / mL human IL- It was used with the addition of 2 ((Ltd.) cells Science Institute). After test compound dissolved in DMSO, final concentration of DMSO was used as diluted so that 0.1% by the culture medium. To the wells of 96-well flat-bottom plates (Corning), splenocytes were prepared in culture medium (3 × 10 5 cells / well) were seeded, the test compound and 10 ng / mL of human IL-23 and (R & D systems) was added Te, 37 ° C., 5% CO 2 and incubated for 3 days under the conditions of. Incidentally, the human IL-23 was not added and a test compound non-addition, and, provided the human IL-23 added and the test compound non-addition of the wells. After completion of the culture, and the IL-17 production amount in the supernatant of the culture supernatant was collected and quantified by ELISA (R & D systems).
[0244]
　IL-17 production inhibition rate (%) was calculated from the following equation 2.

　IL-17 production inhibition rate (%) = (1 - ( (IL-23 added and the test compound IL-17 production amount when added) - (IL-17 production amount of IL-23 not added and the test compound non-addition time )) / ((IL-23 added and the test compound non-addition time of IL-17 production amount) - (IL-23 was not added and the test compound non-addition time of IL-17 production amount))) × 100 ··· formula 2
[0245]
　IL-17 production inhibition rate with the test compound 5 [mu] mol / L of (%) are shown in Table 3-1 and 3-2.
[0246]
[Table 3-1]

　
[0247]
　　
[Table 3-2]

[0248]
　From this result, a cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically was revealed that to suppress IL-17 production.
[0249]
(Example 73) Symptom inhibitory effect on the mouse experimental autoimmune encephalomyelitis models:
　an increase in neuronal symptom score as an indicator of symptom worsening, cyclic amine derivatives in mouse experimental autoimmune encephalomyelitis model (I) or and evaluate the effect of the pharmacologically acceptable salts thereof. Mouse experimental autoimmune encephalomyelitis model, Hindinger et al's method (Journal of Neuroscience Research, 2006 year, volume 84, p.1225-1234) was prepared by partially modified.
[0250]
　4 mg / mL of was adjusted to a concentration myelin oligodendrocyte glycoprotein partially synthetic peptides; the MOG35-55 dosing solution were mixed in equal amounts and complete adjuvant in PBS and Freund containing (MOG35-55 CS Bio, Inc.), C57BL / 6J mice (male, 8 weeks old) was flank both sides of a total of intradermally 0.1mL (one side 0.05mL) inoculation of (Japan Charles River Co., Ltd.). Further, after the inoculation day and 2 days of MOG35-55 dosing solution was 200μL administered pertussis toxin prepared to a concentration of 1 [mu] g / mL of (Sigma) intraperitoneally into mice.
[0251]
　MOG35-55 after inoculation of dosing solution was administered a test compound to mice. As the test compound, the compound of Example 20, using the compound of the compound and Example 57 in Example 29. The compound of Example 20, was suspended in 0.5 w / v% methylcellulose solution, daily after 2 days inoculation of MOG35-55 dosing solution was orally administered once daily at a dose of 3 mg / kg. Compound and the compound of Example 57 Example 29, was suspended in 0.5 w / v% methylcellulose solution, daily after inoculation 13 days of MOG35-55 administration solution, once daily oral administration at a dose of 1 mg / kg did. The group treated with the compound of Example 20 in mice, compound administration groups in Example 20, the group treated with the compound of Example 29, compound administration group of Example 29, the group treated with the compound of Example 57 and a compound-administered group in example 57. The solvent-administered group was administered a solvent (0.5 w / v% methylcellulose solution) for each test compound as well.
[0252]
　MOG35-55 after inoculation of dosing solution, test compound administered group and scoring neurological symptom scores solvent administration group corresponding thereto (0: normal, 1: tail relaxed or hindlimb weakness, 2: tail relaxation and hindlimb weakness, 3: hind limb portion paralysis, 4: hind paralysis, 5: moribund state) was. Scoring method, Current Protocols in Immunology (John Wiley & Sons.Inc, 2000 years, p.15.1.1-15.1.20) using the method described in.
[0253]
　The results are shown in FIGS. 1, 2 and 3. The vertical axis shows the neurological symptom score (mean ± standard error, n = 8 ~ 9). "Solvent" of the horizontal axis indicates the vehicle-treated group, "compound of Example 20" indicates the compound administration groups in Example 20, "compound of Example 29" is a compound-administered group in Example 29 indicates, "compound of example 57" designates a compound-administered group in example 57. 1 after inoculation 13 days of MOG35-55 administration solution, 2 after inoculation 23 days of MOG35-55 administration solution, Fig. 3 shows a neurological symptom score after vaccination 30 days of MOG35-55 dosing solution. * Mark indicates that in comparison with the solvent administration group (Wilcoxon test) is statistically significant (*: P <0.05).
[0254]
　Inoculation of MOG35-55 administration solution, neurological symptom scores solvent administration group was increased between 1.0 and 2.4. This increase in neurological symptoms score, the compound of Example 20, administration of compound or the compound of Example 57 Example 29 was statistically significantly inhibited.
[0255]
　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt, was found to exhibit significant symptoms inhibitory effect on multiple sclerosis.
[0256]
(Example 74) Imiquimod induced mouse model of psoriasis symptoms inhibition on effect:
　salt as an indicator of an increase in the auricle thickness symptoms worsen, which is a cyclic amine derivative (I) or a pharmaceutically acceptable in imiquimod-induced mouse model of psoriasis It was to evaluate the effect of. Imiquimod-induced mouse model of psoriasis is, Schaper et al's method (The Journal of Dermatological Science, 2013 years, the first Vol. 71, No. 1, p.29-36) was prepared by partially modified.
[0257]
　BALB / c mice (male, 7 weeks old) (Charles River Japan, Inc.), pre-bred, was used at 8 weeks of age. In order to induce psoriasis-like symptoms, imiquimod first day of administration (hereinafter, the induction date) 8 days from up to 7 days after the induction, Bethel Na cream 5% once a day, and each 5mg applied to the outside of the mouse left and right ear (imiquimod dose 0.5mg / body / day).
[0258]
　5 days from day 3 after the induction to 7 days post induction, the test compound was administered once daily at a dose of 10 mg / kg in mice. As the test compound, the compound of Example 20, using the compound of the compound and Example 57 in Example 29. The compound of Example 20, the compounds and the compound of Example 57 Example 29 was administered orally suspended in 0.5 w / v% methylcellulose solution. The group treated with the compound of Example 20 in mice, compound administration groups in Example 20, the group treated with the compound of Example 29, compound administration group of Example 29, the group treated with the compound of Example 57 and a compound-administered group in example 57. The solvent-administered group was administered a solvent (0.5 w / v% methylcellulose solution) for each test compound as well.
[0259]
　The thickness of the left and right auricle before imiquimod administration induction date (before induction), the thickness of the auricle of the left and right 8 days after induction, was measured using a digital micrometer (Mitutoyo). The average value of the right and left auricle thickness and auricular thickness, the change - was (induced after 8 days of ear KaiAtsu before induction ear KaiAtsu) as an indicator of the efficacy evaluation.
[0260]
　Results shown in FIGS. 4, 5 and 6 a. The vertical axis shows the change of MimikaiAtsu (mm) (mean ± standard error, n = 6). "Solvent" of the horizontal axis indicates the vehicle-treated group, "compound of Example 20" indicates the compound administration groups in Example 20, "compound of Example 29" is a compound-administered group in Example 29 indicates, "compound of example 57" designates a compound-administered group in example 57. * Mark indicates that in comparison with the solvent administration group (Student's t-test) is statistically significant (*: P <0.05).
[0261]
　The Imiquimod induced ear KaiAtsu day 8 after the induction of the solvent administration group was increased 0.23 mm ~ 0.27 mm with respect to the auricle thickness before induction. This increase in ear thickness, the compound of Example 20, administration of compound or the compound of Example 57 Example 29 was statistically significantly inhibited.
[0262]
　From this result, a cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically was found to exhibit significant symptoms inhibitory effect on psoriasis.
[0263]
(Example 75) DNFB-induced mouse allergic dermatitis model for symptoms inhibitory effect:
　as an indicator of an increase in ear swelling rate symptoms worsen, cyclic amine derivative (I) or a pharmacologically in DNFB-induced mouse allergic dermatitis model and evaluate the effect of acceptable salt basis. DNFB-induced mouse allergic dermatitis model, Curzytek et al. Method (Pharmacological Reports, 2013 year, Vol. 65, P.1237-1246) was prepared by partially modifying.
[0264]
　BALB / c mice (female, 6 weeks old) (Charles River Japan, Inc.), pre-bred, was used at 7 weeks of age. Acetone back of mice: Olive oil: a 0.5 v / v% DNFB solution dissolved was 25μL applied to (4 1). Mice were sensitized by repeating the next day the same operation. Sensitization 4 days later, acetone: olive oil (4: 1) 0.2v / v% DNFB solution in to each 10μL applied to both sides of the right ear of sensitized mice were induced inflammation.
[0265]
　Raised to 1 hour before, the compound of Example 20 in mice, the compound of the compound or Example 57 Example 29 was administered at a dose of 10 mg / kg. The compound of Example 20, the compounds and the compound of Example 57 Example 29 was administered orally suspended in 0.5 w / v% methylcellulose solution. The group treated with the compound of Example 20 in mice, compound administration groups in Example 20, the group treated with the compound of Example 29, compound administration group of Example 29, the group treated with the compound of Example 57 and a compound-administered group in example 57. The solvent administration group, the solvent of the test compound (0.5 w / v% methylcellulose solution) was administered similarly.
[0266]
　The thickness of the right ear of DNFB solution before coating eliciting date (before inducing), the thickness of the right auricle after the induction 24 hours, was measured using a digital micrometer (Mitutoyo). The swelling rate of the auricle was calculated by the following formula 3, was used as an index of the efficacy evaluation.

　Ear swelling rate (%) = ((right auricle thickness after induced 24 h) - (the right auricle thickness before inducing)) / elicit previous right auricle thickness × 100 · · · Formula 3
[0267]
　Results Figure 7, shown in FIGS. 8 and 9. The vertical axis shows ear swelling rate (%) (mean ± standard error, n = 6 ~ 8). "Solvent" of the horizontal axis indicates the vehicle-treated group, "compound of Example 20" indicates the compound administration groups in Example 20, "compound of Example 29" is a compound-administered group in Example 29 indicates, "compound of example 57" designates a compound-administered group in example 57. * Mark indicates that in comparison with the solvent administration group (Student's t-test) is statistically significant (*: P <0.05).
[0268]
　The auricle application of DNFB solution, ear swelling rate of the solvent administration group increased 30.9% ~ 41.7%. This increase in ear swelling rate, the compound of Example 20, administration of compound or the compound of Example 57 Example 29 was statistically significantly inhibited.
[0269]
　From this result, a cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically include allergic dermatitis, to exhibit significant symptoms inhibitory effects on particular contact dermatitis revealed.
[0270]
(Example 76) oxazolone-induced mice atopic dermatitis model for symptoms inhibitory effect:
　as an indicator of an increase in the auricle thickness symptoms worsen, cyclic amine derivative (I) or a pharmacologically in oxazolone-induced mice atopic dermatitis model and evaluate the effect of acceptable salt basis. Oxazolone-induced mice atopic dermatitis model, Nakajima et al. Method (Journal of Investigative Dermatology, 2014 year, the 134 volume, P.2122-2130) was prepared by partially modifying.
[0271]
　BALB / c mice (female, 7 weeks old) (Charles River Japan, Inc.), pre-bred, was used in the 8 or 9 weeks of age. The 3w / v% oxazolone solution in ethanol on the back of the mouse was 25μL applied, mice were sensitized. Every other day from sensitization 5 days until after 13 days, 0.6 w / v% oxazolone solution in ethanol was each 10μL applied to both sides of the right ear of sensitized mice were induced inflammation.
[0272]
　15 days from the sensitization day to 14 days after sensitization, the test compounds were administered once daily at a dose of 10 mg / kg in mice. As the test compound, the compound of Example 20, using the compound of the compound and Example 57 in Example 29. The compound of Example 20, the compounds and the compound of Example 57 Example 29 was administered orally suspended in 0.5 w / v% methylcellulose solution. The group treated with the compound of Example 20 in mice, compound administration groups in Example 20, the group treated with the compound of Example 29, compound administration group of Example 29, the group treated with the compound of Example 57 and a compound-administered group in example 57. The solvent-administered group was administered a solvent (0.5 w / v% methylcellulose solution) for each test compound as well.
[0273]
　And the thickness of the right ear of before oxazolone solution coating of sensitization date (before sensitization), the thickness of the final induced the next day of the right ear, was measured using a digital micrometer (Mitutoyo). Change of MimikaiAtsu - (final induced the next day of the right ear of the thickness before sensitization of the right ear of thickness) was used as an indicator of the efficacy evaluation.
[0274]
　Results Figure 10, shown in FIGS. 11 and 12. The vertical axis shows the change of MimikaiAtsu (mm) (mean ± standard error, n = 7). "Solvent" of the horizontal axis indicates the vehicle-treated group, "compound of Example 20" indicates the compound administration groups in Example 20, "compound of Example 29" is a compound-administered group in Example 29 indicates, "compound of example 57" designates a compound-administered group in example 57. * Mark indicates that in comparison with the solvent administration group (Student's t-test) is statistically significant (*: P <0.05).
[0275]
　The auricle application of oxazolone solution, final elicit day after ear KaiAtsu solvent administration group was increased 0.60 mm ~ 0.70 mm with respect to the auricle thickness before sensitization. This increase in ear thickness, the compound of Example 20, administration of compound or the compound of Example 57 Example 29 was statistically significantly inhibited.
[0276]
　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt, allergic dermatitis, particularly found to exhibit significant symptoms inhibitory effect on atopic dermatitis.
Industrial Applicability
[0277]
　Cyclic amine derivative or a pharmaceutically acceptable salt thereof pharmacologically of the present invention is excellent because it has a RORγ antagonist activity, use as a medicament for diseases that can be expected to ameliorate the improvement or symptoms of the condition by suppressing the function of RORγ can do. In particular, it can be used as a therapeutic or prophylactic agent for allergic diseases allergic dermatitis such as autoimmune disease or contact dermatitis or atopic dermatitis, such as multiple sclerosis or psoriasis.
The scope of the claims
[Claim 1]
　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the following general formula (I).
[Chemical formula 1]

wherein, R 1 represents a 1 to 3 optional hydrogen atom an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, R 2 is a halogen atom represents, R 3 is a hydrogen atom, a halogen atom or a hydroxyl group, R 4 represents a hydrogen atom or a halogen atom, X is, -C (= O) - (CH 2 ) n -R 5 or -S ( = O) 2 -R 6 represent, n is 0 to an integer of 5, R 5 is a hydrogen atom, -OR 7 , -SR 7 , -S (= O) 2 -R 7 , -C ( = O) -OR 7 , -N (R 7 ) R 8 , 1 - 3 or any alkyl group or any of the hydrogen atoms of the hydrogen atom to 1 carbon atoms which may be substituted by a halogen atom 3 carbon It represents a number 1-3 heteroaryl group optionally substituted with an alkyl group, R 6Represents an alkyl group having 1 to 5 carbon atoms, R 7 represents a hydrogen atom or 1 to 3 optional hydrogen atom is an alkyl group of 1-3 1 carbon atoms which may be substituted with a halogen atom, R 8 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkylsulfonyl group of an acyl group or a C 1-3 having 2 to 4 carbon atoms. ]
[Claim 2]
　R 1 is 1 to 3 optional hydrogen atom a fluorine atom or an alkyl group of chlorine to 1 carbon atoms which may be substituted with atoms 3,
　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, a fluorine atom or a chlorine
　atom, R 5 is a hydrogen atom, -OR 7 , -SR 7 , -S ( O =) 2 -R 7 , -C (= O) -OR 7 , -N (R 7 ) R 8 , 1 ~ 3 one arbitrary hydrogen atom a fluorine atom or a carbon atoms which may be substituted by a chlorine atom alkyl group or any hydrogen atoms having 1 to 3 is heteroaryl group optionally substituted with a methyl group,
　R 6 is an alkyl group having 1 to 3 carbon atoms,
　R 7 is a hydrogen atom or substituted 1-3 arbitrary hydrogen atom of a fluorine atom or chlorine atom Is an alkyl group having 1 to 3 carbon atoms also be a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.
[Claim 3]
　R 1 is 1 to 3 optional hydrogen atoms may methoxy group optionally substituted by 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 ~
　4, R 5 is a hydrogen atom, -OR 7 , -N (R 7 ) R 8 , 1 ~ 3 a number of any alkyl group or any 5-membered hydrogen atoms may be substituted with a methyl group heteroaryl groups of the hydrogen atoms to 1 carbon atoms which may be substituted with a fluorine atom 3,
　R 6 is a methyl group or an ethyl group,
　R 7 is a hydrogen atom or 1 to 3 any alkyl group of which a hydrogen atom to 1 carbon atoms which may be substituted with a fluorine atom 3,
　R 8 is a hydrogen atom, a methyl group, 1-3 acyl group or a carbon of a carbon number of 2 to 4 An alkylsulfonyl group, a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.
[Claim 4]
　R 1 is a trifluoromethoxy
　group, R 2 is chlorine
　atom, R 3 is hydrogen
　atom, R 4 is a hydrogen atom,
　X is, -C (= O) - ( CH 2 ) n -R 5 is,
　n is an integer of 0 ~
　3, R 5 is a methyl group, a trifluoromethyl group, -N (R 7 ) R 8 substitution, or any hydrogen atom in a methyl group may be, imidazolyl group, triazolyl group or tetrazolyl group,
　R 7 is a hydrogen atom, a methyl group or an ethyl group,
　R 8 represents a hydrogen atom, a methyl group, an acetyl group, a propionyl group, methylsulfonyl is a group or an ethylsulfonyl group, a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.
[Claim 5]
　Comprising as an active ingredient a cyclic amine derivative or a pharmacologically acceptable salt thereof of any one of claims 1 to 4, a pharmaceutical.
[Claim 6]
　Either containing a cyclic amine derivative or a pharmacologically acceptable salt of one claim as an active ingredient, a retinoid-related orphan receptor γ antagonists of claims 1-4.
[Claim 7]
　Containing a cyclic amine derivative or a pharmacologically acceptable salt thereof of any one of claims 1 to 4 as an active ingredient, an autoimmune disease therapeutic agent or prophylactic agent.
[8.]
　Cyclic amine derivative or a pharmacologically acceptable salt thereof as an active ingredient, the therapeutic agent or prophylactic agent for multiple sclerosis or psoriasis of any one of claims 1-4.
[Claim 9]
　Containing a cyclic amine derivative or active ingredient a pharmaceutically acceptable salt of any one of claims 1 to 4, in allergic diseases therapeutic or prophylactic agent.
[Claim 10]
　Containing a cyclic amine derivative or active ingredient a pharmaceutically acceptable salt of any one of claims 1 to 4, allergic dermatitis therapeutic or prophylactic agents.
[Claim 11]
　Cyclic amine derivative or a pharmacologically acceptable salt thereof as an active ingredient, the therapeutic agent or prophylactic agent for contact dermatitis or atopic dermatitis according to any one of claims 1-4.