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WO2013146970A1 - Nouveau dérivé de quinoléine - Google Patents

Nouveau dérivé de quinoléine 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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Daiichi Sankyo Co Ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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.

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US10899751B2 (en) 2016-06-21 2021-01-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
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US9790219B2 (en) 2014-03-13 2017-10-17 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10738040B2 (en) 2014-06-19 2020-08-11 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
WO2015196071A1 (fr) * 2014-06-19 2015-12-23 Proteostasis Therapeutics, Inc. Composés, compositions et procédés pour augmenter l'activité du cftr
US10174014B2 (en) 2014-06-19 2019-01-08 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
EA031504B1 (ru) * 2014-10-29 2019-01-31 Эли Лилли Энд Компани Новые соединения карбоновых кислот, подходящие для ингибирования микросомальной простагландин-e2-синтазы 1
WO2016069376A1 (fr) * 2014-10-29 2016-05-06 Eli Lilly And Company Nouveaux composés méthyl-pipéridine servant à inhiber la prostaglandine e2 synthase-1 microsomale
CN107001319A (zh) * 2014-10-29 2017-08-01 伊莱利利公司 用于抑制微粒体前列腺素e2合酶‑1的新的羧酸化合物
JP2017537073A (ja) * 2014-10-29 2017-12-14 イーライ リリー アンド カンパニー ミクロソームプロスタグランジンｅ２シンターゼ−１を阻害するのに有用な新規メチルピペリジン化合物
AU2015339737B2 (en) * 2014-10-29 2018-03-15 Eli Lilly And Company Novel carboxylic acid compounds useful for inhibiting microsomal prostaglandin E2 synthase-1
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US9962375B2 (en) 2014-10-29 2018-05-08 Eli Lilly And Company Methyl-piperidine compounds useful for inhibiting microsomal prostaglandin E2 synthase-1
US9969714B2 (en) 2014-10-29 2018-05-15 Eli Lilly And Company Carboxylic acid compounds useful for inhibiting microsomal prostaglandin E2 synthase-1
KR20170063828A (ko) * 2014-10-29 2017-06-08 일라이 릴리 앤드 캄파니 마이크로솜 프로스타글란딘 e2 신타제-1을 억제하는데 유용한 신규한 카르복실산 화합물
KR101898829B1 (ko) * 2014-10-29 2018-09-13 일라이 릴리 앤드 캄파니 마이크로솜 프로스타글란딘 e2 신타제-1을 억제하는데 유용한 신규한 메틸-피페리딘 화합물
KR101903304B1 (ko) 2014-10-29 2018-10-01 일라이 릴리 앤드 캄파니 마이크로솜 프로스타글란딘 e2 신타제-1을 억제하는데 유용한 신규한 카르복실산 화합물
KR20170055025A (ko) * 2014-10-29 2017-05-18 일라이 릴리 앤드 캄파니 마이크로솜 프로스타글란딘 e2 신타제-1을 억제하는데 유용한 신규한 메틸-피페리딘 화합물
WO2016069374A1 (fr) * 2014-10-29 2016-05-06 Eli Lilly And Company Nouveaux composés acide carboxylique servant à inhiber la prostaglandine e2 synthase-1 microsomale
EA032428B1 (ru) * 2014-10-29 2019-05-31 Эли Лилли Энд Компани Новые соединения метилпиперидина, подходящие для ингибирования микросомальной простагландин-e-синтазы 1
CN107074829B (zh) * 2014-10-29 2020-11-13 伊莱利利公司 用于抑制微粒体前列腺素e2合成酶-1的新型甲基-哌啶化合物
CN107074829A (zh) * 2014-10-29 2017-08-18 伊莱利利公司 用于抑制微粒体前列腺素e2合成酶‑1的新型甲基‑哌啶化合物
CN107001319B (zh) * 2014-10-29 2019-10-01 伊莱利利公司 用于抑制微粒体前列腺素e2合酶-1的新的羧酸化合物
US10392378B2 (en) 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Derivatives of 5-phenyl- or 5-heteroarylathiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis
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US10392372B2 (en) 2014-12-23 2019-08-27 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
US10344023B2 (en) 2014-12-23 2019-07-09 Proteostasis Therapeutics, Inc. Derivatives of 3-heteroarylisoxazol-5-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US10738011B2 (en) 2014-12-23 2020-08-11 Proteostasis Therapeutics, Inc. Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis
US11083709B2 (en) 2015-07-24 2021-08-10 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods of increasing CFTR activity
US10548878B2 (en) 2015-07-24 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods of increasing CFTR activity
US10550106B2 (en) 2015-10-06 2020-02-04 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for modulating CFTR
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US10899751B2 (en) 2016-06-21 2021-01-26 Proteostasis Therapeutics, Inc. Compounds, compositions, and methods for increasing CFTR activity
CN111961020A (zh) * 2020-08-31 2020-11-20 南通大学 一种四氢吡喃羧酸衍生物及其合成方法
CN114560779A (zh) * 2022-01-25 2022-05-31 杭州华东医药集团浙江华义制药有限公司 一种米拉贝隆关键中间体的合成方法
WO2024093091A1 (fr) * 2022-11-02 2024-05-10 成都科岭源医药技术有限公司 Procédé de préparation d'intermédiaire d'un composé d'ectéinascidine

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