WO2013146970A1 - Novel quinoline derivative - Google Patents

Novel quinoline derivative Download PDF

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WO2013146970A1
WO2013146970A1 PCT/JP2013/059171 JP2013059171W WO2013146970A1 WO 2013146970 A1 WO2013146970 A1 WO 2013146970A1 JP 2013059171 W JP2013059171 W JP 2013059171W WO 2013146970 A1 WO2013146970 A1 WO 2013146970A1
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piperidine
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勝浩 川上
俊宏 木方
厚 天花寺
清水　弘樹
純市 黒柳
貴博 北村
竜介 杉田
一史 窪田
光太郎 杉本
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第一三共株式会社
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a prostaglandin E 2 production inhibitor containing a quinoline derivative having an anti-inflammatory action, a salt thereof, or a solvate thereof.
  • Arachidonic acid is released from cell membrane phospholipid by phospholipase A 2, and prostaglandin H 2 (PGH 2 ) is synthesized through prostaglandin G 2 (PGG 2 ) by cyclooxygenase (COX).
  • This PGH 2 can be converted into prostaglandin D 2 (PGD 2 ), prostaglandin E 2 (PGE 2 ), prostaglandin F 2 ⁇ (PGF 2 ⁇ ), prostaglandin I 2 (PGI 2 ), and thrombos by each converting enzyme.
  • Prostanoids are produced by conversion to xan A 2 (TXA 2 ).
  • PGE 2 which is considered to be the most abundant prostanoid in the body, has a variety of from the center to the periphery, including hyperalgesia, fever, vascular smooth muscle relaxation, gastric acid secretion suppression, bronchial smooth muscle relaxation, and uterine contraction. It is known to have physiological activity. The physiological activities of not only PGE 2 but also other prostanoids are being elucidated, and they play an important role in maintaining the homeostasis of living organisms. It is considered deeply involved.
  • COX has two isozymes, COX-1 and COX-2.
  • Non-steroidal anti-inflammatory drugs NSAIDs
  • NSAIDs currently used as typical anti-inflammatory analgesics inhibit both COX-1 and COX-2. Since NSAIDs inhibit the production of COX-1-derived prostanoids involved in the gastrointestinal protective action, causing gastrointestinal disorders at a high frequency is a problem (Non-patent Document 1).
  • COX-2 inhibitors that have a selective inhibitory action on COX-2 induced by inflammatory stimuli are drugs with few side effects of gastrointestinal disorders, but the risk of cardiovascular events is a problem. It has become.
  • COX-2 selective inhibitor suppresses the production of PGI 2 derived from COX-2, which plays a role in inhibiting platelet aggregation and cardioprotection, while producing TXA 2 derived from COX-1 which has a contradictory effect in the coagulation system It is considered that one of the causes is not to suppress (Non-patent Document 2).
  • anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the occurrence of side effects has become a problem.
  • non-steroidal anti-inflammatory drugs and new NSAIDs are being developed, but as mentioned above, they still suffer from side effects, and the development of fundamental therapies is desired. ing.
  • rheumatoid arthritis arthritis, osteoarthritis, arthritis-related inflammatory diseases, inflammatory bowel Nerves such as diseases, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, diabetic neuralgia , Pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, strong Dermatosis, atherosclerosis and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstruct
  • an object of the present invention is to provide a novel compound having an excellent anti-inflammatory action with few side effects and a pharmacologically acceptable salt thereof.
  • the present invention (1) A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently substituted with a group selected from a hydrogen atom; a C 1 -C 6 alkyl group; and a substituent group ⁇
  • Y 1 and Y 2 are each independently a hydrogen atom; a hydroxyl group; an oxo group; a methylidene group optionally substituted with a carboxy group; or a group substituted with 1 to 3 groups selected from the substituent group ⁇ good C 1 -C 6 alkyl group; substituted with an oxo group; optionally substituted with C 1 -C 6 alkyl group a carboxy group; which may have a carbamoyl group substituted with a group selected from
  • Ring A represents a 5- to 6-membered saturated or unsaturated hydrocarbon ring or a 5- to 6-membered saturated or unsaturated heterocycle.
  • Substituent group ⁇ is a halogen atom; a C 1 -C 6 alkyl group optionally substituted with a C 1 -C 6 alkoxy group; a C 1 -C 6 alkoxy group; a C 1 -C 6 alkanoyl group; and a carboxy group
  • Substituent group ⁇ is a halogen atom; a cyano group; a C 1 -C 6 alkoxy group optionally substituted with a hydroxyl group; a sulfamoyl group or a hydroxyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups
  • An amino group optionally substituted with a group selected from a C 1 -C 6 alkyl group optionally substituted with, and a C 1 -C 6 alkanoyl group
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, (13)
  • Diseases mediated by prostaglandin E 2 are rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, Edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, self Immune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach,
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent anti-inflammatory action with few side effects, and is used as a prophylactic or therapeutic agent for inflammatory diseases or other inflammation-related diseases for warm-blooded animals (particularly humans). Useful.
  • the vertical axis shows the production of prostaglandin E 2 in the inflamed tissue. 1 shows the dose-dependent inhibitory action of Example Compound 25.
  • the halogen atom is specifically a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
  • the C 1 -C 6 alkyl group may be a straight chain, branched chain or ring structure, and is an aliphatic hydrocarbon group containing 1 to 6 carbon atoms in the chain. means. Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain.
  • Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • a methyl group, an ethyl group, a propyl group, a cyclopropyl group, an isopropyl group, or a tert-butyl group is preferable, and a methyl group, an ethyl group, or a cyclopropyl group is more preferable.
  • the C 1 -C 6 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the C 1 -C 6 alkyl group, and contains 1 to 6 carbon atoms in the chain. Preferably, it has 1 to 3 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy, preferably methoxy group, ethoxy group, propoxy group or isopropoxy group, More preferably, it is a methoxy group.
  • C 1 -C 6 alkyl group optionally substituted by a C 1 -C 6 alkoxy group include a methoxymethyl group, a 1-methoxyethyl group, a 2-methoxyethyl group, and a 1-methoxypropyl group.
  • the C 1 -C 6 alkanoyl group is a group in which a hydrogen atom or a saturated or unsaturated C 1-6 chain, branched or cyclic hydrocarbon group is bonded to a carbonyl group.
  • the ethenyl group or ethynyl group which may be substituted with a group selected from the substituent group ⁇ is preferably a 1-methylethenyl group, a 2-methylethynyl group, a 2-methoxymethylethynyl group, or 2-isopropylethynyl It is a group.
  • Specific examples of the C 1 -C 6 alkoxy group which may be substituted with a hydroxyl group include 2-hydroxyethoxy group, 2-hydroxypropoxy group, 3-hydroxypropoxy group, 2-hydroxybutoxy group, 3-hydroxybutoxy group.
  • C 1 -C 6 alkyl group optionally substituted with a hydroxyl group include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, 3-hydroxypropyl group, cyclopropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxypentyl group, 2-hydroxypentyl group, 3-hydroxypentyl Group, 4-hydroxypentyl group, 5-hydroxypentyl group, 1-hydroxyhexyl group, 2-hydroxyhexyl group, 3-hydroxyhexyl noble, 4-hydroxyhexyl group, 5-hydroxyhexyl group, or 6-hydroxyhexyl group
  • a hydroxymethyl group Is a 2-hydroxyethyl group.
  • the amino group which may be substituted with is preferably an amino group, a dimethylsulfamoylamino group, a 2-hydroxyethylamino group, or an acetylamino group.
  • the phenyl group or pyridinyl group which may be substituted with a group selected from the substituent group ⁇ is preferably a phenyl group, a 3-cyanophenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, 4- Fluorophenyl group, 4-aminophenyl group, 3-[(2-hydroxy) ethoxy] phenyl group, 4-[(2-hydroxy) ethoxy] phenyl group, 3-[(2-hydroxyethyl) amino] phenyl group, 4-[(2-hydroxyethyl) amino] phenyl group, 4- (dimethylsulfamoylamino) phenyl group, or 4- (acetylamino) phenyl group.
  • R 1 is preferably an ethenyl group or ethynyl group optionally substituted with a group selected from substituent group ⁇ , or a phenyl group optionally substituted with a group selected from substituent group ⁇ It is.
  • R 2 , R 3 , R 5 , and R 6 are preferably a hydrogen atom.
  • R 4 is preferably a methyl group.
  • carbamoyl group optionally substituted with a group selected from a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group optionally substituted with a hydroxyl group include a carbamoyl group, a methylcarbamoyl group Ethylcarbamoyl group, propylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, pentylcarbamoyl group, hexylcarbamoyl group, tert-butylcarbamoyl group, 2-hydroxyethylcarbamoyl group, 2-hydroxypropylcarbamoyl group, 3-hydroxypropyl Carbamoyl group, 2-hydroxycyclopropylcarbamoyl group, 2-hydroxybutylcarbamoyl group, 3-hydroxybutylcarbamoyl group, 4-hydroxybutylcarbamo
  • Group, hexylcarboxy group, benzylcarboxy group and the like can be mentioned, and preferred are methylcarboxy group, ethylcarboxy group and propylcarboxy group, and more preferred is ethylcarboxy group.
  • the triazolyl group optionally substituted by an oxo group is 1,2,3-triazolyl group, 1,2,4-triazolyl group, 4,5-dihydro-1,2,3-triazolyl group, 4,5- Dihydro-1,2,4-triazolyl group, 5-oxo-4,5-dihydro-1,2,3-triazolyl group, and 5-oxo-4,5-dihydro-1H-1,2,4-triazolyl group
  • Specific examples of the group include a 5-oxo-4,5-dihydro-1H-1,2,4-triazolyl group.
  • oxadiazolyl group optionally substituted with an oxo group examples include 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 4,5-dihydro -1,2,3-oxadiazolyl group, 4,5-dihydro-1,2,4-oxadiazolyl group, 4,5-dihydro-1,3,4-oxadiazolyl group, 5-oxo-4,5-dihydro- Specific examples include 1,2,3-oxadiazolyl group, 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl group, and 5-oxo-4,5-dihydro-1,3,4-oxadiazolyl group As examples, preferred are 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl group, and 5-oxo-4,5-dihydro-1,3,4-oxadiazo A Le group.
  • the C 1 -C 6 alkyl group optionally substituted with 1 to 3 groups selected from the substituent group ⁇ is preferably a cyanomethyl group, a hydroxymethyl group, a carbamoylmethyl group, a carbamoyl (hydroxy) methyl group.
  • carbamoyl group optionally substituted by 1 to 2 C 1 -C 6 alkyl groups include a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a diethylcarbamoyl group, and a methylethylcarbamoyl group.
  • the C 1 -C 6 alkyl group optionally substituted with a group selected from a carbamoyl group, a hydroxyl group, a halogen atom, and a carboxy group, which may be substituted with 1 to 2 C 1 -C 6 alkyl groups, Preferred are methyl group, dimethyl group, ethyl group, 2-dimethylcarbamoylethyl group, 2-hydroxyethyl group, 2,3-dihydroxypropyl group, 2-fluoroethyl group, or carboxy (dimethyl) methyl group.
  • it is a methylsulfonyl group.
  • the amino group optionally substituted with a group selected from a sulfonyl group optionally substituted with a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, and a C 1 -C 6 alkanoyl group includes: Specifically, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, butylsulfonylamino group, pentylsulfonylamino group, hexylsulfonylamino group, methoxyamino group, ethoxyamino group, propoxyamino group, butoxyamino group, A pentoxyamino group, a hexoxyamino group, an acetylamino group, a propionylamino group, a butyrylamino group and the like can be mentioned, and a methylsulfonyla
  • the carbamoyl group which may be substituted with a group selected from the substituent group ⁇ is preferably a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a methoxycarbamoyl group, an acetylaminocarbamoyl group, a methylsulfonyl group.
  • Aminocarbamoyl group (2-hydroxyethyl) carbamoyl group, 2-fluoroethylcarbamoyl group, (2,3-dihydroxypropyl) aminocarbamoyl group, (2-carboxyethyl) aminocarbamoyl group, (2-dimethylcarbamoylethyl) carbamoyl Or a carboxy (dimethyl) methylcarbamoyl group.
  • Y 1 and Y 2 are each preferably a C 1 -C 6 alkyl group, a substituent, wherein one is a hydrogen atom and may be substituted with 1 to 3 groups selected from substituent group ⁇ A carbamoyl group optionally substituted with a group selected from group ⁇ , or a sulfamoyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups, and more preferably C 1 — A carbamoyl group optionally substituted with a C 6 alkyl group; or a methyl group optionally substituted with a group selected from a C 1 -C 6 alkyl group and a carboxy group.
  • X preferably represents a hydrogen atom
  • n preferably represents 0. formula:
  • Ring A represents a 5-6 membered saturated or unsaturated hydrocarbon ring, or a 5-6 membered saturated or unsaturated heterocycle
  • Specific examples of the 5- to 6-membered saturated or unsaturated hydrocarbon ring include a cyclopentane ring, a cyclopentene ring, a cyclopentadiene ring, a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring, and the like.
  • a cyclopentane ring Preferred is a cyclopentane ring, a cyclohexane ring, or a benzene ring, and more preferred is a cyclopentane ring or a cyclohexane ring.
  • Specific examples of the 5- to 6-membered saturated or unsaturated heterocycle include furan ring, dihydrofuran ring, tetrahydrofuran ring, thiophene ring, dihydrothiophene ring, tetrahydrothiophene ring, pyrrole ring, dihydropyrrole ring, tetrahydropyrrole ring, Examples include a piperidine ring, a pyran ring, a dihydropyran ring, a tetrahydropyran ring, and the like, preferably a tetrahydropyran ring, a tetrahydrothiophene ring, a
  • Ring A is preferably a cyclopentane ring, a tetrahydropyran ring, a benzene ring, a piperidine ring, or a cyclohexane ring, and more preferably a cyclopentane ring or a cyclohexane ring.
  • More preferable examples of the compound having the general formula (I) include the compounds described in Examples. “Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.
  • the “disease mediated by prostaglandin E 2 ” is not particularly limited as long as it is thought that prostaglandin E 2 is involved in the onset of the disease.
  • migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, cancer metastasis and familial colorectal polyposis
  • Rheumatoid arthritis osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis,
  • the compound of the present invention is applied to gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, asthma, fever, or inflammatory anorexia, and more preferably rheumatoid arthritis, osteoarthritis, asthma, chronic Dermatitis including obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis.
  • the “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
  • the pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt.
  • Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamate salts, aspartates, and alkali metal salts are preferred.
  • the pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization.
  • the present invention also includes such various hydrates, solvates and polymorphic compounds.
  • the compound of the present invention, a salt thereof, or a solvate thereof may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer, depending on the type or combination of substituents.
  • the compound of the present invention includes all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures unless otherwise specified. is there. A mixture of these isomers can be separated by a known resolution means.
  • the compound represented by the general formula (I) of the present invention may contain an unnatural ratio of atomic isotopes at one or more of the constituent atoms. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), and carbon-14 ( 14 C). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds represented by general formula (I) are included within the scope of the present invention, whether radioactive or not.
  • the present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions.
  • Drug-forming groups are described in Prog. Med., Volume 5, pp. 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of.
  • the prodrug more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated).
  • hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like.
  • a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidation compound, etc.).
  • Production method The production method for the general formula (I) is exemplified below.
  • the compounds of the present invention represented by the general formula (I) can be produced by various methods. As preferred examples, typical production methods are shown in the following formulas, but are not limited thereto.
  • the substituent is protected with a protecting group as necessary, and the conversion order of each substituent (functional group) is not particularly limited.
  • the compound in a formula includes the case where the salt is formed. When the compound in the formula is commercially available, a commercially available product can be used as it is.
  • Production method A is a method of producing a substituted quinoline (A7) that can be used as a synthetic intermediate when producing a compound represented by formula (I).
  • R 1 to R 6 and X are the same as the definition of the substituent in formula (I), and Z 1 and Z 2 in the formula are halogen atoms (for example, bromine atom and iodine atom) or appropriate elimination
  • P 1 represents a carboxy-protecting group or hydrogen, and specific examples of the protecting group include a methyl group, an ethyl group, and a benzyl group.
  • Step (A-1) is a step of producing compound (A2) by introducing substituent Z 1 into compound (A1). It can be carried out by reacting compound (A1) with an electrophilic halide.
  • the electrophilic halide include N-bromosuccinimide and N-iodosuccinimide.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but dimethylformamide and dimethylacetamide are preferable.
  • Step (A-2) is a step of producing compound (A3) by reacting compound (A2) with an acid halide, acid anhydride or the like.
  • acid halides and acid anhydrides include phosphorus oxychloride and trifluoromethanesulfonic acid anhydride.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane is preferred.
  • Step (A-3) is a step for producing compound (A4) by subjecting compound (A3) to a substitution reaction with Z 2 by acting a piperidine derivative.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but N-methylpyrrolidone and N, N-dimethylacetamide are preferable.
  • Step (A-4) is a condition in which boronic acid or a boronic acid ester is allowed to act on the substituent Z 1 on the quinoline ring in the presence of a palladium catalyst (Suzuki coupling), or a tin compound is allowed to act (Stille coupling).
  • a substituent corresponding to R 1 or a precursor thereof is introduced under conditions such as conditions under which a terminal alkyne is allowed to act in the presence of a palladium and copper catalyst (Sonogashira reaction). This is a step of deprotecting the protecting group and modifying the substituent in R 1 as necessary.
  • Step (A-5) is a step of producing compound (A5) by adding a piperidine derivative to compound (A6), and the same method as in step (A-3) can be used.
  • Step (A-6) is a step of producing a compound (A-7) by deprotecting the protecting group in the compound (A5), and a step of deprotecting the protecting group in R 1 and X as necessary. It is. Although this reaction varies according to the kind of the protecting group P 1, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" can be carried out according to the method described in.
  • Production method B is a method for producing a substituted amine (B19) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • P 1 is as defined above, and m is 0 or 1.
  • [X a represents an oxygen atom or NH
  • X c represents a carbon atom, an oxygen atom, or a nitrogen atom
  • Y a and Y b each represents an oxo group, a fluorine group, an ethylenedioxy group (—OCH 2 CH 2 O—), a hydroxyl group or a hydrogen atom
  • Y 3 represents a hydroxyl group, an amino group, an oxo group, a halogen atom or a hydrogen atom, and these substituents may be protected
  • Y 4 represents an optionally substituted ester group, a carboxylic acid group, an amide group, an alkoxymethyl group, a tetrazolyl group, an imidazolyl group, an acylated hydrazine group
  • R 7 and R 8 each represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group, or hydrogen atom
  • R 10 and R 11 each represents an
  • Step (B-1) is a step of condensing the carboxy group of compound (B1) with a hydroxylamine derivative or a hydrazine derivative in the presence of an appropriate condensing agent and base, and is a step of producing compound (B2). . Add additives to accelerate the reaction if necessary.
  • condensing agent examples include WSC (ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (ie, 1,3-dicyclohexylcarbodiimide), DMT-MM (ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), CDI (ie 1,1′-carbonyldiimidazole), DEPC (ie diethyl phosphorocyanide) DPPA (that is, diphenylphosphoroazideate) and the like can be mentioned.
  • WSC ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC ie, 1,3-dicyclohexylcarbodiimide
  • DMT-MM ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methyl
  • Examples of the base include aromatic amines such as pyridine and lutidine, and tertiary amines such as triethylamine, diisopropylethylamine, and DMAP (that is, 4-dimethylaminopyridine).
  • Representative examples of additives include HOAt (3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol), HOBt (1H-benzotriazol-1-ol), HOSu (N -Hydroxysuccinimide) and the like.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane and N, N-dimethylformamide are preferable.
  • Step (B-2) is a step for producing compound (B3) by allowing a suitable acylating agent to act on compound (B2) or (B6) and then performing cyclization by heating.
  • the acylating agent include isobutyl chloroformate, CDI, phosgene and triphosgene.
  • Step (B-3) is a step of condensing compound (B1), (B8) and (B12) with a compound having an amino group or a compound having a hydroxyl group in the presence of an appropriate condensing agent and a base. In this step, compounds (B4), (B9) and (B13) are produced. Add additives to accelerate the reaction as needed. The same method as in step (B-1) can be used.
  • Step (B-4) is a step of producing compound (B5) by allowing a suitable dehydrating agent to act on compound (B4).
  • the dehydrating agent include ethyl phosphorodichloridate, phosgene, and triphosgene.
  • Step (B-5) is a step of producing compound (B6) by adding a hydroxylamine derivative or a hydrazine derivative to compound (B5).
  • step (B-6) the hydroxyl group of the compound (B7) is oxidized using an appropriate oxidizing agent to form an aldehyde, and then silylcyanation is performed using trimethylsilyl cyanide. The resulting cyano group is subjected to acidic conditions.
  • Step (B-7) is a step of converting compound (B7) into a suitable leaving group and then substituting it with a cyano group, which is a step of producing compound (B10).
  • the leaving group include a methylsulfonyloxy group, a p-toluenesulfonyloxy group, and a halogen atom.
  • Step (B-8) is a step of esterifying the resulting amino acid after hydrolyzing the cyano group under acidic conditions with respect to compound (B10), and is a step of producing compound (B11). If necessary, it includes a step of protecting the amino group again.
  • This reaction varies depending on the type of the protecting groups P 1 to P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
  • the protecting group P 2 is a Boc group (P 3 is a hydrogen atom)
  • di-tert-butyl dicarbonate or the like is used in the presence of a base.
  • sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
  • the protecting group P 2 is a Cbz group (P 3 is a hydrogen atom)
  • benzyl chloroformate or N- (benzyloxycarbonyloxy) succinimide is used in the presence of a base.
  • sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
  • the protecting groups P 2 and P 3 are benzylidene groups
  • benzaldehyde is used in the presence of anhydrous sodium sulfate or anhydrous magnesium sulfate as a reactant.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
  • the protecting groups P 2 and P 3 are diphenylmethylene groups, benzophenone imine is used as a reactant.
  • a base can be used as necessary.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
  • Step (B-9) is a step of producing compound (B12) by hydrolyzing compound (B11).
  • As the base sodium hydroxide, potassium hydroxide and the like can be used.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but ethanol, methanol, tetrahydrofuran, and water may be preferably mixed.
  • Step (B-10) is a step of stepwise alkylating compound (B11), and is a step of producing compound (B14).
  • Step (B-11) is a step of adding a chiral amine to compound (B15) and then reducing, and is a step of producing compound (B16). This step can be performed according to the method described in WO2008 / 153027A1.
  • Step (B-12) is a step of reducing the obtained carboxylic acid after hydrolysis of the ester group for compound (B16), and is a step for producing compound (17).
  • As the reducing agent sodium borohydride or the like can be used.
  • Step (B-13) is a step of deprotecting protecting groups P 2 and P 3 from compound (B18), and is a step of producing compound (B19).
  • the compound (B18) represents the outline of the compound group (B1 to B17) in the production method B
  • the compound (B19) represents the outline of the substituted amine in the production method B.
  • This reaction varies depending on the types of protecting groups P 2 and P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
  • the protecting group P 2 is a Boc group
  • a dioxane solution or an ethyl acetate solution of hydrochloric acid can be used as a reactant. You may add methanol, ethanol, and tetrahydrofuran as needed.
  • the protective group P 2 is a Cbz group or a diphenylmethylene group
  • palladium carbon or palladium hydroxide can be used in a hydrogen atmosphere.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but methanol, ethanol, and tetrahydrofuran are preferable.
  • Production method C is a method for producing the target compound represented by formula (I) by condensing compound (A7) obtained by production method A and substituted amine (B19) obtained by production method B.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y 1 , Y 2 , Y 3 , and Y 4 represent the same groups as described above. ]
  • Step (C-1) is a step of producing compound (C1) by reacting compound (A7) with substituted amine (B19) in the presence of various condensing agents and bases. ) Can be used.
  • Step (C-2) is a step of modifying substituents Y 3 and Y 4 in compound (C1). Hydrolysis reaction, amidation reaction, known deprotection reaction, oxidation reaction, acylation reaction, sulfonylation
  • compound (I) is produced by combining a reaction, heterocycle formation reaction, hydrogenation reaction, alkylation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction alone or in combination of two or more thereof. If necessary, the protecting groups in R 1 to R 6 can be deprotected.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y 3 , and Y 4 represent the same groups as described above.
  • Production method D is another method for producing compound (C1) represented by production method C. That is, the compound (C1) is produced by a method in which the compound (D1) and the substituted amine (B19) are first condensed to obtain the compound (D2) and then reacted with the quinoline derivative (A6).
  • Step (D-1) is a step of producing compound (D2) by condensing compound (D1) and compound (B19) obtained by production method B, and using the same method as in step (B-1) be able to.
  • Step (D-2) is a step of producing compound (C1) by reacting compound (D2) with compound (A6) obtained by production method A, and using the same method as in step (A-3) be able to.
  • the compound of the present invention or a pharmacologically acceptable salt thereof When the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
  • the pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
  • parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like.
  • the preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
  • Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
  • the dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind of drug to be administered in combination, the dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), once or several times a day, orally or parenterally, in an equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
  • the present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof. Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
  • Formulation Example 1 Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender. (Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • A549 cell prostanoid production inhibition assay was performed with reference to a report by Staffan ThoreAn et al. (European Journal of Biochemistry, (2000) 267, 6428-6434).
  • A549 cells suspended in DMEM supplemented with 10% FBS were seeded at 25000 cells / 0.1 mL / well and cultured overnight at 37 ° C. under 5% CO 2 conditions. After washing the cells once with serum-free DMEM, 0.09 mL / well of a compound diluted with serum-free DMEM was added, followed by incubation for 1 hour.
  • the rat macrophage prostanoid production assay was performed with reference to a report by Matsumoto et al. (Biochemical and Biophysical Research Communications, (1996) 230, 110-114). 3-4 days after 5% Peptone and 5% Starch were administered to the rat abdominal cavity, cells infiltrating the intraperitoneal fluid were recovered with RPMI-1640 supplemented with 10% FBS to prepare peritoneal macrophages.
  • the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from rat macrophages.
  • the IC 50 values for TXB 2 production of the compounds of the present invention were all 1000 ng / ml or more, indicating that PGE 2 production was selectively suppressed.
  • Example Compound 25 and Example Compound 28 suppressed paw swelling on day 4 by 16.0% and 26.4%, respectively, as compared to the control group.
  • the reaction mixture was added dropwise to a mixed solution of 1N aqueous hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) under ice cooling, and the mixture was returned to room temperature and stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was pulverized by adding n-hexane and diisopropyl ether to obtain 729 mg (yield 83%) of a solid.
  • reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (70 mL), di-tert-butyl dicarbonate (2.26 g, 10.4 mmol) and triethylamine (4.82 mL, 34.6 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Stir for hours. After adding ethyl acetate to the reaction mixture, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate.
  • the ether layer obtained by the above operation was converted to an ether solution of diazomethane, and ethyl 2- ⁇ cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl ⁇ acrylate obtained in Reference Example 18 (248 mg, 0.834 mmol) And palladium acetate (10 mg, 0.045 mmol) in ether (3 mL) suspension. The resulting mixture was stirred at room temperature for 1 hour. An ether solution of diazomethane was prepared by the above operation, and added to the reaction mixture together with palladium acetate (10 mg, 0.045 mmol) four times every hour. After stirring at room temperature for 5 hours, ethyl acetate was added and filtered through celite.
  • the first peak eluting first was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (56.7 g, optical purity> 98% ee) as a solid.
  • the second peak eluting later was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (55.4 g, optical purity> 98% ee) as a solid.
  • the obtained solid was crystallized from isopropyl alcohol solvent.
  • the absolute steric structure was determined by X-ray crystal structure analysis using the obtained crystal.
  • the absolute configuration was determined to be (1R, 3R) based on the configuration of (1S) -1-phenylethanamine. Therefore, the absolute configuration of the second peak obtained in Reference Example 20 was determined to be (1S, 3S).
  • Reference Example 32 2-[(1S, 3S) -3-Aminocyclohexyl] -N-ethylacetamide [(1S, 3S) -3- ⁇ [(Benzyloxy) carbonyl] amino ⁇ obtained in Reference Example 31 Using [cyclohexyl] acetic acid and commercially available ethylamine (2.0 M tetrahydrofuran solution), a solid (yield 91%) was obtained according to the method of Reference Example 6. Using the resulting solid, the title compound (yield 97%) was obtained according to the method of Reference Example 10.
  • sodium borohydride (1.28 g) was added to 2-methylpropanoic acid (20 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
  • the reaction mixture was ice-cooled again and a solution of the oil (3.40 g) obtained above in 2-methylpropanoic acid (10 mL) was added, followed by stirring at room temperature for 27 hours.
  • the reaction mixture was acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 mL). Under ice-cooling, isobutyl chloroformate (100 ⁇ L) and triethylamine (130 ⁇ L) were added, and the mixture was stirred at the same temperature for 30 minutes. Sodium borohydride (100 mg) was added under ice-cooling, water (200 ⁇ L) was added, and the mixture was stirred at the same temperature for 10 min.
  • the obtained residue was dissolved in a mixed solvent of dichloromethane (15 mL) and a small amount of ethanol, and di-tert-butyl dicarbonate (330 mg, 1.50 mmol) was added, followed by stirring at room temperature for 3 hours.
  • the solvent was distilled off from the reaction mixture under reduced pressure.
  • Reference Example 64 (6-Methyl-3-phenylquinolin-2-yl) -N-piperidin-4-ylpiperidine-4-carboxamide 1- (6-Methyl-3- obtained in Reference Example 2
  • a solid was obtained according to the method of Example 3 using (phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 1-benzylpiperidin-4-amine.
  • the title compound (100%) was obtained according to the method of Reference Example 10 using the obtained solid.
  • Reference Example 65 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(3S) -piperidin-3-yl] piperidin-4-carboxamide 1- ( According to the method of Example 1, using 6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available tert-butyl (3S) -3-aminopiperidine-1-carboxylate An amorphous product (yield 100%) was obtained. The title compound (yield 78%) was obtained according to the method of Reference Example 5 using the obtained amorphous material.
  • Reference Example 68 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid (derived from highly polar substance) According to the method of Reference Example 2, using ethyl 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (high polar form) obtained in Reference Example 67 The title compound (yield 100%) was obtained as a solid.
  • Reference Example 69 1- (6-Methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine-4-carboxylic acid Ethyl 3-hydroxy-1 obtained in Reference Example 66 -(6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (202 mg, 0.517 mmol) and N, N-dimethylpyridin-4-amine (188 mg, 1.54 mmol) in dichloromethane ( 4 mL) was added methanesulfonyl chloride (114 ⁇ L, 0.723 mmol), and the mixture was stirred at room temperature for 1.5 hours and a half.
  • the reaction mixture was diluted with dichloromethane, and then washed with a 0.5N aqueous hydrochloric acid solution and a saturated aqueous sodium hydrogen carbonate solution. After drying with sodium sulfate, the solvent was distilled off under reduced pressure.
  • Commercially available ethyl 4-piperidinecarboxylate (1.84 mL, 11.9 mmol) and 1,4-dioxane (4 mL) were added to the resulting residue, and the mixture was stirred at a bath temperature of 120 ° C. for 2 hours.
  • the reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 82 1- (6-Methyl-3- ⁇ 4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinolin-2-yl) piperidine-4-carboxylic acid PCT WO2010 / 2- ⁇ 2- [4- (4,5,6,6-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy ⁇ tetrahydro-2H-pyran described in the application specification of 116915A1 and Reference Example Using the ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in 72, an oil (41%) was obtained according to the method of Reference Example 73.
  • Reference Example 88 1- (6-Methyl-3- ⁇ 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinolin-2-yl) piperidine-4-carboxylic acid
  • Reference Example 87 2- ⁇ 2- [3- (4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy ⁇ tetrahydro-2H-pyran obtained in 1) and Reference Example Using the ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in 72, an oil (75%) was obtained according to the method of Reference Example 73. The title compound (yield 100%) was obtained as a solid according to the method of Reference Example 2 using the obtained oil.
  • Ethyl (cis-4-aminocyclohexyl) acetate hydrochloride (183 mg, 0.823 mmol) and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 Acid (202 mg, 0.583 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (1.75 g, 12.9 mmol) and N, N-dimethylpyridine-4- Triethylamine (0.41 mL, 291 mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (340 mg, 1.77 mmol) were added to a dichloromethane solution (4 mL) of amine (72.4 mg, 0.593 mmol).
  • Example 2 [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid Ethyl obtained in Example 1 [Cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate (377 mg, 0.733 mmol) in ethanol (5 mL) and An 8N aqueous sodium hydroxide solution (0.7 mL, 5.6 mmol) was added to the water (0.4 mL) suspension, and the mixture was stirred at 60 ° C. for 2.5 hours.
  • the reaction mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 338 mg (yield 95%) of the title compound.
  • Example 4 N- [cis-4- (2-amino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and 2- (cis-4-aminocyclohexyl) acetamide hydrochloride obtained in Reference Example 5 were used. The title compound (yield 91%) was obtained according to the method of Example 1.
  • Example 6 N- ⁇ cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • Reference Example 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in 2 and 2- (cis-4-aminocyclohexyl) -N-methylacetamide obtained in Reference Example 7 Using the hydrochloride, the title compound (yield 94%) was obtained as a solid according to the method of Example 1.
  • Example 7 N- ⁇ cis-4- [2- (methoxyamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • the title compound (yield 80%) was obtained as a solid according to the method of Example 1 using hydrochloride.
  • Example 8 N- (cis-4- ⁇ 2-[(2-hydroxyethyl) amino] -2-oxoethyl ⁇ cyclohexyl) -1- (6-methyl-3-phenylquinolin-2-yl) piperidine- 4-Carboxamide [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid obtained in Example 2 and commercially available The title compound (yield 82%) was obtained as a solid using 2-aminoethanol according to the method of Example 3.
  • Example 9 N- [cis-4- (cyanomethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6 According to the method of Example 1, using -methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and (cis-4-aminocyclohexyl) acetonitrile hydrochloride obtained in Reference Example 8 The compound (yield 92%) was obtained as a solid.
  • Example 10 N- (cis-4-hydroxycyclohexyl) -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-methyl) obtained in Reference Example 2 -3-Phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available cis-4-aminocyclohexanol hydrochloride were used to produce the title compound (81% yield) as a solid according to the method of Example 1 Got as.
  • Example 11 N- [cis-4- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide PCT WO2004 / 087680A1 Using the cis-4-aminocyclohexyl) methanol hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the method of Example 1 was used. The title compound (yield 52%) was obtained accordingly.
  • Example 12 N- [cis-4- (2-amino-1-hydroxy-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • Reference 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Example 2 and 2- (cis-4-aminocyclohexyl) -2-hydroxy obtained in Reference Example 10
  • the title compound (yield 92%) was obtained as a solid using acetamide according to the method of Example 1.
  • Example 13 N- ⁇ cis-4- [1-hydroxy-2- (methylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2- (cis-4-aminocyclohexyl)-obtained in Reference Example 11 The title compound (yield 67%) was obtained as a solid according to the method of Example 1 using 2-hydroxy-N-methylacetamide.
  • Example 14 6-Methyl-3-phenylquinolin-2-yl) -N- ⁇ cis-4-[(5-oxo-4,5-dihydro-1,2,4-oxadiazole) -3-yl) methyl] cyclohexyl ⁇ piperidine-4-carboxamide N- [cis-4- (cyanomethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) obtained in Example 9
  • piperidine-4-carboxamide 233 mg, 0.499 mmol
  • 50% aqueous hydroxylamine solution (0.132 mL, 2.00 mmol
  • Example 15 6-Methyl-3-phenylquinolin-2-yl) -N- ⁇ cis-4-[(5-oxo-4,5-dihydro-1,3,4-oxadiazole -2-yl) methyl] cyclohexyl ⁇ piperidine-4-carboxamide N- [cis-4- (2-hydrazino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenyl) obtained in Reference Example 12 To a solution of quinolin-2-yl) piperidine-4-carboxamide (100 mg, 0.200 mmol) in dichloromethane (6 mL) was added triethylamine (0.042 mL, 0.300 mmol) and commercially available 1,1′-carbonyldiimidazole (38.
  • Example 16 6-Methyl-3-phenylquinolin-2-yl) -N- ⁇ cis-4-[(5-oxo-4,5-dihydro-1H-1,2,4-triazole -3-yl) methyl] cyclohexyl ⁇ piperidine-4-carboxamide N- [cis-4- (2-hydrazino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenyl) obtained in Reference Example 12 To a solution of quinolin-2-yl) piperidine-4-carboxamide (930 mg, 1.86 mmol) in dichloromethane (25 mL), tert-butyl isocyanate (0.255 mL, 2.23 mmol) and triethylamine (0.389 mL, 2.79 mmol) And stirred at room temperature for 15 hours.
  • dichloromethane 5 mL
  • trifluoroacetic acid 15 mL
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • Example 17 Ethyl 2- [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoate Obtained in Reference Example 2
  • Example 1 using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and ethyl 2- (cis-4-aminocyclohexyl) propanoate obtained in Reference Example 15
  • the title compound (yield 89%) was obtained as a solid according to method 1.
  • Example 18 2- [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoic acid Obtained in Example 17
  • Example 2 was used with ethyl 2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoate.
  • the title compound was obtained quantitatively as a solid according to the method.
  • Example 19 N- [cis-4- (2-amino-1-methyl-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 2- [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoic acid obtained in Example 18 and commercially available 7N The title compound (yield 93%) was obtained as a solid according to the method of Example 3 using ammonia-methanol.
  • Example 20 Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoate
  • Reference 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Example 2 and ethyl 2- (cis-4-aminocyclohexyl) -2-yl obtained in Reference Example 17
  • the title compound (yield 79%) was obtained as a solid according to the method of Example 1 using methylpropanoate.
  • Example 21 2-Methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoic acid
  • Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoate obtained in Example 20 was used to give the title compound (yield 16%) as a solid according to the method of Example 2.
  • Example 22 N- [cis-4- (2-amino-1,1-dimethyl-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- Carboxamide 2-Methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl obtained in Example 21] The title compound (yield 50%) was obtained as a solid according to the method of Example 3 using propanoic acid and commercially available 7N ammonia-methanol.
  • Example 23 Ethyl 1- [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] cyclopropanecarboxylate Reference Example The compound obtained according to the method of Reference Example 5 was dissolved in dichloromethane using ethyl 1- ⁇ cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl ⁇ cyclopropanecarboxylate obtained in 19. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1.
  • Example 24 [cis-4-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] cyclopropanecarboxylic acid
  • Example 23 Using ethyl 1- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] cyclopropanecarboxylate obtained in The title compound (yield 72%) was obtained as a solid according to the method of Example 2.
  • Example 25 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- The method of Example 3 using (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and the (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23 To give the title compound (yield 66%).
  • Example 26 N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Obtained in Reference Example 2 Using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, The title compound (yield 87%) was obtained according to the method of Example 3.
  • Example 27 N-[(1S, 3S) -3- (Hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide hydrochloride
  • Example 26 The obtained N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (70.0 mg, 0.153 mmol) 1) Hydrochloric acid ethanol solution was added and suspended, and then the solvent was distilled off under reduced pressure. The obtained solid was suspended in ethanol-ethyl acetate and collected by filtration.
  • Example 28 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and [(1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25 were used. According to the method of Example 1, the title compound (yield 97%) was obtained as a solid.
  • Example 29 Ethyl [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate
  • Reference Example 2 6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in 1 and ethyl [(1S, 3S) -3-aminocyclohexyl] acetate hydrochloride obtained in Reference Example 27
  • the title compound (yield 97%) was obtained as a solid according to the method of Example 1.
  • Example 30 [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid
  • Example 29 Using the obtained ethyl [(1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate
  • the title compound (yield 98%) was obtained as a solid according to the method of Example 2.
  • Example 31 N- ⁇ (1S, 3S) -3- [2- (methoxyamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 Carboxamide [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid obtained in Example 30 The title compound (yield 79%) was obtained as a solid according to the method of Example 1 using commercially available (aminooxy) methane hydrochloride.
  • Example 32 Ethyl 2-methyl-2-[(1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) Cyclohexyl] propanoate Using the ethyl 2- ⁇ (1S, 3S) -3-[(diphenylmethylene) amino] cyclohexyl ⁇ -2-methylpropanoate obtained in Reference Example 28, according to the method of Reference Example 10 The obtained compound was dissolved in dichloromethane. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 99%).
  • Example 33 2-Methyl-2-[(1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl ]
  • Propanoic acid Ethyl 2-methyl-2-[(1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] obtained in Example 32 ]
  • Carbonyl ⁇ amino) cyclohexyl] propanoate was used to obtain the title compound as a solid (yield 26%) according to the method of Example 2.
  • Example 34 Methyl 1-[(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] cyclopropane Carboxylate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and methyl 1- ⁇ (1S, 3S) -3 obtained in Reference Example 30 The title compound (yield 95%) was obtained according to the method of Example 1 using-[(tert-butoxycarbonyl) amino] cyclohexyl ⁇ cyclopropanecarboxylate.
  • Example 35 1-[(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] cyclopropanecarboxylic acid Acid Methyl 1-[(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl obtained in Example 34 The title compound (yield 92%) was obtained using cyclopropanecarboxylate according to the method of Example 2.
  • Example 36 N- ⁇ (1S, 3S) -3- [2- (Ethylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2-[(1S, 3S) -3- The title compound (yield 76%) was obtained using aminocyclohexyl] -N-ethylacetamide according to the method of Example 3.
  • Example 37 N- ⁇ (1S, 3S) -3- [2- (cyclopropylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine- 4-Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2-[(1S, 3S) -3 obtained in Reference Example 33 -Aminocyclohexyl] -N-cyclopropylacetamide was used to give the title compound (76% yield) according to the method of Example 3.
  • Example 38 N-[(1S, 3S) -3- (methoxycarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and (1S, 3S) -3-amino-N-methoxycyclohexanecarboxamide hydrochloride (108 mg) obtained in Reference Example 34 , 0.520 mmol), and the title compound (yield 51%) was obtained according to the method of Example 3.
  • Example 39 N- ⁇ (1S, 3S) -3-[(2-acetylhydrazino) carbonyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Using the benzyl ⁇ (1S, 3S) -3-[(2-acetylhydrazino) carbonyl] cyclohexyl ⁇ carbamate obtained in Reference Example 37, an oily substance was obtained according to the method of Reference Example 10. Using the obtained oil and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound ( Yield 76%) was obtained.
  • Example 40 6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- ⁇ [2- (methylsulfonyl) hydrazino] carbonyl ⁇ cyclohexyl] piperidine-4 -Carboxamide Using the benzyl [(1S, 3S) -3- ⁇ [2- (methylsulfonyl) hydrazino] carbonyl ⁇ cyclohexyl] carbamate obtained in Reference Example 38, an oily substance was obtained according to the method of Reference Example 10. It was.
  • Example 41 6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,3,4- Oxadiazol-2-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] -1- (6-methyl-3-) obtained in Reference Example 39
  • the title compound (88% yield) was obtained according to the method of Example 15 using (phenylquinolin-2-yl) piperidine-4-carboxamide dihydrochloride.
  • Example 42 6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1H-1,2, 4-Triazol-3-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] -1- (6-methyl-3-) obtained in Reference Example 39 The title compound (13% yield) was obtained according to the method of Example 16 using phenylquinolin-2-yl) piperidine-4-carboxamide dihydrochloride.
  • Example 43 6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,2,4- Oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide 3-[(1S, 3S) -3-aminocyclohexyl] -1,2,4-oxadiazole-5 (4H obtained in Reference Example 41 ) -One Using the hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound ( Yield 89%).
  • Example 44 N- ⁇ (1S, 3S) -3-[(2-hydroxyethyl) carbamoyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • the title compound (yield 25%) was obtained according to the method of Example 3 using piperidine-4-carboxylic acid.
  • Example 45 N- ⁇ (1S, 3S) -3-[(2-Fluoroethyl) carbamoyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • the title compound (100% yield) was obtained according to the method of Example 3 using piperidine-4-carboxylic acid.
  • Example 46 N- ⁇ (1S, 3S) -3-[(2,3-dihydroxypropyl) carbamoyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- Carboxamide (1S, 3S) -3-Amino-N-[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] cyclohexanecarboxamide obtained in Reference Example 44 and Reference Example 2 Using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid, an amorphous substance (100%) was obtained according to the method of Example 3.
  • Example 47 Methyl (1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexanecarboxylate
  • Reference Example 45 The resulting methyl (1S, 3S) -3-aminocyclohexanecarboxylate hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 was used to give the title compound (84% yield) according to the method of Example 1.
  • Example 48 (1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexanecarboxylic acid Obtained in Example 47
  • Example 2 Using the resulting methyl (1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexanecarboxylate The title compound (51% yield) was obtained according to the above method.
  • Example 49 N-[(1S, 3S) -3- (dimethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Example 48 (1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexanecarboxylic acid and commercially available dimethylamine hydrochloride According to the method of Example 1, the title compound (yield 87%) was obtained.
  • Example 50 N-[(1S, 3S) -3-Cyanocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide benzyl obtained in Reference Example 40 Using (1S, 3S) -3-cyanocyclohexyl] carbamate, a solid was obtained according to the method of Reference Example 10. Using the obtained solid and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (recovery) was obtained according to the method of Example 3. 21%) was obtained.
  • Example 51 6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (1H-tetrazol-5-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3-cyanocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (400 mg, 1.15 mmol) obtained in Example 50 Trimethylsilyl azide (1.33 g, 11.6 mmol) and di-n-butyltin oxide (575 mg, 2.31 mmol) were added to a dimethoxyethane (20 mL) solution, and microwave irradiation was performed at 125 ° C for 90 minutes.
  • Example 52 N- ⁇ [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] carbonyl ⁇ - ⁇ -alanine hydrochloride tert-butyl N- ⁇ [(1S, 3S) -3-aminocyclohexyl] carbonyl ⁇ - ⁇ -alaninate obtained in Reference Example 46 and 1- (6- According to the method of Example 1, a condensate (90%) was obtained using methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid. Using the obtained compound, the title compound (yield 89%) was obtained according to the method of Reference Example 5.
  • Example 53 N-[(1S, 3S) -3- ⁇ [3- (dimethylamino) -3-oxopropyl] carbamoyl ⁇ cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl ) Piperidine-4-carboxamide N- ⁇ [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] obtained in Example 52] Carbonyl ⁇ amino) cyclohexyl] carbonyl ⁇ - ⁇ -alanine hydrochloride and commercially available dimethylamine hydrochloride were used to give the title compound (68% yield) according to the method of Example 3.
  • Example 54 2-Methyl-N- ⁇ [(1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) Cyclohexyl] carbonyl ⁇ alanine tert-butyl N- ⁇ [(1S, 3S) -3-aminocyclohexyl] carbonyl ⁇ -2-methylalaninate obtained in Reference Example 47 and 1- (6- Using methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid, an amorphous substance (80%) was obtained according to the method of Example 1.
  • Example 55 N-[(1S, 3S) -3- (1H-imidazol-2-yl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,2,4) obtained in Example 43 -Oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide in ethanol was added with 10% palladium on carbon (150 mg), and the mixture was stirred in a hydrogen atmosphere at room temperature and 5 atm for 16 hours.
  • Example 56 Ethyl (1S, 3R, 4R) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexane Carboxylate PCT WO 2007 / 032498A1 Ethyl (1S, 3R, 4R) -3-amino-4-hydroxycyclohexanecarboxylate described in the application specification and 1- (6-methyl-3-phenylquinoline--obtained in Reference Example 2 The title compound (yield 100%) was obtained according to the method of Example 1 using 2-yl) piperidine-4-carboxylic acid.
  • Example 57 N-[(1R, 2R, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Ethyl (1S, 3R, 4R) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino obtained in Example 56 ) Using cyclohexanecarboxylate, a solid (yield 91%) was obtained according to the method of Example 2.
  • Example 58 Ethyl (1S, 3R, 4S) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexane Carboxylate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and ethyl (1S, 3R, 4S) -3- obtained in Reference Example 48 Amino-4-hydroxycyclohexanecarboxylate hydrochloride was used to give the title compound (yield 100%) according to the method of Example 1.
  • Example 59 (1S, 3R, 4S) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl ⁇ amino) cyclohexanecarboxylic Acid
  • the title compound (yield 71%) was obtained as a solid according to the method of Example 2 using amino) cyclohexanecarboxylate.
  • Example 60 N-[(1R, 2S, 5S) -2-Hydroxy-5- (methoxycarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl ⁇ amino) obtained in Example 59
  • the title compound (99% yield) was obtained according to the method of Example 1 using cyclohexanecarboxylic acid and commercially available (aminooxy) methane hydrochloride.
  • Example 61 N-[(1R, 2S, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl ⁇ amino) obtained in Example 59
  • the title compound (yield 100%) was obtained according to the method of Example 3 using cyclohexanecarboxylic acid and commercially available ethylamine (2.0 M tetrahydrofuran solution).
  • Example 62 N-[(1R, 2S, 5S) -2-hydroxy-5- (methylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl ⁇ amino) obtained in Example 59
  • the title compound (73% yield) was obtained according to the method of Example 3 using cyclohexanecarboxylic acid and commercially available methylamine (2.0 M tetrahydrofuran solution).
  • Example 63 N-[(1R, 2S, 5S) -5-carbamoyl-2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • Example 59 (1S, 3R, 4S) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl ⁇ amino) cyclohexanecarboxylic acid obtained in The title compound (yield 96%) was obtained according to the method of Example 3 using commercially available 7N ammonia-methanol.
  • Example 64 N- ⁇ (1R, 2S, 5S) -2-hydroxy-5-[(2-hydroxyethyl) carbamoyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) Piperidine-4-carboxamide (1S, 3R, 4S) -4-hydroxy-3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl] obtained in Example 59 The title compound (yield 86%) was obtained according to the method of Example 3 using) carbonyl ⁇ amino) cyclohexanecarboxylic acid and commercially available 2-aminoethanol.
  • Example 65 N-[(1R, 5S) -5- (Ethylcarbamoyl) -2-oxocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example N-[(1R, 2S, 5S) -2-amino-5- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in 50 (154 mg, 0.299 mmol) in methanol (2.5 mL) was added commercially available 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (86.2 mg, 0.391 mmol).
  • Example 66 N-[(1S, 2R) -2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • Commercially available [(1R, 2S) -2-Aminocyclohexyl] methanol and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 were used according to the method of Example 1. The title compound (yield 83%) was obtained as a solid.
  • Example 67 N-[(1S, 2R) -4-fluoro-2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example Using benzyl [(1S, 2R) -4-fluoro-2- (hydroxymethyl) cyclohexyl] carbamate obtained in 55, the compound obtained according to the method of Reference Example 10 was converted to N, N-dimethylformamide. Dissolved. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 49%) as a solid.
  • Example 68 N-[(1S, 2R) -2- (hydroxymethyl) -4-oxocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example Using benzyl [(7R, 8S) -7- (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-8-yl] carbamate obtained in 56, according to the method of Reference Example 10 The resulting compound was dissolved in N, N-dimethylformamide. Using this reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, a condensate was obtained according to the method of Example 1.
  • Example 69 N-[(1S, 2R) -4,4-Difluoro-2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Using the tert-butyl [(1S, 2R) -4,4-difluoro-2- (hydroxymethyl) cyclohexyl] carbamate obtained in Reference Example 59, the compound obtained according to the method of Reference Example 5 was converted to N , N-dimethylformamide.
  • Example 70 N-[(3R, 4R) -4- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide Using tert-butyl [(3R, 4R) -4- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] carbamate obtained in Reference Example 60, The compound obtained according to the method of Reference Example 5 was dissolved in N, N-dimethylformamide.
  • Example 71 Ethyl [(1R, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl] acetate
  • Reference Example 2 6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and ethyl [(1R, 3S) -3-aminocyclopentyl] acetate hydrochloride obtained in Reference Example 61 were used.
  • Example 72 [(1R, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl] acetic acid Obtained in Example 71
  • Example 2 Using the obtained ethyl [(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl) acetate The title compound was obtained quantitatively according to the above method.
  • Example 73 N- ⁇ (1S, 3R) -3- [2- (methylamino) -2-oxoethyl] cyclopentyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide [(1R, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl] acetic acid obtained in Example 72 and The title compound (yield 79%) was obtained as a solid according to the method of Example 5 using commercially available methylamine (2.0 M tetrahydrofuran solution).
  • Example 74 N-[(1S, 3R) -3- (2-amino-2-oxoethyl) cyclopentyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide [(1R, 3S) -3-( ⁇ [1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl] acetic acid obtained in Example 72 and commercially available 7N The title compound (yield 93%) was obtained according to the method of Example 3 using ammonia-methanol.
  • Example 75 N-[(1S, 3R) -3- ⁇ 2-[(2-hydroxyethyl) amino] -2-oxoethyl ⁇ cyclopentyl] -1- (6-methyl-3-phenylquinoline-2- Yl) piperidine-4-carboxamide [(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino obtained in Example 72 ) Cyclopentyl] The title compound (yield 84%) was obtained as a solid according to the method of Example 1 using acetic acid and commercially available 2-aminoethanol.
  • Example 76 Methyl 2-methyl-N- ⁇ [(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino ) Cyclopentyl] acetyl ⁇ alaninate [(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) obtained in Example 72 The title compound (yield 88%) was obtained as a solid according to the method of Example 1 using cyclopentyl] acetic acid and commercially available methyl 2-methylalaninate hydrochloride.
  • Example 77 Ethyl 2-methyl-2-[(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl ] Propanoate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and ethyl 2-[(1R, 3S) -3 obtained in Reference Example 63 Using -aminocyclopentyl] -2-methylpropanoate, the title compound (yield 68%) was obtained according to the method of Example 1.
  • Example 78 2-Methyl-2-[(1R, 3S) -3-( ⁇ [1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclopentyl ]
  • carbonyl ⁇ amino) cyclopentyl] propanoate the title compound (yield 100%) was obtained as a solid according to the method of Example 2.
  • Example 79 1- (6-Methyl-3-phenylquinolin-2-yl) -N- (4-sulfamoylbenzyl) piperidine-4-carboxamide 1- (6-methyl) obtained in Reference Example 2 -3-Phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 4- (aminomethyl) benzenesulfonamide hydrochloride according to the method of Example 1 (yield 100%) was obtained as a solid.
  • Example 80 (6-Methyl-3-phenylquinolin-2-yl) -N- [4- (methylsulfamoyl) benzyl] piperidine-4-carboxamide 1- ( According to the method of Example 1, using 6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride The compound (yield 87%) was obtained as a solid.
  • Example 82 N-[(3S) -1- (Aminosulfonyl) piperidin-3-yl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • isocyanate 31.4 mL, 0.364 mmol
  • tert-butyl alcohol 120 mg, 0.364 mmol
  • 1- (6-methyl-3-phenylquinolin-2-yl) -N-[(3S) -piperidin-3-yl] piperidine-4-carboxamide 120 mg, 0.
  • Example 83 3-Hydroxy-N- ⁇ cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide
  • the method of Reference Example 2 using ethyl 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (low polarity) obtained in Reference Example 66 According to, a solid (yield 93%) was obtained.
  • 2- (cis-4-aminocyclohexyl) -N-methylacetamide hydrochloride obtained in Reference Example 7 the title compound (yield 52%) was obtained according to the method of Example 1. Obtained.
  • Example 84 3-Hydroxy-N- ⁇ cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained from Reference Example 68 (derived from highly polar substance) and 2 obtained in Reference Example 7 The title compound (yield 69%) was obtained using-(cis-4-aminocyclohexyl) -N-methylacetamide hydrochloride according to the method of Example 1.
  • Example 85 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide
  • Example 86 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1, 2,4-oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- obtained in Reference Example 68 Carboxylic acid (derived from highly polar substance) and 3-[(1S, 3S) -3-aminocyclohexyl] -1,2,4-oxadiazol-5 (4H) -one hydrochloride obtained in Reference Example 41 Used to give the title compound (diastereomer mixture, yield 69%) according to the method of Example 1.
  • Example 87 N-[(1R, 2S, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine -4-carboxamide 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained from Reference Example 68 (derived from highly polar substance) and obtained in Reference Example 48 Using ethyl (1S, 3R, 4S) -3-amino-4-hydroxycyclohexanecarboxylate hydrochloride, a solid (yield 95%) was obtained according to the method of Example 1.
  • Example 88 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine -4-carboxamide obtained in 1- (6-methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine-4-carboxylic acid obtained in Reference Example 69 and Reference Example 25 [(1S, 3S) -3-Amino-N-ethylcyclohexanecarboxamide was used according to the method of Example 1 to obtain the title compound (yield 71%).
  • Example 89 Ethyl [cis-4-( ⁇ [4-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate
  • Reference Example 70 Using ethyl (cis-4- ⁇ [(4-hydroxypiperidin-4-yl) carbonyl] amino ⁇ cyclohexyl) acetate hydrochloride obtained in step 1 and commercially available 2-chloro-6-methyl-3-phenylquinoline, The title compound (yield 57%) was obtained as a solid according to the method of Reference Example 1.
  • Example 90 [cis-4-( ⁇ [4-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid
  • Example 89 Using the obtained ethyl [cis-4-( ⁇ [4-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate The title compound (yield 100%) was obtained as a solid according to the method of Example 2.
  • Example 91 4-Hydroxy-N- ⁇ cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl ⁇ -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide [cis-4-( ⁇ [4-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid obtained in Example 90 The title compound (yield 86%) was obtained according to the method of Example 5 using commercially available methylamine (2.0 M tetrahydrofuran solution).
  • Example 92 [3- (4-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (4-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 73, an amorphous product was prepared according to the method of Reference Example 2. Obtained.
  • Example 93 1- [3- (3-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (3-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 74, an amorphous product was prepared according to the method of Reference Example 2. Obtained.
  • Example 94 1- [3- (2-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (2-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 75, an amorphous product was prepared according to the method of Reference Example 2. Obtained. Using the obtained amorphous product and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, the title compound was obtained according to the method of Example 3.
  • Example 95 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- [6-Methyl-3- (3-methylbut-1-in-1-yl) quinolin-2-yl] piperidine- 4-Carboxamide Reference was made using ethyl 1- [6-methyl-3- (3-methylbut-1-yn-1-yl) quinolin-2-yl] piperidine-4-carboxylate obtained in Reference Example 76. An amorphous material was obtained according to the method of Example 2.
  • Example 96 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- [3- (3-methoxyprop-1-in-1-yl) -6-methylquinolin-2-yl ] Piperidine-4-carboxamide Using ethyl 1- [3- (3-methoxyprop-1-in-1-yl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Reference Example 77 According to the method of Reference Example 2, an oily substance was obtained.
  • Example 97 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-prop-1-in-1-ylquinolin-2-yl) piperidine-4- Carboxamide
  • ethyl 1- (6-methyl-3-prop-1-in-1-ylquinolin-2-yl) piperidine-4-carboxylate obtained in Reference Example 78
  • An amorphous product was obtained.
  • Example 98 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- [3- (3-cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxamide
  • Reference Example 79 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid obtained and (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23 Using the salt, the title compound (yield 97%) was obtained as a solid according to the method of Example 1.
  • Example 99 [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
  • Reference 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid obtained in Example 79 and (1S, 3S) -3-amino obtained in Reference Example 25
  • the title compound (yield 98%) was obtained as a solid according to the method of Example 1 using -N-ethylcyclohexanecarboxamide.
  • Example 100 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-isopropenyl-6-methylquinolin-2-yl) piperidine-4-carboxamide Obtained in Reference Example 80 1- (3-Isopropenyl-6-methylquinolin-2-yl) piperidine-4-carboxylic acid obtained and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25 were used. According to the method of Example 1, the title compound (yield 94%) was obtained as a solid.
  • Example 101 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-pyridin-2-ylquinolin-2-yl) piperidine-4-carboxamide
  • Reference Example 81 1- [6-Methyl-3- (pyridin-2-yl) quinolin-2-yl] piperidine-4-carboxylic acid obtained in 1) and (1S, 3S) -3-amino- obtained in Reference Example 25
  • the title compound (yield 84%) was obtained according to the method of Example 1 using N-ethylcyclohexanecarboxamide.
  • Example 102 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- ⁇ 3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidine -4-carboxamide N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3- ⁇ 4- [2- (tetrahydro-2H-pyran) obtained in Reference Example 83 -2-yloxy) ethoxy] phenyl ⁇ quinolin-2-yl) piperidine-4-carboxamide (977 mg, 1.99 mmol) in ethanol (15 mL) was added 3N aqueous hydrochloric acid (1 mL) and stirred at room temperature for 15 hours.
  • Example 104 1- [3- (4-Aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
  • ethyl 1- (3- ⁇ 4-[(tert-butoxycarbonyl) amino] phenyl ⁇ -6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in Example 84, A solid (yield 100%) was obtained according to the method.
  • Example 105 1- (3- ⁇ 4-[(Dimethylsulfamoyl) amino] phenyl ⁇ -6-methylquinolin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) Cyclohexyl] piperidine-4-carboxamide 1- [3- (4-aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) obtained in Example 104 ) Cyclohexyl] piperidine-4-carboxamide (160 mg, 0.312 mmol) in pyridine, a small amount of N, N-dimethylpyridin-4-amine and dimethylsulfamoyl chloride (150 ⁇ L, 1.40 mmol) were added to room temperature.
  • Example 106 1- ⁇ 3- [4- (acetylamino) phenyl] -6-methylquinolin-2-yl ⁇ -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4 -Carboxamide 1- [3- (4-Aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine obtained in Example 104 Acetic anhydride (0.0184 mL, 0.195 mmol) was added to a pyridine solution of 4-carboxamide (50.0 mg, 0.0973 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3.5 hours.
  • Example 107 Ethyl 2- (cis-4- ⁇ [(1- ⁇ 3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidin-4-yl) carbonyl] Amino ⁇ cyclohexyl) -2-methylpropanoate 1- (6-methyl-3- ⁇ 4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinoline obtained in Reference Example 82 2-yl) piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 and an oily substance according to the method of Example 1 (89%) was obtained.
  • Example 108 2- (cis-4- ⁇ [(1- ⁇ 3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidin-4-yl) carbonyl] amino ⁇ Cyclohexyl) -2-methylpropanoic acid
  • Ethyl 2- (cis-4- ⁇ [(1- ⁇ 3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinoline-2] obtained in Example 107
  • the title compound (yield 74%) was obtained as a solid according to the method of Example 2.
  • Example 109 Ethyl 2- [cis-4-( ⁇ [1- (3- ⁇ 4-[(2-hydroxyethyl) amino] phenyl ⁇ -6-methylquinolin-2-yl) piperidin-4-yl ] Carbonyl ⁇ amino) cyclohexyl] -2-methylpropanoate 1- [3- (4- ⁇ (tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy)] obtained in Reference Example 85 [Ethyl] amino ⁇ phenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 According to the method of Example 1, an oily substance (89%) was obtained.
  • Example 110 2- [cis-4-( ⁇ [1- (3- ⁇ 4-[(2-hydroxyethyl) amino] phenyl ⁇ -6-methylquinolin-2-yl) piperidin-4-yl] Carbonyl ⁇ amino) cyclohexyl] -2-methylpropanoic acid (Example 111) 2- ⁇ cis-4-[( ⁇ 1- [3- (4-aminophenyl) -6-methylquinolin-2-yl] piperidine- 4-yl ⁇ carbonyl) amino] cyclohexyl ⁇ -2-methylpropanoic acid ethyl 2- [cis-4-( ⁇ [1- (3- ⁇ 4-[(2-hydroxyethyl) amino] obtained in Example 109 ]] ⁇ -6-methylquinolin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] -2
  • Example 112 Ethyl 2- (cis-4- ⁇ [(1- ⁇ 3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidin-4-yl) carbonyl] Amino ⁇ cyclohexyl) -2-methylpropanoate 1- (6-methyl-3- ⁇ 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinoline obtained in Reference Example 88 2-yl) piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 and an oily substance according to the method of Example 1 (80%) was obtained.
  • Example 113 2- (cis-4- ⁇ [(1- ⁇ 3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidin-4-yl) carbonyl] amino ⁇ Cyclohexyl) -2-methylpropanoic acid
  • the title compound (yield 60%) was obtained according to the method of Example 2 using -yl ⁇ piperidin-4-yl) carbonyl] amino ⁇ cyclohexyl) -2-methylpropanoate.
  • Example 114 [cis-4-( ⁇ [1- (3- ⁇ 3-[(2-hydroxyethyl) amino] phenyl ⁇ -6-methylquinolin-2-yl) piperidin-4-yl] Carbonyl ⁇ amino) cyclohexyl] -2-methylpropanoic acid 1- [3- (3- ⁇ (tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] obtained in Reference Example 89 Amino ⁇ phenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Example 17 A condensate (64%) was obtained according to the method of Example 1.
  • Example 115 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- ⁇ 3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidine -4-carboxamide 1- (6-methyl-3- ⁇ 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinolin-2-yl) piperidine-4 obtained in Reference Example 88 Using the carboxylic acid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25, a condensate (yield 96%) was obtained according to
  • Example 116 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- ⁇ 3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl ⁇ piperidine-4- Carboxamide 1- (6-Methyl-3- ⁇ 3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl ⁇ quinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 88 Using (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23, an oily substance (yield 70%) was obtained according to the method of Example 1. Using the obtained oil, the title compound (yield 77%) was obtained according to the method of Example 102.

Abstract

Provided are: compounds having a preventive or therapeutic effect against chronic rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, dermatitis, including psoriasis, etc.; a pharmaceutical composition containing said compounds; and a method for preventing or treating inflammatory diseases, characterized in that an effective dose of the pharmaceutical composition is administered to mammals. The present invention involves the compounds represented by general formula (I) or pharmaceutically acceptable salts thereof.

Description

新規キノリン誘導体New quinoline derivatives
　本発明は、抗炎症作用を有するキノリン誘導体、その塩、またはそれらの溶媒和物を含有するプロスタグランジンE2産生抑制剤に関する。 The present invention relates to a prostaglandin E 2 production inhibitor containing a quinoline derivative having an anti-inflammatory action, a salt thereof, or a solvate thereof.
　ホスホリパーゼA2により細胞膜リン脂質からアラキドン酸（AA）が遊離し、それがシクロオキシゲナーゼ（COX）によりプロスタグランジンG2（PGG2）を経てプロスタグランジンH2（PGH2）が合成される。このPGH2がそれぞれの変換酵素によりプロスタグランジンD2（PGD2）、プロスタグランジンE2（PGE2）、プロスタグランジンF2α（PGF2α）、プロスタグランジンI2（PGI2）ならびにトロンボキサンA2（TXA2）に変換されることで、プロスタノイドは産生される。 Arachidonic acid (AA) is released from cell membrane phospholipid by phospholipase A 2, and prostaglandin H 2 (PGH 2 ) is synthesized through prostaglandin G 2 (PGG 2 ) by cyclooxygenase (COX). This PGH 2 can be converted into prostaglandin D 2 (PGD 2 ), prostaglandin E 2 (PGE 2 ), prostaglandin F 2α (PGF 2α ), prostaglandin I 2 (PGI 2 ), and thrombos by each converting enzyme. Prostanoids are produced by conversion to xan A 2 (TXA 2 ).
　中でも、生体内において最も豊富に存在するプロスタノイドと考えられているPGE2は、痛覚過敏、発熱、血管平滑筋弛緩、胃酸分泌抑制、気管支平滑筋弛緩、子宮収縮など、中枢から末梢にわたり多彩な生理活性を有していることが知られている。PGE2のみならず他のプロスタノイドの生理活性も解明されつつあり、これらは、生体の恒常性の維持に重要な役割を担っているが、一方で、様々な病態の形成、進行ならびに持続に深く関与していると考えられている。 Among them, PGE 2 , which is considered to be the most abundant prostanoid in the body, has a variety of from the center to the periphery, including hyperalgesia, fever, vascular smooth muscle relaxation, gastric acid secretion suppression, bronchial smooth muscle relaxation, and uterine contraction. It is known to have physiological activity. The physiological activities of not only PGE 2 but also other prostanoids are being elucidated, and they play an important role in maintaining the homeostasis of living organisms. It is considered deeply involved.
　COXにはCOX-1とCOX-2の２つのアイソザイムが存在する。現在、代表的な消炎鎮痛剤として使用されている非ステロイド性抗炎症薬（NSAIDs）は、COX-1とCOX-2の両方を阻害する。NSAIDsは胃腸保護作用に関与するCOX-1由来のプロスタノイドの産生を阻害するため、胃腸障害を高頻度で惹起することが問題となっている（非特許文献１）。
また、炎症刺激により発現誘導されるCOX-2に対して選択的な阻害作用を示すCOX-2阻害剤は、胃腸障害の副作用は少ない薬剤であるが、心血管系イベント発生のリスクが問題となっている。COX-2選択的阻害剤は血小板凝集抑制や心臓保護の役割を果たしているCOX-2由来のPGI2の産生を抑制する一方、凝固系において相反する作用を有するCOX-1由来のTXA2の産生を抑制しないことがその原因の1つと考えられている（非特許文献２）。 COX has two isozymes, COX-1 and COX-2. Non-steroidal anti-inflammatory drugs (NSAIDs) currently used as typical anti-inflammatory analgesics inhibit both COX-1 and COX-2. Since NSAIDs inhibit the production of COX-1-derived prostanoids involved in the gastrointestinal protective action, causing gastrointestinal disorders at a high frequency is a problem (Non-patent Document 1).
In addition, COX-2 inhibitors that have a selective inhibitory action on COX-2 induced by inflammatory stimuli are drugs with few side effects of gastrointestinal disorders, but the risk of cardiovascular events is a problem. It has become. COX-2 selective inhibitor suppresses the production of PGI 2 derived from COX-2, which plays a role in inhibiting platelet aggregation and cardioprotection, while producing TXA 2 derived from COX-1 which has a contradictory effect in the coagulation system It is considered that one of the causes is not to suppress (Non-patent Document 2).
　従来、炎症性疾患等の治療においては、対症療法としてステロイドなどの抗炎症薬が使用されており、その副作用の発現が問題となっている。また、そうした副作用を回避するために非ステロイド性抗炎症薬や新たなNSAIDsの開発も進められているが、上述のように依然として副作用の発現に苦しんでおり、根本的治療法の開発が望まれている。 Conventionally, in the treatment of inflammatory diseases and the like, anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the occurrence of side effects has become a problem. In addition, in order to avoid such side effects, non-steroidal anti-inflammatory drugs and new NSAIDs are being developed, but as mentioned above, they still suffer from side effects, and the development of fundamental therapies is desired. ing.
　このような背景から、副作用が少なく、優れた抗炎症作用を有する化合物を見出すことが試みられている。これまでに、本発明の背景技術として、以下に示す文献が知られている。 From such a background, an attempt has been made to find a compound having few side effects and an excellent anti-inflammatory action. So far, the following documents are known as background art of the present invention.
WO2006/063466WO2006 / 063466 WO2007/134434WO2007 / 134434 WO2011/023812WO2011 / 023812 WO2007/042816WO2007 / 042816 WO2008/071944WO2008 / 071944 WO2010/034796WO2010 / 034796 WO2012/022793WO2012 / 022793 WO2010/132016WO2010 / 132016 WO2011/077313WO2011 / 077313 WO2011/131975WO2011 / 131975
　本発明者らは、副作用が少なく優れた抗炎症作用を有する新規化合物に関して、長年に亘り鋭意検討を重ねた結果、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、またはアルツハイマー病等に有用である新規化合物を見出して、本発明を完成した。 As a result of intensive studies over many years on novel compounds having excellent anti-inflammatory activity with few side effects, the present inventors have found that rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory diseases, inflammatory bowel Nerves such as diseases, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, diabetic neuralgia , Pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, strong Dermatosis, atherosclerosis and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, frequent Sclerosis, or useful in Alzheimer's disease and the like found a novel compound, and completed the present invention.
　したがって、本発明の課題は、副作用が少なく優れた抗炎症作用を有する新規化合物、その薬理上許容される塩を提供することである。
  Therefore, an object of the present invention is to provide a novel compound having an excellent anti-inflammatory action with few side effects and a pharmacologically acceptable salt thereof.
　すなわち本発明は、
（１）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩。 That is, the present invention
(1) A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000007
 ｛式中、Ｒ１、Ｒ２，Ｒ３、Ｒ４、Ｒ５、およびＲ６は、それぞれ独立に、水素原子；Ｃ１－Ｃ６アルキル基；置換基群αから選択される基で置換されていてもよいエテニル基もしくはエチニル基、又は、置換基群βから選択される基で置換されていてもよいフェニル基もしくはピリジニル基を表わし、
Ｙ１およびＹ２は、それぞれ独立に、水素原子；水酸基；オキソ基；カルボキシ基で置換されていてもよいメチリデン基；置換基群γから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基；置換基群δから選択される基で置換されていてもよいカルバモイル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基；オキソ基で置換されていてもよいトリアゾリル基；オキソ基で置換されていてもよいオキサジアゾリル基；テトラゾリル基；イミダゾリル基；シアノ基；又は１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基を表わし、
Ｘは、水素原子又は水酸基を表わし、
ｎは、０又は１を表わし、
　式：
Figure JPOXMLDOC01-appb-C000007
 {Wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently substituted with a group selected from a hydrogen atom; a C 1 -C 6 alkyl group; and a substituent group α An ethenyl group or an ethynyl group which may be substituted, or a phenyl group or a pyridinyl group which may be substituted with a group selected from the substituent group β,
Y 1 and Y 2 are each independently a hydrogen atom; a hydroxyl group; an oxo group; a methylidene group optionally substituted with a carboxy group; or a group substituted with 1 to 3 groups selected from the substituent group γ good C 1 -C 6 alkyl group; substituted with an oxo group; optionally substituted with C 1 -C 6 alkyl group a carboxy group; which may have a carbamoyl group substituted with a group selected from substituent group δ An optionally substituted triazolyl group; an oxadiazolyl group optionally substituted with an oxo group; a tetrazolyl group; an imidazolyl group; a cyano group; or a sulfamoyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups. Represent,
X represents a hydrogen atom or a hydroxyl group;
n represents 0 or 1,
formula:
Figure JPOXMLDOC01-appb-C000008
 は、式：
Figure JPOXMLDOC01-appb-C000008
 The formula:
Figure JPOXMLDOC01-appb-C000009
 又は、式：
Figure JPOXMLDOC01-appb-C000009
 Or the formula:
Figure JPOXMLDOC01-appb-C000010
 を表わし、
環Ａは、５～６員の飽和もしくは不飽和の炭化水素環、又は５～６員の飽和もしくは不飽和の複素環を表わす。
置換基群αは、ハロゲン原子；Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基；Ｃ１－Ｃ６アルコキシ基；Ｃ１－Ｃ６アルカノイル基；およびカルボキシ基を表し、
置換基群βは、ハロゲン原子；シアノ基；水酸基で置換されていてもよいＣ１－Ｃ６アルコキシ基；１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基、水酸基で置換されていてもよいＣ１－Ｃ６アルキル基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基を表し、
置換基群γは、Ｃ１－Ｃ６アルキル基；水酸基で置換されていてもよいＣ１－Ｃ６アルキル基およびＣ１－Ｃ６アルコキシ基から選択される基で置換されていてもよいカルバモイル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基；シアノ基；水酸基；オキソ基で置換されていてもよいトリアゾリル基；および、オキソ基で置換されていてもよいオキサジアゾリル基を表し、
置換基群δは、１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基、水酸基、ハロゲン原子、およびカルボキシ基から選択される基で置換されていてもよいＣ１－Ｃ６アルキル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいスルホニル基、Ｃ１－Ｃ６アルコキシ基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基；およびＣ１－Ｃ６アルコキシ基を表す。｝、
好適には、
（２）ｎが０である、請求項１に記載の化合物又はその薬理上許容される塩、
（３）　式：
Figure JPOXMLDOC01-appb-C000010
 Represents
Ring A represents a 5- to 6-membered saturated or unsaturated hydrocarbon ring or a 5- to 6-membered saturated or unsaturated heterocycle.
Substituent group α is a halogen atom; a C 1 -C 6 alkyl group optionally substituted with a C 1 -C 6 alkoxy group; a C 1 -C 6 alkoxy group; a C 1 -C 6 alkanoyl group; and a carboxy group Represents
Substituent group β is a halogen atom; a cyano group; a C 1 -C 6 alkoxy group optionally substituted with a hydroxyl group; a sulfamoyl group or a hydroxyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups An amino group optionally substituted with a group selected from a C 1 -C 6 alkyl group optionally substituted with, and a C 1 -C 6 alkanoyl group;
Substituent group γ is a C 1 -C 6 alkyl group; a carbamoyl optionally substituted with a group selected from a C 1 -C 6 alkyl group optionally substituted with a hydroxyl group and a C 1 -C 6 alkoxy group A carboxy group optionally substituted with a C 1 -C 6 alkyl group; a cyano group; a hydroxyl group; a triazolyl group optionally substituted with an oxo group; and an oxadiazolyl group optionally substituted with an oxo group; Represent,
Substituent group δ is 1 or 2 of C 1 -C 6 alkyl carbamoyl group which may be substituted by a group, a hydroxyl group, a halogen atom, and carboxy may be substituted by a group selected from group C 1 - C 6 alkyl group; C 1 -C 6 alkyl optionally sulfonyl group optionally substituted with a group, C 1 -C 6 alkoxy groups, and C 1 -C 6 groups selected from alkanoyl group may be substituted An amino group; and a C 1 -C 6 alkoxy group. },
Preferably,
(2) The compound or pharmacologically acceptable salt thereof according to claim 1, wherein n is 0,
(3) Formula:
Figure JPOXMLDOC01-appb-C000011
 が、式：
Figure JPOXMLDOC01-appb-C000011
 But the formula:
Figure JPOXMLDOC01-appb-C000012
 である、上記（１）又は（２）に記載の化合物又はその薬理上許容される塩、
（４）Ｒ１が、置換基群βから選択される基で置換されていてもよいフェニル基である、上記（１）乃至（３）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（５）Ｒ２，Ｒ３、Ｒ５、およびＲ６がいずれも水素原子である、上記（１）乃至（４）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（６）Ｒ４が、Ｃ１－Ｃ６アルキル基である、上記（１）乃至（５）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（７）環Ａが５～６員の飽和もしくは不飽和の炭化水素環である、上記（１）乃至（６）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（８）環Ａが５～６員の飽和もしくは不飽和の複素環である、上記（１）乃至（６）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（９）環Ａがシクロペンタン環、シクロヘキサン環、又はベンゼン環である、上記（１）乃至（７）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（１０）環Ａがシクロペンタン環、テトラヒドロピラン環、ベンゼン環、ピペリジン環、又はシクロヘキサン環である、上記（１）乃至（９）のいずれか１項に記載の化合物又はその薬理上許容される塩、
Figure JPOXMLDOC01-appb-C000012
 The compound according to the above (1) or (2) or a pharmacologically acceptable salt thereof,
(4) The compound according to any one of (1) to (3) above or a pharmacologically acceptable salt thereof, wherein R 1 is a phenyl group optionally substituted with a group selected from substituent group β. Salt,
(5) The compound according to any one of (1) to (4) or a pharmacologically acceptable salt thereof, wherein R 2 , R 3 , R 5 and R 6 are all hydrogen atoms.
(6) The compound according to any one of (1) to (5) above, wherein R 4 is a C 1 -C 6 alkyl group, or a pharmacologically acceptable salt thereof,
(7) The compound according to any one of the above (1) to (6) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 6-membered saturated or unsaturated hydrocarbon ring,
(8) The compound according to any one of the above (1) to (6) or a pharmacologically acceptable salt thereof, wherein ring A is a 5- to 6-membered saturated or unsaturated heterocyclic ring,
(9) The compound according to any one of (1) to (7) or a pharmacologically acceptable salt thereof, wherein ring A is a cyclopentane ring, a cyclohexane ring, or a benzene ring,
(10) The compound according to any one of (1) to (9) above or a pharmacologically acceptable ring, wherein ring A is a cyclopentane ring, a tetrahydropyran ring, a benzene ring, a piperidine ring, or a cyclohexane ring. salt,
（１１）一般式（Ｉ）を有する化合物が以下の化合物群から選択される化合物である、上記（１）記載の化合物又はその薬理上許容される塩、
２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸、
１－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボン酸、
Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド、
Ｎ－［（１Ｓ，３Ｓ)－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド、
２－メチル－２－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸、
１－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボン酸、
Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－５－（エチルカルバモイル）－２－ヒドロキシシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド、
Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－５－カルバモイル－２－ヒドロキシシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド、
２－メチル－２－［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロペンチル］プロパン酸、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－カルボキサミド、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－｛４－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－カルボキサミド、
２－（シス－４－｛［（１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパン酸、
２－［シス－４－（｛［１－（３－｛３－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパン酸、および、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－カルボキサミド (11) The compound according to (1) or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the following compound group:
2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid,
1- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylic acid,
N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide;
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide;
2-methyl-2-[(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid,
1-[(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylic acid,
N-[(1R, 2S, 5S) -5- (ethylcarbamoyl) -2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide;
N-[(1R, 2S, 5S) -5-carbamoyl-2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide;
2-methyl-2-[(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl] propanoic acid,
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidine-4-carboxamide;
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3- {4-[(2-hydroxyethyl) amino] phenyl} -6-methylquinolin-2-yl) piperidine-4 -Carboxamide,
2- (cis-4-{[(1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidin-4-yl) carbonyl] amino} cyclohexyl) -2 -Methylpropanoic acid,
2- [cis-4-({[1- (3- {3-[(2-hydroxyethyl) amino] phenyl} -6-methylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl ] -2-methylpropanoic acid, and
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidine-4-carboxamide
（１２）一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物、
（１３）プロスタグランジンE2により介在される疾患を予防又は治療するために用いるための、上記（１２）に記載された医薬組成物、
（１４）プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、又はアルツハイマー病である、上記（１３）に記載された医薬組成物、
（１５））プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である、上記（１３）乃至（１４）に記載された医薬組成物、又は、
（１６）一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、炎症性疾患の予防方法又は治療方法、
である。 (12) A pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient,
(13) The pharmaceutical composition according to the above (12) for use in preventing or treating a disease mediated by prostaglandin E 2 ,
(14) Diseases mediated by prostaglandin E 2 are rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, Edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, self Immune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and associated myocardial infarction, In (13) above, which is a stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease Record And pharmaceutical compositions,
(15)) Diseases mediated by prostaglandin E 2 are rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis Or a dermatitis including psoriasis, or a pharmaceutical composition according to the above (13) to (14), or
(16) A method for preventing inflammatory diseases, comprising administering to a mammal an effective amount of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient Method of treatment,
It is.
　本発明の化合物又はその薬理上許容される塩は、副作用が少なく優れた抗炎症作用を有し、温血動物（特に、ヒト）に対する炎症性疾患又はその他炎症関連疾患の予防剤若しくは治療剤として有用である。 The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent anti-inflammatory action with few side effects, and is used as a prophylactic or therapeutic agent for inflammatory diseases or other inflammation-related diseases for warm-blooded animals (particularly humans). Useful.
縦軸には炎症組織中プロスタグランジンE2の産生を示す。実施例化合物２５の用量依存的な抑制作用を示したものである。The vertical axis shows the production of prostaglandin E 2 in the inflamed tissue. 1 shows the dose-dependent inhibitory action of Example Compound 25.
　以下に本明細書中の置換基について説明する。 The substituents in this specification will be described below.
　ハロゲン原子は、具体的には、フッ素原子、塩素原子、臭素原子、又は、ヨウ素原子であり、好適には、フッ素原子、又は、塩素原子であり、さらに好適にはフッ素原子である。
　Ｃ１－Ｃ６アルキル基とは、直鎖であっても分枝鎖であっても環構造であってもよく、鎖中に１乃至６個の炭素原子を含む、脂肪族炭化水素基を意味する。分枝とは、１個以上の低級アルキル基（例えば、メチル基、エチル基又はプロピル基）が、直鎖アルキル鎖に結合していることを意味する。具体的には、メチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等である。好適には、メチル基、エチル基、プロピル基、シクロプロピル基、イソプロピル基、又は、ｔｅｒｔ－ブチル基であり、さらに好適には、メチル基、エチル基、又はシクロプロピル基である。 The halogen atom is specifically a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
The C 1 -C 6 alkyl group may be a straight chain, branched chain or ring structure, and is an aliphatic hydrocarbon group containing 1 to 6 carbon atoms in the chain. means. Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a tert-butyl group, a pentyl group, and a hexyl group. A methyl group, an ethyl group, a propyl group, a cyclopropyl group, an isopropyl group, or a tert-butyl group is preferable, and a methyl group, an ethyl group, or a cyclopropyl group is more preferable.
　Ｃ１－Ｃ６アルコキシ基とは、上記Ｃ１－Ｃ６アルキル基に酸素原子が結合した、アルキル－Ｏ基を意味し、鎖中に１乃至６個の炭素原子を含む。好適には、炭素数１乃至３個である。具体例としては、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、ヘプトキシおよびメチルヒドロキシ等が挙げられ、好適には、メトキシ基、エトキシ基、プロポキシ基、又は、イソプロポキシ基であり、さらに好適には、メトキシ基である。
　Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基とは、具体的には、メトキシメチル基、１－メトキシエチル基、２－メトキシエチル基、１－メトキシプロピル基、２－メトキシプロピル基、３－メトキシプロピル基、エトキシメチル基、１－エトキシエチル基、２－エトキシエチル基、１－エトキシプロピル基、２－エトキシプロピル基、３－エトキシプロピル基、プロポキシメチル基、１－プロポキシエチル基、２－プロポキシエチル基、１－プロポキシプロピル基、２－プロポキシプロピル基、３－プロポキシプロピル基等を挙げることができ、好適には、メトキシメチル基である。
　Ｃ１－Ｃ６アルカノイル基とは、水素原子、又は、飽和若しくは不飽和の炭素数１乃至６の鎖状、分岐、若しくは環状炭化水素基がカルボニル基に結合した基であり、具体例としては、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、シクロプロピオニル基、シクロブチリル基、又は、シクロペンタノイル基等を挙げることができ、好適には、アセチル基、又はプロピオニル基であり、さらに好適には、アセチル基である。 The C 1 -C 6 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the C 1 -C 6 alkyl group, and contains 1 to 6 carbon atoms in the chain. Preferably, it has 1 to 3 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy, preferably methoxy group, ethoxy group, propoxy group or isopropoxy group, More preferably, it is a methoxy group.
Specific examples of the C 1 -C 6 alkyl group optionally substituted by a C 1 -C 6 alkoxy group include a methoxymethyl group, a 1-methoxyethyl group, a 2-methoxyethyl group, and a 1-methoxypropyl group. 2-methoxypropyl group, 3-methoxypropyl group, ethoxymethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group, 1-ethoxypropyl group, 2-ethoxypropyl group, 3-ethoxypropyl group, propoxymethyl group 1-propoxyethyl group, 2-propoxyethyl group, 1-propoxypropyl group, 2-propoxypropyl group, 3-propoxypropyl group and the like, and methoxymethyl group is preferable.
The C 1 -C 6 alkanoyl group is a group in which a hydrogen atom or a saturated or unsaturated C 1-6 chain, branched or cyclic hydrocarbon group is bonded to a carbonyl group. , Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, cyclopropionyl group, cyclobutyryl group, or cyclopentanoyl group. A propionyl group, more preferably an acetyl group.
　置換基群αから選択される基で置換されていてもよいエテニル基もしくはエチニル基は、好適には、１－メチルエテニル基、２－メチルエチニル基、２－メトキシメチルエチニル基、又は２－イソプロピルエチニル基である。
　水酸基で置換されていてもよいＣ１－Ｃ６アルコキシ基は、具体的には、２－ヒドロキシエトキシ基、２－ヒドロキシプロポキシ基、３－ヒドロキシプロポキシ基、２－ヒドロキシブトキシ基、３－ヒドロキシブトキシ基、４－ヒドロキシブトキシ基、２－ヒドロキシペントキシ基、３－ヒドロキシペントキシ基、４－ヒドロキシペントキシ基、５－ヒドロキシペントキシ基、２－ヒドロキシヘキソキシ基、３－ヒドロキシヘキソキシ基、４－ヒドロキシヘキソキシ基、５－ヒドロキシヘキソキシ基、又は６－ヒドロキシヘキソキシ基である。好適には、２－ヒドロキシエトキシ基、又は３－ヒドロキシプロポキシ基であり、さらに好適には、２－ヒドロキシエトキシ基である。
　１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基は、具体的には、スルファモイル基、メチルスルファモイル基、エチルスルファモイル基、プロピルスルファモイル基、イソプロピルスルファモイル基、ジメチルスルファモイル基、メチル（エチル）スルファモイル基、ジエチルスルファモイル基、エチル（プロピル）スルファモイル基、又はジプロピルスルファモイル基等であり、好適には、スルファモイル基、メチルスルファモイル基、又はジメチルスルファモイル基である。 The ethenyl group or ethynyl group which may be substituted with a group selected from the substituent group α is preferably a 1-methylethenyl group, a 2-methylethynyl group, a 2-methoxymethylethynyl group, or 2-isopropylethynyl It is a group.
Specific examples of the C 1 -C 6 alkoxy group which may be substituted with a hydroxyl group include 2-hydroxyethoxy group, 2-hydroxypropoxy group, 3-hydroxypropoxy group, 2-hydroxybutoxy group, 3-hydroxybutoxy group. Group, 4-hydroxybutoxy group, 2-hydroxypentoxy group, 3-hydroxypentoxy group, 4-hydroxypentoxy group, 5-hydroxypentoxy group, 2-hydroxyhexoxy group, 3-hydroxyhexoxy group, 4-hydroxyhexoxy group, 5-hydroxyhexoxy group, or 6-hydroxyhexoxy group. A 2-hydroxyethoxy group or a 3-hydroxypropoxy group is preferable, and a 2-hydroxyethoxy group is more preferable.
Specific examples of the sulfamoyl group which may be substituted with 1 to 2 C 1 -C 6 alkyl groups include sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, A famoyl group, a dimethyl sulfamoyl group, a methyl (ethyl) sulfamoyl group, a diethyl sulfamoyl group, an ethyl (propyl) sulfamoyl group, or a dipropyl sulfamoyl group, preferably a sulfamoyl group, a methyl sulfamoyl group; A moyl group or a dimethylsulfamoyl group.
　水酸基で置換されていてもよいＣ１－Ｃ６アルキル基は、具体的には、ヒドロキシメチル基、１－ヒドロキシエチル基、２－ヒドロキシエチル基、１－ヒドロキシプロピル基、２－ヒドロキシプロピル基、３－ヒドロキシプロピル基、シクロプロピル基、１－ヒドロキシブチル基、２－ヒドロキシブチル基、３－ヒドロキシブチル基、４－ヒドロキシブチル基、１－ヒドロキシペンチル基、２－ヒドロキシペンチル基、３－ヒドロキシペンチル基、４－ヒドロキシペンチル基、５－ヒドロキシペンチル基、１－ヒドロキシヘキシル基、２－ヒドロキシヘキシル基、３－ヒドロキシヘキシル貴、４－ヒドロキシヘキシル基、５－ヒドロキシヘキシル基、又は６－ヒドロキシヘキシル基等を挙げることができ、好適には、ヒドロキシメチル基、又は２－ヒドロキシエチル基である。
　１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基、水酸基で置換されていてもよいＣ１－Ｃ６アルキル基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基は、好適には、アミノ基、ジメチルスルファモイルアミノ基、２－ヒドロキシエチルアミノ基、又はアセチルアミノ基である。 Specific examples of the C 1 -C 6 alkyl group optionally substituted with a hydroxyl group include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, 3-hydroxypropyl group, cyclopropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxypentyl group, 2-hydroxypentyl group, 3-hydroxypentyl Group, 4-hydroxypentyl group, 5-hydroxypentyl group, 1-hydroxyhexyl group, 2-hydroxyhexyl group, 3-hydroxyhexyl noble, 4-hydroxyhexyl group, 5-hydroxyhexyl group, or 6-hydroxyhexyl group Preferably, a hydroxymethyl group, Is a 2-hydroxyethyl group.
A group selected from a sulfamoyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups, a C 1 -C 6 alkyl group optionally substituted with a hydroxyl group, and a C 1 -C 6 alkanoyl group The amino group which may be substituted with is preferably an amino group, a dimethylsulfamoylamino group, a 2-hydroxyethylamino group, or an acetylamino group.
　置換基群βから選択される基で置換されていてもよいフェニル基もしくはピリジニル基は、好適には、フェニル基、３－シアノフェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、４－アミノフェニル基、３－［（２－ヒドロキシ）エトキシ］フェニル基、４－［（２－ヒドロキシ）エトキシ］フェニル基、３－［（２－ヒドロキシエチル）アミノ］フェニル基、４－［（２－ヒドロキシエチル）アミノ］フェニル基、４－（ジメチルスルファモイルアミノ）フェニル基、又は４－（アセチルアミノ）フェニル基である。
　Ｒ１は、好適には、置換基群αから選択される基で置換されていてもよいエテニル基もしくはエチニル基、又は、置換基群βから選択される基で置換されていてもよいフェニル基である。
　Ｒ２、Ｒ３、Ｒ５、及びＲ６は、好適には、水素原子である。
　Ｒ４は、好適には、メチル基である。 The phenyl group or pyridinyl group which may be substituted with a group selected from the substituent group β is preferably a phenyl group, a 3-cyanophenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, 4- Fluorophenyl group, 4-aminophenyl group, 3-[(2-hydroxy) ethoxy] phenyl group, 4-[(2-hydroxy) ethoxy] phenyl group, 3-[(2-hydroxyethyl) amino] phenyl group, 4-[(2-hydroxyethyl) amino] phenyl group, 4- (dimethylsulfamoylamino) phenyl group, or 4- (acetylamino) phenyl group.
R 1 is preferably an ethenyl group or ethynyl group optionally substituted with a group selected from substituent group α, or a phenyl group optionally substituted with a group selected from substituent group β It is.
R 2 , R 3 , R 5 , and R 6 are preferably a hydrogen atom.
R 4 is preferably a methyl group.
　水酸基で置換されていてもよいＣ１－Ｃ６アルキル基およびＣ１－Ｃ６アルコキシ基から選択される基で置換されていてもよいカルバモイル基は、具体的には、カルバモイル基、メチルカルバモイル基、エチルカルバモイル基、プロピルカルバモイル基、シクロプロピルカルバモイル基、ブチルカルバモイル基、ペンチルカルバモイル基、ヘキシルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、２－ヒドロキシエチルカルバモイル基、２－ヒドロキシプロピルカルバモイル基、３－ヒドロキシプロピルカルバモイル基、２－ヒドロキシシクロプロピルカルバモイル基、２－ヒドロキシブチルカルバモイル基、３－ヒドロキシブチルカルバモイル基、４－ヒドロキシブチルカルバモイル基、メトキシカルバモイル基、エトキシカルバモイル基、プロポキシカルバモイル基、ブトキシカルバモイル基、ペントキシカルバモイル基、ヘキソキシカルバモイル基等を挙げることができ、好適には、カルバモイル基、メチルカルバモイル基、２－ヒドロキシエチルカルバモイル基、エチルカルバモイル基、メトキシカルバモイル基、又はシクロプロピルカルバモイル基である。
　Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基は、具体的には、カルボキシ基、メチルカルボキシ基、エチルカルボキシ基、プロピルカルボキシ基、ブチルカルボキシ基、ｔｅｒｔ－ブチルカルボキシ基、ペンチルカルボキシ基、ヘキシルカルボキシ基、ベンジルカルボキシ基等を挙げることができ、好適には、メチルカルボキシ基、エチルカルボキシ基、プロピルカルボキシ基であり、さらに好適には、エチルカルボキシ基である。
　オキソ基で置換されていてもよいトリアゾリル基は、１，２，３－トリアゾリル基、１，２，４－トリアゾリル基、４，５－ジヒドロ－１，２，３－トリアゾリル基、４，５－ジヒドロ－１，２，４－トリアゾリル基、５－オキソ－４，５－ジヒドロ－１，２，３－トリアゾリル基、および５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾリル基等を具体例として挙げることができ、好適には、５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾリル基である。 Specific examples of the carbamoyl group optionally substituted with a group selected from a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group optionally substituted with a hydroxyl group include a carbamoyl group, a methylcarbamoyl group Ethylcarbamoyl group, propylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, pentylcarbamoyl group, hexylcarbamoyl group, tert-butylcarbamoyl group, 2-hydroxyethylcarbamoyl group, 2-hydroxypropylcarbamoyl group, 3-hydroxypropyl Carbamoyl group, 2-hydroxycyclopropylcarbamoyl group, 2-hydroxybutylcarbamoyl group, 3-hydroxybutylcarbamoyl group, 4-hydroxybutylcarbamoyl group, methoxycarbamoyl group, ethoxycarba Yl group, propoxycarbamoyl group, butoxycarbamoyl group, pentoxycarbamoyl group, hexoxycarbamoyl group, and the like, preferably carbamoyl group, methylcarbamoyl group, 2-hydroxyethylcarbamoyl group, ethylcarbamoyl group, methoxy A carbamoyl group or a cyclopropylcarbamoyl group.
Specific examples of the carboxy group which may be substituted with a C 1 -C 6 alkyl group include a carboxy group, a methyl carboxy group, an ethyl carboxy group, a propyl carboxy group, a butyl carboxy group, a tert-butyl carboxy group, a pentyl carboxy group. Group, hexylcarboxy group, benzylcarboxy group and the like can be mentioned, and preferred are methylcarboxy group, ethylcarboxy group and propylcarboxy group, and more preferred is ethylcarboxy group.
The triazolyl group optionally substituted by an oxo group is 1,2,3-triazolyl group, 1,2,4-triazolyl group, 4,5-dihydro-1,2,3-triazolyl group, 4,5- Dihydro-1,2,4-triazolyl group, 5-oxo-4,5-dihydro-1,2,3-triazolyl group, and 5-oxo-4,5-dihydro-1H-1,2,4-triazolyl group Specific examples of the group include a 5-oxo-4,5-dihydro-1H-1,2,4-triazolyl group.
　オキソ基で置換されていてもよいオキサジアゾリル基は、具体的には、１，２，３－オキサジアゾリル基、１，２，４－オキサジアゾリル基、１，３，４－オキサジアゾリル基、４，５－ジヒドロ－１，２，３－オキサジアゾリル基、４，５－ジヒドロ－１，２，４－オキサジアゾリル基、４，５－ジヒドロ－１，３，４－オキサジアゾリル基、５－オキソ－４，５－ジヒドロ－１，２，３－オキサジアゾリル基、５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾリル基、および５－オキソ－４，５－ジヒドロ－１，３，４－オキサジアゾリル基等を具体例として挙げることができ、好適には、５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾリル基、および５－オキソ－４，５－ジヒドロ－１，３，４－オキサジアゾリル基である。
　置換基群γから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基は、好適には、シアノメチル基、ヒドロキシメチル基、カルバモイルメチル基、カルバモイル（ヒドロキシ）メチル基、メチルカルバモイル（ヒドロキシ）メチル基、メチルカルバモイルメチル基、エチルカルバモイルメチル基、２－ヒドロキシエチルカルバモイルメチル基、１－カルバモイルエチル基、メトキシカルバモイルメチル基、カルバモイル（ジメチル）メチル基、１－カルバモイルシクロプロピル基、メチルカルボキシ（ジメチル）メチルカルバモイルメチル基、カルボキシメチル基、エチルカルボキシメチル基、１－カルボキシシクロプロピル基、１－（メチルカルボキシ）シクロプロピル基、（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）メチル基、（５－オキソ－４，５－ジヒドロ－１，３，４－オキサジアゾール－２－イル）メチル基、（５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－３－イル）メチル基、１－カルボキシエチル基、１－（エチルカルボキシ）エチル基、カルボキシ（ジメチル）メチル基、エチルカルボキシ（ジメチル）メチル基、１－カルボキシシクロプロピル基、又は１－エチルカルボキシシクロプロピル基である。
　１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基は、具体的には、カルバモイル基、メチルカルバモイル基、ジメチルカルバモイル基、エチルカルバモイル基、ジエチルカルバモイル基、メチルエチルカルバモイル基、プロピルカルバモイル基、メチルプロピルカルバモイル基、エチルプロピルカルバモイル基、ジプロピルカルバモイル基、ブチルカルバモイル基、メチルブチルカルバモイル基、エチルブチルカルバモイル基、プロピルブチルカルバモイル基、ジブチルカルバモイル基、ペンチルカルバモイル基、メチルペンチルカルバモイル基、エチルペンチルカルバモイル基、プロピルペンチルカルバモイル基、ブチルペンチルカルバモイル基、ジペンチルカルバモイル基、ヘキシルカルバモイル基、メチルヘキシルカルバモイル基、エチルヘキシルカルバモイル基、プロピルヘキシルカルバモイル基、ブチルヘキシルカルバモイル基、ペンチルヘキシルカルバモイル基、ジヘキシルカルバモイル基等が挙げられ、好適には、メチルカルバモイル基、又はジメチルカルバモイル基である。 Specific examples of the oxadiazolyl group optionally substituted with an oxo group include 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, 4,5-dihydro -1,2,3-oxadiazolyl group, 4,5-dihydro-1,2,4-oxadiazolyl group, 4,5-dihydro-1,3,4-oxadiazolyl group, 5-oxo-4,5-dihydro- Specific examples include 1,2,3-oxadiazolyl group, 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl group, and 5-oxo-4,5-dihydro-1,3,4-oxadiazolyl group As examples, preferred are 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl group, and 5-oxo-4,5-dihydro-1,3,4-oxadiazo A Le group.
The C 1 -C 6 alkyl group optionally substituted with 1 to 3 groups selected from the substituent group γ is preferably a cyanomethyl group, a hydroxymethyl group, a carbamoylmethyl group, a carbamoyl (hydroxy) methyl group. Methylcarbamoyl (hydroxy) methyl group, methylcarbamoylmethyl group, ethylcarbamoylmethyl group, 2-hydroxyethylcarbamoylmethyl group, 1-carbamoylethyl group, methoxycarbamoylmethyl group, carbamoyl (dimethyl) methyl group, 1-carbamoylcyclopropyl Group, methylcarboxy (dimethyl) methylcarbamoylmethyl group, carboxymethyl group, ethylcarboxymethyl group, 1-carboxycyclopropyl group, 1- (methylcarboxy) cyclopropyl group, (5-oxo-4,5-dihydro-1 , 2 4-oxadiazol-3-yl) methyl group, (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) methyl group, (5-oxo-4,5- Dihydro-1H-1,2,4-triazol-3-yl) methyl group, 1-carboxyethyl group, 1- (ethylcarboxy) ethyl group, carboxy (dimethyl) methyl group, ethylcarboxy (dimethyl) methyl group, 1 -A carboxycyclopropyl group or a 1-ethylcarboxycyclopropyl group.
Specific examples of the carbamoyl group optionally substituted by 1 to 2 C 1 -C 6 alkyl groups include a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a diethylcarbamoyl group, and a methylethylcarbamoyl group. , Propylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group, dipropylcarbamoyl group, butylcarbamoyl group, methylbutylcarbamoyl group, ethylbutylcarbamoyl group, propylbutylcarbamoyl group, dibutylcarbamoyl group, pentylcarbamoyl group, methylpentylcarbamoyl group Group, ethylpentylcarbamoyl group, propylpentylcarbamoyl group, butylpentylcarbamoyl group, dipentylcarbamoyl group, hexylcarbamoyl group, methyl Shi carbamoyl group, ethylhexyl carbamoyl group, propyl hexylcarbamoyl group, butyl hexylcarbamoyl group, pentylhexyl carbamoyl group, Hye alkoxy carbamoyl group and the like, preferably a methylcarbamoyl group or dimethylcarbamoyl group.
　１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基、水酸基、ハロゲン原子、およびカルボキシ基から選択される基で置換されていてもよいＣ１－Ｃ６アルキル基は、好適には、メチル基、ジメチル基、エチル基、２－ジメチルカルバモイルエチル基、２－ヒドロキシエチル基、２，３－ジヒドロキシプロピル基、２－フルオロエチル基、又はカルボキシ（ジメチル）メチル基である。
　Ｃ１－Ｃ６アルキル基で置換されていてもよいスルホニル基は、具体的には、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、ブチルスルホニル基、ペンチルスルホニル基、ヘキシルスルホニル基等を挙げることができ、好適には、メチルスルホニル基である。
　Ｃ１－Ｃ６アルキル基で置換されていてもよいスルホニル基、Ｃ１－Ｃ６アルコキシ基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基は、具体的には、メチルスルホニルアミノ基、エチルスルホニルアミノ基、プロピルスルホニルアミノ基、ブチルスルホニルアミノ基、ペンチルスルホニルアミノ基、ヘキシルスルホニルアミノ基、メトキシアミノ基、エトキシアミノ基、プロポキシアミノ基、ブトキシアミノ基、ペントキシアミノ基、ヘキソキシアミノ基、アセチルアミノ基、プロピオニルアミノ基、ブチリルアミノ基等を挙げることができ、好適には、メチルスルホニルアミノ基、又はアセチルアミノ基である。 The C 1 -C 6 alkyl group optionally substituted with a group selected from a carbamoyl group, a hydroxyl group, a halogen atom, and a carboxy group, which may be substituted with 1 to 2 C 1 -C 6 alkyl groups, Preferred are methyl group, dimethyl group, ethyl group, 2-dimethylcarbamoylethyl group, 2-hydroxyethyl group, 2,3-dihydroxypropyl group, 2-fluoroethyl group, or carboxy (dimethyl) methyl group.
Specific examples of the sulfonyl group that may be substituted with a C 1 -C 6 alkyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group. Preferably, it is a methylsulfonyl group.
The amino group optionally substituted with a group selected from a sulfonyl group optionally substituted with a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, and a C 1 -C 6 alkanoyl group includes: Specifically, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, butylsulfonylamino group, pentylsulfonylamino group, hexylsulfonylamino group, methoxyamino group, ethoxyamino group, propoxyamino group, butoxyamino group, A pentoxyamino group, a hexoxyamino group, an acetylamino group, a propionylamino group, a butyrylamino group and the like can be mentioned, and a methylsulfonylamino group or an acetylamino group is preferred.
　置換基群δから選択される基で置換されていてもよいカルバモイル基は、好適には、カルバモイル基、メチルカルバモイル基、ジメチルカルバモイル基、エチルカルバモイル基、メトキシカルバモイル基、アセチルアミノカルバモイル基、メチルスルホニルアミノカルバモイル基、（２－ヒドロキシエチル）カルバモイル基、２－フルオロエチルカルバモイル基、（２，３－ジヒドロキシプロピル）アミノカルバモイル基、（２－カルボキシエチル）アミノカルバモイル基、（２－ジメチルカルバモイルエチル）カルバモイル基、又はカルボキシ（ジメチル）メチルカルバモイル基である。
　Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基は、具体的には、カルボキシ基、メチルカルボキシ基、エチルカルボキシ基、プロピルカルボキシ基、イソプロプルカルボキシ基、ブチルカルボキシ基、ペンチルカルボキシ基、ヘキシルカルボキシ基等を挙げることができ、好適には、カルボキシ基、メチルカルボキシ基、又はエチルカルボキシ基である。
　Ｙ１およびＹ２は、好適には、いずれか１が水素原子であり、置換基群γから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基、置換基群δから選択される基で置換されていてもよいカルバモイル基、又は、１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基であり、さらに好適には、Ｃ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基；又はＣ１－Ｃ６アルキル基およびカルボキシ基から選択される基で置換されていてもよいメチル基である。
　Ｘは、好適には、水素原子を表し、
ｎは、好適には、０を表す。
　式： The carbamoyl group which may be substituted with a group selected from the substituent group δ is preferably a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a methoxycarbamoyl group, an acetylaminocarbamoyl group, a methylsulfonyl group. Aminocarbamoyl group, (2-hydroxyethyl) carbamoyl group, 2-fluoroethylcarbamoyl group, (2,3-dihydroxypropyl) aminocarbamoyl group, (2-carboxyethyl) aminocarbamoyl group, (2-dimethylcarbamoylethyl) carbamoyl Or a carboxy (dimethyl) methylcarbamoyl group.
Specific examples of the carboxy group that may be substituted with a C 1 -C 6 alkyl group include a carboxy group, a methyl carboxy group, an ethyl carboxy group, a propyl carboxy group, an isopropyl carboxy group, a butyl carboxy group, and a pentyl carboxy group. , A hexylcarboxy group, and the like, and preferably a carboxy group, a methylcarboxy group, or an ethylcarboxy group.
Y 1 and Y 2 are each preferably a C 1 -C 6 alkyl group, a substituent, wherein one is a hydrogen atom and may be substituted with 1 to 3 groups selected from substituent group γ A carbamoyl group optionally substituted with a group selected from group δ, or a sulfamoyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups, and more preferably C 1 — A carbamoyl group optionally substituted with a C 6 alkyl group; or a methyl group optionally substituted with a group selected from a C 1 -C 6 alkyl group and a carboxy group.
X preferably represents a hydrogen atom,
n preferably represents 0.
formula:
Figure JPOXMLDOC01-appb-C000013
 は、好適には、式：
Figure JPOXMLDOC01-appb-C000013
 Is preferably the formula:
Figure JPOXMLDOC01-appb-C000014
 を表す。
　環Ａは、５～６員の飽和もしくは不飽和の炭化水素環、又は５～６員の飽和もしくは不飽和の複素環を表わし、
　５～６員の飽和もしくは不飽和の炭化水素環は、具体例として、シクロペンタン環、シクロペンテン環、シクロペンタジエン環、シクロヘキサン環、シクロヘキセン環、シクロヘキサジエン環、ベンゼン環、等をあげることができ、好適には、シクロペンタン環、シクロヘキサン環、又はベンゼン環であり、さらに好適には、シクロペンタン環又はシクロヘキサン環である。
　５～６員の飽和もしくは不飽和の複素環は、具体例として、フラン環、ジヒドロフラン環、テトラヒドロフラン環、チオフェン環、ジヒドロチオフェン環、テトラヒドロチオフェン環、ピロール環、ジヒドロピロール環、テトラヒドロピロール環、ピペリジン環、ピラン環、ジヒドロピラン環、テトラヒドロピラン環等を挙げることができ、好適には、テトラヒドロピラン環、テトラヒドロチオフェン環、テトラヒドロピロール環、又はピペリジン環であり、さらに好適には、テトラヒドロピラン環又はピペリジン環である。
　環Ａとしては、好適にはシクロペンタン環、テトラヒドロピラン環、ベンゼン環、ピペリジン環、又はシクロヘキサン環であり、より好適には、シクロペンタン環又はシクロヘキサン環である。
Figure JPOXMLDOC01-appb-C000014
 Represents.
Ring A represents a 5-6 membered saturated or unsaturated hydrocarbon ring, or a 5-6 membered saturated or unsaturated heterocycle,
Specific examples of the 5- to 6-membered saturated or unsaturated hydrocarbon ring include a cyclopentane ring, a cyclopentene ring, a cyclopentadiene ring, a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring, and the like. Preferred is a cyclopentane ring, a cyclohexane ring, or a benzene ring, and more preferred is a cyclopentane ring or a cyclohexane ring.
Specific examples of the 5- to 6-membered saturated or unsaturated heterocycle include furan ring, dihydrofuran ring, tetrahydrofuran ring, thiophene ring, dihydrothiophene ring, tetrahydrothiophene ring, pyrrole ring, dihydropyrrole ring, tetrahydropyrrole ring, Examples include a piperidine ring, a pyran ring, a dihydropyran ring, a tetrahydropyran ring, and the like, preferably a tetrahydropyran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, or a piperidine ring, and more preferably a tetrahydropyran ring. Or a piperidine ring.
Ring A is preferably a cyclopentane ring, a tetrahydropyran ring, a benzene ring, a piperidine ring, or a cyclohexane ring, and more preferably a cyclopentane ring or a cyclohexane ring.
　一般式（Ｉ）を有する化合物として、さらに好適には、実施例に記載の化合物である。
　「治療」とは、病気又は症状を治癒させること又は改善させること或いは症状を抑制させることを意味する。
　「プロスタグランジンE2により介在される疾患」とは、その疾患の発症にプロスタグランジンE2が関与していると考えられているものであれば特に限定されないが、具体的には、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、または又はアルツハイマー病等が挙げられる。好適には、炎症性疾患とされる、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、喘息、発熱、又は炎症性食欲不振に本願発明の化合物が適用され、より好適には、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である。
　「その薬理上許容される塩」とは、医薬として使用することができる塩を示す。本発明の化合物では、酸性基又は塩基性基を有する場合に、塩基又は酸と反応させることにより、塩基性塩又は酸性塩にすることができるので、その塩を示す。
　本発明の化合物の薬理上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩；Ｎ－メチルモルホリン塩、トリエチルアミン塩、トリブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ－メチルピペリジン塩、ピリジン塩、４－ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。 More preferable examples of the compound having the general formula (I) include the compounds described in Examples.
“Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.
The “disease mediated by prostaglandin E 2 ” is not particularly limited as long as it is thought that prostaglandin E 2 is involved in the onset of the disease. Rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, menstruation For dysfunction, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, cancer metastasis and familial colorectal polyposis Accompanied pain, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstruction Lung disease Sudden infant death syndrome, asthma, fever, inflammatory anorexia, and multiple sclerosis, or or Alzheimer's disease and the like. Rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, The compound of the present invention is applied to gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, asthma, fever, or inflammatory anorexia, and more preferably rheumatoid arthritis, osteoarthritis, asthma, chronic Dermatitis including obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis.
The “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
The pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt. Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamate salts, aspartates, and alkali metal salts are preferred.
　本発明の化合物の薬理上許容される「酸性塩」としては、好適には、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、リンゴ酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、最も好適には、ハロゲン化水素酸塩である。 The pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.
　本発明の化合物又はその薬理上許容される塩は、大気中に放置したり又は再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となったりする場合があり、本発明には、そのような各種の水和物、溶媒和物及び結晶多形の化合物も包含する。
　本発明化合物、その塩又はそれらの溶媒和物は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、互変異性体又はｄ体、ｌ体等の光学異性体等の各種異性体が存在し得るが、本発明の化合物は、特に限定していない場合はそれら全ての異性体、立体異性体及びいずれの比率のこれら異性体及び立体異性体混合物をも包含するものである。これらの異性体の混合物は、公知の分割手段により分離することができる。
　本発明の一般式（Ｉ）で表される化合物は、構成する原子の一つ又は複数で非天然の比率の原子同位体を含むこともある。原子同位体としては、例えば、重水素（２Ｈ)、トリチウム（３Ｈ)、ヨウ素－１２５、（１２５Ｉ）又は炭素－１４（１４Ｃ）などが挙げられる。これらの化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。一般式（Ｉ）で表される化合物のすべての同位体変種は、放射性であるかどうかにかかわらず、本発明の範囲内に含まれる。 The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.
The compound of the present invention, a salt thereof, or a solvate thereof may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer, depending on the type or combination of substituents. Although various isomers may exist, the compound of the present invention includes all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures unless otherwise specified. is there. A mixture of these isomers can be separated by a known resolution means.
The compound represented by the general formula (I) of the present invention may contain an unnatural ratio of atomic isotopes at one or more of the constituent atoms. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), and carbon-14 ( 14 C). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds represented by general formula (I) are included within the scope of the present invention, whether radioactive or not.
　また、本発明には、本発明の化合物の薬理上許容されるプロドラッグも包含される。
　薬理上許容されるプロドラッグとは、加水分解により、若しくは、生理学的条件下で、本発明の化合物のアミノ基、水酸基、カルボキシル基等に変換し得る基を有する化合物であり、このようなプロドラッグを形成する基としては、Prog. Med.、第5巻、2157-2161ページ、1985年や、「医薬品の開発」（廣川書店、1990年）第7巻、分子設計163－198ページに記載の基である。当該プロドラッグとして、より具体的には、本発明の化合物に、アミノ基が存在する場合には、そのアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、そのアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物等である）等を挙げることができ、本発明の化合物に、水酸基が存在する場合には、その水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例えば、その水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等である。）等を挙げることができる。 The present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
A pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions. Drug-forming groups are described in Prog. Med., Volume 5, pp. 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of. As the prodrug, more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated). Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- In the case where a hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like.
　また、本発明の化合物に、カルボキシ基が存在する場合には、そのカルボキシ基がエステル化、アミド化された化合物（例えば、そのカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、アミド化又はメチルアミド化された化合物等である。）等が挙げられる。 In addition, when a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidation compound, etc.).
（製造法）
　一般式（Ｉ）に関する製造法を以下に例示する。一般式（Ｉ）で表される本発明の化合物は種々の方法により製造されるが、その好ましい例として代表的な製造法を次式に示し説明するが、これらに限定されるものではない。なお、反応に際しては必要に応じて置換基を保護基で保護して実施し、各置換基（官能基）の変換順序は特に限定されない。また、式中の化合物は、塩を形成している場合も含む。式中の化合物が市販されている場合には市販品をそのまま用いることもできる。
（製造法Ａ）
製造法Ａは式（Ｉ）で表される化合物を製造する際に合成中間体として用いることのできる置換キノリン（Ａ７）を製造する方法である。
式中のＲ１～Ｒ６およびＸは式（Ｉ）の置換基の定義と同様であり、式中のＺ１およびＺ２はハロゲン原子（例えば、臭素原子、ヨウ素原子）または適当な脱離基（例えば、メチルスルホニルオキシ基、ベンゼンスルホニルオキシ基）を表す。Ｐ１はカルボキシ基の保護基あるいは水素を示し、具体的な保護基としてはメチル基、エチル基、ベンジル基などが挙げられる。 (Production method)
The production method for the general formula (I) is exemplified below. The compounds of the present invention represented by the general formula (I) can be produced by various methods. As preferred examples, typical production methods are shown in the following formulas, but are not limited thereto. In the reaction, the substituent is protected with a protecting group as necessary, and the conversion order of each substituent (functional group) is not particularly limited. Moreover, the compound in a formula includes the case where the salt is formed. When the compound in the formula is commercially available, a commercially available product can be used as it is.
(Production method A)
Production method A is a method of producing a substituted quinoline (A7) that can be used as a synthetic intermediate when producing a compound represented by formula (I).
In the formula, R 1 to R 6 and X are the same as the definition of the substituent in formula (I), and Z 1 and Z 2 in the formula are halogen atoms (for example, bromine atom and iodine atom) or appropriate elimination Represents a group (for example, methylsulfonyloxy group, benzenesulfonyloxy group). P 1 represents a carboxy-protecting group or hydrogen, and specific examples of the protecting group include a methyl group, an ethyl group, and a benzyl group.
Figure JPOXMLDOC01-appb-C000015
 ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、及び、Ｘは上述と同様の基を表す。］
　工程（Ａ－１）は化合物（Ａ１）に置換基Ｚ１を導入し化合物（Ａ２）を製造する工程である。化合物（Ａ１）を求電子ハロゲン化物と反応させることにより行うことができる。求電子ハロゲン化物としては、例えばＮ－ブロモスクシイミド、Ｎ－ヨードスクシイミドなどが挙げられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ジメチルホルムアミド、ジメチルアセトアミドが好ましい。
Figure JPOXMLDOC01-appb-C000015
 [Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X represent the same groups as described above. ]
Step (A-1) is a step of producing compound (A2) by introducing substituent Z 1 into compound (A1). It can be carried out by reacting compound (A1) with an electrophilic halide. Examples of the electrophilic halide include N-bromosuccinimide and N-iodosuccinimide. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but dimethylformamide and dimethylacetamide are preferable.
　工程（Ａ－２）は化合物（Ａ２）に対して、酸ハライド、酸無水物などを作用させ化合物（Ａ３）を製造する工程である。酸ハライド、酸無水物としては、例えばオキシ塩化リンやトリフルオロメタンスルホン酸無水物などが挙げられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ジクロロメタンが好ましい。
　工程（Ａ－３）は化合物（Ａ３）に対して、ピペリジン誘導体を作用させてＺ２との置換反応を行うことにより、化合物（Ａ４）を製造する工程である。反応の溶媒は、反応が進行する限り特に限定はされないが、Ｎ－メチルピロリドン、Ｎ，Ｎ－ジメチルアセトアミドが好ましい。
　工程（Ａ－４）はキノリン環上の置換基Ｚ１に対してパラジウム触媒存在下、ボロン酸やボロン酸エステルを作用させる（鈴木カップリンング）条件や、スズ化合物を作用させる（Stilleカップリング）条件、またはパラジウムおよび銅触媒存在下、末端アルキンを作用させる（園頭反応）条件などによりＲ１に相当する置換基もしくはその前駆体となる置換基を導入する工程である。必要に応じてＲ１における保護基の脱保護や置換基の修飾を行う工程である。鈴木カップリンングの例として、Tetrahedron Letters,　32, 20, 1991, 2273-2276、Tetrahedron, 49, 43, 1993, 9713-9720、Synthesis, 18, 2007, 2853-2861、Angewandte Chemie, International Edition, 46, 17, 2007, 3135-3138、Journal of the American Chemical Society, 116, 15, 1994, 6985-6986、Heterocycles, 26, 10, 1987, 2711-2716、Synthetic Communications, 30, 19, 2000, 3501-3510、Tetrahedron Letters, 42, 37, 2001, 6523-6526、Tetrahedron Letters, 42, 33, 2001, 5659-5662、Journal of Organic Chemistry, 68, 24, 2003, 9412-9415、Journal of Organic Chemistry, 68, 20, 2003, 7733-7741、Journal of Organic Chemistry, 70, 6, 2005, 2191-2194、Synlett, 13, 2005, 2057-2061、European Journal of Organic Chemistry, 8, 2006, 1917-1925、Organic Letters, 8, 16, 2006, 3605-3608、Journal of Organic Chemistry, 71, 10, 2006, 3816-3821、Chemistry A European Journal, 12, 19, 2006, 5142-5148、Organic Letters, 5, 6, 2003, 815-818、Journal of Organic Chemistry, 73, 4, 2008, 1429-1434等に記載の方法に準じて行うことができる。 Step (A-2) is a step of producing compound (A3) by reacting compound (A2) with an acid halide, acid anhydride or the like. Examples of acid halides and acid anhydrides include phosphorus oxychloride and trifluoromethanesulfonic acid anhydride. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane is preferred.
Step (A-3) is a step for producing compound (A4) by subjecting compound (A3) to a substitution reaction with Z 2 by acting a piperidine derivative. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but N-methylpyrrolidone and N, N-dimethylacetamide are preferable.
Step (A-4) is a condition in which boronic acid or a boronic acid ester is allowed to act on the substituent Z 1 on the quinoline ring in the presence of a palladium catalyst (Suzuki coupling), or a tin compound is allowed to act (Stille coupling). ) Or a substituent corresponding to R 1 or a precursor thereof is introduced under conditions such as conditions under which a terminal alkyne is allowed to act in the presence of a palladium and copper catalyst (Sonogashira reaction). This is a step of deprotecting the protecting group and modifying the substituent in R 1 as necessary. As an example of Suzuki coupling, Tetrahedron Letters, 32, 20, 1991, 2273-2276, Tetrahedron, 49, 43, 1993, 9713-9720, Synthesis, 18, 2007, 2853-2861, Angelwandte Chemie, International Edition, 46 , 17, 2007, 3135-3138, Journal of the American Chemical Society, 116, 15, 1994, 6985-6986, Heterocycles, 26, 10, 1987, 2711-2716, Synthetic Communications, 30, 19, 2000, 3501-3510 , Tetrahedron Letters, 42, 37, 2001, 6523-6526, Tetrahedron Letters, 42, 33, 2001, 5659-5662, Journal of Organic Chemistry, 68, 24, 2003, 9412-9415, Journal of Organic Chemistry, 68, 20 , 2003, 7733-7741, Journal of Organic Chemistry, 70, 6, 2005, 2191-2194, Synlett, 13, 2005, 2057-2061, European Journal of Organic Chemistry, 8, 2006, 1917-1925, Organic Letters, 8 , 16, 2006, 3605-3608, Journal of Organic Chemistry, 71, 10, 2006, 3816-3821, Chemistry A European Journal, 12, 19, 2006, 5142-5148, Organic Letters, 5, 6, 2003, 815- 818, Journal of Organic Chemistry, 73, 4, 2008, 1429-1434, etc. It can be performed according to the method.
　Stilleカップリングの例として、Angewandte Chemie, International Edition, 25, 6, 1986, 508-524、Tetrahedron Letters, 35, 19, 1994, 3195-3196、Synthesis, 1986 , 7, 564-565　等に記載の方法に準じて行うことができる。
　薗頭反応の例として、Chemical. Review, 107, 2007, 874-922、Journal of Organic Chemistry, 68 , 9, 2003, 3736-3738、Organic Letters, 2, 12, 2000, 1729-1731. 等に記載の方法に準じて行うことができる。
　工程（Ａ－５）は化合物（Ａ６）に対して、ピペリジン誘導体を付加させることにより化合物（Ａ５）を製造する工程であり、工程（Ａ－３）と同様な方法を用いることができる。 Examples of Stille coupling include methods described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524, Tetrahedron Letters, 35, 19, 1994, 3195-3196, Synthesis, 1986, 7, 564-565, etc. It can be performed according to.
Examples of Sonogashira reaction are described in Chemical. Review, 107, 2007, 874-922, Journal of Organic Chemistry, 68, 9, 2003, 3736-3738, Organic Letters, 2, 12, 2000, 1729-1731. It can carry out according to the method of.
Step (A-5) is a step of producing compound (A5) by adding a piperidine derivative to compound (A6), and the same method as in step (A-3) can be used.
　工程（Ａ－６）は化合物（Ａ５）における保護基の脱保護を行い、化合物（Ａ－７）を製造する工程であり、必要に応じてＲ１およびＸにおける保護基の脱保護を行う工程である。本反応は保護基Ｐ１の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。
（製造法Ｂ）
　製造法Ｂは一般式（Ｉ）で表される化合物を製造する際に合成中間体として用いることのできる置換アミン（Ｂ１９）を製造する方法である。Ｐ１は上記の定義と同様であり、ｍは０または１である。 Step (A-6) is a step of producing a compound (A-7) by deprotecting the protecting group in the compound (A5), and a step of deprotecting the protecting group in R 1 and X as necessary. It is. Although this reaction varies according to the kind of the protecting group P 1, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" can be carried out according to the method described in.
(Production method B)
Production method B is a method for producing a substituted amine (B19) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced. P 1 is as defined above, and m is 0 or 1.
Figure JPOXMLDOC01-appb-C000016
 ［Ｘａは酸素原子またはＮＨを表し、Ｘｃは炭素原子、酸素原子、または窒素原子を表し、
Ｙａ、Ｙｂはオキソ基、フッ素基、エチレンジオキシ基（－ＯＣＨ２ＣＨ２Ｏ－）、水酸基または水素原子を表し、
Ｙ３は水酸基、アミノ基、オキソ基、ハロゲン原子または水素原子を表し、これらの置換基は保護されていても良く、
Ｙ４は置換されていても良いエステル基、カルボン酸基、アミド基、アルコキシメチル基、テトラゾリル基、イミダゾリル基、アシル化されていても良いヒドラジン基を表し、
Ｒ７、Ｒ８は置換されていても良いアルキル、アルケニル、アルキニル、シクロアルキル基、または水素原子を表し、
Ｒ１０、Ｒ１１は置換されていてもよいアルキル、アルケニル、アルキニル、シクロアルキル基、－ＣＨ２ＣＨ２－基または水素原子を表し、
　Ｐ2およびＰ３はアミノ基の保護基あるいは水素を示し、具体的な保護基としてはＢｏｃ基（ｔｅｒｔ－ブトキシカルボニル基）、Ｃｂｚ基（ベンジルオキシカルボニル基）、ベンジリデン基、ジフェニルメチレン基などが挙げられる。Ｐ２がベンジルリデン基、ジフェニルメチレン基の場合にはＰ３はＰ２と同一保護基を示す。各工程は必要に応じて置換基の保護や保護基の脱保護を行う工程を含む。］
Figure JPOXMLDOC01-appb-C000016
 [X a represents an oxygen atom or NH, X c represents a carbon atom, an oxygen atom, or a nitrogen atom,
Y a and Y b each represents an oxo group, a fluorine group, an ethylenedioxy group (—OCH 2 CH 2 O—), a hydroxyl group or a hydrogen atom;
Y 3 represents a hydroxyl group, an amino group, an oxo group, a halogen atom or a hydrogen atom, and these substituents may be protected,
Y 4 represents an optionally substituted ester group, a carboxylic acid group, an amide group, an alkoxymethyl group, a tetrazolyl group, an imidazolyl group, an acylated hydrazine group,
R 7 and R 8 each represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group, or hydrogen atom;
R 10 and R 11 each represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group, —CH 2 CH 2 — group or a hydrogen atom;
P 2 and P 3 each represent an amino protecting group or hydrogen, and specific protecting groups include Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), benzylidene group, diphenylmethylene group and the like. Can be mentioned. When P 2 is a benzylidene group or a diphenylmethylene group, P 3 represents the same protecting group as P 2 . Each step includes a step of protecting the substituent and deprotecting the protecting group as necessary. ]
　工程（Ｂ－１）は化合物（Ｂ１）のカルボキシ基を適当な縮合剤および塩基の存在下、ヒドロキシルアミン誘導体またはヒドラジン誘導体との縮合を行う工程であり、化合物（Ｂ２）を製造する工程である。必要に応じて反応を促進する添加剤を加える。縮合剤としては、例えばＷＳＣ（すなわち、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド），ＤＣＣ（すなわち、１，３－ジシクロヘキシルカルボジイミド）、ＤＭＴ－ＭＭ（すなわち、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド）、ＣＤＩ（すなわち、１，１´－カルボニルジイミダゾール）、ＤＥＰＣ（すなわち、ジエチル　ホスホロシアニドエート）、ＤＰＰＡ（すなわち、ジフェニルホスホロアジドエート）などが挙げられる。塩基としては、ピリジン、ルチジンなどの芳香族アミン類やトリエチルアミン、ジイソプロピルエチルアミン、ＤＭＡＰ（すなわち、４－ジメチルアミノピリジン）などの３級アミン類などが挙げられる。添加剤の代表的な例として、ＨＯＡｔ（３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール）、ＨＯＢｔ（１Ｈ－ベンゾトリアゾール－１－オール）、ＨＯＳｕ（Ｎ－ヒドロキシスクシイミド）などが挙げられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミドが好ましい。 Step (B-1) is a step of condensing the carboxy group of compound (B1) with a hydroxylamine derivative or a hydrazine derivative in the presence of an appropriate condensing agent and base, and is a step of producing compound (B2). . Add additives to accelerate the reaction if necessary. Examples of the condensing agent include WSC (ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (ie, 1,3-dicyclohexylcarbodiimide), DMT-MM (ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), CDI ( ie 1,1′-carbonyldiimidazole), DEPC (ie diethyl phosphorocyanide) DPPA (that is, diphenylphosphoroazideate) and the like can be mentioned. Examples of the base include aromatic amines such as pyridine and lutidine, and tertiary amines such as triethylamine, diisopropylethylamine, and DMAP (that is, 4-dimethylaminopyridine). Representative examples of additives include HOAt (3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol), HOBt (1H-benzotriazol-1-ol), HOSu (N -Hydroxysuccinimide) and the like. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane and N, N-dimethylformamide are preferable.
　工程（Ｂ－２）は化合物（Ｂ２）または（Ｂ６）に対して、適当なアシル化剤を作用させた後、加熱により環化を行い、化合物（Ｂ３）を製造する工程である。アシル化剤としては、例えばクロロギ酸イソブチル、ＣＤＩ、ホスゲン、トリホスゲンなどが挙げられる。
　工程（Ｂ－３）は化合物（Ｂ１）、（Ｂ８）および（Ｂ１２）に対して、適当な縮合剤および塩基の存在下、アミノ基を有する化合物または水酸基を有する化合物と縮合する工程であり、それぞれ化合物（Ｂ４），（Ｂ９）、（Ｂ１３）を製造する工程である。必要に応じて反応を促進する添加剤を加える。工程（Ｂ－１）と同様な方法を用いることができる。
　工程（Ｂ－４）は化合物（Ｂ４）に対して、適当な脱水剤を作用させることにより化合物（Ｂ５）を製造する工程である。脱水剤としては、エチル　ホスホロジクロリデート、ホスゲン、トリホスゲンなどが挙げられる。
　工程（Ｂ－５）は化合物（Ｂ５）に対して、ヒドロキシルアミン誘導体またはヒドラジン誘導体を付加させ、化合物（Ｂ６）を製造する工程である。
　工程（Ｂ－６）は化合物（Ｂ７）に対して、水酸基を適当な酸化剤を用いて酸化しアルデヒドとした後、トリメチルシリルシアニドを用いてシリルシアノ化を行い、得られたシアノ基を酸性条件下、加水分解する工程であり、化合物（Ｂ８）を製造する工程である。酸化方法としては、例えばＤＭＳＯ酸化、デスマーチン酸化、スワン酸化などが挙げられる。
工程（Ｂ－７）は化合物（Ｂ７）に対して、水酸基を適当な脱離基へと変換した後、シアノ基へと置換する工程であり、化合物（Ｂ１０）を製造する工程である。脱離基としては、例えばメチルスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基、ハロゲン原子などが挙げられる。 Step (B-2) is a step for producing compound (B3) by allowing a suitable acylating agent to act on compound (B2) or (B6) and then performing cyclization by heating. Examples of the acylating agent include isobutyl chloroformate, CDI, phosgene and triphosgene.
Step (B-3) is a step of condensing compound (B1), (B8) and (B12) with a compound having an amino group or a compound having a hydroxyl group in the presence of an appropriate condensing agent and a base. In this step, compounds (B4), (B9) and (B13) are produced. Add additives to accelerate the reaction as needed. The same method as in step (B-1) can be used.
Step (B-4) is a step of producing compound (B5) by allowing a suitable dehydrating agent to act on compound (B4). Examples of the dehydrating agent include ethyl phosphorodichloridate, phosgene, and triphosgene.
Step (B-5) is a step of producing compound (B6) by adding a hydroxylamine derivative or a hydrazine derivative to compound (B5).
In step (B-6), the hydroxyl group of the compound (B7) is oxidized using an appropriate oxidizing agent to form an aldehyde, and then silylcyanation is performed using trimethylsilyl cyanide. The resulting cyano group is subjected to acidic conditions. Below, it is the process of hydrolyzing and it is the process of manufacturing a compound (B8). Examples of the oxidation method include DMSO oxidation, desmartin oxidation, and swan oxidation.
Step (B-7) is a step of converting compound (B7) into a suitable leaving group and then substituting it with a cyano group, which is a step of producing compound (B10). Examples of the leaving group include a methylsulfonyloxy group, a p-toluenesulfonyloxy group, and a halogen atom.
　工程（Ｂ－８）は化合物（Ｂ１０）に対して、酸性条件下シアノ基を加水分解した後、得られたアミノ酸をエステル化する工程であり、化合物（Ｂ１１）を製造する工程である。必要に応じて、アミノ基を再度保護する工程を含む。本反応は保護基Ｐ１～Ｐ３の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。
　保護基Ｐ２がＢｏｃ基の場合（Ｐ３は水素原子）、塩基存在下においてジ－ｔｅｒｔ－ブチル　ジカーボネートなどが用いられる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素カリウム、トリエチルアミンなどが用いられる。
　保護基Ｐ２がＣｂｚ基の場合（Ｐ３は水素原子）、塩基の存在下において、ベンジル　クロロホルメートまたはＮ－（ベンジルオキシカルボニルオキシ）スクシイミドが用いられる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素カリウム、トリエチルアミンなどが用いられる。
　保護基Ｐ２、Ｐ３がベンジリデン基の場合、反応剤として無水硫酸ナトリウムまたは無水硫酸マグネシウム存在下、ベンズアルデヒドが用いられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ベンゼン、トルエン、ジクロロメタンなどが用いられる。
　保護基Ｐ２、Ｐ３がジフェニルメチレン基の場合、反応剤としてベンゾフェノンイミンが用いられる。必要に応じて塩基を用いることができる。反応の溶媒は、反応が進行する限り特に限定はされないが、ベンゼン、トルエン、ジクロロメタンなどが用いられる。
　工程（Ｂ－９）は化合物（Ｂ１１）に対して加水分解を行い、化合物（Ｂ１２）を製造する工程である。塩基としては水酸化ナトリウム、水酸化カリウムなどを用いることができる。反応の溶媒は、反応が進行する限り特に限定はされないが、エタノール、メタノール、テトラヒドロフラン、水が好ましく混合しても良い。 Step (B-8) is a step of esterifying the resulting amino acid after hydrolyzing the cyano group under acidic conditions with respect to compound (B10), and is a step of producing compound (B11). If necessary, it includes a step of protecting the amino group again. This reaction varies depending on the type of the protecting groups P 1 to P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
When the protecting group P 2 is a Boc group (P 3 is a hydrogen atom), di-tert-butyl dicarbonate or the like is used in the presence of a base. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
When the protecting group P 2 is a Cbz group (P 3 is a hydrogen atom), benzyl chloroformate or N- (benzyloxycarbonyloxy) succinimide is used in the presence of a base. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
When the protecting groups P 2 and P 3 are benzylidene groups, benzaldehyde is used in the presence of anhydrous sodium sulfate or anhydrous magnesium sulfate as a reactant. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
When the protecting groups P 2 and P 3 are diphenylmethylene groups, benzophenone imine is used as a reactant. A base can be used as necessary. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
Step (B-9) is a step of producing compound (B12) by hydrolyzing compound (B11). As the base, sodium hydroxide, potassium hydroxide and the like can be used. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but ethanol, methanol, tetrahydrofuran, and water may be preferably mixed.
　工程（Ｂ－１０）は化合物（Ｂ１１）に対して、段階的にアルキル化を行う工程であり、化合物（Ｂ１４）を製造する工程である。
　工程（Ｂ－１１）は化合物（Ｂ１５）に対して、キラルなアミンを付加させた後、還元する工程であり、化合物（Ｂ１６）を製造する工程である。本工程はＷＯ２００８／１５３０２７Ａ１記載の方法に準じて行うことができる。
　工程（Ｂ－１２）は化合物（Ｂ１６）に対して、エステル基の加水分解を行った後、得られたカルボン酸を還元する工程であり、化合物（１７）を製造する工程である。還元剤としては、水素化ホウ素ナトリウムなどを用いることができる。
　工程（Ｂ－１３）は化合物（Ｂ１８）に対して、保護基Ｐ２およびＰ３を脱保護する工程であり、化合物（Ｂ１９）を製造する工程である。化合物（Ｂ１８）は製造法Ｂにおける化合物群（Ｂ１～Ｂ１７）の概略を表し、化合物（Ｂ１９）は製造法Ｂにおける置換アミンの概略を表す。本反応は保護基Ｐ２およびＰ３の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。
　保護基Ｐ２がＢｏｃ基の場合、反応剤としては塩酸のジオキサン溶液または酢酸エチル溶液を用いることができる。必要に応じて、メタノール、エタノール、テトラヒドロフランを加えても良い。
　保護基Ｐ２がＣｂｚ基およびジフェニルメチレン基の場合、水素雰囲気下、パラジウム炭素または水酸化パラジウムを用いることができる。反応の溶媒は、反応が進行する限り特に限定されないが、メタノール、エタノール、テトラヒドロフランが好ましい。 Step (B-10) is a step of stepwise alkylating compound (B11), and is a step of producing compound (B14).
Step (B-11) is a step of adding a chiral amine to compound (B15) and then reducing, and is a step of producing compound (B16). This step can be performed according to the method described in WO2008 / 153027A1.
Step (B-12) is a step of reducing the obtained carboxylic acid after hydrolysis of the ester group for compound (B16), and is a step for producing compound (17). As the reducing agent, sodium borohydride or the like can be used.
Step (B-13) is a step of deprotecting protecting groups P 2 and P 3 from compound (B18), and is a step of producing compound (B19). The compound (B18) represents the outline of the compound group (B1 to B17) in the production method B, and the compound (B19) represents the outline of the substituted amine in the production method B. This reaction varies depending on the types of protecting groups P 2 and P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
When the protecting group P 2 is a Boc group, a dioxane solution or an ethyl acetate solution of hydrochloric acid can be used as a reactant. You may add methanol, ethanol, and tetrahydrofuran as needed.
When the protective group P 2 is a Cbz group or a diphenylmethylene group, palladium carbon or palladium hydroxide can be used in a hydrogen atmosphere. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but methanol, ethanol, and tetrahydrofuran are preferable.
　保護基Ｐ２、Ｐ３がベンジリデン基の場合、希塩酸を用いることができる。反応の溶媒は、反応が進行する限り特に限定されないが、メタノール、エタノールが好ましい。
（製造法Ｃ）
　製造法Ｃは製造法Ａで得た化合物（Ａ７）と製造法Ｂで得た置換アミン（Ｂ１９）を縮合し、式（Ｉ）で示される目的化合物を製造する方法である。 When the protecting groups P 2 and P 3 are benzylidene groups, dilute hydrochloric acid can be used. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but methanol and ethanol are preferable.
(Production method C)
Production method C is a method for producing the target compound represented by formula (I) by condensing compound (A7) obtained by production method A and substituted amine (B19) obtained by production method B.
Figure JPOXMLDOC01-appb-C000017
 ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｘ、Ｙ１、Ｙ２、Ｙ３、及び、Ｙ４は上述と同様の基を表す。］
Figure JPOXMLDOC01-appb-C000017
 [Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y 1 , Y 2 , Y 3 , and Y 4 represent the same groups as described above. ]
　工程（Ｃ－１）は化合物（Ａ７）に対して、種々の縮合剤および塩基の存在下、置換アミン（Ｂ１９）を作用させて化合物（Ｃ１）を製造する工程であり、工程（Ｂ－１）と同様の方法を用いることができる。
　工程（Ｃ－２）は化合物（Ｃ１）における置換基Ｙ３およびＹ４の修飾を行う工程であり、加水分解反応、アミド化反応、公知の脱保護反応、酸化反応、アシル化反応、スルホニル化反応、ヘテロ環形成反応、水素添加反応、アルキル化反応、還元反応、炭素鎖延長反応、置換基交換反応を単独あるいはその二つ以上を組み合わせることにより、化合物（Ｉ）を製造する工程である。必要に応じてＲ１～Ｒ６における保護基の脱保護を行うことができる。
（製造法Ｄ） Step (C-1) is a step of producing compound (C1) by reacting compound (A7) with substituted amine (B19) in the presence of various condensing agents and bases. ) Can be used.
Step (C-2) is a step of modifying substituents Y 3 and Y 4 in compound (C1). Hydrolysis reaction, amidation reaction, known deprotection reaction, oxidation reaction, acylation reaction, sulfonylation In this step, compound (I) is produced by combining a reaction, heterocycle formation reaction, hydrogenation reaction, alkylation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction alone or in combination of two or more thereof. If necessary, the protecting groups in R 1 to R 6 can be deprotected.
(Production Method D)
Figure JPOXMLDOC01-appb-C000018
 ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｘ、Ｙ３、及び、Ｙ４は上述と同様の基を表す。］
Figure JPOXMLDOC01-appb-C000018
 [Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y 3 , and Y 4 represent the same groups as described above. ]
　製造法Ｄは製造法Ｃで示される化合物（Ｃ１）を製造する別法である。すなわち、化合物（Ｄ１）と置換アミン（Ｂ１９）を先に縮合し、化合物（Ｄ２）を得た後、キノリン誘導体（Ａ６）と反応させる方法により、化合物（Ｃ１）を製造する方法である。
　工程（Ｄ－１）は化合物（Ｄ１）と製造法Ｂで得られた化合物（Ｂ１９）を縮合し、化合物（Ｄ２）を製造する工程であり、工程（Ｂ－１）と同様の方法を用いることができる。
　工程（Ｄ－２）は化合物（Ｄ２）と製造法Ａで得られた化合物（Ａ６）を反応させ、化合物（Ｃ１）を製造する工程であり、工程（Ａ－３）と同様の方法を用いることができる。
　本発明の化合物又はその薬理上許容される塩を哺乳動物（特にヒト）に投与する場合には、全身的又は局所的に、経口又は非経口で投与することができる。
　本発明の医薬組成物は、投与方法に応じて適当な形態を選択し、通常用いられている各種製剤の調製法によって製造できる。 Production method D is another method for producing compound (C1) represented by production method C. That is, the compound (C1) is produced by a method in which the compound (D1) and the substituted amine (B19) are first condensed to obtain the compound (D2) and then reacted with the quinoline derivative (A6).
Step (D-1) is a step of producing compound (D2) by condensing compound (D1) and compound (B19) obtained by production method B, and using the same method as in step (B-1) be able to.
Step (D-2) is a step of producing compound (C1) by reacting compound (D2) with compound (A6) obtained by production method A, and using the same method as in step (A-3) be able to.
When the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
The pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
　経口用の医薬組成物の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。
　非経口用の医薬組成物の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。
　一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与量は、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なるが、通常、一般式（Ｉ）を有する化合物の換算量で、成人一人（体重約６０ｋｇとして）一回につき０．００１ｍｇ～１０００ｍｇの範囲で、全身的又は局所的に、一日一回から数回、経口又は非経口投与されるか、或いは一日１時間～２４時間の範囲で静脈内に持続投与されるのが好ましい。 Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. The preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives. Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
The dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind of drug to be administered in combination, the dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), once or several times a day, orally or parenterally, in an equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
　さらに、本発明の医薬組成物には、本発明の効果を損なわない範囲において、必要に応じ、その他の有効成分を併用して用いることができる。
　本発明には、本発明化合物又はその薬理上許容される塩を投与することを特徴とする前記疾患の防止方法及び／又は治療方法も含まれる。
さらに、本発明には、前記医薬組成物を製造するための本発明化合物、その薬理上許容される塩の使用も含まれる。 Furthermore, in the pharmaceutical composition of the present invention, other active ingredients can be used in combination as necessary, as long as the effects of the present invention are not impaired.
The present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof.
Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
［製剤例］
（製剤例１）散剤
本発明の化合物５ｇ、乳糖８９５ｇおよびトウモロコシデンプン１００ｇをブレンダーで混合することにより、散剤を得る。
（製剤例２）顆粒剤
本発明の化合物５ｇ、乳糖８６５ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥して顆粒剤を得る。
（製剤例３）錠剤
本発明の化合物５ｇ、乳糖９０ｇ、トウモロコシデンプン３４ｇ、結晶セルロース２０ｇおよびステアリン酸マグネシウム１ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤を得る。
［試験例１］炎症組織中プロスタグランジン類産生評価 [Formulation example]
(Formulation Example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender.
(Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
(Formulation Example 3) Tablet After mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, the tablet is obtained by tableting with a tablet machine.
[Test Example 1] Evaluation of prostaglandin production in inflamed tissues
　Opasらの報告を参考に実施した ( Opas EE, Dallob A, Herold E, Luell S and Humes JL. Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation. Biochem Pharmacol. 1987.36:547-551)。流動パラフィンに懸濁したMycobacterium Butyricum死菌体を超音波処理した後に、5または6週齢の雄性Lewisラット右側後足蹠皮内に0.05 ml注射した(100 ug/paw)。処置後19日目にラットを屠殺し、左足組織（非処置足）を回収して液体窒素で瞬間冷凍した後に粉砕し、Indomethacin, EDTAを含んだPBSを加えホモジナイズした。ホモジナイズ上清中のPGE2, PGF1a (PGI2の安定代謝物)およびTXB2 (TXA2の安定代謝物)量をCayman Chemical製のEIAキットを用いて定量した。
　本願実施例２５の化合物は、図１に示すように、１～３０ｍｇ／ｋｇの経口投与により炎症組織中のPGE2産生を用量依存的に抑制した。
［試験例２］A549細胞プロスタノイド産生阻害評価 It was carried out with reference to the report of Opas et al. (Opas EE, Dallob A, Herold E, Luell S and Humes JL. Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation. Biochem Pharmacol. 1987.36: 547-551) After sonicating dead Mycobacterium Butyricum cells suspended in liquid paraffin, 0.05 ml was injected into the right hind footpad of male Lewis rats at 5 or 6 weeks of age (100 ug / paw). On the 19th day after the treatment, the rats were sacrificed, the left paw tissue (untreated paw) was collected, snap-frozen with liquid nitrogen and then crushed, and PBS containing Indomethacin and EDTA was added and homogenized. The amounts of PGE 2 , PGF 1a (stable metabolite of PGI 2 ) and TXB 2 (stable metabolite of TXA 2 ) in the homogenized supernatant were quantified using an EIA kit manufactured by Cayman Chemical.
As shown in FIG. 1, the compound of Example 25 of the present application dose-dependently suppressed PGE 2 production in inflamed tissues by oral administration of 1 to 30 mg / kg.
[Test Example 2] A549 cell prostanoid production inhibition evaluation
　A549細胞プロスタノイド産生阻害アッセイはStaffan ThoreAnらの報告を参考に実施した（European Journal of Biochemistry, (2000) 267, 6428-6434）。10%FBS添加DMEMで懸濁したA549細胞を25000細胞/0.1 mL/ウェル播種し、37°C、5%CO2 条件下で一晩培養した。血清無添加DMEMを用いて細胞を1回洗浄後、血清無添加DMEMで希釈した化合物を0.09 mL/ウェル添加後、1時間培養した。10 ng/mL ヒトIL-1betaを0.01 mL/ウェル添加後、一晩培養した（IL-1betaの終濃度 1 ng/mL）。回収した培養上清中のPGE2濃度は市販のELISAにて測定した。
　表１に示すように、本願実施例の化合物はA549細胞からのPGE2産生に対し、優れた抑制効果を示した。
［試験例３］ラットマクロファージプロスタノイド産生評価 The A549 cell prostanoid production inhibition assay was performed with reference to a report by Staffan ThoreAn et al. (European Journal of Biochemistry, (2000) 267, 6428-6434). A549 cells suspended in DMEM supplemented with 10% FBS were seeded at 25000 cells / 0.1 mL / well and cultured overnight at 37 ° C. under 5% CO 2 conditions. After washing the cells once with serum-free DMEM, 0.09 mL / well of a compound diluted with serum-free DMEM was added, followed by incubation for 1 hour. After adding 10 ng / mL human IL-1beta to 0.01 mL / well, the cells were cultured overnight (final concentration of IL-1beta: 1 ng / mL). The PGE 2 concentration in the collected culture supernatant was measured by a commercially available ELISA.
As shown in Table 1, the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from A549 cells.
[Test Example 3] Evaluation of rat macrophage prostanoid production
　ラットマクロファージプロスタノイド産生アッセイは松本らの報告を参考に実施した（Biochemical and Biophysical Research Communications、（1996）230、110-114）。ラット腹腔に5% Peptone、5% Starchを投与して3-4日後に、腹腔内液に浸潤する細胞を10%FBS添加RPMI-1640で回収して腹腔マクロファージを調製した。調整したマクロファージにアスピリンを終濃度で0.1 mM添加後、96 well プレートに200000細胞/0.1 mL/well 添加し、37°C、5%CO2 条件下で2 時間培養後、RPMI-1640 で2 回洗浄して非付着細胞を除いた。10%FBS添加RPMI-1640 を0.15 mL、4 倍濃度化合物0.05 mL を添加して、37°C、5% CO2条件下で1 時間培養した。その後、LPSを0.005 mL（終濃度 0.01 mg/mL）添加し、37°C、5% CO2条件下で24 時間培養した。翌日に培養上清を200 μL 回収してPGE2 などのプロスタノイドを定量した。
　表１に示すように、本願実施例の化合物はラットマクロファージからのPGE2産生に対し、優れた抑制効果を示した。また、本願発明の化合物のTXB2産生に対するIC50値は、いずれも1000 ng/ml以上であり、PGE2産生を選択的に抑制していることが示された。 The rat macrophage prostanoid production assay was performed with reference to a report by Matsumoto et al. (Biochemical and Biophysical Research Communications, (1996) 230, 110-114). 3-4 days after 5% Peptone and 5% Starch were administered to the rat abdominal cavity, cells infiltrating the intraperitoneal fluid were recovered with RPMI-1640 supplemented with 10% FBS to prepare peritoneal macrophages. After adding 0.1 mM of aspirin to the prepared macrophages at a final concentration, add 200,000 cells / 0.1 mL / well to a 96-well plate, incubate for 2 hours at 37 ° C and 5% CO 2 , and then twice with RPMI-1640 Wash to remove non-adherent cells. RPMI-1640 supplemented with 10% FBS was added at 0.15 mL and 0.05 mL of a 4-fold concentration compound, and cultured at 37 ° C. under 5% CO 2 for 1 hour. Thereafter, 0.005 mL (final concentration 0.01 mg / mL) of LPS was added, and the cells were cultured for 24 hours at 37 ° C. and 5% CO 2 . On the next day, 200 μL of the culture supernatant was collected, and prostanoids such as PGE 2 were quantified.
As shown in Table 1, the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from rat macrophages. In addition, the IC 50 values for TXB 2 production of the compounds of the present invention were all 1000 ng / ml or more, indicating that PGE 2 production was selectively suppressed.
Figure JPOXMLDOC01-appb-T000019
 ［試験例４］実験的ラットアジュバント関節炎モデル評価
　Mycobacterium butyricum の加熱死菌をメノウの乳鉢で微細化後、乾熱滅菌した流動パラフィンに 2 mg/mLの割合になるように懸濁し、さらに超音波処理を行った。調製したアジュバントの0.05 mLを5週齢の雌性Lewisラットの右後足足蹠皮内に接種した。アジュバント投与19日後に接種足の体積を測定し、各群の腫脹体積の平均値がほぼ等値となるように群別した。群別後、0.5% Methyl cellulose (MC)あるいはPropylene glycol:Tween80 = 8:2の混合溶媒(PG/T)に懸濁した試験化合物を３０mｇ/kg、１日１回３日間経口投与し、足体積測定は群別後から１日１回４日間実施した。
　実施例化合物２５および実施例化合物２８は、対照群と比べて４日目の足の腫れをそれぞれ、１６．０％および２６．４％抑制した。
 
Figure JPOXMLDOC01-appb-T000019
 [Test Example 4] Experimental rat adjuvant arthritis model evaluation Heat-killed Mycobacterium butyricum bacteria were refined in an agate mortar, suspended in liquid paraffin sterilized by dry heat at a rate of 2 mg / mL, and then subjected to ultrasound. Processed. 0.05 mL of the prepared adjuvant was inoculated into the right hind paw scab of 5-week-old female Lewis rats. 19 days after administration of the adjuvant, the volume of the inoculated paw was measured, and the groups were divided so that the average value of the swelling volume of each group was almost equal. After grouping, the test compound suspended in 0.5% Methyl cellulose (MC) or Propylene glycol: Tween80 = 8: 2 mixed solvent (PG / T) was orally administered at 30 mg / kg once a day for 3 days. Volume measurement was performed once a day for 4 days after grouping.
Example Compound 25 and Example Compound 28 suppressed paw swelling on day 4 by 16.0% and 26.4%, respectively, as compared to the control group.
（参考例１）エチル １－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボキシレート
　市販の２－クロロ－６－メチル－３－フェニルキノリン（１９．９ｇ，７８．６ｍｍｏｌ）のＮ－メチルピロリドン（６０ｍＬ）溶液に市販のエチル　４－ピペリジンカルボキシレート（４８．５ｍＬ，３１５ｍｍｏｌ）を加え、１６０℃にて１５時間攪拌した。得られた混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水および飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－１／１）にて精製した。得られた固体をヘキサンにて洗浄し、標記化合物２４．２ｇ（収率８２％）を固体として得た。
（参考例２）１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボン酸
　参考例１で得られたエチル １－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボキシレート（２０．８ｇ，５５．５ｍｍｏｌ）のエタノール（５０ｍＬ）、テトラヒドロフラン（１０ｍＬ）及び水（１０ｍＬ）の混合溶液に、８Ｎ水酸化ナトリウム水溶液（１５ｍＬ，１２０ｍｍｏｌ）を加え、５０℃にて１時間、その後室温にて１４時間攪拌した。１Ｎ塩酸水溶液を加えて中和した後、減圧下にて溶媒を留去した。残渣に水を加え、次いでｐＨ４程度になるまで１Ｎ塩酸水溶液を加えたところ固体が析出した。この反応混合物にｎ－ヘキサン及びエーテルを加え、固体を濾取した後、水にて洗浄した。得られた個体を減圧下にて乾燥し、標記化合物１９．３ｇ（収率１００％）を固体として得た。 Reference Example 1 Ethyl 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate Commercially available 2-chloro-6-methyl-3-phenylquinoline (19.9 g, 78.6 mmol) ) In N-methylpyrrolidone (60 mL) was added commercially available ethyl 4-piperidinecarboxylate (48.5 mL, 315 mmol) and stirred at 160 ° C. for 15 hours. Water was added to the obtained mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 9 / 1-1 / 1). The obtained solid was washed with hexane to obtain 24.2 g (yield 82%) of the title compound as a solid.
Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid Ethyl 1- (6-methyl-3-phenylquinolin-2-yl) obtained in Reference Example 1 ) To a mixed solution of piperidine-4-carboxylate (20.8 g, 55.5 mmol) in ethanol (50 mL), tetrahydrofuran (10 mL) and water (10 mL), 8N aqueous sodium hydroxide solution (15 mL, 120 mmol) was added. The mixture was stirred at ° C for 1 hour and then at room temperature for 14 hours. After neutralizing with 1N aqueous hydrochloric acid, the solvent was distilled off under reduced pressure. Water was added to the residue, and then a 1N hydrochloric acid aqueous solution was added until the pH reached about 4, and a solid precipitated. N-Hexane and ether were added to the reaction mixture, and the solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain 19.3 g (yield 100%) of the title compound as a solid.
（参考例３）ｔｅｒｔ－ブチル　［シス－４－（シアノメチル）シクロヘキシル］カーバメート 
　市販のｔｅｒｔ－ブチル　［シス－４－（ヒドロキシメチル）シクロヘキシル］カーバメート（４．７１ｇ，２０．５ｍｍｏｌ）およびトリエチルアミン（５．７２ｍＬ，４１．０ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液に、氷冷下、メタンスルホニルクロリド（２．０６ｍＬ，２６．６ｍｍｏｌ）を滴下し、０℃にて２時間、さらに室温にて１時間攪拌した。反応混合物にジクロロメタンを加え希釈した後、１Ｎ塩酸水溶液を加えて中和洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣のＮ，Ｎ－ジメチルホルムアミド（３０ｍＬ）溶液に、水（５ｍＬ）およびシアン化ナトリウム（３．０５ｇ，６２．２ｍｍｏｌ）を加え、９０℃にて１２時間攪拌した。反応混合物に水を加え酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３／１－１／２）にて精製し、標記化合物４．５７ｇ（収率９３％）を固体として得た。
（参考例４）ｔｅｒｔ－ブチル　［シス－４－（２－アミノ－２－オキソエチル）シクロヘキシル］カーバメート
　参考例３で得られたｔｅｒｔ－ブチル　［シス－４－（シアノメチル）シクロヘキシル］カーバメート（１．２０ｇ，５．０４ｍｍｏｌ）のエタノール溶液（１０ｍＬ）に８Ｎ水酸化ナトリウム溶液（１ｍＬ）を加え９０℃にて２０時間攪拌した。反応混合物を減圧濃縮し、水にて希釈した後、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物５１３ｍｇを固体として得た。 Reference Example 3 tert-Butyl [cis-4- (cyanomethyl) cyclohexyl] carbamate
To a solution of commercially available tert-butyl [cis-4- (hydroxymethyl) cyclohexyl] carbamate (4.71 g, 20.5 mmol) and triethylamine (5.72 mL, 41.0 mmol) in dichloromethane (50 mL) was added methane under ice-cooling. Sulfonyl chloride (2.06 mL, 26.6 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours and further at room temperature for 1 hour. Dichloromethane was added to the reaction mixture for dilution, and 1N hydrochloric acid aqueous solution was added for neutralization washing. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Water (5 mL) and sodium cyanide (3.05 g, 62.2 mmol) were added to a solution of the residue in N, N-dimethylformamide (30 mL), and the mixture was stirred at 90 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 3 / 1-1 / 2) to give 4.57 g of the title compound (93% yield). Was obtained as a solid.
Reference Example 4 tert-Butyl [cis-4- (2-amino-2-oxoethyl) cyclohexyl] carbamate tert-butyl [cis-4- (cyanomethyl) cyclohexyl] carbamate obtained in Reference Example 3 (1.20 g , 5.04 mmol) in ethanol solution (10 mL) was added 8N sodium hydroxide solution (1 mL), and the mixture was stirred at 90 ° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 513 mg of the title compound as a solid.
（参考例５）２－（シス－４－アミノシクロヘキシル）アセトアミド　塩酸塩
　参考例４で得られたｔｅｒｔ－ブチル　［シス－４－（２－アミノ－２－オキソエチル）シクロヘキシル］カーバメート（５１３ｍｇ）に市販の４Ｎ塩酸ジオキサン溶液（６ｍＬ）および市販の５～１０％塩酸メタノール溶液（１ｍＬ）を加え室温にて２時間攪拌した。反応混合物を減圧濃縮した後、酢酸エチルを加え希釈した。減圧下にて溶媒を留去し、標記化合物を定量的に固体として得た。
（参考例６）ｔｅｒｔ－ブチル　｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝カーバメート
　市販の｛シス－４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝酢酸（２．７１ｇ，１０．５ｍｍｏｌ）のジクロロメタン（２５ｍＬ）溶液に、氷冷下、市販の１，１’－カルボニルジイミダゾール（２．０５ｇ，１２．６ｍｍｏｌ）を加え、４０分攪拌した。反応混合物に市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液，１０．５ｍＬ，２１．０ｍｍｏｌ）を加え、室温にて３時間攪拌した。反応液にジクロロメタンを加え希釈した後、１０％硫酸水素カリウム水溶液を加えて中和洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物を固体として得た。 Reference Example 5 2- (cis-4-aminocyclohexyl) acetamide hydrochloride Commercially available tert-butyl [cis-4- (2-amino-2-oxoethyl) cyclohexyl] carbamate (513 mg) obtained in Reference Example 4 4N hydrochloric acid dioxane solution (6 mL) and commercially available 5 to 10% hydrochloric acid methanol solution (1 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the title compound quantitatively as a solid.
Reference Example 6 tert-Butyl {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl} carbamate Commercially available {cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl} acetic acid (2. A commercially available 1,1′-carbonyldiimidazole (2.05 g, 12.6 mmol) was added to a solution of 71 g, 10.5 mmol) in dichloromethane (25 mL) under ice cooling, and the mixture was stirred for 40 minutes. Commercially available methylamine (2.0 M tetrahydrofuran solution, 10.5 mL, 21.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Dichloromethane was added to the reaction solution for dilution, and 10% aqueous potassium hydrogen sulfate solution was added for neutralization washing. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a solid.
（参考例７）２－（シス－４－アミノシクロヘキシル）－Ｎ－メチルアセトアミド　塩酸塩
　参考例６で得られたｔｅｒｔ－ブチル　｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝カーバメートを用いて、参考例５の方法に準じて標記化合物（収率９９％）を得た。
（参考例８）（シス－４－アミノシクロヘキシル）アセトニトリル　塩酸塩
　参考例３で得られたｔｅｒｔ－ブチル　［シス－４－（シアノメチル）シクロヘキシル］カーバメートを用いて、参考例５の方法に準じて標記化合物（収率９９％）を固体として得た。
（参考例９）ベンジル　［シス－４－（２－アミノ－１－ヒドロキシ－２－オキソエチル）シクロヘキシル］カーバメート
　ＵＳ２００９／０１４３３０２Ａ１出願明細書記載のベンジル　（シス－４－ホルミルシクロヘキシル）カーバメート（８００ｍｇ，３．０４ｍｍｏｌ）およびトリメチルシリルシアニド（５１２μＬ，３．６５ｍｍｏｌ）のジクロロメタン（１６ｍＬ）溶液に、氷冷下、トリエチルアミン（５０８μＬ，０．４６ｍｍｏｌ）を滴下した後、室温に戻し４５分間攪拌した。１Ｎ塩酸水溶液（２０ｍＬ）およびテトラヒドロフラン（２０ｍＬ）の混合溶液に氷冷下、反応混合物を滴下した後、室温に戻し３０分間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出後、有機層を合わせ、飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣にｎ－ヘキサンおよびジイソプロピルエーテルを加えて粉末化し、固体７２９ｍｇ（収率８３％）を得た。得られた固体（６００ｍｇ，２．０８ｍｍｏｌ）のテトラヒドロフラン（１１．８ｍＬ）溶液に、アセトアミド（１．２３ｇ，２０．８ｍｍｏｌ）、塩化パラジウム（３６．９ｍｇ，０．２０８ｍｍｏｌ）および水（１２ｍＬ）を加え、室温にて１６時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０－０／１００）にて精製し、標記化合物５５６ｍｇ（収率８７％）を固体として得た。 (Reference Example 7) 2- (cis-4-aminocyclohexyl) -N-methylacetamide hydrochloride tert-butyl obtained in Reference Example 6 {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl } Using the carbamate, the title compound (99% yield) was obtained according to the method of Reference Example 5.
(Reference Example 8) (cis-4-aminocyclohexyl) acetonitrile hydrochloride Using the tert-butyl [cis-4- (cyanomethyl) cyclohexyl] carbamate obtained in Reference Example 3, the title was prepared according to the method of Reference Example 5. The compound (99% yield) was obtained as a solid.
Reference Example 9 Benzyl [cis-4- (2-amino-1-hydroxy-2-oxoethyl) cyclohexyl] carbamate Benzyl (cis-4-formylcyclohexyl) carbamate described in the specification of US2009 / 0143302A1 (800 mg, 3. (04 mmol) and trimethylsilylcyanide (512 μL, 3.65 mmol) in dichloromethane (16 mL) were added dropwise triethylamine (508 μL, 0.46 mmol) under ice-cooling, and the mixture was returned to room temperature and stirred for 45 minutes. The reaction mixture was added dropwise to a mixed solution of 1N aqueous hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) under ice cooling, and the mixture was returned to room temperature and stirred for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was pulverized by adding n-hexane and diisopropyl ether to obtain 729 mg (yield 83%) of a solid. To a solution of the obtained solid (600 mg, 2.08 mmol) in tetrahydrofuran (11.8 mL), acetamide (1.23 g, 20.8 mmol), palladium chloride (36.9 mg, 0.208 mmol) and water (12 mL) were added. And stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-0 / 100) to give 556 mg (yield 87%) of the title compound. Obtained as a solid.
（参考例１０）２－（シス－４－アミノシクロヘキシル）－２－ヒドロキシアセトアミド
　参考例９で得られたベンジル　［シス－４－（２－アミノ－１－ヒドロキシ－２－オキソエチル）シクロヘキシル］カルバマート（２５１ｍｇ，０．８１９ｍｍｏｌ）のエタノール（１６ｍＬ）溶液に、市販の１０％パラジウム炭素（１２６ｍｇ）を加え、水素雰囲気下、室温にて３時間攪拌した。反応混合物をセライトろ過した後、減圧下にて溶媒を留去し、標記化合物を定量的に得た。
（参考例１１）２－（シス－４－アミノシクロヘキシル）－２－ヒドロキシ－Ｎ－メチルアセトアミド
　参考例９で得られたベンジル　［シス－４－（２－アミノ－１－ヒドロキシ－２－オキソエチル）シクロヘキシル］カーバメート（５４６ｍｇ，１．７８ｍｍｏｌ）の１，４－ジオキサン（８．９ｍＬ）溶液に、１Ｎ塩酸（１３．４ｍＬ，１３．４ｍｍｏｌ）を加えて１００℃にて１０時間攪拌した。反応混合物に１Ｎ水酸化ナトリウム水溶液を加え、ジクロロメタンにて洗浄した。有機層を０．２Ｎ水酸化ナトリウム水溶液にて抽出した。水層を合わせて濃塩酸を加えて酸性にした後、ジクロロメタンにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去し、油状物４６４ｍｇを得た。得られた油状物および市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例１の方法に準じてアモルファス状物（収率７６％）を得た。得られたアモルファス状物を用いて、参考例１０の方法に準じて標記化合物（収率９４％）を得た。 Reference Example 10 2- (cis-4-aminocyclohexyl) -2-hydroxyacetamide The benzyl [cis-4- (2-amino-1-hydroxy-2-oxoethyl) cyclohexyl] carbamate obtained in Reference Example 9 To a solution of 251 mg, 0.819 mmol) in ethanol (16 mL) was added commercially available 10% palladium carbon (126 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound quantitatively.
Reference Example 11 2- (cis-4-aminocyclohexyl) -2-hydroxy-N-methylacetamide benzyl obtained in Reference Example 9 [cis-4- (2-amino-1-hydroxy-2-oxoethyl) To a solution of cyclohexyl] carbamate (546 mg, 1.78 mmol) in 1,4-dioxane (8.9 mL) was added 1N hydrochloric acid (13.4 mL, 13.4 mmol), and the mixture was stirred at 100 ° C. for 10 hours. A 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was washed with dichloromethane. The organic layer was extracted with 0.2N aqueous sodium hydroxide solution. The aqueous layers were combined, acidified with concentrated hydrochloric acid, and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 464 mg of an oil. Using the obtained oil and commercially available methylamine (2.0 M tetrahydrofuran solution), an amorphous product (yield 76%) was obtained according to the method of Example 1. Using the obtained amorphous material, the title compound (yield 94%) was obtained according to the method of Reference Example 10.
（参考例１２）Ｎ－［シス－４－（２－ヒドラジノ－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例２で得られた［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸（１．８６ｇ，２．８９ｍｍｏｌ，純度７５％）、ｔｅｒｔ－ブチル　カルバゼート（６８７ｍｇ，５．２０ｍｍｏｌ）のアセトニトリル（３０ｍＬ）溶液に、市販の４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（１．４４ｇ，５．２０ｍｍｏｌ）を加え、室温にて３時間攪拌した。反応混合物に酢酸エチルを加え、水および飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、固体を得た。得られた固体を４Ｎ塩酸－１，４－ジオキサン溶液（１０ｍＬ）に溶解し、室温にて５時間攪拌した。氷冷下、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物１．１０ｇ（収率７６％）を固体として得た。
（参考例１３）エチル　（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）アセテート
　Ｉｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ　（１９８０）， １０，　２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩（５．６０ｇ，２５．３ｍｍｏｌ）に飽和炭酸水素ナトリウム水溶液を用いて中和し、クロロホルムにて抽出した。さらに水層に０．１Ｎ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣を乾燥し、油状物３．５０ｇを得た。得られた油状物（１．８０ｇ，９．７２ｍｍｏｌ）のメタノール（４９ｍＬ）溶液に、無水硫酸ナトリウム（９．００ｇ）およびベンズアルデヒド（０．９８２ｍＬ，９．７２ｍｍｏｌ）を加えて室温にて１６時間攪拌した。反応混合物をろ過し、減圧下にて溶媒を留去し、標記化合物を得た。 Reference Example 12 N- [cis-4- (2-hydrazino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Example 2 [Cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid (1.86 g, 2.89 mmol, purity 75 %), Tert-butyl carbazate (687 mg, 5.20 mmol) in acetonitrile (30 mL) was added commercially available 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol. Folinium chloride (1.44 g, 5.20 mmol) was added and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain a solid. The obtained solid was dissolved in 4N hydrochloric acid-1,4-dioxane solution (10 mL) and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.10 g (yield 76%) of the title compound as a solid.
(Reference Example 13) Ethyl (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) acetate The described ethyl (cis-4-aminocyclohexyl) acetate hydrochloride (5.60 g, 25.3 mmol) was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. Further, a 0.1N aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dried to obtain 3.50 g of an oily substance. To a solution of the obtained oil (1.80 g, 9.72 mmol) in methanol (49 mL), anhydrous sodium sulfate (9.00 g) and benzaldehyde (0.982 mL, 9.72 mmol) were added and stirred at room temperature for 16 hours. did. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound.
（参考例１４）エチル　２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエート
　窒素雰囲気下、１．１４Ｍリチウムジイソプロピルアミドのテトラヒドロフラン溶液（０．３５３ｍＬ，０．４０２ｍｍｏｌ）に、ドライアイス－メタノールで冷却下、参考例１３で得られたエチル　（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）アセテート（５０．０ｍｇ，０.１８３ｍｍｏｌ）のテトラヒドロフラン溶液（０．９２ｍＬ）を加えた。氷冷下、２０分間撹拌した後、再びドライアイス－メタノールにて冷却した。ヨウ化メチル（３４．２μＬ，０.５４９ｍｍｏｌ）およびヘキサメチルリン酸トリアミド（７０．０μＬ，０.４０２ｍｍｏｌ）のテトラヒドロフラン溶液（０．９２ｍＬ）を加え、室温にて２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物を得た。
（参考例１５）エチル　２－（シス－４－アミノシクロヘキシル）プロパノエート
　参考例１４で得られたエチル　２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエート（４９２ｍｇ，１．５６ｍｍｏｌ相当）のジクロロメタン（７．８ｍＬ）溶液に、氷冷下、トリフルオロ酢酸（０．１７９ｍＬ，２．３４ｍｍｏｌ）を加えて室温にて２時間攪拌した。減圧下にて溶媒を留去した後、市販の４Ｎ塩酸－酢酸エチル（２ｍＬ）を加えて再び減圧下にて溶媒を留去した。水を加えてトルエンにて洗浄後、４Ｎ水酸化ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物２４０ｍｇ（収率７７％）を得た。 Reference Example 14 Ethyl 2- (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) propanoate Under a nitrogen atmosphere, to a tetrahydrofuran solution (0.353 mL, 0.402 mmol) of 1.14M lithium diisopropylamide Under cooling with dry ice-methanol, a solution of ethyl (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) acetate (50.0 mg, 0.183 mmol) obtained in Reference Example 13 in tetrahydrofuran (0 .92 mL) was added. The mixture was stirred for 20 minutes under ice cooling, and then cooled again with dry ice-methanol. A tetrahydrofuran solution (0.92 mL) of methyl iodide (34.2 μL, 0.549 mmol) and hexamethylphosphoric triamide (70.0 μL, 0.402 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
Reference Example 15 Ethyl 2- (cis-4-aminocyclohexyl) propanoate Ethyl 2- (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) propanoate obtained in Reference Example 14 (492 mg, 1 Trifluoroacetic acid (0.179 mL, 2.34 mmol) was added to a dichloromethane (7.8 mL) solution of .56 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, commercially available 4N hydrochloric acid-ethyl acetate (2 mL) was added, and the solvent was distilled off again under reduced pressure. Water was added and the mixture was washed with toluene, 4N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 240 mg (yield 77%) of the title compound.
（参考例１６）エチル　２－メチル－２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエート
　参考例１４で得られたエチル　２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエートを用いて、参考例１４の方法に準じて標記化合物を定量的に得た。
（参考例１７）エチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエート
　参考例１６で得られたエチル　２－メチル－２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエートを用いて、参考例１５の方法に準じて標記化合物（収率９２％）を得た。 Reference Example 16 Ethyl 2-methyl-2- (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) propanoate Ethyl 2- (cis-4-{[(1E ) -Phenylmethylene] amino} cyclohexyl) propanoate was used to quantitatively obtain the title compound according to the method of Reference Example 14.
Reference Example 17 Ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate Ethyl 2-methyl-2- (cis-4-{[(1E) -phenylmethylene obtained in Reference Example 16 ] The title compound (yield 92%) was obtained according to the method of Reference Example 15 using amino} cyclohexyl) propanoate.
（参考例１８）エチル　２－｛シス－４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝アクリレート
　参考例１３で得られたエチル　（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）アセテート（１．７２ｇ，６．６３ｍｍｏｌ）およびパラホルムアルデヒドを用いて、参考例１４の方法に準じて得られた化合物をジクロロメタン（３０ｍＬ）に溶解した。反応混合物にトリフルオロ酢酸（０．７６８ｍＬ，１０．４ｍｍｏｌ）を加え、室温にて３時間攪拌した。反応混合物を減圧濃縮した後、ジクロロメタン（７０ｍＬ）に溶解し、ジ－ｔｅｒｔ－ブチルジカーボネート（２．２６ｇ，１０．４ｍｍｏｌ）およびトリエチルアミン（４．８２ｍＬ，３４．６ｍｍｏｌ）を加え、室温にて２０時間攪拌した。反応混合物に酢酸エチルを加えた後、混合物を飽和塩化アンモニウム水溶液および飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１）にて精製し、油状物３３４ｍｇ（収率１５％）を得た。得られた油状物（３３４ｍｇ，１．０６ｍｍｏｌ）、メタンスルホニルクロリド（０．０９８ｍＬ，１．２７ｍｍｏｌ）、およびトリエチルアミン（０．２０６ｍＬ，１．４８ｍｍｏｌ）のジクロロメタン（８ｍＬ）混合液を、室温にて１５時間攪拌した。酢酸エチルを加えた後、反応混合物を水および飽和食塩水にて洗浄した。無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をジクロロメタン（８ｍＬ）に溶解し、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（０．２０５ｍＬ，１．３８ｍｍｏｌ）を加え、室温にて２時間攪拌した。酢酸エチルを加えた後、反応混合物を飽和塩化アンモニウム水溶液および飽和食塩水にて洗浄した。無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／１）にて精製し、標記化合物２４８ｍｇ（収率７９％）を得た。 Reference Example 18 Ethyl 2- {cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl} acrylate Ethyl (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl obtained in Reference Example 13 ) The compound obtained according to the method of Reference Example 14 was dissolved in dichloromethane (30 mL) using acetate (1.72 g, 6.63 mmol) and paraformaldehyde. Trifluoroacetic acid (0.768 mL, 10.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (70 mL), di-tert-butyl dicarbonate (2.26 g, 10.4 mmol) and triethylamine (4.82 mL, 34.6 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Stir for hours. After adding ethyl acetate to the reaction mixture, the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 1/1) to obtain 334 mg (yield 15%) of an oil. A mixture of the obtained oil (334 mg, 1.06 mmol), methanesulfonyl chloride (0.098 mL, 1.27 mmol), and triethylamine (0.206 mL, 1.48 mmol) in dichloromethane (8 mL) was added at room temperature. Stir for hours. After adding ethyl acetate, the reaction mixture was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (8 mL), 1,8-diazabicyclo [5.4.0] -7-undecene (0.205 mL, 1.38 mmol) was added, and the mixture was stirred at room temperature for 2 hr. After adding ethyl acetate, the reaction mixture was washed with saturated aqueous ammonium chloride solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1) to obtain 248 mg (yield 79%) of the title compound.
（参考例１９）エチル　１－｛シス－４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝シクロプロパンカルボキシレート
　エーテル（５ｍＬ）および１０Ｎ水酸化ナトリウム水溶液（５ｍＬ）の混合液に、氷冷下、市販の１－メチル－３－ニトロ－１－ニトロソグアニジン（約５０％　水湿潤品）（４００ｍｇ，１．３６ｍｍｏｌ）を加え、０℃にて１５分間攪拌した。上記操作で得られたエーテル層を、ジアゾメタンのエーテル溶液とし、参考例１８で得られたエチル　２－｛シス－４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝アクリレート（２４８ｍｇ，０．８３４ｍｍｏｌ）および酢酸パラジウム（１０ｍｇ，０．０４５ｍｍｏｌ）のエーテル（３ｍＬ）懸濁液に加えた。得られた混合物を室温にて１時間攪拌した。上記操作によりジアゾメタンのエーテル溶液を作成し、酢酸パラジウム（１０ｍｇ，０．０４５ｍｍｏｌ）とともに１時間おきに合計４回、反応混合物に加えた。室温にて５時間攪拌した後、酢酸エチルを加え、セライトろ過した。ろ液を飽和食塩水にて洗浄し、無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝４／１）にて精製し、標記化合物２５０ｍｇ（収率９６％）を得た。
（参考例２０）（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸　および
（１Ｒ，３Ｒ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸
　ＰＣＴ　ＷＯ２００８／０７５１９６出願明細書記載のトランス－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸（１２０ｇ）を用いて超臨海流体クロマトグラフィー（ダイセル　キラルパックＡＤ－Ｈ、二酸化炭素／メタノール＝７５：２５）にて光学分割を行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、標記化合物（５６．７ｇ，光学純度　＞９８％ｅｅ）を固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、標記化合物（５５．４ｇ，光学純度　＞９８％ｅｅ）を固体として得た。 (Reference Example 19) A mixture of ethyl 1- {cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl} cyclopropanecarboxylate ether (5 mL) and 10N aqueous sodium hydroxide solution (5 mL) was added under ice cooling. Commercially available 1-methyl-3-nitro-1-nitrosoguanidine (about 50% wet product in water) (400 mg, 1.36 mmol) was added, and the mixture was stirred at 0 ° C. for 15 minutes. The ether layer obtained by the above operation was converted to an ether solution of diazomethane, and ethyl 2- {cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl} acrylate obtained in Reference Example 18 (248 mg, 0.834 mmol) And palladium acetate (10 mg, 0.045 mmol) in ether (3 mL) suspension. The resulting mixture was stirred at room temperature for 1 hour. An ether solution of diazomethane was prepared by the above operation, and added to the reaction mixture together with palladium acetate (10 mg, 0.045 mmol) four times every hour. After stirring at room temperature for 5 hours, ethyl acetate was added and filtered through celite. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 250 mg (yield 96%) of the title compound.
Reference Example 20 (1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and (1R, 3R) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid PCT WO2008 Supercritical fluid chromatography using the trans-3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid (120 g) described in the specification of the above-mentioned application (Daicel Chiral Pack AD-H, carbon dioxide / methanol = 75: 25) Optical resolution was performed. The first peak eluting first was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (56.7 g, optical purity> 98% ee) as a solid. The second peak eluting later was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (55.4 g, optical purity> 98% ee) as a solid.
（参考例２１）ベンジル　［（１Ｒ，３Ｒ）－３－｛［（１Ｓ）－１－フェニルエチル］カルバモイル｝シクロヘキシル］カーバメート
　参考例２０で得られた第一ピーク（３００ｍｇ，１．０８ｍｍｏｌ）のジクロロメタン（１１ｍＬ）溶液に、３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール（２９４ｍｇ，２．１６ｍｍｏｌ）、（１Ｓ）－１－フェニルエタンアミン（１３８μＬ，１．０８ｍｍｏｌ）、１－エチル－３－(３－ジメチルアミノプロピル) カルボジイミド　塩酸塩（４１４ｍｇ，２．１６ｍｍｏｌ）、およびトリエチルアミン（０．４５２ｍＬ，３．２４ｍｍｏｌ）を加え、室温にて２０時間攪拌した。反応混合物に水を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０－０／１００）にて精製し、標記化合物３９４ｍｇ（収率９６％）を固体として得た。得られた固体を用いてイソプロピルアルコール溶媒から結晶化を行った。得られた結晶を用いてＸ線結晶構造解析によって絶対立体構造を決定した。絶対立体配置は（１Ｓ）－１－フェニルエタンアミンの立体配置を基に（１Ｒ，３Ｒ）であると決定した。よって、参考例２０で得られた第二ピークの絶対立体配置は（１Ｓ，３Ｓ）であると決定した。
（参考例２２）ベンジル　［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］カーバメート
　参考例２０で得られた第二ピーク（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販のアンモニア水を用いて、参考例６の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例２３）（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩
　参考例２２で得られたベンジル　［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］カーバメート（３．００ｇ，１０．９ｍｏｌ）のエタノール（１００ｍＬ）溶液に、市販の１０％パラジウム炭素（３００ｍｇ）を加え、水素雰囲気下、室温にて２．５時間攪拌した。反応混合物をセライトろ過した後、減圧下にて溶媒を留去した。得られた残渣に１Ｎ塩酸エタノール溶液を加えて懸濁させた後、減圧下にて溶媒を留去した。得られた残渣を乾燥し、標記化合物１．９５ｇ（収率９７％）を固体として得た。 (Reference Example 21) benzyl [(1R, 3R) -3-{[(1S) -1-phenylethyl] carbamoyl} cyclohexyl] carbamate dichloromethane of the first peak (300 mg, 1.08 mmol) obtained in Reference Example 20 (11 mL) in solution, 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (294 mg, 2.16 mmol), (1S) -1-phenylethanamine (138 μL, 1. 08 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (414 mg, 2.16 mmol), and triethylamine (0.452 mL, 3.24 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-0 / 100) to obtain 394 mg (yield 96%) of the title compound as a solid. The obtained solid was crystallized from isopropyl alcohol solvent. The absolute steric structure was determined by X-ray crystal structure analysis using the obtained crystal. The absolute configuration was determined to be (1R, 3R) based on the configuration of (1S) -1-phenylethanamine. Therefore, the absolute configuration of the second peak obtained in Reference Example 20 was determined to be (1S, 3S).
(Reference Example 22) benzyl [(1S, 3S) -3-carbamoylcyclohexyl] carbamate Second peak (1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid obtained in Reference Example 20 The title compound (yield 100%) was obtained as a solid according to the method of Reference Example 6 using commercially available aqueous ammonia.
Reference Example 23 (1S, 3S) -3-Aminocyclohexanecarboxamide hydrochloride The benzyl [(1S, 3S) -3-carbamoylcyclohexyl] carbamate (3.00 g, 10.9 mol) ethanol obtained in Reference Example 22 (100 mL) To the solution was added commercially available 10% palladium carbon (300 mg), and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. A 1N hydrochloric acid ethanol solution was added to the obtained residue to suspend it, and then the solvent was distilled off under reduced pressure. The obtained residue was dried to obtain 1.95 g (yield 97%) of the title compound as a solid.
（参考例２４）［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］メタノール　塩酸塩
　ＰＣＴ　ＷＯ２００９／１５３７２０Ａ１出願明細書記載のベンジル　［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］カーバメートを用いて、参考例２３の方法に準じて標記化合物（収率９７％）を得た。
（参考例２５）［（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミド
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、参考例６の方法に準じて油状物を得た。得られた油状物を用いて、参考例１０の方法に準じて標記化合物を固体として得た。
（参考例２６）ベンジル　［（１Ｓ，３Ｓ）－３－（シアノメチル）シクロヘキシル］カーバメート
　ＰＣＴ　ＷＯ２００９／１５３７２０Ａ１出願明細書記載のベンジル　［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］カーバメートを用いて参考例３の方法に準じて標記化合物（収率９２％）を得た。
（参考例２７）エチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩
　参考例２６で得られたベンジル　［（１Ｓ，３Ｓ）－３－（シアノメチル）シクロヘキシル］カーバメート（１．９ｇ，６．９８ｍｍｏｌ）を濃塩酸（３０ｍＬ）に溶解し、加熱還流下１５時間攪拌した。減圧下にて溶媒を留去し、残渣をトルエン共沸して得られた固体をｎ－ヘキサンにて洗浄し、固体１．５８ｇ（収率１００％、純度８６％）を得た。得られた固体（１．５８ｇ）のエタノール（２０ｍＬ）溶液に、チオニルクロリド（１ｍＬ）を加え、加熱還流下１５時間攪拌した。反応混合物を減圧濃縮した後、残渣をトルエン共沸し、標記化合物１．７５ｇ（収率１００％、純度８８％）を固体として得た。 (Reference Example 24) [(1S, 3S) -3-Aminocyclohexyl] methanol hydrochloride PCT WO2009 / 153720A1 Application specification benzyl [(1S, 3S) -3- (hydroxymethyl) cyclohexyl] carbamate The title compound (yield 97%) was obtained according to the method of Reference Example 23.
Reference Example 25 [(1S, 3S) -3-Amino-N-ethylcyclohexanecarboxamide (1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid obtained in Reference Example 20 and An oily substance was obtained in accordance with the method of Reference Example 6 using commercially available ethylamine (2.0 M tetrahydrofuran solution). The title compound was obtained as a solid according to the method of Reference Example 10 using the obtained oil.
(Reference Example 26) Benzyl [(1S, 3S) -3- (cyanomethyl) cyclohexyl] carbamate PCT WO2009 / 153720A1 Using benzyl [(1S, 3S) -3- (hydroxymethyl) cyclohexyl] carbamate described in the application specification The title compound (yield 92%) was obtained according to the method of Reference Example 3.
(Reference Example 27) Ethyl [(1S, 3S) -3-aminocyclohexyl] acetate hydrochloride The benzyl [(1S, 3S) -3- (cyanomethyl) cyclohexyl] carbamate (1.9 g, 6) obtained in Reference Example 26 .98 mmol) was dissolved in concentrated hydrochloric acid (30 mL) and stirred with heating under reflux for 15 hours. The solvent was distilled off under reduced pressure, and the residue was azeotroped with toluene. The solid obtained was washed with n-hexane to obtain 1.58 g of solid (yield 100%, purity 86%). To a solution of the obtained solid (1.58 g) in ethanol (20 mL) was added thionyl chloride (1 mL), and the mixture was stirred with heating under reflux for 15 hr. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with toluene to obtain 1.75 g (yield 100%, purity 88%) of the title compound as a solid.
（参考例２８）エチル　２－｛（１Ｓ，３Ｓ）－３－［（ジフェニルメチレン）アミノ］シクロヘキシル｝－２－メチルプロパノエート
　参考例２７で得られたエチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩および市販のベンゾフェノンイミンを用いて、参考例１３の方法に準じて油状物（収率８５％）を得た。得られた油状物を用いて、参考例１４の方法に準じて油状物（収率９６％）を得た。さらに、得られた油状物を用いて、参考例１４の方法に準じて標記化合物（収率９３％）を得た。
（参考例２９）メチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩
　参考例２６で得られたベンジル　［（１Ｓ，３Ｓ）－３－（シアノメチル）シクロヘキシル］カーバメートおよびメタノールを用いて、参考例２７の方法に準じて標記化合物（収率１００％、純度８５％）を固体として得た。
（参考例３０）メチル　１－｛（１Ｓ，３Ｓ）－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝シクロプロパンカルボキシレート
　参考例２９で得られたメチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩を用いて、参考例１３の方法に準じて油状物（収率９７％）を得た。得られた油状物を用いて、参考例１８の方法に準じて油状物（収率８６％）を得た。得られた油状物を用いて、参考例１９の方法に準じて標記化合物（収率９７％）を得た。
（参考例３１）［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］酢酸
　参考例２７で得られたエチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩（５８８ｍｇ，２．６５ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶解に、氷冷下、トリエチルアミン（７．４ｍｌ，５３．１ｍｍｏｌ）、Ｎ－（ベンジルオキシカルボニルオキシ）コハク酸イミド（１．３２ｇ，５．３０ｍｍｏｌ）を加え、室温にて１９時間攪拌した。反応液に水を加え、酢酸エチルにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１９／１－１３／７）にて精製し、標記化合物６１８ｍｇ（収率７３％）を油状物質として得た。得られた油状物を用いて、参考例２の方法に準じて標記化合物（収率９４％）を得た。 Reference Example 28 Ethyl 2-{(1S, 3S) -3-[(diphenylmethylene) amino] cyclohexyl} -2-methylpropanoate Ethyl obtained in Reference Example 27 [(1S, 3S) -3- Aminocyclohexyl] acetate An oil (yield 85%) was obtained using hydrochloride and commercially available benzophenone imine according to the method of Reference Example 13. Using the obtained oil, an oil (yield 96%) was obtained according to the method of Reference Example 14. Furthermore, the title compound (yield 93%) was obtained according to the method of Reference Example 14 using the obtained oil.
(Reference Example 29) Methyl [(1S, 3S) -3-aminocyclohexyl] acetate hydrochloride Using the benzyl [(1S, 3S) -3- (cyanomethyl) cyclohexyl] carbamate and methanol obtained in Reference Example 26, The title compound (yield 100%, purity 85%) was obtained as a solid according to the method of Reference Example 27.
(Reference Example 30) Methyl 1-{(1S, 3S) -3-[(tert-butoxycarbonyl) amino] cyclohexyl} cyclopropanecarboxylate Methyl [(1S, 3S) -3-amino obtained in Reference Example 29 Cyclohexyl] acetate hydrochloride was used to give an oil (yield 97%) according to the method of Reference Example 13. Using the obtained oil, an oil (yield 86%) was obtained according to the method of Reference Example 18. Using the obtained oil, the title compound (yield 97%) was obtained according to the method of Reference Example 19.
Reference Example 31 [(1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} cyclohexyl] acetic acid Ethyl [(1S, 3S) -3-aminocyclohexyl] acetate hydrochloride obtained in Reference Example 27 (588 mg, 2.65 mmol) in dichloromethane (20 ml) was dissolved in ice-cooled triethylamine (7.4 ml, 53.1 mmol), N- (benzyloxycarbonyloxy) succinimide (1.32 g, 5.30 mmol). And stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 19 / 1-13 / 7) to obtain 618 mg (yield 73%) of the title compound. Obtained as an oil. The title compound (yield 94%) was obtained according to the method of Reference Example 2 using the obtained oil.
（参考例３２）２－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－Ｎ－エチルアセトアミド
　参考例３１で得られた［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］酢酸および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、参考例６の方法に準じて固体（収率９１％）を得た。得られた固体を用いて、参考例１０の方法に準じて標記化合物（収率９７％）を得た。
（参考例３３）２－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－Ｎ－シクロプロピルアセトアミド
　参考例３１で得られた［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］酢酸およびシクロプロピルアミンを用いて、参考例６の方法に準じて固体（収率７８％）を得た。得られた固体を用いて、参考例１０の方法に準じて標記化合物（収率１００％）を得た。
（参考例３４）（１Ｓ，３Ｓ）－３－アミノ－Ｎ－メトキシシクロヘキサンカルボキサミド　塩酸塩
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販の（アミノオキシ）メタン　塩酸塩を用いて、実施例３の方法に準じて油状物（収率６９％）を得た。得られた油状物を用いて、参考例２３の方法に準じて標記化合物（収率１００％）を得た。 Reference Example 32 2-[(1S, 3S) -3-Aminocyclohexyl] -N-ethylacetamide [(1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} obtained in Reference Example 31 Using [cyclohexyl] acetic acid and commercially available ethylamine (2.0 M tetrahydrofuran solution), a solid (yield 91%) was obtained according to the method of Reference Example 6. Using the resulting solid, the title compound (yield 97%) was obtained according to the method of Reference Example 10.
(Reference Example 33) 2-[(1S, 3S) -3-aminocyclohexyl] -N-cyclopropylacetamide [(1S, 3S) -3-{[(benzyloxy) carbonyl] amino obtained in Reference Example 31 } Cyclohexyl] A solid (yield 78%) was obtained using acetic acid and cyclopropylamine according to the method of Reference Example 6. Using the resulting solid, the title compound (yield 100%) was obtained according to the method of Reference Example 10.
Reference Example 34 (1S, 3S) -3-Amino-N-methoxycyclohexanecarboxamide hydrochloride (1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid obtained in Reference Example 20 And an oily substance (yield 69%) was obtained according to the method of Example 3 using commercially available (aminooxy) methane hydrochloride. Using the obtained oil, the title compound (yield 100%) was obtained according to the method of Reference Example 23.
（参考例３５）ｔｅｒｔ－ブチル　２－｛［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］カルボニル｝ヒドラジンカルボキシレート
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸およびｔｅｒｔ－ブチル　ヒドラジンカルボキシレートを用いて、実施例３の方法に準じて標記化合物（収率９８％）を得た。
（参考例３６）ベンジル　［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］カーバメート　塩酸塩
　参考例３５で得られたｔｅｒｔ－ブチル　２－｛［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］カルボニル｝ヒドラジンカルボキシレートを用いて、参考例５の方法に準じて標記化合物（収率８２％）を得た。
（参考例３７）ベンジル　｛（１Ｓ，３Ｓ）－３－［（２－アセチルヒドラジノ）カルボニル］シクロヘキシル｝カーバメート
　参考例３６で得られたベンジル　［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］カーバメート　塩酸塩（８２．１ｍｇ，０．２５１ｍｍｏｌ）のピリジン（２ｍＬ）溶液に、氷冷下、無水酢酸（０．０３５６ｍＬ，０．３７６ｍｍｏｌ）を加え、室温にて２２０分間攪拌した。反応混合物を減圧濃縮し、得られた残渣に飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸マグネシウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝９／１）にて精製し、標記化合物６３．７ｍｇ（収率７６％）を固体として得た。 Reference Example 35 tert-Butyl 2-{[(1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} cyclohexyl] carbonyl} hydrazinecarboxylate (1S, 3S)-obtained in Reference Example 20 The title compound (yield 98%) was obtained according to the method of Example 3 using 3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and tert-butyl hydrazinecarboxylate.
(Reference Example 36) benzyl [(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] carbamate hydrochloride tert-butyl 2-{[(1S, 3S) -3-{[( Using benzyloxy) carbonyl] amino} cyclohexyl] carbonyl} hydrazinecarboxylate, the title compound (yield 82%) was obtained according to the method of Reference Example 5.
(Reference Example 37) Benzyl {(1S, 3S) -3-[(2-acetylhydrazino) carbonyl] cyclohexyl} carbamate Benzyl [(1S, 3S) -3- (hydrazinocarbonyl) obtained in Reference Example 36 Acetic anhydride (0.0356 mL, 0.376 mmol) was added to a pyridine (2 mL) solution of cyclohexyl] carbamate hydrochloride (82.1 mg, 0.251 mmol) under ice cooling, and the mixture was stirred at room temperature for 220 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 9/1) to obtain 63.7 mg (yield 76%) of the title compound as a solid. .
（参考例３８）ベンジル　［（１Ｓ，３Ｓ）－３－｛［２－（メチルスルホニル）ヒドラジノ］カルボニル｝シクロヘキシル］カーバメート
　参考例３６で得られたベンジル　［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］カーバメート　塩酸塩およびメタンスルホニルクロリドを用いて、参考例３７の方法に準じて標記化合物（収率８１％）を得た。
（参考例３９）Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド　２塩酸塩
　参考例３５で得られたｔｅｒｔ－ブチル　２－｛［（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキシル］カルボニル｝ヒドラジンカルボキシレートを用いて、参考例１０の方法に準じて油状物を得た。得られた油状物を用いて、実施例３の方法に準じてアモルファス状物（収率５６％）を得た。得られたアモルファス状物を用いて、参考例５の方法に準じて標記化合物（収率１００％）を得た。
（参考例４０）ベンジル　［（１Ｓ，３Ｓ）－３－シアノシクロヘキシル］カーバメート
　参考例２２で得られたベンジル　［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］カーバメート（１８０ｍｇ，０．６５１ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、氷冷下、エチル　ホスホロジクロリデート（０．３０５ｍＬ，２．６１ｍｍｏｌ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（０．５８３ｍＬ，３．９１ｍｍｏｌ）を加え、室温にて３０分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、標記化合物１３８ｍｇ（収率８２％）を固体として得た。 Reference Example 38 Benzyl [(1S, 3S) -3-{[2- (methylsulfonyl) hydrazino] carbonyl} cyclohexyl] carbamate Benzyl [(1S, 3S) -3- (hydrazino) obtained in Reference Example 36 [Carbonyl) cyclohexyl] carbamate The title compound (yield 81%) was obtained according to the method of Reference Example 37 using hydrochloride and methanesulfonyl chloride.
Reference Example 39 N-[(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide dihydrochloride Reference Example Using tert-butyl 2-{[(1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexyl] carbonyl} hydrazine carboxylate obtained in 35, an oily oil was prepared according to the method of Reference Example 10. I got a thing. Using the obtained oily substance, an amorphous substance (yield 56%) was obtained according to the method of Example 3. Using the resulting amorphous material, the title compound (yield 100%) was obtained according to the method of Reference Example 5.
(Reference Example 40) Benzyl [(1S, 3S) -3-cyanocyclohexyl] carbamate The benzyl [(1S, 3S) -3-carbamoylcyclohexyl] carbamate (180 mg, 0.651 mmol) obtained in Reference Example 22 in dichloromethane ( 5 mL) solution under ice cooling, ethyl phosphorodichloridate (0.305 mL, 2.61 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (0.583 mL, 3.91 mmol) And stirred for 30 minutes at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 138 mg (yield 82%) of the title compound as a solid.
（参考例４１）３－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－１，２，４－オキサジアゾール－５（４Ｈ）－オン　塩酸塩
　参考例４０で得られたベンジル　［（１Ｓ，３Ｓ）－３－シアノシクロヘキシル］カーバメートを用いて、実施例１４の方法に準じてアモルファス状物（１００％）を得た。得られたアモルファス状物を用いて、参考例２３の方法に準じて標記化合物（収率９９％）を固体として得た。
（参考例４２）（１Ｓ，３Ｓ）－３－アミノ－Ｎ－（２－ヒドロキシエチル）シクロヘキサンカルボキサミド
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販の２－アミノエタノールを用いて、参考例６の方法に準じて油状物（収率９０％）を得た。得られた油状物を用いて、参考例１０の方法に準じて標記化合物（収率９９％）を得た。
（参考例４３）（１Ｓ，３Ｓ）－３－アミノ－Ｎ－（２－フルオロエチル）シクロヘキサンカルボキサミド　塩酸塩
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および２－フルオロエチルアミン　塩酸塩を用いて、参考例６の方法に準じて固体（収率８０％）を得た。得られた固体を用いて、参考例２３の方法に準じて標記化合物（収率１００％）を得た。
（参考例４４）（１Ｓ，３Ｓ）－３－アミノ－Ｎ－［（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル］シクロヘキサンカルボキサミド
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および１－（２，２－ジメチル－１，３－ジオキソラン－４－イル）メタンアミンを用いて、参考例６の方法に準じてアモルファス状物（収率９４％）を得た。得られたアモルファス状物を用いて、参考例１０の方法に準じて標記化合物（収率１００％）を得た。 (Reference Example 41) 3-[(1S, 3S) -3-Aminocyclohexyl] -1,2,4-oxadiazol-5 (4H) -one hydrochloride The benzyl obtained in Reference Example 40 [(1S, 3S) -3-Cyanocyclohexyl] carbamate was used to obtain an amorphous product (100%) according to the method of Example 14. Using the obtained amorphous material, the title compound (yield 99%) was obtained as a solid according to the method of Reference Example 23.
Reference Example 42 (1S, 3S) -3-Amino-N- (2-hydroxyethyl) cyclohexanecarboxamide (1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} obtained in Reference Example 20 Using cyclohexanecarboxylic acid and commercially available 2-aminoethanol, an oil (yield 90%) was obtained according to the method of Reference Example 6. The title compound (yield 99%) was obtained according to the method of Reference Example 10 using the obtained oil.
(Reference Example 43) (1S, 3S) -3-Amino-N- (2-fluoroethyl) cyclohexanecarboxamide hydrochloride (1S, 3S) -3-{[(Benzyloxy) carbonyl] obtained in Reference Example 20 A solid (yield 80%) was obtained in accordance with the method of Reference Example 6 using amino} cyclohexanecarboxylic acid and 2-fluoroethylamine hydrochloride. Using the obtained solid, the title compound (yield 100%) was obtained according to the method of Reference Example 23.
Reference Example 44 (1S, 3S) -3-Amino-N-[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] cyclohexanecarboxamide obtained in Reference Example 20 (1S, 3S ) -3-{[(Benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and 1- (2,2-dimethyl-1,3-dioxolan-4-yl) methanamine according to the method of Reference Example 6. An amorphous product (yield 94%) was obtained. Using the obtained amorphous material, the title compound (yield 100%) was obtained according to the method of Reference Example 10.
（参考例４５）メチル　（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキシレート　塩酸塩
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸およびメタノールを用いて、参考例６の方法に準じて固体（収率９２％）を得た。得られた固体を用いて、参考例２３の方法に準じて標記化合物（収率７２％）を固体として得た。
（参考例４６）ｔｅｒｔ－ブチル　Ｎ－｛［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］カルボニル｝－β－アラニネート
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販のｔｅｒｔ－ブチル　β－アラニネート　塩酸塩を用いて、実施例１の方法に準じて縮合体（収率９１％）を得た。得られた化合物を用いて、参考例１０の方法に準じて標記化合物（収率１００％）を得た。
（参考例４７）ｔｅｒｔ－ブチル　Ｎ－｛［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］カルボニル｝－２－メチルアラニネート
　参考例２０で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販のｔｅｒｔ－ブチル　２－メチルアラニネート　塩酸塩を用いて、実施例１の方法に準じて縮合体（収率９４％）を得た。得られた化合物を用いて、参考例１０の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例４８）エチル　（１Ｓ，３Ｒ，４Ｓ）－３－アミノ－４－ヒドロキシシクロヘキサンカルボキシレート　塩酸塩
　ＰＣＴ　ＷＯ２００７／０３２４９８Ａ１出願明細書記載のエチル　（１Ｓ，３Ｒ，４Ｒ）－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－４－ヒドロキシシクロヘキサンカルボキシレート（５．０４ｇ，１７．５ｍｍｏｌ）、市販のｐ－ニトロ安息香酸（４．７１ｇ，２８．２ｍｍｏｌ）およびトリフェニルホスフィン（６．４４ｇ，２４．６ｍｍｏｌ）のトルエン（５０ｍＬ）溶液に氷冷下、市販のジエチル　アゾジカルボキシレート（約２．２Ｍトルエン溶液、１２．０ｍＬ，２６．４ｍｍｏｌ）をゆっくり滴下し０℃にて１時間攪拌した。さらに室温にて１２時間攪拌した後、得られた混合物を減圧濃縮した。残渣にエーテルを加え、析出した固体をろ過にて取り除いた後、再度、減圧下にて溶媒を留去した。残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝６／１－１／２）にて精製し、固体５．４４ｇ（収率７１％）を得た。得られた固体（３．１３ｇ，７．１６ｍｍｏｌ）のエタノール（２０ｍＬ）溶液に炭酸カリウム（５．０ｇ，３．６２ｍｍｏｌ）を加え、２時間加熱還流した。反応混合物に酢酸エチルを加えた後、ろ過し、減圧下にて溶媒を留去した。残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３／１－１／２）にて精製し、固体１．６９ｇ（収率８２％）を得た。得られた固体を用いて、参考例５の方法に準じて標記化合物を定量的に固体として得た。 (Reference Example 45) Methyl (1S, 3S) -3-aminocyclohexanecarboxylate hydrochloride (1S, 3S) -3-{[(Benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and methanol obtained in Reference Example 20 In accordance with the method of Reference Example 6, a solid (yield 92%) was obtained. Using the obtained solid, the title compound (yield 72%) was obtained as a solid according to the method of Reference Example 23.
Reference Example 46 tert-butyl N-{[(1S, 3S) -3-aminocyclohexyl] carbonyl} -β-alaninate The (1S, 3S) -3-{[(benzyloxy) obtained in Reference Example 20 Carbonyl] amino} cyclohexanecarboxylic acid and commercially available tert-butyl β-alaninate hydrochloride were obtained according to the method of Example 1 to obtain a condensate (yield 91%). Using the obtained compound, the title compound (yield 100%) was obtained according to the method of Reference Example 10.
(Reference Example 47) tert-butyl N-{[(1S, 3S) -3-aminocyclohexyl] carbonyl} -2-methylalaninate (1S, 3S) -3-{[(benzyl) obtained in Reference Example 20 Oxy) carbonyl] amino} cyclohexanecarboxylic acid and commercially available tert-butyl 2-methylalaninate hydrochloride were obtained according to the method of Example 1 (yield 94%). The title compound (yield 100%) was obtained as a solid according to the method of Reference Example 10 using the obtained compound.
(Reference Example 48) Ethyl (1S, 3R, 4S) -3-Amino-4-hydroxycyclohexanecarboxylate Hydrochloride Ethyl (1S, 3R, 4R) -3-[(tert- Butoxycarbonyl) amino] -4-hydroxycyclohexanecarboxylate (5.04 g, 17.5 mmol), commercially available p-nitrobenzoic acid (4.71 g, 28.2 mmol) and triphenylphosphine (6.44 g, 24.6 mmol). ) In toluene (50 mL) under ice cooling, commercially available diethyl azodicarboxylate (about 2.2 M toluene solution, 12.0 mL, 26.4 mmol) was slowly added dropwise and stirred at 0 ° C. for 1 hour. After further stirring at room temperature for 12 hours, the resulting mixture was concentrated under reduced pressure. Ether was added to the residue, and the precipitated solid was removed by filtration, and then the solvent was distilled off again under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 6 / 1-1 / 2) to obtain 5.44 g (yield 71%) of a solid. To a solution of the obtained solid (3.13 g, 7.16 mmol) in ethanol (20 mL) was added potassium carbonate (5.0 g, 3.62 mmol), and the mixture was heated to reflux for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 3 / 1-1 / 2) to obtain 1.69 g (82% yield) of a solid. Using the obtained solid, the title compound was quantitatively obtained as a solid according to the method of Reference Example 5.
（参考例４９）ベンジル　［（１Ｓ，２Ｒ，４Ｓ）－２－アミノ－４－（エチルカルバモイル）シクロヘキシル］カーバメート　塩酸塩
　ＰＣＴ　ＷＯ２００７／０３２４９８Ａ１出願明細書記載の［（１Ｓ，３Ｒ，４Ｓ）－４－｛［（ベンジルオキシ）カルボニル］アミノ｝－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキサンカルボン酸および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、参考例６の方法に準じて油状物を得た。得られた油状物を用いて、参考例５の方法に準じて標記化合物を定量的に固体として得た。
（参考例５０）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－２－アミノ－５－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例４９で得られたベンジル　［（１Ｓ，２Ｒ，４Ｓ）－２－アミノ－４－（エチルカルバモイル）シクロヘキシル］カーバメート　塩酸塩を用いて、実施例１の方法に準じてアモルファス状物（収率９４％）を得た。得られたアモルファス状物を用いて、参考例１０の方法に準じて標記化合物（収率１００％）を得た。
（参考例５１）エチル　（７Ｒ，８Ｓ）－８－｛［（１Ｓ）－１－フェニルエチル］アミノ｝－１，４－ジオキサスピロ［４．５］デカン－７－カルボキシレート
　ＷＯ２００８／１５３０２７Ａ１の出願明細書記載のエチル　８－ヒドロキシ－１，４－ジオキサスピロ［４．５］デカ－７－エン－７－カルボキシレート(７．９９ｇ，３５．００ｍｍｏｌ)のトルエン（１００ｍＬ）溶液に、（１Ｓ）－１－フェニルエタンアミン（５ｍＬ）およびイットリビウムトリフラート（４６０ｍｇ）を加え、Ｄｅａｎ－Ｓｔａｒｋ装置にて１８時間加熱還流した。反応混合物を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝４／１) にて精製し、油状物１１．５ｇ（収率９９％）を得た。次に、氷冷下、２－メチルプロパン酸（２０ｍＬ）に水素化ホウ素ナトリウム（１．２８ｇ）を加えた後、室温にて３０分間攪拌した。反応混合物を再び氷冷し、先ほど得られた油状物（３．４０ｇ）の２－メチルプロパン酸（１０ｍＬ）溶液を加えた後、室温にて２７時間攪拌した。氷冷下、反応混合物に水および８Ｍ水酸化ナトリウム水溶液を加えｐＨ１０として酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去し標記化合物３．１５ｇ（収率９２％）を得た。 (Reference Example 49) benzyl [(1S, 2R, 4S) -2-amino-4- (ethylcarbamoyl) cyclohexyl] carbamate hydrochloride PCT WO2007 / 032498A1 Description of application [(1S, 3R, 4S) -4- {[(Benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylic acid and commercially available ethylamine (2.0 M tetrahydrofuran solution), an oily substance according to the method of Reference Example 6 Got. The title compound was quantitatively obtained as a solid according to the method of Reference Example 5 using the obtained oil.
Reference Example 50 N-[(1R, 2S, 5S) -2-amino-5- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and benzyl [(1S, 2R, 4S) -2-amino acid obtained in Reference Example 49 Using -4- (ethylcarbamoyl) cyclohexyl] carbamate hydrochloride, an amorphous product (yield 94%) was obtained according to the method of Example 1. Using the obtained amorphous material, the title compound (yield 100%) was obtained according to the method of Reference Example 10.
Reference Example 51 Ethyl (7R, 8S) -8-{[(1S) -1-phenylethyl] amino} -1,4-dioxaspiro [4.5] decane-7-carboxylate Application specification of WO2008 / 153027A1 Into a toluene (100 mL) solution of ethyl 8-hydroxy-1,4-dioxaspiro [4.5] dec-7-ene-7-carboxylate (7.99 g, 35.00 mmol) as described in (1S) -1 -Phenylethanamine (5 mL) and yttrium triflate (460 mg) were added, and the mixture was heated to reflux with a Dean-Stark apparatus for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to give 11.5 g (99% yield) of an oil. Next, sodium borohydride (1.28 g) was added to 2-methylpropanoic acid (20 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled again and a solution of the oil (3.40 g) obtained above in 2-methylpropanoic acid (10 mL) was added, followed by stirring at room temperature for 27 hours. Under ice cooling, water and 8M aqueous sodium hydroxide solution were added to the reaction mixture to adjust the pH to 10, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.15 g (yield 92%) of the title compound.
（参考例５２）エチル　（７Ｒ，８Ｓ）－８－｛［（ベンジルオキシ）カルボニル］アミノ｝－１，４－ジオキサスピロ［４．５］デカン－７－カルボキシレート
　参考例５１で得られたエチル　（７Ｒ，８Ｓ）－８－｛［（１Ｓ）－１－フェニルエチル］アミノ｝－１，４－ジオキサスピロ［４．５］デカン－７－カルボキシレート（３．１５ｇ，９．４５ｍｍｏｌ)のエタノール（２００ｍＬ）溶液に、１０％パラジウム炭素（３ｇ）を加え、水素雰囲気下、５０℃にて１５時間攪拌した。反応混合物をろ過後、減圧下にて溶媒を留去した。得られた残渣のテトラヒドロフラン（４０ｍＬ）と水（２０ｍＬ）の混合溶媒に、炭酸ナトリウム（２．６５ｇ）およびクロロギ酸ベンジル（１．４３ｍＬ，１０ｍｍｏｌ）を加えた後、室温にて２５時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝４／１－２／１) にて精製し、標記化合物２．８０ｇ（収率８２％）を得た。
（参考例５３）エチル　（１Ｒ，２Ｓ）－２－｛［（ベンジルオキシ）カルボニル］アミノ｝－５－オキソシクロヘキサンカルボキシレート
　参考例５２で得られたエチル　（７Ｒ，８Ｓ）－８－｛［（ベンジルオキシ）カルボニル］アミノ｝－１，４－ジオキサスピロ［４．５］デカン－７－カルボキシレート（１．３５ｇ，３．７０ｍｍｏｌ)のアセトン（１２ｍＬ）溶液に２Ｎ塩酸水溶液（６ｍＬ）を加え、室温にて２４時間攪拌した。反応混合物を減圧下にて濃縮し、得られた残渣に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝２／１) にて精製し、標記化合物１．００ｇ（収率８４％）を固体として得た。 (Reference Example 52) Ethyl (7R, 8S) -8-{[(Benzyloxy) carbonyl] amino} -1,4-dioxaspiro [4.5] decane-7-carboxylate Ethyl obtained in Reference Example 51 7R, 8S) -8-{[(1S) -1-phenylethyl] amino} -1,4-dioxaspiro [4.5] decane-7-carboxylate (3.15 g, 9.45 mmol) in ethanol (200 mL ) 10% palladium carbon (3 g) was added to the solution, and the mixture was stirred at 50 ° C. for 15 hours in a hydrogen atmosphere. After filtering the reaction mixture, the solvent was distilled off under reduced pressure. Sodium carbonate (2.65 g) and benzyl chloroformate (1.43 mL, 10 mmol) were added to a mixed solvent of the obtained residue tetrahydrofuran (40 mL) and water (20 mL), and the mixture was stirred at room temperature for 25 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1-2 / 1) to give 2.80 g (yield 82%) of the title compound. )
(Reference Example 53) Ethyl (1R, 2S) -2-{[(Benzyloxy) carbonyl] amino} -5-oxocyclohexanecarboxylate Ethyl (7R, 8S) -8-{[( To a solution of (benzyloxy) carbonyl] amino} -1,4-dioxaspiro [4.5] decane-7-carboxylate (1.35 g, 3.70 mmol) in acetone (12 mL) was added 2N aqueous hydrochloric acid (6 mL) at room temperature. For 24 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to give 1.00 g (yield 84%) of the title compound as a solid. Obtained.
（参考例５４）エチル　（１Ｒ，２Ｓ）－２－｛［（ベンジルオキシ）カルボニル］アミノ｝－５－フルオロシクロヘキサンカルボキシレート
　参考例５３で得られたエチル　（１Ｒ，２Ｓ）－２－｛［（ベンジルオキシ）カルボニル］アミノ｝－５－オキソシクロヘキサンカルボキシレート（１．００ｇ，３．１３ｍｍｏｌ)のエタノール（３０ｍＬ）溶液に、氷冷下、水素化ホウ素ナトリウム（２４５ｍｇ）を加えた後、同温にて１５分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、室温にて１５分間攪拌した後、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣のジクロロメタン（２０ｍＬ）溶液に、氷冷下、市販のＤｅｏｘｏ－ｆｌｕｏｒ（６７５μＬ，３．６６ｍｍｏｌ）を加えた後、徐々に室温まで昇温し２０時間攪拌した。反応混合物に氷冷下、飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝７／１) にて精製し、標記化合物１８０ｍｇ（収率１８％）を得た。
（参考例５５）ベンジル　［（１Ｓ，２Ｒ）－４－フルオロ－２－（ヒドロキシメチル）シクロヘキシル］カーバメート
　参考例５４で得られたエチル　（１Ｒ，２Ｓ）－２－｛［（ベンジルオキシ）カルボニル］アミノ｝－５－フルオロシクロヘキサンカルボキシレート（１７５ｍｇ，０．５４ｍｍｏｌ）のエタノール（３ｍＬ）とテトラヒドロフラン（１ｍＬ）の混合溶液に、２Ｎ水酸化ナトリウム水溶液（１．２ｍＬ）を加え、室温にて１５時間攪拌した。反応混合物に１０％クエン酸水溶液を加え酸性とした後、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をテトラヒドロフラン（５ｍＬ）に溶解した。氷冷下、クロロギ酸イソブチル（１００μＬ）およびトリエチルアミン（１３０μＬ）を加え、同温にて３０分間攪拌した。氷冷下、水素化ホウ素ナトリウム（１００ｍｇ）を加えた後、水（２００μＬ）を加え、同温にて１０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、室温に昇温し３０分間攪拌した後、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝２／１) にて精製し、標記化合物１２２ｍｇ（収率８０％）を得た。 (Reference Example 54) Ethyl (1R, 2S) -2-{[(Benzyloxy) carbonyl] amino} -5-fluorocyclohexanecarboxylate Ethyl (1R, 2S) -2-{[( To a solution of (benzyloxy) carbonyl] amino} -5-oxocyclohexanecarboxylate (1.00 g, 3.13 mmol) in ethanol (30 mL) was added sodium borohydride (245 mg) under ice-cooling, and the same temperature was maintained. And stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes and extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. A commercially available Deoxo-fluor (675 μL, 3.66 mmol) was added to a solution of the obtained residue in dichloromethane (20 mL) under ice cooling, and the mixture was gradually warmed to room temperature and stirred for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, followed by extraction with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/1) to obtain 180 mg (yield 18%) of the title compound.
(Reference Example 55) Benzyl [(1S, 2R) -4-fluoro-2- (hydroxymethyl) cyclohexyl] carbamate Ethyl (1R, 2S) -2-{[(benzyloxy) carbonyl] obtained in Reference Example 54 To a mixed solution of amino} -5-fluorocyclohexanecarboxylate (175 mg, 0.54 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was added 2N aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at room temperature for 15 hours. did. The reaction mixture was acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 mL). Under ice-cooling, isobutyl chloroformate (100 μL) and triethylamine (130 μL) were added, and the mixture was stirred at the same temperature for 30 minutes. Sodium borohydride (100 mg) was added under ice-cooling, water (200 μL) was added, and the mixture was stirred at the same temperature for 10 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was warmed to room temperature, stirred for 30 minutes, and extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to obtain 122 mg (yield 80%) of the title compound.
（参考例５６）ベンジル　［（７Ｒ，８Ｓ）－７－（ヒドロキシメチル）－１，４－ジオキサスピロ［４．５］デカ－８－イル］カーバメート
　参考例５２で得られたエチル　（７Ｒ，８Ｓ）－８－｛［（ベンジルオキシ）カルボニル］アミノ｝－１，４－ジオキサスピロ［４．５］デカン－７－カルボキシレートを用いて、参考例５５の方法に準じて標記化合物（収率１００％）を得た。
（参考例５７）エチル　（１Ｒ，２Ｓ）－５，５－ジフルオロ－２－｛［（１Ｓ）－１－フェニルエチル］アミノ｝シクロヘキサンカルボキシレート
　ＷＯ２００８／１５３０２７Ａ１出願明細書記載のエチル　５，５－ジフルオロ－２－ヒドロキシシクロヘキサ－１－エン－１－カルボキシレートおよび（１Ｓ）－１－フェニルエタンアミンを用いて、参考例５１の方法に準じて標記化合物（収率７３％）を得た。
（参考例５８）エチル　（１Ｒ，２Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－５，５－ジフルオロシクロヘキサンカルボキシレート
　参考例５７で得られたエチル　（１Ｒ，２Ｓ）－５，５－ジフルオロ－２－｛［（１Ｓ）－１－フェニルエチル］アミノ｝シクロヘキサンカルボキシレート（３９０ｍｇ，１．２５ｍｍｏｌ)のエタノール（３００ｍＬ）溶液に、１０％パラジウム炭素（５００ｍｇ）を加え、水素雰囲気下、５０℃にて１７時間攪拌した。反応混合物をろ過後、減圧下にて溶媒を留去した。得られた残渣をジクロロメタン（１５ｍＬ）と少量のエタノールの混合溶媒に溶解し、ジ－ｔｅｒｔ－ブチルジカーボネート（３３０ｍｇ，１．５０ｍｍｏｌ）を加えた後、室温にて３時間攪拌した。反応混合物を減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (ｎ－ヘキサン／酢酸エチル＝８／１) にて精製し、標記化合物２７４ｍｇ（収率７１％）を得た。 (Reference Example 56) Benzyl [(7R, 8S) -7- (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-8-yl] carbamate Ethyl (7R, 8S) obtained in Reference Example 52 -8-{[(Benzyloxy) carbonyl] amino} -1,4-dioxaspiro [4.5] decane-7-carboxylate and the title compound according to the method of Reference Example 55 (yield 100%) Got.
(Reference Example 57) Ethyl (1R, 2S) -5,5-difluoro-2-{[(1S) -1-phenylethyl] amino} cyclohexanecarboxylate Ethyl 5,5-difluoro described in the application specification of WO2008 / 153027A1 The title compound (73% yield) was obtained according to the method of Reference Example 51 using -2-hydroxycyclohex-1-ene-1-carboxylate and (1S) -1-phenylethanamine.
(Reference Example 58) Ethyl (1R, 2S) -2-[(tert-butoxycarbonyl) amino] -5,5-difluorocyclohexanecarboxylate Ethyl (1R, 2S) -5,5- To a solution of difluoro-2-{[(1S) -1-phenylethyl] amino} cyclohexanecarboxylate (390 mg, 1.25 mmol) in ethanol (300 mL) was added 10% palladium on carbon (500 mg), and 50% under a hydrogen atmosphere. Stir at 17 ° C. for 17 hours. After filtering the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of dichloromethane (15 mL) and a small amount of ethanol, and di-tert-butyl dicarbonate (330 mg, 1.50 mmol) was added, followed by stirring at room temperature for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 8/1) to obtain 274 mg (yield 71%) of the title compound.
（参考例５９）ｔｅｒｔ－ブチル　［（１Ｓ，２Ｒ）－４，４－ジフルオロ－２－（ヒドロキシメチル）シクロヘキシル］カーバメート
　参考例５８で得られたエチル　（１Ｒ，２Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－５，５－ジフルオロシクロヘキサンカルボキシレートを用いて、参考例５５の方法に準じて標記化合物（収率８８％）を得た。
（参考例６０）ｔｅｒｔ－ブチル　［（３Ｒ，４Ｒ）－４－（ヒドロキシメチル）テトラヒドロ－２Ｈ－ピラン－３－イル］カーバメート
　ＷＯ２００２／０２５２５出願明細書記載エチル　３－オキソテトラヒドロ－２Ｈ－ピラン－４－カルボキシレートを用いて、参考例５１の方法に準じて油状物（収率９１％）を得た。得られた油状物を用いて、参考例５８の方法に準じて油状物（収率９０％）を得た。さらに、得られた油状物を用いて、参考例５５の方法に準じて標記化合物（収率７０％）を固体として得た。
（参考例６１）エチル　［（１Ｒ，３Ｓ）－３－アミノシクロペンチル］アセテート　塩酸塩
　ＷＯ２００１／０４６１９９Ａ１出願明細書記載の［（１Ｒ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル］酢酸　塩酸塩を用いて、参考例２７の方法に準じて標記化合物を定量的に固体として得た。 (Reference Example 59) tert-butyl [(1S, 2R) -4,4-difluoro-2- (hydroxymethyl) cyclohexyl] carbamate Ethyl (1R, 2S) -2-[(tert- By using butoxycarbonyl) amino] -5,5-difluorocyclohexanecarboxylate, the title compound (yield 88%) was obtained according to the method of Reference Example 55.
(Reference Example 60) tert-butyl [(3R, 4R) -4- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] carbamate Ethyl 3-oxotetrahydro-2H-pyran-4 described in the specification of WO2002 / 02525 Using -carboxylate, an oil (yield 91%) was obtained according to the method of Reference Example 51. Using the obtained oil, an oil (yield 90%) was obtained according to the method of Reference Example 58. Further, using the obtained oil, the title compound (yield 70%) was obtained as a solid according to the method of Reference Example 55.
(Reference Example 61) Ethyl [(1R, 3S) -3-aminocyclopentyl] acetate hydrochloride [(1R, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclopentyl] described in WO2001 / 046199A1 The title compound was quantitatively obtained as a solid according to the method of Reference Example 27 using acetic acid hydrochloride.
（参考例６２）エチル　２－メチル－２－［（１Ｒ，３Ｓ）－３－｛［（Ｅ）－フェニルメチリデン］アミノ｝シクロペンチル］プロパノエート
　参考例６１で得られたエチル　［（１Ｒ，３Ｓ）－３－アミノシクロペンチル］アセテート　塩酸塩を用いて、参考例１３の方法に準じて油状物を得た。得られた油状物を用いて、参考例１４の方法に準じて油状物を得た。さらに、得られた油状物を用いて、参考例１４の方法に準じて標記化合物を得た。
（参考例６３）エチル　２－［（１Ｒ，３Ｓ）－３－アミノシクロペンチル］－２－メチルプロパノエート
　参考例６２で得られたエチル　２－メチル－２－［（１Ｒ，３Ｓ）－３－｛［（Ｅ）－フェニルメチリデン］アミノ｝シクロペンチル］プロパノエートを用いて、参考例１５の方法に準じて標記化合物（収率６４％）を得た。
（参考例６４）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－ピペリジン－４－イルピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および市販の１－ベンジルピペリジン－４－アミンを用いて、実施例３の方法に準じて固体を得た。得られた固体を用いて、参考例１０の方法に準じて標記化合物（１００％）を得た。 (Reference Example 62) Ethyl 2-methyl-2-[(1R, 3S) -3-{[(E) -phenylmethylidene] amino} cyclopentyl] propanoate Ethyl obtained in Reference Example 61 [(1R, 3S) -3-Aminocyclopentyl] acetate Using the hydrochloride, an oil was obtained according to the method of Reference Example 13. Using the obtained oil, an oil was obtained according to the method of Reference Example 14. Furthermore, the title compound was obtained according to the method of Reference Example 14 using the obtained oil.
Reference Example 63 Ethyl 2-[(1R, 3S) -3-aminocyclopentyl] -2-methylpropanoate Ethyl 2-methyl-2-[(1R, 3S) -3- obtained in Reference Example 62 The title compound (64% yield) was obtained using {[(E) -phenylmethylidene] amino} cyclopentyl] propanoate according to the method of Reference Example 15.
Reference Example 64 1- (6-Methyl-3-phenylquinolin-2-yl) -N-piperidin-4-ylpiperidine-4-carboxamide 1- (6-Methyl-3- obtained in Reference Example 2 A solid was obtained according to the method of Example 3 using (phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 1-benzylpiperidin-4-amine. The title compound (100%) was obtained according to the method of Reference Example 10 using the obtained solid.
（参考例６５）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（３Ｓ）－ピペリジン－３－イル］ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボン酸および市販のｔｅｒｔ－ブチル　（３Ｓ）－３－アミノピペリジン－１－カルボキシレートを用いて、実施例１の方法に準じてアモルファス状物（収率１００％）を得た。得られたアモルファス状物を用いて、参考例５の方法に準じて標記化合物（収率７８％）を得た。
（参考例６６）、（参考例６７）
エチル　シス－３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキシレート　および
エチル　トランス－３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキシレート
　ＵＳ２００５／００８００９５Ａ１出願明細書記載のエチル　３－ヒドロキシピペリジン－４－カルボキシレートを用いて、参考例１の方法に準じて標記化合物（参考例６６；低極性体；収率３６％）を固体として、標記化合物（参考例６７；高極性体；収率３１％）を得た。
（参考例６８）３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸　（高極性体由来）
　参考例６７で得られたエチル　３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキシレート（高極性体）を用いて、参考例２の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例６９）１－（６－メチル－３－フェニルキノリン－２－イル）－１，２，３，６－テトラヒドロピリジン－４－カルボン酸
　参考例６６で得られたエチル　３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキシレート（２０２ｍｇ，０．５１７ｍｍｏｌ）およびＮ，Ｎ－ジメチルピリジン－４－アミン（１８８ｍｇ，１．５４ｍｍｏｌ）のジクロロメタン溶液（４ｍＬ）にメタンスルホニルクロリド（１１４μＬ，０．７２３ｍｍｏｌ）を加え、室温にて１．５時間半攪拌した。反応混合物にジクロロメタンを加え希釈した後、０．１Ｎ塩酸水溶液を加えて中和洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣のテトラヒドロフラン溶液（５ｍＬ）に１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（１５５μＬ，１．０４ｍｍｏｌ）を加え、室温にて１３時間攪拌した。反応混合物に酢酸エチルを加え希釈した後、０．１Ｎ塩酸水溶液を加えて中和洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝２０／１－４／１）にて精製し、油状物１３９ｍｇ（収率７２％）を得た。得られた油状物を用いて、参考例２の方法に準じて標記化合物（収率９３％、純度９０％）を固体として得た。 Reference Example 65 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(3S) -piperidin-3-yl] piperidin-4-carboxamide 1- ( According to the method of Example 1, using 6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available tert-butyl (3S) -3-aminopiperidine-1-carboxylate An amorphous product (yield 100%) was obtained. The title compound (yield 78%) was obtained according to the method of Reference Example 5 using the obtained amorphous material.
(Reference Example 66), (Reference Example 67)
Ethyl cis-3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate and ethyl trans-3-hydroxy-1- (6-methyl-3-phenylquinoline-2 -Yl) piperidine-4-carboxylate Using ethyl 3-hydroxypiperidine-4-carboxylate described in the specification of US2005 / 0080095A1 according to the method of Reference Example 1 (Reference Example 66; low polar substance; The title compound (Reference Example 67; highly polar product; yield 31%) was obtained as a solid with a yield of 36%.
Reference Example 68 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid (derived from highly polar substance)
According to the method of Reference Example 2, using ethyl 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (high polar form) obtained in Reference Example 67 The title compound (yield 100%) was obtained as a solid.
Reference Example 69 1- (6-Methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine-4-carboxylic acid Ethyl 3-hydroxy-1 obtained in Reference Example 66 -(6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (202 mg, 0.517 mmol) and N, N-dimethylpyridin-4-amine (188 mg, 1.54 mmol) in dichloromethane ( 4 mL) was added methanesulfonyl chloride (114 μL, 0.723 mmol), and the mixture was stirred at room temperature for 1.5 hours and a half. Dichloromethane was added to the reaction mixture for dilution, and then 0.1N hydrochloric acid aqueous solution was added for neutralization washing. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. 1,8-Diazabicyclo [5.4.0] undec-7-ene (155 μL, 1.04 mmol) was added to a tetrahydrofuran solution (5 mL) of the residue, and the mixture was stirred at room temperature for 13 hours. Ethyl acetate was added to the reaction mixture for dilution, and 0.1N aqueous hydrochloric acid solution was added for neutralization washing. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 20 / 1-4 / 1) to obtain 139 mg (yield 72%) of an oil. Using the obtained oil, the title compound (yield 93%, purity 90%) was obtained as a solid according to the method of Reference Example 2.
（参考例７０）エチル　（シス－４－｛［（４－ヒドロキシピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）アセテート　塩酸塩
　Ｉｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ　（１９８０）， １０，　２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩および市販の１－（ｔｅｒｔ－ブトキシカルボニル）－４－ヒドロキシピペリジン－４－カルボン酸を用いて、実施例１の方法に準じてアモルファス状物（収率８４％）を得た。得られたアモルファス状物を用いて、参考例５の方法に準じて標記化合物（収率９４％）を固体として得た。
（参考例７１）３－ブロモ－６－メチルキノリン－２（１Ｈ）－オン
　ＵＳ２００９／２４７５７９Ａ１出願明細書記載の６－メチルキノリン－２（１Ｈ）－オン（７００ｍｇ，４．４０ｍｍｏｌ）、Ｎ－ブロモスクシンイミド（９３９ｍｇ，５．２８ｍｍｏｌ）およびジメチルホルムアミド（１４ｍＬ）からなる懸濁液を室温にて６４時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出後、有機層を水にて洗浄し、硫酸ナトリウムにて乾燥した。ろ過後、減圧濃縮し、析出した固体をろ取した。得られた固体を酢酸エチルにて洗浄し、標記化合物７４０ｍｇ（収率７１％）を固体として得た。
（参考例７２）エチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート
　参考例７１で得られた３－ブロモ－６－メチルキノリン－２（１Ｈ）－オン（７０９ｍｇ，２．９８ｍｍｏｌ）および２，６-ルチジン（５２０μＬ，４．４７ｍｍｏｌ）の脱水ジクロロメタン（１２ｍＬ）懸濁液に、氷冷下、トリフルオロメタンスルホン酸無水物（６００μＬ，３．５７ｍｍｏｌ）を滴下した後、０℃にて５０分間攪拌した。反応混合物にジクロロメタンを加え希釈した後、０．５Ｎ塩酸水溶液、飽和炭酸水素ナトリウム水溶液にて洗浄した。硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣に、市販のエチル　４－ピペリジンカルボキシレート（１．８４ｍＬ，１１．９ｍｍｏｌ）および１，４－ジオキサン（４ｍＬ）を加え、浴温１２０℃にて２時間攪拌した。反応混合物を放冷後、水を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムにて乾燥し、減圧下にて溶媒を留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－８／２）により精製し、標記化合物１．１２ｇ（収率１００％）を得た。
（参考例７３）エチル　１－［３－（４－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート（２２２ｍｇ，０．５９ｍｍｏｌ）、４－フルオロフェニルボロン酸（１２７ｍｇ，１．１８ｍｍｏｌ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（１：１）（７４ｍｇ，０．０９ｍｍｏｌ）、リン酸カリウム（３９４ｍｇ，１．７７ｍｍｏｌ）およびジメチルホルムアミド（４ｍＬ）からなる混合物を窒素雰囲気下、１２０℃にて２時間攪拌した。反応混合物に酢酸エチルを加えた後、セライトろ過した。ろ液に酢酸エチルおよび水を加え、分液後、水層を酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。ろ液を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物２０４ｍｇ（収率８８％）を固体として得た。 (Reference Example 70) Ethyl (cis-4-{[(4-hydroxypiperidin-4-yl) carbonyl] amino} cyclohexyl) acetate hydrochloride Using the ethyl (cis-4-aminocyclohexyl) acetate hydrochloride described above and commercially available 1- (tert-butoxycarbonyl) -4-hydroxypiperidine-4-carboxylic acid, an amorphous product was prepared according to the method of Example 1. (Yield 84%) was obtained. Using the resulting amorphous material, the title compound (yield 94%) was obtained as a solid according to the method of Reference Example 5.
Reference Example 71 3-Bromo-6-methylquinolin-2 (1H) -one 6-methylquinolin-2 (1H) -one (700 mg, 4.40 mmol), N-bromo described in US2009 / 247579A1 A suspension consisting of succinimide (939 mg, 5.28 mmol) and dimethylformamide (14 mL) was stirred at room temperature for 64 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration. The obtained solid was washed with ethyl acetate to obtain 740 mg (yield 71%) of the title compound as a solid.
Reference Example 72 Ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate 3-bromo-6-methylquinolin-2 (1H) -one obtained in Reference Example 71 (709 mg, 2.98 mmol) and 2,6-lutidine (520 μL, 4.47 mmol) in a suspension of dehydrated dichloromethane (12 mL) were added dropwise trifluoromethanesulfonic anhydride (600 μL, 3.57 mmol) under ice cooling. Then, the mixture was stirred at 0 ° C. for 50 minutes. The reaction mixture was diluted with dichloromethane, and then washed with a 0.5N aqueous hydrochloric acid solution and a saturated aqueous sodium hydrogen carbonate solution. After drying with sodium sulfate, the solvent was distilled off under reduced pressure. Commercially available ethyl 4-piperidinecarboxylate (1.84 mL, 11.9 mmol) and 1,4-dioxane (4 mL) were added to the resulting residue, and the mixture was stirred at a bath temperature of 120 ° C. for 2 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-8 / 2) to obtain 1.12 g (yield 100%) of the title compound.
Reference Example 73 Ethyl 1- [3- (4-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate Ethyl 1- (3-bromo-6- Methylquinolin-2-yl) piperidine-4-carboxylate (222 mg, 0.59 mmol), 4-fluorophenylboronic acid (127 mg, 1.18 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride A mixture of dichloromethane complex (1: 1) (74 mg, 0.09 mmol), potassium phosphate (394 mg, 1.77 mmol) and dimethylformamide (4 mL) was stirred at 120 ° C. for 2 hours under a nitrogen atmosphere. did. Ethyl acetate was added to the reaction mixture, followed by filtration through celite. Ethyl acetate and water were added to the filtrate, and after separation, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to give 204 mg (yield 88%) of the title compound as a solid. It was.
（参考例７４）エチル　１－［３－（３－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび３－フルオロフェニルボロン酸を用いて、参考例７３の方法に準じて標記化合物（収率９２％）を固体として得た。
（参考例７５）エチル　１－［３－（２－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび２－フルオロフェニルボロン酸を用いて、参考例７３の方法に準じて標記化合物（収率８１％）を得た。
（参考例７６）エチル　１－［６－メチル－３－（３－メチルブチ－１－イン－１－イル）キノリン－２－イル］ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート（２２０ｍｇ，０．５８ｍｍｏｌ）、３－メチル－１－ブチン（２３７μＬ，２．３３ｍｍｏｌ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（１：１）（４９ｍｇ，０．０６ｍｍｏｌ）、ヨウ化銅（Ｉ）（２２ｍｇ，０．１２ｍｍｏｌ）、ジイソプロピルエチルアミン（３０１μＬ，１．７５ｍｍｏｌ）およびジメチルホルムアミド（３ｍＬ）からなる混合物を窒素雰囲気下、８５℃にて１５時間加熱攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を水にて洗浄し、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物６４ｍｇ（収率３０％）を得た。 Reference Example 74 Ethyl 1- [3- (3-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate Ethyl 1- (3-bromo-6- The title compound (yield 92%) was obtained as a solid according to the method of Reference Example 73 using methylquinolin-2-yl) piperidine-4-carboxylate and 3-fluorophenylboronic acid.
Reference Example 75 Ethyl 1- [3- (2-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate Ethyl 1- (3-bromo-6- The title compound (81% yield) was obtained according to the method of Reference Example 73 using methylquinolin-2-yl) piperidine-4-carboxylate and 2-fluorophenylboronic acid.
(Reference Example 76) Ethyl 1- [6-methyl-3- (3-methylbut-1-yn-1-yl) quinolin-2-yl] piperidine-4-carboxylate (3-Bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate (220 mg, 0.58 mmol), 3-methyl-1-butyne (237 μL, 2.33 mmol), [1,1′-bis (Diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (49 mg, 0.06 mmol), copper (I) iodide (22 mg, 0.12 mmol), diisopropylethylamine (301 μL, 1.75 mmol) And dimethylformamide (3 mL) were stirred with heating at 85 ° C. for 15 hours under a nitrogen atmosphere. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 64 mg (yield 30%) of the title compound.
（参考例７７）エチル　１－［３－（３－メトキシプロプ－１－イン－１－イル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび３－メトキシプロピンを用いて、参考例７６の方法に準じて標記化合物（収率６０％）を得た。
（参考例７８）エチル　１－（６－メチル－３－プロプ－１－イン－１－イルキノリン－２－イル）ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例７６の方法に準じて標記化合物（収率６０％）を得た。
（参考例７９）１－［３－（３－シアノフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび３－シアノフェニルボロン酸を用いて、参考例７３の方法に準じて固体（収率７６％）を得た。得られた固体を用いて、参考例２の方法に準じて標記化合物（収率１００％）を固体として得た。 Reference Example 77 Ethyl 1- [3- (3-methoxyprop-1-in-1-yl) -6-methylquinolin-2-yl] piperidine-4-carboxylate Ethyl 1- obtained in Reference Example 72 Using (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate and 3-methoxypropyne, the title compound (yield 60%) was obtained according to the method of Reference Example 76.
Reference Example 78 Ethyl 1- (6-methyl-3-prop-1-in-1-ylquinolin-2-yl) piperidine-4-carboxylate Ethyl 1- (3-bromo-) obtained in Reference Example 72 The title compound (yield 60%) was obtained according to the method of Reference Example 76 using 6-methylquinolin-2-yl) piperidine-4-carboxylate.
Reference Example 79 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid Ethyl 1- (3-bromo-6-methyl obtained in Reference Example 72 A solid (76% yield) was obtained using quinolin-2-yl) piperidine-4-carboxylate and 3-cyanophenylboronic acid according to the method of Reference Example 73. Using the obtained solid, the title compound (yield 100%) was obtained as a solid according to the method of Reference Example 2.
（参考例８０）１－（３－イソプロペニル－６－メチルキノリン－２－イル）ピペリジン－４－カルボン酸
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび４，４，５，５－テトラメチル－２－（プロプ－１－エン－２－イル）－１，３，２－ジオキサボロランを用いて、参考例７３の方法に準じてアモルファス状物（収率４０％）を得た。得られたアモルファス状物を用いて、参考例２の方法に準じて標記化合物（収率１００％、純度９４％）を固体として得た。
（参考例８１）１－［６－メチル－３－（ピリジン－２－イル）キノリン－２－イル］ピペリジン－４－カルボン酸
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート（３７７ｍｇ，０．９９９ｍｍｏｌ）、トリブチル（２－ピリジル）スズ（０．３８４ｍＬ，１．２０ｍｍｏｌ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（３５ｍｇ，０．０５ｍｍｏｌ）および２，６－ジ－ｔｅｒｔ－ブチル－ｐ－クレゾール（３ｍｇ）のトルエン（１２ｍＬ）懸濁液を、加熱還流下１５時間攪拌した。反応混合物をろ過後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１／１）にて精製し、固体３１０ｍｇ（収率８３％）を得た。得られた固体を用いて、参考例２の方法に準じて標記化合物２８７ｍｇ（収率１００％）を固体として得た。 Reference Example 80 1- (3-Isopropenyl-6-methylquinolin-2-yl) piperidine-4-carboxylic acid Ethyl 1- (3-bromo-6-methylquinoline-2-) obtained in Reference Example 72 Yl) piperidine-4-carboxylate and 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane, the method of Reference Example 73 According to the above, an amorphous product (yield 40%) was obtained. Using the obtained amorphous material, the title compound (yield 100%, purity 94%) was obtained as a solid according to the method of Reference Example 2.
Reference Example 81 1- [6-Methyl-3- (pyridin-2-yl) quinolin-2-yl] piperidine-4-carboxylic acid Ethyl 1- (3-bromo-6- Methylquinolin-2-yl) piperidine-4-carboxylate (377 mg, 0.999 mmol), tributyl (2-pyridyl) tin (0.384 mL, 1.20 mmol), bis (triphenylphosphine) palladium (II) dichloride ( 35 mg, 0.05 mmol) and 2,6-di-tert-butyl-p-cresol (3 mg) in toluene (12 mL) were stirred with heating under reflux for 15 hours. After filtering the reaction mixture, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to obtain 310 mg of solid (yield 83%). Using the obtained solid, 287 mg (yield 100%) of the title compound was obtained as a solid according to the method of Reference Example 2.
（参考例８２）１－（６－メチル－３－｛４－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸
　ＰＣＴ　ＷＯ２０１０／１１６９１５Ａ１出願明細書記載の２－｛２－［４－（４，５，６，６－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノキシ］エトキシ｝テトラヒドロ－２Ｈ－ピランおよび参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例７３の方法に準じて油状物（４１％）を得た。得られた油状物を用いて、参考例２の方法に準じて標記化合物（収率９９％）を得た。
（参考例８３）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－｛４－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例８２で得られた１－（６－メチル－３－｛４－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率７５％）を得た。 Reference Example 82 1- (6-Methyl-3- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinolin-2-yl) piperidine-4-carboxylic acid PCT WO2010 / 2- {2- [4- (4,5,6,6-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} tetrahydro-2H-pyran described in the application specification of 116915A1 and Reference Example Using the ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in 72, an oil (41%) was obtained according to the method of Reference Example 73. Using the obtained oil, the title compound (yield 99%) was obtained according to the method of Reference Example 2.
Reference Example 83 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] Phenyl} quinolin-2-yl) piperidine-4-carboxamide 1- (6-methyl-3- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl obtained in Reference Example 82 } Quinolin-2-yl) piperidine-4-carboxylic acid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25 according to the method of Example 1 (Yield 75%) was obtained.
（参考例８４）エチル　１－（３－｛４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび市販の４－（Ｎ－ｔｅｒｔ－ブチルオキシカルボニルアミノ）フェニルボロン酸を用いて、参考例７３の方法に準じて標記化合物（収率５０％）を固体として得た。
（参考例８５）１－［３－（４－｛（ｔｅｒｔ－ブトキシカルボニル）［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アミノ｝フェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸
　参考例８４で得られたエチル　１－（３－｛４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレート（１．２４ｇ，２．５３ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（２００ｍＬ）溶液に、水素化ナトリウム（０．６００ｇ，１５．２ｍｍｏｌ）および２－（２－ブロモエトキシ）テトラヒドロ－２Ｈ－ピラン（２．３５ｍＬ，１５．２ｍｍｏｌ）を加え、窒素雰囲気下、２１時間攪拌した。反応混合物に水を加え、ｎ－ヘキサンにて洗浄した後、１Ｎ塩酸水溶液にて水層をｐＨ３とし、クロロホルムにて抽出した。無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去し、標記化合物１．３９ｇ（収率９３％）を得た。 Reference Example 84 Ethyl 1- (3- {4-[(tert-butoxycarbonyl) amino] phenyl} -6-methylquinolin-2-yl) piperidine-4-carboxylate Ethyl 1 obtained in Reference Example 72 According to the method of Reference Example 73, using-(3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate and commercially available 4- (N-tert-butyloxycarbonylamino) phenylboronic acid The title compound (yield 50%) was obtained as a solid.
Reference Example 85 1- [3- (4-{(tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino} phenyl) -6-methylquinolin-2-yl] Piperidine-4-carboxylic acid Ethyl 1- (3- {4-[(tert-butoxycarbonyl) amino] phenyl} -6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in Reference Example 84 1.24 g, 2.53 mmol) in N, N-dimethylformamide (200 mL) was added to sodium hydride (0.600 g, 15.2 mmol) and 2- (2-bromoethoxy) tetrahydro-2H-pyran (2. 35 mL, 15.2 mmol) was added, and the mixture was stirred for 21 hours under a nitrogen atmosphere. Water was added to the reaction mixture, washed with n-hexane, the aqueous layer was adjusted to pH 3 with 1N aqueous hydrochloric acid solution, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.39 g (yield 93%) of the title compound.
（参考例８６）ｔｅｒｔ－ブチル　｛４－［２－（４－｛［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］カルバモイル｝ピペリジン－１－イル）－６－メチルキノリン－３－イル］フェニル｝［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］カーバメート
　参考例８５で得られた１－［３－（４－｛（ｔｅｒｔ－ブトキシカルボニル）［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アミノ｝フェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物４６２ｍｇ（収率８０％）を得た。
（参考例８７）２－｛２－［３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノキシ］エトキシ｝テトラヒドロ－２Ｈ－ピラン
　市販の３－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノール（２．５０ｇ，１１．４ｍｍｏｌ）および市販の２－（２－ブロモエトキシ）テトラヒドロ－２Ｈ－ピラン（３．３３ｇ，１５．９ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド溶液に炭酸カリウム（４．０８ｇ，２９．５ｍｍｏｌ）を加え、窒素雰囲気下、１００℃にて１８時間攪拌した。反応混合物を減圧濃縮し、得られた残渣に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３／２）にて精製し、標記化合物３．００ｇ（収率７６％）を得た。
（参考例８８）１－（６－メチル－３－｛３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸
　参考例８７で得られた２－｛２－［３－（４，４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェノキシ］エトキシ｝テトラヒドロ－２Ｈ－ピランおよび参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例７３の方法に準じて油状物（７５％）を得た。得られた油状物を用いて、参考例２の方法に準じて標記化合物（収率１００％）を固体として得た。 Reference Example 86 tert-butyl {4- [2- (4-{[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamoyl} piperidin-1-yl) -6-methylquinolin-3-yl ] Phenyl} [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] carbamate 1- [3- (4-{(tert-butoxycarbonyl) [2- (tetrahydro-2H--] obtained in Reference Example 85 Pyran-2-yloxy) ethyl] amino} phenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid and (1S, 3S) -3-amino-N-ethylcyclohexane obtained in Reference Example 25 Using carboxamide, 462 mg (yield 80%) of the title compound was obtained according to the method of Example 1.
Reference Example 87 2- {2- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} tetrahydro-2H-pyran (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (2.50 g, 11.4 mmol) and commercially available 2- (2-bromoethoxy) tetrahydro-2H-pyran To a solution of (3.33 g, 15.9 mmol) in N, N-dimethylformamide was added potassium carbonate (4.08 g, 29.5 mmol), and the mixture was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/2) to obtain 3.00 g (yield 76%) of the title compound.
Reference Example 88 1- (6-Methyl-3- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinolin-2-yl) piperidine-4-carboxylic acid Reference Example 87 2- {2- [3- (4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} tetrahydro-2H-pyran obtained in 1) and Reference Example Using the ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in 72, an oil (75%) was obtained according to the method of Reference Example 73. The title compound (yield 100%) was obtained as a solid according to the method of Reference Example 2 using the obtained oil.
（参考例８９）１－［３－（３－｛（ｔｅｒｔ－ブトキシカルボニル）［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アミノ｝フェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸
　参考例７２で得られたエチル　１－（３－ブロモ－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートおよび市販の３－（Ｎ－ｔｅｒｔ－ブチルオキシカルボニルアミノ）フェニルボロン酸を用いて、参考例７３の方法に準じてアモルファス状物（収率６８％）を得た。得られたアモルファス状物を用いて、参考例８５の方法に準じてアルキル化体（収率３９％）を得た。得られた化合物を用いて、参考例２の方法に準じて標記化合物（収率５８％）を得た。 Reference Example 89 1- [3- (3-{(tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino} phenyl) -6-methylquinolin-2-yl] Piperidine-4-carboxylic acid Ethyl 1- (3-bromo-6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in Reference Example 72 and commercially available 3- (N-tert-butyloxycarbonylamino) ) Using phenylboronic acid, an amorphous substance (yield 68%) was obtained according to the method of Reference Example 73. Using the resulting amorphous material, an alkylated product (yield 39%) was obtained according to the method of Reference Example 85. Using the obtained compound, the title compound (yield 58%) was obtained according to the method of Reference Example 2.
　参考例に記載の化合物の構造式および物理化学データを以下に示す。 The structural formula and physicochemical data of the compounds described in Reference Examples are shown below.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
（実施例１）エチル　［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート
　Ｉｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ　（１９８０）， １０，　２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩（１８３ｍｇ，０．８２３ｍｍｏｌ）および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸（２０２ｍｇ，０．５８３ｍｍｏｌ）、３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール（１．７５ｇ，１２．９ｍｍｏｌ）およびＮ，Ｎ－ジメチルピリジン－４－アミン（７２．４ｍｇ，０．５９３ｍｍｏｌ）のジクロロメタン溶液（４ｍＬ）にトリエチルアミン（０．４１ｍＬ，２９１ｍｏｌ）および１－エチル－３－(３－ジメチルアミノプロピル) カルボジイミド　塩酸塩（３４０ｍｇ，１．７７ｍｍｏｌ）を加え、室温にて１５時間半攪拌した。ジクロロメタンを加え希釈した後、０．１Ｎ塩酸水溶液を加えて中和洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル（１０％メタノール）＝６／１－１／２）にて精製し標記化合物２６２ｍｇ（収率８８％）を固体として得た。
（実施例２）［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸
　実施例１で得られたエチル　［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート（３７７ｍｇ，０．７３３ｍｍｏｌ）のエタノール（５ｍＬ）および水（０．４ｍＬ）懸濁液に、８Ｎ水酸化ナトリウム水溶液（０．７ｍＬ，５．６ｍｍｏｌ）を加えて６０℃にて２．５時間攪拌した。反応混合物に１Ｎ塩酸水溶液を加えて酸性とした後、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物３３８ｍｇ（収率９５％）を得た。 Example 1 Ethyl [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate Izvestiya Akademii Nauk SSSR, SeriyaKimicheskaya ( 1980), 10, 2374-2379. Ethyl (cis-4-aminocyclohexyl) acetate hydrochloride (183 mg, 0.823 mmol) and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 Acid (202 mg, 0.583 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (1.75 g, 12.9 mmol) and N, N-dimethylpyridine-4- Triethylamine (0.41 mL, 291 mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (340 mg, 1.77 mmol) were added to a dichloromethane solution (4 mL) of amine (72.4 mg, 0.593 mmol). In addition, the mixture was stirred at room temperature for 15 hours and a half. After diluting with dichloromethane, 0.1N aqueous hydrochloric acid solution was added for neutralization washing. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate (10% methanol) = 6 / 1-1 / 2) to obtain 262 mg (yield 88%) of the title compound as a solid.
Example 2 [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid Ethyl obtained in Example 1 [Cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate (377 mg, 0.733 mmol) in ethanol (5 mL) and An 8N aqueous sodium hydroxide solution (0.7 mL, 5.6 mmol) was added to the water (0.4 mL) suspension, and the mixture was stirred at 60 ° C. for 2.5 hours. The reaction mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 338 mg (yield 95%) of the title compound.
（実施例３）Ｎ－（シス－４－カルバモイルシクロヘキシル）－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　ＰＣＴ　ＷＯ２００９／０５４４６８Ａ１出願明細書記載のシス－４－アミノシクロヘキサンカルボキサミド　および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸のアセトニトリル（４ｍＬ）溶液に市販の４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（９８．７ｍｇ，０．３５７ｍｍｏｌ）を加え、室温にて１８時間攪拌した。反応混合物を減圧濃縮後、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）およびＮＨシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、標記化合物１０１ｍｇ（収率７１％）を固体として得た。
（実施例４）Ｎ－［シス－４－（２－アミノ－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例５で得られた２－（シス－４－アミノシクロヘキシル）アセトアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９１％）を得た。 Example 3 N- (cis-4-carbamoylcyclohexyl) -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide PCT WO2009 / 054468A1 described in the application specification Commercially available 4- (4,6-dimethoxy) was added to a solution of aminocyclohexanecarboxamide and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 in acetonitrile (4 mL). -1,3,5-Triazin-2-yl) -4-methylmorpholinium chloride (98.7 mg, 0.357 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) and NH silica gel column chromatography (chloroform / methanol = 10/1) to obtain 101 mg (yield 71%) of the title compound as a solid.
Example 4 N- [cis-4- (2-amino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and 2- (cis-4-aminocyclohexyl) acetamide hydrochloride obtained in Reference Example 5 were used. The title compound (yield 91%) was obtained according to the method of Example 1.
（実施例５）Ｎ－｛シス－４－［２－（エチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例２で得られた［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸（１２０ｍｇ，０．２４７ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、氷冷下、市販の１，１’－カルボニルジイミダゾール（９９ｍｇ，０．６１ｍｍｏｌ）を加え、１時間攪拌した。反応混合物に市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液、０．７４ｍＬ，１．４８ｍｍｏｌ）を加え室温にて一晩攪拌した。反応混合物にジクロロメタンを加え希釈した後、０．１Ｎ塩酸水溶液にて洗浄した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルクロマトグラフィー（ｎ－ヘキサン／酢酸エチル（１０％メタノール）＝４／１－１／２）にて精製し標記化合物９７．８ｍｇ（収率７７％）を固体として得た。
（実施例６）Ｎ－｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例７で得られた２－（シス－４－アミノシクロヘキシル）－Ｎ－メチルアセトアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９４％）を固体として得た。 Example 5 N- {cis-4- [2- (ethylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Example Of [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid (120 mg, 0.247 mmol) obtained in Commercially available 1,1′-carbonyldiimidazole (99 mg, 0.61 mmol) was added to a dichloromethane (3 mL) solution under ice cooling, and the mixture was stirred for 1 hour. Commercially available ethylamine (2.0 M tetrahydrofuran solution, 0.74 mL, 1.48 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After diluting the reaction mixture with dichloromethane, the reaction mixture was washed with 0.1N aqueous hydrochloric acid. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate (10% methanol) = 4 / 1-1 / 2) to obtain 97.8 mg (77% yield) of the title compound as a solid.
Example 6 N- {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in 2 and 2- (cis-4-aminocyclohexyl) -N-methylacetamide obtained in Reference Example 7 Using the hydrochloride, the title compound (yield 94%) was obtained as a solid according to the method of Example 1.
（実施例７）Ｎ－｛シス－４－［２－（メトキシアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例２で得られた［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸および市販の（アミノオキシ）メタン　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８０％）を固体として得た。
（実施例８）Ｎ－（シス－４－｛２－［（２－ヒドロキシエチル）アミノ］－２－オキソエチル｝シクロヘキシル）－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例２で得られた［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸および市販の２－アミノエタノールを用いて、実施例３の方法に準じて標記化合物（収率８２％）を固体として得た。
（実施例９）Ｎ－［シス－４－（シアノメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例８で得られた（シス－４－アミノシクロヘキシル）アセトニトリル　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９２％）を固体として得た。 Example 7 N- {cis-4- [2- (methoxyamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Example [Cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid obtained in step 2 and commercially available (aminooxy) methane The title compound (yield 80%) was obtained as a solid according to the method of Example 1 using hydrochloride.
Example 8 N- (cis-4- {2-[(2-hydroxyethyl) amino] -2-oxoethyl} cyclohexyl) -1- (6-methyl-3-phenylquinolin-2-yl) piperidine- 4-Carboxamide [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid obtained in Example 2 and commercially available The title compound (yield 82%) was obtained as a solid using 2-aminoethanol according to the method of Example 3.
Example 9 N- [cis-4- (cyanomethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6 According to the method of Example 1, using -methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and (cis-4-aminocyclohexyl) acetonitrile hydrochloride obtained in Reference Example 8 The compound (yield 92%) was obtained as a solid.
（実施例１０）Ｎ－（シス－４－ヒドロキシシクロヘキシル）－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および市販のシス－４－アミノシクロヘキサノール　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８１％）を固体として得た。
（実施例１１）Ｎ－［シス－４－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　ＰＣＴ　ＷＯ２００４／０８７６８０Ａ１出願明細書記載の（シス－４－アミノシクロヘキシル）メタノール　塩酸塩および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率５２％）を得た。
（実施例１２）Ｎ－［シス－４－（２－アミノ－１－ヒドロキシ－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例１０で得られた２－（シス－４－アミノシクロヘキシル）－２－ヒドロキシアセトアミドを用いて、実施例１の方法に準じて標記化合物（収率９２％）を固体として得た。 Example 10 N- (cis-4-hydroxycyclohexyl) -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-methyl) obtained in Reference Example 2 -3-Phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available cis-4-aminocyclohexanol hydrochloride were used to produce the title compound (81% yield) as a solid according to the method of Example 1 Got as.
Example 11 N- [cis-4- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide PCT WO2004 / 087680A1 Using the cis-4-aminocyclohexyl) methanol hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the method of Example 1 was used. The title compound (yield 52%) was obtained accordingly.
Example 12 N- [cis-4- (2-amino-1-hydroxy-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Example 2 and 2- (cis-4-aminocyclohexyl) -2-hydroxy obtained in Reference Example 10 The title compound (yield 92%) was obtained as a solid using acetamide according to the method of Example 1.
（実施例１３）Ｎ－｛シス－４－［１－ヒドロキシ－２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例１１で得られた２－（シス－４－アミノシクロヘキシル）－２－ヒドロキシ－Ｎ－メチルアセトアミドを用いて、実施例１の方法に準じて標記化合物（収率６７％）を固体として得た。
（実施例１４）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－｛シス－４－［（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）メチル］シクロヘキシル｝ピペリジン－４－カルボキサミド
　実施例９で得られたＮ－［シス－４－（シアノメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド　（２３３ｍｇ，０．４９９ｍｍｏｌ）のエタノール（１２ｍＬ）溶液に、室温にて５０％ヒドロキシルアミン水溶液（０．１３２ｍＬ，２．００ｍｍｏｌ）を加え、加熱還流下、２０時間攪拌した。反応混合物を減圧濃縮した後、飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、アモルファス状物２１６ｍｇ（収率８７％）を得た。得られたアモルファス状物（１２８ｍｇ，０．２５６ｍｍｏｌ）およびトリエチルアミン（０．０５７ｍＬ，０．４１０ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、氷冷下、クロロギ酸エチル（０．０３２ｍＬ，０．３３３ｍｍｏｌ）を加え、室温にて１時間攪拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、アモルファス状物１６４ｍｇを得た。得られたアモルファス状物のトルエン（２０ｍＬ）溶液を、加熱還流下、１１時間攪拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、標記化合物４３ｍｇ（収率３２％）を得た。 Example 13 N- {cis-4- [1-hydroxy-2- (methylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2- (cis-4-aminocyclohexyl)-obtained in Reference Example 11 The title compound (yield 67%) was obtained as a solid according to the method of Example 1 using 2-hydroxy-N-methylacetamide.
Example 14 1- (6-Methyl-3-phenylquinolin-2-yl) -N- {cis-4-[(5-oxo-4,5-dihydro-1,2,4-oxadiazole) -3-yl) methyl] cyclohexyl} piperidine-4-carboxamide N- [cis-4- (cyanomethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) obtained in Example 9 To a solution of piperidine-4-carboxamide (233 mg, 0.499 mmol) in ethanol (12 mL) was added 50% aqueous hydroxylamine solution (0.132 mL, 2.00 mmol) at room temperature, and the mixture was stirred with heating under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 216 mg (yield 87%) of an amorphous substance. To a solution of the obtained amorphous substance (128 mg, 0.256 mmol) and triethylamine (0.057 mL, 0.410 mmol) in dichloromethane (3 mL) was added ethyl chloroformate (0.032 mL, 0.333 mmol) under ice cooling. And stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 164 mg of an amorphous substance. A solution of the obtained amorphous product in toluene (20 mL) was stirred for 11 hours under heating to reflux. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 43 mg (yield 32%) of the title compound.
（実施例１５）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－｛シス－４－［（５－オキソ－４，５－ジヒドロ－１，３，４－オキサジアゾール－２－イル）メチル］シクロヘキシル｝ピペリジン－４－カルボキサミド
　参考例１２で得られたＮ－［シス－４－（２－ヒドラジノ－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド（１００ｍｇ，０．２００ｍｍｏｌ）のジクロロメタン（６ｍＬ）溶液に、トリエチルアミン（０．０４２ｍＬ，０．３００ｍｍｏｌ）および市販の１，１’－カルボニルジイミダゾール（３８．９ｍＬ，０．２４ｍｍｏｌ）を加え、室温にて２時間攪拌した。反応混合物に酢酸エチルを加えた後、水および飽和食塩水にて洗浄した。得られた有機層を無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、標記化合物７２ｍｇ（収率６８％）を固体として得た。
（実施例１６）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－｛シス－４－［（５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－３－イル）メチル］シクロヘキシル｝ピペリジン－４－カルボキサミド
　参考例１２で得られたＮ－［シス－４－（２－ヒドラジノ－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド（９３０ｍｇ，１．８６ｍｍｏｌ）のジクロロメタン（２５ｍＬ）溶液に、ｔｅｒｔ－ブチルイソシアネート（０．２５５ｍＬ，２．２３ｍｍｏｌ）およびトリエチルアミン（０．３８９ｍＬ，２．７９ｍｍｏｌ）を加え、室温にて１５時間攪拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、固体９９１ｍｇ（収率８９％）を得た。得られた固体（９８８ｍｇ，１．６５ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、室温にてトリフルオロ酢酸（１５ｍＬ）を加えて３時間攪拌した。反応混合物を減圧濃縮した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製した。得られた粗生成体に２Ｎ水酸化ナトリウム水溶液（２０ｍＬ）を加え、１００℃にて３時間攪拌した。反応混合物に水を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、標記化合物８ｍｇ（収率１％）を固体として得た。 Example 15 1- (6-Methyl-3-phenylquinolin-2-yl) -N- {cis-4-[(5-oxo-4,5-dihydro-1,3,4-oxadiazole -2-yl) methyl] cyclohexyl} piperidine-4-carboxamide N- [cis-4- (2-hydrazino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenyl) obtained in Reference Example 12 To a solution of quinolin-2-yl) piperidine-4-carboxamide (100 mg, 0.200 mmol) in dichloromethane (6 mL) was added triethylamine (0.042 mL, 0.300 mmol) and commercially available 1,1′-carbonyldiimidazole (38. 9 mL, 0.24 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 72 mg (yield 68%) of the title compound as a solid.
Example 16 1- (6-Methyl-3-phenylquinolin-2-yl) -N- {cis-4-[(5-oxo-4,5-dihydro-1H-1,2,4-triazole -3-yl) methyl] cyclohexyl} piperidine-4-carboxamide N- [cis-4- (2-hydrazino-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenyl) obtained in Reference Example 12 To a solution of quinolin-2-yl) piperidine-4-carboxamide (930 mg, 1.86 mmol) in dichloromethane (25 mL), tert-butyl isocyanate (0.255 mL, 2.23 mmol) and triethylamine (0.389 mL, 2.79 mmol) And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 991 mg (89% yield) of a solid. To a solution of the obtained solid (988 mg, 1.65 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (15 mL) at room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1). A 2N aqueous sodium hydroxide solution (20 mL) was added to the resulting crude product, and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 8 mg (yield 1%) of the title compound as a solid.
（実施例１７）エチル　２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例１５で得られたエチル　２－（シス－４－アミノシクロヘキシル）プロパノエートを用いて、実施例１の方法に準じて標記化合物（収率８９％）を固体として得た。
（実施例１８）２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例１７で得られたエチル　２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例２の方法に準じて標記化合物を定量的に固体として得た。
（実施例１９）Ｎ－［シス－４－（２－アミノ－１－メチル－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例１８で得られた２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸および市販の７Ｎアンモニア－メタノールを用いて、実施例３の方法に準じて標記化合物（収率９３％）を固体として得た。 Example 17 Ethyl 2- [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate Obtained in Reference Example 2 Example 1 using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and ethyl 2- (cis-4-aminocyclohexyl) propanoate obtained in Reference Example 15 The title compound (yield 89%) was obtained as a solid according to method 1.
Example 18 2- [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid Obtained in Example 17 Example 2 was used with ethyl 2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate. The title compound was obtained quantitatively as a solid according to the method.
Example 19 N- [cis-4- (2-amino-1-methyl-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 2- [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid obtained in Example 18 and commercially available 7N The title compound (yield 93%) was obtained as a solid according to the method of Example 3 using ammonia-methanol.
（実施例２０）エチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例１７で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率７９％）を固体として得た。
（実施例２１）２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例２０で得られたエチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例２の方法に準じて標記化合物（収率１６％）を固体として得た。
（実施例２２）Ｎ－［シス－４－（２－アミノ－１，１－ジメチル－２－オキソエチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例２１で得られた２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸および市販の７Ｎアンモニア－メタノールを用いて、実施例３の方法に準じて標記化合物（収率５０％）を固体として得た。 Example 20 Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate Reference 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Example 2 and ethyl 2- (cis-4-aminocyclohexyl) -2-yl obtained in Reference Example 17 The title compound (yield 79%) was obtained as a solid according to the method of Example 1 using methylpropanoate.
Example 21 2-Methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate obtained in Example 20 Was used to give the title compound (yield 16%) as a solid according to the method of Example 2.
Example 22 N- [cis-4- (2-amino-1,1-dimethyl-2-oxoethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- Carboxamide 2-Methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl obtained in Example 21] The title compound (yield 50%) was obtained as a solid according to the method of Example 3 using propanoic acid and commercially available 7N ammonia-methanol.
（実施例２３）エチル　１－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボキシレート
　参考例１９で得られたエチル　１－｛シス－４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝シクロプロパンカルボキシレートを用いて、参考例５の方法に準じて得られた化合物をジクロロメタンに溶解した。本反応溶液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率９９％）を得た。
（実施例２４）１－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボン酸
　実施例２３で得られたエチル　１－［シス－４－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボキシレートを用いて、実施例２の方法に準じて標記化合物（収率７２％）を固体として得た。
（実施例２５）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例２３で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率６６％）を得た。 Example 23 Ethyl 1- [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylate Reference Example The compound obtained according to the method of Reference Example 5 was dissolved in dichloromethane using ethyl 1- {cis-4-[(tert-butoxycarbonyl) amino] cyclohexyl} cyclopropanecarboxylate obtained in 19. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 99%).
Example 24 1- [cis-4-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylic acid Example 23 Using ethyl 1- [cis-4-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylate obtained in The title compound (yield 72%) was obtained as a solid according to the method of Example 2.
Example 25 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- The method of Example 3 using (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and the (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23 To give the title compound (yield 66%).
（実施例２６）Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例２４で得られた［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］メタノール　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率８７％）を得た。
（実施例２７）Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド　塩酸塩
　実施例２６で得られたＮ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド（７０．０ｍｇ，０．１５３ｍｍｏｌ）に１Ｎ塩酸エタノール溶液を加えて懸濁させた後、減圧下にて溶媒を留去した。得られた固体をエタノール－酢酸エチルに懸濁させた後、ろ取した。酢酸エチルにて洗浄し、標記化合物７０．１ｍｇ（収率９３％）を固体として得た。
（実施例２８）Ｎ－［（１Ｓ，３Ｓ)－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例２５で得られた［（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率９７％）を固体として得た。 Example 26 N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Obtained in Reference Example 2 Using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, The title compound (yield 87%) was obtained according to the method of Example 3.
Example 27 N-[(1S, 3S) -3- (Hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide hydrochloride In Example 26 The obtained N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (70.0 mg, 0.153 mmol) 1) Hydrochloric acid ethanol solution was added and suspended, and then the solvent was distilled off under reduced pressure. The obtained solid was suspended in ethanol-ethyl acetate and collected by filtration. Washing with ethyl acetate gave 70.1 mg (yield 93%) of the title compound as a solid.
Example 28 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and [(1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25 were used. According to the method of Example 1, the title compound (yield 97%) was obtained as a solid.
（実施例２９）エチル　［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例２７で得られたエチル　［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］アセテート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９７％）固体として得た。
（実施例３０）［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸
　実施例２９で得られたエチル　［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテートを用いて、実施例２の方法に準じて標記化合物（収率９８％）を固体として得た。
（実施例３１）Ｎ－｛（１Ｓ，３Ｓ）－３－［２－（メトキシアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例３０で得られた［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸および市販の（アミノオキシ）メタン　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率７９％）を固体として得た。
（実施例３２）エチル　２－メチル－２－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例２８で得られたエチル　２－｛（１Ｓ，３Ｓ）－３－［（ジフェニルメチレン）アミノ］シクロヘキシル｝－２－メチルプロパノエートを用いて、参考例１０の方法に準じて得られた化合物をジクロロメタンに溶解した。本反応溶液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率９９％）を得た。 Example 29 Ethyl [(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in 1 and ethyl [(1S, 3S) -3-aminocyclohexyl] acetate hydrochloride obtained in Reference Example 27 The title compound (yield 97%) was obtained as a solid according to the method of Example 1.
Example 30 [(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid In Example 29 Using the obtained ethyl [(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate The title compound (yield 98%) was obtained as a solid according to the method of Example 2.
Example 31 N-{(1S, 3S) -3- [2- (methoxyamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 Carboxamide [(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid obtained in Example 30 The title compound (yield 79%) was obtained as a solid according to the method of Example 1 using commercially available (aminooxy) methane hydrochloride.
Example 32 Ethyl 2-methyl-2-[(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) Cyclohexyl] propanoate Using the ethyl 2-{(1S, 3S) -3-[(diphenylmethylene) amino] cyclohexyl} -2-methylpropanoate obtained in Reference Example 28, according to the method of Reference Example 10 The obtained compound was dissolved in dichloromethane. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 99%).
（実施例３３）２－メチル－２－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例３２で得られたエチル　２－メチル－２－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例２の方法に準じて標記化合物（収率２６％）を固体として得た。
（実施例３４）メチル　１－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボキシレート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例３０で得られたメチル　１－｛（１Ｓ，３Ｓ）－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝シクロプロパンカルボキシレートを用いて、実施例１の方法に準じて標記化合物（収率９５％）を得た。
（実施例３５）１－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボン酸
　実施例３４で得られたメチル　１－［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］シクロプロパンカルボキシレートを用いて、実施例２の方法に準じて標記化合物（収率９２％）を得た。 Example 33 2-Methyl-2-[(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl ] Propanoic acid Ethyl 2-methyl-2-[(1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] obtained in Example 32 ] Carbonyl} amino) cyclohexyl] propanoate was used to obtain the title compound as a solid (yield 26%) according to the method of Example 2.
Example 34 Methyl 1-[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropane Carboxylate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and methyl 1-{(1S, 3S) -3 obtained in Reference Example 30 The title compound (yield 95%) was obtained according to the method of Example 1 using-[(tert-butoxycarbonyl) amino] cyclohexyl} cyclopropanecarboxylate.
Example 35 1-[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] cyclopropanecarboxylic acid Acid Methyl 1-[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl obtained in Example 34 The title compound (yield 92%) was obtained using cyclopropanecarboxylate according to the method of Example 2.
（実施例３６）Ｎ－｛（１Ｓ，３Ｓ）－３－［２－（エチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例３２で得られた２－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－Ｎ－エチルアセトアミドを用いて、実施例３の方法に準じて標記化合物（収率７６％）を得た。
（実施例３７）Ｎ－｛（１Ｓ，３Ｓ）－３－［２－（シクロプロピルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸と参考例３３で得られた２－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－Ｎ－シクロプロピルアセトアミドを用いて、実施例３の方法に準じて標記化合物（収率７６％）を得た。
（実施例３８）Ｎ－［（１Ｓ，３Ｓ）－３－（メトキシカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸と参考例３４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－メトキシシクロヘキサンカルボキサミド　塩酸塩（１０８ｍｇ，０．５２０ｍｍｏｌ）を用いて、実施例３の方法に準じて標記化合物（収率５１％）を得た。 Example 36 N-{(1S, 3S) -3- [2- (Ethylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2-[(1S, 3S) -3- The title compound (yield 76%) was obtained using aminocyclohexyl] -N-ethylacetamide according to the method of Example 3.
Example 37 N-{(1S, 3S) -3- [2- (cyclopropylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine- 4-Carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and 2-[(1S, 3S) -3 obtained in Reference Example 33 -Aminocyclohexyl] -N-cyclopropylacetamide was used to give the title compound (76% yield) according to the method of Example 3.
Example 38 N-[(1S, 3S) -3- (methoxycarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and (1S, 3S) -3-amino-N-methoxycyclohexanecarboxamide hydrochloride (108 mg) obtained in Reference Example 34 , 0.520 mmol), and the title compound (yield 51%) was obtained according to the method of Example 3.
（実施例３９）Ｎ－｛（１Ｓ，３Ｓ）－３－［（２－アセチルヒドラジノ）カルボニル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例３７で得られたベンジル　｛（１Ｓ，３Ｓ）－３－［（２－アセチルヒドラジノ）カルボニル］シクロヘキシル｝カーバメートを用いて、参考例１０の方法に準じて油状物を得た。得られた油状物および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じて標記化合物（収率７６％）を得た。
（実施例４０）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－｛［２－（メチルスルホニル）ヒドラジノ］カルボニル｝シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例３８で得られたベンジル　［（１Ｓ，３Ｓ）－３－｛［２－（メチルスルホニル）ヒドラジノ］カルボニル｝シクロヘキシル］カーバメートを用いて、参考例１０の方法に準じて油状物を得た。得られた油状物および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じて標記化合物（収率４３％）を得た。
（実施例４１）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（５－オキソ－４，５－ジヒドロ－１，３，４－オキサジアゾール－２－イル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例３９で得られたＮ－［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド　２塩酸塩を用いて実施例１５の方法に準じて標記化合物（収率８８％）を得た。 Example 39 N-{(1S, 3S) -3-[(2-acetylhydrazino) carbonyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Using the benzyl {(1S, 3S) -3-[(2-acetylhydrazino) carbonyl] cyclohexyl} carbamate obtained in Reference Example 37, an oily substance was obtained according to the method of Reference Example 10. Using the obtained oil and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound ( Yield 76%) was obtained.
Example 40 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3-{[2- (methylsulfonyl) hydrazino] carbonyl} cyclohexyl] piperidine-4 -Carboxamide Using the benzyl [(1S, 3S) -3-{[2- (methylsulfonyl) hydrazino] carbonyl} cyclohexyl] carbamate obtained in Reference Example 38, an oily substance was obtained according to the method of Reference Example 10. It was. Using the obtained oil and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound ( Yield 43%).
Example 41 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,3,4- Oxadiazol-2-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] -1- (6-methyl-3-) obtained in Reference Example 39 The title compound (88% yield) was obtained according to the method of Example 15 using (phenylquinolin-2-yl) piperidine-4-carboxamide dihydrochloride.
（実施例４２）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－３－イル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例３９で得られたＮ－［（１Ｓ，３Ｓ）－３－（ヒドラジノカルボニル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド　２塩酸塩を用いて、実施例１６の方法に準じて標記化合物（収率１３％）を得た。
（実施例４３）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例４１で得られた３－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－１，２，４－オキサジアゾール－５（４Ｈ）－オン　塩酸塩および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率８９％）を得た。
（実施例４４）Ｎ－｛（１Ｓ，３Ｓ）－３－［（２－ヒドロキシエチル）カルバモイル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例４２で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－（２－ヒドロキシエチル）シクロヘキサンカルボキサミドおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じて標記化合物（収率２５％）を得た。 Example 42 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1H-1,2, 4-Triazol-3-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3- (hydrazinocarbonyl) cyclohexyl] -1- (6-methyl-3-) obtained in Reference Example 39 The title compound (13% yield) was obtained according to the method of Example 16 using phenylquinolin-2-yl) piperidine-4-carboxamide dihydrochloride.
Example 43 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,2,4- Oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide 3-[(1S, 3S) -3-aminocyclohexyl] -1,2,4-oxadiazole-5 (4H obtained in Reference Example 41 ) -One Using the hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound ( Yield 89%).
Example 44 N-{(1S, 3S) -3-[(2-hydroxyethyl) carbamoyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference (1S, 3S) -3-Amino-N- (2-hydroxyethyl) cyclohexanecarboxamide obtained in Example 42 and 1- (6-methyl-3-phenylquinolin-2-yl) obtained in Reference Example 2 The title compound (yield 25%) was obtained according to the method of Example 3 using piperidine-4-carboxylic acid.
（実施例４５）Ｎ－｛（１Ｓ，３Ｓ）－３－［（２－フルオロエチル）カルバモイル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例４３で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－（２－フルオロエチル）シクロヘキサンカルボキサミド　塩酸塩および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じて標記化合物（収率１００％）を得た。
（実施例４６）Ｎ－｛（１Ｓ，３Ｓ）－３－［（２，３－ジヒドロキシプロピル）カルバモイル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例４４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－［（２，２－ジメチル－１，３－ジオキソラン－４－イル）メチル］シクロヘキサンカルボキサミドおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じてアモルファス状物（１００％）を得た。得られたアモルファス状物（２７８ｍｇ，０．４７５ｍｍｏｌ）のメタノール（１５ｍＬ）に溶液に、ｐ－トルエンスルホン酸一水和物（９．０ｍｇ，０．０４７５ｍｍｏｌ）を加えて室温で６時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、減圧下にて溶媒を留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝９／１）にて精製し、標記化合物１１８ｍｇ（収率４６％）を固体として得た。 Example 45 N-{(1S, 3S) -3-[(2-Fluoroethyl) carbamoyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference (1S, 3S) -3-Amino-N- (2-fluoroethyl) cyclohexanecarboxamide hydrochloride obtained in Example 43 and 1- (6-methyl-3-phenylquinoline-2-hydrochloride obtained in Reference Example 2 Yl) The title compound (100% yield) was obtained according to the method of Example 3 using piperidine-4-carboxylic acid.
Example 46 N-{(1S, 3S) -3-[(2,3-dihydroxypropyl) carbamoyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- Carboxamide (1S, 3S) -3-Amino-N-[(2,2-dimethyl-1,3-dioxolan-4-yl) methyl] cyclohexanecarboxamide obtained in Reference Example 44 and Reference Example 2 Using 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid, an amorphous substance (100%) was obtained according to the method of Example 3. To a solution of the obtained amorphous product (278 mg, 0.475 mmol) in methanol (15 mL), p-toluenesulfonic acid monohydrate (9.0 mg, 0.0475 mmol) was added and stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 9/1) to obtain 118 mg (yield 46%) of the title compound as a solid.
（実施例４７）メチル　（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレート
　参考例４５で得られたメチル　（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキシレート　塩酸塩およびと参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率８４％）を得た。
（実施例４８）（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボン酸
　実施例４７で得られたメチル　（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレートを用いて、実施例２の方法に準じて標記化合物（収率５１％）を得た。
（実施例４９）Ｎ－［（１Ｓ，３Ｓ）－３－（ジメチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例４８で得られた（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボン酸および市販のジメチルアミン　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８７％）を得た。 Example 47 Methyl (1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylate In Reference Example 45 The resulting methyl (1S, 3S) -3-aminocyclohexanecarboxylate hydrochloride and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 Was used to give the title compound (84% yield) according to the method of Example 1.
Example 48 (1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylic acid Obtained in Example 47 Example 2 Using the resulting methyl (1S, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylate The title compound (51% yield) was obtained according to the above method.
Example 49 N-[(1S, 3S) -3- (dimethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in Example 48 (1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylic acid and commercially available dimethylamine hydrochloride According to the method of Example 1, the title compound (yield 87%) was obtained.
（実施例５０）Ｎ－［（１Ｓ，３Ｓ）－３－シアノシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例４０で得られたベンジル　［（１Ｓ，３Ｓ）－３－シアノシクロヘキシル］カーバメートを用いて、参考例１０の方法に準じて固体を得た。得られた固体および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボン酸を用いて、実施例３の方法に準じて標記化合物（収率２１％）を得た。
（実施例５１）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（１Ｈ－テトラゾール－５－イル）シクロヘキシル］ピペリジン－４－カルボキサミド
　実施例５０で得られたＮ－［（１Ｓ，３Ｓ）－３－シアノシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド（４００ｍｇ，１．１５ｍｍｏｌ）のジメトキシエタン（２０ｍＬ）溶液に、トリメチルシリルアジド（１．３３ｇ，１１．６ｍｍｏｌ）およびジ－ｎ－ブチルチンオキシド（５７５ｍｇ，２．３１ｍｍｏｌ）を加えて１２５℃にて９０分間マイクロウェーブ照射した。反応混合物に１Ｎ塩酸水溶液を加え２時間攪拌した後、１Ｎ水酸化ナトリウム水溶液にてｐＨ５とした。混合物をクロロホルムにて抽出し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－０／１）にて精製し、標記化合物２９１ｍｇ（収率５１％）を得た。
（実施例５２）Ｎ－｛［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］カルボニル｝－β－アラニン　塩酸塩
　参考例４６で得られたｔｅｒｔ－ブチル　Ｎ－｛［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］カルボニル｝－β－アラニネートおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて縮合体（９０％）を得た。得られた化合物を用いて、参考例５の方法に準じて標記化合物（収率８９％）を得た。 Example 50 N-[(1S, 3S) -3-Cyanocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide benzyl obtained in Reference Example 40 Using (1S, 3S) -3-cyanocyclohexyl] carbamate, a solid was obtained according to the method of Reference Example 10. Using the obtained solid and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (recovery) was obtained according to the method of Example 3. 21%) was obtained.
Example 51 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (1H-tetrazol-5-yl) cyclohexyl] piperidine-4-carboxamide N-[(1S, 3S) -3-cyanocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (400 mg, 1.15 mmol) obtained in Example 50 Trimethylsilyl azide (1.33 g, 11.6 mmol) and di-n-butyltin oxide (575 mg, 2.31 mmol) were added to a dimethoxyethane (20 mL) solution, and microwave irradiation was performed at 125 ° C for 90 minutes. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was stirred for 2 hours, and then adjusted to pH 5 with a 1N aqueous sodium hydroxide solution. The mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1-0 / 1) to obtain 291 mg (yield 51%) of the title compound.
Example 52 N-{[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] carbonyl} -Β-alanine hydrochloride tert-butyl N-{[(1S, 3S) -3-aminocyclohexyl] carbonyl} -β-alaninate obtained in Reference Example 46 and 1- (6- According to the method of Example 1, a condensate (90%) was obtained using methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid. Using the obtained compound, the title compound (yield 89%) was obtained according to the method of Reference Example 5.
（実施例５３）Ｎ－［（１Ｓ，３Ｓ）－３－｛［３－（ジメチルアミノ）－３－オキソプロピル］カルバモイル｝シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５２で得られたＮ－｛［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］カルボニル｝－β－アラニン　塩酸塩および市販のジメチルアミン　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率６８％）を得た。
（実施例５４）２－メチル－Ｎ－｛［（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］カルボニル｝アラニン
　参考例４７で得られｔｅｒｔ－ブチル　Ｎ－｛［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］カルボニル｝－２－メチルアラニネートおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じてアモルファス状物（８０％）を得た。得られたアモルファス状物を用いて、参考例５の方法に準じて標記化合物（収率１００％）を得た。
（実施例５５）Ｎ－［（１Ｓ，３Ｓ）－３－（１Ｈ－イミダゾール－２－イル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例４３で得られた１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）シクロヘキシル］ピペリジン－４－カルボキサミドのエタノール溶液に、１０％パラジウム炭素（１５０ｍｇ）を加えて、水素雰囲気下、室温、５気圧で１６時間攪拌した。反応混合物をろ過した後、減圧下にて溶媒を留去した。得られた残渣をＮ，Ｎ－ジメチルホルムアミドに溶解し、炭酸カリウム（１０１ｍｇ，０．７２６ｍｍｏｌ）およびクロロアセトアルデヒド（４０％水溶液）（０．２３９ｍＬ，１．４６ｍｍｏｌ）を加えて６０℃にて９０分間攪拌した。反応混合物を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル）にて精製し、標記化合物８２．７ｍｇ（収率２３％）を得た。 Example 53 N-[(1S, 3S) -3-{[3- (dimethylamino) -3-oxopropyl] carbamoyl} cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl ) Piperidine-4-carboxamide N-{[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] obtained in Example 52] Carbonyl} amino) cyclohexyl] carbonyl} -β-alanine hydrochloride and commercially available dimethylamine hydrochloride were used to give the title compound (68% yield) according to the method of Example 3.
Example 54 2-Methyl-N-{[(1S, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) Cyclohexyl] carbonyl} alanine tert-butyl N-{[(1S, 3S) -3-aminocyclohexyl] carbonyl} -2-methylalaninate obtained in Reference Example 47 and 1- (6- Using methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid, an amorphous substance (80%) was obtained according to the method of Example 1. Using the resulting amorphous material, the title compound (yield 100%) was obtained according to the method of Reference Example 5.
Example 55 N-[(1S, 3S) -3- (1H-imidazol-2-yl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1,2,4) obtained in Example 43 -Oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide in ethanol was added with 10% palladium on carbon (150 mg), and the mixture was stirred in a hydrogen atmosphere at room temperature and 5 atm for 16 hours. After filtering the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide, potassium carbonate (101 mg, 0.726 mmol) and chloroacetaldehyde (40% aqueous solution) (0.239 mL, 1.46 mmol) were added, and then at 60 ° C. for 90 minutes. Stir. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain 82.7 mg (yield 23%) of the title compound.
（実施例５６）エチル （１Ｓ，３Ｒ，４Ｒ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－イル]カルボニル}アミノ)シクロヘキサンカルボキシレート
　ＰＣＴ　ＷＯ２００７／０３２４９８Ａ１出願明細書記載のエチル　（１Ｓ，３Ｒ，４Ｒ）－３－アミノ－４－ヒドロキシシクロヘキサンカルボキシレートおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率１００％）を得た。
（実施例５７）Ｎ－［（１Ｒ，２Ｒ，５Ｓ)－５－（エチルカルバモイル）－２－ヒドロキシシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５６で得られたエチル （１Ｓ，３Ｒ，４Ｒ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－イル]カルボニル}アミノ)シクロヘキサンカルボキシレートを用いて、実施例２の方法に準じて固体（収率９１％）を得た。得られた固体および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例３の方法に準じて標記化合物（収率９７％）を固体として得た。
（実施例５８）エチル （１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－イル]カルボニル}アミノ)シクロヘキサンカルボキシレート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例４８で得られたエチル　（１Ｓ，３Ｒ，４Ｓ）－３－アミノ－４－ヒドロキシシクロヘキサンカルボキシレート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率１００％）を得た。 Example 56 Ethyl (1S, 3R, 4R) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexane Carboxylate PCT WO 2007 / 032498A1 Ethyl (1S, 3R, 4R) -3-amino-4-hydroxycyclohexanecarboxylate described in the application specification and 1- (6-methyl-3-phenylquinoline--obtained in Reference Example 2 The title compound (yield 100%) was obtained according to the method of Example 1 using 2-yl) piperidine-4-carboxylic acid.
Example 57 N-[(1R, 2R, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Ethyl (1S, 3R, 4R) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino obtained in Example 56 ) Using cyclohexanecarboxylate, a solid (yield 91%) was obtained according to the method of Example 2. The title compound (yield 97%) was obtained as a solid according to the method of Example 3 using the obtained solid and commercially available ethylamine (2.0 M tetrahydrofuran solution).
Example 58 Ethyl (1S, 3R, 4S) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexane Carboxylate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and ethyl (1S, 3R, 4S) -3- obtained in Reference Example 48 Amino-4-hydroxycyclohexanecarboxylate hydrochloride was used to give the title compound (yield 100%) according to the method of Example 1.
（実施例５９）（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸
　実施例５８で得られたエチル （１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－イル］カルボニル}アミノ)シクロヘキサンカルボキシレートを用いて、実施例２の方法に準じて標記化合物（収率７１％）を固体として得た。
（実施例６０）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－２－ヒドロキシ－５－（メトキシカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５９で得られた（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸および市販の（アミノオキシ）メタン　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９９％）を得た。
（実施例６１）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－５－（エチルカルバモイル）－２－ヒドロキシシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５９で得られた（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例３の方法に準じて標記化合物（収率１００％）を得た。 Example 59 (1S, 3R, 4S) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl} amino) cyclohexanecarboxylic Acid Ethyl (1S, 3R, 4S) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} obtained in Example 58} The title compound (yield 71%) was obtained as a solid according to the method of Example 2 using amino) cyclohexanecarboxylate.
Example 60 N-[(1R, 2S, 5S) -2-Hydroxy-5- (methoxycarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-({[1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl} amino) obtained in Example 59 The title compound (99% yield) was obtained according to the method of Example 1 using cyclohexanecarboxylic acid and commercially available (aminooxy) methane hydrochloride.
Example 61 N-[(1R, 2S, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-({[1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl} amino) obtained in Example 59 The title compound (yield 100%) was obtained according to the method of Example 3 using cyclohexanecarboxylic acid and commercially available ethylamine (2.0 M tetrahydrofuran solution).
（実施例６２）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－２－ヒドロキシ－５－（メチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５９で得られた（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸および市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例３の方法に準じて標記化合物（収率７３％）を得た。
（実施例６３）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－５－カルバモイル－２－ヒドロキシシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５９で得られた（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸および市販の７Ｎアンモニア－メタノールを用いて、実施例３の方法に準じて標記化合物（収率９６％）を得た。
（実施例６４）Ｎ－｛（１Ｒ，２Ｓ，５Ｓ)－２－ヒドロキシ－５－［（２－ヒドロキシエチル）カルバモイル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例５９で得られた（１Ｓ，３Ｒ，４Ｓ)－４－ヒドロキシ－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル]ピペリジン－４－イル）カルボニル}アミノ)シクロヘキサンカルボン酸および市販の２－アミノエタノールを用いて、実施例３の方法に準じて標記化合物（収率８６％）を得た。 Example 62 N-[(1R, 2S, 5S) -2-hydroxy-5- (methylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide (1S, 3R, 4S) -4-Hydroxy-3-({[1- (6-Methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl} amino) obtained in Example 59 The title compound (73% yield) was obtained according to the method of Example 3 using cyclohexanecarboxylic acid and commercially available methylamine (2.0 M tetrahydrofuran solution).
Example 63 N-[(1R, 2S, 5S) -5-carbamoyl-2-hydroxycyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Example 59 (1S, 3R, 4S) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl) carbonyl} amino) cyclohexanecarboxylic acid obtained in The title compound (yield 96%) was obtained according to the method of Example 3 using commercially available 7N ammonia-methanol.
Example 64 N-{(1R, 2S, 5S) -2-hydroxy-5-[(2-hydroxyethyl) carbamoyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) Piperidine-4-carboxamide (1S, 3R, 4S) -4-hydroxy-3-({[1- (6-methyl-3-phenylquinolin-2-yl] piperidin-4-yl] obtained in Example 59 The title compound (yield 86%) was obtained according to the method of Example 3 using) carbonyl} amino) cyclohexanecarboxylic acid and commercially available 2-aminoethanol.
（実施例６５）Ｎ－［（１Ｒ，５Ｓ)－５－（エチルカルバモイル）－２－オキソシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５０で得られたＮ－［（１Ｒ，２Ｓ，５Ｓ)－２－アミノ－５－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル)ピペリジン－４－カルボキサミド（１５４ｍｇ，０．２９９ｍｍｏｌ）のメタノール（２．５ｍＬ）溶液に、市販の３，５－ジ－ｔｅｒｔ－ブチルシクロヘキサ－３，５－ジエン－１，２－ジオン（８６．２ｍｇ，０．３９１ｍｍｏｌ）を加え、４０℃にて１時間攪拌した。反応混合物にテトラヒドロフラン（１ｍＬ）、水（０．５ｍＬ）およびシュウ酸二水和物（７４．９ｍｇ，０．５９４ｍｍｏｌ）を加え、室温にて１時間攪拌した。減圧下にて溶媒を留去した後、０．１Ｎ塩酸水溶液を加え、エーテルにて洗浄した。得られた混合物に１Ｎ水酸化ナトリウム水溶液を加え、ジクロロメタンにて抽出した。有機層を合わせ飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル（１０％メタノール）＝４／１－０／１）にて精製した後、アセトニトリルにて洗浄し、標記化合物４０．１ｍｇ（収率２７％）を固体として得た。
（実施例６６）Ｎ－［（１Ｓ，２Ｒ）－２－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　市販の［（１Ｒ，２Ｓ）－２－アミノシクロヘキシル］メタノールおよび参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率８３％）を固体として得た。
（実施例６７）Ｎ－［（１Ｓ，２Ｒ）－４－フルオロ－２－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５５で得られたベンジル　［（１Ｓ，２Ｒ）－４－フルオロ－２－（ヒドロキシメチル）シクロヘキシル］カーバメートを用いて、参考例１０の方法に準じて得られた化合物をＮ，Ｎ－ジメチルホルムアミドに溶解した。本反応液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率４９％）を固体として得た。 Example 65 N-[(1R, 5S) -5- (Ethylcarbamoyl) -2-oxocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example N-[(1R, 2S, 5S) -2-amino-5- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide obtained in 50 (154 mg, 0.299 mmol) in methanol (2.5 mL) was added commercially available 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (86.2 mg, 0.391 mmol). ) And stirred at 40 ° C for 1 hour. Tetrahydrofuran (1 mL), water (0.5 mL) and oxalic acid dihydrate (74.9 mg, 0.594 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. After the solvent was distilled off under reduced pressure, a 0.1N hydrochloric acid aqueous solution was added, and the mixture was washed with ether. A 1N aqueous sodium hydroxide solution was added to the resulting mixture, and the mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate (10% methanol) = 4 / 1-0 / 1) and then washed with acetonitrile. Thus, 40.1 mg (yield 27%) of the title compound was obtained as a solid.
Example 66 N-[(1S, 2R) -2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Commercially available [(1R, 2S) -2-Aminocyclohexyl] methanol and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 were used according to the method of Example 1. The title compound (yield 83%) was obtained as a solid.
Example 67 N-[(1S, 2R) -4-fluoro-2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example Using benzyl [(1S, 2R) -4-fluoro-2- (hydroxymethyl) cyclohexyl] carbamate obtained in 55, the compound obtained according to the method of Reference Example 10 was converted to N, N-dimethylformamide. Dissolved. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 49%) as a solid.
（実施例６８）Ｎ－［（１Ｓ，２Ｒ）－２－（ヒドロキシメチル）－４－オキソシクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５６で得られたベンジル　［（７Ｒ，８Ｓ）－７－（ヒドロキシメチル）－１，４－ジオキサスピロ［４．５］デカ－８－イル］カーバメートを用いて、参考例１０の方法に準じて得られた化合物をＮ，Ｎ－ジメチルホルムアミドに溶解した。本反応溶液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて縮合体を得た。得られた化合物を用いて、参考例５３の方法に準じて標記化合物（収率４４％）を固体として得た。
（実施例６９）Ｎ－［（１Ｓ，２Ｒ）－４，４－ジフルオロ－２－（ヒドロキシメチル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５９で得られたｔｅｒｔ－ブチル　［（１Ｓ，２Ｒ）－４，４－ジフルオロ－２－（ヒドロキシメチル）シクロヘキシル］カーバメートを用いて、参考例５の方法に準じて得られた化合物をＮ，Ｎ－ジメチルホルムアミドに溶解した。本反応溶液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて標記化合物（収率７９％）を固体として得た。
（実施例７０）Ｎ－［（３Ｒ，４Ｒ）－４－（ヒドロキシメチル）テトラヒドロ－２Ｈ－ピラン－３－イル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６０で得られたｔｅｒｔ－ブチル　［（３Ｒ，４Ｒ）－４－（ヒドロキシメチル）テトラヒドロ－２Ｈ－ピラン－３－イル］カーバメートを用いて、
参考例５の方法に準じて得られた化合物をＮ，Ｎ－ジメチルホルムアミドに溶解した。本反応溶液および参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸を用いて、実施例１の方法に準じて実施例１の方法に準じて標記化合物（収率４７％）を固体として得た。 Example 68 N-[(1S, 2R) -2- (hydroxymethyl) -4-oxocyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example Using benzyl [(7R, 8S) -7- (hydroxymethyl) -1,4-dioxaspiro [4.5] dec-8-yl] carbamate obtained in 56, according to the method of Reference Example 10 The resulting compound was dissolved in N, N-dimethylformamide. Using this reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, a condensate was obtained according to the method of Example 1. . Using the obtained compound, the title compound (yield 44%) was obtained as a solid according to the method of Reference Example 53.
Example 69 N-[(1S, 2R) -4,4-Difluoro-2- (hydroxymethyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Using the tert-butyl [(1S, 2R) -4,4-difluoro-2- (hydroxymethyl) cyclohexyl] carbamate obtained in Reference Example 59, the compound obtained according to the method of Reference Example 5 was converted to N , N-dimethylformamide. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the title compound (yield) was obtained according to the method of Example 1. 79%) was obtained as a solid.
Example 70 N-[(3R, 4R) -4- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide Using tert-butyl [(3R, 4R) -4- (hydroxymethyl) tetrahydro-2H-pyran-3-yl] carbamate obtained in Reference Example 60,
The compound obtained according to the method of Reference Example 5 was dissolved in N, N-dimethylformamide. Using the reaction solution and 1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2, the method of Example 1 according to the method of Example 1 The title compound (47% yield) was obtained as a solid.
（実施例７１）エチル　［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］アセテート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例６１で得られたエチル　［（１Ｒ，３Ｓ）－３－アミノシクロペンチル］アセテート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８９％）を固体として得た。
（実施例７２）［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］酢酸
　実施例７１で得られたエチル　［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル）アセテートを用いて、実施例２の方法に準じて標記化合物を定量的に得た。
（実施例７３）Ｎ－｛（１Ｓ，３Ｒ)－３－［２－（メチルアミノ）－２－オキソエチル］シクロペンチル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例７２で得られた［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］酢酸および市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例５の方法に準じて標記化合物（収率７９％）を固体として得た。 Example 71 Ethyl [(1R, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl] acetate In Reference Example 2 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained and ethyl [(1R, 3S) -3-aminocyclopentyl] acetate hydrochloride obtained in Reference Example 61 were used. Was used to give the title compound (89% yield) as a solid according to the method of Example 1.
Example 72 [(1R, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl] acetic acid Obtained in Example 71 Example 2 Using the obtained ethyl [(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl) acetate The title compound was obtained quantitatively according to the above method.
Example 73 N-{(1S, 3R) -3- [2- (methylamino) -2-oxoethyl] cyclopentyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide [(1R, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl] acetic acid obtained in Example 72 and The title compound (yield 79%) was obtained as a solid according to the method of Example 5 using commercially available methylamine (2.0 M tetrahydrofuran solution).
（実施例７４）Ｎ－［（１Ｓ，３Ｒ)－３－（２－アミノ－２－オキソエチル）シクロペンチル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例７２で得られた［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］酢酸および市販の７Ｎアンモニア－メタノールを用いて、実施例３の方法に準じて標記化合物（収率９３％）を得た。
（実施例７５）Ｎ－［（１Ｓ，３Ｒ)－３－｛２－［（２－ヒドロキシエチル）アミノ］－２－オキソエチル｝シクロペンチル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例７２で得られた［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］酢酸および市販の２－アミノエタノールを用いて、実施例１の方法に準じて標記化合物（収率８４％）を固体として得た。
（実施例７６）メチル　２－メチル－Ｎ－｛［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロペンチル］アセチル｝アラニネート
　実施例７２で得られた［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］酢酸および市販のメチル　２－メチルアラニネート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８８％）を固体として得た。
（実施例７７）エチル　２－メチル－２－［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］プロパノエート
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例６３で得られたエチル　２－［（１Ｒ，３Ｓ）－３－アミノシクロペンチル］－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率６８％）を得た。 Example 74 N-[(1S, 3R) -3- (2-amino-2-oxoethyl) cyclopentyl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide [(1R, 3S) -3-({[1- (6-Methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl] acetic acid obtained in Example 72 and commercially available 7N The title compound (yield 93%) was obtained according to the method of Example 3 using ammonia-methanol.
Example 75 N-[(1S, 3R) -3- {2-[(2-hydroxyethyl) amino] -2-oxoethyl} cyclopentyl] -1- (6-methyl-3-phenylquinoline-2- Yl) piperidine-4-carboxamide [(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino obtained in Example 72 ) Cyclopentyl] The title compound (yield 84%) was obtained as a solid according to the method of Example 1 using acetic acid and commercially available 2-aminoethanol.
Example 76 Methyl 2-methyl-N-{[(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino ) Cyclopentyl] acetyl} alaninate [(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) obtained in Example 72 The title compound (yield 88%) was obtained as a solid according to the method of Example 1 using cyclopentyl] acetic acid and commercially available methyl 2-methylalaninate hydrochloride.
Example 77 Ethyl 2-methyl-2-[(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl ] Propanoate 1- (6-Methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 2 and ethyl 2-[(1R, 3S) -3 obtained in Reference Example 63 Using -aminocyclopentyl] -2-methylpropanoate, the title compound (yield 68%) was obtained according to the method of Example 1.
（実施例７８）２－メチル－２－［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロペンチル］プロパン酸
　実施例７７で得られたエチル　２－メチル－２－［（１Ｒ，３Ｓ)－３－（｛［１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４イル］カルボニル｝アミノ）シクロペンチル］プロパノエートを用いて、実施例２の方法に準じて標記化合物（収率１００％）を固体として得た。
（実施例７９）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－（４－スルファモイルベンジル）ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および市販の４－（アミノメチル）ベンゼンスルホンアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率１００％）を固体として得た。
（実施例８０）１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［４－（メチルスルファモイル）ベンジル］ピペリジン－４－カルボキサミド
　参考例２で得られた１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸および市販の４－（アミノメチル）－Ｎ－メチルベンゼンスルホンアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８７％）を固体として得た。
（実施例８１）Ｎ－｛１－［２－（メトキシアミノ）－２－オキソエチル］ピペリジン－４－イル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６４で得られた１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－ピペリジン－４－イルピペリジン－４－カルボキサミド（４９８ｍｇ，１．１６ｍｍｏｌ）および炭酸カリウム（２４１ｍｇ，１．７４ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１２ｍＬ）溶液に、氷冷下、ブロモ酢酸エチル（０．１３５ｍＬ，１．２２ｍｍｏｌ）を加え、室温にて１８時間攪拌した。反応混合物に酢酸エチルを加え、水および飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）にて精製し、アモルファス状物５７７ｍｇ（９６％）を得た。得られたアモルファス状物を用いて、実施例２の方法に準じて固体（１００％）を得た。得られた固体および市販の（アミノオキシ）メタン　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率３９％）を固体として得た。 Example 78 2-Methyl-2-[(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclopentyl ] Propanoic acid Ethyl 2-methyl-2-[(1R, 3S) -3-({[1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] obtained in Example 77] Using carbonyl} amino) cyclopentyl] propanoate, the title compound (yield 100%) was obtained as a solid according to the method of Example 2.
Example 79 1- (6-Methyl-3-phenylquinolin-2-yl) -N- (4-sulfamoylbenzyl) piperidine-4-carboxamide 1- (6-methyl) obtained in Reference Example 2 -3-Phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 4- (aminomethyl) benzenesulfonamide hydrochloride according to the method of Example 1 (yield 100%) Was obtained as a solid.
Example 80 1- (6-Methyl-3-phenylquinolin-2-yl) -N- [4- (methylsulfamoyl) benzyl] piperidine-4-carboxamide 1- ( According to the method of Example 1, using 6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid and commercially available 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride The compound (yield 87%) was obtained as a solid.
Example 81 N- {1- [2- (methoxyamino) -2-oxoethyl] piperidin-4-yl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinolin-2-yl) -N-piperidin-4-ylpiperidin-4-carboxamide (498 mg, 1.16 mmol) and potassium carbonate (241 mg, 1) obtained in Reference Example 64 .74 mmol) in N, N-dimethylformamide (12 mL) was added with ethyl bromoacetate (0.135 mL, 1.22 mmol) under ice cooling and stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain 577 mg (96%) of an amorphous substance. Using the obtained amorphous material, a solid (100%) was obtained according to the method of Example 2. The title compound (yield 39%) was obtained as a solid according to the method of Example 3 using the obtained solid and commercially available (aminooxy) methane hydrochloride.
（実施例８２）Ｎ－［（３Ｓ）－１－（アミノスルホニル）ピペリジン－３－イル］－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　市販のクロロスルホニルイソシアネート（３１．４ｍＬ，０．３６４ｍｍｏｌ）のジクロロメタン溶液に、氷冷下、ｔｅｒｔ－ブチルアルコール（１２０ｍｇ，０．３６４ｍｍｏｌ）を加え、窒素雰囲気下２５分間攪拌した。反応混合物に参考例６５で得られた１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（３Ｓ）－ピペリジン－３－イル］ピペリジン－４－カルボキサミド（１２０ｍｇ，０．２８０ｍｍｏｌ）およびトリエチルアミン（３９μＬ，０．２８０ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液を滴下し、室温にて１４時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－０／１）にて精製し、油状物８５．０ｍｇ（収率５０％）を得た。得られた油状物を用いて、参考例５の方法に準じて標記化合物（収率７３％）を得た。
（実施例８３）３－ヒドロキシ－Ｎ－｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６６で得られたエチル　３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキシレート（低極性体）を用いて、参考例２の方法に準じて固体（収率９３％）を得た。得られた固体および参考例７で得られた２－（シス－４－アミノシクロヘキシル）－Ｎ－メチルアセトアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率５２％）を得た。 Example 82 N-[(3S) -1- (Aminosulfonyl) piperidin-3-yl] -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Commercially available chlorosulfonyl To a dichloromethane solution of isocyanate (31.4 mL, 0.364 mmol) was added tert-butyl alcohol (120 mg, 0.364 mmol) under ice cooling, and the mixture was stirred for 25 minutes under a nitrogen atmosphere. To the reaction mixture, 1- (6-methyl-3-phenylquinolin-2-yl) -N-[(3S) -piperidin-3-yl] piperidine-4-carboxamide (120 mg, 0. 280 mmol) and triethylamine (39 μL, 0.280 mmol) in dichloromethane (5 mL) were added dropwise and stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1-0 / 1) to give 85.0 mg of oil (yield 50%). ) Using the resulting oily matter, the title compound (yield 73%) was obtained according to the method of Reference Example 5.
Example 83 3-Hydroxy-N- {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide The method of Reference Example 2 using ethyl 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylate (low polarity) obtained in Reference Example 66 According to, a solid (yield 93%) was obtained. Using the obtained solid and 2- (cis-4-aminocyclohexyl) -N-methylacetamide hydrochloride obtained in Reference Example 7, the title compound (yield 52%) was obtained according to the method of Example 1. Obtained.
（実施例８４）３－ヒドロキシ－Ｎ－｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６８で得られた３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸（高極性体由来）および参考例７で得られた２－（シス－４－アミノシクロヘキシル）－Ｎ－メチルアセトアミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率６９％）を得た。
（実施例８５）Ｎ－［（１Ｓ，３Ｓ)－３－（エチルカルバモイル）シクロヘキシル］－３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６８で得られた３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸（高極性体由来）および参考例２５で得られた［（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（ジアステレオマー混合物、収率９２％）を得た。 Example 84 3-Hydroxy-N- {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained from Reference Example 68 (derived from highly polar substance) and 2 obtained in Reference Example 7 The title compound (yield 69%) was obtained using-(cis-4-aminocyclohexyl) -N-methylacetamide hydrochloride according to the method of Example 1.
Example 85 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxamide Reference Example 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained from No. 68 (derived from a highly polar substance) and obtained in Reference Example 25 [(1S, 3S ) Using 3-amino-N-ethylcyclohexanecarboxamide, the title compound (diastereomer mixture, yield 92%) was obtained according to the method of Example 1.
（実施例８６）３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ)－３－（５－オキソ－４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例６８で得られた３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸（高極性体由来）および参考例４１で得られた３－［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］－１，２，４－オキサジアゾール－５（４Ｈ）－オン　塩酸塩を用いて、実施例１の方法に準じて標記化合物（ジアステレオマー混合物、収率６９％）を得た。
（実施例８７）Ｎ－［（１Ｒ，２Ｓ，５Ｓ)－５－（エチルカルバモイル）－２－ヒドロキシシクロヘキシル］－３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例６８で得られた３－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボン酸（高極性体由来）および参考例４８で得られたエチル　（１Ｓ，３Ｒ，４Ｓ）－３－アミノ－４－ヒドロキシシクロヘキサンカルボキシレート　塩酸塩を用いて、実施例１の方法に準じて固体（収率９５％）を得た。得られた固体を用いて、実施例２の方法に準じて固体（収率１００％）を得た。得られた固体および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液）用いて、実施例３の方法に準じて標記化合物（ジアステレオマー混合物、収率９６％）を得た。
（実施例８８）Ｎ－［（１Ｓ，３Ｓ)－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノリン－２－イル）－１，２，３，６－テトラヒドロピリジン－４－カルボキサミド
　参考例６９で得られた１－（６－メチル－３－フェニルキノリン－２－イル）－１，２，３，６－テトラヒドロピリジン－４－カルボン酸および参考例２５で得られた［（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率７１％）を得た。 Example 86 3-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) -N-[(1S, 3S) -3- (5-oxo-4,5-dihydro-1, 2,4-oxadiazol-3-yl) cyclohexyl] piperidine-4-carboxamide 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4- obtained in Reference Example 68 Carboxylic acid (derived from highly polar substance) and 3-[(1S, 3S) -3-aminocyclohexyl] -1,2,4-oxadiazol-5 (4H) -one hydrochloride obtained in Reference Example 41 Used to give the title compound (diastereomer mixture, yield 69%) according to the method of Example 1.
Example 87 N-[(1R, 2S, 5S) -5- (Ethylcarbamoyl) -2-hydroxycyclohexyl] -3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine -4-carboxamide 3-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4-carboxylic acid obtained from Reference Example 68 (derived from highly polar substance) and obtained in Reference Example 48 Using ethyl (1S, 3R, 4S) -3-amino-4-hydroxycyclohexanecarboxylate hydrochloride, a solid (yield 95%) was obtained according to the method of Example 1. Using the obtained solid, a solid (yield 100%) was obtained according to the method of Example 2. Using the obtained solid and commercially available ethylamine (2.0 M tetrahydrofuran solution), the title compound (diastereomer mixture, yield 96%) was obtained according to the method of Example 3.
Example 88 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine -4-carboxamide obtained in 1- (6-methyl-3-phenylquinolin-2-yl) -1,2,3,6-tetrahydropyridine-4-carboxylic acid obtained in Reference Example 69 and Reference Example 25 [(1S, 3S) -3-Amino-N-ethylcyclohexanecarboxamide was used according to the method of Example 1 to obtain the title compound (yield 71%).
（実施例８９）エチル　［シス－４－（｛［４－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート
　参考例７０で得られたエチル　（シス－４－｛［（４－ヒドロキシピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）アセテート　塩酸塩および市販の２－クロロ－６－メチル－３－フェニルキノリンを用いて、参考例１の方法に準じて標記化合物（収率５７％）を固体として得た。
（実施例９０）［シス－４－（｛［４－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸
　実施例８９で得られたエチル　［シス－４－（｛［４－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテートを用いて、実施例２の方法に準じて標記化合物（収率１００％）を固体として得た。
（実施例９１）４－ヒドロキシ－Ｎ－｛シス－４－［２－（メチルアミノ）－２－オキソエチル］シクロヘキシル｝－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－カルボキサミド
　実施例９０で得られた［シス－４－（｛［４－ヒドロキシ－１－（６－メチル－３－フェニルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸および市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例５の方法に準じて標記化合物（収率８６％）を得た。 Example 89 Ethyl [cis-4-({[4-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate Reference Example 70 Using ethyl (cis-4-{[(4-hydroxypiperidin-4-yl) carbonyl] amino} cyclohexyl) acetate hydrochloride obtained in step 1 and commercially available 2-chloro-6-methyl-3-phenylquinoline, The title compound (yield 57%) was obtained as a solid according to the method of Reference Example 1.
Example 90 [cis-4-({[4-Hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid In Example 89 Using the obtained ethyl [cis-4-({[4-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate The title compound (yield 100%) was obtained as a solid according to the method of Example 2.
Example 91 4-Hydroxy-N- {cis-4- [2- (methylamino) -2-oxoethyl] cyclohexyl} -1- (6-methyl-3-phenylquinolin-2-yl) piperidine-4 -Carboxamide [cis-4-({[4-hydroxy-1- (6-methyl-3-phenylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid obtained in Example 90 The title compound (yield 86%) was obtained according to the method of Example 5 using commercially available methylamine (2.0 M tetrahydrofuran solution).
（実施例９２）１－［３－（４－フルオロフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例７３で得られたエチル　１－［３－（４－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例２４で得られた［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］メタノール　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率７８％）を得た。
（実施例９３）１－［３－（３－フルオロフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例７４で得られたエチル　１－［３－（３－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例２４で得られた［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］メタノール　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率６３％）を得た。
（実施例９４）１－［３－（２－フルオロフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（ヒドロキシメチル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例７５で得られたエチル　１－［３－（２－フルオロフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例２４で得られた［（１Ｓ，３Ｓ）－３－アミノシクロヘキシル］メタノール　塩酸塩を用いて、実施例３の方法に準じて標記化合物を得た。 Example 92 1- [3- (4-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (4-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 73, an amorphous product was prepared according to the method of Reference Example 2. Obtained. Using the obtained amorphous substance and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, the title compound (yield 78%) was prepared according to the method of Example 3. Obtained.
Example 93 1- [3- (3-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (3-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 74, an amorphous product was prepared according to the method of Reference Example 2. Obtained. Using the obtained amorphous substance and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, the title compound (yield 63%) was obtained according to the method of Example 3. Obtained.
Example 94 1- [3- (2-Fluorophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (hydroxymethyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- [3- (2-fluorophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Example 75, an amorphous product was prepared according to the method of Reference Example 2. Obtained. Using the obtained amorphous product and [(1S, 3S) -3-aminocyclohexyl] methanol hydrochloride obtained in Reference Example 24, the title compound was obtained according to the method of Example 3.
（実施例９５）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－［６－メチル－３－（３－メチルブチ－１－イン－１－イル）キノリン－２－イル］ピペリジン－４－カルボキサミド
　参考例７６で得られたエチル　１－［６－メチル－３－（３－メチルブチ－１－イン－１－イル）キノリン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例２３で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例３の方法に準じて標記化合物（収率４９％）を得た。
（実施例９６）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－［３－（３－メトキシプロプ－１－イン－１－イル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキサミド
　参考例７７で得られたエチル　１－［３－（３－メトキシプロプ－１－イン－１－イル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じて油状物を得た。得られた油状物および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例３の方法に準じて標記化合物（収率８３％）を固体として得た。
（実施例９７）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－プロプ－１－イン－１－イルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例７８で得られたエチル　１－（６－メチル－３－プロプ－１－イン－１－イルキノリン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例２の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例３の方法に準じて標記化合物（収率６３％）を固体として得た。 Example 95 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- [6-Methyl-3- (3-methylbut-1-in-1-yl) quinolin-2-yl] piperidine- 4-Carboxamide Reference was made using ethyl 1- [6-methyl-3- (3-methylbut-1-yn-1-yl) quinolin-2-yl] piperidine-4-carboxylate obtained in Reference Example 76. An amorphous material was obtained according to the method of Example 2. Using the obtained amorphous product and (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23, the title compound (yield 49%) was obtained according to the method of Example 3. .
Example 96 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- [3- (3-methoxyprop-1-in-1-yl) -6-methylquinolin-2-yl ] Piperidine-4-carboxamide Using ethyl 1- [3- (3-methoxyprop-1-in-1-yl) -6-methylquinolin-2-yl] piperidine-4-carboxylate obtained in Reference Example 77 According to the method of Reference Example 2, an oily substance was obtained. Using the obtained oil and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25, the title compound (yield 83%) was solidified according to the method of Example 3. Got as.
Example 97 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-prop-1-in-1-ylquinolin-2-yl) piperidine-4- Carboxamide In accordance with the method of Reference Example 2, using ethyl 1- (6-methyl-3-prop-1-in-1-ylquinolin-2-yl) piperidine-4-carboxylate obtained in Reference Example 78 An amorphous product was obtained. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25, the title compound (yield 63%) was obtained according to the method of Example 3. Obtained as a solid.
（実施例９８）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－［３－（３－シアノフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボキサミド
　参考例７９で得られた１－［３－（３－シアノフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸および参考例２３で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９７％）を固体として得た。
（実施例９９）１－［３－（３－シアノフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例７９で得られた１－［３－（３－シアノフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率９８％）を固体として得た。
（実施例１００）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－イソプロペニル－６－メチルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例８０で得られた１－（３－イソプロペニル－６－メチルキノリン－２－イル）ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率９４％）を固体として得た。 Example 98 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- [3- (3-cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxamide In Reference Example 79 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid obtained and (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23 Using the salt, the title compound (yield 97%) was obtained as a solid according to the method of Example 1.
Example 99 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference 1- [3- (3-Cyanophenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid obtained in Example 79 and (1S, 3S) -3-amino obtained in Reference Example 25 The title compound (yield 98%) was obtained as a solid according to the method of Example 1 using -N-ethylcyclohexanecarboxamide.
Example 100 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-isopropenyl-6-methylquinolin-2-yl) piperidine-4-carboxamide Obtained in Reference Example 80 1- (3-Isopropenyl-6-methylquinolin-2-yl) piperidine-4-carboxylic acid obtained and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25 were used. According to the method of Example 1, the title compound (yield 94%) was obtained as a solid.
（実施例１０１）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－ピリジン－２－イルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例８１で得られた１－［６－メチル－３－（ピリジン－２－イル）キノリン－２－イル］ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８４％）を得た。
（実施例１０２）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－カルボキサミド
　参考例８３で得られたＮ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－｛４－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボキサミド（９７７ｍｇ，１．９９ｍｍｏｌ）のエタノール（１５ｍＬ）溶液に、３Ｎ塩酸水溶液（１ｍＬ）を加え室温にて１５時間攪拌した。反応混合物を減圧濃縮して得られた残渣に水を加え、クロロホルムにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝２４／１）にて精製し、標記化合物７２８ｍｇ（収率６５％）を得た。 Example 101 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-pyridin-2-ylquinolin-2-yl) piperidine-4-carboxamide Reference Example 81 1- [6-Methyl-3- (pyridin-2-yl) quinolin-2-yl] piperidine-4-carboxylic acid obtained in 1) and (1S, 3S) -3-amino- obtained in Reference Example 25 The title compound (yield 84%) was obtained according to the method of Example 1 using N-ethylcyclohexanecarboxamide.
Example 102 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidine -4-carboxamide N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3- {4- [2- (tetrahydro-2H-pyran) obtained in Reference Example 83 -2-yloxy) ethoxy] phenyl} quinolin-2-yl) piperidine-4-carboxamide (977 mg, 1.99 mmol) in ethanol (15 mL) was added 3N aqueous hydrochloric acid (1 mL) and stirred at room temperature for 15 hours. . Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was extracted with chloroform. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 24/1) to obtain 728 mg (yield 65%) of the title compound.
（実施例１０３）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－｛４－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－カルボキサミド
　参考例８６で得られたｔｅｒｔ－ブチル　｛４－［２－（４－｛［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］カルバモイル｝ピペリジン－１－イル）－６－メチルキノリン－３－イル］フェニル｝［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］カーバメート（５７０ｍｇ，０．７６８ｍｍｏｌ）のジクロロメタン（１５ｍＬ）溶液に、トリフルオロ酢酸（５ｍＬ）および水（０．５ｍＬ）を加え、室温にて２時間攪拌した。反応混合物を減圧濃縮し、得られた残渣に水を加えた後、ジクロロメタンにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝９／１）にて精製し、標記化合物３３０ｍｇ（収率７７％）を得た。
（実施例１０４）１－［３－（４－アミノフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例８４で得られたエチル　１－（３－｛４－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－カルボキシレートを用いて、実施例２の方法に準じて固体（収率１００％）を得た。得られた固体および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じてアモルファス状物（６９％）を得た。得られたアモルファス状物を用いて、実施例１０３の方法に準じて標記化合物（収率９６％）を得た。 Example 103 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3- {4-[(2-hydroxyethyl) amino] phenyl} -6-methylquinoline-2- Yl) piperidine-4-carboxamide tert-butyl obtained in Reference Example 86 {4- [2- (4-{[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamoyl} piperidin-1-yl) To a solution of -6-methylquinolin-3-yl] phenyl} [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] carbamate (570 mg, 0.768 mmol) in dichloromethane (15 mL), trifluoroacetic acid (5 mL) And water (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 9/1) to obtain 330 mg (yield 77%) of the title compound.
Example 104 1- [3- (4-Aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference Using the ethyl 1- (3- {4-[(tert-butoxycarbonyl) amino] phenyl} -6-methylquinolin-2-yl) piperidine-4-carboxylate obtained in Example 84, A solid (yield 100%) was obtained according to the method. Using the obtained solid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25, an amorphous substance (69%) was obtained according to the method of Example 1. Using the resulting amorphous material, the title compound (yield 96%) was obtained according to the method of Example 103.
（実施例１０５）１－（３－｛４－［（ジメチルスルファモイル）アミノ］フェニル｝－６－メチルキノリン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　実施例１０４で得られた１－［３－（４－アミノフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド（１６０ｍｇ，０．３１２ｍｍｏｌ）のピリジンに溶液に、少量のＮ，Ｎ－ジメチルピリジン－４－アミンおよびジメチルスルファモイルクロリド（１５０μＬ，１．４０ｍｍｏｌ）を加え、室温にて２２時間攪拌した。反応混合物を減圧濃縮して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝１００／０－１９／１）にて精製し、標記化合物８０．８ｍｇ（収率４２％）を得た。
（実施例１０６）１－｛３－［４－（アセチルアミノ）フェニル］－６－メチルキノリン－２－イル｝－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　実施例１０４で得られた１－［３－（４－アミノフェニル）－６－メチルキノリン－２－イル］－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド（５０．０ｍｇ，０．０９７３ｍｍｏｌ）のピリジン溶液に、窒素雰囲気下、無水酢酸（０．０１８４ｍＬ，０．１９５ｍｍｏｌ）を加え、室温にて３．５時間攪拌した。反応混合物を減圧濃縮して得られた残渣に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝９７／３）にて精製し、標記化合物４６．８ｍｇ（収率８７％）を得た。 Example 105 1- (3- {4-[(Dimethylsulfamoyl) amino] phenyl} -6-methylquinolin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) Cyclohexyl] piperidine-4-carboxamide 1- [3- (4-aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) obtained in Example 104 ) Cyclohexyl] piperidine-4-carboxamide (160 mg, 0.312 mmol) in pyridine, a small amount of N, N-dimethylpyridin-4-amine and dimethylsulfamoyl chloride (150 μL, 1.40 mmol) were added to room temperature. For 22 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 100 / 0-19 / 1) to obtain 80.8 mg (yield 42%) of the title compound. .
Example 106 1- {3- [4- (acetylamino) phenyl] -6-methylquinolin-2-yl} -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4 -Carboxamide 1- [3- (4-Aminophenyl) -6-methylquinolin-2-yl] -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine obtained in Example 104 Acetic anhydride (0.0184 mL, 0.195 mmol) was added to a pyridine solution of 4-carboxamide (50.0 mg, 0.0973 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 97/3) to obtain 46.8 mg (yield 87%) of the title compound.
（実施例１０７）エチル　２－（シス－４－｛［（１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパノエート
　参考例８２で得られた１－（６－メチル－３－｛４－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸および参考例１７で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて油状物（８９％）を得た。得られた油状物を用いて、実施例１０２の方法に準じて標記化合物（収率１００％）を得た。
（実施例１０８）２－（シス－４－｛［（１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパン酸
　実施例１０７で得られたエチル　２－（シス－４－｛［（１－｛３－［４－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパノエートを用いて、実施例２の方法に準じて標記化合物（収率７４％）を固体として得た。 Example 107 Ethyl 2- (cis-4-{[(1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidin-4-yl) carbonyl] Amino} cyclohexyl) -2-methylpropanoate 1- (6-methyl-3- {4- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinoline obtained in Reference Example 82 2-yl) piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 and an oily substance according to the method of Example 1 (89%) was obtained. The title compound (yield 100%) was obtained according to the method of Example 102 using the obtained oil.
Example 108 2- (cis-4-{[(1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidin-4-yl) carbonyl] amino } Cyclohexyl) -2-methylpropanoic acid Ethyl 2- (cis-4-{[(1- {3- [4- (2-hydroxyethoxy) phenyl] -6-methylquinoline-2] obtained in Example 107 Using -yl} piperidin-4-yl) carbonyl] amino} cyclohexyl) -2-methylpropanoate, the title compound (yield 74%) was obtained as a solid according to the method of Example 2.
（実施例１０９）エチル　２－［シス－４－（｛［１－（３－｛４－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパノエート
　参考例８５で得られた１－［３－（４－｛（ｔｅｒｔ－ブトキシカルボニル）［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アミノ｝フェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸および参考例１７で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて油状物（８９％）を得た。得られた油状物を用いて、実施例１０３の方法に準じて標記化合物（収率８８％）を得た。
（実施例１１０）２－［シス－４－（｛［１－（３－｛４－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパン酸
（実施例１１１）２－｛シス－４－［（｛１－［３－（４－アミノフェニル）－６－メチルキノリン－２－イル］ピペリジン－４－イル｝カルボニル）アミノ］シクロヘキシル｝－２－メチルプロパン酸
　実施例１０９で得られたエチル　２－［シス－４－（｛［１－（３－｛４－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパノエートを用いて、実施例２の方法に準じて実施例１１０（収率１９％）を得た。また、実施例１１１（収率８．４％）を得た。 Example 109 Ethyl 2- [cis-4-({[1- (3- {4-[(2-hydroxyethyl) amino] phenyl} -6-methylquinolin-2-yl) piperidin-4-yl ] Carbonyl} amino) cyclohexyl] -2-methylpropanoate 1- [3- (4-{(tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy)] obtained in Reference Example 85 [Ethyl] amino} phenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 According to the method of Example 1, an oily substance (89%) was obtained. Using the obtained oil, the title compound (yield 88%) was obtained according to the method of Example 103.
Example 110 2- [cis-4-({[1- (3- {4-[(2-hydroxyethyl) amino] phenyl} -6-methylquinolin-2-yl) piperidin-4-yl] Carbonyl} amino) cyclohexyl] -2-methylpropanoic acid (Example 111) 2- {cis-4-[({1- [3- (4-aminophenyl) -6-methylquinolin-2-yl] piperidine- 4-yl} carbonyl) amino] cyclohexyl} -2-methylpropanoic acid ethyl 2- [cis-4-({[1- (3- {4-[(2-hydroxyethyl) amino] obtained in Example 109 ]]}}-6-methylquinolin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2-methylpropanoate according to the method of Example 2 To obtain the rate 19%). Moreover, Example 111 (yield 8.4%) was obtained.
（実施例１１２）エチル　２－（シス－４－｛［（１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパノエート
　参考例８８で得られた１－（６－メチル－３－｛３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸および参考例１７で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて油状物（８０％）を得た。得られた油状物を用いて、実施例１０２の方法に準じて標記化合物（収率８１％）を得た。
（実施例１１３）２－（シス－４－｛［（１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパン酸
　実施例１１２で得られたエチル　２－（シス－４－｛［（１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－イル）カルボニル］アミノ｝シクロヘキシル）－２－メチルプロパノエートを用いて、実施例２の方法に準じて標記化合物（収率６０％）を得た。 Example 112 Ethyl 2- (cis-4-{[(1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidin-4-yl) carbonyl] Amino} cyclohexyl) -2-methylpropanoate 1- (6-methyl-3- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinoline obtained in Reference Example 88 2-yl) piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Reference Example 17 and an oily substance according to the method of Example 1 (80%) was obtained. Using the obtained oil, the title compound (yield 81%) was obtained according to the method of Example 102.
Example 113 2- (cis-4-{[(1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidin-4-yl) carbonyl] amino } Cyclohexyl) -2-methylpropanoic acid Ethyl 2- (cis-4-{[(1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinoline-2] obtained in Example 112 The title compound (yield 60%) was obtained according to the method of Example 2 using -yl} piperidin-4-yl) carbonyl] amino} cyclohexyl) -2-methylpropanoate.
（実施例１１４）２－［シス－４－（｛［１－（３－｛３－［（２－ヒドロキシエチル）アミノ］フェニル｝－６－メチルキノリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパン酸
　参考例８９で得られた１－［３－（３－｛（ｔｅｒｔ－ブトキシカルボニル）［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］アミノ｝フェニル）－６－メチルキノリン－２－イル］ピペリジン－４－カルボン酸および実施例１７で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて縮合体（６４％）を得た。得られた化合物を用いて、実施例２の方法に準じてアモルファス状物（収率６０％）を得た。得られたアモルファス状物を用いて、実施例１０３の方法に準じて標記化合物（収率４１％）を固体として得た。
（実施例１１５）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－カルボキサミド
　参考例８８で得られた１－（６－メチル－３－｛３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸および参考例２５で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて縮合体（収率９６％）を得た。得られた化合物を用いて、実施例１０２の方法に準じて標記化合物（収率８０％）を得た。
（実施例１１６）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－｛３－［３－（２－ヒドロキシエトキシ）フェニル］－６－メチルキノリン－２－イル｝ピペリジン－４－カルボキサミド
　参考例８８で得られた１－（６－メチル－３－｛３－［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エトキシ］フェニル｝キノリン－２－イル）ピペリジン－４－カルボン酸および参考例２３で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩用いて、実施例１の方法に準じて油状物（収率７０％）を得た。得られた油状物を用いて、実施例１０２の方法に準じて標記化合物（収率７７％）を得た。 Example 114 2- [cis-4-({[1- (3- {3-[(2-hydroxyethyl) amino] phenyl} -6-methylquinolin-2-yl) piperidin-4-yl] Carbonyl} amino) cyclohexyl] -2-methylpropanoic acid 1- [3- (3-{(tert-butoxycarbonyl) [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] obtained in Reference Example 89 Amino} phenyl) -6-methylquinolin-2-yl] piperidine-4-carboxylic acid and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate obtained in Example 17 A condensate (64%) was obtained according to the method of Example 1. Using the obtained compound, an amorphous substance (yield 60%) was obtained according to the method of Example 2. Using the obtained amorphous material, the title compound (yield 41%) was obtained as a solid according to the method of Example 103.
Example 115 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidine -4-carboxamide 1- (6-methyl-3- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinolin-2-yl) piperidine-4 obtained in Reference Example 88 Using the carboxylic acid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 25, a condensate (yield 96%) was obtained according to the method of Example 1. Using the obtained compound, the title compound (yield 80%) was obtained according to the method of Example 102.
Example 116 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- {3- [3- (2-hydroxyethoxy) phenyl] -6-methylquinolin-2-yl} piperidine-4- Carboxamide 1- (6-Methyl-3- {3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] phenyl} quinolin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 88 Using (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 23, an oily substance (yield 70%) was obtained according to the method of Example 1. Using the obtained oil, the title compound (yield 77%) was obtained according to the method of Example 102.
　実施例に記載の化合物の構造式および物理化学データを以下に示す。 The structural formulas and physicochemical data of the compounds described in the examples are shown below.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
  
Figure JPOXMLDOC01-appb-T000048
  

Claims (15)

  1. 一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ｛式中、Ｒ１、Ｒ２，Ｒ３、Ｒ４、Ｒ５、およびＲ６は、それぞれ独立に、水素原子；Ｃ１－Ｃ６アルキル基；置換基群αから選択される基で置換されていてもよいエテニル基もしくはエチニル基、又は、置換基群βから選択される基で置換されていてもよいフェニル基もしくはピリジニル基を表わし、
    Ｙ１およびＹ２は、それぞれ独立に、水素原子；水酸基；オキソ基；カルボキシ基で置換されていてもよいメチリデン基；置換基群γから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基；置換基群δから選択される基で置換されていてもよいカルバモイル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基；オキソ基で置換されていてもよいトリアゾリル基；オキソ基で置換されていてもよいオキサジアゾリル基；テトラゾリル基；イミダゾリル基；シアノ基；又は１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基を表わし、
    Ｘは、水素原子又は水酸基を表わし、
    ｎは、０又は１を表わし、
    　式：
    Figure JPOXMLDOC01-appb-C000002
     は、式：
    Figure JPOXMLDOC01-appb-C000003
     又は、式：
    Figure JPOXMLDOC01-appb-C000004
     を表わし、
    環Ａは、５～６員の飽和もしくは不飽和の炭化水素環、又は５～６員の飽和もしくは不飽和の複素環を表わす。
    置換基群αは、ハロゲン原子；Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基；Ｃ１－Ｃ６アルコキシ基；Ｃ１－Ｃ６アルカノイル基；およびカルボキシ基を表し、
    置換基群βは、ハロゲン原子；シアノ基；水酸基で置換されていてもよいＣ１－Ｃ６アルコキシ基；１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいスルファモイル基、水酸基で置換されていてもよいＣ１－Ｃ６アルキル基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基を表し、
    置換基群γは、Ｃ１－Ｃ６アルキル基；水酸基で置換されていてもよいＣ１－Ｃ６アルキル基およびＣ１－Ｃ６アルコキシ基から選択される基で置換されていてもよいカルバモイル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基；シアノ基；水酸基；オキソ基で置換されていてもよいトリアゾリル基；および、オキソ基で置換されていてもよいオキサジアゾリル基を表し、
    置換基群δは、１乃至２のＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基、水酸基、ハロゲン原子、およびカルボキシ基から選択される基で置換されていてもよいＣ１－Ｃ６アルキル基；Ｃ１－Ｃ６アルキル基で置換されていてもよいスルホニル基、Ｃ１－Ｃ６アルコキシ基、およびＣ１－Ｃ６アルカノイル基から選択される基で置換されていてもよいアミノ基；および；Ｃ１－Ｃ６アルコキシ基を表す。｝     A compound represented by formula (I) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     {Wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently substituted with a group selected from a hydrogen atom; a C 1 -C 6 alkyl group; and a substituent group α An ethenyl group or an ethynyl group which may be substituted, or a phenyl group or a pyridinyl group which may be substituted with a group selected from the substituent group β,
    Y 1 and Y 2 are each independently a hydrogen atom; a hydroxyl group; an oxo group; a methylidene group optionally substituted with a carboxy group; or a group substituted with 1 to 3 groups selected from the substituent group γ good C 1 -C 6 alkyl group; substituted with an oxo group; optionally substituted with C 1 -C 6 alkyl group a carboxy group; which may have a carbamoyl group substituted with a group selected from substituent group δ An optionally substituted triazolyl group; an oxadiazolyl group optionally substituted with an oxo group; a tetrazolyl group; an imidazolyl group; a cyano group; or a sulfamoyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups. Represent,
    X represents a hydrogen atom or a hydroxyl group;
    n represents 0 or 1,
    formula:
    Figure JPOXMLDOC01-appb-C000002
     The formula:
    Figure JPOXMLDOC01-appb-C000003
     Or the formula:
    Figure JPOXMLDOC01-appb-C000004
     Represents
    Ring A represents a 5- to 6-membered saturated or unsaturated hydrocarbon ring or a 5- to 6-membered saturated or unsaturated heterocycle.
    Substituent group α is a halogen atom; a C 1 -C 6 alkyl group optionally substituted with a C 1 -C 6 alkoxy group; a C 1 -C 6 alkoxy group; a C 1 -C 6 alkanoyl group; and a carboxy group Represents
    Substituent group β is a halogen atom; a cyano group; a C 1 -C 6 alkoxy group optionally substituted with a hydroxyl group; a sulfamoyl group or a hydroxyl group optionally substituted with 1 to 2 C 1 -C 6 alkyl groups An amino group optionally substituted with a group selected from a C 1 -C 6 alkyl group optionally substituted with, and a C 1 -C 6 alkanoyl group;
    Substituent group γ is a C 1 -C 6 alkyl group; a carbamoyl optionally substituted with a group selected from a C 1 -C 6 alkyl group optionally substituted with a hydroxyl group and a C 1 -C 6 alkoxy group A carboxy group optionally substituted with a C 1 -C 6 alkyl group; a cyano group; a hydroxyl group; a triazolyl group optionally substituted with an oxo group; and an oxadiazolyl group optionally substituted with an oxo group; Represent,
    Substituent group δ is 1 or 2 of C 1 -C 6 alkyl carbamoyl group which may be substituted by a group, a hydroxyl group, a halogen atom, and carboxy may be substituted by a group selected from group C 1 - C 6 alkyl group; C 1 -C 6 alkyl optionally sulfonyl group optionally substituted with a group, C 1 -C 6 alkoxy groups, and C 1 -C 6 groups selected from alkanoyl group may be substituted An amino group; and; a C 1 -C 6 alkoxy group. }
  2. ｎが０である、請求項１に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to claim 1, wherein n is 0.
  3. 式：
    Figure JPOXMLDOC01-appb-C000005
     が、式：
    Figure JPOXMLDOC01-appb-C000006
     である、請求項１又は請求項２に記載の化合物又はその薬理上許容される塩。     formula:
    Figure JPOXMLDOC01-appb-C000005
     But the formula:
    Figure JPOXMLDOC01-appb-C000006
     The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof.
  4. Ｒ１が置換基群βから選択される基で置換されていてもよいフェニル基である、請求項１乃至請求項３のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is a phenyl group which may be substituted with a group selected from substituent group β.
  5. Ｒ２，Ｒ３、Ｒ５、およびＲ６がいずれも水素原子である、請求項１乃至請求項４のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 , R 3 , R 5 , and R 6 are all hydrogen atoms.
  6. Ｒ４が、Ｃ１－Ｃ６アルキル基である、請求項１乃至請求項５のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 4 is a C 1 -C 6 alkyl group.
  7. 環Ａが５～６員の飽和もしくは不飽和の炭化水素環である、請求項１乃至請求項６のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is a 5- to 6-membered saturated or unsaturated hydrocarbon ring.
  8. 環Ａが５～６員の飽和もしくは不飽和の複素環である、請求項１乃至請求項６のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is a 5- or 6-membered saturated or unsaturated heterocyclic ring.
  9. 環Ａがシクロペンタン環、シクロヘキサン環、又はベンゼン環である、請求項１乃至請求項７のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein ring A is a cyclopentane ring, a cyclohexane ring, or a benzene ring.
  10. 環Ａがシクロペンタン環、テトラヒドロピラン環、ベンゼン環、ピペリジン環、又はシクロヘキサン環である、請求項１乃至請求項９のいずれか１項に記載の化合物又はその薬理上許容される塩、 Ring A is a cyclopentane ring, a tetrahydropyran ring, a benzene ring, a piperidine ring, or a cyclohexane ring, The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 9,
  11. 一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  12. プロスタグランジンE2により介在される疾患を予防又は治療するために用いるための、請求項１１に記載された医薬組成物。 For use for preventing or treating a disease mediated by prostaglandin E 2, the pharmaceutical composition according to claim 11.
  13. プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、又はアルツハイマー病である、請求項１２に記載された医薬組成物。 Diseases mediated by prostaglandin E 2 include rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammation Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis Gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and associated myocardial infarction, stroke, abdomen The medical agent according to claim 12, which is aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease. Composition.
  14. プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である、請求項１２乃至請求項１３に記載された医薬組成物。 Diseases mediated by prostaglandin E 2 are rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis The pharmaceutical composition according to claim 12, which is dermatitis comprising
  15. 一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、炎症性疾患の予防方法又は治療方法。 A method for preventing or treating an inflammatory disease, comprising administering to a mammal an effective amount of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
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