Heterocyclic compound

Abstract

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): (I) wherein each symbol is as described in the description, or a salt thereof is useful as an agent for the prophylaxis or treatment of narcolepsy.

Description

HETEROCYCLIC COMPOUNDTECHNICAL FIELD

[0001] The present invention relates to a heterocyclic compound, particularly, a heterocyclic compound having an orexin type 2 receptor agonist activity.BACKGROUND OF THE INVENTION

[0002] Orexin is a neuropeptide specifically produced in particular neurons located sparsely in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptors, which are G protein-coupled receptors mainly present in the brain, and two types of subtypes, type 1 and type 2, are known for the orexin receptors (nonpatent document 1).

[0003] Since orexin-producing neurons (orexin neurons) are localized in the vicinity of the feeding center, and intraventricular administration of orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide having a feeding behavioral regulation. Thereafter, however, it was reported that the cause of dog narcolepsy is genetic variation of orexin type 2 receptor (non-patent document 2), and the role of orexin in controlling sleep and wakefulness has been also attracted.

[0004] From the studies using a transgenic mouse having denatured orexin neurons and a double transgenic mouse obtained by crossing this mouse with orexin overexpressing transgenic mouse, it was clarified that narcolepsy-like symptoms that appear by degeneration of orexin neurons disappear due to sustained expression of orexin.Similarly, when orexin peptide was intraventricularly administered to a transgenic mouse having denatured orexin neuron, improvement of narcolepsy-like symptoms was also observed (non-patent document 3). Studies of orexin type 2 receptor knockout mice have suggested that orexin type 2 receptor is important for maintaining arousal (non-patent document 4, non-patent document 5). Such background suggests that orexin type 2 receptor agonists become therapeutic drugs for narcolepsy or therapeutic drugs for other sleep disorders exhibiting excessive sleepiness (non-patent document 6).

[0005] In addition, it is suggested that a peptidic agonist that selectively acts on the orexin type 2 receptor improves obesity due to high fat diet load in mice (non-patent document 7).

[0006] In addition, it is suggested that intraventricular administration of orexin peptide shortens the systemic anesthetic time of rat (non-patent document 8).

[0007] In addition, it is suggested that patients with sleep apnea syndrome show low orexin A concentration levels in plasma (non-patent document 9).

[0008] In addition, it is suggested that intraventricular administration of orexin peptide improves memory retention of senescence-accelerated model mouse (SAMP8) with cognitive dysfunction (non-patent document 10).

[0009] In addition, it is suggested that Orexin type 2 receptor agonist will be a therapeutic drug for cardiac failure (patent document 1, non-patent document 11).

[0010] In addition, it is suggested that the daytime sleepiness of Parkinson’s disease patients is caused by orexin nerve fallout (non-patent document 12).

[0011] In addition, it is suggested that orexin regulates bone formation and bone loss, and orexin type 2 receptor agonist will be a therapeutic drug for diseases related to bone loss such as osteoporosis, rheumatoid arthritis and the like (patent document 2).

[0012] In addition, it is suggested that orexin receptor agonist is useful for the prophylaxis or treatment of sepsis, severe sepsis and septic shock, since the mortality was significantly improved by mere continuous administration of orexin from the periphery in septic shock model mouse (patent document 3).

[0013] Therefore, a compound having an orexin type 2 receptor agonist activity is expected to be useful as a novel therapeutic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbance of consciousness such as coma and the like, narcolepsy syndrome accompanied by narcolepsy -like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain- Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis and the like, further, anesthetic antagonist, a prophylactic or therapeutic drug for side effects and complications due to anesthesia.

[0014] As sulfonamide derivatives, the following compounds have been reported.

[0015] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 4).

[0016] Compounds registered as CAS numbers 2306497-71-0, 2306491-53-0, 2286390- 01-8, 2286389-97-5, 2286389-37-3, 2286389-02-2, 2286386-50-1 and 2286386-27-2.

[0017] In addition, as compounds having an orexin type 2 receptor agonist activity, the following compounds have been reported.

[0018] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 5).

[0019] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 6).

[0020] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 7).

[0021] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 8).

[0022] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 9).

[0023] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 10).

[0024] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 11).

[0025] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 12).

[0026] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 13).

[0027] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 14).

[0028] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 15).

[0029] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 16).

[0030] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 17).

[0031] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 18).

[0032] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 19).

[0033] A compound represented by the formulawherein each symbol is as described in the document (Patent Document 20).

[0034] However, these compounds are considered to be insufficient in terms of activity, pharmacokinetics or safety, and development of compounds compound having an orexin type 2 receptor agonist activity is still desired.[Document List][Patent Document]Patent Document 1 : WO 2015 / 073707 AlPatent Document 2: WO 2015 / 048091 AlPatent Document 3: WO 2015 / 147240 AlPatent Document 4: WO 2012 / 137982 A9Patent Document 5: WO 2017 / 135306 AlPatent Document 6: WO 2018 / 164191 AlPatent Document 7: WO 2018 / 164192 AlPatent Document 8: WO 2019 / 027003 AlPatent Document 9: WO 2019 / 027058 AlPatent Document 10: WO 2020 / 004536 AlPatent Document 11 : WO 2020 / 004537 AlPatent Document 12: WO 2020 / 122092 AlPatent Document 13: WO 2020 / 122093 AlPatent Document 14: WO 2020 / 158958 AlPatent Document 15: WO 2020 / 167701 AlPatent Document 16: WO 2020 / 167706 AlPatent Document 17: WO 2021 / 106975 AlPatent Document 18: WO 2024 / 095133 AlPatent Document 19: WO 2023 / 199091 AlPatent Document 20: WO 2024 / 116086 Al[Non-Patent Document]Non-Patent Document 1 : Cell, Vol.92, 573-585, 1998Non-Patent Document 2: Cell, Vol.98, 365-376, 1999Non-Patent Document 3: Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004Non-Patent Document 4: Cell, Vol.98, 437-451, 1999Non-Patent Document 5: Neuron, Vol.38, 715-730, 2003Non-Patent Document 6: CNS Drugs, Vol.27, 83-90, 2013Non-Patent Document 7: Cell Metabolism, Vol.9, 64-76, 2009Non-Patent Document 8: Neuroscience, Vol.121, 855-863, 2003Non-Patent Document 9: Respiration, Vol.71, 575-579, 2004Non-Patent Document 10: Peptides, Vol.23, 1683-1688, 2002Non-Patent Document 11 : Journal of the American College of Cardiology. Vol. 66, 2015,Pages 2522-2533Non-Patent Document 12: Brain. Vol. 130, 2007, Pages 1586-1595SUMMARY OF THE INVENTION[Problems to be Solved by the Invention]

[0035] The present invention aims to provide a heterocyclic compound having an orexin type 2 receptor agonist activity.[Means of Solving the Problems]

[0036] The present inventors have found that a compound represented by the following formula (I) or a salt thereof (sometimes to be referred to as compound (I) in the present specification) has an orexin type 2 receptor agonist activity. As a result of further studies, they have completed the present invention.

[0037] Accordingly, the present invention provides the following.

[0038] [1] A compound represented by the formula (I):

[0039] wherein

[0040] R1is an optionally substituted C2-6 alkyl group, or an optionally substituted cyclic group;

[0041] R2is an optionally substituted Ci-6 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted mono- or di-Ci-6 alkylamino group, or an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group;

[0042] L is

[0043] (1) an optionally substituted methylene group,

[0044] (2) -O-,

[0045] (3) -NRa- wherein Rais a hydrogen atom or a substituent,

[0046] (4) an optionally substituted ethylene group,

[0047] (5) -O-(an optionally substituted methylene group)-,

[0048] (6) -(an optionally substituted methylene group)-O-,

[0049] (7) -NRb-(an optionally substituted methylene group)- wherein Rbis a hydrogen atom or a substituent, or

[0050] (8) -(an optionally substituted methylene group)-NRc- wherein Rcis a hydrogen atom or a substituent;

[0051] Ring A is an optionally substituted 5- or 6-membered monocycle; and

[0052] Ring B is a 7- or 8-membered nitrogen-containing monocyclic heterocycle or a 7- or 8-membered nitrogen-containing fused heterocycle, each optionally substituted,

[0053] or a salt thereof.

[0054] [2] The compound or salt of the above-mentioned [1], wherein

[0055] R1is

[0056] (1) a C2-6 alkyl group,

[0057] (2) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group,

[0058] (3) a Ce-io aryl group optionally substituted by 1 to 3 halogen atoms,

[0059] (4) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by1 to 3 C1-6 alkyl groups,

[0060] (5) a 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to3 C1-6 alkyl groups, or

[0061] (6) an 8- to 14-membered fused bicyclic aromatic heterocyclic group;

[0062] R2is

[0063] (1) an optionally halogenated C1-6 alkyl group,

[0064] (2) a C3-10 cycloalkyl group,

[0065] (3) a di-Ci-6 alkylamino group, or

[0066] (4) a 3- to 7-membered nitrogen-containing heterocyclic group;

[0067] L is

[0068] (1) a methylene group optionally substituted by 1 or 2 substituents selected from(i) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (ii) a hydroxy group, and (iii) an oxo group,

[0069] (2) -O-,

[0070] (3) -NRa- wherein Rais a hydrogen atom or a C1-6 alkyl group,

[0071] (4) an ethylene group,

[0072] (5) -O-CH2-,

[0073] (6) -CH2-O-,

[0074] (7) -NRb-CH2- wherein Rbis a C1-6 alkyl group, or

[0075] (8) -CH2-NRC- wherein Rcis a hydrogen atom or a C1-6 alkyl group;

[0076] Ring A is

[0077] (1) a 5-membered ring optionally substituted by 1 or 2 Ci-6 alkyl groups, or

[0078] (2) a 6-membered ring optionally substituted by 1 to 3 substituents selected from

[0079] (i) a halogen atom,

[0080] (ii) a halogenated thio group,

[0081] (iii) a cyano group,

[0082] (iv) a hydroxy group,

[0083] (v) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a Ci-6 alkoxy group,

[0084] (vi) a C3-10 cycloalkyl group,

[0085] (vii) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; and

[0086] Ring B is

[0087] (1) a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a Ci- 6 alkyl group, or

[0088] (2) an 8-membered nitrogen-containing fused heterocycle optionally substituted by 1 to 3 halogen atoms.

[0089] [3] The compound or salt of the above-mentioned [1], wherein

[0090] R1is a Ce-io aryl group optionally substituted by 1 to 3 halogen atoms;

[0091] R2is a C1-6 alkyl group;

[0092] L is -NH-;

[0093] Ring A is a 6-membered ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C1-6 alkyl group; and

[0094] Ring B is a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by 1 to 3 halogen atoms.

[0095] [4] The compound or salt of the above-mentioned [1], wherein

[0096] R1is a phenyl group optionally substituted by 1 to 3 halogen atoms;R2is a C1-6 alkyl group;

[0097] L is -NH-;

[0098] Ring A is a benzene ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom and (ii) a halogenated C1-6 alkyl group; and

[0099] Ring B is a azepane ring optionally substituted by 1 to 3 halogen atoms.

[0100] [5] The compound or salt of the above-mentioned [1], which is (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l,r- biphenyl]-2-yl]azepane-l-carboxamide.

[0101] [6] The compound or salt of the above-mentioned [1], which is (5R)-N-(5-bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l- carb oxami de.

[0102] [7] The compound or salt of the above-mentioned [1], which is (5R)-N-(5-bromo-2',3,6'-trifluoro[l,T-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l- carb oxami de.

[0103] [8] A medicament comprising the compound or salt of any one of the above- mentioned [1] to [7],

[0104] [9] The medicament of the above-mentioned [8], which is an orexin type 2 receptor agonist.

[0105]

[0010] The medicament of the above-mentioned [8], which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

[0106]

[0011] The medicament of the above-mentioned [8], which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0107]

[0012] The medicament of the above-mentioned [8], which is an agent for the prophylaxis or treatment of narcolepsy.

[0108]

[0013] The medicament of the above-mentioned [8] to

[0012] , wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'- trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide; (5R)-N-(5- bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5- [(methanesulfonyl)amino]azepane-l -carboxamide; and (5R)-N-(5-bromo-2',3,6'- trifluoro[ 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

[0109]

[0014] The compound or salt of any one of the above-mentioned [1] to [7] for use as an orexin type 2 receptor agonist.

[0110]

[0015] The compound or salt of any one of the above-mentioned [1] to [7] for use in the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

[0111]

[0016] The compound or salt of the above-mentioned

[0015] for use in the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0112]

[0017] The compound or salt of the above-mentioned

[0015] for use in the prophylaxis or treatment of narcolepsy.

[0113]

[0018] The compound or salt of any one of the above-mentioned

[0014] to

[0017] , wherein the compound is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N- [2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide; (5R)-N- (5-bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5- [(methanesulfonyl)amino]azepane-l -carboxamide; and (5R)-N-(5-bromo-2',3,6'- trifluoro[ 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

[0114]

[0019] A method for the prophylaxis or treatment of a disease or disorder associated with an orexin type 2 receptor in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the compound or salt of any one of the above-mentioned [1] to [7],

[0115]

[0020] The method of the above-mentioned

[0019] , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy -like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

[0116]

[0021] The method of the above-mentioned

[0019] , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0117]

[0022] The method of the above-mentioned

[0019] , wherein the disease or disorder is narcolepsy.

[0118]

[0023] The method of any one of the above-mentioned

[0019] to

[0022] , wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N- [2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide; (5R)-N- (5-bromo-2 6'-difhioro[l,T-biphenyl]-2-yl)-4,4-difluoro-5- [(methanesulfonyl)amino]azepane-l -carboxamide; and (5R)-N-(5-bromo-2',3,6'- trifluoro[ 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

[0119]

[0024] Use of the compound or salt of any one of the above-mentioned [1] to [7] in the manufacture of a medicament for the treatment of a disease or disorder associated with an orexin type 2 receptor.

[0120]

[0025] The use of the above-mentioned

[0024] , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy -like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

[0121]

[0026] The use of the above-mentioned

[0024] , wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0122]

[0027] The use of the above-mentioned

[0024] , wherein the disease or disorder is narcolepsy.

[0123]

[0028] The use of any one of the above-mentioned

[0024] to

[0027] , wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N- [2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide; (5R)-N- (5-bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5- [(methanesulfonyl)amino]azepane-l -carboxamide; and (5R)-N-(5-bromo-2',3,6'- trifluoro[ 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

[0124]

[0029] A pharmaceutical composition comprising the compound or salt of any one of the above-mentioned [1] to [7],[Effect of the Invention]

[0125] The compound of the present invention has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.DETAILED DESCRIPTION OF THE INVENTION

[0126] The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.

[0127] In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.

[0128] As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term "(Ci-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. In the present specification, examples of the “Ci-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1- ethylpropyl, hexyl, isohexyl, 1,1 -dimethylbutyl, 2,2-dimethylbutyl, 3, 3 -dimethylbutyl and 2-ethylbutyl.

[0129] In the present specification, examples of the “C2-6 alkyl group” include for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, 1 -ethylpropyl, hexyl, isohexyl, 1,1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl and 2-ethylbutyl.

[0130] "Alkoxy" refers to a group containing an alkyl radical, defined hereina bove, attached through an oxygen linking atom. The term “(Ci-Ce)alkoxy” refers to a straighter branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary “(Ci-C4)alkoxy” groups useful in the present invention include methoxy, ethoxy, / / -propoxy, isopropoxy, / / -butoxy, .s-butoxy, isobutoxy, / -butoxy, n-pentyloxy, and n-hexyloxy.

[0131] In the present specification, examples of the “optionally halogenated C1-6 alkyl group” include a C1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

[0132] The term “halo(Ci-C6)alkyl,” as used in the present specification, refers to a (Ci- Ce)alkyl group substituted with one, two, three, four, five, six, or seven halogen atoms.

[0133] The term “((Ci-Ce)alkyl)-OH,” as used in the present specification, refers to a (Ci- Ce)alkyl group substituted with a hydroxy group.

[0134] In the present specification, examples of the “C2-6 alkenyl group” include ethenyl,1 -propenyl, 2-propenyl, 2 -m ethyl- 1 -propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 4-methyl-3 -pentenyl, 1- hexenyl, 3 -hexenyl and 5 -hexenyl.

[0135] In the present specification, examples of the “C2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4- methyl-2-pentynyl.

[0136] As used herein, "5- or 6-membered heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0137] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. In the present specification, examples of the “C3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0138] In the present specification, examples of the “optionally halogenated C3-10 cycloalkyl group” include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3 -difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0139] In the present specification, examples of the “C3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0140] In the present specification, examples of the “Ce-14 aryl group” include phenyl, 1- naphthyl, 2-naphthyl, 1 -anthryl, 2-anthryl and 9-anthryl.

[0141] In the present specification, examples of the “C7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0142] In the present specification, examples of the “C1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyl oxy.

[0143] In the present specification, examples of the “optionally halogenated C1-6 alkoxy group” include a C1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0144] In the present specification, examples of the “C3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0145] In the present specification, examples of the “C1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

[0146] In the present specification, examples of the “optionally halogenated C1-6 alkylthio group” include a C1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4- trifluorobutylthio, pentylthio and hexylthio.

[0147] In the present specification, examples of the “C1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3 -methylbutanoyl, 2- methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.

[0148] In the present specification, examples of the “optionally halogenated C1-6 alkylcarbonyl group” include a C1-6 alkyl-carbonyl group optionally having 1 to 7, preferably 1to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

[0149] In the present specification, examples of the “Ci-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxy carbonyl and hexyloxy carbonyl.

[0150] In the present specification, examples of the “Ce-14 aryl-carbonyl group” include benzoyl, 1 -naphthoyl and 2-naphthoyl.

[0151] In the present specification, examples of the “C7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.

[0152] In the present specification, examples of the “5- to 14-membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0153] In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0154] In the present specification, examples of the “mono- or di-Ci-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0155] In the present specification, examples of the “mono- or di-C?-i6 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

[0156] In the present specification, examples of the “C1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, secbutyl sulfonyl and tert-butyl sulfonyl.

[0157] In the present specification, examples of the “optionally halogenated C1-6 alkylsulfonyl group” include a C1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentyl sulfonyl and hexyl sulfonyl.

[0158] In the present specification, examples of the “Ce-14 arylsulfonyl group” include phenylsulfonyl, 1 -naphthyl sulfonyl and 2-naphthylsulfonyl.

[0159] In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionallysubstituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.

[0160] In the present specification, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a Ce-14 aryl group and a C7-16 aralkyl group.

[0161] In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following Substituent group A.[Substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C1-6 alkoxy group,(7) a Ce-14 aryloxy group (e.g., phenoxy, naphthoxy),(8) a C7-16 aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy),(11) a C1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a Ce-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1 -naphthoyloxy, 2-naphthoyloxy),(13) a C1-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),(15) a Ce-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthyl carb amoy 1 oxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated Ci-6 alkylsulfonyloxy group (e.g., methyl sulfonyloxy, tri fluoromethylsulfonyloxy),(19) a Ce-i4 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated Ci-6 alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated Ci-6 alkyl-carbonyl group,(26) a Ce-i4 aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a Ci-6 alkoxy-carbonyl group,(30) a Ce-i4 aryloxy-carbonyl group (e.g., phenyloxy carbonyl, 1-naphthyloxycarbonyl, 2- naphthyloxy carbonyl),(31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-Ci-6 alkyl-carbamoyl group,(35) a Ce-14 aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridyl carbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C1-6 alkylsulfonyl group,(39) a Ce-14 arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclyl sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C1-6 alkylsulfinyl group,(42) a Ce-14 arylsulfinyl group (e.g., phenylsulfinyl, 1 -naphthylsulfinyl, 2- naphthyl sulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-Ci-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutyl amino, N-ethy 1 -N -methyl amino),(46) a mono- or di-Ce-14 arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino),(48) a C7-16 aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C1-6 alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino),(51) a (C1-6 alkyl)(Ci-6 alkyl-carbonyl) amino group (e.g., N-acetyl-N-methylamino),(52) a Ce-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthyl carb ony 1 amino),(53) a C1-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tertbutoxycarbonylamino),(54) a C7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino),(55) a C1-6 alkylsulfonylamino group (e.g., methyl sulfonylamino, ethylsulfonylamino),(56) a Ce-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C1-6 alkyl group,(58) a C2-6 alkenyl group,(59) a C2-6 alkynyl group,(60) a C3-10 cycloalkyl group,(61) a C3-10 cycloalkenyl group, and(62) a Ce-14 aryl group.

[0162] The number of the above-mentioned substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0163] Unless otherwise specified, in the present specification, examples of the “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0164] In the present specification, examples of the “aromatic heterocyclic group” (including “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14- membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0165] Preferable examples of the “aromatic heterocyclic group” include 5- or 6- membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

[0166] 8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotri azolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, IH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, p- carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0167] In the present specification, examples of the “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14- membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0168] Preferable examples of the “non-aromatic heterocyclic group” include 3- to 8- membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and

[0169] 9- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-p- carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[0170] In the present specification, preferable examples of the “7- to 10-membered bridged heterocyclic group” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0171] In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ringconstituting atom.

[0172] In the present specification, "3-8-membered heterocyclyl" represents a group or moiety comprising a non aromatic, monovalent monocyclic radical, which is saturated or partially unsaturated, containing 3, 4, 5, 6, 7, or 8 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen.

[0173] In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the above-mentioned Substituent group A.

[0174] The number of the substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0175] In the present specification, examples of the “acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”.

[0176] Examples of the “acyl group” also include a hydrocarbon-sulfonyl group, a heterocyclyl sulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclyl sulfinyl group.

[0177] Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclyl sulfinyl group means a heterocyclic group-bonded sulfinyl group.

[0178] Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a Ce-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a Ce-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-Ci-6 alkylcarbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-Ce-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C?-i6 aralkylcarbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenylthiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-Cs-io cycloalkylthiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-Ce-14 aryl -thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di- C7-16 aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfino group, a C1-6 alkylsulfinyl group (e.g., methylsulfinyl, ethyl sulfinyl), a sulfo group, a C1-6 alkyl sulfonyl group, a Ce-14 aryl sulfonyl group, a phosphono group and a mono- or di-Ci-6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0179] In the present specification, examples of the “optionally substituted amino group” include an amino group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14- membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkylcarbamoyl group, a mono- or di-C?-i6 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a Ce-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0180] Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C1-6 alkyl) amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6 alkenylamino group (e.g., diallylamino), a mono- or di- C3-10 cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di- Ce-14 arylamino group (e.g., phenylamino), a mono- or di-C7-i6 aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C1-6 alkyl)- carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-Ce-14 arylcarbonylamino group (e.g., benzoylamino), a mono- or di-C7-ie aralkyl-carbonylamino group (e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g.,piperidinylcarbonylamino), a mono- or di-Ci-6 alkoxy-carbonylamino group (e.g., tertbutoxycarbonylamino), a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-Ci-6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino), a (mono- or di-C?-i6 aralkyl-carbamoyl) amino group (e.g., benzylcarbamoylamino), a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a Ce-14 arylsulfonylamino group (e.g., phenylsulfonylamino), a (Ci-6 alkyl)(Ci-6 alkyl-carbonyl) amino group (e.g., N-acetyl-N- methylamino) and a (Ci-6 alkyl)(Ce-i4 aryl-carbonyl) amino group (e.g., N-benzoyl-N- methylamino).

[0181] In the present specification, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally having “1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C?-i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0182] Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenylcarbamoyl group (e.g., diallylcarbamoyl), a mono- or di-Cs-io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-Ce-14 arylcarbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-i6 aralkyl-carbamoyl group, a mono- or di-Ci-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-Ce-14 aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., py ri dy 1 carb amoy 1) .

[0183] In the present specification, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group,a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C?-i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0184] Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-Cs-io cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-Ce-14 arylthiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C?-i6 aralkylthiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-Ci-6 alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-Ce-14 aryl-carbonyl-thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

[0185] In the present specification, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally having “1 or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C?-i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0186] Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C2-6 alkenyl-sulfamoyl group (e.g., diallyl sulfamoyl), a mono- or di-Cs-io cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-Ce-14 aryl-sulfamoyl group (e.g., phenyl sulfamoyl), a mono- or di-C7-i6 aralkylsulfamoyl group (e.g., benzylsulfamoyl, phenethyl sulfamoyl), a mono- or di-Ci-6 alkyl- carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di-Ce-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclyl sulfamoyl group (e.g., pyridylsulfamoyl).

[0187] In the present specification, examples of the “optionally substituted hydroxy group” include a hydroxy group optionally having “a substituent selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group, a C7-16 aralkylcarbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C?-i6 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a Ce-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0188] Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6 alkoxy group, a C2-6 alkenyloxy group (e.g., allyloxy, 2- butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy), a Ce-14 aryloxy group (e.g., phenoxy, naphthyloxy), a C7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a Ce-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C7-16 aralkyl-carbonyloxy group (e.g., benzyl carbonyl oxy), a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14- membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a C1-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C1-6 alkylcarbamoyloxy group (e.g., methylcarbamoyloxy), a C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a Ce-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[0189] In the present specification, examples of the “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a Ce-14 aryl-carbonyl group and a 5- to 14- membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent group A” and a halogenated sulfanyl group.

[0190] Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, a Ci-6 alkylthio group, a C2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C3-10 cycloalkylthio group (e.g., cyclohexylthio), a Ce-14 arylthio group (e.g., phenylthio, naphthylthio), a C7-16 aralkylthio group (e.g., benzylthio, phenethylthio), a C1-6 alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a Ce-14 aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio).

[0191] In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A”.

[0192] Preferable examples of the optionally substituted silyl group include a tri-Ci-6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0193] In the present specification, examples of the “hydrocarbon ring” include a Ce-14 aromatic hydrocarbon ring, C3-10 cycloalkane and C3-10 cycloalkene.

[0194] In the present specification, examples of the “Ce-14 aromatic hydrocarbon ring” include benzene and naphthalene.

[0195] In the present specification, examples of the “C3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

[0196] In the present specification, examples of the “C3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

[0197] In the present specification, examples of the “heterocycle” include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0198] In the present specification, examples of the “aromatic heterocycle” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “aromatic heterocycle” include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4- thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and

[0199] 7- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotri azole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, IH-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, p-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like.

[0200] In the present specification, examples of the “non-aromatic heterocycle” include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “non- aromatic heterocycle” include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and the like; and

[0201] 7- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-p-carboline, tetrahydroacridine,tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline, octahydrocyclopentapyrrole and the like.

[0202] In the present specification, examples of the “nitrogen-containing heterocycle” include a heterocycle containing at least one nitrogen atom as a ring-constituting atom, from among the “heterocycle”.

[0203] In the present specification, examples of the “cyclic group” include a “C3-10 cycloalkyl group”, a “C3-10 cycloalkenyl group”, a “Ce-14 aryl group” and a “heterocyclic group”.

[0204] In the present specification, examples of the “3- to 7-membered nitrogencontaining heterocyclic group” include a 3- to 7-membered group, from among the “nitrogen-containing heterocyclic group”.

[0205] In the present specification, examples of the “5- or 6-membered monocyclic” include a benzene ring, a C5-6 cycloalkane, a C5-6 cycloalkene, a 5- or 6-membered monocyclic aromatic heterocycle and a 5- or 6-membered monocyclic non-aromatic heterocycle. Examples of the “5- or 6-membered monocyclic non-aromatic heterocycle” include a 5- or 6-membered heterocycle, from among the “3- to 8-membered monocyclic non-aromatic heterocycle”.

[0206] In the present specification, examples of the “7- or 8-membered nitrogencontaining monocyclic heterocycle” include a 7- or 8-membered monocyclic heterocycle, from among the “nitrogen-containing heterocycle”. Specific examples thereof include azepane, diazepane, azepine, azocane, diazocane, oxepane and the like.

[0207] In the present specification, examples of the “7- or 8-membered nitrogencontaining fused heterocycle” include a 7- or 8-membered fused heterocycle, from among the “nitrogen-containing heterocycle”. Specific examples thereof include octahydrocyclopentapyrrole and the like.

[0208] The definition of each symbol in the formula (I) is explained in detail.

[0209] R1is an optionally substituted C2-6 alkyl group, or an optionally substituted cyclic group.

[0210] Examples of the substituent of the above-mentioned “optionally substituted C2-6 alkyl group” and “optionally substituted cyclic group” include substituents disclosed herein and selected from Substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0211] R1is preferably

[0212] (1) a C2-6 alkyl group (e.g., isopropyl),

[0213] (2) a C3-10 cycloalkyl group (e.g., cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group (e.g., methoxy),

[0214] (3) a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom),

[0215] (4) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl,1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl),

[0216] (5) a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, pyrimidinyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl), or

[0217] (6) an 8- to 14-membered fused bicyclic aromatic heterocyclic group (e.g., b enzothi opheny 1) .

[0218] R1is preferably

[0219] (1) a C2-6 alkyl group (e.g., isopropyl),

[0220] (2) a C3-10 cycloalkyl group (e.g., cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group (e.g., methoxy),

[0221] (3) a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom),

[0222] (4) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl,1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl),

[0223] (5) a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, pyrimidinyl, thienyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl), or

[0224] (6) an 8- to 14-membered fused bicyclic aromatic heterocyclic group (e.g., b enzothi opheny 1) .

[0225] In some embodiments, R1is an optionally substituted C2-6 alkyl group selected from ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. In some embodiments, R1is an optionally substituted isopropyl group.

[0226] In some embodiments, R1is an optionally substituted C3-10 cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R1isan optionally substituted cyclopentyl group. In some embodiments, R1is an optionally substituted cyclohexyl group.

[0227] In some embodiments, the C3-10 cyclic group is substituted by 1 or more substituents selected from alkyl, halogen, hydroxy, and alkoxy. In some embodiments, the C3-10 cyclic group is substituted by a hydroxy group. In some embodiments, the C3-10 cyclic group is substituted by a methoxy group.

[0228] In some embodiments, R1is an optionally substituted 3- to 8-membered nonaromatic heterocyclic group selected from tetrahydropyranyl and 1,1- dioxidotetrahydrothiopyranyl. In some embodiments, R1is a tetrahydropyranyl group. In some embodiments, the tetrahydropyranyl group is substituted by an alkyl group. In some embodiments, the tetrahydropyranyl group is substituted by a methyl group.

[0229] In some embodiments, R1is an optionally substituted 5- or 6-membered aromatic heterocyclic group selected from furyl, pyridyl, and pyrimidinyl. In some embodiments, R1is a pyrimidinyl group. In some embodiments, R1is a furyl group. In some embodiments, the furyl group is substituted by an alkyl group. In some embodiments, the furyl group is substituted by a methyl group.

[0230] In some embodiments, R1is an optionally substituted 8- to 14-membered fused bicyclic aromatic heterocyclic group. In some embodiments, R1is a benzothiophenyl group. In some embodiments, the benzothiophenyl group is selected from:

[0231] R1is more preferably a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0232] R1is more preferably a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0233] R1is more preferably a phenyl group optionally substituted by 1 or 2 halogen atoms. In some embodiments, R1is a phenyl group substituted by 2 halogens. In some embodiments, R1is a phenyl group substituted by 2 halogens at the 2 and 6 positions of the phenyl group. In some embodiments, R1is a phenyl group substituted by 2 halogens at the 2 and 5 positions of the phenyl group. In some embodiments, R1is a phenyl groupsubstituted by 2 halogens at the 2 and 4 positions of the phenyl group. In some embodiments, R1 is a phenyl group substituted by 2 fluorine atoms. In some embodiments, R1 is a phenyl group substituted by 2 fluorine atoms at the 2 and 6 positions of the phenyl group.

[0234] In some embodiments, R1is a phenyl group having the structure:

[0235] R2is an optionally substituted Ci-6 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted mono- or di-Ci-6 alkylamino group, or an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group.

[0236] Examples of the substituent of the above-mentioned “optionally substituted” groups include substituents disclosed herein and selected from Substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0237] R2is preferably

[0238] (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, fluoromethyl, ethyl),

[0239] (2) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0240] (3) a di-Ci-6 alkylamino group (e.g., dimethylamino), or

[0241] (4) a 3- to 7-membered nitrogen-containing heterocyclic group (e.g., azetidinyl).

[0242] R2is more preferably a C1-6 alkyl group (e.g., methyl, ethyl) or a di-Ci-6 alkylamino group (e.g., dimethylamino).

[0243] R2is preferably

[0244] (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, fluoromethyl, ethyl, propyl),

[0245] (2) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0246] (3) a di-Ci-6 alkylamino group (e.g., dimethylamino), or

[0247] (4) a 3- to 7-membered nitrogen-containing heterocyclic group (e.g., azetidinyl).

[0248] R2is more preferably a C1-6 alkyl group (e.g., methyl, ethyl).

[0249] In some embodiments, R2is an optionally substituted C1-6 alkyl group. In some embodiments, R2is a methyl group, an ethyl group, or a propyl group. In some embodiments, R2is a methyl group. In some embodiments, R2is an ethyl group. In some embodiments, R2is a propyl group. In some embodiments, R2is a methyl groupsubstituted by a halogen. In some embodiments, R2is a methyl group substituted by a fluorine atom.

[0250] In some embodiments, R2is an optionally substituted C3-10 cycloalkyl group. In some embodiments, R2is an optionally substituted cyclopropyl group.

[0251] In some embodiments, R2is an optionally substituted mono- or di-Ci-6 alkylamino group. In some embodiments, R2is an optionally substituted dimethyl amino group.

[0252] In some embodiments, R2is an optionally substituted 3- to 7-membered nitrogencontaining heterocyclic group. In some embodiments, R2is an optionally substituted azetidine. In some embodiments, R2is an azetidine having the structure:.

[0253] L is

[0254] (1) an optionally substituted methylene group,

[0255] (2) -O-,

[0256] (3) -NRa- wherein Rais a hydrogen atom or a substituent,

[0257] (4) an optionally substituted ethylene group,

[0258] (5) -O-(an optionally substituted methylene group)-,

[0259] (6) -(an optionally substituted methylene group)-O-,

[0260] (7) -NRb-(an optionally substituted methylene group)- wherein Rbis a hydrogen atom or a substituent, or

[0261] (8) -(an optionally substituted methylene group)-NRc- wherein Rcis a hydrogen atom or a substituent.

[0262] Examples of the substituent of the above-mentioned “optionally substituted” groups include substituents disclosed herein and selected from Substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0263] In some embodiments, L is an optionally substituted methylene group. In some embodiments, L is an optionally substituted ethylene group. In some embodiments, L is a methylene group substituted by an oxo group. In some embodiments, L is a methylene group substituted by a hydroxy group. In some embodiments, L is a methylene group substituted by an optionally substituted C1-6 alkyl group. In some embodiments, L is a methylene group substituted by a methyl group. In some embodiments, L is a methylenegroup substituted by a methyl group, wherein the methyl group is substituted by a hydroxy group.

[0264] In some embodiments, L is -O-. In some embodiments, L is -O-(an optionally substituted methylene group)-. In some embodiments, L is -(an optionally substituted methylene group)-O-.

[0265] In some embodiments, L is -NRa- wherein Rais a hydrogen atom or a substituent. In some embodiments, Rais a hydrogen atom. In some embodiments, Rais a methyl group.

[0266] In some embodiments, L is -(an optionally substituted methylene group)-NRc- wherein Rcis a hydrogen atom or a substituent. In some embodiments, Rcis a hydrogen atom. In some embodiments, Rcis a Ci-6 alkyl group. In some embodiments, Rcis a methyl group.

[0267] In some embodiments, L is -NRb-(an optionally substituted methylene group)- wherein Rbis a hydrogen atom or a substituent. In some embodiments, Rbis a hydrogen atom. In some embodiments, Rbis a Ci-6 alkyl group. In some embodiments, Rbis a methyl group.

[0268] L is preferably

[0269] (1) a methylene group optionally substituted by 1 or 2 substituents selected from(i) a Ci-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 hydroxy groups, (ii) a hydroxy group, and (iii) an oxo group,

[0270] (2) -O-,

[0271] (3) -NRa- wherein Rais a hydrogen atom or a Ci-6 alkyl group (e.g., methyl),

[0272] (4) an ethylene group,

[0273] (5) -O-CH2-,

[0274] (6) -CH2-O-,

[0275] (7) -NRb-CH2- wherein Rbis a C1-6 alkyl group (e.g., methyl), or

[0276] (8) -CH2-NRC- wherein Rcis a hydrogen atom or a C1-6 alkyl group (e.g., methyl).

[0277] L is more preferably -NH-.

[0278] Ring A is an optionally substituted 5- or 6-membered monocycle.

[0279] Examples of the substituent of the above-mentioned “optionally substituted 5- or 6-membered monocycle” include substituents disclosed herein and selected from Substituent group A. The number of the substituents is preferably 1 to 3. When thenumber of the substituents is 2 or more, the respective substituents may be the same or different.

[0280] Ring A is preferably

[0281] (1) a 5-membered ring (e.g., thiophene, thiazole) optionally substituted by 1 or 2Ci-6 alkyl groups (e.g., methyl), or

[0282] (2) a 6-membered ring (e.g., cyclohexane, benzene, pyridine) optionally substituted by 1 to 3 substituents selected from

[0283] (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),

[0284] (ii) an optionally halogenated Ci-6 alkyl group (e.g., methyl, trifluoromethyl, ethyl),

[0285] (iii) a C3-10 cycloalkyl group (e.g., cyclopropyl), and

[0286] (iv) a C1-6 alkoxy group (e.g., methoxy).

[0287] In some embodiments, Ring A is (1) a 5-membered ring (e.g., thiophene, thiazole, pyrazol) optionally substituted by 1 or 2 C1-6 alkyl groups (e.g., methyl), or

[0288] (2) a 6-membered ring (e.g., cyclohexane, benzene, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from

[0289] (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom),

[0290] (ii) a halogenated thio group (e.g., pentafluorothio),

[0291] (iii) a cyano group,

[0292] (iv) a hydroxy group,

[0293] (v) a C1-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom), a hydroxy group, and a C1-6 alkoxy group (e.g., methoxy),

[0294] (vi) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0295] (vii) a C1-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0296] In some embodiments, Ring A is a 5-membered ring optionally substituted by 1 or 2 C1-6 alkyl groups. In some embodiments, Ring A is an optionally substituted thiazole group. In some embodiments, Ring A is a thiazole group substituted by a C1-6 alkyl group. In some embodiments, Ring A is a thiazole group substituted by a methyl group. In some embodiments, Ring A is an optionally substituted thiophene group. In some embodiments, Ring A is an optionally substituted pyrazole group. In some embodiments, Ring A is an optionally substituted pyrazole group substituted by a methyl group.

[0297] In some embodiments, Ring A is selected from:

[0298] In some embodiments, Ring A is an optionally substituted C3-10 cycloalkyl group. In some embodiments, Ring A is an optionally substituted cyclohexyl group.

[0299] Ring A is more preferably a 6-membered ring (e.g., benzene, pyridine) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, trifluorom ethyl).

[0300] Ring A is more preferably a 6-membered ring (e.g., benzene) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), and (ii) an optionally halogenated C1-6 alkyl group (e.g., trifluorom ethyl).

[0301] Ring A is more preferably a benzene ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a bromine atom), and (ii) a halogenated C1-6 alkyl group (e.g., trifluoromethyl).

[0302] In some embodiments, Ring A is a phenyl group optionally substituted by 1, 2, or 3 substituents selected from (i) a halogen atom and (ii) a halogenated C1-6 alkyl group.

[0303] In some embodiments, Ring A is a phenyl group substituted by a chlorine atom. In some embodiments, Ring A is a phenyl group substituted by two chlorine atoms. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom. In some embodiments, Ring A is a phenyl group substituted by two fluorine atoms. In some embodiments, Ring A is a phenyl group substituted by three fluorine atoms. In some embodiments, Ring A is a phenyl group substituted by a bromine atom. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a bromine atom. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom anda chlorine atom. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom and two fluorine atoms.

[0304] In some embodiments, Ring A is a phenyl group substituted by a halogenated methyl group. In some embodiments, Ring A is a phenyl group substituted by a trifluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a difluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a halogen atom and a difluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a difluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a halogen atom and a trifluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a trifluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by two fluorine atoms and a trifluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom and a trifluoromethyl group. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom, a fluorine atom, and a trifluoromethyl group.

[0305] In some embodiments, Ring A is a phenyl group substituted by one or more substituents selected from a halogen atom, a cyano group, a hydroxy group, a Ci-6 alkoxy group, a halogenated Ci-6 alkoxy group, an optionally substituted Ci-6 alkyl group, or an optionally substituted C3-10 cycloalkyl group.

[0306] In some embodiments, Ring A is a phenyl group substituted by a cyano group. In some embodiments, Ring A is a phenyl group substituted by a hydroxy group. In some embodiments, Ring A is a phenyl group substituted by a methoxy group. In some embodiments, Ring A is a phenyl group substituted by a trifluoromethoxy group. In some embodiments, Ring A is a phenyl group substituted by a methyl group. In some embodiments, Ring A is a phenyl group substituted by a methyl group, wherein the methyl group is substituted by a methoxy group. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a methyl group, wherein the methyl group is substituted by a methoxy group. In some embodiments, Ring A is a phenyl group substituted by a methyl group, wherein the methyl group is substituted by a hydroxy group. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a methyl group, wherein the methyl group is substituted by a hydroxt group.

[0307] In some embodiments, Ring A is a phenyl group substituted by an ethyl group. In some embodiments, Ring A is a phenyl group substituted by an ethyl group, wherein theethyl group is substituted by a halogen atom. In some embodiments, Ring A is a phenyl group substituted by an ethyl group, wherein the ethyl group is substituted by a fluorine atom.

[0308] In some embodiments, Ring A is a phenyl group substituted by a cyclopropyl group. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom and a cyclopropyl group. In some embodiments, Ring A is a phenyl group substituted by a fluorine atom and a methyl group. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom and a methyl group. In some embodiments, Ring A is a phenyl group substituted by a chlorine atom, a fluorine atom, and a methyl group.

[0309] In some embodiments, Ring A is a phenyl group substituted by a halogenated thio group. In some embodiments, Ring A is a phenyl group substituted by a pentafluorothio group.

[0310] In some embodiments, Ring A is an optionally substituted phenyl group having the structurewherein each hydrogen is optionally replaced with a substituent as disclosed herein. In some embodiments, Ring A is selected from:

[0311] In some embodiments, Ring A is an optionally substituted pyridyl group. In some embodiments, Ring A is a pyridyl group substituted by one or more substituents selected from a halogen atom, a Ci-6 alkyl group, and a C3-10 cycloalkyl group. In some embodiments, Ring A is a pyridyl group substituted by a chlorine atom. In some embodiments, Ring A is a pyridyl group substituted by a methyl group. In some embodiments, Ring A is a pyridyl group substituted by an ethyl group. In some embodiments, Ring A is a pyridyl group substituted by a cyclopropyl group.

[0312] In some embodiments, Ring A is an optionally substituted pyrimidinyl group. In some embodiments, Ring A is a pyrimidinyl group substituted by a C1-6 alkyl group. In some embodiments, Ring A is a pyrimidinyl group substituted by a methyl group.

[0314] Ring B is a 7- or 8-membered nitrogen-containing monocyclic heterocycle or a 7- or 8-membered nitrogen-containing fused heterocycle, each of which is optionally substituted.

[0315] Examples of the substituent of the above-mentioned “optionally substituted” groups include substituents disclosed herein and selected from Substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0316] Ring B is preferably

[0317] (1) a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane, oxazepane) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom), a hydroxy group and a Ci-6 alkyl group (e.g., methyl), or

[0318] (2) an 8-membered nitrogen-containing fused heterocycle (e.g., octahydrocyclopentapyrrole) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0319] Ring B is more preferably a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0320] Ring B is more preferably a azepane ring optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0321] In some embodiments, Ring B is a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by 1 or 2 halogen atoms. In some embodiments, RingB is a 7-membered nitrogen-containing monocyclic heterocycle substituted by 2 halogen atoms. In some embodiments, Ring B is a 7-membered nitrogen-containing monocyclic heterocycle substituted by 2 fluorine atoms. In some embodiments, Ring B is an azepane substituted by 2 halogen atoms. In some embodiments, Ring B is an azepane substituted by 2 fluorine atoms. In some embodiments, Ring B is an azepane substituted by a fluorine atom. In some embodiments, Ring B is an azepane substituted by a fluorine atom and a methyl group.

[0322] In some embodiments, Ring B is a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by a hydroxy group or an optionally substituted Ci-6 alkyl group. In some embodiments, Ring B is an azepane substituted by a methyl group. In some embodiments, Ring B is an azepane substituted by a hydroxy group.

[0323] In some embodiments, Ring B is an optionally substituted oxazepane.

[0324] In some embodiments, Ring B is a 8-membered nitrogen-containing fused heterocycle optionally substituted by 1 to 3 halogen atoms. In some embodiments, Ring B is an octahydrocyclopentapyrrole. In some embodiments, Ring B is an octahydrocyclopentapyrrole substituted with a fluorine atom. In some embodiments, Ring B is an octahydrocyclopentapyrrole substituted with two fluorine atoms.

[0325] In some embodiments, Ring A is selected from:wherein each hydrogen is optionally replaced with a substituent as disclosed herein. In some embodiments, Ring A is:[Compound A]

[0326] Preferable compound is compound (I) wherein

[0327] R1is

[0328] (1) a C2-6 alkyl group (e.g., isopropyl),

[0329] (2) a C3-10 cycloalkyl group (e.g., cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group (e.g., methoxy),

[0330] (3) a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom),

[0331] (4) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl,1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl),

[0332] (5) a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, pyrimidinyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl), or

[0333] (6) a 8- to 14-membered fused bicyclic aromatic heterocyclic group (e.g., b enzothi opheny 1) ;

[0334] R2is

[0335] (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, fluoromethyl, ethyl),

[0336] (2) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0337] (3) a di-Ci-6 alkylamino group (e.g., dimethylamino), or

[0338] (4) a 3- to 7-membered nitrogen-containing heterocyclic group (e.g., azetidinyl);

[0339] L is

[0340] (1) a methylene group optionally substituted by 1 or 2 substituents selected from(i) a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 hydroxy groups, (ii) a hydroxy group, and (iii) an oxo group,

[0341] (2) -O-,

[0342] (3) -NRa- wherein Rais a hydrogen atom or a C1-6 alkyl group (e.g., methyl),

[0343] (4) an ethylene group,

[0344] (5) -O-CH2-,

[0345] (6) -CH2-O-,

[0346] (7) -NRb-CH2- wherein Rbis a C1-6 alkyl group (e.g., methyl), or

[0347] (8) -CH2-NRC- wherein Rcis a hydrogen atom or a C1-6 alkyl group (e.g., methyl);

[0348] Ring A is

[0349] (1) a 5-membered ring (e.g., thiophene, thiazole) optionally substituted by 1 or 2Ci-6 alkyl groups (e.g., methyl), or

[0350] (2) a 6-membered ring (e.g., cyclohexane, benzene, pyridine) optionally substituted by 1 to 3 substituents selected from

[0351] (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),

[0352] (ii) an optionally halogenated Ci-6 alkyl group (e.g., methyl, trifluoromethyl, ethyl),

[0353] (iii) a C3-10 cycloalkyl group (e.g., cyclopropyl), and

[0354] (iv) a C1-6 alkoxy group (e.g., methoxy); and

[0355] Ring B is

[0356] (1) a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane, oxazepane) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom), a hydroxy group and a C1-6 alkyl group (e.g., methyl), or

[0357] (2) a 8-membered nitrogen-containing fused heterocycle (e.g., octahydrocyclopentapyrrole) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).[Compound B]

[0358] More preferable compound is compound (I) wherein

[0359] R1is a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);

[0360] R2is a C1-6 alkyl group (e.g., methyl, ethyl) or a di-Ci-6 alkylamino group (e.g., dimethylamino);

[0361] L is -NH-;

[0362] Ring A is a 6-membered ring (e.g., benzene, pyridine) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a chlorine atom) and (ii) an optionally halogenated C1-6 alkyl group (e.g., methyl, trifluoromethyl); and

[0363] Ring B is a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).[Compound C]

[0364] Compound (I) is preferably compound (I) wherein

[0365] R1is

[0366] (1) a C2-6 alkyl group (e.g., isopropyl),

[0367] (2) a C3-10 cycloalkyl group (e.g., cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group (e.g., methoxy),

[0368] (3) a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom),

[0369] (4) a 3- to 8-membered non-aromatic heterocyclic group (e.g., tetrahydropyranyl,1,1-dioxidotetrahydrothiopyranyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl),

[0370] (5) a 5- or 6-membered aromatic heterocyclic group (e.g., furyl, pyrimidinyl, thienyl) optionally substituted by 1 to 3 C1-6 alkyl groups (e.g., methyl), or

[0371] (6) an 8- to 14-membered fused bicyclic aromatic heterocyclic group (e.g., b enzothi opheny 1) ;

[0372] R2is

[0373] (1) an optionally halogenated C1-6 alkyl group (e.g., methyl, fluoromethyl, ethyl, propyl),

[0374] (2) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0375] (3) a di-Ci-6 alkylamino group (e.g., dimethylamino), or

[0376] (4) a 3- to 7-membered nitrogen-containing heterocyclic group (e.g., azetidinyl);

[0377] L is

[0378] (1) a methylene group optionally substituted by 1 or 2 substituents selected from(i) a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 hydroxy groups, (ii) a hydroxy group, and (iii) an oxo group,

[0379] (2) -O-,

[0380] (3) -NRa- wherein Rais a hydrogen atom or a C1-6 alkyl group (e.g., methyl),

[0381] (4) an ethylene group,

[0382] (5) -O-CH2-,

[0383] (6) -CH2-O-,

[0384] (7) -NRb-CH2- wherein Rbis a C1-6 alkyl group (e.g., methyl), or

[0385] (8) -CH2-NRC- wherein Rcis a hydrogen atom or a C1-6 alkyl group (e.g., methyl);

[0386] Ring A is (1) a 5-membered ring (e.g., thiophene, thiazole, pyrazol) optionally substituted by 1 or 2 Ci-6 alkyl groups (e.g., methyl), or

[0387] (2) a 6-membered ring (e.g., cyclohexane, benzene, pyridine, pyrimidine) optionally substituted by 1 to 3 substituents selected from

[0388] (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom),

[0389] (ii) a halogenated thio group (e.g., pentafluorothio),

[0390] (iii) a cyano group,

[0391] (iv) a hydroxy group,

[0392] (v) a Ci-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom), a hydroxy group, and a Ci-6 alkoxy group (e.g., methoxy),

[0393] (vi) a C3-10 cycloalkyl group (e.g., cyclopropyl),

[0394] (vii) a C1-6 alkoxy group (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom); and

[0395] Ring B is

[0396] (1) a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane, oxazepane) optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom), a hydroxy group and a C1-6 alkyl group (e.g., methyl), or

[0397] (2) an 8-membered nitrogen-containing fused heterocycle (e.g., octahydrocyclopentapyrrole) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).[Compound D]

[0398] Compound (I) is more preferably compound (I) wherein

[0399] R1is a Ce-io aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);

[0400] R2is a C1-6 alkyl group (e.g., methyl, ethyl);

[0401] L is -NH-;

[0402] Ring A is a 6-membered ring (e.g., benzene) optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), and (ii) an optionally halogenated C1-6 alkyl group (e.g., trifluoromethyl); and

[0403] Ring B is a 7-membered nitrogen-containing monocyclic heterocycle (e.g., azepane) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).[Compound E]

[0404] Compound (I) is more preferably compound (I) wherein

[0405] R1is a phenyl group optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);

[0406] R2is a Ci-6 alkyl group (e.g., methyl, ethyl);

[0407] L is -NH-;

[0408] Ring A is a benzene ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom (e.g., a fluorine atom, a bromine atom), and (ii) a halogenated Ci- 6 alkyl group (e.g., trifluoromethyl); and

[0409] Ring B is a azepane ring optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[0410] Specific examples of compound (I) include the compounds of the below- mentioned Examples 1 to 286.

[0411] Specifically, compound (I) is preferably

[0412] (5R)-N-(5-chl oro-2', 6'-difluoro[ 1, l'-biphenyl]-2-yl)-4, 4-difluoro-5-[(methanesulfonyl)amino]azepane-l -carboxamide or a salt thereof (Example 139);

[0413] (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide or a salt thereof (Example 147);

[0414] (5R)-4,4-difluoro-5-[(methanesulfonyl)amino]-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamideor a salt thereof (Example 150);

[0415] (5R)-N-(5-bromo-2',6'-difluoro[l,r-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l -carboxamide or a salt thereof (Example 206);

[0416] (5R)-N-(5-bromo-2',3,6'-trifluoro[l,r-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l -carboxamide or a salt thereof (Example 254);or

[0417] (5R)-N-(5-bromo-2',3,6'-trifluoro[l,r-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide or a salt thereof (Example 255);

[0418] Compound (I) is particularly preferably

[0419] (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5- (trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide or a salt thereof (Example 147);

[0420] (5R)-N-(5-bromo-2',6'-difluoro[l,r-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l -carboxamide or a salt thereof (Example 206);or

[0421] (5R)-N-(5-bromo-2',3,6'-trifluoro[l,r-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide or a salt thereof (Example 255);

[0422] The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formulae (I) as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

[0423] As a salt of a compound represented by the formula (I), a pharmacologically acceptable salt is preferable, and examples of such salt include a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like.

[0424] Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like.

[0425] Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

[0426] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0427] Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

[0428] Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.

[0429] Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

[0430] Because of its potential use in medicine, it will be appreciated that a salt of a compound of Formula (I) are ideally pharmaceutically acceptable. Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 66, 1- 19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley- VCH / VHCA (2011) (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0431] Optionally the acid or base can be added to the compound of Formula (I) in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

[0432] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2, 5 -dihydroxybenzoate, di succinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1,2-di sulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (A,A'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-l,5-disulfonate (napadisylate), naphthalene-2- sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p- aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, -toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

[0433] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS), arginine, benethamine CV-benzylphenethylamine), benzathine (N,N ’-dibenzylethylenediamine), Z>z'5-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine- 1 ’ -ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-m ethylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, tromethamine (trz'5(hydroxymethyl)aminomethane), and zinc.

[0434] Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I). If a basic compound of Formulae (I) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of Formula (I) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid.

[0435] It will be understood that if a compound of Formula (I) contains two or more basic moi eties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.

[0436] Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula (I) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

[0437] In certain embodiments the present disclosure provides a pharmaceutically acceptable salt of any of the embodiments disclosed herein.

[0438] The production method of the compound of the present invention is explained below.

[0439] The raw material compound and reagent used and the compound obtained in each step in the following production method may be each in a form of a salt, and examples ofsuch salt include those similar to the salts of the compound represented by the formula (I), and the like.

[0440] When the compound obtained in each step is a free form, it can be converted to the objective salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or the other salt according to a method known per se.

[0441] The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.

[0442] When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly.

[0443] In the reaction in each step, while the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min - 48 hr, preferably 10 min - 8 hr, unless otherwise specified.

[0444] In the reaction in each step, while the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally -78°C - 300°C, preferably - 78°C - 150°C, unless otherwise specified.

[0445] In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm - 20 atm, preferably 1 atm - 3 atm, unless otherwise specified.

[0446] Microwave synthesizer such as Initiator manufactured by Biotage and the like may be used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally room temperature - 300°C, preferably 50°C - 250°C, unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min - 48 hr, preferably 1 min - 8 hr, unless otherwise specified.

[0447] In the reaction in each step, the reagent is used in an amount of 0.5 equivalents - 20 equivalents, preferably 0.8 equivalents - 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent - 1 equivalent, preferably 0.01 equivalent - 0.2 equivalent,relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in a solvent amount.

[0448] Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending the raw material compound in a suitable solvent.Examples of the solvent include those described in Examples and the following solvents.

[0449] alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like;

[0450] ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxy ethane and the like;

[0451] aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

[0452] saturated hydrocarbons: cyclohexane, hexane and the like;

[0453] amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;

[0454] halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like;

[0455] nitriles: acetonitrile and the like;

[0456] sulfoxides: dimethyl sulfoxide and the like;

[0457] aromatic organic bases: pyridine and the like;

[0458] anhydrides: acetic anhydride and the like;

[0459] organic acids: formic acid, acetic acid, trifluoroacetic acid and the like;

[0460] inorganic acids: hydrochloric acid, sulfuric acid and the like;

[0461] esters: ethyl acetate and the like;

[0462] ketones: acetone, methyl ethyl ketone and the like;

[0463] water.

[0464] The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio.

[0465] When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.

[0466] inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like;

[0467] organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like;

[0468] metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;

[0469] alkali metal hydrides: sodium hydride and the like;

[0470] metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like;

[0471] organic lithiums: n-butyllithium and the like.

[0472] When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts.

[0473] inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;

[0474] organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like;

[0475] Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

[0476] Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I- VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. l -Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in Examples.

[0477] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), or the like, or the method described in Examples.

[0478] Examples of the protecting group for a hydroxy group of an alcohol and the like and a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester-type protecting groups such as acetate ester and the like; sulfonate ester-type protecting groups such as methanesulfonate ester and the like;carbonate ester-type protecting groups such as tert-butyl carb onate and the like, and the like.

[0479] Examples of the protecting group for a carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal and the like; cyclic acetal-type protecting groups such as 1,3 -di oxane and the like, and the like.

[0480] Examples of the protecting group for a carbonyl group of a ketone include ketal- type protecting groups such as dimethylketal and the like; cyclic ketal-type protecting groups such as 1,3-dioxane and the like; oxime-type protecting groups such as O- methyloxime and the like; hydrazone-type protecting groups such as N,N- dimethylhydrazone and the like, and the like.

[0481] Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; amide-type protecting groups such as N,N-dimethylamide and the like, and the like.

[0482] Examples of the protecting group for a thiol include ether-type protecting groups such as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.

[0483] Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenylmethylamine and the like; sulfonamide-type protecting groups such as methanesulfonamide and the like, and the like.

[0484] The protecting groups can be removed according to a method known per se, for example, by employing a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethyl silyl iodide, trimethyl silyl bromide) and the like, a reduction method, and the like.

[0485] When reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL- H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When carbon-carbon doublebond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar’s catalyst and the like may be employed.

[0486] When oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPB A), hydrogen peroxide, tert-butylhydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6- di cyano- 1,4-benzoquinone (DDQ) and the like.

[0487] When radical cyclization reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4’-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributyl stannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like.

[0488] When Wittig reaction is carried out in each step, examples of the Wittig reagent to be used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0489] When Homer-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithiums and the like.

[0490] When Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin etc.) is used as a reagent. Alternatively, an organicacid or an inorganic acid can also be used instead of a Lewis acid, and an anhydride such as acetic anhydride and the like can also be used instead of an acid chloride.

[0491] When aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g., an organic base etc.) are used as a reagent.

[0492] When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, and examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

[0493] When Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent.

[0494] When Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron withdrawing groups (e.g., malonic acid, diethyl mal onate, malononitrile etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as a reagent.

[0495] When Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (e.g., N,N-dimethylformamide etc.) are used as a reagent.

[0496] When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenylphosphorylazide (DPP A), trimethylsilylazide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and the like are employed.

[0497] When reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and thelike. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like.

[0498] When Mitsunobu reaction is carried out in each step, an azodi carb oxy late (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and triphenylphosphine are used as a reagent.

[0499] When esterification reaction, amidation reaction or urea formation reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as acid anhydrides, activated esters, sulfates and the like. Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1- carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPP A); benzotriazol- 1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-l -methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof and the like. When carbodiimide condensing agent is used, an additive such as 1- hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system.

[0500] When coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), l,l’-bis(diphenylphosphino)ferrocene palladium(II) chloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases and the like.

[0501] When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a l,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4- methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) etc.) can also be used instead of phosphorus pentasulfide.

[0502] When Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide, azobi si sobutyronitrile and the like to the reaction system reaction.

[0503] When halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed. Alternatively, a method of producing an alkyl halide via two steps comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed.

[0504] When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0505] When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

[0506] When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane and the like may be added to reductively-trap tert-butyl cation which is by-produced.

[0507] When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N,N’ -di cyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0508] Compound (I) can be produced from compound (1) according to the method shown in the following Scheme 1. In the formulas, P1is a protecting group, LG1is aleaving group, L1is a bond or an optionally substituted methylene group, R3is a hydrogen atom or a substituent, and the other symbols are as defined above.

[0001] Scheme 1

[0002]

[0509] Examples of the “protecting group” for P1include those exemplified as the above- mentioned “protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like”.

[0510] Examples of the “leaving group” for LG1include halogen atoms, optionally halogenated Ci-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), Ce-14 arylsulfonyloxy optionally substituted by Ci-6 alkyl (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like.

[0511] Compound (1) may be commercially easily available or can be produced according to a method known per se.

[0512] Compound (3) can be produced by subjecting compound (1) to a sulfonamidation reaction with compound (2). Examples of compound (2) to be used include sulfonyl chloride, sulfamoyl chloride and the like. Compound (2) may be commercially easily available or can be produced according to a method known per se.

[0513] Compound (I) can be produced by subjecting compound (4) to a condensation reaction with compound (5) or compound (6) or compound (7). The condensation reaction includes amidation reaction, urea formation reaction, carbamation reaction andthe like. Compound (5) and compound (6) and compound (7) may be commercially easily available or can be produced according to a method known per se.

[0514] In the thus-obtained compound (I), an intramolecular functional group can also be converted to an object functional group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like.

[0515] In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in the peptide chemistry may be introduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction.

[0516] Compound (I) obtained by the above-mentioned production method can be isolated and purified by a known means, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.

[0517] When compound (I) contains optical isomer, stereoisomer, regio isomer and rotamer, these compounds are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also encompassed in compound (I).

[0518] Here, an optical isomer can be produced by a method known per se.

[0519] Compound (I) may be a crystal.

[0520] A crystal of compound (I) (hereinafter sometimes to be abbreviated as the crystal of the present invention) can be produced by crystallizing compound (I), by applying a crystallization method known per se.

[0521] In the thus-obtained compound (I), an intramolecular functional group can also be converted to an object functional group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like.

[0522] In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in the peptide chemistry may beintroduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction.

[0523] Compound (I) obtained by the above-mentioned production method can be isolated and purified by a known means, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.

[0524] When compound (I) contains optical isomer, stereoisomer, regio isomer and rotamer, these compounds are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also encompassed in compound (I).

[0525] Here, an optical isomer can be produced by a method known per se.

[0526] Compound (I) may be a crystal.

[0527] A crystal of compound (I) (hereinafter sometimes to be abbreviated as the crystal of the present invention) can be produced by crystallizing compound (I), by applying a crystallization method known per se.

[0528] In the present specification, the melting point means a melting point measured, for example, by micro melting point apparatus (Yanako, MP-500D or Buchi, B-545), DSC (differential scanning calorimetry analysis) apparatus (METTLER TOLEDO, DSC1) and the like.

[0529] Generally, the melting point sometimes varies depending on the measurement device, measurement condition and the like. The crystal in the present specification may be a crystal showing a melting point different from the values described in the present specification as long as the difference is within a general error range.

[0530] The crystal of the present invention is superior in the physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy expression), and is extremely useful as a medicament.

[0531] Compound (I) may be used as a prodrug. A prodrug of the compound (I) means a compound which is converted to the compound (I) of the present invention with a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to the compound (I) of the present invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compoundwhich is converted to the compound (I) of the present invention by hydrolysis etc. due to gastric acid, etc.

[0532] A prodrug of compound (I) may be

[0533] a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxy carbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tertbutyl ati on, etc.);

[0534] a compound obtained by subjecting a hydroxy group in compound (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting a hydroxy group in compound (I) to an acetylation, palmitoylation, propanoylation, pivaloyl ati on, succinylation, fumarylation, alanylation, dimethyl aminomethyl carb ony 1 ati on, etc . ) ;

[0535] a compound obtained by subjecting a carboxyl group in compound (I) to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (I) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyl oxy methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-l,3- dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification and methyl amidation, etc.)

[0536] and the like. Any of these compounds can be produced from compound (I) by a method known per se.

[0537] A prodrug for compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

[0538] In the present specification, a prodrug may form a salt, and as such salt, those exemplified as a salt of the compound represented by the above-mentioned formula (I) can be mentioned.

[0539] Compound (I) may be labeled with an isotope (e.g.,3H,13C,14C,18F,35S,125I) and the like.

[0540] Compound (I) labeled with or substituted by an isotope can be used, for example, as a tracer used for Positron Emission Tomography (PET) (PET tracer), and is useful in the field of medical diagnosis and the like.

[0541] Furthermore, compound (I) may be a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

[0542] Compound (I) also encompasses a deuterium conversion form whereinTH is converted to2H(D).

[0543] Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal salt means a crystalline substance constituted with two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt can be produced by a cocrystallization method known per se.

[0544] Compound (I) or a prodrug thereof (hereinafter sometimes to be simply abbreviated as the compound of the present invention) can be used as it is or in the form of a pharmaceutical composition (also referred to as a medicament) by mixing with a pharmacologically acceptable carrier etc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the prophylaxis or treatment of various diseases mentioned below.

[0545] As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.

[0546] Preferable examples of the excipient include lactose, sucrose, D-mannitol, D- sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low- substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium alumino metasilicate.

[0547] Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

[0548] Preferable examples of the binder include gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

[0549] Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low- substituted hydroxypropylcellulose.

[0550] Preferable examples of the solvent include water for injection, physiological brine, Ringer’s solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

[0551] Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

[0552] Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbates; and polyoxyethylene hydrogenated castor oil.

[0553] Preferable examples of the isotonicity agent include sodium chloride, glycerol, D- mannitol, D-sorbitol and glucose.

[0554] Preferable examples of the buffer include buffers of phosphate, acetate, carbonate, citrate etc.

[0555] Preferable examples of the soothing agent include benzyl alcohol.

[0556] Preferable examples of the preservative include p-oxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

[0557] Preferable examples of the antioxidant include sulfite salts and ascorbate salts.

[0558] Preferable examples of the colorant include aqueous food tar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like food colors), water insoluble lake dyes (e.g., aluminum salt of the above-mentioned aqueous food tar color), natural dyes (e.g., p- carotene, chlorophyll, red iron oxide) and the like.

[0559] Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

[0560] Examples of the dosage form of the above-mentioned pharmaceutical composition include oral preparations such as tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet), capsule (including soft capsule, microcapsule), pill, granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g., orally disintegrable films, oral mucosa-adhesive film) and the like; and parenteral agents such as injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion), external preparation (e.g., transdermal absorption type preparation, ointment, lotion, adhesive preparation), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like. The compound and medicament of the present invention can be respectively safely administered orally or parenterally (e.g., intrarectal, intravenous, intraarterial, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administrations, and administration to the lesion).

[0561] These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate-release preparation, a sustained-release preparation and the like.

[0562] The pharmaceutical composition can be produced according to a method conventionally used in the field of pharmaceutical formulation, for example, the method described in the Japanese Pharmacopoeia, and the like.

[0563] While the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1 to 100 wt%.

[0564] When an oral preparation is produced, coating may be applied where necessary for the purpose of taste masking, enteric solubility or sustainability.

[0565] Examples of the coating base used for coating include sugar coating base, water- soluble film coating base, enteric film coating base, and sustained-release film coating base.

[0566] As the sugar coating base, sucrose is used, and one or more kinds selected from talc, and the precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be further used in combination.

[0567] Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and the like.

[0568] Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] and the like; and naturally-occurring substances such as shellac and the like.

[0569] Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose and the like; and acrylic acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like.

[0570] Two or more kinds of the above-mentioned coating bases may be used in a mixture at an appropriate ratio. In addition, for example, light shielding agents such as titanium oxide, red ferric oxide and the like may also be used during coating.

[0571] Since the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and less side effects, it can be used as a prophylactic or therapeutic agent, or diagnostic agent for various diseases in mammals (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat).

[0572] The compound of the present invention has an excellent an orexin type 2 receptor agonist activity, and may treat, prevent or ameliorate the risk of various neurological and psychiatric diseases associated with an orexin type 2 receptor. The compound of the present invention is useful as an agent for the prophylaxis or treatment of various diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy -like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Kleine Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson’s disease, progressive supranuclear paralysis, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome,Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen’s encephalitis, Wernicke’s encephalitis, limbic encephalitis, Hashimoto’s encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer’s disease, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, sleep disturbance, sleep problem, insomnia, Intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of alternating worker, sleep disorder, night terror, depression, major depression, sleepwalking disease, enuresis, sleep disorder, Alzheimer’s dusk, diseases associated with circadian rhythm, fibromyalgia, condition arising from decline in the quality of sleep, overeating, obsessive compulsive eating disorder, obesity- related disease, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive cardiac failure, cardiac failure, coronary heart disease, cardiovascular disorder, sudden death, polycysticovarian disease, craniopharingioma, Froelich’s syndrome, growth hormone deficient, normal mutant short stature, Turner’s syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, declining fertility, infertility, male gonadal function decline, sexual and reproductive dysfunction such as female male hirsutism, fetal defects associated with pregnant women obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gall bladder disease, gout, kidney cancer, risk of secondary outcomes of obesity such as lowering the risk of left ventricular hypertrophy, migraine pain, headache, neuropathic pain, Parkinson’s disease, psychosis, schizophrenia, facial flushing, night sweats, diseases of the genital / urinary system, diseases related to sexual function or fertility, dysthymicdisorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral deficit, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders associated with muscle spasticity, delirium, amnestic disorder, age- related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism syndrome, Jill-do La Tourette’s syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavior disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury.

[0573] Particularly, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, and the like, or anesthetic antagonist.

[0574] While the dose of the compound of the present invention varies depending on the subject of administration, administration route, target disease, symptom and the like, for example, when the compound of the present invention is administered orally or parenterally to an adult patient, its dose is for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose and more preferably 0.5 to 20 mg / kg body weight per dose. This amount is desirably administered in one to 3 portions daily.

[0575] The compound of the present invention can be used in combination with other drugs (hereinafter to be abbreviated as concomitant drug).

[0576] By combining the compound of the present invention and a concomitant drug, a superior effect, for example,

[0577] (1) the dose can be reduced as compared to single administration of the compound of the present invention or a concomitant drug,

[0578] (2) the drug to be combined with the compound of the present invention can be selected according to the condition of patients (mild case, severe case and the like),

[0579] (3) the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from the compound of the present invention,

[0580] (4) a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from the compound of the present invention,

[0581] (5) a synergistic effect can be afforded by a combined use of the compound of the present invention and a concomitant drug, and the like, can be achieved.

[0582] In the present specification, the compound of the present invention and a concomitant drug used in combination are referred to as the “combination agent of the present invention”.

[0583] When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.

[0584] The administration mode of the combination agent of the present invention and the concomitant drug is not particularly limited, and the compound of the present invention and the concomitant drug only need to be combined on administration. Examples of such administration mode include the following:

[0585] (1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administrationroute, (3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.

[0586] The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptom, combination and the like.

[0587] For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation.

[0588] The content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation.

[0589] The content of additives such as a carrier and the like in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.99 wt%, preferably from about 10 to about 90 wt%, based on the preparation.

[0590] Similar contents may be employed even when the compound of the present invention and a concomitant drug are separately formulated into preparations.

[0591] Examples of the concomitant drug include the followings. A therapeutic drug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drug (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine,liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trade mark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil, idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor of p amyloid protein production, secretion, accumulation, aggregation and / or deposition, p secretase inhibitor (e.g., 6-(4- biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy- 2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N- dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4’-methoxybiphenyl-4- yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2- (N,N-dimethylamino)ethyl]-6-(4’-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N- dimethylamino)ethyl]-6-(4’-methoxybiphenyl-4-yl)methoxytetralin, 6-(2’,4’- dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(l ,3- benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3’,4’- dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, an optically active form thereof, a salt thereof and a hydrate thereof, OM99-2 (WOO 1 / 00663)), y secretase inhibitor, p amyloid protein aggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), p amyloid vaccine, p amyloid-degrading enzyme and the like, brain function enhancer (e.g., aniracetam, nicergoline), therapeutic drug for Parkinson’s disease [(e.g., dopamine receptor agonist (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)], therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factor), therapeutic drug for abnormal behavior accompanying progress of dementia, wandering and the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regenerate promoter (e.g., leteprinim, xaliproden; SR-57746-A), SB- 216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4- methylphenyl)-2,3-dihydro-l-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-l-benzofuran-5-yl]isoindoline, 6-[3- (4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-l-benzofuran-5-yl]-6,7-dihydro- 5H-[l,3]dioxolo[4,5-f]isoindole and an optically active form, salt or hydrate thereof), non-steroidal antiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin etc.), steroid drug (dexamethasone, hexestrol, cortisone acetate etc.), disease-modifying anti -rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for incontinence, frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitor (e.g., sildenafil(citrate)), dopamine agonist (e.g., apomorphine), anti arrhythmic drugs (e.g., mexiletine), sex hormone or a derivative thereof (e.g., progesterone, estradiol, estradiol benzoate), therapeutic agent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drug for insomnia (e.g., benzodiazepines medicament, non-benzodiazepines medicament, melatonin agonist, orexin receptor antagonists), therapeutic drug for schizophrenia (e.g., typical antipsychotic agents such as haloperidol and the like; atypical antipsychotic agents such as clozapine, olanzapine, risperidone, aripiprazole and the like; medicament acting on metabotropic glutamate receptor or ion channel conjugated-type glutamate receptor; phosphodiesterase inhibitor), benzodiazepines medicament (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam etc.), L-type calcium channel inhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.), serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HTIA agonist, (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride etc.), 5-HT2A antagonist, 5-HT2A inverse agonist, 5-HTs antagonist (cyamemazine etc.), heart non-selective p inhibitor (propranolol hydrochloride, oxprenolol hydrochloride etc.), histamine Hi antagonist (hydroxyzine hydrochloride etc.),CRF antagonist, other antianxiety drug (meprobamate etc.), tachykinin antagonist (MK- 869, saredutant etc.), medicament that acts on metabotropic glutamate receptor, CCK antagonist, p3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabine hydrochloride etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist (memantine etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin Vlb antagonist, vasopressin Via antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate hydrochloride, methamphetamine hydrochloride etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headache, therapeutic drug for quitting smoking, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for male and female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambler, therapeutic drug for restless legs syndrome, therapeutic drug for substance addiction, therapeutic drug for alcohol-related syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for lipid abnormality such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeutic drug for abnormal behavior or suppressant of dromomania due to dementia (sedatives, antianxiety drug etc.), therapeutic drug for diabetes, therapeutic agent for diabetic complications, therapeutic drug for hypertension, therapeutic drug for hypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, anti-cancer agent and the like.

[0592] Two or more kinds of the above-mentioned concomitant drug may be used in a mixture at an appropriate ratio.

[0593] When the compound of the present invention is applied to each of the above- mentioned diseases, it can also be used in combination with biologies (e.g., antibodydrug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation), or can be used in combination with a gene therapy method and the like, or can also be used in combination with a treatment in psychiatric field without using drugs.

[0594] Examples of the antibody drug and vaccine preparation include vaccine preparation against angiotensin II, vaccine preparation against CETP, CETP antibody, antibody against TNFa antibody and other cytokines, amyloid p vaccine preparation, vaccine for type 1 diabetes (e.g., DIAPEP-277 of Peptor), anti-HIV antibody and HIV vaccine preparation, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin type enzymes and products thereof, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines relating to enzymes and proteins involved in blood coagulation or fibrinolysis system, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, and the like. In addition, it can be used in combination with biologies relating to growth factors such as GH, IGF and the like.

[0595] Examples of the gene therapy method include a treatment method using gene relating to cytokine, renin-angiotensin type enzyme and product thereof, G protein, G protein conjugated receptor and phosphorylating enzyme thereof, a treatment method using a DNA decoy such as NFKB decoy and the like, a treatment method using antisense, a treatment method using a gene relating to an enzyme or protein involved in blood lipid metabolism (e.g., a gene relating to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid), a treatment method using a gene relating to an enzyme or protein involved in angiogenesis therapy for peripheral vascular obstruction and the like (e.g., growth factors such as HGF, VEGF etc.), a treatment method using a gene relating to a protein involved in glucose metabolism and insulin resistance, antisense against cytokines such as TNF etc., and the like.

[0596] Examples of the treatment method in the psychiatric field without using drug include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy and the like.

[0597] The compound of the present invention can also be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, revascularization and the like, cell transplantation therapyutilizing bone marrow cells (bone marrow-derived mononuclear cell, myelogenic stem cell), or artificial organ utilizing tissue engineering (e.g., artificial blood vessel, cardiomyocyte sheet).EXAMPLES

[0598] The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples. However, the examples do not limit the present invention and the examples can be modified within the scope of the present invention.

[0599] The “room temperature” in the following Examples is generally about 10°C to about 35°C. The ratio for mixed solvent is, unless otherwise specified, a volume mixing ratio and % means wt% unless otherwise specified.

[0600] The elution by column chromatography in the Examples was performed under the observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the observation by TLC, 60 F254 manufactured by Merck was used as a TLC plate, the solvent used as an elution solvent in column chromatography was used as an eluent, and UV detector was used for the detection. In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel and the indication of DIOL means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. Preparative HPLC (high performance liquid chromatography) was performed under the following conditions; column: Boston Prime C18 (150 mm x 30 mm, 5 pm), Xtimate C18 (100 mm x 30 mm, 3 pm), Gemini NX C18 (150 mm x 30 mm, 5 pm), YMC Triart C18 (250 mm x 50 mm, 7 pm), Exsil plus Cl 8 (150 mm x 50 mm, 5 pm), or Water Xbridge Cl 8 (150 mm x 30 mm, 5 pm), mobile phase: 0.05% aqueous ammonia / MeCN. The indication of C18 means use of octadecyl-bonded silica gel. The ratio for elution solvent is, unless otherwise specified, a volume mixing ratio.

[0601] For the analysis of ’H NMR, ACD / SpecManager (trade name) software and the like were used. Peaks of a hydroxyl group, an amino group and the like, having very mild proton peak, are not sometimes described.

[0602] MS was measured by LC / MS. As the ionization method, ESI method, or APCI method was used. The data indicates actual measured value (found). While molecularion peak is generally observed, a fragment ion is sometimes observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.

[0603] In the following Examples, the following abbreviations are used.

[0604] MS: mass spectrum

[0605] M: mol concentration

[0606] N: normality

[0607] CDCh: deuterochloroform

[0608] DMSO-de: deuterodimethyl sulfoxide

[0609] NMR: proton nuclear magnetic resonance

[0610] LC / MS: liquid chromatograph mass spectrometer

[0611] ESI: electrospray ionization

[0612] APCI: atmospheric pressure chemical ionization

[0613] IPE: diisopropyl ether

[0614] NBS: N-bromosuccinimide

[0615] DMF : N,N-dimethylformamide

[0616] THF: tetrahydrofuran

[0617] MeOH: methanol

[0618] CPME: cyclopentyl methyl ether

[0619] DME: 1,2-dimethoxy ethane

[0620] XPhosPdG3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'- amino-1, l'-biphenyl)]palladium(II) methanesulfonate

[0621] TEA: triethylamine

[0622] DPP A: diphenylphosphoryl azide

[0623] DMAP: 4-dimethylaminopyridineExample 54

[0624] (4S)-4-[(dimethylsulfamoyl)amino]-N-(2',3,6'-trifluoro[l,r-biphenyl]-2- yl)azepane- 1 -carboxamide

[0625] A) N'-[(4S)-azepan-4-yl]-N,N-dimethylsulfuric diamide hydrochloride

[0626] To a mixture of tert-butyl (4S)-4-aminoazepane-l -carboxylate (200 mg), TEA(0.390 mL) and DME (5.0 mL) were added dimethyl sulfamoyl chloride (0.138 mL) andDMAP (57.0 mg) at 0°C. The mixture was stirred at 60°C for 6 hr, and purified by silicagel column chromatography (ethyl acetate / hexane). A mixture of the obtained compound and 4 M hydrogen chloride / CPME solution (1 mL) was stirred overnight at room temperature. The mixture was concentrated, and the obtained solid was washed with IPE to give the title compound (141 mg).

[0627] XH NMR (400 MHz, DMSO-de) 5 1.54-1.75 (2H, m), 1.77-1.89 (2H, m), 1.91- 2.01 (1H, m), 2.02-2.12 (1H, m), 2.65 (6H, s), 2.91-3.25 (4H, m), 3.30-3.47 (1H, m), 7.33 (1H, br d, J = 7.3 Hz), 8.73-9.11 (2H, m).

[0628] B) 2',3,6'-trifluoro[l,r-biphenyl]-2-amine

[0629] To a mixture of 2-bromo-6-fluoroaniline (600 mg), (2,6-difluorophenyl)boronic acid (997 mg), 1 M aqueous potassium phosphate solution (9.47 mL) and DME (7.0 mL) was added XPhosPdG3 (401 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (370 mg).

[0630] MS: [M+H]+224.0.

[0631] C) (4S)-4-[(dimethylsulfamoyl)amino]-N-(2',3,6'-trifluoro[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0632] To a mixture of 2',3,6'-trifluoro[l,l'-biphenyl]-2-amine (21.7 mg), TEA (0.041 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (17.3 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N'- [(4S)-azepan-4-yl]-N,N-dimethylsulfuric diamide hydrochloride (20 mg), TEA (0.041 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (21 mg).

[0633] ’H NMR (300 MHz, CDCh) 5 1.35-2.01 (6H, m), 2.79 (6H, s), 3.03-3.24 (1H, m), 3.26-3.43 (3H, m), 3.48-3.62 (1H, m), 3.81-3.91 (1H, m), 5.83-5.96 (1H, m), 6.96-7.07 (2H, m), 7.11-7.25 (3H, m), 7.30-7.38 (1H, m).Example 61

[0634] (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)azepane-l- carb oxami de

[0635] A) tert-butyl (4S)-4-[(ethanesulfonyl)amino]azepane-l-carboxylate

[0636] To a mixture of tert-butyl (4S)-4-aminoazepane-l -carboxylate (457 mg), TEA (0.892 mL) and DME (10 mL) was added ethanesulfonyl chloride (0.283 mL) at 0°C. The mixture was stirred at the same temperature for 1 hr, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (650 mg).

[0637] MS: [M+H-Boc]+207.0.

[0638] B) N-[(4S)-azepan-4-yl]ethanesulfonamide hydrochloride

[0639] A mixture of tert-butyl (4 S)-4-[(ethanesulfonyl)amino] azepane- 1 -carboxylate(650 mg) and 4 M hydrogen chloride / CPME solution (10 mL) was stirred overnight at room temperature, and the reaction solution was concentrated to give the title compound (463 mg).

[0640] MS: [M+H]+207.0.

[0641] C) (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6'-trifluoro[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0642] To a mixture of 2',3,6'-trifluoro[l,r-biphenyl]-2-amine (23.0 mg), TEA (0.034 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (12.2 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N- [(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (20 mg), TEA (0.043 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (36 mg).

[0643] 1H NMR (300 MHz, CDCh) 5 1.36 (3H, t, J = 7.5 Hz), 1.42-1.68 (3H, m), 1.71- 1.86 (1H, m), 1.86-2.04 (2H, m), 3.02 (2H, q, J = 7.5 Hz), 3.09-3.21 (1H, m), 3.28-3.50 (3H, m), 3.51-3.65 (1H, m), 3.91-4.04 (1H, m), 5.85-5.97 (1H, m), 6.98-7.07 (2H, m), 7.11-7.41 (4H, m).Example 71

[0644] (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,5,6'-tetrafluoro[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0645] A) 2',3,5,6'-tetrafluoro[l,l'-biphenyl]-2-amine

[0646] To a mixture of 2-bromo-4,6-difluoroaniline (500 mg), (2,6- difluorophenyl)boronic acid (759 mg), 1 M aqueous potassium phosphate solution (7.21 mL) and DME (5.0 mL) was added XPhosPdG3 (305 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (310 mg).

[0647] MS: [M+H]+241.9.

[0648] B) (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,5,6'-tetrafluoro[l,T-biphenyl]-2- yl)azepane- 1 -carboxamide

[0649] To a mixture of 2',3,5,6'-tetrafluoro[l,T-biphenyl]-2-amine (18.6 mg), TEA(0.039 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (13.8 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N- [(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (15 mg), TEA (0.032 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (15 mg).

[0650] 1H NMR (300 MHz, CDCh) 5 1.36 (3H, t, J = 7.3 Hz), 1.46-2.05 (6H, m), 3.02 (2H, q, J = 7.4 Hz), 3.08-3.20 (1H, m), 3.31-3.64 (4H, m), 3.90-4.01 (1H, m), 5.76-5.85 (1H, m), 6.88-7.08 (4H, m), 7.31-7.42 (1H, m).Example 74

[0651] (4S)-N-(5-chloro-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0652] A) 5-chloro-2',3,6'-trifluoro[l,l'-biphenyl]-2-amine

[0653] To a mixture of 2-bromo-4-chloro-6-fluoroaniline (500 mg), (2,6- difluorophenyl)boronic acid (704 mg), 1 M aqueous potassium phosphate solution (6.68 mL) and DME (5.0 mL) was added XPhosPdG3 (283 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (180 mg).

[0654] MS: [M+H]+257.9.

[0655] B) (4S)-N-(5-chloro-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-4- [(ethanesulfonyl)amino]azepane-l-carboxamide

[0656] To a mixture of 5-chloro-2(3,6Mrifhioro[l,l'-biphenyl]-2-amine (19.9 mg), TEA (0.039 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (13.8 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N- [(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (15 mg), TEA (0.032 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (23 mg).

[0657] ’H NMR (300 MHz, CDCh) 5 1.32-2.06 (9H, m), 3.02 (2H, q, J = 7.2 Hz), 3.08- 3.19 (1H, m), 3.29-3.48 (3H, m), 3.50-3.62 (1H, m), 3.90-3.99 (1H, m), 5.81-5.87 (1H, m), 6.98-7.08 (2H, m), 7.14-7.25 (2H, m), 7.32-7.41 (1H, m).Example 81

[0658] (4S)-N-(2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-yl)-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0659] A) 2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-amine

[0660] To a mixture of 2-bromo-4-methylaniline (0.067 mL), (2,6- difluorophenyl)boronic acid (255 mg), 1 M aqueous potassium phosphate solution (2.15 mL) and DME (2.0 mL) was added XPhosPdG3 (68.2 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (34.5 mg).

[0661] MS: [M+H]+220.0.

[0662] B) (4S)-N-(2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-yl)-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0663] To a mixture of 2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-amine (34.5 mg), TEA(0.040 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (14.3 mg) at 0°C.The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N- [(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (15.6 mg), TEA (0.034 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (25.7 mg).

[0664] 1H NMR (300 MHz, CDCh) 5 1.35 (3H, t, J = 7.3 Hz), 1.50-1.66 (3H, m), 1.67-1.84 (1H, m), 1.88-2.07 (2H, m), 2.35 (3H, s), 3.01 (2H, q, J = 7.5 Hz), 3.14 (1H, ddd, J = 15.0, 8.9, 3.2 Hz), 3.22-3.32 (2H, m), 3.37-3.64 (2H, m), 4.07 (1H, d, J = 7.9 Hz), 6.07 (1H, s), 7.00-7.10 (3H, m), 7.23 (1H, dd, J = 8.8, 2.1 Hz), 7.32-7.44 (1H, m), 7.83 (1H, d, J = 8.3 Hz).Example 82

[0665] (4S)-N-[2',6'-difluoro-5-(trifluoromethyl)[l,l'-biphenyl]-2-yl]-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0666] A) 2',6'-difluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-amine

[0667] To a mixture of 2-bromo-4-(trifluoromethyl)aniline (0.071 mL), (2,6- difluorophenyl)boronic acid (197 mg), 1 M aqueous potassium phosphate solution (1.67 mL) and DME (2.0 mL) was added XPhosPdG3 (52.9 mg) at room temperature. The mixture was stirred at 80°C for 1 hr, the aqueous layer was removed, and the mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (35.8 mg).

[0668] MS: [M+H]+274.0.

[0669] B) (4S)-N-[2',6'-difluoro-5-(trifluoromethyl)[l,l'-biphenyl]-2-yl]-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0670] To a mixture of 2',6'-difluoro-5-(trifluoromethyl)[l,l'-biphenyl]-2-amine (21.4 mg), TEA (0.039 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (13.9 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N-[(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (15.2 mg), TEA (0.033 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (27.5 mg).

[0671] 1H NMR (300 MHz, CDCh) 5 1.35 (3 H, t, J = 7.3 Hz), 1.50-1.69 (3H, m), 1.71-1.85 (1H, m), 1.92-2.12 (2H, m), 3.02 (2H, q, J = 7.2 Hz), 3.16 (1H, ddd, J = 14.7, 9.2, 3.2 Hz), 3.28 (2H, t, J = 5.5 Hz), 3.39-3.63 (2H, m), 4.08 (1H, d, J = 7.9 Hz), 6.31 (1H, s),7.05-7.18 (2H, m), 7.40-7.56 (2H, m), 7.67 (1H, dd, J = 8.7, 1.9 Hz), 8.31 (1H, d, J = 8.7 Hz).Example 92

[0672] (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6,6'-tetrafluoro[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0673] A) 2-bromo-4-chl oro-3, 6-difluoroaniline

[0674] To a mixture of 4-chloro-2,5-difluoroaniline (503 mg) and DMF (10 mL) was added NBS (547 mg) at 0°C. The mixture was stirred at room temperature for 1 hr, the mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (646 mg).

[0675] 1H NMR (300 MHz, CDCh) 5 4.26 (2H, br s), 7.02-7.11 (1H, m).

[0676] B) 5-chloro-2',3,6,6'-tetrafluoro[l,T-biphenyl]-2-amine

[0677] To a mixture of 2-bromo-4-chl oro-3, 6-difluoroaniline (546 mg), (2,6- difluorophenyl)boronic acid (711 mg), 1 M aqueous potassium phosphate solution (6.76 mL) and DME (5.0 mL) was added XPhosPdG3 (286 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (300 mg).

[0678] MS: [M+H]+275.9.

[0679] C) (4S)-N-(5-chloro-2',3,6,6'-tetrafluoro[l,l'-biphenyl]-2-yl)-4-[(ethanesulfonyl)amino]azepane-l-carboxamide

[0680] To a mixture of 5-chloro-2',3,6,6'-tetrafluoro[l,r-biphenyl]-2-amine (42.6 mg),TEA (0.078 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (27.5 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N-[(4S)-azepan-4-yl]ethanesulfonamide hydrochloride (30 mg), TEA (0.065 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (40 mg).

[0681] MS: [M+H]+508.0.

[0682] D) (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6,6'-tetrafluoro[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0683] A mixture of (4S)-N-(5-chloro-2',3,6,6'-tetrafluoro[l,r-biphenyl]-2-yl)-4-[(ethanesulfonyl)amino]azepane-l-carboxamide (30 mg), 10% palladium on carbon (10 mg) and MeOH (1.0 mL) was stirred overnight under normal pressure of hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (22 mg).

[0684] 1H NMR (300 MHz, CDCh) 5 1.37 (3H, t, J = 7.3 Hz), 1.41-1.66 (3H, m), 1.70- 2.03 (3H, m), 3.03 (2H, q, J = 7.2 Hz), 3.08-3.20 (1H, m), 3.29-3.48 (3H, m), 3.49-3.63 (1H, m), 3.88-4.01 (1H, m), 5.90 (1H, s), 6.96-7.10 (3H, m), 7.13-7.23 (1H, m), 7.35-7.43 (1H, m).Example 95

[0685] rel-(5R)-4,4-difhioro-5-[(methanesulfonyl)amino]-N-(2(3,6'-trifluoro[l,l'- biphenyl]-2-yl)azepane-l -carboxamide

[0686] A) tert-butyl {5,5-difhioro-l-[(2(3,6Mrifhioro[l,l'-biphenyl]-2- yl)carbamoyl]azepan-4-yl}carbamate

[0687] To a mixture of 2',3,6'-trifluoro[l,T-biphenyl]-2-amine (55.7 mg), TEA (0.125 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (44.5 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of tertbutyl (5,5-difluoroazepan-4-yl)carbamate (50 mg), TEA (0.104 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (75 mg).

[0688] MS: [M+H-Boc]+400.1.

[0689] B) 5-amino-4,4-difluoro-N-(2',3 ,6'-trifluoro[ 1 , 1 '-biphenyl]-2-yl)azepane- 1 - carboxamide hydrochloride

[0690] A mixture of tert-butyl {5,5-difluoro-l-[(2',3,6'-trifluoro[l,l'-biphenyl]-2- yl)carbamoyl]azepan-4-yl}carbamate (60 mg) and 4M hydrogen chloride / CPME solution (3.0 mL) was stirred overnight at room temperature. The reaction solution was concentrated to give the title compound (52 mg).

[0691] MS: [M+H]+400.2.

[0692] C) rel-(5R)-4,4-difluoro-5-[(methanesulfonyl)amino]-N-(2',3,6'-trifluoro[l,l'- biphenyl]-2-yl)azepane-l -carboxamide

[0693] To a mixture of 5-amino-4,4-difluoro-N-(2',3,6'-trifluoro[l,l'-biphenyl]-2- yl)azepane-l -carboxamide hydrochloride (20 mg), TEA (0.019 mL) and DME (1.0 mL) was added methanesulfonic anhydride (9.59 mg) at room temperature. The mixture was stirred at room temperature for 3 days, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained residue was resolved by HPLC (column: CHIRALPAK IG, 20 mmIDx250 mmL, 5pm, mobile phase: hexane / ethanol= 750 / 250) to give the title compound (7.8 mg) having a shorter retention time.

[0694] ’H NMR (300 MHz, CDCk) 5 1.82-2.30 (4H, m), 3.04 (3H, s), 3.23-3.40 (2H, m), 3.41-3.54 (1H, m), 3.61-3.71 (1H, m), 3.72-3.91 (1H, m), 4.69 (1H, d, J = 9.0 Hz), 5.95 (1H, s), 6.98-7.10 (2H, m), 7.13-7.41 (4H, m).Example 98

[0695] (4S)-N-(5-chl oro-2', 6'-difluoro[l, l'-biphenyl]-2-yl)-4-[(methanesulfonyl)amino]azepane-l-carboxamide

[0696] A) 5-chl oro-2', 6'-difluoro[l,T-biphenyl]-2-amine

[0697] To a mixture of 2-bromo-4-chloroaniline (500 mg), (2,6-difluorophenyl)boronic acid (765 mg), 1 M aqueous potassium phosphate solution (7.27 mL) and DME (5.0 mL) was added XPhosPdG3 (307 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, the aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (340 mg).

[0698] MS: [M+H]+239.9.

[0699] B) tert-butyl (4S)-4-[(methanesulfonyl)amino]azepane-l-carboxylate

[0700] To a mixture of tert-butyl (4S)-4-aminoazepane-l -carboxylate (2 g), TEA (2.59 mL) and THF (20 mL) was added methanesulfonic anhydride (1.95 g) at 0°C. The mixture was stirred under nitrogen atmosphere at room temperature for 3 hr, and partitioned between ethyl acetate-water, and the organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and water, driedover anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.7 g).

[0701] 1HNMR (300 MHz, CDCh) 5 1.47 (9H, s), 1.59-1.79 (3H, m), 1.79-2.02 (2H, m), 2.06-2.16 (1H, m), 2.97 (3H, s), 3.09-3.23 (1H, m), 3.26-3.78 (4H, m), 4.27-4.44 (1H, m).

[0702] C) N-[(4S)-azepan-4-yl]methanesulfonamide hydrochloride

[0703] A mixture of tert-butyl (4S)-4-[(methanesulfonyl)amino]azepane-l -carboxylate(2.7 g) and 4 M hydrogen chloride / CPME solution (23.1 mL) was stirred at room temperature for 5 hr, and the reaction solution was concentrated. The obtained residue was solidified from methanol / di ethyl ether, and the resulting solid was collected by filtration. The solid was washed with diethyl ether, and dried to give the title compound (1.8 g).

[0704] 1H NMR (300 MHz, DMSO-de) 5 1.50-1.76 (2H, m), 1.76-1.91 (2H, m), 1.91- 2.01 (1H, m), 2.01-2.15 (1H, m), 2.92 (3H, s), 2.96-3.21 (4H, m), 3.40-3.56 (1H, m), 7.21 (1H, d, J = 7.2 Hz), 8.83-9.20 (2H, m).

[0705] D) (4S)-N-(5-chl oro-2', 6'-difluoro[l, l'-biphenyl]-2 -yl)-4-[(methanesulfonyl)amino]azepane-l-carboxamide

[0706] To a mixture of 5-chloro-2',6'-difluoro[l,T-biphenyl]-2-amine (19.6 mg), TEA (0.041 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (14.6 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and a mixture of N- [(4S)-azepan-4-yl]methanesulfonamide hydrochloride (15 mg), TEA (0.034 mL) and THF (1.0 mL) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (22 mg).

[0707] 1H NMR (300 MHz, CDCh) 5 1.58-1.84 (3H, m), 1.89-2.12 (2H, m), 2.96 (3H, s), 3.08-3.22 (1H, m), 3.23-3.32 (2H, m), 3.40-3.62 (3H, m), 4.12-4.22 (1H, m), 6.12 (1H, s), 7.02-7.13 (2H, m), 7.22-7.25 (1H, m), 7.36-7.50 (2H, m), 7.96-8.08 (1H, m).Example 100

[0708] (4S)-N-(2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-yl)-4-[(methanesulfonyl)amino]azepane-l-carboxamide

[0709] To a mixture of 2',6'-difluoro-5-methyl[l,l'-biphenyl]-2-amine (20.3 mg), TEA(0.046 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (16.5 mg) at 0°C.The reaction mixture was stirred at the same temperature for 30 min, and N-[(4S)-azepan- 4-yl]methanesulfonamide hydrochloride (16.9 mg) and TEA (0.039 mL) were added thereto at 0°C. The mixture was stirred at room temperature for 2 hr, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (22.5 mg).

[0710] 1H NMR (300 MHz, CDCk) 5 1.49-1.67 (3H, m), 1.69-1.84 (1H, m), 1.87-2.10 (2H, m), 2.35 (3H, s), 2.95 (3H, s), 3.16 (1H, ddd, J = 14.9, 8.8, 3.4 Hz), 3.22-3.35 (2H, m), 3.41-3.67 (2H, m), 4.21 (1H, d, J = 7.5 Hz), 6.08 (1H, s), 7.00-7.12 (3H, m), 7.19- 7.25 (1H, m), 7.38 (1H, tt, J = 8.5, 6.4 Hz), 7.83 (1H, d, J = 8.7 Hz).Example 105

[0711] (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6'-trifluoro-5-methyl[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0712] A) 2-bromo-6-fluoro-4-methylbenzeneamine

[0713] To a mixture of 2-fluoro-4-methylaniline (1.5 g) and DMF (15 mL) was added N- bromosuccinimide (2.13 g) at 0°C in several portions. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 14 hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (2.28 g).

[0714] ’H NMR (400 MHz, CDCk) 5 2.22 (3H, s), 3.95 (2H, br s), 6.78 (1H, d, J = 10.4 Hz), 7.03 (1H, s).

[0715] B) 2',3,6'-trifluoro-5-methyl[l,r-biphenyl]-2-amine

[0716] To a mixture of 2-bromo-6-fluoro-4-methylbenzeneamine (300 mg), XPhosPdG3 (124 mg), 1 M aqueous potassium phosphate solution (4.41 mL) and DME (6 mL) was added dropwise a mixture of (2,6-difluorophenyl)boronic acid (697 mg) and DME (6 mL) at 80°C over 9 min. The mixture was stirred under nitrogen atmosphere at 80°C for 1 hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (80 mg). MS: [M+H]+238.1.

[0717] C) (4S)-4-[(ethanesulfonyl)amino]-N-(2',3,6'-trifluoro-5-methyl[l,l'-biphenyl]-2- yl)azepane- 1 -carboxamide

[0718] To a mixture of 2\3,6'-trifluoro-5-methyl[l '-biphenyl]-2-amine (15.9 mg), TEA (0.034 mL) and THF (2 mL) was added bis(trichloromethyl) carbonate (11.9 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and N-[(4S)-azepan- 4-yl]ethanesulfonamide hydrochloride (13.0 mg) and TEA (0.028 mL) were added thereto at 0°C. The mixture was stirred at room temperature for 2 hr, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (8.5 mg).

[0719] 1H NMR (300 MHz, CDCk) 5 1.36 (3H, t, J = 7.5 Hz), 1.42-1.68 (3H, m), 1.71- 1.84 (1H, m), 1.85-2.03 (2H, m), 2.38 (3H, s), 3.02 (2H, q, J = 7.5 Hz), 3.13 (1H, ddd, J = 14.6, 8.9, 3.2 Hz), 3.26-3.49 (3H, m), 3.50-3.62 (1H, m), 3.99 (1H, d, J = 7.9 Hz), 5.81 (1H, s), 6.92-7.07 (4H, m), 7.27-7.39 (1H, m).Example 106

[0720] (4S)-N-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4-[(methanesulfonyl)amino]azepane-l-carboxamide

[0721] A) (4S)-N-(3-bromo-5-methylpyridin-2-yl)-4-[(methanesulfonyl)amino]azepane-1 -carboxamide

[0722] To a mixture of 3-bromo-5-methylpyridine-2-carboxylic acid (100 mg), TEA(0.194 mL) and toluene (2 mL) was added DPPA (0.150 mL) at room temperature. The reaction mixture was stirred at 100°C for 1 hr, and N-[(4S)-azepan-4- yl]methanesulfonamide hydrochloride (127 mg) and TEA (0.194 mL) were added thereto. The mixture was stirred under nitrogen atmosphere at 100°C for 3 hr, and the reaction mixture was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (154 mg).

[0723] MS: [M+H]+405.0.

[0724] B) (4S)-N-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4-[(methanesulfonyl)amino]azepane-l-carboxamide

[0725] To a mixture of (4S)-N-(3-bromo-5-methylpyridin-2-yl)-4-[(methanesulfonyl)amino]azepane-l-carboxamide (153 mg), 3 M aqueous potassium phosphate solution (0.377 mL), XPhosPdG3 (16.0 mg) and DME (1.0 mL) was added amixture of (2,6-difluorophenyl)boronic acid (119 mg) and DME (1.5 mL) at 80°C. The reaction mixture was stirred at 80°C for 1 hr, (2,6-difluorophenyl)boronic acid (139 mg) was added thereto, and the mixture was stirred at 100°C for 1 hr. To the reaction mixture were added (2,6-difluorophenyl)boronic acid (119 mg) and XPhosPdG3 (16.0 mg), and the mixture was subjected to microwave irradiation at 120°C for 1 hr. The aqueous layer was removed, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and HPLC (column: YMC- Actus Triant Cl 8, mobile phase: water / acetonitrile (containing 10 mM ammonium bicarbonate)) to give the title compound (2.0 mg).

[0726] 1H NMR (300 MHz, CDCk) 5 1.43-1.54 (2H, m), 1.76-1.99 (3H, m), 2.35 (3H, s), 2.96 (3H, s), 3.07 (1H, t, J = 10.9 Hz), 3.22-3.70 (5H, m), 4.46 (1H, d, J = 8.3 Hz), 6.61 (1H, br s), 6.94-7.07 (2H, m), 7.28-7.36 (1H, m), 7.49 (1H, s), 8.25 (1H, d, J = 1.5 Hz).Example 139

[0727] (5R)-N-(5-chl oro-2', 6'-difluoro[ 1, l'-biphenyl]-2-yl)-4, 4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0728] A) benzyl (5R)-4,4-difluoro-5-(2,2,2-trifluoroacetamido)azepane-l -carboxylate

[0729] rac-Benzyl 4,4-difluoro-5-(2,2,2-trifluoroacetamido)azepane-l-carboxylate (40.0 g) was separated by SFC (column: DAICEL CHIRALPAK AD, 250mm x 50mm, lOum, mobile phase: carbon dioxide / (MeOH / NH3H2O = 1000 / 1) = 890 / 110 (v / v)) to give the title compound (17.0 g) having a longer retention time.

[0730] ’H NMR (400 MHz, CDCk) 5 2.01-2.05 (2H, m), 2.20-2.38 (2H, m), 3.40-3.65 (3H, m), 3.77-3.79 (1H, m), 4.39- 4.45 (1H, m), 5.13-5.21 (2H, m), 6.78 (1H, br d, J = 7.6 Hz), 7.33-7.40 (5H, m).

[0731] B) benzyl (5R)-5-amino-4,4-difluoroazepane-l-carboxylate

[0732] To a mixture of benzyl (5R)-4,4-difluoro-5-(2,2,2-trifluoroacetamido)azepane-l- carboxylate (5.08 g), MeOH (100 mL) and water (50 mL) was added 5 M aqueous potassium carbonate solution (14 mL) at room temperature. The mixture was stirred at 50 °C overnight. After being concentrated in vacuo, to the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate. The mixture was passed through NH silica gel pad (ethyl acetate) to give the title compound (3.77 g).

[0733] MS: [M+H]+285.0.

[0734] C) benzyl (5R)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l -carboxylate

[0735] To a mixture of benzyl (5R)-5-amino-4,4-difluoroazepane-l-carboxylate (1.88 g), TEA (2.0 mL), DMAP (0.407 g) and THF (30 mL) was added Methanesulfonic anhydride (1.8 g) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 days. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 0.1 M aqueous hydrogen chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.36 g).

[0736] MS: [M+Na]+385.0.

[0737] D) N-[(4R)-5,5-difluoroazepan-4-yl]methanesulfonamide

[0738] A mixture of benzyl (5R)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l- carboxylate (2.36 g), 10 % Pd on carbon (236 mg), EtOH (40 mL), and ethyl acetate (20 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.34 g).

[0739] MS: [M+H]+228.9.

[0740] E) (5R)-N-(5-chl oro-2', 6'-difhioro[l,l'-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0741] To a mixture of 5-chl oro-2', 6'-difhioro-[l,l'-biphenyl]-2-amine (126 mg), TEA(0.366 mL) and THF (5.0 mL) was added bis(trichloromethyl) carbonate (62.4 mg) at 0 °C. After being stirred at 0 °C under nitrogen atmosphere for 30 min, to the mixture was added N-[(4R)-5,5-difluoroazepan-4-yl]methanesulfonamide (120 mg) at 0 °C. The mixture was stirred at 0 °C for 30 min, then was stirred at room temperature under nitrogen atmosphere overnight. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate / hexane). The residue was crystallized from ethyl acetate-hexane to give the title compound (206 mg).

[0742] XH NMR (300 MHz, DMSO-de) 5 1.69-2.20 (4H, m), 2.94 (3H, s), 3.03-3.20 (1H, m), 3.22-3.45 (3H, m), 3.50-3.70 (1H, m), 7.07-7.19 (2H, m), 7.34-7.52 (4H, m), 7.63- 7.75 (1H, m), 8.13 (1H, s).Example 147

[0743] (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide

[0744] A) 2',3,6'-trifluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-amine

[0745] To a mixture of 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (4.21 g), 2-(2,6- difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (7.83 g), potassium fluoride (2.84 g), tri -tert-butyl phosphonium tetrafluoroborate (0.473 g), water (3.5 mL) and DME (26 mL) was added Tris(dibenzylideneacetone)dipalladium (0) (0.747 g) at room temperature. The mixture was stirred at 80 °C under nitrogen atmosphere overnight. To the mixture was added ethyl acetate, then the mixture was passed through NH silica gel pad. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3.80 g).

[0746] ’H NMR (400 MHz, DMSO-de) 5 5.72 (2H, s), 7.14-7.27 (3H, m), 7.44-7.59 (2H, m).

[0747] B) benzyl (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxylate

[0748] To a mixture of benzyl (5R)-5-amino-4,4-difluoroazepane-l-carboxylate (1.89 g), TEA (2.0 mL), DMAP (0.406 g) and THF (30 mL) was added ethanesulfonyl chloride (0.96 mL) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 days. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 0.1 M aqueous hydrogen chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.25 g).

[0749] MS: [M+H]+377.0.

[0750] C) N-[(4R)-5,5-difluoroazepan-4-yl]ethanesulfonamide

[0751] A mixture of benzyl (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l- carboxylate (2.25 g), 10 % Pd on carbon (225 mg), EtOH (40 mL), and ethyl acetate (20 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with EtOH (40 mL) and ethyl acetate (20 mL). To the mixture was added 10 % Pd on carbon (225 mg). The mixture was stirred at room temperature under hydrogenwith balloon pressure for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (1.35 g).

[0752] MS: [M+H]+243.0.

[0753] D) (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide

[0754] To a mixture of 2',3,6'-trifluoro-5-(trifluoromethyl)-[l,r-biphenyl]-2-amine (507 mg), TEA (748 mg) and toluene (8.0 mL) was added a mixture of bis(tri chloromethyl) carbonate (365 mg) and toluene (4.0 mL) at room temperature. The mixture was stirred at 60 °C under nitrogen atmosphere for 20 min. After being cooled to room temperature, to the mixture was added a mixture of hexane / di ethyl ether (1 / 1 v / v). The insoluble material was removed by filtration (hexane / di ethyl ether (1 / 1 v / v)), and the filtrate was concentrated in vacuo. The residue was diluted with THF (4.0 mL), and was added to a mixture of N-[(4R)-5,5-difluoroazepan-4-yl]ethanesulfonamide (370 mg), TEA (187 mg) and THF (8.0 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was passed through NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained residue was crystallized from ethyl acetate / heptane to give the title compound (573 mg).

[0755] 1H NMR (400 MHz, CDCh) 5 1.40 (3H, t, J = 7.3 Hz), 1.79-1.97 (1H, m), 1.98- 2.22 (3H, m), 3.04-3.20 (2H, m), 3.23-3.34 (1H, m), 3.34-3.45 (1H, m), 3.46-3.57 (1H, m), 3.60-3.79 (2H, m), 4.51 (1H, d, J = 9.4 Hz), 6.08 (1H, s), 7.08 (2H, q, J = 8.4 Hz), 7.33-7.42 (1H, m), 7.43-7.50 (2H, m).Example 150

[0756] (5R)-4,4-difluoro-5-[(methanesulfonyl)amino]-N-[2',3,6'-trifluoro-5- (trifluoromethyl)[l , 1 '-biphenyl]-2-yl]azepane- 1 -carboxamide

[0757] A) (5R)-4,4-difluoro-5-[(methanesulfonyl)amino]-N-[2',3,6'-trifluoro-5-(trifluoromethyl)[l , 1 '-biphenyl]-2-yl]azepane- 1 -carboxamide

[0758] To a mixture of 2',3,6'-trifluoro-5-(trifluoromethyl)-[l,l'-biphenyl]-2-amine (281 mg), TEA (0.672 mL) and THF (8.0 mL) was added bis(trichloromethyl) carbonate (114 mg) at 0 °C. After being stirred at 0 °C under nitrogen atmosphere for 30 min, to the mixture was added N-[(4R)-5,5-difluoroazepan-4-yl]methanesulfonamide (200 mg) at 0°C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 h. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give a solid. The solid was crystallized from ethyl acetate / heptane to give the title compound (350 mg).

[0759] 1H NMR (300 MHz, DMSO-de) 5 1.68-2.23 (4H, m), 2.94 (3H, s), 3.07-3.21 (1H, m), 3.33-3.51 (3H, m), 3.52-3.70 (1H, m), 7.17 (2H, t, J = 8.5 Hz), 7.38-7.53 (1H, m), 7.58 (1H, s), 7.64-7.75 (1H, m), 7.79-7.91 (1H, m), 8.40 (1H, br s).Example 206

[0760] (5R)-N-(5-bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0761] A) 5-bromo-2',6'-difluoro-[l,T-biphenyl]-2-amine

[0762] To a mixture of 4-bromo-2-iodoaniline (2.00 g), 2-(2,6-difluorophenyl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (1.93 g), potassium fluoride (1.21 g), tri- / c / 7- butylphosphonium tetrafluoroborate (0.195 g), water (3.0 mL) and THF (18 mL) was added tris(dibenzylideneacetone)dipalladium (0) (0.307 g) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. To the mixture was added ethyl acetate, then the mixture was passed through NH silica gel pad (ethyl acetate). After being concentrated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.451 g).

[0763] MS: [M+H]+283.8.

[0764] B) (5R)-N-(5-bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0765] To a mixture of 5-bromo-2(6'-difhioro-[l,l'-biphenyl]-2-amine (150 mg), TEA(0.309 mL) and toluene (2.0 mL) was added a mixture of bis(trichloromethyl)carbonate (62.7 mg) and toluene (1.0 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. To the mixture was added a mixture of hexane / di ethyl ether (1 / 1 v / v). The insoluble material was removed by filtration (hexane / di ethyl ether (1 / 1 v / v)), and the filtrate was concentrated in vacuo. A mixture of the obtained residue and THF (1 mL) was added to a mixture of N-[(4R)-5,5-difluoroazepan-4-yl]methanesulfonamide (110 mg), TEA (0.134 mL) and THF (1 mL) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated invacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The residue was recrystallized from ethyl acetate / hexane to give the title compound (214 mg).

[0766] ’H NMR (400 MHz, CDCh) 5 2.01-2.34 (4H, m), 3.01 (3H, s), 3.20 (1H, ddd, J = 12.9, 8.0, 4.9 Hz), 3.29-3.41 (1H, m), 3.44-3.60 (2H, m), 3.74-3.92 (1H, m), 4.73 (1H, d, J = 9.4 Hz), 6.14 (1H, s), 7.05-7.15 (2H, m), 7.39-7.49 (2H, m), 7.54 (1H, dd, J = 8.8, 2.3 Hz), 7.90 (1H, d, J = 8.9 Hz).Example 254

[0767] (5R)-N-(5-bromo-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0768] A) 5-bromo-2',3,6'-trifluoro-[l,r-biphenyl]-2-amine

[0769] To a mixture of 2',3,6'-trifluoro-[l,r-biphenyl]-2-amine (5.62 g) and acetonitrile (120 mL) was added N-bromosuccinimide (4.93 g) at room temperature. The mixture was stirred at room temperature for 10 min. To the mixture was added aqueous sodium thiosulfate solution and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate / hexane) to give the title compound (6.73 g).

[0770] MS: [M+H]+301.9.

[0771] B) (5R)-N-(5-bromo-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide

[0772] To a mixture of 5-bromo-2',3,6'-trifluoro-[l,r-biphenyl]-2-amine (300 mg), TEA(0.581 mL) and toluene (4.0 mL) was added a mixture of bis(trichloromethyl)carbonate (147 mg) and toluene (2.0 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. To the mixture was added a mixture of hexane / di ethyl ether (1 / 1 v / v). The insoluble material was removed by filtration (hexane / di ethyl ether (1 / 1 v / v)), and the filtrate was concentrated in vacuo to give 5-bromo-2',3,6'-trifluoro-2-isocyanato-l,l'- biphenyl (326 mg). To a mixture of N-[(4R)-5,5-difluoroazepan-4- yl]methanesulfonamide (103 mg), TEA (0.126 mL) and THF (1 mL) was added a mixture of 5-bromo-2',3,6'-trifluoro-2-isocyanato-l,l'-biphenyl (163 mg) and THF (1 mL) at roomtemperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The solid was recrystallized from ethyl acetate / hexane to give the title compound (201 mg).

[0773] XH NMR (400 MHz, CDCh) 5 1.82-2.24 (4H, m), 3.04 (3H, s), 3.23-3.40 (2H, m), 3.44-3.54 (1H, m), 3.59-3.69 (1H, m), 3.70-3.85 (1H, m), 4.64 (1H, d, J = 9.3 Hz), 5.88 (1H, s), 6.99-7.12 (2H, m), 7.30-7.44 (3H, m).Example 255

[0774] (5R)-N-(5-bromo-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 -carboxamide

[0775] A) ((5R)-N-(5-bromo-2',3,6'-trifluoro[l,l'-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide

[0776] To a mixture of 5-bromo-2',3,6'-trifluoro-[l,r-biphenyl]-2-amine (300 mg), TEA(0.581 mL) and toluene (4.0 mL) was added a mixture of bis(trichloromethyl)carbonate (147 mg) and toluene (2.0 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. To the mixture was added a mixture of hexane / di ethyl ether (1 / 1 v / v). The insoluble material was removed by filtration (hexane / di ethyl ether (1 / 1 v / v)), and the filtrate was concentrated in vacuo to give 5-bromo-2',3,6'-trifluoro-2-isocyanato-l,l'- biphenyl (326 mg). To a mixture of N-[(4R)-5,5-difluoroazepan-4-yl]ethanesulfonamide (109 mg), TEA (0.126 mL) and THF (1 mL) was added a mixture of 5-bromo-2',3,6'- trifluoro-2-isocyanato- 1,1 '-biphenyl (163 mg) and THF (1 mL) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The solid was recrystallized from ethyl acetate / hexane to give the title compound (241 mg).

[0777] 1H NMR (400 MHz, CDCh) 5 1.40 (3H, t, J = 7.3 Hz), 1.80-1.97 (1H, m), 1.98- 2.25 (3H, m), 3.05-3.17 (2H, m), 3.24-3.40 (2H, m), 3.45-3.55 (1H, m), 3.58-3.67 (1H, m), 3.68-3.81 (1H, m), 4.48 (1H, d, J = 9.7 Hz), 5.89 (1H, s), 7.05 (2H, q, J = 8.6 Hz), 7.31-7.41 (3H, m).

[0778] The compounds of Examples are shown in the following tables. MS in the tables means actual measured value. The compounds of Examples 1 to 53, 55 to 60, 62 to 70,72, 73, 75 to 80, 83 to 91, 93, 94, 96, 97, 99, 101 to 104, 107 to 138, 140 to 146, 148, 149, 151 to 205, 207 to 253, and 256 to 286 in the following tables were produced according to the methods described in the above-mentioned Examples, or methods analogous thereto.Table 1-1Table 1-2Table 1-3Table 1-4Table 1-5Table 1-6Table 1-7Table 1-8Table 1-9Table 1-10Table 1-11Table 1-12Table 1-13Table 1-14Table 1-15Table 1-16Table 1-17Table 1-18Table 1-19Table 1-20Table 1-21Table 1-22Table 1-23Table 1-24Table 1-25Table 1-26Table 1-27Table 1-28Table 1-29Table 1-30Table 1-31Table 1-32Table 1-33Table 1-34Table 1-35Table 1-36Table 1-37Table 1-38Table 1-39Table 1-40Table 1-41

[0802] Experimental Example 1 : Obtainment of cell stably expressing human orexin type 2 receptor (hOX2R)

[0803] To obtain a cell clone stably expressing human orexin type 2 receptor, human orexin type 2 receptor cDNA was inserted into pcDNA3.1(+) plasmid vector (Invitrogen), and a plasmid DNA for expression of human orexin type 2 receptor (pcDNA3.1(+) / hOX2R) was cloned. The plasmid DNA was introduced into CHO-K1 cell by an electroporation method, and human orexin type 2 receptor expressing clone cells were obtained by limiting dilution method by using G418 drug resistance as a selection marker.

[0804] Experimental Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells forcibly expressing human OX2 receptor were seeded in each well of 384 well black transparent bottom plate (BD Falcon) at 10,000 cells / well, and cultured for one day in a 5% CO2 incubator at 37°C. After removal of the medium in the cell plate, assay buffer A containing a calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 pg / mL Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mMprobenecid (DOJINDO Chemical)) was added at 30 pL / well. The plate was stood for 30 min in a 5% CO2 incubator at 37°C, and further stood at room temperature for 30 min. A test compound prepared by diluting with assay buffer B (HBSS, 20 mM HEPES, 0.1 % BSA) was added at 10 pL / well, and the fluorescence value was measured by FDSSpCELL (Hamamatsu Photonics K.K.) every one sec for 1 min, and thereafter every two sec for 1 min 40 sec. The activity (%) of the test compound was calculated assuming that variation in the fluorescence value when DMSO was added instead of the test compound was 0%, and variation in the fluorescence value when orexin A (human) (PEPTIDE INSTITUTE, INC.) was added at the final concentration of 10 nM was 100%. The activity of each compound at the concentration of 3 pM was shown in Tables 2-1 and 2-2. As is clear from the results, the compound of the present invention was shown to have an agonist activity on human orexin type 2 receptor.Table 2-1Table 2-2

[0805] Experimental Example 3 : Evaluation of wake-promoting effects in cynomolgus monkeys

[0806] The wake-promoting effects were evaluated by measuring the electroencephalogram (EEG) and electromyogram (EMG) in cynomolgus monkeys. Under isoflurane anesthesia (0.5-5%, Pfizer Japan Inc., Tokyo, Japan), male cynomolgus monkeys (2-3 years old, Hamri Co., Ltd., Ibaraki, Japan) were surgically implanted with radio-telemetry transmitters (L03-F3, Data Sciences International Inc., MN, USA). EEG electrodes were screwed into the skull at the parietal area. EMG electrodes were implanted on the cervical muscles. After the surgery, each monkey was given penicillin (100,000 units / head, i.m., Meiji Seika Pharma Co., Ltd., Tokyo, Japan), buprenorphine (0.02 mg / kg, i.m., Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and prednisolone (1 mg / kg, s.c., Kyoritsu Seiyaku Co., Ltd., Tokyo, Japan) daily for one week. After at least a 1 -month recovery period in home cages, the monkeys were habituated to the recording chamber placed in a soundproof room. EEG and EMG signals were recorded using the telemetry system (Ponemah software, Data Sciences International Inc., MN, USA) and the signals were analyzed using SleepSign software (Kissei Comtec Co., Ltd., Nagano, Japan). After confirming long sleep in dark phase in the experimental room, we used animals to examine the wake-promoting effect of compounds. Test compounds (10 mg / kg) suspended in 0.5% methylcellulose aqueous solution, or vehicle (i.e., 0.5% methylcellulose aqueous solution) was administered orally (p.o.) to monkeys at zeitgeber time 12 (ZT12) in a volume of 5 mL / kg body weight in pre-post design (n = 2). EEG and EMG recordings were performed for 4 h after the compound administration. The time spent in wakefulness for 4 h after administration (% of vehicle treatment) was calculated by using SleepSign. The results are shown in Table 3-1.Table 3-1

[0807] As is clear from Table 3-1, the test compounds of the present invention increased the wakefulness time compared to the vehicle treatment group in cynomolgus monkeys. That is, these compounds were suggested to be potential therapeutics for narcolepsy. Formulation Example 1 (production of capsule)1) compound of Example 1 30 mg2) crystalline cellulose 1 0 mg3) lactose 19 mg4) magnesium stearate _ 1 mg total 60 mg1), 2), 3) and 4) are mixed and filled in a gelatin capsule. Formulation Example 2 (production of tablet)1) compound of Example 1 30 g2) lactose 50 g3) cornstarch 15 g4) calcium carboxymethylcellulose 44 g5) magnesium stearate _ 1 g1000 tablets 140 g in total

[0808] The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.[Industrial Applicability]

[0809] The compound of the present invention has an orexin type 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

Claims

CLAIMS1. A compound represented by the formula (I):whereinR1is an optionally substituted C2-6 alkyl group, or an optionally substituted cyclic group;R2is an optionally substituted Ci-6 alkyl group, an optionally substituted C3-10 cycloalkyl group, an optionally substituted mono- or di-Ci-6 alkylamino group, or an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group;L is(1) an optionally substituted methylene group,(2) -O-,(3) -NRa- wherein Rais a hydrogen atom or a substituent,(4) an optionally substituted ethylene group,(5) -O-(an optionally substituted methylene group)-,(6) -(an optionally substituted methylene group)-O-,(7) -NRb-(an optionally substituted methylene group)- wherein Rbis a hydrogen atom or a substituent, or(8) -(an optionally substituted methylene group)-NRc- wherein Rcis a hydrogen atom or a substituent;Ring A is an optionally substituted 5- or 6-membered monocycle; andRing B is a 7- or 8-membered nitrogen-containing monocyclic heterocycle or a 7- or 8-membered nitrogen-containing fused heterocycle, each optionally substituted, or a salt thereof.

2. The compound or salt of claim 1, wherein(1) a C2-6 alkyl group,(2) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group,(3) a Ce-io aryl group optionally substituted by 1 to 3 halogen atoms,(4) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 C1-6 alkyl groups,(5) a 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 3 C1-6 alkyl groups, or(6) an 8- to 14-membered fused bicyclic aromatic heterocyclic group;R2is(1) an optionally halogenated C1-6 alkyl group,(2) a C3-10 cycloalkyl group,(3) a di-Ci-6 alkylamino group, or(4) a 3- to 7-membered nitrogen-containing heterocyclic group;L is(1) a methylene group optionally substituted by 1 or 2 substituents selected from(i) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (ii) a hydroxy group, and (iii) an oxo group,(2) -O-,(3) -NRa- wherein Rais a hydrogen atom or a C1-6 alkyl group,(4) an ethylene group,(5) -O-CH2-,(6) -CH2-O-,(7) -NRb-CH2- wherein Rbis a C1-6 alkyl group, or(8) -CH2-NRC- wherein Rcis a hydrogen atom or a C1-6 alkyl group;Ring A is(1) a 5-membered ring optionally substituted by 1 or 2 C1-6 alkyl groups, or(2) a 6-membered ring optionally substituted by 1 to 3 substituents selected from(i) a halogen atom,(ii) a halogenated thio group,(iii) a cyano group,(iv) a hydroxy group,(v) a Ci-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, and a Ci-6 alkoxy group,(vi) a C3-10 cycloalkyl group,(vii) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; andRing B is(1) a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group and a Ci- 6 alkyl group, or(2) an 8-membered nitrogen-containing fused heterocycle optionally substituted by 1 to 3 halogen atoms.

3. The compound or salt of claim 1, whereinR1is a Ce-io aryl group optionally substituted by 1 to 3 halogen atoms;R2is a C1-6 alkyl group;L is -NH-;Ring A is a 6-membered ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C1-6 alkyl group; andRing B is a 7-membered nitrogen-containing monocyclic heterocycle optionally substituted by 1 to 3 halogen atoms.

4. The compound or salt according to claim 1, whereinR1is a phenyl group optionally substituted by 1 to 3 halogen atoms;R2is a C1-6 alkyl group;L is -NH-;Ring A is a benzene ring optionally substituted by 1 to 3 substituents selected from (i) a halogen atom and (ii) a halogenated C1-6 alkyl group; andRing B is a azepane ring optionally substituted by 1 to 3 halogen atoms.

5. The compound or salt according to claim 1, which is (5R)-5-[(ethanesulfonyl)amino]-4,4- difluoro-N-[2',3 ,6'-trifluoro-5-(trifluoromethyl)[ 1 , 1 '-biphenyl]-2-yl]azepane- 1 - carboxamide.

6. The compound or salt according to claim 1, which is (5R)-N-(5-bromo-2',6'-difluoro[l,T- biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane-l-carboxamide.

7. The compound or salt according to claim 1, which is (5R)-N-(5-bromo-2',3,6'- trifluorof 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

8. A medicament comprising the compound or salt according to any one of claims 1 to 7.

9. The medicament according to claim 8, which is an orexin type 2 receptor agonist.

10. The medicament according to claim 8, which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

11. The medicament according to claim 8, which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

12. The medicament according to claim 8, which is an agent for the prophylaxis or treatment of narcolepsy.

13. The medicament according to any one of claims 8 to 12, wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro- 5-(trifluoromethyl)[l,T-biphenyl]-2-yl]azepane-l -carboxamide; (5R)-N-(5-bromo-2',6'- difluorof 1 , 1 '-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane- 1 -carboxamide; and (5R)-N-(5-bromo-2 3,6'-trifluoro[l,T-biphenyl]-2-yl)-5- [(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide.

14. The compound or salt according to any one of claims 1 to 7 for use as an orexin type 2 receptor agonist.

15. The compound or salt according to any one of claims 1 to 7 for use in the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy -like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

16. The compound or salt according to claim 15 for use in the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

17. The compound or salt according to claim 15 for use in the prophylaxis or treatment of narcolepsy.

18. The compound or salt according to any one of claims 14 to 17, wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'- trifluoro-5-(trifluoromethyl)[l,r-biphenyl]-2-yl]azepane-l-carboxamide; (5R)-N-(5- bromo-2',6'-difluoro[l,T-biphenyl]-2-yl)-4,4-difluoro-5- [(methanesulfonyl)amino]azepane-l -carboxamide; and (5R)-N-(5-bromo-2',3,6'- trifluorof 1 , 1 '-biphenyl]-2-yl)-5-[(ethanesulfonyl)amino]-4,4-difluoroazepane- 1 - carboxamide.

19. A method for the prophylaxis or treatment of a disease or disorder associated with an orexin type 2 receptor in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the compound or salt thereof according to any one of claims 1 to 7.

20. The method according to claim 19, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

21. The method according to claim 19, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

22. The method according to claim 19, wherein the disease or disorder is narcolepsy.

23. The method according to any one of claims 19 to 22, wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro- 5-(trifluoromethyl)[l,T-biphenyl]-2-yl]azepane-l -carboxamide; (5R)-N-(5-bromo-2',6'- difluorof 1 , 1 '-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane- 1 - carboxamide; and (5R)-N-(5-bromo-2\3,6'-trifluoro[l,T-biphenyl]-2-yl)-5- [(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide.

24. Use of the compound or salt thereof according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a disease or disorder associated with an orexin type 2 receptor.

25. The use of claim 24, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, side effects and complications due to anesthesia.

26. The use of claim 24, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

27. The use of claim 24, wherein the disease or disorder is narcolepsy.

28. The use according to any one of claims 24 to 27, wherein the compound or salt thereof is selected from (5R)-5-[(ethanesulfonyl)amino]-4,4-difluoro-N-[2',3,6'-trifluoro-5- (trifluoromethyl)[l,T-biphenyl]-2-yl]azepane-l -carboxamide; (5R)-N-(5-bromo-2',6'- difluorof 1 , 1 '-biphenyl]-2-yl)-4,4-difluoro-5-[(methanesulfonyl)amino]azepane- 1 - carboxamide; and (5R)-N-(5-bromo-2\3,6'-trifluoro[l,T-biphenyl]-2-yl)-5- [(ethanesulfonyl)amino]-4,4-difluoroazepane-l -carboxamide.

29. A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 7.

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