Heterocyclic compounds

Abstract

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

Description

[Technical field]

[0001] The present invention relates to a heterocyclic compound, in particular a heterocyclic compound having orexin type 2 receptor agonist activity.

[0002] BACKGROUND OF THEINVENTION Orexin is a neuropeptide that is specifically produced by certain neurons scattered in the lateral hypothalamus and its surrounding areas, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptor, a G protein-coupled receptor that exists mainly in the brain, and two subtypes of the orexin receptor, type 1 and type 2, are known (Non-Patent Document 1).

[0003] Orexin-producing neurons (orexin neurons) are localized near the feeding center, and intracerebroventricular administration of orexin peptides increases food intake. Therefore, when orexin was first discovered, it attracted attention as a neuropeptide that regulates feeding. However, it was later reported that canine narcolepsy is caused by genetic mutations in the orexin type 2 receptor (Non-Patent Document 2), and attention has also been focused on the role of orexin in regulating sleep and wakefulness.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice crossed with transgenic mice with orexin overexpression have revealed that narcolepsy-like symptoms caused by degeneration of orexin neurons disappear with sustained expression of orexin. Similarly, when orexin peptides were administered intracerebroventricularly to transgenic mice with degenerated orexin neurons, narcolepsy-like symptoms were improved (Non-Patent Document 3). Studies on orexin type 2 receptor knockout mice have also suggested that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Document 4, Non-Patent Document 5). In light of this background, it has been suggested that orexin type 2 receptor agonists could be used as a treatment for narcolepsy and other sleep disorders that exhibit hypersomnia (Non-Patent Document 6).

[0005] In addition, it has been suggested that a peptide agonist that selectively acts on the orexin type 2 receptor improves obesity induced by a high-fat diet in mice (Non-Patent Document 7). It has also been suggested that intracerebroventricular administration of orexin peptides shortens the time of general anesthesia in rats (Non-Patent Document 8). It has also been suggested that patients with sleep apnea syndrome have low plasma orexin A concentration levels (Non-Patent Document 9). It has also been suggested that intracerebroventricular administration of orexin peptides improves memory retention in senescence-accelerated mouse model (SAMP8) with cognitive impairment (Non-Patent Document 10). In addition, it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11). It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by loss of orexin neurons (Non-Patent Document 12). In addition, orexin controls bone formation and bone loss, and it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). Furthermore, since it was found that the mortality rate was significantly improved by simply continuously administering orexin from the peripheral blood in a septic shock model mouse, it has been suggested that orexin receptor agonists are useful for preventing or treating sepsis, severe sepsis, and septic shock (Patent Document 3).

[0006] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be useful as therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, and the like, as well as anesthetic antagonists and as preventive or therapeutic agents for side effects and complications caused by anesthesia.

[0007] On the other hand, as sulfonamide derivatives, formula

[0008] [ka]

[0009] (The symbols in the formula are as described in the literature.) A compound represented by the following formula (Patent Document 4) has been reported.

[0010] In addition, the following compounds have been reported as having orexin type 2 receptor agonist activity. formula

[0011] [ka]

[0012] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 5). formula

[0013] [ka]

[0014] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 6). formula

[0015] [ka]

[0016] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 7).

[0017] formula

[0018] [ka]

[0019] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 8).

[0020] formula

[0021] [ka]

[0022] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 9).

[0023] formula

[0024] [ka]

[0025] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 10).

[0026] formula

[0027] [ka]

[0028] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 11).

[0029] formula

[0030] [ka]

[0031] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 12).

[0032] formula

[0033] [ka]

[0034] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 13).

[0035] formula

[0036] [ka]

[0037] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 14).

[0038] formula

[0039] [ka]

[0040] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 15).

[0041] formula

[0042] [ka]

[0043] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 16).

[0044] However, these compounds are considered to be insufficient in terms of activity, pharmacokinetics, or safety, and there is still a need for the development of compounds having orexin type 2 receptor agonist activity. [Prior art documents] [Patent documents]

[0045] [Patent Document 1] WO 2015 / 073707 A1 [Patent Document 2] WO 2015 / 048091 A1 [Patent Document 3] WO 2015 / 147240 A1 [Patent Document 4] WO 2012 / 137982 A9 [Patent Document 5] WO 2017 / 135306 A1 [Patent Document 6] WO 2018 / 164191 A1 [Patent Document 7] WO 2018 / 164192 A1 [Patent Document 8] WO 2019 / 027003 A1 [Patent Document 9] WO 2019 / 027058 A1 [Patent Document 10] WO 2020 / 004536 A1 [Patent Document 11] WO 2020 / 004537 A1 [Patent Document 12] WO 2020 / 122092 A1 [Patent Document 13] WO 2020 / 122093 A1 [Patent Document 14] WO 2020 / 158958 A1 [Patent Document 15] WO 2020 / 167701 A1 [Patent Document 16] WO 2020 / 167706 A1 [Non-patent literature]

[0046] [Non-Patent Document 1] Cell, Vol.92, 573-585, 1998 [Non-Patent Document 2] Cell, Vol.98, 365-376, 1999 [Non-Patent Document 3] Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, pp. 4649-4654, 2004(Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004) [Non-Patent Document 4] Cell, Vol.98, 437-451, 1999 [Non-Patent Document 5] Neuron, Vol.38, 715-730, 2003 [Non-Patent Document 6] CNS Drugs, Vol.27, 83-90, 2013 [Non-Patent Document 7] Cell Metabolism, Vol.9, 64-76, 2009 [Non-Patent Document 8] Neuroscience, Vol.121, 855-863, 2003 [Non-Patent Document 9] Respiration, Vol.71, 575-579, 2004 [Non-Patent Document 10] Peptides, Vol.23, 1683-1688, 2002 [Non-Patent Document 11] Journal of the American College of Cardiology. Vol. 66, 2015, Pages 2522-2533 [Non-Patent Document 12] Brain. Vol. 130, 2007, Pages 1586-1595 Summary of the Invention [Problem to be solved by the invention]

[0047] An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0048] The present inventors found that a compound represented by the following formula (I) or a salt thereof (sometimes referred to as compound (I) in this specification) has orexin type 2 receptor agonist activity, and as a result of further research, they have completed the present invention.

[0049] That is, the present invention relates to the following. [1] formula:

[0050] [ka]

[0051] [In the formula, R 1 is an optionally substituted C 1-6 Alkyl group, optionally substituted mono- or di-C 1-6 Alkylamino group or optionally substituted C 3-6 represents a cycloalkyl group; R 2 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl group or optionally substituted C 1-6 represents an alkoxy group; R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl group or optionally substituted C 1-6 represents an alkoxy group; R 4 is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 6-10 an aryl group or an optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6a cycloalkoxy group, or an optionally substituted 4- to 6-membered heterocyclic group. A compound represented by the formula:

[0052] [2] R 2 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl group or optionally substituted C 1-6 Alkoxy groups; R 3 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl group or optionally substituted C 1-6 Alkoxy groups; R 4 may be substituted C 1-6 Alkyl groups, optionally substituted C 6-10 an aryl group or an optionally substituted C 1-6 The compound according to the above-mentioned [1] or a salt thereof, wherein R is an alkoxy group.

[0053] [3] R 1 But, C 1-6 Alkyl group, mono- or di-C 1-6 Alkylamino group, or C 3-6 Cycloalkyl groups; R 2 is a hydrogen atom, a halogen atom, a cyano group, C 1-6 Alkyl group, C 3-6 Cycloalkyl group, or C 1-6 Alkoxy groups; R 3 C optionally substituted by a hydrogen atom, a halogen atom, a cyano group, or one to three hydroxy groups 1-6 Alkyl group, C 3-6 Cycloalkyl group, or C 1-6 Alkoxy groups; and R 4 but, (1) Halogen atoms, hydroxyl groups, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C1-6 C optionally substituted by 1 to 3 substituents selected from an alkoxy-carbonyl group and a 3- to 14-membered non-aromatic heterocyclic oxy group 1-6 Alkyl groups, (2) 1 to 3 C’s 1-6 C optionally substituted with an alkyl group 3-6 Cycloalkyl groups, (3) C 2-6 Alkenyl groups, (4) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group 2-6 Alkynyl groups, (5) Halogen atom, optionally halogenated C 1-6 Alkyl groups, and C 1-6 C optionally substituted with 1 to 3 substituents selected from an alkoxy group 6-10 Aryl groups, (6) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkoxy group 1-6 Alkoxy groups, (7) C 3-6 a cycloalkoxy group, or (8) 1 to 3 C’s 1-6 4- to 6-membered heterocyclic group optionally substituted with an alkyl group The compound according to the above-mentioned [1], or a salt thereof.

[0054] [4] R 1 But, C 1-6 Alkyl group, mono- or di-C 1-6 Alkylamino group, or C 3-6 Cycloalkyl groups; R 2 but hydrogen atoms; R 3 But, C 1-6 an alkyl group; and R 4 but, (1) C 1-6 Alkyl groups, (2) C 3-6 Cycloalkyl groups, (3) C2-6 Alkenyl groups, (4) C 2-6 Alkynyl groups, (5) C 6-10 an aryl group, or (6) C 1-6 Alkoxy group The compound according to the above-mentioned [1], or a salt thereof.

[0055] [5] R 1 But, C 1-6 Alkyl groups; R 2 but hydrogen atoms; R 3 But, C 1-6 an alkyl group; and R 4 but, (1) C 1-6 Alkyl groups, (2) C 2-6 an alkynyl group, or (3) C 1-6 Alkoxy group The compound according to the above-mentioned [1], or a salt thereof.

[0056] [6] N-[4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide or a salt thereof. [7] N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide or a salt thereof. [8] N-[4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide or a salt thereof.

[0057] [9] A pharmaceutical composition comprising the compound or a salt thereof according to the above-mentioned [1].

[10] The pharmaceutical agent according to the above-mentioned [9], which is an orexin type 2 receptor agonist.

[11] The pharmaceutical agent according to the above-mentioned [9], which is a preventive or therapeutic agent for narcolepsy.

[0058]

[12] The compound or salt thereof according to the above-mentioned [1] for use in the prevention or treatment of narcolepsy.

[13] A method for agonizing orexin type 2 receptor in a mammal, which comprises administering to the mammal an effective amount of the compound according to the above-mentioned [1] or a salt thereof.

[14] A method for preventing or treating narcolepsy in a mammal, which comprises administering to the mammal an effective amount of the compound according to the above-mentioned [1] or a salt thereof.

[15] Use of the compound according to the above-mentioned [1] or a salt thereof for the manufacture of an agent for the prophylaxis or treatment of narcolepsy. Effect of the Invention

[0059] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for the prevention or treatment of narcolepsy.

[0060] Detailed Description of the Invention The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "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. In the present specification, "optionally halogenated C 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkyl group 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. In this specification, "C 2-6 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-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. In this specification, "C 2-6 Examples of the "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. In this specification, "C 3-10 Examples of the "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. In the present specification, "optionally halogenated C 3-10 The "cycloalkyl group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms.3-10 Specific examples of the cycloalkyl group include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16 The aralkyl group includes, for example, benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0061] In this specification, "C 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In the present specification, "optionally halogenated C 1-6 The "alkoxy group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkoxy group include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. In this specification, "C 1-6Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. In the present specification, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, C alkylthio groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio. In this specification, "C 1-6 Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. In the present specification, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, C alkyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of the alkyl-carbonyl group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16The "aralkyl-carbonyl group" includes, for example, phenylacetyl and phenylpropionyl.

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0062] As used herein, "mono- or di-C 1-6 The "alkyl-carbamoyl group" includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" includes, for example, benzylcarbamoyl and phenethylcarbamoyl. In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In the present specification, "optionally halogenated C 1-6 The "alkylsulfonyl group" includes, for example, C alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0063] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted 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. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of such groups include aralkyl groups.

[0064] In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent 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) Optionally halogenated C 1-6 Alkoxy groups, (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy), (11) C 1-6Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15) C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 Alkylthio groups, (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) Optionally halogenated C 1-6 Alkyl-carbonyl groups, (26)C 6-14 Aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl groups, (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups, (35)C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 Alkylsulfonyl groups, (39)C 6-14 Arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 Alkylsulfinyl groups, (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) Mono- or di-C 1-6alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 Alkyl groups, (58)C 2-6 Alkenyl groups, (59)C2-6 Alkynyl groups, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0065] 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 2 or more, the respective substituents may be the same or different. In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in "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 of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0066] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 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, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0067] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0068] In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" which contain at least one nitrogen atom as a ring-constituting atom. In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0069] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of the heterocyclic 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 of which optionally has "1 or 2 substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group." Further, the "acyl group" also includes a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0070] As used herein, the term "optionally substituted amino group" refers to, for example, "amino group optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an arylsulfonyl group, optionally having 1 or 2 substituents selected from the group consisting of arylsulfonyl groups. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0071] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and aralkyl-carbamoyl groups, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted carbamoyl group include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples of the aryl-carbonyl-carbamoyl group include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0072] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have 1 or 2 substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples of such groups include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0073] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which may optionally have 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and an aralkyl-carbamoyl group, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted sulfamoyl group include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0074] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups, each of which may have a substituent selected from the group consisting of arylsulfonyl groups and arylsulfonyl groups. Preferable examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C 6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0075] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 and a halogenated sulfanyl group, which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples of such groups include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0076] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples of the silyl groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0077] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkane, C 3-10 Cycloalkenes are mentioned. In this specification, "C 6-14 The aromatic hydrocarbon ring includes, for example, benzene and naphthalene. In this specification, "C 3-10 Examples of the "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10Examples of the "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0078] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. 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, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzene, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0079] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms 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, and oxepane; Examples of the heterocyclic ring include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) 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-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom. In the present specification, the "4- to 6-membered heterocyclic group" includes aromatic or non-aromatic 4- to 6-membered heterocyclic groups, and specific examples thereof include oxetanyl, furyl, pyrazolyl, pyridyl and pyrimidinyl.

[0080] The definition of each symbol in formula (I) is explained in detail below. In the formula, R 1 is an optionally substituted C 1-6 Alkyl group, optionally substituted mono- or di-C 1-6 Alkylamino group or optionally substituted C 3-6 This represents a cycloalkyl group. R 1 As for C 1-6 Alkyl groups (e.g., methyl, ethyl), mono- or di-C 1-6 Alkylamino group (e.g., methylamino, dimethylamino), or C 3-6 Cycloalkyl groups (eg cyclopropyl) are preferred. R 1 Among them, C 1-6 Alkyl groups (eg, methyl, ethyl) are preferred.

[0081] R 2 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl group or optionally substituted C 1-6 This represents an alkoxy group. R 2 Examples of the alkyl group include a hydrogen atom, a halogen atom (e.g., a fluorine atom, a bromine atom), a cyano group, and C 1-6 Alkyl group (e.g., methyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), or C 1-6 Alkoxy groups (eg, methoxy) are preferred. R 2 Among these, a hydrogen atom is preferable as the group.

[0082] R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6Alkyl groups, optionally substituted C 3-6 Cycloalkyl group or optionally substituted C 1-6 This represents an alkoxy group. R 3 is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a bromine atom), a cyano group, a C 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), or C 1-6 Alkoxy groups (eg, methoxy) are preferred. R 3 Among them, C 1-6 Alkyl groups (eg, methyl) are preferred.

[0083] R 4 is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 6-10 Aryl group, optionally substituted C 1-6 Alkoxy group, optionally substituted C 3-6 It represents a cycloalkoxy group, or an optionally substituted 4- to 6-membered heterocyclic group. R 4 As for the following: (1) Halogen atoms (e.g., fluorine atoms), hydroxyl groups, C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 1-6 Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy), C 1-6 C optionally substituted by 1 to 3 substituents selected from an alkoxy-carbonyl group (e.g., ethoxycarbonyl) and a 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy); 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl), (2) 1 to 3 C’s 1-6C optionally substituted with an alkyl group (e.g., methyl) 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (3) C 2-6 Alkenyl groups (e.g., ethenyl, propenyl, butenyl), (4) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl) 2-6 Alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, isopentynyl), (5) Halogen atom (e.g., fluorine atom), optionally halogenated C 1-6 Alkyl groups (e.g., methyl, trifluoromethyl), and C 1-6 C optionally substituted with 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 6-10 Aryl groups (e.g., phenyl), (6) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkoxy group (e.g., cyclopropyl) 1-6 Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), (7) C 3-6 a cycloalkoxy group (e.g., cyclobutoxy), or (8) 1 to 3 C’s 1-6 4- to 6-membered heterocyclic groups (e.g., oxetanyl, furyl, pyrazolyl, pyridyl) optionally substituted with an alkyl group (e.g., methyl); is preferred. R 4 Among others, (1) C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl), (2) C 3-6 cycloalkyl groups (e.g., cyclopropyl); (3) C 2-6 Alkenyl groups (e.g., propenyl), (4) C 2-6 Alkynyl groups (e.g., propynyl), (5) C 6-10 an aryl group (e.g., phenyl), or (6) C1-6 Alkoxy groups (e.g., ethoxy) is preferred. R 4 In particular, (1) C 1-6 Alkyl groups (e.g., ethyl), (2) C 2-6 an alkynyl group (e.g., propynyl), or (3) C 1-6 Alkoxy groups (e.g., ethoxy) is preferred.

[0084] Compound (I) may be R 1 But, C 1-6 Alkyl groups (e.g., methyl, ethyl), mono- or di-C 1-6 Alkylamino group (e.g., methylamino, dimethylamino), or C 3-6 a cycloalkyl group (e.g., cyclopropyl); R 2 is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a bromine atom), a cyano group, C 1-6 Alkyl group (e.g., methyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), or C 1-6 an alkoxy group (e.g., methoxy); R 3 may be substituted by a hydrogen atom, a halogen atom (e.g., a fluorine atom, a bromine atom), a cyano group, or one to three hydroxy groups; 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), or C 1-6 an alkoxy group (e.g., methoxy); and R 4 but, (1) Halogen atoms (e.g., fluorine atoms), hydroxyl groups, C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 1-6 Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy), C 1-6C optionally substituted by 1 to 3 substituents selected from an alkoxy-carbonyl group (e.g., ethoxycarbonyl) and a 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy); 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl), (2) 1 to 3 C’s 1-6 C optionally substituted with an alkyl group (e.g., methyl) 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl); (3) C 2-6 Alkenyl groups (e.g., ethenyl, propenyl, butenyl), (4) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl) 2-6 Alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, isopentynyl), (5) Halogen atom (e.g., fluorine atom), optionally halogenated C 1-6 Alkyl groups (e.g., methyl, trifluoromethyl), and C 1-6 C optionally substituted with 1 to 3 substituents selected from alkoxy groups (e.g., methoxy) 6-10 Aryl groups (e.g., phenyl), (6) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkoxy group (e.g., cyclopropyl) 1-6 Alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), (7) C 3-6 a cycloalkoxy group (e.g., cyclobutoxy), or (8) 1 to 3 C’s 1-6 4- to 6-membered heterocyclic groups (e.g., oxetanyl, furyl, pyrazolyl, pyridyl) optionally substituted with an alkyl group (e.g., methyl); Preferred are compounds,

[0085] Compound (I) is, among others, R 1 But, C 1-6Alkyl groups (e.g., methyl, ethyl), mono- or di-C 1-6 Alkylamino group (e.g., methylamino, dimethylamino), or C 3-6 a cycloalkyl group (e.g., cyclopropyl); R 2 is a hydrogen atom; R 3 But, C 1-6 is an alkyl group (e.g., methyl); and R 4 but, (1) C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl), (2) C 3-6 cycloalkyl groups (e.g., cyclopropyl); (3) C 2-6 Alkenyl groups (e.g., propenyl), (4) C 2-6 Alkynyl groups (e.g., propynyl), (5) C 6-10 an aryl group (e.g., phenyl), or (6) C 1-6 Alkoxy groups (e.g., ethoxy) Preferred are compounds,

[0086] Compound (I) is particularly R 1 But, C 1-6 an alkyl group (e.g., methyl, ethyl); R 2 is a hydrogen atom; R 3 But, C 1-6 is an alkyl group (e.g., methyl); and R 4 but, (1) C 1-6 Alkyl groups (e.g., ethyl), (2) C 2-6 an alkynyl group (e.g., propynyl), or (3) C 1-6 Alkoxy groups (e.g., ethoxy) Preferred are compounds,

[0087] Specific examples of compound (I) include the compounds of Examples 1 to 149 described below. Specific examples of the compound (I) include N-[7-methyl-4-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 1) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 6) or a salt thereof, N-[4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 9) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1r,4S)-4-propylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (Example 78) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 109) or a salt thereof, N-{7-methyl-6-oxo-4-[({(1s,4S)-4-[(1Z)-prop-1-en-1-yl]cyclohexyl}oxy)methyl]-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide (Example 110) or a salt thereof, N-[4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 111) or a salt thereof, N-[4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (Example 112) or a salt thereof, N-[4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (Example 113) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (Example 121) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (Example 122) or a salt thereof, N-{7-methyl-6-oxo-4-[({(1s,4S)-4-[(1Z)-prop-1-en-1-yl]cyclohexyl}oxy)methyl]-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}ethanesulfonamide (Example 127) or a salt thereof, N-{7-methyl-6-oxo-4-[({(1s,4S)-4-[(1Z)-prop-1-en-1-yl]cyclohexyl}oxy)methyl]-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}cyclopropanesulfonamide (Example 128) or a salt thereof, N,N-dimethyl-N'-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide (Example 144) or a salt thereof, N-[4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Examples 59 and 145) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Examples 109 and 146) or a salt thereof, N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (Examples 121 and 147) or a salt thereof, N-[-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (Examples 122 and 148) or a salt thereof, or N-methyl-N'-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide (Example 149) or a salt thereof It is.

[0088] Particularly preferred specific examples of compound (I) include N-[4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Example 9) or a salt thereof, N-[4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (Examples 59 and 145) or a salt thereof, or N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (Examples 121 and 147) or a salt thereof It is.

[0089] As the salt of the compound represented by formula (I), a pharmacologically acceptable salt is preferable. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts, and the like. Suitable examples of salts with organic bases 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. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids 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. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0090] The process for producing the compound of the present invention is explained below.

[0091] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compound represented by formula (I) above.

[0092] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.

[0093] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in accordance with a conventional method.

[0094] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0095] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0096] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0097] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0098] In the reactions of each step, a microwave synthesis device such as Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but is usually room temperature to 300° C., preferably 50° C. to 250° C., unless otherwise specified. The reaction time may vary depending on the reagents and solvents used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0099] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in an amount equivalent to the solvent.

[0100] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0101] When a base is used in the reaction of each step, for example, the base shown below or the base described in the Examples can be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0102] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0103] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers The method may be carried out in accordance with the method described in, for example, the 1989 issue of "The Method for Producing a Fluorescent Protein," published by the Japanese Patent Laid-Open Publication No. 2002-2003444, or the method described in the Examples.

[0104] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or a method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0105] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar catalyst may be used.

[0106] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0107] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0108] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0109] When the Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organolithium compounds and the like.

[0110] In each step, when the Friedel-Crafts reaction is carried out, examples of the reagent used include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0111] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0112] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0113] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0114] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0115] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0116] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a method using trimethylsilyl azide and a Lewis acid.

[0117] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0118] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0119] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, active esters, and sulfates. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-Chloro-1-methyl-pyridinium iodide (Mukaiyama's Reagent); Thionyl chloride; Lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0120] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may be added to the reaction, and examples of such bases include inorganic bases.

[0121] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0122] In each step, when the Wohl-Ziegler reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0123] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc. may be mentioned. In addition, a method of obtaining an alkyl halide from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

[0124] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0125] When a sulfonylation reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0126] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0127] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0128] Compound (6) used in the reaction scheme 2 described below can be produced from compound (1) by the method shown in reaction scheme 1 below. 1 and L.G. 2each independently represents a leaving group, R 5 and R 6 each independently represents an optionally substituted C 1-6 The alkyl group represents an alkyl group, and the other symbols are as defined above.

[0129] [ka]

[0130] LG 1 or LG 2 The "leaving group" represented by the formula (I) is a halogen atom, an optionally halogenated C 1-6 Alkyl sulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with an alkyl group 6-14 Examples of the arylsulfonyloxy group include arylsulfonyloxy groups (for example, benzenesulfonyloxy, toluenesulfonyloxy).

[0131] R 5 or R 6 "Optionally substituted C 1-6 As the "alkyl group", among the above-mentioned "optionally substituted hydrocarbon groups", the hydrocarbon group is 1-6 Examples of the alkyl group include those which are alkyl groups.

[0132] Compound (1) may be a commercially available product as is, or may be produced by a known method or a method analogous thereto.

[0133] Compound (3) can be produced by a nucleophilic substitution reaction between compound (1) and compound (2). Compound (2) can be a commercially available product or can be produced by a method known per se or a method similar thereto. Examples of the base used include alkali metal hydrides and organolithium compounds.

[0134] Compound (5) can be produced by a coupling reaction between compound (3) and compound (4). Compound (4) can be a commercially available product or can be produced by a method known per se or a method analogous thereto.

[0135] Compound (8) used in the below-described reaction scheme 3 can be produced from compound (6) by the method shown in the following reaction scheme 2. In the formula, each symbol has the same meaning as defined above.

[0136] [ka]

[0137] Compound (7) can be produced by condensation reaction of compound (6) in the presence of a base. Examples of the base to be used include inorganic bases, organic bases, and alkali metal hydrides.

[0138] Compound (8) can be produced by decarboxylation of compound (7) in the presence of an acid, which may be an inorganic acid or an organic acid.

[0139] Compound (I) can be produced from compound (8) by the method shown in the following reaction scheme 3. 3 and L.G. 4 each independently represents a leaving group, and the other symbols are as defined above.

[0140] [ka]

[0141] LG 3 or LG 4 The "leaving group" represented by is LG 1 Examples of the "leaving group" include the same as those exemplified as the "leaving group" represented by the following formula:

[0142] Compound (9) can be produced by alkylation reaction of compound (8) with aldehydes in the presence of a base. The aldehydes used include formaldehyde, etc. The bases used include inorganic bases, etc.

[0143] Compound (12) can be produced by a nucleophilic substitution reaction between compound (10) and compound (11) in the presence of a base. Examples of the base used include inorganic bases. An additive such as an organic boron compound may be added to the reaction, and examples of the organic boron compound used include 10H-phenoxaborin-10-ol and 2,8-dimethyl-10H-phenoxaborin-10-ol. Compound (11) can be a commercially available product as is, or can be produced by a method known per se or a method equivalent thereto.

[0144] Compound (14) can be produced by the reductive amination reaction of compound (13). Examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, and formic acid. Examples of the amine used include ammonia. A metal catalyst may be added, and an example of the catalyst used is an iridium catalyst. Alternatively, a method of synthesis via a two-step reaction in which compound (13) is converted to an oxime and then reduced may be used. Examples of the amines used to form the oxime include hydroxylamine and O-methylhydroxylamine. Examples of the reducing agent used include boranes such as borane tetrahydrofuran complex, sodium borohydride, and the like. A metal catalyst may be added, and an example of the catalyst used is molybdenum trioxide (VI).

[0145] Compound (I) can be produced by sulfonamidation reaction of compound (14) and compound (15) in the presence of a base. Examples of the base to be used include organic bases. Compound (15) can be a commercially available product as is, or can be produced by a method known per se or a method equivalent thereto.

[0146] In the compound (I) thus obtained, the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0147] In the above-mentioned production methods, when the starting compound has an amino group, a carboxyl group, a hydroxyl group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0148] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, and the like. When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I). Here, the optical isomers can be produced by methods known per se. Compound (I) may be in a crystalline form. The crystals of compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing compound (I) using a crystallization method known per se.

[0149] In this specification, the melting point means a melting point measured, for example, using a micro melting point analyzer (Yanaco, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1) or the like. In general, the melting point may vary depending on the measuring instrument, the measuring conditions, etc. The crystals in this specification may be crystals that show a melting point different from that described in this specification, so long as it is within the normal error range. The crystals of the present invention have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), pharmacological activity), and are extremely useful as pharmaceuticals.

[0150] Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is enzymatically oxidized, reduced, hydrolyzed, or the like to convert to compound (I), or a compound that is hydrolyzed by gastric acid or the like to convert to compound (I). Prodrugs of compound (I) include A compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); A compound in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); Examples of such compounds include compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidated). These compounds can be produced from compound (I) by methods known per se.

[0151] In addition, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990. In the present specification, the prodrug may be in the form of a salt, and such salts include those exemplified as the salts of the compound represented by the above formula (I). In addition, compound (I) may contain isotopes (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 I) or the like. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer used in positron emission tomography (PET) (PET tracer), and is useful in fields such as medical diagnosis. Furthermore, compound (I) may be a hydrate, a non-hydrate, a non-solvate (eg, anhydrous), or a solvate (eg, hydrate). moreover, 1 H 2 Deuterium converted to H(D) is also encompassed in compound (I). Furthermore, compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se.

[0152] Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) can be used as it is or as a pharmaceutical composition (also referred to as a medicine) by mixing it with a pharmacologically acceptable carrier or the like, as an agent for preventing or treating various diseases described later in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys). Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are used, and are blended as excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary.

[0153] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Suitable 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. Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. A suitable example of a soothing agent is benzyl alcohol. Preferable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of the antioxidant include sulfites and ascorbates. Suitable examples of coloring agents include water-soluble edible coal-tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble edible coal-tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Suitable examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0154] Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), capsules (including soft capsules and microcapsules), pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal patch films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compound and the medicament of the present invention can be safely administered orally or parenterally (e.g., administration into the rectum, intravenously, intraarterially, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, by eye drop, intracerebral, intravaginally, intraperitoneally, inside a tumor, in the vicinity of a tumor, or directly to a lesion). These formulations may be immediate release formulations or controlled release formulations, such as sustained release formulations (eg, sustained release microcapsules).

[0155] The pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, for example, a method described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight. When preparing oral preparations, coating may be carried out, if necessary, for the purposes of taste masking, enteric properties or durability.

[0156] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. As the sugar-coating base, white sugar is used, and one or more substances selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination. Examples of water-soluble film coating bases include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural products such as shellac. Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)). The above-mentioned coating bases may be used in combination of two or more kinds in an appropriate ratio. In addition, a light-shielding agent such as titanium oxide, ferric oxide, etc. may be used during coating.

[0157] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent, or a diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0158] The compound of the present invention has excellent orexin type 2 receptor agonist activity and can treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor. The compound of the present invention can be used to treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor, 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 accompanied by hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral 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 mast cells, exogenous obesity, hyperinsulinemia obesity, hyperplasmocytosis, pituitary obesity, hypoplasmocytosis, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications from anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms Convulsions, REM sleep interruption, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight syndrome, disorders related to circadian rhythm, fibromyalgia, conditions resulting from poor quality sleep, overeating, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat , arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, Syndrome X, reproductive hormonal abnormalities, sexual and reproductive dysfunction such as reduced fertility, infertility, hypogonadism in men, and hirsutism in women, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome),Respiratory disorders such as dyspnea, inflammation such as systemic inflammation of the vascular system, risk of secondary consequences of obesity such as arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, reducing the risk of left ventricular hypertrophy, acute neurological and psychiatric disorders such as migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, disorders of the genital / urinary system, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, cerebral defects following cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, extraspinal It is useful as a preventive or therapeutic agent for various diseases such as trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinson's syndrome, Gilles de la Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury.

[0159] In particular, the compound of the present invention is useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, side effects and complications due to anesthesia, and the like, and as an anesthetic antagonist.

[0160] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose is usually about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, and more preferably 0.5 to 20 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

[0161] The compound of the present invention can be used in combination with other drugs (hereinafter, abbreviated as concomitant drugs). By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to the case where the compound is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0162] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes with a time lag (for example, administration in the order of the compound of the present invention; the combination drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total preparation. In addition, when the compound of the present invention and the concomitant drug are separately formulated, the contents may be similar.

[0163] Examples of concomitant drugs include the following: narcolepsy treatment drugs (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromoclopridine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia drugs (e.g., memantine), β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors, β-secretase inhibitors (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-(1,3-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, their optically active forms, their salts and their hydrates,OM99-2 (International Publication No. 01 / 00663)), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP Patent Publication No. 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), beta amyloid vaccines, beta amyloid decomposing enzymes, etc., brain function enhancers (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-dopa, -pa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline (remacemide), riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], amyotrophic lateral sclerosis drugs (e.g., riluzole, neurotrophic factors), abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-13 47), neuronal differentiation and regeneration promoters (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-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3 -(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active substances, salts, and hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors,MAP kinase inhibitors), urinary incontinence / frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine), antiarrhythmics (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatments (e.g., alphacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, disodium pamidronate, arendolone, incadronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, insomnia medications (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), schizophrenia medications (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs acting on metabotropic glutamate receptors or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines ( Chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1A agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT2A antagonists, 5-HT2A inverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardiac selective beta blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists,Other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3 adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel inhibitors, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists Antihypertensives, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium titer channel inhibitors, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for alcoholism, drugs for autism, drugs for chronic fatigue syndrome, drugs for convulsions, drugs for fibromyalgia, drugs for headaches, drugs for smoking cessation, drugs for myasthenia gravis, drugs for cerebral infarction, drugs for mania, drugs for hypersomnia, drugs for pain, drugs for dysthymia, drugs for autonomic nervous system imbalance, drugs for male and female sexual dysfunction, drugs for migraines, drugs for pathological gambling, drugs for restless legs syndrome, drugs for substance dependence, alcohol drugs for treating related diseases, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wandering caused by dementia (sedatives, anti-anxiety drugs, etc.), drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating high blood pressure, drugs for treating low blood pressure, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anticancer drugs, etc.

[0164] The above-mentioned concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. Furthermore, when the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in combination with a biological preparation (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, or a vaccine preparation), and can also be used in combination with a gene therapy method or the like, or in combination with a drug-free psychiatric therapy. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 by Peptor), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in blood coagulation and fibrinolysis systems, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, etc. In addition, they can be used in combination with biological preparations related to growth factors such as GH and IGF. Examples of gene therapy methods include therapy using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes, therapy using DNA decoys such as NFκB decoys, therapy using antisense, therapy using genes related to enzymes and proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion, and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids), therapy using genes related to enzymes and proteins involved in angiogenesis therapy targeting peripheral vascular occlusion etc. (e.g., growth factors such as HGF and VEGF), therapy using genes related to proteins involved in glucose metabolism and insulin resistance, and antisense against cytokines such as TNF. Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy including cognitive behavioral therapy. In addition, the compound of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, cardiomyocyte sheets). EXAMPLES

[0165] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified. In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The developing solvent was the same as that used as the elution solvent in column chromatography. A UV detector was used for detection. In silica gel column chromatography, when NH is used, aminopropylsilane-bonded silica gel was used, and when DIOL is used, 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel was used. In preparative HPLC (high performance liquid chromatography), when C18 is used, octadecyl-bonded silica gel was used. The ratios shown in the elution solvents are volume ratios unless otherwise specified. 1 H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shows actual measurements (found values). Molecular ion peaks are usually observed, but may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed. 6-Bromopyridin-2-ol in the examples may exist as the tautomer 6-bromopyridin-2(1H)-one. The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization TMSCl: Trimethylsilyl chloride n-BuLi: n-butyl lithium Dess-Martin Periodinane: 1,1,1-Tris(acetyloxy)-1lambda~5~,2-benzoiodoxol-3(1H)-one MeOH: Methanol NBS: N-bromosuccinimide EtOH: Ethanol TEA: Triethylamine DIPEA: Diisopropylethylamine THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide NH3. H2O: Ammonium hydroxide SFC: Supercritical Fluid Chromatography EtOAc: Ethyl acetate DMAP: 4-Dimethylaminopyridine

[0166] Example 1 The rel-N-[(3S,4R)-7-methyl-4-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the longer retention time in SFC (column: CHIRALPAK AD-H, mobile phase: carbon dioxide / MeOH)

[0167] A) 6-Bromopyridin-2-ol To a mixture of 2-bromo-6-methoxypyridine (4.64 g), sodium iodide (18.5 g) and acetonitrile (120 mL) was added TMSCl (13.4 g) at 0 °C. The mixture was stirred at 50 °C for 5 hours. The mixture was poured into a saturated aqueous solution of sodium bicarbonate at 0 °C and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.58 g). MS: [M+H] + 173.8.

[0168] B) Methyl (6-bromo-2-oxopyridin-1(2H)-yl)acetate To a mixture of 6-bromopyridin-2-ol (3.58 g) and THF (40 mL), lithium 2-methylpropan-2-olate (1.73 g) was added at room temperature. After 15 minutes, methyl bromoacetate (15.7 g) was added, and the mixture was refluxed for 2 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.57 g). MS: [M+H]+ 245.8.

[0169] C) Ethyl (2E)-3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate A mixture of methyl (6-bromo-2-oxopyridin-1(2H)-yl)acetate (2.95 g), ethyl acrylate (6.00 g), DIPEA (4.65 g), palladium(II) acetate (0.215 g), tris(2-methylphenyl)phosphine (0.438 g), and acetonitrile (30 mL) was separated into two containers and irradiated with microwaves at 150 ° C. for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.32 g). MS: [M+H] + 266.0.

[0170] D) Ethyl (2E)-3-[5-bromo-1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate To a mixture of ethyl (2E)-3-[1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate (1.42 g) and acetonitrile (5.5 mL) was added NBS (1.00 g) at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The obtained solid was triturated in water, and the solid was collected by filtration. The obtained solid was washed with hexane to obtain the title compound (1.64 g). MS: [M+H] + 344.0.

[0171] E) Ethyl (2E)-3-[1-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate To a mixture of trimethylboroxine (0.740 g) and toluene (8.0 mL), ethyl (2E)-3-[5-bromo-1-(2-methoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate (0.803 g), potassium carbonate (0.807 g), bis[4-(di-tert-butylphosphino)-N,N-dimethylaniline]dichloropalladium(II) (0.0431 g), and water (2.4 mL) were added at room temperature. The mixture was stirred at 80 °C for 30 minutes under a nitrogen atmosphere. After cooling the mixture in an ice bath, the aqueous layer was separated and extracted with ethyl acetate. The original organic layer and the extracted organic layer were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.578 g). MS: [M+H] + 280.1.

[0172] F) Ethyl 3-[1-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-1,6-dihydropyridin-2-yl]propanoate A mixture of ethyl (2E)-3-[1-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-1,6-dihydropyridin-2-yl]prop-2-enoate (26.1 g), 10% palladium on carbon (2.61 g), ethyl acetate (170 mL) and MeOH (85 mL) was stirred overnight at room temperature under normal pressure hydrogen atmosphere, and then stirred for 1 day. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (26.2 g). MS: [M+H] + 282.2.

[0173] G) 4-(hydroxymethyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione To a mixture of ethyl 3-[1-(2-methoxy-2-oxoethyl)-5-methyl-6-oxo-1,6-dihydropyridin-2-yl]propanoate (11.1 g) and THF (200 mL), 28% sodium methanolate in methanol (8.68 mL) was added with stirring at 0 °C. After 30 minutes, the mixture was concentrated under reduced pressure. 6 M hydrochloric acid was added to the residue and refluxed for 60 minutes, and the mixture was concentrated under reduced pressure. Saturated saline was added to the residue, and the mixture was extracted with THF-ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue, THF (150 mL), and water (40 mL), sodium carbonate (3.35 g) was added at room temperature, followed by the addition of 37% aqueous formaldehyde solution (3.52 g). After 30 minutes, salt was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (8.88 g). MS: [M+H] + 208.1.

[0174] H) rac-7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one Sodium borohydride (1.85 g) was added to the stirred MeOH (160 mL) at 0°C. After 5 minutes, 4-(hydroxymethyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione (6.77 g) was added to the mixture, and the mixture was warmed to room temperature. After 60 minutes, 2 M hydrochloric acid (24.5 mL) was added, and the mixture was concentrated under reduced pressure. Methanol was added to the mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / ethyl acetate) to give the title compound (5.31 g). MS: [M+H] + 210.1.

[0175] I) 10H-phenoxaborin-10-ol A 1.6 M n-BuLi hexane solution (190 mL) was added to a mixture of 1,1'-oxydibenzene (25.0 g) and THF (300 mL) at -78 °C. After stirring at -78 °C for 2 hours, the mixture was stirred at room temperature overnight. Trimethyl borate (22.9 g) was added to the mixture at room temperature, and the mixture was stirred at 70 °C for 2 hours under a nitrogen atmosphere. 2 M hydrochloric acid was added to the mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / heptane, and the obtained solid was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (5.14 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.28 (2H, t, J = 7.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.67 (2H, t, J = 7.7 Hz), 8.14 (2H, d, J = 7.5 Hz), 9.84 (1H, s).

[0176] J) (1r,4r)-4-Methylcyclohexyl methanesulfonate A mixture of (1r,4r)-4-methylcyclohexanol (1.38 g), TEA (3.03 g), methanesulfonic anhydride (5.22 g), and THF (40 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.16 g). 1 H NMR (400 MHz, CDCl3) δ 0.90 (3H, d, J = 6.5 Hz), 1.01-1.16 (2H, m), 1.31-1.45 (1H, m), 1.50-1.64 (2H, m), 1.73-1.84 (2H, m), 2.10-2.22 (2H, m), 2.99 (3H, s), 4.59 (1H, tt, J = 11.2, 4.6 Hz).

[0177] K) 7-Hydroxy-3-methyl-6-({[(1s,4s)-4-methylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.483 g), (1r,4r)-4-methylcyclohexyl methanesulfonate (2.16 g), 10H-phenoxaborin-10-ol (0.181 g), cesium carbonate (3.76 g), and acetonitrile (15 mL) was stirred in a sealed tube at 95° C. for 3 days. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.278 g). MS: [M+H] + 306.1.

[0178] L) 7-Methyl-4-({[(1s,4s)-4-methylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 7-hydroxy-3-methyl-6-({[(1s,4s)-4-methylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.395 g) and acetonitrile (8 mL) was added Dess-Martin Periodinane (1.10 g) at 0 ° C. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.198 g). MS: [M+H] + 304.1.

[0179] M) rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-methyl-4-({[(1s,4s)-4-methylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione (0.198 g), hydroxylamine hydrochloride (0.181 g), sodium acetate (0.321 g), and EtOH (5 mL) was stirred at 90 °C for 1 hour under argon atmosphere. The mixture was concentrated under reduced pressure, diluted with THF and saturated saline, and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue, molybdenum trioxide (VI) (0.125 g), and MeOH (5.8 mL) was added sodium borohydride (0.110 g) at room temperature. The mixture was stirred at room temperature for 1 hour, and sodium borohydride (0.110 g) was added. The mixture was further stirred at room temperature for 1 hour, and sodium borohydride (0.110 g) was added. The mixture was neutralized with saturated aqueous sodium bicarbonate at 0°C and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to obtain the title compound (0.0977 g). MS: [M+H] + 305.2.

[0180] N) rac-N-[(3S,4R)-7-methyl-4-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (74 mg), TEA (40 mg), and dichloromethane (4.0 mL) was added methanesulfonyl chloride (34 mg) at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and concentrated under reduced pressure. The residue was purified by HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 .The resulting fraction was concentrated under reduced pressure and then freeze-dried to give the title compound (44 mg). MS: [M+H] + 383.3.

[0181] O) The rel-N-[(3S,4R)-7-methyl-4-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the longer retention time in SFC (column: CHIRALPAK AD-H, mobile phase: carbon dioxide / MeOH) rac-N-[(3S,4R)-7-methyl-4-({[(1s,4S)-4-methylcyclohexyl]oxy}methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (34 mg) was purified by SFC (CHIRALPAK AD-H, 20 mmID×250 mmL, mobile phase: carbon dioxide / methanol=800 / 200 (v / v)) to obtain the title compound (13 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.68-0.80 (4H, m), 0.97-1.34 (7H, m), 1.45-1.55 (1H, m), 1.63-1.75 (1H, m), 1.82-1.93 (1H, m), 1.96 (3H, s), 2.09-2.25 (1H, m), 2.90-3.05 (5H, m), 3.58-3.71 (2H, m), 3.75-3.84 (1H, m), 4.86-4.97 (1H, m), 5.97 (1H, d, J = 7.0 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.49 (1H, d, J = 6.2 Hz).

[0182] Example 6 The rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the shortest retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH)

[0183] A) (1r,4r)-4-Phenylcyclohexan-1-ol To a mixture of 4-phenylcyclohexanone (50.0 g), THF (300 mL), and MeOH (30 mL) was added sodium borohydride (13.0 g) at 0°C. The mixture was stirred under a nitrogen atmosphere at 15°C for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (42.5 g). 1 H NMR (400 MHz, CDCl3) δ 1.45-1.59 (4H, m), 1.92-1.98 (2H, m), 2.09-2.15 (2H, m), 2.47-2.57 (1H, m), 3.67-3.75 (1H, m), 7.18-7.34 (5H, m).

[0184] B) (1r,4r)-4-Phenylcyclohexyl methanesulfonate To a mixture of (1r,4r)-4-phenylcyclohexan-1-ol (1.0 g) and THF (20 mL), methanesulfonyl chloride (0.812 g) and TEA (0.861 g) were added at 0° C. The mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.35 g). 1H NMR (300 MHz, CDCl3) δ 1.51-1.83 (4H, m), 1.94-2.07 (2H, m), 2.22-2.35 (2H, m), 2.54 (1H, tt, J = 11.8, 3.3 Hz), 3.04 (3H, s), 4.65-4.78 (1H, m), 7.12-7.36 (5H, m).

[0185] C) 7-Hydroxy-3-methyl-6-({[(1s,4s)-4-phenylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (1.00 g), (1r,4r)-4-phenylcyclohexyl methanesulfonate (4.86 g), 10H-phenoxaborin-10-ol (0.562 g), cesium carbonate (7.79 g), and acetonitrile (34 mL) was separated into two sealed tubes and stirred at 120°C for 44 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.995 g). MS: [M+H] + 368.2.

[0186] D) 7-Methyl-4-({[(1s,4s)-4-phenylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 7-hydroxy-3-methyl-6-({[(1s,4s)-4-phenylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.995 g) and acetonitrile (10 mL) was added Dess-Martin Periodinane (2.30 g) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.600 g). MS: [M+H]+ 366.2.

[0187] E) rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-methyl-4-({[(1s,4s)-4-phenylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione (0.600 g), hydroxylamine hydrochloride (0.171 g), sodium acetate (0.269 g), and EtOH (16.3 mL) was stirred at 70° C. for 1 hour under nitrogen atmosphere. Saturated aqueous sodium bicarbonate and sodium chloride were added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium borohydride (0.186 g) was added to a mixture of the residue, molybdenum trioxide (VI) (0.355 g), and MeOH (8.2 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the mixture under ice-cooling, and the mixture was warmed to room temperature, sodium chloride was added, and the mixture was extracted with ethyl acetate-THF. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.530 g). MS: [M+H] + 367.2.

[0188] F) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.242 g), TEA (0.200 g), and THF (5.0 mL) was added methanesulfonic anhydride (0.262 g) at room temperature. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.180 g). MS: [M+H] + 445.2.

[0189] G) rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with a shorter retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (0.180 g) was purified by SFC (CHIRALCEL OJ-H, 20 mmID x 250 mmL, mobile phase: carbon dioxide / methanol = 800 / 200 (v / v)) to obtain the title compound (0.082 g). 1H NMR (400 MHz, CDCl3) δ 1.55-1.80 (5H, m), 1.94-2.21 (6H, m), 2.24-2.35 (1H, m), 2.47-2.59 (1H, m), 2.90-3.13 (5H, m), 3.67-3.88 (5H, m), 5.30-5.37 (1H, m), 5.96 (1H, d, J = 7.0 Hz), 6.27 (1H, d, J = 8.7 Hz), 7.11-7.15 (1H, m), 7.16-7.34 (5H, m).

[0190] Example 9 The rel-N-[(3S,4R)-4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the shortest retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH)

[0191] A) (1r,4r)-4-Ethylcyclohexyl methanesulfonate To a mixture of (1r,4r)-4-ethylcyclohexan-1-ol (1.79 g), TEA (2.83 g), and THF (70 mL) was added methanesulfonic anhydride (2.63 g) at 0° C. The mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.86 g). 1 H NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J = 7.3 Hz), 0.94-1.29 (5H, m), 1.49-1.60 (2H, m), 1.78-1.93 (2H, m), 2.10-2.20 (2H, m), 3.00 (3H, s), 4.59 (1H, tt, J = 11.2, 4.6 Hz).

[0192] B) 6-({[(1s,4s)-4-ethylcyclohexyl]oxy}methyl)-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.500 g), (1r,4r)-4-ethylcyclohexyl methanesulfonate (2.96 g), cesium carbonate (4.67 g), 10H-phenoxaborin-10-ol (0.375 g), and acetonitrile (20 mL) was stirred at 120° C. for 50 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (0.760 g). MS: [M+H] + 320.2.

[0193] C) 4-({[(1s,4s)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 6-({[(1s,4s)-4-ethylcyclohexyl]oxy}methyl)-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.500 g) and acetonitrile (15 mL) was added Dess-Martin Periodinane (1.33 g) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.334 g). MS: [M+H] + 318.2.

[0194] D) rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 4-({[(1s,4s)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione (0.334 g), hydroxylamine hydrochloride (0.110 g), sodium acetate (0.173 g), and EtOH (10 mL) was stirred at 70° C. for 1 hour under nitrogen atmosphere. Saturated aqueous sodium bicarbonate and sodium chloride were added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium borohydride (0.159 g) was added to a mixture of the residue, molybdenum trioxide (VI) (0.227 g), and MeOH (10 mL) at room temperature. After stirring at room temperature for 30 minutes, sodium borohydride (0.119 g) was added to the mixture. After stirring at room temperature for 30 minutes, the mixture was cooled in an ice bath, and saturated aqueous sodium bicarbonate was added to the mixture. After cooling to room temperature, the mixture was added with sodium chloride and extracted with ethyl acetate The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.263 g). MS: [M+H] + 319.2.

[0195] E) rel-N-[(3S,4R)-4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with a shorter retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH) To a mixture of rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (0.263 g), TEA (0.251 g), and THF (10 mL) was added methanesulfonic anhydride (0.288 mg) at room temperature. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and then purified by SFC (CHIRALCEL OJ-H, 20 mmID×250 mmL, mobile phase: carbon dioxide / methanol=900 / 100(v / v)) to obtain the title compound (0.062 g). 1 H NMR (400 MHz, CDCl3) δ 0.87 (3H, t, J = 7.2 Hz), 1.04-1.30 (5H, m), 1.33-1.61 (4H, m), 1.75-1.96 (2H, m), 2.03-2.17 (4H, m), 2.22-2.33 (1H, m), 2.89-3.10 (5H, m), 3.59-3.83 (4H, m), 5.30 (1H, dt, J = 8.6, 4.3 Hz), 5.94 (1H, d, J = 7.0 Hz), 6.32 (1H, d, J = 8.7 Hz), 7.12 (1H, d, J = 6.2 Hz).

[0196] Example 78 The rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1r,4S)-4-propylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide with the shortest retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH)

[0197] A) 2,8-Dimethyl-10H-phenoxaborin-10-ol A 1.6 M n-BuLi hexane solution (374 mL) was added dropwise to a mixture of 1,1'-oxybis(4-methylbenzene) (47.5 g), N,N,N',N'-tetramethylethane-1,2-diamine (69.6 g), and THF (480 mL) at -78°C. The mixture was stirred at room temperature for 3 hours, then cooled to -78°C, and trimethylborate (62.2 g) was added dropwise to the mixture. The mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (500 mL) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 5 hours. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (20 mL) and hexane (200 mL) were added to the residue, and the solid was collected by filtration. The obtained solid was washed with hexane and then suspended in ethyl acetate. The solid was collected by filtration and washed with ethyl acetate to obtain the title compound (16.8 g). MS: [MH] - 223.1.

[0198] B) 7-hydroxy-3-methyl-6-({[(1r,4s)-4-propylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one To a stirred mixture of 4-propylcyclohexanone (32.0 g), THF (150 mL), and MeOH (20 mL) was added sodium borohydride (4.32 g) at 0 °C. After stirring for 15 minutes, water was added to the mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give (1s,4r)-4-propylcyclohexan-1-ol (19.0 g). To a stirred mixture of (1s,4r)-4-propylcyclohexan-1-ol (19.0 g), TEA (22 g), and THF (200 mL) was added methanesulfonic anhydride (29.1 g) at 0 °C. After stirring for 30 minutes, saturated aqueous sodium bicarbonate was added to the mixture and concentrated under reduced pressure. Water and ethyl acetate were added to the residue. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane and (1s,4r)-4-propylcyclohexyl methanesulfonate seed crystals were added to the residue, and the solid was collected by filtration. The solid was washed with hexane to obtain (1s,4r)-4-propylcyclohexyl methanesulfonate. A mixture of the obtained (1s,4r)-4-propylcyclohexyl methanesulfonate, 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (4.65 g), 2,8-dimethyl-10H-phenoxaborin-10-ol (5.98 g), cesium carbonate (43.5 g), and acetonitrile (150 mL) was stirred at 80 °C for 72 hours, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.30 g). MS: [M+H] + 334.3.

[0199] C) 7-Methyl-4-({[(1r,4s)-4-propylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 7-hydroxy-3-methyl-6-({[(1r,4s)-4-propylcyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (2.30 g) and acetonitrile (69 mL) was added Dess-Martin Periodinane (3.51 g) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.11 g). MS: [M+H] + 332.2.

[0200] D) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1r,4S)-4-propylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide A mixture of 7-methyl-4-({[(1r,4s)-4-propylcyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione (69.9 mg), ammonium formate (133 mg), chloro[4-(dimethylamino)-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III) (1.1 mg) and MeOH (1 mL) was stirred at 70 °C for 1 hour and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution, and concentrated under reduced pressure. The residue was diluted with THF (1 mL) and stirred, and TEA (64 mg) and cyclopropanesulfonyl chloride (53 mg) were added at 0 °C. After stirring for 15 minutes, saturated aqueous sodium bicarbonate solution was added to the mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (53.4 mg). MS: [M+H] + 437.3.

[0201] E) rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1r,4S)-4-propylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide with a shorter retention time in SFC (column: CHIRALCEL OJ-H, mobile phase: carbon dioxide / MeOH) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1r,4S)-4-propylcyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (52.6 mg) was separated by SFC (column: CHIRALCEL OJ-H, 20 mmID×250 mmL, mobile phase: carbon dioxide / methanol = 900 / 100) to obtain the title compound (22.4 mg). 1 H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J = 7.1 Hz), 0.99-1.59 (15H, m), 1.74-1.95 (2H, m), 2.06-2.18 (4H, m), 2.20-2.34 (1H, m), 2.42-2.60 (1H, m), 2.84-3.17 (2H, m), 3.56-3.90 (4H, m), 5.37-5.48 (1H, m), 5.91-5.98 (1H, m), 6.27 (1H, d, J = 8.7 Hz), 7.12 (1H, dd, J = 7.0, 1.0 Hz).

[0202] Example 109 rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide

[0203] A) Ethyl (1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexane-1-carboxylate A mixture of ethyl trans-4-hydroxycyclohexanecarboxylate (25 g), tert-butyl(chloro)diphenylsilane (41.9 g), 1H-imidazole (10.9 g), and DMF (300 mL) was stirred at room temperature overnight. 0.1 M hydrochloric acid was added to the mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (54.8 g). 1 H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 1.17-1.23 (3H, m), 1.25-1.45 (4H, m), 1.25-1.45 (4H, m), 1.80-1.95 (4H, m), 2.14-2.26 (1H, m), 3.53-3.69 (1H, m), 3.97-4.18 (2H, m), 7.33-7.45 (6H, m), 7.62-7.69 (4H, m).

[0204] B) [(1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl]methanol A mixture of ethyl (1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexane-1-carboxylate (108 g) and THF (100 mL) was added to a stirred mixture of lithium aluminum hydride (9.98 g) and THF (100 mL) under ice bath. After stirring at 0 °C for 30 minutes, water (5 mL) and 1 M aqueous sodium hydroxide solution (1 mL) were added in sequence and stirred for 30 minutes. Water (3 mL) was further added and stirred at room temperature for 30 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (90 g). 1H NMR (400 MHz, CDCl3) δ 0.69-0.92 (2H, m), 1.05 (9H, s), 1.22-1.28 (1H, m), 1.31-1.47 (3H, m), 1.61-1.77 (2H, m), 1.80-1.91 (2H, m), 3.28-3.40 (2H, m), 3.51-3.62 (1H, m), 7.30-7.48 (6H, m), 7.58-7.76 (4H, m).

[0205] C) (1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexane-1-carbaldehyde To a stirred mixture of [(1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl]methanol (10 g), TEA (8.24 g), and DMSO (70 mL) was added sulfur trioxide pyridine complex (13.0 g) in small portions. After stirring at room temperature for 3 hours, the mixture was poured into water and extracted with diethyl ether. The organic layer was separated, washed with 1M hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (8.79 g). 1 H NMR (300 MHz, CDCl3) δ 1.00-1.11 (9H, m), 1.14-1.31 (2H, m), 1.34-1.53 ​​(2H, m), 1.78-1.99 (4H, m), 2.12-2.25 (1H, m), 3.53-3.69 (1H, m), 7.32-7.49 (6H, m), 7.63-7.73 (4H, m), 9.54-9.61 (1H, m).

[0206] D) (1r,4r)-4-(prop-1-yn-1-yl)cyclohexyl methanesulfonate A mixture of (1r,4r)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexane-1-carbaldehyde (1 g), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.495 mL), potassium carbonate (0.754 g), and MeOH (10 mL) was stirred at room temperature for 2 hours. Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.1 mL) was added to the mixture and stirred for 30 minutes. The mixture was poured into water and extracted with diethyl ether. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give tert-butyl{[(1r,4r)-4-ethynylcyclohexyl]oxy}diphenylsilane (798 mg). To a stirred mixture of tert-butyl{[(1r,4r)-4-ethynylcyclohexyl]oxy}diphenylsilane (1.27 g) and THF (15 ml), 1.6 M n-BuLi hexane solution (2.85 mL) was added at -78 °C. After stirring for 15 minutes, iodomethane (795 mg) was added to the mixture. After the mixture was warmed to room temperature, the mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with THF (7 mL), and then 1 M tetrabutylammonium fluoride THF solution (7.0 mL) was added and stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give (1r,4r)-4-(prop-1-yn-1-yl)cyclohexan-1-ol (305 mg). To a stirred mixture of (1r,4r)-4-(prop-1-yn-1-yl)cyclohexan-1-ol (305 mg), TEA (357 mg) and THF (6.6 mL) was added methanesulfonic anhydride (481 mg) at 0 °C. After stirring for 30 minutes, water was added to the mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (437 mg). 1H NMR (300 MHz, CDCl3) δ1.43-1.54 (2H, m), 1.58-1.73 (2H, m), 1.78 (3H, d, J = 2.3 Hz), 1.90-2.02 (2H, m), 2.07-2.18 (2H, m), 2.30-2.43 (1H, m), 3.00 (3H, s), 4.64-4.77 (1H, m).

[0207] E) 7-hydroxy-3-methyl-6-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (168 mg), (1r,4r)-4-(prop-1-yn-1-yl)cyclohexyl methanesulfonate (435 mg), 2,8-dimethyl-10H-phenoxaborin-10-ol (216 mg), cesium carbonate (655 mg), and acetonitrile (3.7 mL) was stirred at 80 °C for 72 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, and the organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (105 mg). MS: [M+H] + 330.2.

[0208] F) 7-methyl-4-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 7-hydroxy-3-methyl-6-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (105 mg) and acetonitrile (3.2 mL) was added Dess-Martin Periodinane (162 mg) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (98.8 mg). MS: [M+H] + 328.2.

[0209] G) 7-(hydroxyimino)-3-methyl-6-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-methyl-4-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-2H-quinolizine-3,6(1H,4H)-dione (98.8 mg), sodium acetate (49.5 mg), hydroxylamine hydrochloride (31.5 mg), and EtOH (1.5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (103 mg). MS: [M+H] + 343.2.

[0210] H) rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one To a stirred mixture of 7-(hydroxyimino)-3-methyl-6-({[(1s,4s)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (103 mg) and MeOH (3 ml) was added molybdenum trioxide (VI) (87 mg) and sodium borohydride (68.3 mg) at room temperature. After stirring for 15 minutes, the mixture was cooled to 0°C, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and concentrated under reduced pressure to obtain the title compound (84.5 mg). MS: [M+H] + 329.3.

[0211] I) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide To a stirred mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (42.0 mg) and THF (1 mL) were added TEA (26 mg) and methanesulfonic anhydride (29.0 mg) at room temperature. After stirring for 15 minutes, water was added to the mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (20.5 mg). 1H NMR (300 MHz, CDCl3) δ 1.57-1.88 (11H, m), 2.05-2.18 (4H, m), 2.22-2.35 (1H, m), 2.42-2.53 (1H, m), 2.85-3.12 (5H, m), 3.38-3.50 (1H, m), 3.66-3.88 (3H, m), 5.23-5.37 (1H, m), 5.91-6.01 (1H, m), 6.14-6.27 (1H, m), 7.13 (1H, dd, J = 7.0, 1.1 Hz).

[0212] Example 110 rac-N-{(3S,4R)-7-methyl-6-oxo-4-[({(1s,4S)-4-[(1Z)-prop-1-en-1-yl]cyclohexyl}oxy)methyl]-1,3,4,6-tetrahydro-2H-quinolizin-3-yl}methanesulfonamide

[0213] A mixture of rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (16.1 mg), palladium-polyethylenimine (trade name) (1.6 mg) and MeOH (0.4 mL) was stirred at room temperature under normal pressure for 1 day under hydrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (5.0 mg). 1H NMR (300 MHz, CDCl3) δ 1.31-1.64 (9H, m), 1.76-1.98 (2H, m), 2.06-2.19 (4H, m), 2.21-2.43 (2H, m), 2.85-3.16 (5H, m), 3.57-3.65 (1H, m), 3.67-3.88 (3H, m), 5.20-5.47 (3H, m), 5.95 (1H, d, J = 7.0 Hz), 6.30 (1H, d, J = 8.5 Hz), 7.07-7.17 (1H, m).

[0214] Example 111 rel-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with a shorter retention time in HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH)

[0215] A) [(1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]methanol A mixture of tert-butyl(chloro)dimethylsilane (20 g) and DMF (80 mL) was added to a mixture of ethyl trans-4-hydroxycyclohexanecarboxylate (18.8 g), 1H-imidazole (8.35 g), and DMF (150 mL) at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted with diethyl ether. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with THF (250 mL), and the mixture was added to a mixture of 2.5 M lithium aluminum hydride in THF (66 mL) and THF (130 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour under a nitrogen atmosphere. Water (6.6 mL), 4 M sodium hydroxide solution (6.6 mL), and water (17 mL) were added to the mixture successively at 0 °C. The mixture was stirred at room temperature for 15 minutes, and then anhydrous magnesium sulfate was added. After stirring the mixture at room temperature for 5 minutes, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (26.5 g). 1 H NMR (300 MHz, CDCl3) δ 0.03-0.08 (6H, m), 0.82-1.10 (11H, m), 1.21-1.53 ​​(4H, m), 1.74-1.95 (4H, m), 3.40-3.59 (3H, m).

[0216] B) (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexane-1-carbaldehyde A mixture of sulfur trioxide pyridine complex (51.8 g) and DMSO (260 mL) was added with a mixture of [(1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]methanol (26.5 g), TEA (109 g) and EtOAc (100 ml) at 0 °C (internal temperature: 15 °C to 25 °C). The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water was added to the mixture at 0 °C (internal temperature: 15 °C to 30 °C), and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with 0.1 M hydrochloric acid, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (21.8 g). 1 H NMR (300 MHz, CDCl3) δ 0.05 (6H, s), 0.86-0.91 (9H, m), 1.29-1.46 (4H, m), 1.78-2.07 (4H, m), 2.11-2.28 (1H, m), 3.46-3.70 (1H, m), 9.64 (1H, d, J = 1.1 Hz).

[0217] C) tert-Butyl{[(1r,4r)-4-ethenylcyclohexyl]oxy}dimethylsilane To a mixture of methyl(triphenyl)phosphonium bromide (79.2 g) and THF (450 mL), 1.6 M n-BuLi hexane solution (140 mL) was added at 0 °C. After stirring for 20 minutes at 0 °C under nitrogen atmosphere, a mixture of (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexane-1-carbaldehyde (26.9 g) and THF (50 mL) was added at 0 °C. The mixture was stirred for 1 hour at 0 °C under nitrogen atmosphere. A saturated aqueous solution of ammonium chloride was added to the mixture at 0 °C, and the mixture was extracted with a mixture of ethyl acetate and hexane (1:1). The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with a mixture of ethyl acetate and hexane (1:9), and the solid was crushed. The insoluble matter of the mixture was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (18.7 g). 1 H NMR (400 MHz, CDCl3) δ 0.05 (6H, s), 0.89 (9H, s), 1.01-1.51 (4H, m), 1.69-1.98 (5H, m), 3.46-3.58 (1H, m), 4.84-5.02 (2H, m), 5.68-5.81 (1H, m).

[0218] D) tert-Butyl{[(1r,4r)-4-cyclopropylcyclohexyl]oxy}dimethylsilane To dichloromethane (53 mL), 1 M diethylzinc hexane solution (85 mL) and a mixture of TFA (9.48 g) and dichloromethane (60 mL) were added successively at 0 °C. After stirring for 10 minutes at 0 °C under nitrogen atmosphere, a mixture of diiodomethane (22.3 g) and dichloromethane (30 mL) was added to the mixture at 0 °C. After stirring for 10 minutes at 0 °C under nitrogen atmosphere, a mixture of tert-butyl{[(1r,4r)-4-ethenylcyclohexyl]oxy}dimethylsilane (10.1 g) and dichloromethane (45 mL) was added to the mixture. The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The mixture was diluted with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (10.3 g). 1 H NMR (300 MHz, CDCl3) δ 0.01-0.09 (8H, m), 0.31-0.50 (4H, m), 0.86-0.90 (9H, m), 1.00-1.33 (4H, m), 1.73-1.91 (4H, m), 3.45-3.60 (1H, m).

[0219] E) (1r,4r)-4-Cyclopropylcyclohexyl methanesulfonate To a mixture of tert-butyl{[(1r,4r)-4-cyclopropylcyclohexyl]oxy}dimethylsilane (10.3 g) and EtOH (100 mL), 6 M hydrochloric acid (10 mL) was added. The mixture was stirred under nitrogen atmosphere at 40 °C for 30 minutes. Water was added to the mixture at 0 °C, and the mixture was extracted with diethyl ether. The organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with THF (100 mL), and methanesulfonic anhydride (10.2 g) and TEA (8.0 g) were added successively at 0 °C. The mixture was stirred under nitrogen atmosphere at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (8.04 g). 1 H NMR (300 MHz, CDCl3) δ 0.01-0.09 (2H, m), 0.35-0.55 (4H, m), 1.12-1.30 (2H, m), 1.41-1.59 (2H, m), 1.85-1.97 (2H, m), 2.10-2.22 (2H, m), 3.00 (3H, s), 4.54-4.69 (1H, m).

[0220] F) 6-({[(1s,4s)-4-cyclopropylcyclohexyl]oxy}methyl)-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (3.10 g), (1r,4r)-4-cyclopropylcyclohexyl methanesulfonate (8.04 g), 2,8-dimethyl-10H-phenoxaborin-10-ol (3.50 g), cesium carbonate (12.0 g), and acetonitrile (75 mL) was stirred at 80 °C (internal temperature) for 4 days. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.38 g). MS: [M+H]+ 332.2.

[0221] G) 4-({[(1s,4s)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione To a mixture of 6-({[(1s,4s)-4-cyclopropylcyclohexyl]oxy}methyl)-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (1.38 g) and acetonitrile (42 mL), Dess-Martin Periodinane (2.12 g) was added at room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.16 g). MS: [M+H] + 330.2.

[0222] H) rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one A mixture of 4-({[(1s,4s)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-2H-quinolizine-3,6(1H,4H)-dione (1.04 g), ammonium formate (1.99 g), AcOH (0.190 g), chloro[4-(dimethylamino)-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III) (0.017 g), and MeOH (16 mL) was stirred at 60 ° C. for 1 hour. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.01 g). MS: [M+H] + 331.3.

[0223] I) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide To a mixture of rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (111 mg) and THF (1.7 mL), TEA (54 mg) and methanesulfonic anhydride (70.2 mg) were added at 0° C. After stirring for 15 minutes, water was added to the mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (114 mg). MS: [M+H] + 409.2.

[0224] J) rel-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with a shorter retention time by HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (114 mg) was separated by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, mobile phase: hexane / ethanol=800 / 200) to obtain the title compound (41.9 mg). 1H NMR (300 MHz, CDCl3) δ-0.03-0.06 (2H, m), 0.32-0.42 (2H, m), 0.43-0.68 (2H, m), 1.25-1.46 (4H, m), 1.57-1.67 (2H, m), 1.76-2.00 (2H, m), 2.05-2.20 (4H, m), 2.21-2.37 (1H, m), 2.87-3.14 (5H, m), 3.55-3.63 (1H, m), 3.66-3.86 (3H, m), 5.25-5.38 (1H, m), 5.95 (1H, d, J = 7.0 Hz), 6.36 (1H, d, J = 8.5 Hz), 7.13 (1H, dd, J = 6.9, 1.0 Hz).

[0225] Example 112 rel-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide with a shorter retention time in HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH)

[0226] A) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide A mixture of rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (111 mg) and THF (1.7 mL) was stirred, and TEA (102 mg) and ethanesulfonyl chloride (64.8 mg) were added at 0° C. After stirring for 15 minutes, water was added to the mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (100 mg). MS: [M+H] + 423.3.

[0227] B) rel-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide with a shorter retention time by HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (88 mg) was separated by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, mobile phase: hexane / ethanol=850 / 150) to obtain the title compound (38.5 mg). 1 H NMR (300 MHz, CDCl3) δ-0.03-0.07 (2H, m), 0.32-0.42 (2H, m), 0.44-0.66 (2H, m), 1.25-1.50 (7H, m), 1.51-1.67 (2H, m), 1.76-1.99 (2H, m), 2.03-2.20 (4H, m), 2.22-2.37 (1H, m), 2.86-3.14 (4H, m), 3.54-3.62 (1H, m), 3.64-3.82 (3H, m), 5.23-5.36 (1H, m), 5.94 (1H, d, J = 7.0 Hz), 6.28 (1H, d, J = 8.6 Hz), 7.12 (1H, dd, J = 7.0, 0.9 Hz).

[0228] Example 113 HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH) showed a shorter retention time.

[0229] A) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide To a stirred mixture of rac-(6R,7S)-7-amino-6-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (111 mg) and THF (1.7 mL), TEA (204 mg), cyclopropanesulfonyl chloride (142 mg), and DMAP (41.0 mg) were added at room temperature. The mixture was stirred at 60 °C for 1 hour. Water was added to the mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (109 mg). MS: [M+H] + 435.2.

[0230] B) rel-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide with a shorter retention time by HPLC (column: CHIRALCEL OJ-H, mobile phase: hexane / EtOH) rac-N-[(3S,4R)-4-({[(1s,4S)-4-cyclopropylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (96.7 mg) was separated by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, mobile phase: hexane / ethanol=850 / 150) to obtain the title compound (43.2 mg). 1H NMR (300 MHz, CDCl3) δ -0.03-0.07 (2H, m), 0.33-0.44 (2H, m), 0.45-0.66 (2H, m), 0.98-1.50 (8H, m), 1.51-1.70 (2H, m), 1.75-1.98 (2H, m), 2.02-2.19 (4H, m), 2.21-2.36 (1H, m), 2.43-2.56 (1H, m), 2.86-3.15 (2H, m), 3.51-3.64 (1H, m), 3.65-3.89 (3H, m), 5.39-5.48 (1H, m), 5.95 (1H, d, J = 7.0 Hz), 6.31 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 7.0, 1.0 Hz).

[0231] Example 121 rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (1.40 g) and dichloromethane (25 mL), TEA (1.29 g) and ethanesulfonyl chloride (1.10 g) were added at 0 °C. The mixture was stirred at 25 °C for 14 hours under a nitrogen atmosphere. Water was added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 . The mixture was purified using a HO-containing system and freeze-dried to obtain the title compound (760 mg). MS: [M+H] + 421.3.

[0232] Example 122 rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (500 mg) and dichloromethane (10 mL), TEA (462 mg) and cyclopropanesulfonyl chloride (321 mg) were added at 0° C. The mixture was stirred at 20° C. for 14 hours under a nitrogen atmosphere. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (350 mg). MS: [M+H] + 433.4.

[0233] Example 144 The rel-N,N-dimethyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide with the shortest retention time in SFC (column: CHIRALPAK AS-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH)

[0234] A) rac-N,N-dimethyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (200 mg) and dichloromethane (10 mL), TEA (246 mg) and dimethylsulfamyl chloride (262 mg) were added at 25°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 . The fraction was separated using a HO-containing system, and the obtained fraction was concentrated. The residue was freeze-dried to obtain the title compound (20.1 mg). 1 H NMR (400 MHz, CDCl3) δ 1.44-1.55 (2H, m), 1.58-1.74 (5H, m), 1.76-1.86 (4H, m), 2.00-2.15 (4H, m), 2.23-2.36 (1H, m), 2.39-2.51 (1H, m), 2.83 (6H, s), 2.87-3.10 (2H, m), 3.36-3.47 (1H, m), 3.63-3.75 (2H, m), 3.76-3.84 (1H, m), 5.23-5.33 (1H, m), 5.93 (1H, d, J= 6.8 Hz), 5.99 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 7.2 Hz).

[0235] B) The rel-N,N-dimethyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide with the shorter retention time in SFC (column: CHIRALPAK AS-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH) rac-N,N-dimethyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide (15.0 mg) was purified by SFC (column: CHIRALPAK AS, 30 mmID x 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . H2O) = 850 / 150) and HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 . The fraction was collected using a HO-containing system. The resulting fraction was concentrated and freeze-dried to give the title compound (2.2 mg). 1 H NMR (400 MHz, CDCl3) δ 1.44-1.56 (2H, m), 1.59-1.74 (5H, m), 1.75-1.86 (4H, m), 2.00-2.15 (4H, m), 2.23-2.36 (1H, m), 2.39-2.50 (1H, m), 2.82 (6H, s), 2.87-3.10 (2H, m), 3.36-3.47 (1H, m), 3.63-3.75 (2H, m), 3.76-3.84 (1H, m), 5.23-5.33 (1H, m), 5.93 (1H, d, J= 6.8 Hz), 5.98 (1H, d, J = 8.4 Hz), 7.12 (1H, d, J = 7.2 Hz).

[0236] Example 145 The rel-N-[(3S,4R)-4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the longer retention time in SFC (column: CHIRALPAK AD-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH)

[0237] A) (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexan-1-ol To a mixture of trans-cyclohexane-1,4-diol (20.0 g) and DMF (200 mL), 1H-imidazole (17.6 g) and tert-butyl(chloro)dimethylsilane (28.6 g) were added at 0° C. The mixture was stirred at 0° C. for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (32.1 g). 1 H NMR (400 MHz, CDCl3) δ 0.05 (6H, s), 0.88 (9H, s), 1.22-1.48 (4H, m), 1.76-2.01 (4H, m), 3.52-3.83 (2H, m).

[0238] B) tert-Butyl{[(1r,4r)-4-ethoxycyclohexyl]oxy}dimethylsilane To a mixture of (1r,4r)-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexan-1-ol (9 g) and DMF (50 mL) was added 60% sodium hydride (7.81 g) at 0 °C. The reaction mixture was stirred at the same temperature for 10 minutes, and then iodoethane (15.6 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (8.15 g). 1 H NMR (300 MHz, CDCl3) δ 0.00 (6H, s), 0.83 (9H, s), 1.08-1.18 (3H, m), 1.21-1.36 (4H, m), 1.72-1.85 (2H, m), 1.85-1.98 (2H, m), 3.12-3.29 (1H, m), 3.37-3.48 (2H, m), 3.51-3.67 (1H, m).

[0239] C) (1r,4r)-4-Ethoxycyclohexan-1-ol To a mixture of tert-butyl{[(1r,4r)-4-ethoxycyclohexyl]oxy}dimethylsilane (7.25 g) and THF (1 mL), 1M tetrabutylammonium fluoride THF solution (56 mL) was added at room temperature, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.43 g). 1 H NMR (300 MHz, CDCl3) δ 1.15-1.23 (3H, m), 1.28-1.37 (4H, m), 1.42-1.46 (1H, m), 1.89-2.09 (4H, m), 3.19-3.31 (1H, m), 3.49 (2H, s), 3.60-3.75 (1H, m).

[0240] D) (1r,4r)-4-Ethoxycyclohexyl methanesulfonate To a mixture of (1r,4r)-4-ethoxycyclohexan-1-ol (20.1 g) and dichloromethane (150 mL), TEA (42.3 g) was added, and then methanesulfonyl chloride (31.9 g) was added in portions at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (20.2 g). 1 H NMR (400 MHz, CDCl3) δ 1.17 (3H, t, J = 6.8 Hz), 1.42-1.53 ​​(2H, m), 1.60-1.68 (2H, m), 1.91-2.01 (2H, m), 2.04-2.14 (2H, m), 2.99 (3H, s), 3.30-3.40 (1H, m), 3.47 (2H, q, J = 6.4 Hz), 4.65-4.80 (1H, m).

[0241] E) 6-{[(4-ethoxycyclohexyl)oxy]methyl}-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one To a mixture of 7-hydroxy-6-(hydroxymethyl)-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (2.50 g) and acetonitrile (30 mL), (1r,4r)-4-ethoxycyclohexyl methanesulfonate (7.97 g), cesium carbonate (19.5 g), and 2,8-dimethyl-10H-phenoxaborin-10-ol (3.21 g) were added. The mixture was stirred in a sealed tube at 120 °C for 48 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (2.65 g). MS: [M+H] + 336.2.

[0242] F) 4-{[(4-ethoxycyclohexyl)oxy]methyl}-7-methyl-2H-quinolizine-3,6(1H,4H)-dione Dess-Martin Periodinane (13.4 g) was added to a mixture of 6-{[(4-ethoxycyclohexyl)oxy]methyl}-7-hydroxy-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (5.30 g) and dichloromethane (50 mL). The mixture was stirred at 25 °C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (4.92 g). MS: [M+H] + 334.0.

[0243] G) (6RS,7SR)-7-Amino-6-{[(4-ethoxycyclohexyl)oxy]methyl}-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one To a mixture of 4-{[(4-ethoxycyclohexyl)oxy]methyl}-7-methyl-2H-quinolizine-3,6(1H,4H)-dione (4.92 g) and EtOH (50 mL), hydroxylamine hydrochloride (2.05 g) and sodium acetate (2.42 g) were added. The mixture was stirred at 80 °C for 30 minutes and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and MeOH (50 mL), molybdenum(VI) oxide (3.30 g) and sodium borohydride (2.89 g) were added in portions at 0 °C. The mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.84 g). MS: [M+H] + 335.0.

[0244] H) N-[(3SR,4RS)-4-({[4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide To a stirred mixture of (6RS,7SR)-7-amino-6-{[(4-ethoxycyclohexyl)oxy]methyl}-3-methyl-6,7,8,9-tetrahydro-4H-quinolizin-4-one (1.84 g), TEA (2.23 g), and dichloromethane (20 mL) was added methanesulfonyl chloride in portions at 0 °C. The mixture was stirred at 25 °C under nitrogen atmosphere for 1 hour. Water was added to the mixture, which was then extracted with dichloromethane. The organic layer was separated, 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 (1.70 g). MS: [M+H] + 413.4.

[0245] I) rel-N-[(3S,4R)-4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with a longer retention time in SFC (column: CHIRALPAK AD-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH) Each batch of N-[(3SR,4RS)-4-({[4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (900 mg and 700 mg) was analyzed by SFC (column: CHIRALPAK AD, 30 mmID × 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . Another batch of N-[(3SR,4RS)-4-({[4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (1.70 g) was separated by SFC (column: CHIRALPAK AD, 30 mmID x 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . The fraction was collected by HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 . The mixture was purified using a HO-containing system, and the resulting fraction was concentrated. The residue was freeze-dried to give the title compound (255 mg). 1H NMR (400 MHz, CDCl3) δ 1.18 (3H, t, J = 7.2 Hz), 1.58-1.66 (5H, m), 1.68-1.76 (2H, m), 1.78-1.91 (1H, m), 2.04-2.16 (4H, m), 2.18-2.32 (1H, m), 2.88-3.10 (5H, m), 3.28-3.37 (1H, m), 3.41-3.52 (3H, m), 3.66-3.87 (3H, m), 5.23-5.31 (1H, m), 5.94 (1H, d, J= 7.2 Hz), 6.12 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J = 7.2 Hz).

[0246] Example 146 The rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide with the longer retention time in SFC (column: CHIRALPAK AD-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide (550 mg) was purified by SFC (column: CHIRALPAK AD, 30 mmID x 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . The resulting fraction was concentrated under reduced pressure and freeze-dried to give the title compound (193 mg). 1H NMR (400 MHz, CDCl3) δ 1.46-1.58 (2H, m), 1.60-1.76 (5H, m), 1.77-1.88 (4H, m), 2.03-2.16 (4H, m), 2.21-2.33 (1H, m), 2.40-2.52 (1H, m), 2.87-3.11 (5H, m), 3.37-3.48 (1H, m), 3.67-3.85 (3H, m), 5.22-5.32 (1H, m), 5.95 (1H, d, J= 6.8 Hz), 6.20 (1H, d, J = 8.8 Hz), 7.13 (1H, d, J = 6.8 Hz).

[0247] Example 147 The rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide with the shortest retention time in SFC (column: CHIRALCEL OJ-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide (760 mg) was purified by SFC (column: CHIRALCEL OJ-H, 30 mmID x 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . The resulting fraction was concentrated and freeze-dried to give the title compound (293 mg). 1H NMR (400 MHz, CDCl3) δ 1.43 (3H, t, J = 7.2 Hz), 1.48-1.58 (2H, m), 1.60-1.75 (5H, m), 1.76-1.87 (4H, m), 2.03-2.17 (4H, m), 2.22-2.34 (1H, m), 2.40-2.51 (1H, m), 2.88-3.14 (4H, m), 3.36-3.48 (1H, m), 3.66-3.84 (3H, m), 5.20-5.31 (1H, m), 5.94 (1H, d, J = 6.8 Hz), 6.11 (1H, d, J = 8.4 Hz), 7.12 (1H, d, J = 6.8 Hz).

[0248] Example 148 The rel-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide with the longer retention time in SFC (column: CHIRALPAK AD-3, mobile phase: carbon dioxide / 0.05% diethylamine in EtOH) rac-N-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]cyclopropanesulfonamide (770 mg) was purified by SFC (column: CHIRALPAK AD, 30 mmID x 250 mmL, mobile phase: carbon dioxide / EtOH (0.1% NH3 . H2O) = 650 / 350) and HPLC (C18, mobile phase: water / acetonitrile (0.05% NH3 . The resulting fraction was concentrated and freeze-dried to give the title compound (173 mg). 1H NMR (400 MHz, CDCl3) δ 0.98-1.28 (4H, m), 1.47-1.58 (2H, m), 1.62-1.75 (5H, m), 1.76-1.86 (4H, m), 2.02-2.17 (4H, m), 2.21-2.32 (1H, m), 2.40-2.56 (2H, m), 2.87-3.11 (2H, m), 3.37-3.47 (1H, m), 3.67-3.87 (3H, m), 5.34-5.44 (1H, m), 5.94 (1H, d, J = 6.8 Hz), 6.15 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J = 7.2 Hz).

[0249] Example 149 The rel-N-methyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide with the longer retention time in HPLC (column: CHIRALPAK IC, mobile phase: hexane / EtOH)

[0250] A) rac-N-methyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide To a mixture of rac-(6R,7S)-7-amino-3-methyl-6-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one (102 mg), TEA (291 mg), N,N-dimethylpyridin-4-amine (11.3 mg), and THF (2.0 mL), a mixture of methylsulfamyl chloride (150 mg) and THF (2.0 mL) was added at 0° C. The mixture was stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (47.1 mg). MS: [M+H] + 422.1.

[0251] B) The rel-N-methyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide with the longer retention time in HPLC (column: CHIRALPAK IC, mobile phase: hexane / EtOH). rac-N-methyl-N'-[(3S,4R)-7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]sulfuric acid diamide (40.0 mg) was separated by HPLC (column: CHIRALPAK IC, 20 mmID×250 mmL, mobile phase: hexane / EtOH = 600 / 400) to obtain the title compound (14.7 mg). 1H NMR (300 MHz, CDCl3) δ 1.47-1.88 (12H, m), 2.06-2.17 (3H, m), 2.22-2.36 (1H, m), 2.39-2.53 (1H, m), 2.80 (3H, d, J = 5.3 Hz), 2.84-3.13 (2H, m), 3.35-3.47 (1H, m), 3.61-3.88 (3H, m), 4.16-4.34 (1H, m), 5.25-5.36 (1H, m), 5.89-6.13 (2H, m), 7.08-7.16 (1H, m).

[0252] The example compounds are shown in the following table. MS in the table indicates an actually measured value. The compounds of Examples 2 to 5, 7, 8, 10 to 77, 79 to 108, 114 to 120, and 123 to 143 in the following table were produced according to the methods shown in the above examples or methods similar thereto.

[0253] [Table 1-1]

[0254] [Table 1-2]

[0255] [Table 1-3]

[0256] [Table 1-4]

[0257] [Table 1-5]

[0258] [Table 1-6]

[0259]

Table 1-7

[0260]

Table 1-8

[0261]

Table 1-9

[0262]

Table 1-10

[0263]

Table 1-11

[0264]

Table 1-12

[0265]

Table 1-13

[0266]

Table 1-14

[0267]

Table 1-15

[0268]

Table 1-16

[0269] [Table 1-17]

[0270] [Table 1-18]

[0271] [Table 1-19]

[0272] [Table 1-20]

[0273] [Table 1-21]

[0274] Test Example 1: Acquisition of human orexin type 2 receptor (hOX2R) stably expressing cells 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 the plasmid DNA for human orexin type 2 receptor expression (pcDNA3.1(+) / hOX2R) was cloned. This plasmid DNA was introduced into CHO-K1 cells by electroporation, and human orexin type 2 receptor-expressing clone cells were obtained by limiting dilution using G418 drug resistance as a selection marker.

[0275] Test Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells expressing human OX2 receptor were seeded at 10,000 cells / well in a 384-well black clear-bottom plate (BD Falcon) and cultured for one day in a 37°C, 5% CO2 incubator. After removing the medium from the cell plate, 30μL / well of assay buffer A containing calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5μg / mL Fluo-4 AM (Dojindo Chemical), 0.08% Pluronic F127 (Dojindo Chemical), 1.25 mM probenecid (Dojindo Chemical)) was added. The plate was left for 30 minutes in a 37°C, 5% CO2 incubator, and then left for another 30 minutes at room temperature. Test compounds diluted with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) were added at 10 μL / well, and the fluorescence value was measured every 1 second for 1 minute, and then every 2 seconds for 1 minute and 40 seconds using FDSSμCELL (Hamamatsu Photonics). The activity (%) of the test compounds was calculated by defining the amount of change in fluorescence value when DMSO was added instead of the test compound as 0% and the amount of change in fluorescence when orexin A (human) (Peptide Institute) was added at a final concentration of 10 nM as 100%. Table 2 shows the activity of each compound at a concentration of 3 μM. As is clear from these results, it was shown that the compounds of the present invention have orexin type 2 receptor agonist activity.

[0276] [Table 2-1]

[0277] [Table 2-2]

[0278] Test Example 3: Evaluation of wakefulness-promoting effect in SD rats The wake-promoting effect was evaluated by recording electroencephalograms (EEG) and electromyograms (EMG) of SD rats (Crl:CD(SD), CHARLES RIVER LABORATORIES JAPAN, Kanagawa, Japan.) using a chronic experiment telemetry automatic measurement system (PhysioTel (R) and PONEMAH TM Transmitter implantation was performed on male SD rats aged 8 weeks under sodium pentobarbital anesthesia (50 mg / kg, intraperitoneal, Somnopentyl(R), Kyoritsu Seiyaku, Tokyo, Japan). The EEG leads were attached to the dura mater at two points on the parietal region and fixed to the skull with dental cement. The EMG leads were fixed to two points on the dorsal cervical muscle, the transmitter was implanted subcutaneously on the back of the head, and the scalp was sutured. After recovery for at least 1 week, the cortical EEG and EMG signals of the SD rats were recorded using a high-end data acquisition and real-time analysis system (PONEMAH TM ) was used to record the EEG and EMG. Signals were automatically scored at 4-second epochs by a sleep evaluation system (SleepSign®, Kissei Comtec Co., Ltd. Nagano, Japan.). Test compounds (1 or 10 mg / kg, Table 3) dissolved in a mixed solution containing 10% DMSO, 10% Cremophor EL, 20% PEG400, and 60% H2O, or vehicle (i.e., a mixed solution containing 10% DMSO, 10% Cremophor EL, 20% PEG400, and 60% H2O) were subcutaneously administered (sc) to SD rats at a volume of 5 mL / kg at Zeitgeber time (ZT) 5 (ZT0 is the start of the light cycle). EEG and EMG were recorded for 3 hours after compound administration. The wakefulness time (% relative to the vehicle group) 3 hours after administration was calculated using SleepSign. The results are shown in Table 3.

[0279] [Table 3]

[0280] As is apparent from the results, the test compound of the present invention increased the wakefulness time in SD rats as compared to the vehicle group.

[0281] Test Example 4: Evaluation of wakefulness-promoting effect in cynomolgus monkeys The wake-promoting effect was evaluated by measuring the electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) of cynomolgus monkeys. Under isoflurane anesthesia (1-5%, Pfizer Japan Inc., Tokyo, Japan), male cynomolgus monkeys (2-3 years old, Hamri Co., Ltd., Ibaraki, Japan) were surgically implanted with a radiotelemetry transmitter (TL10M3-D70-EEE, Data Sciences International Inc., MN, USA). EEG leads were stereotactically placed on the parietal region and fixed to the skull with stainless steel screws in contact with the dura mater. A unilateral EOG lead was placed at the supraorbital rim of one eye and fixed with a stainless steel screw. Bilateral EMG leads were implanted in the dorsal neck muscles. After surgery, each cynomolgus monkey was given penicillin (100,000 units / head, im, Meiji Seika Pharma Co., Ltd., Tokyo, Japan), buprenorphine (0.02 mg / kg, im, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), and prednisolone (1 mg / kg, sc, Kyoritsu Seiyaku Co., Ltd., Tokyo, Japan) daily for 1 week. After at least 1 month of recovery in the cage, the cynomolgus monkey was habituated in a recording chamber (acrylic cage, 60W x 55D x 75H (cm)) in an electrically shielded, soundproof room. After ensuring that the cynomolgus monkey was sleeping adequately in the experimental room, cortical EEG, EMG, and EOG signals were recorded using Dataquest ART software (Data Sciences International Inc., MN, USA). Signals were semi-automatically scored at 20-s epochs using a sleep evaluation system (SleepSign, Kissei Comtec Co., Ltd., Nagano, Japan). This primary score was visually confirmed and corrected if necessary.Test compounds (0.1, 0.3, 1, or 10 mg / kg, Table 4) dissolved in a mixed solution containing 5% DMSO, 5% Cremophor EL, 20% PEG400, and 70% soluplus (1% (w / v)), or vehicle (i.e., a mixed solution containing 5% DMSO, 5% Cremophor EL, 20% PEG400, and 70% soluplus (1% (w / v))) were subcutaneously administered (sc) to cynomolgus monkeys at ZT12 in a volume of 0.5 mL / kg in a pre-post design. EEG, EMG, and EOG were recorded for 4 hours after compound administration. The wakefulness time (% relative to the vehicle group) 4 hours after administration was calculated using SleepSign. The results are shown in Table 4.

[0282] [Table 4]

[0283] As is clear from the results, the test compounds of the present invention increased the wakefulness time in cynomolgus monkeys compared to the vehicle group, indicating that these compounds are effective in treating narcolepsy.

[0284] Formulation Example 1 (Capsule Production) 1) Compound of Example 1 30 mg 2) Fine powdered cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg Total 60mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0285] Formulation Example 2 (Tablet Production) 1) Compound of Example 1 30 g 2) Lactose 50g 3) 15g corn starch 4) Calcium carboxymethylcellulose 44g 5) Magnesium stearate 1g 1000 tablets total 140g The total amount of 1), 2), 3) and 30g of 4) are mixed with water, vacuum dried, and then granulated. 14g of 4) and 1g of 5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 30mg of the compound of Example 1 per tablet are obtained. [Industrial Applicability]

[0286] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for the prevention or treatment of narcolepsy.

[0287] This application is based on Japanese Patent Application No. 2019-214206 filed on November 27, 2019 and Japanese Patent Application No. 2020-093604 filed on May 28, 2020, the contents of which are incorporated in their entirety herein.

Claims

1. formula: 【Chemistry 1】 [In the formula, R １ is C １－６ Alkyl group, mono- or di-C １－６ Alkylamino group, or C ３－６ represents a cycloalkyl group; R ２ is a hydrogen atom, a halogen atom, a cyano group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, or C １－６ represents an alkoxy group; R ３ is a C optionally substituted by a hydrogen atom, a halogen atom, a cyano group, or 1 to 3 hydroxy groups. １－６ Alkyl group, C ３－６ Cycloalkyl group, or C １－６ represents an alkoxy group; R ４ teeth, (1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a hydroxy group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl group, and a 3- to 14-membered non-aromatic heterocyclyloxy group, (2) a C 3-6 cycloalkyl group optionally substituted by 1 to 3 C 1-6 alkyl groups, (3) a C2-6 alkenyl group, (4) a C 2-6 alkynyl group optionally substituted by 1 to 3 C 3-6 cycloalkyl groups, (5) a C 6-10 aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1-6 alkyl group, and a C 1-6 alkoxy group; (6) a C 1-6 alkoxy group optionally substituted by 1 to 3 C 3-6 cycloalkoxy groups, (7) a C 3-6 cycloalkoxy group, or (8) A 4- to 6-membered heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups. A compound represented by the formula:

2. R １ But, C １－６ Alkyl group, mono- or di-C １－６ Alkylamino group, or C ３－６ cycloalkyl group; R ２ is a hydrogen atom; R ３ But, C １－６ an alkyl group; and R ４ but, (1) C １－６ Alkyl groups, (2) C ３－６ Cycloalkyl groups, (3) C ２－６ Alkenyl groups, (4) C ２－６ Alkynyl groups, (5) C ６－１０ an aryl group, or (6) C １－６ Alkoxy group 2. The compound according to claim 1, wherein:

3. R １ But, C １－６ Alkyl groups; R ２ is a hydrogen atom; R ３ But, C １－６ an alkyl group; and R ４ but, (1) C １－６ Alkyl groups, (2) C ２－６ an alkynyl group, or (3) C １－６ Alkoxy group 2. The compound according to claim 1, wherein:

4. N-[4-({[(1s,4S)-4-ethoxycyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide or a salt thereof.

5. N-[7-methyl-6-oxo-4-({[(1s,4S)-4-(prop-1-yn-1-yl)cyclohexyl]oxy}methyl)-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]ethanesulfonamide or a salt thereof.

6. N-[4-({[(1s,4S)-4-ethylcyclohexyl]oxy}methyl)-7-methyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizin-3-yl]methanesulfonamide or a salt thereof.

7. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof.

8. The pharmaceutical agent according to claim 7 for use as an orexin type 2 receptor agonist.

9. The pharmaceutical composition according to claim 8, wherein the use is for treating a disease or disorder selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications caused by anesthesia; or for antagonizing anesthesia.

10. The pharmaceutical composition according to claim 8, wherein the use is in the treatment of a disease or disorder selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

11. The pharmaceutical composition according to claim 8, wherein the use is in the treatment of narcolepsy.

12. 10. A compound according to claim 1 or a salt thereof for use in therapy.

13. 13. The compound or salt thereof according to claim 12, wherein the therapy comprises treatment of a disease or disorder associated with the orexin type 2 receptor.

14. The compound or salt thereof according to claim 13, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications due to anesthesia.

15. 14. The compound or salt thereof according to claim 13, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

16. 14. The compound or salt thereof according to claim 13, wherein the disease or disorder is narcolepsy.

17. 13. The compound or salt thereof according to claim 12, wherein the therapy comprises antagonizing anesthesia.

18. 13. Use of a compound according to claim 1 or a salt thereof for the manufacture of a medicament for use in the treatment of a disease or disorder associated with the orexin type 2 receptor.

19. The use according to claim 18, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications due to anesthesia.

20. 19. The use according to claim 18, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

21. 19. The use according to claim 18, wherein the disease or disorder is narcolepsy.

22. 13. Use of the compound according to claim 1 or a salt thereof for the manufacture of an anesthesia antagonist.

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