Pharmaceutical compositions containing cycloalkylurea derivatives

Abstract

To provide an agent for treating or preventing diseases associated with an orexin receptor, particularly an orexin 2 receptor.SOLUTION: This invention relates to an agent for treating or preventing diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, the agent containing a novel compound having a urea skeleton represented by formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a therapeutic or prophylactic agent for diseases involving orexin receptors, particularly orexin type 2 receptors, comprising a novel compound having a urea skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, it relates to a therapeutic or prophylactic agent for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. [Background technology]

[0002] Orexin is a neuropeptide specifically produced in certain nerve cells scattered throughout the lateral hypothalamus and surrounding areas of the brain. Orexin is an endogenous ligand for the orexin receptor, a G protein-coupled receptor primarily found in the brain, and binds to it. Two subtypes of the orexin receptor, type 1 and type 2, are known (Non-Patent Literature 1).

[0003] It has been reported that narcolepsy-like symptoms occurring in transgenic mice with degenerated orexin neurons are improved by intracerebroventricular administration of orexin peptide (Non-Patent Literature 2), and that narcolepsy-like symptoms are induced by knockout (KO) of preproorexin, an orexin precursor protein (Non-Patent Literature 3). Furthermore, it has been revealed that orexin concentrations in the cerebrospinal fluid of narcolepsy patients are significantly reduced (Non-Patent Literature 4), suggesting that narcolepsy is caused by orexin deficiency. Furthermore, mutations in the orexin type 2 receptor have been reported in dogs with hereditary narcolepsy (Non-Patent Literature 5), suggesting the involvement of the orexin type 2 receptor in sleep-wake cycles. Moreover, it has been shown that narcolepsy-like symptoms are induced in orexin type 2 receptor knockout mice (Non-Patent Literature 6), strongly suggesting the involvement of orexin type 2 receptor stimulation in maintaining wakefulness. Against this backdrop, orexin type 2 receptor agonists are expected to be promising therapeutic agents for diseases exhibiting hypersomnia symptoms, including narcolepsy.

[0004] In recent years, compounds exhibiting orexin type 2 receptor agonist activity have been reported (Patent Document 1). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2017 / 135306 [Non-patent literature]

[0006] [Non-Patent Document 1] Cell, Vol. 92, pp. 573-585, 1998. [Non-Patent Document 2] Proceedings of the National Academy of Sciences of United States of America, Vol. 101, pp. 4649-4654, 2004. [Non-Patent Document 3] Cell, Vol. 98, pp. 437-451, 1999. [Non-Patent Document 4] The Lancet, Vol. 355, pp. 39-40, 2000. [Non-Patent Document 5] Cell, Vol. 98, pp. 365-376, 1999. [Non-Patent Document 6] Neuron, Vol.38, pp. 715-730, 2003. [Non-Patent Document 7] Brain, Vol. 130, pp. 1577-1585, 2007. [Non-Patent Document 8] Neuroscience Letters, Vol. 569, pp. 68-73, 2014. [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide a therapeutic or preventive agent for diseases involving the orexin type 2 receptor, specifically narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and other such diseases. [Means for solving the problem]

[0008] As a result of diligent research, the present inventors have discovered that a compound represented by the following formula (1) (sometimes referred to as "the compound represented by formula (I)" in this specification) or a pharmaceutically acceptable salt thereof has therapeutic and preventive effects on diseases involving the orexin type 2 receptor, specifically narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and other such diseases, and have completed the present invention.

[0009] In other words, the present invention is as follows:

[0010] [Section A1] Formula (1): [ka] [In the formula, R 1 C may be substituted 6-10 Aromatic carbocyclic groups, substituted or unsubstituted 5-10 member aromatic heterocyclic groups, and substituted or unsubstituted C 3-6 A saturated carbocyclic group, a substituted 4-10 member saturated heterocyclic group, or a cyano group; L 1 and L 2 Each of these independently represents a single bond, -CH2-, or an oxygen atom; R 2represents a hydrogen atom, a hydroxy group, a halogen atom, cyano, or an optionally substituted C 1-4 alkyl; also when L 1 is a single bond, R 1 and R 2 together form a spiro ring and may form an optionally substituted C 3-6 saturated carbon ring or an optionally substituted 4-10 membered saturated heterocyclic ring; R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, cyano, -(C=O)NR 5 R 6 a carboxy group, -(C=O)O-R 7 an optionally substituted C 1-4 alkyl, or an optionally substituted C​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof.

[0011] [Section A2] R 2 ~R 7 "C that may be replaced" 1-4 The substituted substituents in the alkyl group are, independently, one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkoxy, or C 3-7 It is a cycloalkyl group, and "may be substituted C 1-4 The substituted substituents in "alkoxy" are, independently, one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 3-7 It is a cycloalkyl, R 1 C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, independently, hydrogen atoms, halogen atoms, hydroxyl groups, and C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with a cycloalkyl group), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy or C 3-7 (May be substituted with a cycloalkyl group), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with a cycloalkyl group), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), cyano, C 1-4 Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxyl group, or one or more identical or different halogen atoms) 1-4 Alkyl, or C 3-7 (may be substituted with a cycloalkyl group) and a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group having one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 One or more substituents selected from the group consisting of (which may be substituted with cycloalkyl groups), Ring G's C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, respectively, a halogen atom and a C atom. 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy or C 3-7 (May be substituted with a cycloalkyl group), C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with a cycloalkyl group), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 3-7 (May be substituted with a cycloalkyl group), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), and C 3-7Cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, C 1-4 alkyl, C 1-4 alkoxy or C 3-7 cycloalkyl), or, when there are a plurality of substituents, two of them may be bonded via C 1-6 alkylene to form any bicyclic structure possible chemically among condensed rings, spiro rings, or bridged rings, The pharmaceutical composition according to item A1.

[0012] [Item A3] R 2 ~R 7 In "optionally substituted C 1-4 alkyl", the substitutable substituents are each independently one or more identical or different halogen atoms, or C 1-4 alkoxy, and in "optionally substituted C 1-4 alkoxy", the substituents are each independently one or more identical or different halogen atoms, or C 1-4 alkyl, R 1 The substitutable substituents in the C 6-10 aromatic carbocyclic group, 5- to 10-membered aromatic heterocyclic group, C 3-6 saturated carbocyclic group, and 4- to 10-membered saturated heterocyclic group are each independently a hydrogen atom, a halogen atom, a hydroxy group, C 6-10 aromatic carbocyclic group (the C 6-10 aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C 1-4 alkyl, C 1-4 alkoxy or C 3-7 cycloalkyl), C 1-4 alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C 1-4 alkoxy or C 3-7 cycloalkyl), C 3-7 cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), cyano, C 1-4 Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxyl group, or one or more identical or different halogen atoms) 1-4 Alkyl, or C 3-7 (may be substituted with a cycloalkyl group) and a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group having one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 One or more substituents selected from the group consisting of (which may be substituted with cycloalkyl groups), Ring G's C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, independently, halogen atoms and C. 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), and C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4One or more substituents selected from the group consisting of (which may be substituted with alkoxys), or if there are multiple substituents, two of them are C 1-6 They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or crosslinking rings. A pharmaceutical composition as described in either item A1 or item A2.

[0013] [Section A4] R 1 However, from equation (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a7 Each is independent of the others (CR a6 If there are multiple R a6 (Each is independent of the others), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 R represents an aromatic heterocyclic group that may be substituted with an alkoxy group or has 5 to 10 members. a4 and R a5 If chemically possible, they may be bonded to the same carbon atom; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above; q 1 [This is an integer, either 1 or 2.] A pharmaceutical composition according to any one of items A1 to A3, which is selected from any one of the following.

[0014] [Section A5] Ring G is as follows (1b-1) to (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6 and W 7 Each of these is independently a nitrogen atom or CR b4 It represents; W 2 , W 4 and W 8 , NR b5 , oxygen atom or CR b6 R b7 It represents; R b1 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4(Each of them is independent), hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 [They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings.] A pharmaceutical composition according to any one of items A1 to A4, which is selected from any one of the following.

[0015] [Section A6] Formula (2): [ka] [In the formula, R 1 From equation (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a7 Each is independent of the others (CR a6 If multiple exist, each CR a6 (Each is independent of the others), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-6 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 R represents an aromatic heterocyclic group that may be substituted with an alkoxy group or has 5 to 10 members. a4 and R a5 If chemically possible, they may be bonded to the same carbon atom; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above; q 1 [This is an integer, either 1 or 2.] One of the following will be selected; L 1 and L 2 Each of these independently represents a single bond, -CH2-, or an oxygen atom; R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or a substituted C 1-4 Represents alkyl; R 3 and R 4 Each of these is independently a hydrogen atom, a halogen atom, and C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy, or C 3-7 (may be substituted with a cycloalkyl group), or C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 3-7 (may be cycloalkyl substituted), and also R 3 and R 4 If chemically possible, it may be bonded to the same carbon atom, R 3 and R 4 When bonded to another carbon atom on the ring, they may bond to each other via C1-6 alkylene to form a fused ring or a bridging ring; Ring G is as follows (1b-1) to (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6 and W 7 Each of these is independently a nitrogen atom or CR b4 It represents; W2 , W 4 and W 8 , NR b5 , oxygen atom or CR b6 R b7 It represents; R b1 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4 (Each of them is independent), hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 [They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings.] One of the following will be selected; A 1 represents an oxygen atom or a sulfur atom; A 2 represents an oxygen atom or -NH-; A 3 A pharmaceutical composition according to any of items A1 to A5, represented by -CH-, a nitrogen atom, or a carbon atom.

[0016] [Section A7] R 1 However, the following equations (1a-1), (1a-2), and (1a-3-1): [ka] [In equations (1a-1), (1a-2), and (1a-3-1), X 1 ~X 6 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a3 , R a6 and R a7 Each is independent (CR a6 If there are multiple R a6 Each of them is independent of the others: hydrogen atoms, halogen atoms, C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 Represents an aromatic heterocyclic group (which may be substituted with an alkoxy group) or a 5-10 membered aromatic heterocyclic group; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above. A pharmaceutical composition according to item A6, which is one of the following selected from:

[0017] [Section A8] Ring G is as follows: (1b-1), (1b-2), or (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6 and W 7 Each of these is independently a nitrogen atom or CR b4 It represents; W 2 and W 4 , NR b5 or CR b6 R b7 It represents; R b1 , R b2 and R b4 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4 (Each of them is independent), hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 They may be bonded via alkylene to form a cross-linked bicyclic structure. A pharmaceutical composition as described in either item A6 or item A7.

[0018] [Section A9] Ring G is as follows: (1b-1) or (1b-2): [ka] [In the formula, W 1 and W 3 is a nitrogen atom or CR b4 It represents; W 2 and W 4 , NR b5 or CR b6 R b7 It represents; R b1 , R b2 and R b4 ~R b7 Each of them is independently a hydrogen atom, C1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 They may be bonded via alkylene to form a cross-linked bicyclic structure. A pharmaceutical composition as described in any of items A6 to A8.

[0019] [Section A10] Formula (3): [ka] [In the formula, R 1 This is expressed by the following equations (1a-1), (1a-2), or (1a-3-1): [ka] (In equations (1a-1), (1a-2), and (1a-3-1), X1 ~X 6 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 represents an oxygen atom or a sulfur atom; R a1 ~R a3 and R a6 Each is independent (CR a6 If there are multiple R a6 Each of them is independent of the others: hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl group is one or more identical or different halogen atoms, hydroxyl groups, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 Represents (which may be substituted with an alkoxy); however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above. It is represented by; L 1 and L 2 Each of these independently represents a single bond or an oxygen atom; R 2 is a hydrogen atom, a halogen atom, or C 1-4 Alkyl (the alkyl group may be substituted with one or more identical or different halogen atoms or hydroxyl groups); R 3 and R 4Each of these independently represents a halogen atom; Ring G is given by the following equations (1b-1), (1b-2-1), (1b-2-2), or (1b-2-3): [ka] (In formulas (1b-1-1), (1b-2-1), (1b-2-2), or (1b-2-3), R b5 is a hydrogen atom, or C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 Represents (may be substituted with alkoxy); A 1 This represents an oxygen atom or a sulfur atom. A pharmaceutical composition as described in any of items A1 to A9.

[0020] [Section A11] R 1 The above equation (1a-2) is given by R a1 However, hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy) or C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 A pharmaceutical composition according to any of items A4 to A10, representing one selected from the group consisting of (which may be substituted with alkyl).

[0021] [Section A12] R 1 The above equation (1a-2) is true, and X 4 and X 5 A pharmaceutical composition according to either item A10 or item A11, wherein all of the atoms are nitrogen atoms.

[0022] [Section A13] Ring G is represented by the above formula (1b-1-1), and R b5 However, C may be substituted with one or more identical or different halogen atoms. 1-4 A pharmaceutical composition according to any of items A10 to A12, wherein the composition is alkyl.

[0023] [Section A14] Ring G is represented by the above formula (1b-2-1), and R b5 However, hydrogen atoms or C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 A pharmaceutical composition according to any of items A10 to A12, which may be substituted with an alkoxy.

[0024] [Section A15] Formula (4): [ka] [In the formula, R 1 This is expressed by the following equation (1a-2-1): [ka] (In formula (1a-2-1), Q 2 represents an oxygen atom or a sulfur atom; R a2 C 3-7 Cycloalkyl groups (the cycloalkyl group consists of one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with an alkoxy) or a cycloalkoxy group (the cycloalkoxy is one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with an alkoxy.) It is represented by; R 2 C 1-4 Represents alkyl; Ring G is given by the following equation (1b-1) or (1b-2-1): [ka] (In formula (1b-1-1) or (1b-2-1), R b5 C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkyl.) It represents; L 2 [This represents a single bond or an oxygen atom.] A pharmaceutical composition as described in any of items A1 to A12.

[0025] [Section A16] R a2 C may be substituted with one or more identical or different halogens. 3-7 It is a cycloalkyl group and R 2 The pharmaceutical composition according to item A15, wherein is a methyl group.

[0026] [Section A17] R a2 R is a cyclopropyl group which may be substituted with one or more identical or different halogens, and 2 A pharmaceutical composition according to either item A15 or item A16, wherein is a methyl group.

[0027] [Section A18] Ring G is given by the above formula (1b-2-1), and R b8 A pharmaceutical composition according to any of items A15 to A17, wherein is an isopropyl group.

[0028] [Section A19] Ring G is given by the above formula (1b-1-1), and R b5 is an isopropyl group and L 2 A pharmaceutical composition according to any of items A15 to A17, wherein is an oxygen atom.

[0029] [Section A20] Q 2A pharmaceutical composition according to any of items A15 to A19, wherein is an oxygen atom.

[0030] [Section A21] The pharmaceutical composition according to item A1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide [ka] Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 79: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide [ka] Example 80: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide. [ka]

[0031] [Section A22] The pharmaceutical composition according to item A1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 64: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide [ka] Example 71: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 76: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide [ka]

[0032] [Section A23] A therapeutic agent for diseases involving orexin receptors, comprising a pharmaceutical composition described in any one of items A1 to A22.

[0033] [Section A24] A pharmaceutical composition containing any one of items A1 to A22 is used for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, 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-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity ( For example, malignant mast cells, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, plasmacemic obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-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, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome XSexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female hirsutism, fetal defects associated with gestational obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, respiratory disorders such as obesity hypoventilation syndrome (Pickwick syndrome) and dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, secondary consequences of obesity such as a reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / Disorders of the urinary tract, disorders relating to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, circulatory disorders, 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, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral agenesis, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, Treatment for cognitive impairment, muscle spasms, tremors, epilepsy, muscle spasm-associated disorders, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced Parkinsonian syndrome, Gilles de la Tourette 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 injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury.

[0034] [Section A25] A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, comprising the pharmaceutical composition described in any one of items A1 to A22.

[0035] [Section A26] A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, characterized by administering a therapeutically effective amount of the pharmaceutical composition described in any one of items A1 to A22 to a patient in need of treatment.

[0036] [Section A27] Use of any one of the pharmaceutical compositions described in paragraphs A1 to A22 for the manufacture of a therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

[0037] The present invention also provides the following:

[0038] [Section 1] Formula (1): [ka] [In the formula, R 1 C may be substituted 6-10 Aromatic carbocyclic groups, substituted or unsubstituted 5-10 member aromatic heterocyclic groups, and substituted or unsubstituted C 3-6 A saturated carbocyclic group, a substituted 4-10 member saturated heterocyclic group, or a cyano group; L 1 and L 2 Each is independently a single bond, methylene (the methylene is one or more identical or different C 1-4 (may be substituted with alkyl), -NR 8 -, -C(=O)-, -OC(=O)-, -SO-, -SO2-, -S-, or represent an oxygen atom; R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or a substituted C 1-4 Represents alkyl; Also L 1 If it is a single bond, R 1 and R 2These come together to form a spiro ring, and C may be substituted. 3-6 They may form saturated carbocyclic rings or substituted 4-10 member saturated heterocyclic rings; R 3 and R 4 These are, independently, a hydrogen atom, a halogen atom, a cyanonucleotide, and a -(C=O)NR molecule. 5 R 6 carboxyl group, -(C=O)OR 7 , C which may be substituted 1-4 Alkyl or optionally substituted C 1-4 It represents an alkoxy, and also R 3 and R 4 If chemically possible, it may be bonded to the same carbon atom, R 3 and R 4 When bonded to another carbon atom on the ring, C 1-6 They may be bonded via alkylene to form a fused ring or a crosslinked ring; R 5 ~R 7 Each of these is independently a hydrogen atom, a halogen atom, or a substituted C 1-4 Represents alkyl; R 8 Each of these is independently a hydrogen atom or a substituted C 1-4 Represents alkyl; n is an integer, either 1, 2, 3, or 4; Ring G may be substituted with C 6-10 Aromatic carbocyclic groups, substituted or unsubstituted 5-10 member aromatic heterocyclic groups, and substituted or unsubstituted C 3-6 Represents a saturated carbocyclic group, or a saturated heterocyclic group of 4 to 10 members, which may be substituted; A 1 represents an oxygen atom or a sulfur atom; A 2 is an oxygen atom or -NR 8 - represents; A 3 -CH- represents a nitrogen atom or a carbon atom; The dashed lines represent, independently, single or double bonds. A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof.

[0039] [Section 2] R 2 ~R 8 "C that may be replaced" 1-4 The substituted substituents in the alkyl group are, independently, one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkoxy, C 6-10 Aromatic carbon ring group, or C 3-7 It is a cycloalkyl group, and "may be substituted C 1-4 The substituted substituents in "alkoxy" are, independently, one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 3-7 It is a cycloalkyl, R 1 C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, independently, hydrogen atoms, halogen atoms, hydroxyl groups, and C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 1-6 Alkylamino (The alkyl group in the alkylamino is a halogen atom, a hydroxyl group, or C 3-7 (May be substituted with cycloalkyl), C3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), cyano, C 1-4 Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxyl group, or one or more identical or different halogen atoms) 1-4 Alkyl, or C 3-7 (may be substituted with a cycloalkyl group) and a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group having one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 One or more substituents selected from the group consisting of (which may be substituted with cycloalkyl groups), Ring G's C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, respectively, a halogen atom and a C atom. 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 3-7 (May be substituted with cycloalkyl), C 1-6 Alkylamino (The alkyl group in the alkylamino is a halogen atom, a hydroxyl group, or C 3-7(May be substituted with cycloalkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), and C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 One or more substituents selected from the group consisting of (which may be substituted with cycloalkyl groups), or if there are multiple substituents, two of them are C 1-6 They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or crosslinking rings. The pharmaceutical composition described in item 1.

[0040] [Section 3] R 2 ~R 7 "C that may be replaced" 1-4 The substituted substituents in the alkyl group are, independently, one or more identical or different halogen atoms, or C 1-4 It is an alkoxy, and "may be substituted C" 1-4 Each substituent of the "alkoxy" independently consists of one or more identical or different halogen atoms, or C 1-4 It is alkyl, R 1 C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, independently, hydrogen atoms, halogen atoms, hydroxyl groups, and C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy or C 3-7 (May be substituted with cycloalkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 (may be substituted with cycloalkyl), cyano, C 1-4 Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxyl group, or one or more identical or different halogen atoms) 1-4 Alkyl, or C 3-7 (may be substituted with a cycloalkyl group) and a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group having one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 One or more substituents selected from the group consisting of (which may be substituted with cycloalkyl groups), Ring G's C 6-10 Aromatic carbocyclic groups, 5-10 member aromatic heterocyclic groups, C 3-6 The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, respectively, a halogen atom and a C atom. 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-6 Alkylamino (The alkyl group in the alkylamino is a halogen atom, a hydroxyl group, or C 3-7 (may be substituted with cycloalkyl), and C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 One or more substituents selected from the group consisting of (which may be substituted with alkoxys), or if there are multiple substituents, two of them are C 1-6 They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or crosslinking rings. A pharmaceutical composition as described in either item 1 or item 2.

[0041] [Section 4] R 1 However, from equation (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a7 Each is independent of the others (CR a6 If there are multiple R a6 (Each is independent of the others), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 R represents an aromatic heterocyclic group that may be substituted with an alkoxy group or has 5 to 10 members. a4 and R a5 If chemically possible, they may be bonded to the same carbon atom; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above; q 1 [This is an integer, either 1 or 2.] A pharmaceutical composition according to any one of items 1 to 3, which is selected from any one of the following.

[0042] [Section 5] Ring G is as follows (1b-1) to (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6 , W 7 , W 11 , W 12 , W13 , W 15 , W 16 , W 17 , W 19 , and W 25 Each of these is independently a nitrogen atom or CR b4 It represents; W 2 , W 4 , W 8 , W 9 , W 10 , W 14 , W 18 , W 20 , W 21 , W 22 , W 23 , and W 24 , NR b5 , oxygen atom or CR b6 R b7 It represents; R b1 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4 (Each is independent of the others), hydrogen atom, -N(R b8 )R b9 , C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, C) 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C 1-4 The C may be substituted with alkyl, 1-4 (Alkyl may be substituted with a halogen atom) or C 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group has one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4(may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings; R b8 and R b9 Each of them is independently a hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, C) 1-4 Alkoxy, C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C 1-4 The C may be substituted with alkyl, 1-4 The alkyl group may be substituted with a halogen atom, or with a 5-10 member aromatic heterocyclic group, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group has one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy) Here, R b8 and R b9 They may combine to form a 3- to 7-membered nitrogen-containing saturated heterocycle with the nitrogen atom to which they bond. A pharmaceutical composition according to any one of items 1 to 4, which is selected from any one of them.

[0043] [Section 6] Formula (2): [ka] [In the formula, R 1 From equation (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a7 Each is independent of the others (CR a6 If multiple exist, each CR a6 (Each is independent of the others), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-6 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 R represents an aromatic heterocyclic group that may be substituted with an alkoxy group or has 5 to 10 members. a4 and R a5 If chemically possible, they may be bonded to the same carbon atom; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above; q 1 [This is an integer, either 1 or 2.] One of the following will be selected; L 1 and L 2 Each of these independently represents a single bond, -CH2-, or an oxygen atom; R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or a substituted C 1-4 Represents alkyl; R 3 and R 4 Each of these is independently a hydrogen atom, a halogen atom, and C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkoxy, or C 3-7 (may be substituted with a cycloalkyl group), or C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 3-7 (may be cycloalkyl substituted), and also R3 and R 4 If chemically possible, it may be bonded to the same carbon atom, R 3 and R 4 When bonded to another carbon atom on the ring, they may bond to each other via C1-6 alkylene to form a fused ring or a bridging ring; Ring G is as follows (1b-1) to (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6 and W 7 Each of these is independently a nitrogen atom or CR b4 It represents; W 2 , W 4 and W 8 , NR b5 , oxygen atom or CR b6 R b7 It represents; R b1 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4 (Each of them is independent), hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 [They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings.] One of the following will be selected; A 1 represents an oxygen atom or a sulfur atom; A 2 represents an oxygen atom or -NH-; A 3 The pharmaceutical composition described in any of items 1 to 5, which is represented by -CH-, a nitrogen atom, or a carbon atom.

[0044] [Section 7] R 1 However, the following equations (1a-1), (1a-2), and (1a-3-1): [ka] [In equations (1a-1), (1a-2), and (1a-3-1), X 1 ~X 6 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 is an oxygen atom, -NR a7 -or represents a sulfur atom; R a1 ~R a3 , R a6 and R a7 Each is independent (CR a6 If there are multiple R a6 Each of them is independent of the others: hydrogen atoms, halogen atoms, C 6-10 Aromatic carbocyclic group (the C 6-10Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, hydroxyl groups, and C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, C 1-4 Represents an aromatic heterocyclic group (which may be substituted with an alkoxy group) or a 5-10 membered aromatic heterocyclic group; however, X 1 and X 3 All of them are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above. A pharmaceutical composition according to item 6, which is one of the following selected from:

[0045] [Section 8] Ring G is as follows: (1b-1), (1b-2), or (1b-4): [ka] [In the formula, W 1 , W 3 , W 5 , W 6and W 7 Each of these is independently a nitrogen atom or CR b4 It represents; W 2 and W 4 , NR b5 or CR b6 R b7 It represents; R b1 , R b2 and R b4 ~R b7 Each is independent of the others (CR b4 If there are multiple R b4 (Each of them is independent), hydrogen atom, C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 6-10 Aromatic carbocyclic group (the C 6-10 An aromatic carbocyclic group contains one or more identical or different halogen atoms, C 1-4 Alkyl, or C 1-4 (May be substituted with alkoxy), C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, or C) 1-4 (may be substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), or C 3-7 Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, C) 1-4 Alkyl, or C 1-4 R represents (which may be substituted with an alkoxy), b1 and R b2 It may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 C 1-6 They may be bonded via alkylene to form a cross-linked bicyclic structure. A pharmaceutical composition as described in either item 6 or item 7.

[0046] [Item 9] Ring G is as follows: (1b-1) or (1b-2): [Chemical Formula] [In the formula: W 1 and W 3 each represents a nitrogen atom or CR b4 ; W 2 and W 4 each represents NR b5 or CR b6 R b7 ; R b1 、R b2 and R b4 ~R b7 each independently represents a hydrogen atom, C 1-6 alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C 1-4 alkoxy), C 6-10 aromatic carbocyclic group (the C 6-10 aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, C 1-4 alkyl, or C 1-4 alkoxy), C 1-4 alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, or C 1-4 alkyl), C 3-7 cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C 1-4 alkyl, or C 1-4 alkoxy), or C 3-7 cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, C 1-4 alkyl, or C 1-4 alkoxy), and R b1 and R b2 may be bonded to the same carbon atom if chemically possible; Here, R b1 and R b2 are C1-6 They may be bonded via alkylene to form a cross-linked bicyclic structure. A pharmaceutical composition according to any one of claims 6 to 8, represented by [the formula shown].

[0047] [Section 10] Formula (3): [ka] [In the formula, R 1 This is expressed by the following equations (1a-1), (1a-2), or (1a-3-1): [ka] (In equations (1a-1), (1a-2), and (1a-3-1), X 1 ~X 6 Each of them independently consists of a nitrogen atom or CR a6 It represents; Q 1 and Q 2 represents an oxygen atom or a sulfur atom; R a1 ~R a3 and R a6 Each is independent (CR a6 If there are multiple R a6 Each of them is independent of the others: hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl group is one or more identical or different halogen atoms, hydroxyl groups, or C 1-4 (May be substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, or C 1-4 (may be substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C 1-4 Alkyl, or C 1-4 Represents (which may be substituted with an alkoxy); however, X 1 and X 3 All of them are CR a6In the case of R a6 and R a6 The carbon atoms bonded to it are both X 1 , X 2 and X 3 A 6-membered carbon ring may be formed by condensation with a 5-membered ring composed of the above. It is represented by; L 1 and L 2 Each of these independently represents a single bond or an oxygen atom; R 2 is a hydrogen atom, a halogen atom, or C 1-4 Alkyl (the alkyl group may be substituted with one or more identical or different halogen atoms or hydroxyl groups); R 3 and R 4 Each of these independently represents a halogen atom; Ring G is given by the following equations (1b-1), (1b-2-1), (1b-2-2), or (1b-2-3): [ka] (In formulas (1b-1-1), (1b-2-1), (1b-2-2), or (1b-2-3), R b5 is a hydrogen atom, or C 1-6 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 Represents (may be substituted with alkoxy); A 1 This represents an oxygen atom or a sulfur atom. A pharmaceutical composition as described in any of items 1 to 9.

[0048] [Section 11] R 1 The above equation (1a-2) is given by R a1 However, hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl is one or more identical or different halogen atoms, or C) 1-4 (May be substituted with alkoxy), C 3-7Cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C 1-4 alkyl, or C 1-4 alkoxy) or C 1-4 alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, or C 1-4 alkyl), and represents any one selected from the group consisting of, the pharmaceutical composition according to any one of items 4 to 10.

[0049] [Item 12] R 1 is the above formula (1a-2), and X 4 and X 5 are both nitrogen atoms, the pharmaceutical composition according to any one of items 10 or 11.

[0050] [Item 13] Ring G is represented by the above formula (1b-1-1), and R b5 is C 1-4 alkyl which may be substituted with one or more identical or different halogen atoms, the pharmaceutical composition according to any one of items 10 to 12.

[0051] [Item 14] Ring G is represented by the above formula (1b-2-1), and R b5 is a hydrogen atom or C 1-4 )) alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C 1-4 alkoxy), the pharmaceutical composition according to any one of items 10 to 12.

[0052] [Item 15] Formula (4):

Chemical formula

Chemical formula

[0053] [Section 16] R a2 C may be substituted with one or more identical or different halogens. 3-7 It is a cycloalkyl group and R 2 The pharmaceutical composition according to item 15, wherein is a methyl group.

[0054] [Section 17] R a2 R is a cyclopropyl group which may be substituted with one or more identical or different halogens, and 2A pharmaceutical composition according to either item 15 or 16, wherein is a methyl group.

[0055] [Section 18] Ring G is given by the above formula (1b-2-1), and R b5 A pharmaceutical composition according to any one of claims 15 to 17, wherein is an isopropyl group.

[0056] [Section 19] Ring G is given by the above formula (1b-1-1), and R b5 A pharmaceutical composition according to any one of claims 15 to 17, wherein is an isobutyl group.

[0057] [Section 20] Ring G is given by the above formula (1b-1-1), and R b5 is an isopropyl group and L 2 A pharmaceutical composition according to any one of items 15 to 17, wherein is an oxygen atom.

[0058] [Section 21] Q 2 A pharmaceutical composition according to any one of items 15 to 20, wherein is an oxygen atom.

[0059] [Section 22] The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide [ka] Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 79: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide [ka] Example 80: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide. [ka]

[0060] [Section 23] The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 64: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide [ka] Example 71: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 76: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide [ka]

[0061] [Section 24] The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 82: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 95: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 96: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 97: 4-(5-cyclobutyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 99: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 110: N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 111: N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 112: N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 114: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 115: N-[(1R,6S)-6-{(3S)-3-[cyclopropyl(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 128: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidine-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 136: N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidine-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 137: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 138: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxamide [ka] Example 139: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 152: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 156-A: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-N-{(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 156-B: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-N-{(1S,2R,6R)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 157: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 158: N-[(1R,6S)-6-{4-[(cyclopropylmethyl)(methyl)amino]piperidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 159: N-[(1R,6S)-6-{4-[cyclobutyl(methyl)amino]piperidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 161: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka]

[0062] [Section 25] The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any of the compounds represented by the following compound names or structural formulas or a pharmaceutically acceptable salt thereof. Example 83: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 84: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 102: 4-(5-cyclobutyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 103: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide [ka] Example 107: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 116: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 118: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 119: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 120: N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 121: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 122: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxamide [ka] Example 126: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide [ka] Example 133: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidine-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 143: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka]

[0063] [Section 26] A therapeutic agent for diseases involving orexin receptors, comprising the pharmaceutical composition described in any one of items 1 to 25.

[0064] [Section 27] A pharmaceutical composition containing any one of paragraphs 1 to 25 is used for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, 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-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity ( For example, malignant mast cells, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, plasmacemic obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-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, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome XSexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female hirsutism, fetal defects associated with gestational obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, respiratory disorders such as obesity hypoventilation syndrome (Pickwick syndrome) and dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, secondary consequences of obesity such as a reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / Disorders of the urinary tract, disorders relating to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, circulatory disorders, 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, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral agenesis, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, Treatment for cognitive impairment, muscle spasms, tremors, epilepsy, muscle spasm-associated disorders, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced Parkinsonian syndrome, Gilles de la Tourette 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 injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury.

[0065] [Section 28] A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, comprising a pharmaceutical composition described in any one of paragraphs 1 to 25.

[0066] [Section 29] A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, characterized by administering a therapeutically effective amount of the pharmaceutical composition described in any one of items 1 to 25 to a patient in need of treatment.

[0067] [Section 30] Use of any one of the pharmaceutical compositions in paragraphs 1 to 25 for the manufacture of a therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia. [Effects of the Invention]

[0068] The present invention provides a pharmaceutical composition that exhibits strong agonist activity against orexin receptors, containing a novel compound having a urea skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention is useful as a therapeutic or prophylactic agent for diseases involving orexin receptors, particularly orexin type 2 receptors, and is specifically applicable to patients with narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and the like. [Modes for carrying out the invention]

[0069] The present invention will be described in further detail below. In this specification, the number of carbon atoms in the definition of a "substituent" may be, for example, "C 1-6 It may also be written as "C 1-6 The term "alkyl" is synonymous with alkyl groups having 1 to 6 carbon atoms. Furthermore, in this specification, substituents that are not explicitly referred to as "may be substituted" or "substituted" refer to "unsubstituted" substituents. For example, "C 1-6 "Alkyl" refers to "unsubstituted C 1-6 It means "alkyl".

[0070] Furthermore, the term "group" may be omitted in the descriptions of substituents in this specification. Where defined as "may be substituted," the number of substituents present is not particularly limited as long as they are substituted, and can be one or more. That is, it indicates that the group may be substituted by a substituted carbon atom, or by a number of substituted substituents on carbon and nitrogen atoms. Also, unless otherwise specified, the description of each group applies even if that group is a part of or a substituent of another group.

[0071] The bonding positions of substituents are any chemically possible positions unless otherwise specified herein.

[0072] Examples of "halogens" include fluorine, chlorine, bromine, or iodine. Preferably, fluorine or chlorine is used.

[0073] "C 1-4 "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 4 carbon atoms, and is a "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. 1-4 Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, and "C 1-6 Specific examples of "alkyl" include, in addition to the above, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and their structural isomers. 1-6 "Alkyl" or "C 1-4 As for the alkyl group, methyl, ethyl, propyl, and isopropyl are preferred, with methyl and isopropyl being more preferred.

[0074] "C 1-6 "Alkylene" refers to a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, in a linear or branched chain configuration. 1-6 "alkylene" is preferably "C 1-4 "Alkylene" is one example, and more preferably "C1-3 "Alkylene" is one example. 1-3 Specific examples of "alkylenes" include, for example, methylene, ethylene, propylene, and trimethylene. 1-4 A specific example of "alkylene" is, for example, the aforementioned "C 1-3 In addition to the examples listed as "alkylenes," other examples include butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, and 2-methyltrimethylene. 1-6 A specific example of "alkylene" is, for example, the aforementioned "C 1-4 In addition to the examples listed as "alkylenes," other examples include pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, and hexylene.

[0075] "C 3-7 "Cycloalkyl" refers to a cyclic non-aromatic hydrocarbon group (saturated hydrocarbon group and partially unsaturated hydrocarbon group) having 3 to 7 carbon atoms. Preferably, "C 3-6 It is a cycloalkyl. 3-7 "Cycloalkyl" also includes cross-linked compounds. 3-7 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.

[0076] Said “C 3-7 "Cycloalkyl" is a type of "C 3-7 This also includes bicyclic groups formed by the fusion of a "cycloalkyl" with a ring containing one heteroatom selected from a benzene ring or a 5- or 6-membered nitrogen, sulfur, or oxygen ring, or two or more heteroatoms (e.g., 2 to 4) that are identical or different (e.g., 2 to 4). (For example, the 5- or 6-membered monocyclic heteroaryl and the 4- to 10-membered saturated heterocycle described below, which are 5 or 6-membered rings.)

[0077] "C 1-4 "Alkoxy" refers to the aforementioned "C1-4 This refers to an oxy group substituted with "alkyl," meaning "C 1-4 "Alkoxy" refers to the aforementioned "C 1-4 This refers to an oxy group substituted with "alkyl". 1-4 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. 1-4 Preferred examples of "alkoxy" include methoxy, ethoxy, and isopropoxy.

[0078] "C 3-7 "Cycloalkoxy" refers to the aforementioned "C 3-7 This refers to an oxy group substituted with "cycloalkyl". Preferably "C 3-6 It is "cycloalkoxy". 3-7 Specific examples of "cycloalkoxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Cyclohexyloxy is preferred.

[0079] "C 6-10 An "aromatic carbon ring group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 It is also called "aryl." More preferably, it is phenyl. 6-10 Specific examples of "aromatic carbon ring groups" include, for example, phenyl, 1-naphthyl, or 2-naphthyl.

[0080] Said “C 6-10 The term "aromatic carbocyclic group" also includes groups formed by the fusion of "phenyl" with a 5 or 6-membered ring containing one or more (e.g., 2 to 4) heteroatoms selected from nitrogen, sulfur, or oxygen (e.g., a 5 or 6-membered ring from the "5 or 6-membered monocyclic aromatic heterocyclic groups" and "4 to 10-membered saturated heterocyclic rings" described below), or a 5 to 7-membered cycloalkyl ring (e.g., cyclopentane, cyclohexane, or cycloheptane).

[0081] "5-10 membered aromatic heterocyclic group" means a monocyclic or polycyclic aromatic group with 5-10 members, containing one heteroatom selected from nitrogen, sulfur, or oxygen in addition to carbon as atoms constituting the ring, or two or more (e.g., 2-4) identical or different heteroatoms. Preferably, it is a "5 or 6 membered monocyclic aromatic heterocyclic group." "5 or 6 membered monocyclic aromatic heterocyclic group" means a monocyclic 5 or 6 membered aromatic group among the "5-10 membered aromatic heterocyclic groups."

[0082] Specifically, the polycyclic aromatic heterocyclic groups in the aforementioned "5-10 member aromatic heterocyclic groups" include those formed by the fusion of two identical or different monocyclic aromatic heterocyclic rings, or those formed by the fusion of a monocyclic aromatic heterocyclic ring with an aromatic ring (e.g., benzene) or an aromatic ring (e.g., cyclohexane). Specific examples of "5-10 member aromatic heterocyclic groups" include pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridadinyl. In another embodiment, preferably, benzofuranyl (bonded on a heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, and pyridadinyl are used.

[0083] "C 3-6 A "saturated carbon ring" refers to a monocyclic saturated or partially unsaturated hydrocarbon ring with 3 to 6 carbon atoms. 3-6 Specific examples of "saturated carbocyclic compounds" include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, and cyclohexadiene. Cyclopropane or cyclobutane are preferred.

[0084] A "4-10 member saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle composed of 4 to 10 atoms, including, in addition to carbon, one or more identical or different heteroatoms (e.g., 2 to 4, preferably 2 to 3, more preferably 2) selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and including those with some unsaturated bonds, some with partially bridged structures, and some with partially spirated structures. Preferably, it is a 5- or 6-membered saturated heterocycle. Bicyclic saturated heterocycles also include those formed by the fusion of a monocyclic saturated heterocycle with benzene or a monocyclic 5- to 6-membered aromatic heterocycle. Furthermore, the saturated heterocycle may contain one or two carbonyl, thiocarbonyl, sulfinyl, or sulfonyl groups, and cyclic groups such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, and cyclic thiocarbamate are also included in the saturated heterocycle. Here, the oxygen atoms of carbonyl, sulfinyl, and sulfonyl compounds, and the sulfur atoms of thiocarbonyl compounds are not included in the number of members (ring size) and the number of heteroatoms constituting the ring. Preferably, the "4-10 member saturated heterocycle" is a monocyclic or bicyclic "4-8 member saturated heterocycle", more preferably a monocyclic "4-6 member saturated heterocycle", and even more preferably a monocyclic "5 or 6 member saturated heterocycle". Specific examples of "4-10 member saturated heterocycles" include piperazine, oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, homopiperidinyl, oxetanyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxoxozolidinyl, dioxoxozolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydropyridinyl. Preferably, these are pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.Specific examples of bicyclic saturated heterocycles include dihydroindolyl, dihydroisoindolyl, dihydroprinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, and tetrahydropyridazepinyl.

[0085] "4-6 member saturated heterocyclic group" refers to a substituent in which the "4-6 member saturated heterocyclic group" among the above "4-10 member saturated heterocyclic groups" is a monovalent group. Preferred examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranil, and tetrahydropyranil. R b8 and R b9 The "3-7 member nitrogen-containing saturated heterocycle" formed by these atoms together with the nitrogen atom they bond to is a saturated heterocycle of which the number of atoms constituting the ring is 3 to 7, and in addition to carbon atoms, it contains one nitrogen atom.

[0086] The compounds represented by formula (I) include various hydrates, solvates, and crystalline polymorphs.

[0087] Furthermore, the compound represented by formula (I) contains isotopic elements (for example, D, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 The compounds may be substituted with (I, etc.), and these compounds are also included in the compounds represented by formula (I).

[0088] In this invention, "pharmaceutically acceptable salt" means acid addition salts and base addition salts that are permitted for pharmaceutically acceptable use. "Pharmaceutically acceptable salts" are not limited to these, but include, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, p-toluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, Examples include acid addition salts such as xinafoate, pamoate, cinnamate, adipine, cysteine ​​salt, N-acetylcysteine ​​salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0089] The compound represented by formula (I) can be administered orally or parenterally, either directly or in an appropriate dosage form, as a preparation, pharmaceutical, or pharmaceutical composition. Specific examples of these dosage forms, but not limited to these, include tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These preparations can also be manufactured by known methods using additives commonly used as pharmaceutical excipients.

[0090] Depending on the purpose, these additives may include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. Specific examples of these additives, though not limited to these, include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium dioxide, talc, and the like.

[0091] The dosage of the compound represented by formula (I) is appropriately selected depending on the target animal, route of administration, disease, patient's age, weight, and symptoms. For example, in the case of oral administration, for adults, per day The lower limit is 0.01 mg and the upper limit is 10,000 mg, and this amount can be administered once a day or in several divided doses.

[0092] The compound represented by formula (I) is a compound that has agonist activity against orexin receptors. Therefore, it can be a useful preventive or therapeutic agent for diseases related to orexin receptors. Specific examples of these diseases include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, 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-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity ( For example, malignant mast cells, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, plasmacemic obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-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, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome XSexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female hirsutism, fetal defects associated with gestational obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, respiratory disorders such as obesity hypoventilation syndrome (Pickwick syndrome) and dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, secondary consequences of obesity such as a reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / Disorders of the urinary tract, disorders of sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclophobia, 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, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral agenesis, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy These include cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Gilles de la Tourette 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, arthralgia, toothache, cataplexy, and traumatic brain injury. Preferably, these include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with Lewy body dementia.

[0093] The following describes, with examples, a method for producing the compound represented by formula (1) in the present invention, but the present invention is not limited thereto.

[0094] Manufacturing method The compound represented by formula (I) may be synthesized by a combination of the manufacturing method shown below and known synthesis methods. The reaction equations include cases where the compounds each form a salt, and examples of such salts are those similar to the "pharmaceutically acceptable salts" described above. These reactions are merely examples, and compounds represented by formula (I) can be prepared by other methods as appropriate, based on the knowledge of those proficient in organic synthesis chemistry.

[0095] In each of the manufacturing methods described below, even if the use of protecting groups is not explicitly stated, if there are functional groups that require protection, those functional groups may be protected as necessary, and the target product may be obtained by deprotecting them after the reaction is complete or after a series of reactions have been carried out.

[0096] As protecting groups, for example, ordinary protecting groups described in literature such as (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) can be used. More specifically, as protecting groups for amino groups, for example, tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, tetrahydropyranyl, etc., as protecting groups for hydroxyl groups, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl, etc., as protecting groups for aldehyde groups, for example, dialkylacetal, cyclic alkylacetal, etc., and as protecting groups for carboxyl groups, for example, tert-butyl ester, orthoester, amide, etc.

[0097] The introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis (for example, the methods described in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) or similar methods.

[0098] Manufacturing method 1: Among the compounds represented by formula (1) or their pharmaceutically acceptable salts, A 3 Compounds represented by formula (s-1-1), in which the atom is a nitrogen atom, or their pharmaceutically acceptable salts, can be produced, for example, by the following method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 (The dashed sections are equivalent to those in Section 1.)

[0099] Process (1-1): Compound (s-1-1) can be produced by reacting compounds (s-1-2) and (s-1-3) in a suitable inert solvent under commonly used urea bond formation conditions. Examples of reaction conditions include those using triphosgene, 4-nitrophenyl chloroformate, 1,1'-carbonyldiimidazole, or thiophosgene. A base is used in this reaction, such as triethylamine or diisopropylethylamine. Inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0100] In step (1-1), the intermediate isocyanate or the like may be isolated and the subsequent transformation may be carried out.

[0101] Manufacturing method 2: Of the compounds represented by formula (s-1-3), the compound represented by formula (s-2-1) that does not have an unsaturated bond in the ring can be produced, for example, by the following method. (However, L 2 is an oxygen atom or -NR 10 - Compound or L 2 This is limited to compounds in which the bond is a single bond and the ring G is linked to a cycloalkyl group via a nitrogen atom. Here, R 10 is H or C 1-4 (This represents alkyl, and is synonymous unless otherwise explained.) [ka] (In the formula, R 3 , R 4 , L 2 n, ring G, and the dashed section are equivalent to term 1. Also, P 1 (where indicates a suitable protecting group, and LG indicates a suitable leaving group; the same meaning applies unless otherwise specified.)

[0102] Compound (s-2-1) can be synthesized from compound (s-2-2) via steps (2-1) and (2-2).

[0103] Process (2-1): Compound (s-2-4) can be produced by reacting compound (s-2-2) and compound (s-2-3) in a suitable inert solvent under conditions without additives, in the presence of an acid, or in the presence of a base. Examples of acids used in this reaction include protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, as well as Lewis acids such as zinc(II) chloride, scandium triflate(III), copper(I) chloride, boron trifluoride, boronic acid, and boronic acid esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU, inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate, metal alkoxides such as tert-butoxypotassium, organometallic reagents such as n-butyllithium and isopropylmagnesium chloride, and metal amide reagents such as LDA and LHMDS. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0104] Process (2-2): Compound (s-2-1) can be produced by reacting compound (s-2-4) with compound (s-2-4) in a suitable inert solvent or, if necessary, under a hydrogen atmosphere, under commonly used nitro group reduction reaction conditions. Examples of reaction conditions include those using iron, zinc, tin(II) chloride, Raney nickel, palladium carbon, or palladium(II) hydroxide. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, ester solvents such as ethyl acetate and methyl acetate, and alcohol solvents such as methanol and ethanol. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0105] Compound (s-2-1) can also be synthesized from compound (s-2-5) via steps (2-3) and (2-4).

[0106] Process (2-3): Compound (s-2-6) can be produced by subjecting compound (s-2-5) and compound (s-2-3) in a suitable inert solvent to the usual ring-opening reaction conditions for aziridine, either without additives, in the presence of an acid, or in the presence of a base. Examples of acids used in this reaction include protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, as well as Lewis acids such as zinc(II) chloride, scandium triflate(III), copper(I) chloride, boron trifluoride, boronic acid, and boronic acid esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU, inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate, metal alkoxides such as tert-butoxypotassium, organometallic reagents such as n-butyllithium and isopropylmagnesium chloride, and metal amide reagents such as LDA and LHMDS. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0107] Process (2-4): Compound (s-2-1) is synthesized from compound (s-2-6) by known methods (e.g., Protective Groups in Organic Synthesis 3) rd It is manufactured by deprotecting the protecting group in a manner similar to that described in Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by RC Larocque, VCH publisher Inc., 1989, etc.

[0108] Compound (s-2-1) can also be synthesized from compound (s-2-7) via steps (2-5) to (2-7) and step (2-4).

[0109] Process (2-5): Compound (s-2-8) can be produced by subjecting compound (s-2-7) and compound (s-2-3) to a ring-opening reaction under commonly used epoxide conditions, either without additives, in the presence of an acid, or in the presence of a base, in a suitable inert solvent. Examples of acids used in this reaction include protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, as well as Lewis acids such as boron trifluoride, zinc(II) chloride, scandium triflate(III), copper(I) chloride, boronic acid, and boronic acid esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU, inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate, metal alkoxides such as tert-butoxypotassium, organometallic reagents such as n-butyllithium and isopropylmagnesium chloride, and metal amide reagents such as LDA and LHMDS. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0110] Process (2-6): Compound (s-2-9) can be produced by subjecting compound (s-2-8) to commonly used hydroxyl group-to-leading group conversion reaction conditions in a suitable inert solvent. Examples of reaction conditions include those using methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride. A base is also used in this reaction, and examples of bases that can be used include organic bases such as triethylamine, diisopropylethylamine, or DBU, inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as tert-butoxypotassium, organometallic reagents such as n-butyllithium or isopropylmagnesium chloride, and metal amide reagents such as LDA or LHMDS. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically between 1 and 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0111] Process (2-7): Compound (s-2-6) is compound (s-2-9) and P 1 It can be synthesized by reacting NH2 and a base under general nucleophilic substitution conditions. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as tert-butoxypotassium; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. Examples of solvents used include carbon halogens such as chloroform and dichloromethane; ether solvents such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0112] Steps (2-6) and (2-7) may be carried out in a single step without isolating the intermediate. Alternatively, steps (2-6) and (2-7) may be carried out in a single step by using the conditions of the Mitsunobu reaction.

[0113] Manufacturing method 3-1: Among the compounds represented by formula (s-2-1), L 2 Compounds represented by formula (s-3-1), in which a single bond exists and ring G is linked to a cycloalkyl group via a nitrogen atom, can also be produced, for example, by the following method. [ka] (In the formula, R 3 , R 4 n, and ring G are equivalent to term 1.

[0114] Compound (s-3-1) can be produced from compound (s-2-2) through steps (3-1) to (3-3).

[0115] Process (3-1): Compound (s-3-2) can be produced by reacting compound (s-2-2) with ammonia or an equivalent reagent (including cases where a deprotection reaction is carried out after reaction with a protected amine reagent, or cases where an azide introduction reagent is reacted and then converted to an amino group by a reduction reaction) under the same conditions as in step (2-1).

[0116] Process (3-2): Compound (s-3-3) can be produced by a reaction step that forms a nitrogen-containing heterocycle using compound (s-3-2). For example, if ring G is piperazine, it can be produced by a step that involves reacting it with N-benzyl-bis(2-chloroethyl)amine followed by a deprotection reaction and alkylation.

[0117] Process (3-3): Compound (s-3-1) can be produced using compound (s-3-3) under the same conditions as in step (2-2).

[0118] Compound (s-3-1) can also be synthesized from compound (s-2-5) via steps (3-4) to (3-6).

[0119] Process (3-4): Compound (s-3-4) can be produced by reacting compound (s-2-5) with ammonia or an equivalent reagent (including cases where a deprotection reaction is carried out after reaction with a protected amine reagent, or cases where an azide introduction reagent is reacted and then converted to an amino group by a reduction reaction) under the same conditions as in step (2-3).

[0120] Process (3-5): Compound (s-3-5) can be synthesized using compound (s-3-4) by a reaction process similar to that of step (3-2).

[0121] Process (3-6): Compound (s-3-1) can be produced using compound (s-3-5) under the same deprotection conditions as in step (2-4).

[0122] Manufacturing method 3-2: The compound represented by formula (s-3-1) can also be produced by, for example, the following method. [ka] (In the formula, R 3 , R 4 n, and ring G are equivalent to term 1.

[0123] Compound (s-3-1) can be produced from compound (s-3-6) through steps (3-7) and (3-8).

[0124] Process (3-7): Compound (s-3-6) is one of the compounds (s-2-9) shown in manufacturing method 2, L 2This compound has a single bond and the G ring is linked to a cycloalkyl group via a nitrogen atom. Compound (s-3-7) can be synthesized by reacting compound (s-3-6) with commonly used bases under general intramolecular nucleophilic substitution reaction conditions similar to those in steps (2-7). Compound (s-3-7) may be used in the next reaction without isolation.

[0125] Process (3-8): Compound (s-3-1) can be produced by subjecting compound (s-3-7) to general ring-opening reaction conditions using ammonia or an equivalent reagent (including cases where a deprotection reaction is carried out after reaction with a protected amine reagent, or where an azide introduction reagent is reacted and then converted to an amino group by a reduction reaction).

[0126] Manufacturing method 4: Among the compounds represented by formula (s-2-1), L 2 is O or NR 10 The compound represented by formula (s-4-1) can also be produced by, for example, the following method. [ka] (In the formula, R 3 , R 4 n and ring G are equivalent to term 1. Also, Y is O or NR 10 (Yes, and the meaning is the same even if no further explanation is given below.)

[0127] Compound (s-4-1) can be synthesized from compound (s-2-2) via steps (4-1) to (4-3).

[0128] Process (4-1): Compound (s-4-2) is YH2 or an equivalent reagent (protected reagent P 2 This includes the case where YH is reacted with the pesticide followed by a deprotection reaction: where P 2 The compound (s-2-2) can be produced by reacting it with a suitable protecting group () under the same conditions as in step (2-1).

[0129] Process (4-2): Compound (s-4-3) can be synthesized by reacting compound (s-4-2) with a ring G having a leaving group and a base under general nucleophilic substitution conditions or aromatic nucleophilic substitution conditions. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as tert-butoxypotassium; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. Examples of solvents used include carbon halogens such as chloroform and dichloromethane; ether solvents such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0130] Process (4-3): Compound (s-4-1) can be produced using compound (s-4-3) under the same conditions as in step (2-2).

[0131] Compound (s-4-1) can also be synthesized from compound (s-2-5) via steps (4-4) to (4-6).

[0132] Process (4-4): Compound (s-4-4) can be produced by reacting compound (s-2-5) with YH2 or an equivalent reagent (including reacting with the protected reagent P2YH followed by a deprotection reaction) under the same conditions as in step (2-3).

[0133] Process (4-5): Compound (s-4-5) can be synthesized using compound (s-4-4) by a reaction process similar to that of step (4-2).

[0134] Process (4-6): Compound (s-4-1) can be produced using compound (s-4-5) under the same deprotection conditions as in step (2-4).

[0135] Manufacturing method 5: The compound represented by formula (s-2-5) can be produced, for example, by the following method. [ka] (In the formula, R 3 , R 4 , and n are equivalent to term 1.

[0136] Compound (s-2-5) can be synthesized from compound (s-5-1) via steps (5-1) through (5-4).

[0137] Process (5-1): Compound (s-2-7) can be produced by reacting compound (s-5-1) in a suitable inert solvent under commonly used epoxide-forming conditions. Examples of reaction conditions include those using oxidizing agents such as hydrogen peroxide, mCPBA, tert-butyl hydroperoxide, or oxone. A metal catalyst containing V, Mo, Al, Ti, Fe, Ta, Zr, Nb, W, Re, etc., may be added to the reaction as needed. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0138] Process (5-2): Compound (s-5-2) can be synthesized by subjecting compound (s-2-7) and P1NH2 to a suitable inert solvent under the same conditions as in step (2-5).

[0139] Step (5-2) involves reacting compound (s-2-7) with ammonia or an equivalent reagent (including cases where a deprotection reaction is performed after reaction with a protected amine reagent, or where an azide introduction reagent is reacted and then converted to an amino group by reduction), followed by the formation of a protecting group P 1 Synthesis is possible even under conditions that require protection.

[0140] Process (5-3): Compound (s-5-3) can be produced by using compound (s-5-2) in a suitable inert solvent and subjecting it to the same conditions as in step (2-6).

[0141] Process (5-4): Compound (s-2-5) can be prepared by subjecting compound (s-5-3) to a commonly used intramolecular cyclization reaction in the presence of a base in a suitable inert solvent. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, or DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate; metal alkoxides such as tert-butoxypotassium; organometallic reagents such as n-butyllithium or isopropylmagnesium chloride; and metal amide reagents such as LDA or LHMDS. Examples of inert solvents include carbon halogens such as chloroform and dichloromethane; ether solvents such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0142] Steps (5-3) and (5-4) may be carried out in a single step without isolating the intermediate. Alternatively, steps (5-3) and (5-4) may be carried out in a single step by using the conditions of the Mitsunobu reaction.

[0143] Compound (s-2-5) can also be synthesized from compound (s-5-1) via step (5-5).

[0144] Process (5-5): Compound (s-2-5) can be produced by reacting compound (s-5-1) in a suitable inert solvent under commonly used aziridine-forming conditions. The conditions for this reaction are, for example, P 1 Conditions for using NH2 and oxidizing agents such as iodosylbenzene under a metal catalyst, and hydroxylamine derivatives P 1 These are the conditions under which N(H)O-LG and a metal catalyst are used.

[0145] Manufacturing method 6: Among the compounds represented by formula (s-1-1), the compound represented by formula (s-6-1) which has an unsaturated bond in the ring, can be produced, for example, by the following method. [ka] (In the formula, R 3 , R 4 , L 2 , n, and ring G are synonymous with item 1. Also, Z represents a boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin, zinc halide, or hydrogen atom, and X represents a halogen.

[0146] Compound (s-6-1) can be synthesized from compound (s-6-6) via step (6-7). Furthermore, compound (s-6-6) can be synthesized from compound (s-6-2) via steps (6-1) to (6-3), or via steps (6-4) to (6-6).

[0147] Process (6-1): Among the compounds (s-6-4), L 2 is a single bond or methylene (the methylene is one or more identical or different C 1-4Compounds (which may be alkyl-substituted) are prepared by reacting compound (s-6-2) in a suitable inert solvent with compound (s-6-3), in the presence of a palladium catalyst and a phosphine ligand, and optionally a base, where Z is represented by a boronic acid, a boronic acid ester, BF3K, BF3Na, trialkyltin, or zinc halide. Compound (s-6-3) can be purchased commercially or synthesized by known or similar methods. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), palladium acetate(0), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Examples of phosphine ligands include o-tolylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANT-Phos), and bis(2-(diphenylphosphino)phenyl) ether (DPE-Phos). Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, and potassium hydroxide. Examples of inert solvents include 1,4-dioxane, THF, 1,2-dimethoxyethane, acetonitrile, water, and mixtures thereof. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0148] Also, among the compounds (s-6-4), L 2 is O or NR 10 The compound can also be produced by reacting compound (s-6-2) with compound (s-6-3), in which Z is represented by a hydrogen atom, in a suitable inert solvent in the presence of a palladium catalyst, a phosphine ligand, and a base.

[0149] Process (6-2): Compound (s-6-5) can be produced using compound (s-6-4) under the same conditions as in step (2-6).

[0150] Process (6-3): Compound (s-6-6) is compound (s-6-5) and P 1 NH2 can be produced by subjecting it to the same conditions as in process (2-7).

[0151] Step (6-3) involves reacting compound (s-6-5) with ammonia or an equivalent reagent (including cases where a deprotection reaction is performed after reaction with a protected amine reagent, or where an azide introduction reagent is reacted and then converted to an amino group by reduction), followed by the formation of a protecting group P 1 The condition for protection is also acceptable.

[0152] Steps (6-2) and (6-3) may be carried out in a single step without isolating the intermediate. Alternatively, steps (6-2) and (6-3) may be carried out in a single step by using the conditions of the Mitsunobu reaction.

[0153] Process (6-4): Compound (s-6-7) can be produced using compound (s-6-2) under the same conditions as in step (6-2).

[0154] Process (6-5): Compound (s-6-8) can be produced using compound (s-6-7) under the same conditions as in step (6-3).

[0155] Step (6-5) involves reacting compound (s-6-7) with ammonia or an equivalent reagent (including cases where a deprotection reaction is performed after reaction with a protected amine reagent, or where an azide introduction reagent is reacted and then converted to an amino group by reduction), followed by the formation of a protecting group P 1 The condition for protection is also acceptable.

[0156] Steps (6-4) and (6-5) may be carried out in a single step without isolating the intermediate. Alternatively, steps (6-4) and (6-5) may be carried out in a single step by using the conditions of the Mitsunobu reaction.

[0157] Process (6-6): Compound (s-6-6) can be produced using compound (s-6-8) under the same conditions as in step (6-1).

[0158] Process (6-7): Compound (s-6-1) can be produced using compound (s-6-6) under the same deprotection conditions as in step (2-4).

[0159] Manufacturing method 7: Among the compounds represented by formula (s-1-1), the compound represented by formula (s-7-1) that does not have an unsaturated bond in the ring can also be produced by, for example, the following method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 , n, ring G, and A 1 This is synonymous with item 1.

[0160] Compound (s-7-1) can be synthesized from compound (s-7-4) via step (7-6). Compound (s-7-4) can also be synthesized from compound (s-5-3) via steps (7-1) to (7-3), or from compound (s-2-5) via steps (7-4) and (7-5).

[0161] Process (7-1): Compound (s-7-2) can be produced using compound (s-5-3) under the same deprotection conditions as in step (2-4).

[0162] Process (7-2): Compound (s-7-3) can be produced using compound (s-7-2) and compound (s-1-2) under the same urea formation conditions as in step (1-1). In this step, hydroxyl group protection and deprotection may be performed if necessary.

[0163] Process (7-3): Compound (s-7-4) can be produced using compound (s-7-3) by following the same steps as in steps (5-3) and (5-4).

[0164] Process (7-4): Compound (s-7-5) can be produced using compound (s-2-5) under the same deprotection conditions as in step (2-4).

[0165] Process (7-5): Compound (s-7-4) can be produced using compound (s-7-5) and compound (s-1-2) under the same urea formation conditions as in step (1-1).

[0166] Process (7-6): Compound (s-7-1) can be produced using compounds (s-7-4) and (s-2-3) under the same aziridine ring-opening reaction conditions as in step (2-3).

[0167] Manufacturing method 8: The compound represented by formula (s-1-1) can also be produced by going through steps (8-1) to (8-3) from compound (s-8-1). [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 (The dashed sections are equivalent to those in Section 1.)

[0168] Process (8-1): Compound (s-8-2) can be produced by reacting compound (s-8-1) in a suitable inert solvent under commonly used acyl azide formation conditions. These reaction conditions include, for example, those using diphenyl phosphate azide, or those involving conversion to an acid halide followed by reaction with a metal azide. Examples of inert solvents include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ester solvents such as ethyl acetate and methyl acetate; and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0169] Process (8-2): Compound (s-8-3) can be produced by reacting compound (s-8-2) with compound (s-8-2) under commonly used Curtius rearrangement conditions in a suitable inert solvent. Compound (s-8-2) used here does not need to be isolated in the previous step.

[0170] Process (8-3): Compound (s-1-1) can be produced by reacting compound (s-8-3) and compound (s-1-2) in a suitable inert solvent under commonly used addition reaction conditions. Compound (s-8-3) used here does not need to be isolated in the previous step.

[0171] Manufacturing method 9: Compounds represented by formula (s-9-1) that do not have an unsaturated bond in the ring can be produced, for example, by the following method. [ka] (In the formula, R 3 , R 4 , L 2 , n, and ring G are equivalent to term 1. Also P 3is a suitable protecting group or C 1-3 (This indicates alkyl, and is synonymous unless otherwise explained.)

[0172] Compound (s-9-1) can be synthesized from compound (s-9-2) via steps (9-1) and (9-2).

[0173] Process (9-1): Compound (s-9-3) can be produced by subjecting compound (s-9-2) and compound (s-2-3) to the same conditions as in step (2-1).

[0174] Process (9-2): Compound (s-9-1) can be produced by subjecting compound (s-9-3) to general hydrolysis conditions or deprotection conditions.

[0175] Compound (s-9-1) can be synthesized from compound (s-2-9) via steps (9-3) and (9-4).

[0176] Process (9-3): Compound (s-9-4) can be produced by subjecting compound (s-2-9) and a metal cyanide to the same conditions as in step (2-7).

[0177] Process (9-4): Compound (s-9-1) can be produced by reacting compound (s-9-4) with compound (s-9-4) in a suitable inert solvent under commonly used hydrolysis conditions.

[0178] Manufacturing method 10: Compounds represented by formula (s-10-1) that have an unsaturated bond in the ring, among the compounds (s-8-1), can be produced, for example, by the following method. [ka] (In the formula, R 3 , R 4 , L 2, n, and ring G are synonymous with item 1. Also, Z represents a boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin, zinc halide, or hydrogen atom, and X represents a halogen.

[0179] Compound (s-10-1) can be synthesized from compound (s-10-2) via step (10-2). Compound (s-10-2) can also be synthesized from compound (s-6-5) via step (10-1), or from compound (s-6-7) via steps (10-3) and (10-4).

[0180] Process (10-1): Compound (S-10-2) can be produced using compound (S-6-5) and a metal cyanide under the same conditions as in step (2-7).

[0181] Process (10-2): Compound (S-10-1) can be produced by reacting compound (S-10-2) with compound (S-10-2) in a suitable inert solvent under commonly used hydrolysis conditions.

[0182] Process (10-3): Compound (S-10-3) can be produced using compound (S-6-7) and a metal cyanide under the same conditions as in step (10-1).

[0183] Process (10-4): Compound (s-10-2) can be produced using compound (s-10-3) and compound (s-6-3) under the same conditions as in step (6-1).

[0184] Manufacturing method 11: Among the compounds represented by formula (1) or their pharmaceutically acceptable salts, A 3 Compounds represented by formula (s-11-1), in which carbon atoms are represented, or pharmaceutically acceptable salts thereof, can be produced, for example, by the following method. [ka] (In the formula, R 1~R 4 , L 1 , L 2 n, ring G, and the dashed section are equivalent to term 1.

[0185] Process (11-1): Compound (s-11-1) can be produced by reacting compounds (s-11-2) and (s-1-3) in a suitable inert solvent under commonly used amide bond formation conditions. The conditions for this reaction include those using a coupling agent and a base. Examples of coupling agents include carbodiimides such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrahydroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Examples include hexafluorophosphate (HATU). Examples of bases include organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBU, pyridine, and dimethylaminopyridine. Examples of inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, ester solvents such as ethyl acetate and methyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0186] Compound (s-11-1) can also be synthesized from compound (s-11-2) via steps (11-2) and (11-3).

[0187] Process (11-2): Compound (S-11-3) can be synthesized by adding compound (S-11-2) to commonly used acid halide formation conditions in a suitable inert solvent. Conditions for this reaction include those using a halogenating agent, such as thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus tribromide, and phosphorus pentachloride. Inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0188] Process (11-3): Compound (s-11-1) is obtained by reacting compound (s-11-3) and compound (s-1-3) in the presence of a base in a suitable inert solvent. Examples of bases include organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBU, pyridine, and dimethylaminopyridine, and inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate. Examples of inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0189] Manufacturing method 12: Among the compounds represented by formula (1) or their pharmaceutically acceptable salts, A 2Compounds represented by formula (s-12-1), in which oxygen atoms are represented, or pharmaceutically acceptable salts thereof, can be produced, for example, by the following method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 (The dashed sections are equivalent to those in Section 1.)

[0190] Process (12-1): Compound (s-12-1) can be produced by reacting compound (s-1-2) and compound (s-12-2) in a suitable inert solvent under commonly used carbamate-forming conditions. Examples of reaction conditions include those using triphosgene, 4-nitrophenyl chloroformate, or thiophosgene. A base is used in this reaction, such as triethylamine or diisopropylethylamine. Inert solvents include chloroform, dichloromethane, and other halogenated carbons; ether solvents such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0191] For compounds represented by formula (s-12-2), if there are no unsaturated bonds in the ring, the manufacturing method is the same as that for compound (s-2-8). If there are unsaturated bonds in the ring, the manufacturing method is the same as that for compound (s-6-4).

[0192] Manufacturing method 13: Of the compounds represented by formula (s-1-2), the compound represented by formula (s-13-1) can be produced, for example, by the following method. [ka] (In the formula, R2 This is equivalent to item 1. R a1 and Q 2 This is equivalent to item 4. Also, P 4 (This indicates an appropriate protecting group, and the same applies unless otherwise stated.)

[0193] Process (13-1): Compound (s-13-4) can be produced by reacting compounds (s-13-2) and (s-13-3) in a suitable inert solvent under commonly used addition reaction conditions. Examples of inert solvents include carbon halides such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, alcohol solvents such as methanol and ethanol, and water. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0194] Process (13-2): Compound (s-13-6) can be produced by reacting compounds (s-13-4) and (s-13-5) in a suitable inert solvent under commonly used condensation reaction conditions. Examples of reaction conditions include those using HATU, DCC, or CDI. A base is used in this reaction, such as triethylamine or diisopropylethylamine. Suitable solvents include carbon halogens such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0195] Process (13-3): Compound (s-13-7) can be produced by reacting compound (s-13-6) in a suitable inert solvent under commonly used dehydration conditions. This reaction may optionally use a base such as triethylamine or DBU. Examples of inert solvents include carbon halides such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0196] Process (13-4): Compound (s-13-1) is synthesized from compound (s-13-7) by known methods (e.g., Protective Groups in Organic Synthesis 3) rd It is manufactured by deprotecting the protecting group in a manner similar to that described in Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by RC Larocque, VCH publisher Inc., 1989, etc.

[0197] Manufacturing method 14: Among the compounds represented by formula (s-1-2), L 1 It is a single bond and R 1 A compound represented by formula (s-14-1), which is a five-membered aromatic heterocyclic group that may be substituted, can be produced, for example, by the following method. [ka] (In the formula, R 2 This is synonymous with item 1, and X 4 and R a1 This is synonymous with item 4.

[0198] Compound (s-14-1) can be synthesized from compound (s-14-2) via steps (14-1) to (14-3).

[0199] Process (14-1): Compound (s-14-3) can be produced by reacting compound (s-14-2) in a suitable inert solvent under commonly used chlorolysis conditions. Examples of reaction conditions include those using chlorine, N-chlorosuccinimide, or benzyltrimethylammonium tetrachloroiodate. Suitable inert solvents include chloroform, carbon halogens such as dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide, or water, or mixtures thereof. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0200] Process (14-2): Compound (s-14-5) can be produced by reacting compound (s-14-3) and compound (s-14-4) in a suitable inert solvent under commonly used 1,3-dipolar cyclization reaction conditions. Examples of reaction conditions include those using a base. Suitable bases include inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium t-butoxide, sodium hydroxide, potassium hydroxide, and potassium fluoride, or organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, or NMM. Suitable inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically between 1 and 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0201] Process (14-3): Compound (s-14-1) can be produced using compound (s-14-5) in the same manner as in step (13-4).

[0202] Manufacturing method 15: Of the compounds represented by formula (s-1-2), the compound represented by formula (s-15-1) can be produced, for example, by the following method. [ka] (In the formula, R 2 This is synonymous with item 1, and X 1 ~X 3 Q 1 and R a6 This is synonymous with item 4.

[0203] Process (15-1): Compound (S-15-4) can be produced by reacting compounds (S-15-2) and (S-15-3) in a suitable inert solvent under condensation reaction conditions similar to those in step (13-2).

[0204] Process (15-2): Compound (S-15-5) can be produced by reacting compound (S-15-4) in a suitable inert solvent under commonly used dehydration reaction conditions, or under cyclization reaction conditions after treatment with Lawson's reagent, etc.

[0205] Process (15-3): Compound (s-15-1) can be produced using compound (s-15-5) in the same manner as in step (13-4).

[0206] Manufacturing method 16: Among the compounds represented by formula (s-1-2), L 1 It is a single bond and R 1 C may be substituted. 6-10Compounds represented by formula (s-16-5) or formula (s-16-8), which are aromatic carbocyclic groups or optionally substituted 5-10 membered aromatic heterocyclic groups, can be produced, for example, by the following method. [ka] (In the formula, R 1 and R 2 This is synonymous with item 1. Z is exemplified in the following step (16-1). X is a halogen.

[0207] Compound (s-16-5) can be synthesized from compound (s-16-1) via steps (16-1) to (16-3).

[0208] Process (16-1): Compound (s-16-3) can be produced by performing various coupling reactions on compound (s-16-1) in the presence of a base and a metal catalyst, using organoboron compounds (e.g., Z = B(OH)2), organozinc compounds (e.g., Z = ZnCl), alkenyl compounds, alkynyl compounds, hydroxy compounds (e.g., Z = OH), amine compounds (e.g., Z = NH2), metal cyanides (e.g., CuCN), etc. As the base, inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium t-butoxide, sodium hydroxide, potassium hydroxide, potassium fluoride, or organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, or NMM. In some cases, a base may not be used depending on the type of coupling. Suitable metal catalysts include, for example, bis(tris-tert-butylphosphine)palladium, bis(tris-o-tolylphosphine)dichloropalladium, bis(tris-o-tolylphosphine)palladium, tetrakistriphenylphosphine palladium, dichloropalladium (acetonitrile), bis(tris-o-tolylphosphine)dichloropalladium, (1,1'-bis(diphenylphosphineno)ferrocene)dichloropalladium, and PEPPSI™·IPr((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride). For palladium acetate and palladium chloride, appropriate ligands or related ligands described in palladium reagents and catalysts, John Wiley & Sons Inc. (2004) can also be selected and used.Examples of solvents that can be used include ether-based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, or 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, or xylene; ester-based solvents such as ethyl acetate or methyl acetate; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide; water; or mixtures thereof. The reaction temperature varies depending on the type of starting compound used, but is usually about 0°C to about 250°C, preferably about 20°C to about 200°C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

[0209] Process (16-2): Compound (s-16-4) can be produced by reacting compound (s-16-3) in a suitable inert solvent or, if necessary, under a hydrogen atmosphere, under commonly used alkene reduction conditions. Examples of reaction conditions include those using reducing agents such as palladium carbon, palladium(II) hydroxide, platinum carbon, platinum(IV) oxide, Raney nickel, ruthenium carbon, and chlorotris(triphenylphosphine)rhodium(I). Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, alcohol solvents such as methanol and ethanol, and ester solvents such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0210] Process (16-3): Compound (s-16-5) can be produced using compound (s-16-4) in the same manner as in step (13-4).

[0211] Compound (s-16-8) can be synthesized from compound (s-16-1) via steps (16-1) and (16-4) through (16-6).

[0212] Process (16-4): Compound (s-16-6) is converted to compound (s-16-3) and alkylating agent R in a suitable inert solvent under alkylation reaction conditions. 2 -X and a base can be reacted to produce it. Examples of bases used in this reaction include LDA, LHMDS, and n-butyllithium. Examples of inert solvents include ether-based solvents such as diethyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbon solvents such as benzene, toluene, and xylene. The reaction time is usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0213] Process (16-5): Compound (s-16-7) can be produced by reacting compound (s-16-6) in a suitable inert solvent in the same manner as in step (16-2) (however, sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride may be used as the reducing agent).

[0214] Process (16-6): Compound (s-16-8) can be produced using compound (s-16-7) in the same manner as in step (13-4).

[0215] Manufacturing method 17: Of the compounds represented by formula (s-1-2), the compound represented by formula (s-17-1) can be produced, for example, by the following method. [ka] (In the formula, R 1 This is equivalent to item 1. R 8 is C 1-3 (Represents alkyl.)

[0216] Process (17-1): Compound (s-17-3) is subjected to alkylation reaction conditions similar to those in step (16-4) in a suitable inert solvent with compound (s-17-2) and alkylating agent R. 1 It can be produced by reacting with -X (where X represents a halogen).

[0217] Process (17-2): Compound (s-17-4) can be produced by reacting compound (s-17-3) in a suitable inert solvent under commonly used reduction reaction conditions. Examples of reaction conditions include those using LAH or DIBAL. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbon solvents such as benzene, toluene, and xylene. The reaction time is typically about 1 to 24 hours, and the reaction temperature ranges from -20°C to the boiling point of the solvent.

[0218] Process (17-3): Compound (S-17-5) can be produced by reacting compound (S-17-4) in a suitable inert solvent under Burton-McCombee deoxygenation reaction conditions.

[0219] Process (17-4): Compound (s-17-1) can be produced using compound (s-17-5) in the same manner as in step (13-4). [Examples]

[0220] The present invention will be described in more detail below with reference examples, examples, and test examples, but the present invention is not limited thereto. Note that the compound names shown in the following reference examples and examples do not necessarily follow IUPAC nomenclature.

[0221] In this specification, the following abbreviations may be used. CDCl3: Deuterated chloroform DMSO-d6: Deuterated Dimethyl Sulfoxide Rt: retention time min: minutes HATU:O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DCC:N,N'-Dicyclohexylcarbodiimide CDI: Carbonyldiimidazole THF: Tetrahydrofuran TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide CPME: Cyclopentyl methyl ether Boc:tert-butoxycarbonyl Ns: 2-nitrobenzenesulfonyl group Tf: Trifluoromethanesulfonyl group DBU: Diazabicycloundecene DBN:1,5-Diazabicyclo[4.3.0]nona-5-ene LDA: Lithium diisopropylamide LHMDS: Lithium bis(trimethylsilyl)amide mCPBA: Metachloroperbenzoic acid DABCO:1,4-Diazabicyclo[2.2.2]Octane NMM: N-methylmorpholine LAH: Lithium aluminum hydride DIBAL: Diisobutylaluminum hydride Abs: Absolute Configuration; The abbreviation Abs enclosed in a square indicates that the chemical structure of a compound represents the wedge-shaped bond as an absolute configuration. However, this does not necessarily mean that the chemical structure of a compound without this abbreviation is not an absolute configuration representation; this should be determined according to the description of the compound in question in this specification, the context, and the common sense of those skilled in the art.

[0222] In the reference examples and examples, column chromatography and amino chromatography were performed using silica gel columns and amino columns manufactured by Yamazen Corporation. For purification using TLC, Silica gel 60F254 (Merck) was used for TLC (silica gel plates), and TLC plate NH (FujiSilysia) was used for TLC (NH silica gel plates).

[0223] The following reaction apparatus was used in the reference examples and examples. The physicochemical data described in the reference examples and examples were obtained using the following equipment. Microwave reactor: Biotage AB Initiator 1 H-NMR:JEOL JNM-AL400;JEOL JNM-ECS400;Brucker AVANCE 400 Spectrometer

[0224] In NMR, the symbols used are as follows: s for single line, d for double line, dd for double double line, ddd for double double double line, dddd for double double double double line, t for triple line, td for triple double line, q for quadruple line, m for multiline, br for broad single or multiline, and J for coupling constant.

[0225] LC / MS data for each compound in the examples and reference examples were obtained using one of the following instruments. Method A Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) SYSTEM Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Method B Detection equipment: Shimadzu LCMS-2020 Column: Phenomenex Kinetex (C18, 1.7 μm, 2.1 mm × 50 mm) Method C Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) SYSTEM Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm)

[0226] The measurement conditions for high-performance liquid chromatography-mass spectrometry (LC / MS) are as follows, and the observed mass spectrometry value [MS(m / z)] is recorded as [M+H]. + The holding time is indicated by Rt (min). For each measured value, the measurement conditions used are indicated by one of A to D. Method A Solvents: Solution A; 0.06% formic acid / H2O, Solution B; 0.06% formic acid / acetonitrile Gradient conditions: 0.0-1.3 minutes (linear gradient from B 2% to B 96%) Flow rate: 0.8 mL / min; detection UV: 220 nm and 254 nm; temperature: 40℃ The following LC-MS data are those measured using Method A unless otherwise specified. Method B Solvents: Solution A; 0.05% TFA / H2O, Solution B; acetonitrile Gradient conditions: 0.0-1.7 minutes (linear gradient from B 10% to B 99%) Flow rate: 0.5 mL / min; Detection UV: 220 nm; Temperature: 40°C Method C Solvents: Solution A; 0.05% formic acid / H2O, Solution B; acetonitrile Gradient conditions: 0.0-1.3 min (linear gradient from B 10% to B 95%), 1.3-1.5 min (B 10%) Flow rate: 0.8 mL / min; detection UV: 220 nm and 254 nm; temperature: 40℃

[0227] Example 1: rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}piperidine-1-carboxamide [ka] Reference Example 1 (211 mg) (Raw Material A), triethylamine (0.391 mL), and chloroform (3 mL) were mixed with 4-nitrophenyl chloroformate (208 mg) at 0°C and stirred at the same temperature for 40 minutes. 4-(4-methylphenyl)piperidine hydrochloride (238 mg) (Raw Material B) was added to the reaction mixture at 0°C and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound (346 mg). 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.04-1.11 (1H, m), 1.12-1.40 (3H, m), 1.58-1.71 (3H, m), 1.76-1.93 (4H, m), 2.27 (1H, dd, J = 10.4, 3.6 Hz), 2.32 (3H, s), 2.35-2.54 (6H, m), 2.54-2.65 (3H, m), 2.65-2.75 (2H, m), 2.78-2.91 (2H, m), 3.25-3.33 (1H, m), 4.08-4.19 (2H, m), 5.76 (1H, s), 7.09 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz).

[0228] Examples 2-16: Using commercially available compounds or reference compounds listed in the table below as compounds corresponding to raw materials A and B described in Example 1, the compounds of Examples 2 to 16 shown in the table below were prepared in the same manner as in Example 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0229] The compound names for Examples 2 to 16 are listed below. Example 2: rac-N-[(1R,2S)-2-(4-ethylpiperazin-1-yl)cyclohexyl]-4-(4-methylphenyl)piperidine-1-carboxamide Example 3: rac-4-methyl-4-(5-methyl-1,2,4-oxadiazole-3-yl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}piperidine-1-carboxamide Example 4: rac-N-{(1R,2S,6S)-2-methoxy-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 5: rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclopentyl}piperidine-1-carboxamide Example 6: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methyl-N-{(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclopentyl}piperidine-1-carboxamide Example 7: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,2S)-3,3-difluoro-2-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 8: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 9: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxylate Example 10: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-methyl-4-(5-methyl-1,2,4-oxadiazole-3-yl)piperidine-1-carboxylate Example 11: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2-oxazole-3-yl)-4-methylpiperidine-1-carboxylate Example 12: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-[5-(difluoromethyl)-1,2,4-oxadiazole-3-yl]-4-methylpiperidine-1-carboxylate Example 13: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-(1-cyclopropyl-1H-1,2,4-triazole-3-yl)-4-methylpiperidine-1-carboxylate Example 14: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxylate Example 15: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methyl-N-{2-[6-(propan-2-yl)pyridine-3-yl]cyclohexa-2-en-1-yl}piperidine-1-carboxamide Example 16: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methyl-N-{2-[6-(propan-2-yl)pyridine-3-yl]cyclohexa-2-en-1-yl}piperidine-1-carboxamide

[0230] Example 17: rac-N-[(1S,2S)-2-(4-ethylpiperazine-1-yl)cyclohexyl]-4-(4-methylphenyl)piperidine-1-carboxamide [ka] A mixture of Reference Example 2 (73.7 mg), sodium acetate (18.9 mg), acetaldehyde (0.054 ml), and dichloromethane (2 mL) was mixed with sodium borohydride triacetate (122 mg) at 0°C, and the mixture was heated to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (24 mg). 1H-NMR (CDCl3) δ: 1.02-1.12 (1H, m), 1.07 (3H, t, J = 7.3 Hz), 1.14-1.41 (3H, m), 1.57-1.71 (3H, m), 1.75-1.96 (5H, m), 2.16-2.78 (15H, m), 2.78-2.90 (2H, m), 3.24-3.39 (1H, m), 4.05-4.18 (2H, m), 5.72 (1H, s), 7.09 (2H, d, J = 7.9 Hz), 7.12 (2H, d, J = 7.9 Hz).

[0231] Example 18: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methyl-N-{2-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridine-4-yl]cyclohexa-2-en-1-yl}piperidine-1-carboxamide [ka] To a chloroform solution (2 mL) of Reference Example 13 (13.5 mg), hydrogen chloride / acetic acid solution (4 M, 0.198 mL) was added and stirred at room temperature. After confirming the disappearance of the starting material, the mixture was concentrated under reduced pressure, and sodium acetate (8.66 mg), acetone (0.058 mL), and chloroform (2 mL) were added. Sodium borohydride triacetate (33.6 mg) was added at 0°C, and the mixture was heated to room temperature and stirred. After the reaction was complete, water was added to the reaction mixture under ice cooling and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (10 mg). 1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.1 Hz), 1.17-1.22 (4H, m), 1.23-1.32 (2H, m), 1.29 (3H, s), 1.43-1.66 (3H, m), 1.91-1.98 (1H, m), 2.08-2.26 (6H, m), 2.26-2.41 (1H, m), 2.50 (1H, ddd, J = 11.2, 7.2, 4.8 Hz), 2.63-2.76 (2H, m), 2.97-3.13 (3H, m), 3.13-3.23 (1H, m), 3.52-3.63 (2H, m), 4.43 (1H, d, J = 7.3 Hz), 4.63-4.69 (1H, m), 5.78-5.84 (1H, m), 5.85-5.91 (1H, m).

[0232] Example 19: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] A mixture of Reference Example 14 (84.6 mg) (Raw Material A), triethylamine (0.318 mL), and chloroform (2 mL) was mixed with triphosgene (27.1 mg) at 0°C and stirred at the same temperature for 40 minutes. Reference Example 8 (66.7 mg) (Raw Material B) was added to the reaction mixture at 0°C and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound (99.1 mg). 1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 6.0 Hz), 1.01 (3H, d, J = 6.0 Hz), 1.17-1.22 (4H, m), 1.23-1.30 (1H, m), 1.30-1.48 (2H, m), 1.31 (3H, s), 1.57-1.70 (2H, m), 1.75-1.84 (1H, m), 1.89-1.97 (1H, m), 2.10-2.27 (4H, m), 2.32-2.53 (7H, m), 2.53-2.64 (1H, m), 2.68-2.78 (2H, m), 3.08 (1H, ddd, J = 13.6, 10.7, 3.1 Hz), 3.16 (1H, ddd, J = 13.6, 10.7, 3.1 Hz), 3.66 (1H, ddd, J = 13.6, 4.7, 4.1 Hz), 3.77 (1H, ddd, J = 13.6, 4.7, 4.1 Hz), 4.10-4.21 (1H, m), 4.54 (1H, d, J = 7.3 Hz).

[0233] Examples 20-76: Examples 20 to 76, shown in the table below, were prepared using the same method as in Example 19, with commercially available compounds or reference examples listed in the table below as compounds corresponding to raw materials A and B described in Example 19. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20]

[0234] The compound names for Examples 20 to 76 are listed below. Example 20: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 21: rac-4-(1,3-benzoxazole-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 26: rac-4-cyclopentyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 27: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-(4,5,6,7-tetrahydro-1,3-benzoxazole-2-yl)piperidine-1-carboxamide Example 28: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-ethyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxamide Example 29: rac-4-(1-cyclopropyl-1H-1,2,4-triazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 30: rac-4-(4,4-difluorocyclohexyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 31: rac-4-(5-cyclopropyl-1,2,4-thiadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 32: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(pyridine-2-yl)piperidine-1-carboxamide Example 33: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-8-azaspiro[4.5]decane-8-carboxamide Example 34: rac-4-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 35: rac-4-cyclohexyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}piperidine-1-carboxamide Example 36: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(pyrimidine-2-yl)piperidine-1-carboxamide Example 37: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-hydroxy-4-(pyridine-2-yl)piperidine-1-carboxamide Example 38: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-phenylpiperidine-1-carboxamide Example 39: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-phenylpiperidine-1-carboxamide Example 40: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-hydroxy-4-phenylpiperidine-1-carboxamide Example 41: rac-4-(4-chlorophenyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-hydroxypiperidine-1-carboxamide Example 42: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-[(pyridine-2-yl)oxy]piperidine-1-carboxamide Example 43: 4-(5-cyclopropyl-1,2,4-thiadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 44: 4-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 45: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-methoxy-1,2,4-thiadiazole-3-yl)-4-methylpiperidine-1-carboxamide Example 46: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-fluoro-4-(pyridine-2-yl)piperidine-1-carboxamide Example 47: rac-4-(2-cyclopropyl-1,3-thiazole-4-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 48: rac-4-(5-cyclopropyl-1,3-thiazole-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 49: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 50: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-methylpyridine-2-yl)piperidine-1-carboxamide Example 51: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(3-fluoro-5-methylpyridine-2-yl)piperidine-1-carboxamide Example 52: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-fluoropyridine-2-yl)piperidine-1-carboxamide Example 53: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-methoxypyridine-2-yl)piperidine-1-carboxamide Example 54: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(5-methylpyrimidine-2-yl)piperidine-1-carboxamide Example 55: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-[5-(trifluoromethyl)pyridine-2-yl]piperidine-1-carboxamide Example 56: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-(2-fluoro-4-methylphenyl)-4-methylpiperidine-1-carboxamide Example 57: 4-[5-(cyclopropyloxy)-1,2,4-thiadiazole-3-yl]-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 58: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 59: rac-4-[4-(difluoromethyl)phenyl]-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 60: 4-(2-cyano-4-methylphenyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 61: N-{(1R,6S)-2,2-difluoro-6-[6-(propan-2-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 64: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide Example 70: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazole-3-yl]piperidine-1-carboxamide Example 71: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 76: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide

[0235] Example 77: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4'-methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxamide [ka] To a chloroform solution (2 mL) of 4-(4-methylphenyl)-cyclohexa-1-ene-carboxylic acid (64.3 mg), oxalyl chloride (0.036 mL) and DMF (5 μL) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure, and chloroform (2 mL), triethylamine (0.120 mL), and Reference Example 14 (53.3 mg) were added and the mixture was stirred. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (55.6 mg). 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.23-1.50 (2H, m), 1.71-1.91 (4H, m), 1.93-2.11 (2H, m), 2.13-2.68 (14H, m), 2.69-2.89 (4H, m), 4.27-4.44 (1H, m), 5.68-5.77 (1H, m), 6.67-6.77 (1H, m), 7.09-7.20 (4H, m).

[0236] Example 78: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl 4'-methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxylate Instead of Reference Example 14 in Example 77, Reference Example 6 was used, and the compound of Example 78 shown in the table below was prepared in the same manner as in Example 77. [Table 3]

[0237] Example 79: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide [ka] A mixture of Reference Example 14 (10.0 mg) (Raw Material A), N,N-diisopropylamine (0.034 mL), and chloroform (0.2 mL) was mixed with thiophosgene (4.40 mg) at 0°C and stirred at the same temperature for 40 minutes. Reference Example 8 (66.7 mg) (Raw Material B) was added to the reaction mixture at 0°C and stirred at room temperature for 1 hour. The reaction solution was then purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (9.6 mg). 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 5.6 Hz), 1.14-1.27 (4H, m), 1.27-1.50 (2H, m), 1.50-1.91 (8H, m), 1.91-2.04 (1H, m), 2.08-2.24 (2H, m), 2.24-2.35 (2H, m), 2.35-2.55 (5H, m), 2.55-2.70 (2H, m), 2.79-3.00 (2H, m), 3.33 (1H, t, J = 11.2 Hz), 3.49 (1H, t, J = 11.2 Hz), 4.16 (1H, d, J = 12.8 Hz), 4.49 (1H, d, J = 12.8 Hz), 5.02-5.26 (1H, m), 5.42 (1H, d, J = 8.0 Hz).

[0238] Example 80: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide Using Reference Example 15 as raw material A in Example 79 and Reference Example 8 as raw material B in Example 79, the compound of Example 80 shown in the table below was produced in the same manner as in Example 79. [Table 4]

[0239] Example 81: rac-4-(4-methylphenyl)-N-[(1S,4R)-3-{[4-(propan-2-yl)piperazine-1-yl]methyl}bicyclo[2.2.1]heptan-2-yl]piperidine-1-carboxamide [ka] To a chloroform solution (0.5 mL) of Reference Example 40 (20 mg), TFA (0.057 mL) was added at room temperature and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate). The resulting residue was dissolved in chloroform (0.284 mL) and N,N-diisopropylethiamine (36.8 mg) and triphosgene (8.4 mg) were added at 0°C and the mixture was stirred at the same temperature for 1 hour. Then, 4-(4-methylphenyl)piperidine (0.057 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (8 mg). 1H-NMR (CDCl3) δ: 1.24 (6H, d, J = 7.3 Hz), 1.31-1.49 (7H, m), 1.54-1.67 (4H, m), 1.84 (2H, m), 2.24 (1H, m), 2.32 (3H, s), 2.63 (2H, m), 2.80-2.99 (4H, m), 3.06-3.49 (8H, m), 4.05-4.14 (3H, m), 7.07-7.13 (4H, m).

[0240] Examples 82-156: Examples 82 to 156, shown in the table below, were prepared using the same method as in Example 19, with commercially available compounds or reference examples listed in the table below as compounds corresponding to raw materials A and B described in Example 19. [Table 5] TIFF2022183120000162.tif253170 TIFF2022183120000163.tif223170 TIFF2022183120000164.tif232170 TIFF2022183120000165.tif214170 TIFF2022183120000166.tif218166 TIFF2022183120000167.tif227170 TIFF2022183120000168.tif249164 TIFF2022183120000169.tif208168 TIFF2022183120000170.tif230170 TIFF2022183120000171.tif237170 TIFF2022183120000172.tif210170 TIFF2022183120000173.tif252170 TIFF2022183120000174.tif205170 TIFF2022183120000175.tif213166 TIFF2022183120000176.tif207168 TIFF2022183120000177.tif216170 TIFF2022183120000178.tif223168 TIFF2022183120000179.tif232170 TIFF2022183120000180.tif212170 TIFF2022183120000181.tif215170 TIFF2022183120000182.tif220170 TIFF2022183120000183.tif207168 TIFF2022183120000184.tif184170

[0241] The compound names for Examples 82 to 155 are listed below. Example 82: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 83: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 84: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 85: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazole-3-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 86: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazole-3-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 87: N-[(1R,6S)-2,2-difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazole-5-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 88: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 89: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)azetidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 90: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 91: N-[(1R,6S)-6-{benzyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 92: N-[(1R,6S)-2,2-difluoro-6-{[2-(propan-2-yl)pyrimidine-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 93: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazole-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 94: N-{(1R,6S)-2,2-difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazole-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 95: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 96: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 97: 4-(5-cyclobutyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 98: N-[(1R,6S)-2,2-difluoro-6-{[(1R,3s,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 99: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 100: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8r)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octane-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 101: N-[(1R,6S)-2,2-difluoro-6-{4-[(propan-2-yl)oxy]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 102: 4-(5-cyclobutyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 103: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine-1-carboxamide Example 104: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8s)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octane-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 105: N-[(1R,6S)-2,2-difluoro-6-{[(1R,3r,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octane-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 106: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,6s)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 107: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 108: N-[(1R,6S)-2,2-difluoro-6-{[(3R,4R)-4-methoxy-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 109: N-[(1R,6S)-2,2-difluoro-6-{[4-methyl-1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 110: N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 111: N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 112: N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 113: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 114: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 115: N-[(1R,6S)-6-{(3S)-3-[cyclopropyl(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 116: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 117: N-[(1R,6R)-2,2-difluoro-6-{[4-(propan-2-yl)piperazine-1-yl]methyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 118: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 119: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide Example 120: N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 121: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 122: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxamide Example 123: N-[(1R,6S)-2,2-difluoro-6-{methyl[1-(propan-2-yl)piperidine-4-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 124: N-{(1R,6S)-2,2-difluoro-6-[4-(pyrroridine-1-yl)piperidine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 125: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 126: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide Example 127: N-{(1R,6S)-2,2-difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decane-8-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 128: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 129: N-{(1R,6S)-6-[4-(diethylamino)piperidine-1-yl]-2,2-difluorocyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 130: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 131: N-[(1R,6S)-2,2-difluoro-6-{4-methyl-4-[methyl(propan-2-yl)amino]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 132: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-carbonyl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 133: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidine-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 135: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 136: N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidine-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 137: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 138: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidine-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carboxamide Example 139: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 140: N-{(1R,6S)-2,2-difluoro-6-[4-(methyl{[1-(trifluoromethyl)cyclopropyl]methyl}amino)piperidine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 141: N-[(1R,6S)-6-{(1R,3R,5S)-3-[(cyclopropylmethyl)(methyl)amino]-8-azabicyclo[3.2.1]octan-8-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 142: N-[(1R,6S)-6-{(1R,3S,5S)-3-[(cyclopropylmethyl)(methyl)amino]-8-azabicyclo[3.2.1]octan-8-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 143: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 144: N-[(1R,6S)-6-{(4S)-4-[(cyclopropylmethyl)(methyl)amino]azepan-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 145: N-[(1R,6S)-6-{(4R)-4-[(cyclopropylmethyl)(methyl)amino]azepan-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 146: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-N,4-dimethylpiperidine-1-carboxamide Example 147: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 148: N-[(1R,6S)-2,2-difluoro-6-{3-[methyl(propan-2-yl)amino]azetidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 149: N-[(1R,6S)-6-{3-[(cyclopropylmethyl)(methyl)amino]azetidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 150: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidine-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 151: rac-4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methyl-N-{(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cycloheptyl}piperidine-1-carboxamide Example 152: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 153: (1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carbonyl)amino]cyclohexyl 4-(propan-2-yl)piperazine-1-carboxylate Example 154: N-[(1S,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]sulfanyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 155: N-{(1S,6S)-2,2-difluoro-6-[1-(propan-2-yl)piperidine-4-sulfonyl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide

[0242] The compound of Reference Example 124, which is a diastereomixture, or the intermediates leading to its synthesis, can be used to obtain a single enantiomer by, for example, optical resolution by chiral column chromatography or crystallization with an acid having an asymmetric center. Furthermore, the compound of Reference Example 124 can also be synthesized as a single enantiomer by using an optically active epoxide as a starting material. Therefore, by further preparative or asymmetric synthesis of Reference Example 124, it is possible to identify each diastereomer of the diastereomixture of the compound of Example 156.

[0243] Furthermore, the compound of Example 156, which is a diastereomixture, can be obtained as a single enantiomer by optical resolution by chiral column chromatography or crystallization with an acid having an asymmetric center. Therefore, each of the two diastereomers contained in Example 156 can be further isolated and identified.

[0244] The compound of Example 156 is a diastereomixture containing two different diastereomers. As described above, these can be selectively synthesized or separated by chiral chromatography. In other words, it can be said that the two diastereomers were substantially synthesized. [Table 6]

[0245] Examples 157-160: Using the compound from Reference Example 80 and the corresponding commercially available aldehyde or ketone, the compounds of Examples 157 to 160 shown in the table below were prepared in the same manner as in Example 17. [Table 7]

[0246] The compound names for Examples 157 to 160 are listed below. Example 157: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidine-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 158: N-[(1R,6S)-6-{4-[(cyclopropylmethyl)(methyl)amino]piperidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 159: N-[(1R,6S)-6-{4-[cyclobutyl(methyl)amino]piperidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide Example 160: N-[(1R,6S)-6-{4-[ethyl(methyl)amino]piperidine-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide

[0247] Example 161: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka] A mixture of Reference Example 90 (175 mg) and ethanol (1.3 mL) was mixed with palladium-carbon (6.4 mg) at room temperature and stirred under a hydrogen atmosphere. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite, concentrated under reduced pressure, and the residue was purified by HPLC (eluate: acetonitrile / water / TFA) to obtain the title compound (44.1 mg). 1H-NMR (CDCl3) δ: 1.03-1.31 (2H, m), 1.13 (6H, d, J = 6.0 Hz), 1.34 (3H, s), 1.38-1.88 (13H, m), 1.91-2.23 (3H, m), 2.27 (2H, d, J = 13.2 Hz), 2.33-2.42 (1H, m), 2.42-2.54 (1H, m), 2.95-3.21 (2H, m), 3.32-3.54 (1H, brs), 3.58-3.80 (2H, m), 3.91-4.08 (1H, m), 4.65 (1H, d, J = 9.2 Hz), 4.93 (1H, dddd, J = 63.6, 6.4, 6.4, 4.0 Hz).

[0248] Reference example 1: rac-(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0249] Process (i): Compound 1 (1.13 g) and dichloromethane (2 mL) were mixed with 1-isopropylpiperazine (1.14 g) at room temperature and stirred for 17 hours. After confirming that the starting materials had disappeared, diethyl ether was added to the reaction mixture, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 2 (1.82 g). LCMS: [M+H] + / Rt (min): 256 / 0.48

[0250] Step (ii): A mixture of compound 2 (1.14 g), acetic acid (2.04 mL), and ethanol (15 mL) was mixed with palladium-carbon (0.95 g) at room temperature and stirred under a hydrogen atmosphere for 18 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: chloroform) to obtain the title compound 3 (0.370 g). LCMS: [M+H] + / Rt (min): 226 / 0.31

[0251] Reference example 2: rac-4-(4-methylphenyl)-N-[(1S,2S)-2-(piperazin-1-yl)cyclohexyl]piperidine-1-carboxamide dihydrochloride [ka]

[0252] Process (i): Using compound 1 (1.17 g) and 1-Boc-piperazine (1.72 g), the title compound 4 (1.28 g) was obtained by following the same method as in step (i) of Reference Example 1.

[0253] Step (ii): To an ethanol solution (9 mL) of compound 4 (593 mg), palladium hydroxide (266 mg) was added at room temperature and the mixture was stirred under a hydrogen atmosphere. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound 5 (560 mg).

[0254] Step (iii): A mixed solution of compound 5 (370 mg), triethylamine (0.91 mL), and dichloromethane (5 mL) was mixed with 4-nitrophenyl chloroformate (316 mg) at 0°C and stirred for 2 hours. Then, 4-(4-methylphenyl)piperidine (297 mg) was added at 0°C and stirred at room temperature. After confirming the disappearance of the reaction intermediate, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 6 (435 mg).

[0255] Step (iv): A mixture of compound 6 (430 mg) and chloroform (3 mL) was mixed with hydrogen chloride / dioxane solution (4 M, 2.22 mL) at 0°C and stirred for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound 7 (310 mg). LCMS: [M+H] + / Rt (min): 385 / 0.71

[0256] Reference example 3: rac-(1R,2S)-2-(4-ethylpiperazine-1-yl)cyclohexane-1-amine [ka] Process (i): A mixture of compound 8 (312 mg) and acetic acid (5 mL) was mixed with platinum(IV) oxide (86 mg) and stirred at 70°C under a hydrogen atmosphere for 6 hours. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to obtain the crude product. The crude product was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 9 (9 mg). LCMS: [M+H] + / Rt (min): 212 / 0.15

[0257] Reference example 4: rac-(1R,2S,6S)-2-methoxy-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine trihydrochloride [ka]

[0258] Process (i): Using compound 10 (407 mg), the title compound 11 (424 mg) was obtained by following the same method as in step (i) of Reference Example 3. LCMS: [M+H] + / Rt (min): 146 / 0.15

[0259] Step (ii): A mixture of compound 11 (424 mg), triethylamine (1.22 mL), and acetonitrile (10 mL) was mixed with Boc2O (765 mg) at room temperature and stirred at room temperature. After confirming the completion of the reaction by LC-MS, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 12 (310 mg). LCMS: [M+H] + / Rt (min): 246 / 0.78

[0260] Step (iii): A mixture of compound 12 (141 mg), triethylamine (0.160 mL), and THF (3 mL) was cooled on ice, to which ethanesulfonyl chloride (0.160 mL) was added, and the mixture was heated to room temperature and stirred. After confirming the completion of the reaction by LC-MS, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 13 (180 mg). LCMS: [M+H] + / Rt (min): 338 / 0.86

[0261] Step (iv): A mixed solution of compound 13 (155 mg), 1-isopropylpiperazine (236 mg), and 1,4-dioxane (4 mL) was mixed with potassium carbonate (76 mg) at room temperature and heated and stirred at 150°C under microwave irradiation for 13 hours. Water was then added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 14 (17 mg). LCMS: [M+H] + / Rt (min): 356 / 0.81

[0262] Process (v): Compound 15 (16.8 mg) was obtained using compound 14 (16.3 mg) in the same manner as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 256 / 0.32

[0263] Reference example 5: rac-(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cyclopentan-1-amine [ka]

[0264] Process (i): A mixture of compound 16 (315 mg), triethylamine (0.289 mL), and THF (5 mL) was mixed with ethanesulfonyl chloride (0.15 mL) and stirred at room temperature for 15 hours. After confirming the disappearance of the starting materials, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: ethyl acetate / hexane) to obtain the title compound 17 (140 mg). LCMS: [M+H] + / Rt (min): 231 / 0.44

[0265] Step (ii): Sodium azide (77 mg) was added to a mixture of compound 17 (136 mg) and DMF (4 mL), and the mixture was stirred at 80°C for 3.5 hours. After confirming the disappearance of the starting materials, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 18 (137 mg). LCMS: [M+H] + / Rt (min): 238 / 0.42

[0266] Step (iii): Compound 18 (42.4 mg), hydrochloric acid / ethyl acetate solution (4.0 M, 0.711 mL), and ethanol (2.8 mL) were mixed with palladium carbon (202 mg), and the mixture was stirred under a hydrogen atmosphere for 8 hours. After confirming the completion of the reaction by LC-MS, methanol and aqueous sodium bicarbonate solution were added to the reaction mixture, filtered through Celite, and extracted with chloroform / methanol (6 / 1) solution. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 19 (98.7 mg). LCMS: [M+H] + / Rt (min): 212 / 0.15

[0267] Reference example 6: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-ol [ka] Process (i): A mixture of compound 20 (688 mg) and ethanol (20 mL) was mixed with 1-isopropylpiperazine (723 mg) at room temperature, and the mixture was heated to 80°C and stirred for 9 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 21 (830 mg). LCMS: [M+H] + / Rt (min): 263 / 0.35

[0268] Reference example 7: rac-(1R,2S)-3,3-difluoro-2-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0269] Process (i): Oxalyl chloride (0.075 mL) was added to a mixture of DMSO (0.081 mL) and dichloromethane (2 mL) at -78°C and the mixture was stirred for 20 minutes. Then, a solution of compound 21 (150 mL) in dichloromethane (2 mL) was added and the mixture was stirred again at -78°C for 30 minutes. Triethylamine (0.398 mL) was added, the temperature was raised to 0°C, and the mixture was stirred for 30 minutes. Sodium borohydride was then added and the mixture was stirred for 30 minutes. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 22 (27 mg). LCMS: [M+H] + / Rt (min): 263 / 0.38

[0270] Step (ii): A mixture of compound 22 (27 mg), triethylamine (0.029 mL), and THF (2 mL) was mixed with ethanesulfonyl chloride (0.015 mL) and stirred at room temperature. After confirming the disappearance of the starting materials, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 23 (23 mg). LCMS: [M+H] + / Rt (min): 354 / 0.65

[0271] Step (iii): Using compound 23 (23.4 mg), the title compound 24 (16.0 mg) was obtained by following the same method as in step (ii) of Reference Example 5. LCMS: [M+H] + / Rt (min): 288 / 0.60

[0272] Step (iv): Triphenylphosphine (25.6 mg) was added at room temperature to a mixture of compound 24 (14 mg), THF (1 mL), and water (1 mL), and the mixture was heated to 50°C and stirred for 4.5 hours. After cooling to room temperature, hydrochloric acid aqueous solution was added and washed with ethyl acetate, and then sodium bicarbonate aqueous solution was added to the aqueous layer and extracted with chloroform / methanol (3 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 25 (7.8 mg). LCMS: [M+H] + / Rt (min): 262 / 0.31

[0273] Reference example 8: 4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine monohydrochloride [ka]

[0274] Process (i): To a solution of compound 26 (50.0 g) in ethanol (446 mL), 132 mL of 50% hydroxylamine aqueous solution was added and the mixture was stirred at 70°C for 8 hours. After cooling to room temperature, water (892 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The resulting white crystals were filtered off and then resuspended in water (344 mL) and stirred at room temperature for 30 minutes. The resulting white solid was filtered off and dried to obtain the title compound 27 (52.3 g). LCMS: [M+H] + / Rt (min): 258 / 0.52 (Method C)

[0275] Step (ii): Under ice bath conditions, triethylamine (142 mL) was slowly added dropwise to a mixture of compound 27 (52.3 g), cyclopropanecarboxylic acid (18.4 g), HATU (85 g), and THF (406 mL), and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (406 mL) was added to the reaction mixture, and the mixture was washed with water (406 mL) and saturated brine (406 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 28 (59.1 g). LCMS: [M+H] + / Rt (min): 326 / 0.77 (Method C)

[0276] Step (iii): A mixture of compound 28 (59.1 g), DBU (54.2 mL), and toluene (727 mL) was heated under reflux and stirred for 1 hour. After cooling to room temperature, the mixture was washed with water (727 mL), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 29 (54.5 g). LCMS: [M+H] + / Rt (min): 308 / 1.11

[0277] Step (iv): Using compound 29 (54.5 g), the title compound 30 (35.3 g) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 208 / 0.30 (Method C)

[0278] Reference example 9~12' In Reference Example 8, the compounds shown in Reference Examples 9 to 12' in the table below were synthesized using the method described in Reference Example 8, with the corresponding starting compound used instead of the cyclopropanecarboxylic acid in step (ii). [Table 8]

[0279] Reference Example 9: 4-(5-ethyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine monohydrochloride Reference Example 10: 4-[5-(difluoromethyl)-1,2,4-oxadiazole-3-yl]-4-methylpiperidine monohydrochloride Reference Example 11: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine monohydrochloride Reference Example 12: 4-Methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine monohydrochloride Reference Example 12': 4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine monohydrochloride

[0280] Reference example 13: rac-tert-butyl 4-(6-{[4-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine-1-carbonyl]amino}cyclohexa-1-en-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0281] Process (i): A mixture of compound 35 (192 mg), cerium(III) chloride heptahydrate (309 mg), and methanol (3 mL) was cooled on ice, and sodium borohydride (51.4 mg) was added. The mixture was stirred at the same temperature for 3 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with chloroform / methanol (6 / 1). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 36 (120 mg). LCMS: [M+H] + / Rt (min): 280 / 0.97

[0282] Step (ii): A mixture of compound 36 (115 mg), triethylamine (0.143 mL), and THF (2 mL) was mixed with ethanesulfonyl chloride (0.058 mL) under ice cooling and stirred for 30 minutes. Then, sodium azide (107 mg) was added to the reaction mixture, and after raising the temperature to room temperature, the mixture was stirred. After confirming the disappearance of the reaction intermediate, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 37 (80 mg). LCMS: [M+H] + / Rt (min): 305 / 1.25

[0283] Process (iii) Using compound 37 (73 mg), the title compound 38 (35 mg) was obtained by following the same method as in step (iv) of Reference Example 7. LCMS: [M+H] + / Rt (min): 279 / 0.74

[0284] Process (iv) Using compound 38 (14.4 mg), title compound 39 (14.0 mg) was obtained by following the same method as in step (iii) of Reference Example 2. LCMS: [M+H] + / Rt (min): 512 / 1.14

[0285] Reference example 14: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine trihydrochloride [ka]

[0286] Process (i): Using compound 40 (1.69 g), the title compound 41 (1.59 g) was obtained by following the same method as in step (ii) of Reference Example 4. LCMS: [M+H] + / Rt (min): 252 / 0.73

[0287] Step (ii): Potassium tert-butoxide (1.01 g) was added to a mixture of compound 41 (1.5 g) and THF (30 mL) under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. Then, tosyl chloride (1.37 g) was added under ice cooling, and the mixture was stirred for a further 2.5 hours. After that, water was added under ice cooling to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (30 mL). Tosyl chloride (1.37 g) was added under ice cooling, and the mixture was heated to 100°C and stirred for 30 minutes. The reaction mixture was cooled to room temperature, aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform / ethanol (3 / 1). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 42 (1.09 g). LCMS: [M+H] + / Rt (min): 234 / 1.01

[0288] Step (iii): A mixture of compound 42 (1.09 g), 1-isopropylpiperazine (0.899 g), and ethanol (10 mL) was heated and stirred at 120°C under microwave irradiation for 8 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 43 (1.32 g). LCMS: [M+H] + / Rt (min): 362 / 0.74

[0289] Step (iv): Using compound 43 (1.31 g), the title compound 44 (1.40 g) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 262 / 0.19

[0290] Reference examples 15~17 The compounds of Reference Examples 15 to 17 shown in the table below were synthesized in accordance with the method described in Reference Example 14, using the optically active form of compound 40 (raw material A) instead of compound 40 in step (i) of Reference Example 14, and using the corresponding raw material compound (raw material B) instead of 1-isopropylpiperazine in step (iii). [Table 9]

[0291] Reference Example 15: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine trihydrochloride Reference example 15': (1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine Reference Example 16: (1R,6S)-2,2-difluoro-6-[6-(propan-2-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclohexane-1-amine Reference Example 17: (1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl]cyclohexane-1-amine

[0292] Reference example 18: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0293] Process (i): A mixture of compound 48 (5.94 g), sodium bicarbonate (13.2 g), and THF (131 mL) was mixed at room temperature with 2-nitrobenzenesulfonyl chloride (10.5 g) added and stirred at the same temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in THF (131 mL), and triethylamine (11 mL) and methanesulfonyl chloride (3.67 mL) were added under ice cooling and stirred. After confirming that the starting materials had disappeared, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (393 mL), potassium carbonate (16.3 mg) was added, and the mixture was heated and stirred at 80°C for 1 hour. Subsequently, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 49 (9.25 g). LCMS: [M+H] + / Rt (min): 319 / 0.94

[0294] Step (ii): Compound 49 (7.1 g), 1-isopropylpiperazine (3.56 mL), and toluene (22.3 mL) were heated and stirred at 110°C for 1 hour. After confirming the disappearance of the starting material, the mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 50 (9.79 g). LCMS: [M+H] + / Rt (min): 447 / 0.68

[0295] Step (iii): A mixture of benzenethiol (0.530 mL) and toluene (11.2 mL) was mixed with sodium hydride (55%, 0.215 g) under ice cooling, and the mixture was stirred for 10 minutes while gradually increasing the temperature to room temperature. Then, a toluene solution (9 mL) of compound 50 (1 g) was added and the mixture was heated and stirred at 60°C. After confirming the disappearance of the starting materials, the reaction mixture was cooled to 0°C, a 40% sodium hydroxide aqueous solution was added, and extraction was performed with toluene. 5M hydrochloric acid was added to the organic layer under ice cooling, and extraction was performed in the aqueous layer. Further extraction was performed in the resulting aqueous layer by adding a 40% sodium hydroxide aqueous solution and extracting again with toluene. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 51 (0.47 g). LCMS: [M+H] + / Rt (min): 262 / 0.17

[0296] Reference example 19: 2-(4-methylpiperidine-4-yl)-4,5,6,7-tetrahydro-1,3-benzoxazole [ka] Process (i): A mixture of compound 52 (120 mg), 2-chlorocyclohexanone (68.9 mg), and DMF (1.5 mL) was heated and stirred at 130°C under microwave irradiation for 11 hours. Then, hydrogen chloride / 1,4-dioxane solution (0.25 mL) was added to the reaction mixture and heated and stirred at 130°C under microwave irradiation for 6 hours. After concentrating the reaction mixture under reduced pressure, it was dissolved in ethanol, and 15% sodium hydroxide aqueous solution (2 mL) was added and heated and stirred at 150°C under microwave irradiation for 3 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 53 (14 mg). LCMS: [M+H] + / Rt (min): 221 / 0.57

[0297] Reference example 20: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine monohydrochloride [ka]

[0298] Process (i): A mixture of compound 54 (900 mg), sodium acetate (650 mg), and methanol (5 mL) was mixed with hydroxylamine hydrochloride (550 mg) and stirred at room temperature for 24 hours. The reaction solution was cooled to 0°C, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound 55 (1.23 g).

[0299] Step (ii): A mixture of compound 55 (416 mg) and DMF (4 mL) was mixed with N-chlorosucciimide (252 mg) and stirred for 3 hours. The reaction solution was cooled to 0°C, water (6 mL) was added, and the precipitated solid was filtered and dried to obtain the title compound 56 (326 mg).

[0300] Step (iii): Compound 56 (326 mg) and sodium bicarbonate (198 mg) were added to a mixture of ethinylcyclopropane (117 mg) and toluene (5 mL), and the mixture was stirred at room temperature. After confirming that the starting materials had disappeared, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 57 (348 mg). LCMS: [M+H] + / Rt (min): 307 / 1.13

[0301] Step (iv): Using compound 57 (337 mg), the title compound 58 (307 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 207 / 0.49

[0302] Reference example 21 2-(4-methylpiperidine-4-yl)-1,3-benzoxazole [ka]

[0303] Process (i): To a THF solution (30 mL) of compound 59 (1.46 g), isobutyl chloroformate (819 mg) and diisopropylethylamine (3.88 g) were added under ice cooling and stirred for 1 hour. Then, 2-aminophenol (655 mg) was added under ice cooling and heated and stirred at 70°C for 6 hours. The reaction mixture was purified directly by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 60 (710 mg). LCMS: [M+H] + / Rt (min): 335 / 2.28 (Method B)

[0304] Step (ii): A mixture of compound 60 (204 mg) and acetic acid (1.10 mL) was heated and stirred at 90°C for 2 hours, and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (2 mL), trifluoromethanesulfonic acid (2.1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate and aqueous sodium bicarbonate solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: ethyl acetate / hexane) to obtain the title compound 61 (99 mg). LCMS: [M+H] + / Rt (min): 217 / 1.36 (Method B)

[0305] Reference example 22 4-Cyclopentyl-4-methylpiperidine monohydrochloride [ka]

[0306] Process (i): Lithium diisopropylamide (2M, 5.18mL) was added to a mixture of compound 62 (700mg) and THF (14mL) at -78°C, and the mixture was stirred at the same temperature for 2 hours. Then, bromocyclopentane (1.23mL) and potassium iodide (478mg) were added to the reaction mixture, and the temperature was raised to room temperature and stirred overnight. After that, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 63 (468mg). LCMS: [M+H] + / Rt (min): 312 / 1.26

[0307] Step (ii): A mixture of lithium aluminum hydride (104 mg) and THF (3 mL) was mixed with a mixture of compound 63 (371 mg) and THF (6 mL) under ice cooling and stirred for 4 hours. After confirming the disappearance of the starting materials, water (0.104 mL), 15% sodium hydroxide aqueous solution (0.104 mL), and water (0.312 mL) were sequentially added to the reaction mixture at 0°C and stirred. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 64 (320 mg). LCMS: [M+H] + / Rt (min): 284 / 1.06

[0308] Step (iii): A mixture of compound 64 (314 mg), triethylamine (0.309 mL), and THF (5 mL) was mixed with methaneulfonyl chloride (0.104 mL) and stirred at room temperature. After confirming the disappearance of the starting materials, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: ethyl acetate / hexane) to obtain the title compound 65 (290 mg). LCMS: [M+H] + / Rt (min): 362 / 1.15

[0309] Step (iv): A mixture of compound 65 (278 mg) and THF (3 mL) was mixed with lithium triethylborohydride (0.99 M, 1.55 mL) and stirred at room temperature. The reaction mixture was then heated to 70 °C, and after confirming the disappearance of the starting materials, it was cooled to 0 °C and aqueous ammonium chloride solution was added. The mixture was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 66 (100 mg). LCMS: [M+H] + / Rt (min): 268 / 1.42

[0310] Process (v): Using compound 66 (90 mg), title compound 67 (58.5 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 168 / 0.62

[0311] Reference example 23: 4-(4,4-difluorocyclohexyl)-4-methylpiperidine monohydrochloride In Reference Example 22, instead of bromocyclopentane in step (i), 1,1-difluoro-4-iodocyclohexane was used, and the compound of Reference Example 23 shown in the table below was synthesized according to the method described in Reference Example 22. [Table 10]

[0312] Reference example 24: 4-(5-cyclopropyl-1,3,4-thiadiazole-2-yl)-4-methylpiperidine monohydrochloride [ka]

[0313] Process (i): Compound 59 (399 mg), cyclopropanecarbohydrazide hydrochloride (269 mg), and DMF (5 mL) were mixed with HATU (686 mg) and diisopropylethylamine (1.15 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 69 (520 mg). LCMS: [M+H] + / Rt (min): 326 / 0.74

[0314] Step (ii): A mixture of compound 69 (255 mg) and toluene (6 mL) was mixed with Lawson's reagent (349 mg) and heated and stirred under reflux for 1 hour. After cooling the reaction mixture to 0°C, aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluate: hexane / ethyl acetate), followed by amino silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 70 (102 mg). LCMS: [M+H] + / Rt (min): 324 / 1.08

[0315] Step (iii): Using compound 70 (92 mg), the title compound 71 (78 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 224 / 0.45

[0316] Reference example 25: 4-(5-cyclopropyl-1,3-thiazole-2-yl)-4-methylpiperidine monohydrochloride [ka]

[0317] Process (i): Using compound 59 (718 mg) and 2-amino-1-cyclopropylethane-1-one hydrochloride (400 mg), the title compound 72 (796 mg) was obtained by following the same method as in step (i) of Reference Example 24. LCMS: [M+H] + / Rt (min): 325 / 0.83

[0318] Step (ii): A mixture of compound 72 (127 mg), pyridine (0.063 mL), and toluene (3 mL) was mixed with Lawson's reagent (205 mg) and heated and stirred under reflux for 14 hours. After the reaction mixture cooled to room temperature, aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 73 (76.3 mg). LCMS: [M+H] + / Rt (min): 323 / 1.43

[0319] Step (iii): Using compound 73 (77 mg), the title compound 74 (66.5 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 223 / 0.67

[0320] Reference example 26: 4-(2-cyclopropyl-1,3-thiazole-4-yl)-4-methylpiperidine monohydrochloride [ka]

[0321] Process (i): Compound 75 (532 mg) and a methanol solution (6 mL) of cyclopropanecarbothioamide (168 mg) were stirred under reflux for 2.5 hours. After the resulting mixture cooled to room temperature, saturated sodium bicarbonate aqueous solution was added and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 76 (119 mg).

[0322] Step (ii): Using compound 76 (119 mg), the title compound 77 (137 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 223 / 0.572

[0323] Reference example 27: 4-(1-cyclopropyl-1H-1,2,4-triazole-3-yl)-4-methylpiperidine dihydrochloride [ka]

[0324] Process (i): Using compound 59 (611 mg) and cyclopropylhydrazine hydrochloride (300 mg), the title compound 78 (648 mg) was obtained by following the same method as in step (i) of Reference Example 24. LCMS: [M+H] + / Rt (min): 298 / 0.80

[0325] Step (ii): A mixture of compound 78 (374 mg), ammonium formate (1.43 g), and trimethyl orthoformate (2.78 mL) was heated to 100°C and stirred. After the reaction was complete, the reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 79 (163 mg). LCMS: [M+H] + / Rt (min): 307 / 0.89

[0326] Step (iii): Using compound 79 (144 mg), the title compound 80 (142 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 207 / 0.39

[0327] Reference example 28: 4-(5-cyclopropyl-1,2,4-thiadiazole-3-yl)-4-methylpiperidine [ka]

[0328] Process (i): Thiocarbonylimidazole (0.864 mg) was added to a THF solution (1.04 g) of compound 27 (15 mL) under ice cooling and stirred at room temperature. After the starting material was consumed, the reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in THF (15 mL), and boron trifluoride diethyl ether complex (1.52 mL) was added at 0°C. The mixture was then heated to room temperature while stirring. After the reaction was complete, aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate). To a THF solution (15 mL) of the purified compound, a hydrogen chloride / dioxane solution (4 M, 5.05 mL) was added at 0°C, and the mixture was heated to room temperature and stirred. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in THF (15 mL). Then, triethylamine (3.38 mL) and 2-nitrobenzenesulfonyl chloride (0.985 g) were added, and the mixture was stirred at room temperature. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 81 (627 mg). LCMS: [M+H] + / Rt (min): 385 / 0.93

[0329] Step (ii): Compound 81 (590 mg), pyridine (0.248 mL), and toluene (7 mL) were mixed with phosphoryl chloride (0.572 mL) and heated under reflux. After the reaction was complete, the reaction mixture was added to an aqueous sodium bicarbonate solution cooled to 0°C, filtered, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 82 (432 mg). LCMS: [M+H] + / Rt (min): 403 / 1.21

[0330] Step (iii): Compound 82 (210 mg), cyclopropylzinc(II) bromide (0.5 M, 3.13 mL), and THF (2 mL) were mixed with tetrakis(triphenylphosphine)palladium(0) (30.1 mg) and stirred at 60°C for 1.5 hours. After the reaction was complete, aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 83 (84 mg). LCMS: [M+H] + / Rt (min): 409 / 1.24

[0331] Step (iv): Compound 83 (71.4 mg), 1-dodecanethiol (0.251 mL), and acetonitrile (3 mL) were mixed with potassium carbonate (145 mg) and stirred at 80°C. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform / methanol (6 / 1). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate → chloroform / methanol) to obtain the title compound 84 (38 mg). LCMS: [M+H] + / Rt (min): 224 / 0.52

[0332] Reference example 29: 4-(5-methoxy-1,2,4-thiadiazole-3-yl)-4-methylpiperidine [ka]

[0333] Process (i): A methanol solution (2 mL) of compound 82 (119 mg) was mixed with sodium methoxy (28%, 285 mg) and stirred at room temperature. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The mixture was then concentrated under reduced pressure to obtain the title compound 85 (97.1 mg). LCMS: [M+H] + / Rt (min): 399 / 1.18

[0334] Step (ii): Using compound 85 (91.6 mg), the title compound 86 (14.9 mg) was obtained by following the same method as in step (iv) of Reference Example 28. LCMS: [M+H] + / Rt (min): 214 / 0.48

[0335] Reference example 30: 4-[5-(cyclopropyloxy)-1,2,4-thiadiazole-3-yl]-4-methylpiperidine In Reference Example 29, instead of sodium methoxy in step (i), cyclopropyl alcohol and sodium hydride were used to synthesize the compound of Reference Example 30 shown in the table below, following the method described in Reference Example 29. [Table 11]

[0336] Reference example 31: 2-[(4-methylpiperidine-4-yl)oxy]pyridine monohydrochloride [ka]

[0337] Process (i): To a 2 mL solution of compound 88 (183 mg) in DMF, sodium hydride (55%, 48.2 mg) was added under ice cooling and the mixture was stirred for 20 minutes. Then, 2-fluoropyridine (0.109 mL) was added and the mixture was stirred at room temperature. After the reaction was complete, the mixture was cooled to 0°C, water was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 89 (18 mg). LCMS: [M+H] + / Rt (min): 293 / 1.29

[0338] Step (ii): Using compound 89 (14.7 mg), the title compound 90 (13.2 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 193 / 0.48

[0339] Reference example 32: 4-(2-fluoro-4-methylphenyl)-4-methylpiperidine [ka]

[0340] Process (i): Compound 91 (211 mg), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (274 mg), potassium carbonate (386 mg), 1,2-dimethoxymethane (4 mL), and water (1 mL) were mixed with dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (45.6 mg) at room temperature, and then heated under reflux. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 92 (32 mg). LCMS: [M+H] + / Rt (min): 206 / 0.51

[0341] Step (ii): To a THF solution (3 mL) of compound 92 (137 mg), n-butyllithium solution (1.57 M, 0.68 mL) was added at -18°C, and the reaction mixture was further cooled to -50°C. Dimethyl sulfuric acid was slowly added dropwise to the reaction mixture and stirred at -50°C for 1 hour. Aqueous ammonia solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was obtained. The resulting residue was dissolved in methanol (3 mL), and sodium borohydride (80 mg) was added under ice cooling. After the reaction was complete, aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 93 (32 mg). LCMS: [M+H] + / Rt (min): 222 / 0.63

[0342] Step (iii): To a 3 mL solution of compound 93 (30.4 mg) in 1,2-dichloroethane, 1-chloroethyl chloroformate (0.045 mL) was added at room temperature, and the mixture was heated under reflux. The reaction mixture was concentrated under reduced pressure, chloroform and aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature before extraction with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 94 (22 mg). LCMS: [M+H] + / Rt (min): 208 / 0.66

[0343] Reference example 33: 4-[4-(difluoromethyl)phenyl]-4-methylpiperidine monohydrochloride [ka]

[0344] Process (i): To a THF solution (6 mL) of compound 95 (490 mg), n-butyllithium solution (1.57 M, 1.15 mL) was added at -78°C and the mixture was stirred for 30 minutes. Then, DMF (0.535 mL) was added to the reaction mixture and the temperature was raised to 0°C. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 96 (256 mg). LCMS: [M+H] + / Rt (min): 304 / 1.10

[0345] Step (ii): Deoxo-Fluor(R) (0.285 mL) was added to a 2 mL dichloromethane solution of compound 96 (157 mg) under ice cooling, and the mixture was then stirred at room temperature. After the reaction was complete, the reaction mixture was added to an ice-cooled aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 97 (110 mg). LCMS: [M+H] + / Rt (min): 326 / 1.20

[0346] Step (iii): Using compound 97 (104.8 mg), the title compound 98 (84.5 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 226 / 0.60

[0347] Reference example 34: 5-Methyl-2-(4-methylpiperidine-4-yl)benzonitrile [ka]

[0348] Process (i): A mixture of compound 99 (267 mg) and m-cresol (1.20 mL) was mixed with trifluoromethanesulfonic acid (1.01 mL) and stirred at room temperature. After the reaction was complete, the reaction mixture was added to an aqueous sodium bicarbonate solution cooled to 0°C and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 100 (388 mg). LCMS: [M+H] + / Rt (min): 278 / 1.01

[0349] Step (ii): A mixture of compound 100 (113 mg), potassium carbonate (169 mg), and THF (4 mL) was mixed with N-phenylbis(trifluoromethanesulfonimide) (175 mg) and heated and stirred at 120°C under microwave irradiation. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 101 (138 mg). LCMS: [M+H] + / Rt (min): 410 / 1.26

[0350] Step (iii): Using compound 101 (130 mg) and zinc cyanide (55.8 mg), the title compound 102 (40.8 mg) was obtained by following the same method as in step (iii) of Reference Example 28. LCMS: [M+H] + / Rt (min): 287 / 1.07

[0351] Step (iv): Potassium hydroxide (78 mg) was added to a 2-propanol solution (3 ml) of compound 102 (40 mg) at room temperature, and the mixture was stirred at 110°C under microwave irradiation. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform / ethanol (4 / 1). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 103 (20.6 mg). LCMS: [M+H] + / Rt (min): 215 / 0.57

[0352] Reference example 35: (3S,4S)-4-fluoro-1-(propan-2-yl)pyrroridine-3-ol [ka] Process (i): To a chloroform solution (2 mL) of compound 104 (500 mg), hydrogen chloride / 1,4-dioxane (4 M, 6 mL) was added at 0°C, and the mixture was heated to room temperature and stirred. After confirming the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in chloroform (2 mL), and acetone (1.79 mL), sodium acetate (200 mg), and sodium borohydride triacetate (1.03 g) were added at 0°C, and the mixture was heated to room temperature and stirred. After the reaction was complete, an aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform / methanol (5 / 1). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 105 (348 mg). LCMS: [M+H] + / Rt (min): 148 / 0.17

[0353] Reference example 36: (3R)-4,4-difluoro-1-(propan-2-yl)pyrroridine-3-ol Instead of compound 104 in step (i) of Reference Example 35, the compound of Reference Example 36 shown in the table below was synthesized using the corresponding starting compound, following the method described in Reference Example 35. [Table 12]

[0354] Reference example 37: (1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine [ka]

[0355] Process (i): Compound 49 (1.5 g), (S)-1-isopropylpyrrolidine-3-ol (0.792 mg), and NMP (1 mL) were heated and stirred at 150°C. After confirming the disappearance of the starting materials, the reaction solution was purified directly by silica gel column chromatography (eluate: chloroform / methanol / triethylamine), followed by amino silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 106 (1.03 g). LCMS: [M+H] + / Rt (min): 448 / 0.78

[0356] Step (ii): Using compound 106 (100 mg), the title compound 107 (43 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 263 / 0.22

[0357] Reference examples 38~40: Instead of (S)-1-isopropylpyrrolidine-3-ol in step (i) of Reference Example 37, the compound of Reference Example 38 shown in the table below was synthesized using the corresponding starting compound in accordance with the method described in Reference Example 37. [Table 13]

[0358] Reference Example 38: (1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 39: (1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 40: (1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexane-1-amine

[0359] Reference example 41: 3-Fluoro-5-methyl-2-(piperidine-4-yl)pyridine [ka]

[0360] Process (i): Compound 109 (90.5 mg) was obtained using compound 108 (72.4 mg) and 1-carbobenzoxy-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, following the same procedure as in step (i) of Reference Example 32. LCMS: [M+H] + / Rt (min): 327 / 1.04 (Method C)

[0361] Step (ii): Palladium-carbon (88.0 mg) was added to an ethyl acetate solution (1.5 mL) of compound 109 (88.0 mg), and the mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound 110 (22.2 mg). LCMS: [M+H] + / Rt (min): 195 / 0.35 (Method C)

[0362] Reference example 42: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-ol [ka]

[0363] Process (i): N-benzyl-N,N-bis(2-chloroethyl)amine hydrochloride (586 mg) was added to an ethanol solution (10 mL) of compound 111 (300 mg) and sodium bicarbonate (634 mg), and the mixture was heated and stirred at 120°C under microwave irradiation. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 112 (398 mg). LCMS: [M+H] + / Rt (min): 311 / 0.46

[0364] Step (ii): Using compound 112 (389 mg), title compound 113 (289 mg) was obtained by following the same method as in step (ii) of Reference Example 2. LCMS: [M+H] + / Rt (min): 221 / 0.16

[0365] Step (iii): A mixture of compound 113 (389 mg), acetone (1.73 mL), and dichloromethane (6 mL) was mixed with sodium borohydride triacetate (1.5 g) at 0°C, and the mixture was heated to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 114 (255 mg). LCMS: [M+H] + / Rt (min): 263 / 0.36

[0366] Reference example 43: tert-butyl [(1S,4R)-3-{[4-(propan-2-yl)piperazine-1-yl]methyl}bicyclo[2.2.1]heptan-2-yl]carbamate [ka] Process (i): Compound 115 (239 mg), 1-isopropylaziridine (128 mg), acetic acid (0.086 mL), and THF (2.5 mL) were mixed with sodium borohydride triacetate (635 mg) at room temperature and stirred at the same temperature for 3 hours. Sodium bicarbonate aqueous solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 116 (310 mg). LCMS: [M+H] + / Rt (min): 352 / 1.35 (Method B)

[0367] Reference example 44: rac-2-[6-(propan-2-yl)pyridine-3-yl]cyclohexa-2-en-1-amine [ka]

[0368] Process (i): Compound 117 (350 mg), 6-isopropylpyridine-3-ylboronic acid (273 mg), cesium carbonate (1.28 g), 1,4-dioxane (5 mL), and water (1 mL) were mixed with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (129 mg) at room temperature and stirred at 90°C for 3 hours. Water was added to the reaction mixture at 0°C and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 118 (168 mg).

[0369] Step (ii)~Step (iv): Using compound 118 (68.2 mg), the title compound 121 (29.7 mg) was obtained by following the same method as in steps (i) to (iii) of Reference Example 13. LCMS: [M+H] + / Rt (min): 217 / 0.39

[0370] Reference example 45: N-methyl-N-[(1-methylcyclopropyl)methyl]piperidine-4-amine [ka]

[0371] Process (i): 584 mg of tert-butyl 4-(methylamino)piperidine-1-carboxylate, 300 mg of 1-methylcyclopropane-1-carboxylic acid, and 0.76 ml of triethylamine were mixed in a DMF solution (4 ml). HATU (1.24 g) was added to the mixture and the reaction was stirred at room temperature. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 123 (926 mg).

[0372] Step (ii): To a chloroform solution (4.5 ml) of compound 123 (806 mg), hydrochloric acid (CPME solution, 5 M, 2.7 ml) was added at 0°C, and the reaction mixture was heated to room temperature and stirred. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 124 (477 mg).

[0373] Step (iii): Using compound 124 (413 mg), title compound 125 (203 mg) was obtained by following the same method as in step (ii) of Reference Example 22. LCMS: [M+H] + / Rt (min): 183 / 0.15

[0374] Reference examples 46~47 The compounds of Reference Examples 46-47 shown in the table below were synthesized using the method described in Reference Example 45, with the corresponding starting compound used instead of 1-methylcyclopropane-1-carboxylic acid in step (i) of Reference Example 45. [Table 14]

[0375] Reference Example 46: N-[(1-fluorocyclopropyl)methyl]-N-methylpiperidine-4-amine Reference Example 47: N-methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidine-4-amine

[0376] Reference Example 48: (3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidine-3-ol [ka]

[0377] Process (i): Using (S)-3-pyrrolidinol (103 mg) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (200 mg), the title compound 127 (196 mg) was obtained by following the same method as in step (i) of Reference Example 45.

[0378] Step (ii): Using compound 127 (184 mg), title compound 128 (87.2 mg) was obtained by following the same method as in step (iii) of Reference Example 45. LCMS: [M+H] + / Rt (min): 210 / 0.30

[0379] Reference example 49: (1R,3s,5S)-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octane-3-amine [ka]

[0380] Process (i): Using compound 129 (146 mg) and cyclopropanecarbaldehyde (170 mg), the title compound 130 (178 mg) was obtained by following the same method as in step (iii) of Reference Example 42.

[0381] Step (ii): Using compound 130 (166 mg), title compound 131 (106 mg) was obtained by following the same method as in step (ii) of Reference Example 45. LCMS: [M+H] + / Rt (min): 195 / 0.14 Reference examples 50~52 Using the corresponding starting compound instead of compound 129 in step (i) of Reference Example 49, the compounds of Reference Examples 50 to 52 shown in the table below were synthesized in accordance with the method described in Reference Example 49. [Table 15]

[0382] Reference Example 50: (1R,3r,5S)-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octane-3-amine Reference Example 51: (4S)-N-(cyclopropylmethyl)-N-methylazepan-4-amine Reference Example 52: (4R)-N-(cyclopropylmethyl)-N-methylazepan-4-amine

[0383] Reference example 53: (1R,3s,5S)-8-(propane-2-yl)-8-azabicyclo[3.2.1]octane-3-ol [ka]

[0384] Process (i): Using compound 132 (3g), the title compound was obtained by following the same method as in step (iv) of Reference Example 2. Step (ii): Using compound 133 and acetone (1.3 g), the title compound 134 (1.98 g) was obtained by following the same method as in step (iii) of Reference Example 42. LCMS: [M+H] + / Rt (min): 170 / 0.15

[0385] Reference examples 54~57 Using the corresponding starting compound instead of compound 132 in step (i) of Reference Example 53, the compounds of Reference Examples 54 to 57 shown in the table below were synthesized in accordance with the method described in Reference Example 53. [Table 16]

[0386] Reference example 54: (1R,5S,8r)-3-(propane-2-yl)-3-azabicyclo[3.2.1]octane-8-ol Reference example 55: (1R,5S,8s)-3-(propane-2-yl)-3-azabicyclo[3.2.1]octane-8-ol Reference example 56: (1R,3r,5S)-8-(propane-2-yl)-8-azabicyclo[3.2.1]octane-3-ol Reference example 57: (1R,5S,6s)-3-(propane-2-yl)-3-azabicyclo[3.1.0]hexane-6-ol

[0387] Reference examples 58~79 The compounds of Reference Examples 58 to 79 shown in the table below were synthesized using the method described in Reference Example 18, with the corresponding starting compound used instead of 1-isopropylpiperazine in step (ii) of Reference Example 18. [Table 17] TIFF2022183120000233.tif230157 TIFF2022183120000234.tif227157 TIFF2022183120000235.tif221157 TIFF2022183120000236.tif92157

[0388] Reference Example 58: (1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine Reference Example 59: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidine-3-amine Reference Example 60: (1R,6S)-2,2-difluoro-6-{4-[(propan-2-yl)oxy]piperidine-1-yl}cyclohexane-1-amine Reference Example 61: (1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine Reference Example 62: (1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine Reference example 63: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[1-(propan-2-yl)piperidine-4-yl]cyclohexane-1,2-diamine Reference Example 64: (1R,6S)-2,2-difluoro-6-[4-(pyrrolidine-1-yl)piperidine-1-yl]cyclohexane-1-amine Reference Example 65: (1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl]cyclohexane-1-amine Reference example 66: (1R,6S)-2,2-difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decane-8-yl]cyclohexane-1-amine Reference example 67: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,N-diethylpiperidine-4-amine Reference Example 68: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,4-dimethyl-N-(propan-2-yl)piperidine-4-amine Reference Example 69: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-[(1-methylcyclopropyl)methyl]piperidine-4-amine Reference example 70: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-[(1-fluorocyclopropyl)methyl]-N-methylpiperidine-4-amine Reference Example 71: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidine-4-amine Reference Example 72: (1R,3R,5S)-8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octane-3-amine Reference Example 73: (1R,3S,5S)-8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octane-3-amine Reference Example 74: (4S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazepan-4-amine Reference Example 75: (4R)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazepan-4-amine Reference example 76: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)azetidine-3-amine Reference Example 77: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazetidine-3-amine Reference Example 78: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexane-1-amine Reference example 79: tert-butyl {1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]piperidine-4-yl}methylcarbamate

[0389] Reference example 80: N-{(1R,6S)-2,2-difluoro-6-[4-(methylamino)piperidine-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carboxamide [ka]

[0390] Process (i): Using the compound from Reference Example 79 (2.61 g), the title compound 136 (2.92 g) was obtained by following the same method as in Example 19.

[0391] Step (ii): To a toluene solution (24 ml) of compound 136 (2.92 g), TFA (5.56 g) was added and the mixture was stirred at room temperature for 3.5 hours. After concentrating the reaction mixture, the residue was dissolved in water, sodium bicarbonate aqueous solution was added, and the mixture was extracted with chloroform. The organic layer was then concentrated to obtain the title compound 137 (2.38 g). LCMS: [M+H] + / Rt (min):499 / 0.49 (Method C)

[0392] Reference example 81: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]cyclohexane-1,2-diamine [ka]

[0393] Process (i): Compound 138 (2.61 g) was synthesized using tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate instead of 1-isopropylpiperazine in step (ii) of Reference Example 18, following the method described in step (ii) of Reference Example 18.

[0394] Step (ii): Using compound 138 (2.61 g), title compound 139 (2.59 g) was obtained by following the same method as in step (iv) of Reference Example 2.

[0395] Step (iii): Using compound 139 (2.59 g) and acetone (3.87 ml), the title compound 140 (1.97 g) was obtained by following the same procedure as in step (iii) of Reference Example 42.

[0396] Step (iv): Using compound 140 (1.97 g), the title compound 141 (925 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 276 / 0.15

[0397] Reference examples 82~88 The compounds of Reference Examples 82 to 88 shown in the table below were synthesized in accordance with the method described in Reference Example 81, using the corresponding starting material (starting material A) instead of tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate in step (i) of Reference Example 81, and using the corresponding starting material compound (starting material B) instead of acetone in step (iii). [Table 18] TIFF2022183120000240.tif134170

[0398] Reference Example 82: (3R)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidine-3-amine Reference Example 83: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[(3R)-1-(propan-2-yl)pyrrolidine-3-yl]cyclohexane-1,2-diamine Reference example 84: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)piperidine-4-amine Reference Example 85: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-cyclopropyl-N-methylpyrrolidine-3-amine Reference Example 86: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(2-methylpropyl)pyrrolidine-3-amine Reference Example 87: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylpyrrolidine-3-amine Reference Example 88: (1S,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]sulfanyl}cyclohexane-1-amine

[0399] Reference example 89: (1S,2R)-N 1 -benzyl-3,3-difluoro-N 1 -[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]cyclohexane-1,2-diamine [ka]

[0400] Process (i): Compound 142 (2.19 g) was synthesized according to the method described in step (ii) of Reference Example 18, using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate instead of 1-isopropylpiperazine in step (ii) of Reference Example 18.

[0401] Step (ii): Using compound 142 (990 mg) and benzaldehyde (312 mg), the title compound 143 (240 mg) was obtained by following the same method as in step (iii) of Reference Example 42.

[0402] Step (iii): Using compound 143 (235 mg), the title compound 144 (161 mg) was obtained by following the same method as in steps (ii) and (iii) of Reference Example 81.

[0403] Step (iv): Using compound 144 (158 mg), title compound 145 (87.4 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 352 / 0.42 (Method C)

[0404] Reference example 90: Benzyl {(1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine-1-carbonyl)amino]cyclohexyl}[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]carbamate [ka]

[0405] Process (i): To a dioxane / water mixture (10 ml / 3.3 ml) of compound 142 (680 mg), benzyl chloroformate (345 mg) and sodium acetate (116 mg) were added at 0°C, and the reaction mixture was heated under reflux for 2 hours. After the reaction was complete, extraction was performed with chloroform, and the organic layer was concentrated to obtain the title compound 146 (530 mg).

[0406] Step (ii): Using compound 146 (530 mg), title compound 147 (256 mg) was obtained by following the same method as in steps (ii) and (iii) of Reference Example 81.

[0407] Step (iii): Using compound 147 (254 mg), the title compound 148 (137 mg) was obtained by following the same method as in step (iii) of Reference Example 18.

[0408] Step (iv): Using compound 148 (135 mg), title compound 149 (175 mg) was obtained according to the same method as in Example 19. LCMS: [M+H] + / Rt (min): 647 / 0.79 (Method C)

[0409] Reference example 91: (1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazole-3-yl]cyclohexane-1-amine [ka]

[0410] Process (i): A reaction mixture containing 2.01 g of compound 49 in acetonitrile (12.6 ml), sodium cyanide (495 mg), and lithium perchlorate (67 mg) was added and heated under reflux for 3 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 150 (2.05 g).

[0411] Step (ii): Using compound 150 (2.04 g), title compound 151 (1.88 g) was obtained by following the same method as in step (i) of Reference Example 8.

[0412] Step (iii): Using compound 151 (200 mg) and isobutyric acid (53.6 mg), the title compound 152 (89.7 mg) was obtained by following the same method as in steps (ii) and (iii) of Reference Example 8.

[0413] Step (iv): Using compound 152 (87.7 mg), title compound 153 (41.5 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min):246 / 0.37 (Method C)

[0414] Reference example 92: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazole-1-yl]cyclohexane-1-amine [ka]

[0415] Process (i): Sodium azide (490 mg) was added to an acetonitrile / water mixture (23 ml / 2.5 ml) of compound 49 (1.6 g), and the reaction mixture was heated at 70°C for 1.5 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 154 (1.78 g).

[0416] Step (ii): To a methanol / THF mixture (11.4 ml / 2.3 ml / 4 ml) of compound 154 (550 mg), sodium ascorbate (30.2 mg), tris(2-benzimidazolylmethyl)amine (46.5 mg), and 3-methylbuta-1-yine (156 mg) were added. Then, an aqueous solution of copper sulfate (18.2 mg) (3.8 ml) was added to the reaction mixture, and the reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was filtered by Celite, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 155 (353 mg).

[0417] Step (iii): Using compound 155 (353 mg), the title compound 156 (168 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 245 / 0.42

[0418] Reference example 93: (1R,6S)-2,2-difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazole-1-yl]cyclohexane-1-amine In Reference Example 92, instead of 3-methylbuta-1-yine in step (ii), 4-methylpenta-1-yine was used, and the compound of Reference Example 93 shown in the table below was synthesized in accordance with the method described in Reference Example 92. [Table 19]

[0419] Reference example 94: [(1S,2R)-2-amino-3,3-difluorocyclohexyl][4-(propan-2-yl)piperazine-1-yl]methanone [ka]

[0420] Process (i): A reaction solution of compound 150 (555 mg) in DMSO (6 ml) was mixed with hydrochloric acid aqueous solution (9 ml) and heated to 120°C. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 157 (600 mg).

[0421] Step (ii): To a 1.5 ml solution of compound 157 (476 mg) in DMF, 1-isopropylpiperazine (234 mg), triethylamine (308 mg), and HATU (753 mg) were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: chloroform / methanol) to obtain the title compound 158 (610 mg). LCMS: [M+H] + / Rt (min): 475 / 0.59

[0422] Step (iii): Using compound 158 (605 mg), title compound 159 (180 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 290 / 0.16

[0423] Reference example 95: (1R,6R)-2,2-difluoro-6-{[4-(propan-2-yl)piperazine-1-yl]methyl}cyclohexane-1-amine [ka]

[0424] Process (i): Using compound 159 (171 mg), title compound 160 (112 mg) was obtained by following the same method as in step (ii) of Reference Example 22. LCMS: [M+H] + / Rt (min): 276 / 0.24

[0425] Reference examples 96~114: Instead of (S)-1-isopropylpyrrolidine-3-ol in step (i) of Reference Example 37, the corresponding starting compound was used, and the compounds shown in the table below were synthesized in accordance with the method described in Reference Example 37. [Table 20] TIFF2022183120000249.tif220156 TIFF2022183120000250.tif224156 TIFF2022183120000251.tif186156

[0426] Reference Example 96: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexane-1-amine Reference Example 97: (1R,6S)-2,2-difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazole-5-yl]oxy}cyclohexane-1-amine Reference Example 98: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazole-4-yl]oxy}cyclohexane-1-amine Reference Example 99: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)azetidine-3-yl]oxy}cyclohexane-1-amine Reference Example 100: (1R,6S)-2,2-difluoro-6-{[(1R,3s,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octane-3-yl]oxy}cyclohexane-1-amine Reference Example 101: (1R,6S)-2,2-difluoro-6-{[(1R,5S,8r)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octane-8-yl]oxy}cyclohexane-1-amine Reference Example 102: (1R,6S)-2,2-difluoro-6-{[(1R,5S,8s)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octane-8-yl]oxy}cyclohexane-1-amine Reference Example 103: (1R,6S)-2,2-difluoro-6-{[(1R,3r,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octane-3-yl]oxy}cyclohexane-1-amine Reference Example 104: (1R,6S)-2,2-difluoro-6-{[(1R,5S,6s)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-yl]oxy}cyclohexane-1-amine Reference Example 105: (1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 106: (1R,6S)-2,2-difluoro-6-{[(3R,4R)-4-methoxy-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 107: (1R,6S)-2,2-difluoro-6-{[4-methyl-1-(propan-2-yl)piperidine-4-yl]oxy}cyclohexane-1-amine Reference Example 108: (1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexane-1-amine Reference Example 109: (1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidine-3-yl]oxy}-2,2-difluorocyclohexane-1-amine Reference Example 110: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexane-1-amine Reference Example 111: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidine-3-yl}oxy)cyclohexane-1-amine Reference Example 112: (1R,6S)-2,2-difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 113: (1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidine-3-yl]oxy}cyclohexane-1-amine Reference Example 114: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidine-3-yl}oxy)cyclohexane-1-amine

[0427] Reference examples 115~118 The compounds of Reference Examples 115 to 118 shown in the table below were synthesized in the same manner as described in Reference Example 8, using the corresponding starting material (starting material A) instead of compound 26 in step (i) of Reference Example 8, and using the corresponding starting material compound (starting material B) instead of cyclopropanecarboxylic acid in step (iii). [Table 21]

[0428] Reference Example 115: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine Reference Example 116: 4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-4-methylpiperidine Reference Example 117: 4-(5-cyclobutyl-1,2,4-oxadiazole-3-yl)-4-methylpiperidine monohydrochloride Reference Example 118: 4-Ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}piperidine

[0429] Reference example 119: (1R,6S)-2,2-difluoro-6-{[2-(propan-2-yl)pyrimidine-4-yl]oxy}cyclohexane-1-amine [ka]

[0430] Process (i): To a THF solution (3 ml) of compound 161 (148 mg) known from the literature, sodium hydride (55%, 30 mg) was added at 0°C, followed by the addition of 4-chloro-2-(propan-2-yl)pyrimidine. The reaction mixture was then heated to room temperature and stirred. After the reaction was complete, water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 162 (209 mg).

[0431] Step (ii): To a 2 mL ethyl acetate solution of compound 162 (113 mg), palladium hydroxide (17 mg) was added at room temperature and the mixture was stirred under a hydrogen atmosphere. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound 163 (33.5 mg). LCMS: [M+H] + / Rt (min): 272 / 0.47

[0432] Reference example 120: (1R,6S)-2,2-difluoro-N-methyl-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0433] Process (i): To a 3 ml solution of compound 50 (173 mg) in DMF, cesium carbonate (253 mg) and methyl iodide (72 mg) were added at 0°C. The reaction mixture was then heated to room temperature and stirred. After the reaction was complete, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 164 (159 mg).

[0434] Step (ii): Using compound 164 (134 mg), title compound 165 (71 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 276 / 0.15

[0435] Reference example 121: rac-(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0436] Process (i): A solution of compound 166 (283 mg) in 2-propanol (8 ml) was mixed with aqueous ammonia (6 g) and heated under reflux. After the starting material was consumed, the reaction mixture was concentrated and used for the subsequent reaction.

[0437] Step (ii): Using compound 167, title compound 168 (64.3 mg) was obtained by following the same method as in step (i) of Reference Example 18.

[0438] Step (iii): Using compound 168 (60.8 mg), title compound 169 (102 mg) was obtained by following the same method as in step (ii) of Reference Example 18.

[0439] Step (iv): Using compound 169 (102 mg), the title compound 170 (40.2 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 254 / 0.43

[0440] Reference example 122: rac-(1S,2S)-2-[4-(propan-2-yl)piperazine-1-yl]cycloheptan-1-amine The compounds shown in the table below were synthesized using 8-oxabicyclo[5.1.0]octane instead of compound 166 in step (i) of Reference Example 120, following the method described in Reference Example 120. [Table 22]

[0441] Reference example 123: rac-(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0442] Process (i): Compound 171 (403 mg) and a toluene solution (1 ml) of tetrabutylammonium trihydrogen trifluoride (1.78 g) were heated to 150°C under microwave irradiation. After the reaction was complete, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 172 (323 mg).

[0443] Step (ii): Compound 172 (457 mg) was dissolved in THF (4.1 mL), and triethylamine (1.13 mL) and methanesulfonyl chloride (0.318 mL) were added under ice cooling and the mixture was stirred. After confirming that the starting materials had disappeared, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 173 (578 mg).

[0444] Step (iii): To a 3.5 mL ethanol solution of compound 173 (571 mg), palladium hydroxide (20%, 133 mg) was added at room temperature and the mixture was stirred under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through Celite, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 174 (400 mg).

[0445] Step (iv): Compound 174 (176 mg) was dissolved in 1,4-dioxane (3.5 mL), and DBU (0.25 mL) was added and the mixture was heated and stirred at 85°C. After confirming that the starting material had disappeared, the mixture was then subjected to the conditions up to methanesulfonylation in steps (i) and (ii) of Reference Example 121. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 175 (86 mg).

[0446] Process (v): Using compound 175 (86 mg), the title compound 176 (92.8 mg) was obtained by following the cyclization reaction conditions of step (ii) in Reference Example 121 and the same method as in step (ii) in Reference Example 18.

[0447] Process (vi): Using compound 176 (86.1 mg), title compound 177 (35.1 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 244 / 0.19

[0448] Reference example 124: rac-(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexane-1-amine [ka]

[0449] Process (i): Using compound 178 (929 mg), the title compound 179 (953 mg) was obtained by following the same method as in step (i) of Reference Example 123.

[0450] Step (ii): Compound 179 (283 mg) was dissolved in chloroform (6 mL), and pyridine (0.51 mL) and trifluoromethanesulfonic acid anhydride (0.256 mL) were added under ice cooling and the mixture was stirred. After confirming that the starting materials had disappeared, aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate) to obtain the title compound 180 (424 mg).

[0451] Step (iii): Sodium azide (229 mg) was added to a DMF solution (4 ml) of compound 180 (418 mg), and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 181 (102 mg).

[0452] Step (iv): To a 2 mL ethanol solution of compound 181 (102 mg), palladium hydroxide (20%, 58 mg) was added at room temperature and the mixture was stirred under a hydrogen atmosphere. The reaction mixture was filtered through Celite, concentrated, and then dissolved again in ethanol (2 mL). Hydrogen chloride solution (cyclopentylmethyl solution, 5 M, 0.327 mL) and palladium carbon (10%, 71 mg) were added and the mixture was stirred under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound 182 (76.8 mg).

[0453] Process (v): Using compound 182 (103 mg), title compound 183 (69 mg) was obtained by following the same method as in steps (i) and (ii) of Reference Example 18.

[0454] Process (vi): Using compound 183 (72 mg), title compound 184 (34.3 mg) was obtained by following the same method as in step (iii) of Reference Example 18. LCMS: [M+H] + / Rt (min): 244 / 0.14

[0455] Reference example 125: (1S,2R)-2-amino-3,3-difluorocyclohexyl 4-(propan-2-yl)piperazine-1-carboxylate [ka]

[0456] Process (i): Boc2O (238 mg) was added to an acetonitrile solution (3 ml) of compound 185, a known compound in the literature, and the reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain compound 186 (216 mg).

[0457] Step (ii): Using compound 186 (95.7 mg), the title compound 187 (118 mg) was obtained by following the same method as in step (iii) of Reference Example 2.

[0458] Step (iii): Using compound 187 (118 mg), the title compound 188 (99.7 mg) was obtained by following the same method as in step (iv) of Reference Example 2. LCMS: [M+H] + / Rt (min): 306 / 0.25

[0459] Reference example 126: N-{(1S,6S)-2,2-difluoro-6-[1-(propan-2-yl)piperidine-4-sulfonyl]cyclohexyl}-4-nitrobenzene-1-sulfonamide [ka]

[0460] Process (i): Using compound 49 (399 mg) and tert-butyl 4-sulfanylpiperidine-1-carboxylate (300 mg), the title compound 189 (402 mg) was obtained by following the same method as in step (ii) of Reference Example 18.

[0461] Step (ii): After adding m-CPBA (242 mg) to a chloroform solution (2 ml) of compound 189 (210 mg), the reaction mixture was stirred at room temperature. After the reaction was complete, an aqueous sodium thiosulfate solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 190 (250 mg).

[0462] Step (iii): Using compound 190 (250 mg), the title compound 191 (223 mg) was obtained by following the same method as in steps (i) and (ii) of Reference Example 53.

[0463] Step (iv): Using compound 191 (223 mg), the title compound 192 (102 mg) was obtained by following the same method as in Reference Example 18 (iii). LCMS: [M+H] + / Rt (min): 325 / 0.21

[0464] Test Example 1: Measurement of Orexin 2 receptor agonist activity Human orexin type 2 receptor and apoaequorin were transiently expressed in CHO cells, and their activating properties were evaluated using the amount of calcium influx into the cells in response to ligand stimulation. Transiently expressed cells were seeded at 2,000 cells / well in 384-well plates and cultured for 16-22 hours. After returning the plates to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added and the cells were allowed to stand at room temperature for 2 hours. Then, Orexin A (Peptide Laboratories, Inc., Lot. 641114) or the test compound was added, and the luminescence of the cells was measured using FDSS7000 (Hamamatsu Photonics). Orexin A and the test compound were dissolved in DMSO (final concentration 0.1%) and diluted with buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin type 2 receptor activating properties of the test compound were calculated as a relative value, with the luminescence value after treatment with Orexin A (100 pM) set to 100%.

[0465] Test results: The compounds obtained in the examples were measured for orexin type 2 receptor agonism, and it was observed that the compound represented by formula (I) exhibited agonism towards the orexin type 2 receptor. The relative values ​​of the orexin type 2 receptor agonism of the compounds obtained in the examples at 10 μM, with the luminescence value during treatment with Orexin A (100 pM) set to 100%, are shown in the table below. [Table 23]

[0466] Test Example 2: Measurement of Orexin 2 Receptor Agonist Activity Human orexin type 2 receptor and apoaequorin were transiently expressed in CHO cells, and their activating properties were evaluated using the amount of calcium influx into the cells in response to ligand stimulation. Transiently expressed cells were seeded at 2,000 cells / well in 384-well plates and cultured for 16-22 hours. After returning the plates to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added and the cells were allowed to stand at room temperature for 2 hours. Then, Orexin A (Peptide Laboratories, Inc., Lot. 671009) or the test compound was added, and the luminescence of the cells was measured using FDSS7000 (Hamamatsu Photonics). Orexin A and the test compound were dissolved in DMSO (final concentration 0.1%) and diluted with buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin type 2 receptor activating properties of the test compound were calculated as a relative value, with the luminescence value after treatment with Orexin A (100 pM) set to 100%.

[0467] Test results: The compounds obtained in the examples were measured for orexin type 2 receptor agonism, and it was observed that the compound represented by formula (I) exhibited agonism towards the orexin type 2 receptor. The relative values ​​of the orexin type 2 receptor agonism of the compounds obtained in the examples at 10 μM, with the luminescence value during treatment with Orexin A (100 pM) set to 100%, are shown in the table below. [Table 24] [Industrial applicability]

[0468] The pharmaceutical composition of the present invention exhibits strong agonist activity against orexin receptors and is useful as a therapeutic or preventive agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with Lewy body dementia.

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, R １ is an optionally substituted C ６－１０ Aromatic carbocyclic groups, optionally substituted 5- to 10-membered aromatic heterocyclic groups, optionally substituted C ３－６ represents a saturated carbocyclic group, an optionally substituted 4- to 10-membered saturated heterocyclic group, or cyano; L １ and L ２ each independently represents a single bond, a methylene (the methylene is one or more of the same or different C １－４ optionally substituted with alkyl), —NR ８ -, -C(=O)-, -OC(=O)-, -SO-, -SO ２ represents -, -S-, or an oxygen atom; R ２ represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or an optionally substituted C １－４ represents alkyl; Also L １ When is a single bond, R １ and R ２ are taken together to form a spiro ring, and optionally substituted C ３－６ It may form a saturated carbocyclic ring or an optionally substituted 4- to 10-membered saturated heterocyclic ring; R ３ and R ４ are each independently a hydrogen atom, a halogen atom, cyano, or —(C═O)NR ５ R ６ , carboxy group, —(C═O)O—R ７ , optionally substituted C １－４ Alkyl or optionally substituted C １－４ represents alkoxy, and R ３ and R ４ may be bonded to the same carbon atom if chemically possible, and R ３ and R ４ are bonded to different carbon atoms on the ring, １－６ may be linked via an alkylene to form a fused or bridged ring; R ５ ~R ７ are each independently a hydrogen atom, a halogen atom, or an optionally substituted C １－４ represents alkyl; R ８ are each independently a hydrogen atom or an optionally substituted C １－４ represents alkyl; n is an integer of 1, 2, 3, or 4; Ring G is an optionally substituted C ６－１０ Aromatic carbocyclic groups, optionally substituted 5- to 10-membered aromatic heterocyclic groups, optionally substituted C ３－６ represents a saturated carbocyclic group or an optionally substituted 4- to 10-membered saturated heterocyclic group; A １ represents an oxygen atom or a sulfur atom; A ２ represents an oxygen atom or -NR ８ represents -; A ３ represents —CH—, a nitrogen atom or a carbon atom; Each dashed line independently represents a single or double bond. A pharmaceutical composition comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

2. R ２ ~R ８ "Optionally substituted C" １－４ The substitutable substituents in "alkyl" are each independently one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, C ６－１０ Aromatic carbocyclic group, or C ３－７ cycloalkyl, and "optionally substituted C １－４ The substitutable substituents in "alkoxy" are each independently one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C ３－７ is cycloalkyl, R １ C ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a hydrogen atom, a halogen atom, a hydroxy group, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－６ Alkylamino (the alkyl group in the alkylamino is a halogen atom, a hydroxy group, C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), cyano, C １－４ Alkoxy (the alkoxy may be optionally substituted with one or more of the same or different halogen atoms, a hydroxy group, or one or more of the same or different halogen atoms). １－４ Alkyl, or C ３－７ and 5- to 10-membered aromatic heterocyclic groups (the aromatic heterocyclic groups may contain one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ and one or more substituents selected from the group consisting of: C of Ring G ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a halogen atom, C １－６ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C ３－７ optionally substituted with cycloalkyl), C １－６ Alkylamino (the alkyl group in the alkylamino is a halogen atom, a hydroxy group, C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), and C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ and when there are a plurality of substituents, two of them are C １－６ may be bonded via an alkylene to form any chemically feasible bicyclic structure among fused, spiro or bridged rings; The pharmaceutical composition of claim 1.

3. R ２ ~R ７ "Optionally substituted C" １－４ The substitutable substituents in "alkyl" are each independently one or more of the same or different halogen atoms, or C １－４ Alkoxy is "optionally substituted C １－４ The substituents of "alkoxy" are each independently one or more of the same or different halogen atoms, or C １－４ is alkyl, R １ C ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a hydrogen atom, a halogen atom, a hydroxy group, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ optionally substituted with cycloalkyl), cyano, C １－４ Alkoxy (the alkoxy may be optionally substituted with one or more of the same or different halogen atoms, a hydroxy group, or one or more of the same or different halogen atoms). １－４ Alkyl, or C ３－７ and 5- to 10-membered aromatic heterocyclic groups (the aromatic heterocyclic groups may contain one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ and one or more substituents selected from the group consisting of: C of Ring G ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a halogen atom, C １－６ Alkyl (the alkyl is one or more of the same or different halogen atoms or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, C １－４ Alkyl or C １－４ optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－６ Alkylamino (the alkyl group in the alkylamino is a halogen atom, a hydroxy group or C ３－７ optionally substituted with cycloalkyl), and C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ and when there are a plurality of substituents, two of them are C １－６ may be bonded via an alkylene to form any chemically feasible bicyclic structure among fused, spiro or bridged rings; A pharmaceutical composition according to claim 1 or claim 2.

4. R １ is expressed by the following formulas (1a-1) to (1a-4): 【Chemistry 2】 [In the formula, X １ ~X ７ are each independently a nitrogen atom or CR ａ６ represents; Q １ and Q ２ represents an oxygen atom, -NR ａ７ - or a sulfur atom; R ａ１ ~R ａ７ are each independently (CR ａ６ If there are multiple R ａ６ each independently), a hydrogen atom, a halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ R represents a 5- to 10-membered aromatic heterocyclic group, which may be substituted with an alkoxy group; ａ４ and R ａ５ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are CR ａ６ In the case of ａ６ and R ａ６ The carbon atoms bonded to X １ , X ２ and X ３ may form a 6-membered carbocyclic ring fused with a 5-membered ring composed of q １ is an integer of 1 or 2. The pharmaceutical composition according to any one of claims 1 to 3, which is any one selected from the following:

5. Ring G is selected from the following (1b-1) to (1b-4): 【Transformation 3】 [In the formula, W １ , W ３ , W ５ , W ６ , W ７ , W １１ , W １２ , W １３ , W １５ , W １６ , W １７ , W １９ , and W ２５ are each independently a nitrogen atom or CR ｂ４ represents; W ２ , W ４ , W ８ , W ９ , W １０ , W １４ , W １８ , W ２０ , W ２１ , W ２２ , W ２３ , and W ２４ is NR ｂ５ , oxygen atom or CR ｂ６ R ｂ７ represents; R ｂ１ ~R ｂ７ are each independently (CR ｂ４ If there are multiple R ｂ４ each independently), a hydrogen atom, —N(R ｂ８ ) R ｂ９ , C １－６ Alkyl (the alkyl is one or more of the same or different halogen atoms, C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms or C １－４ may be substituted with alkyl, １－４ alkyl may be substituted with a halogen atom) or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ a 5- to 10-membered aromatic heterocyclic group (which may be substituted with one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ substituted with alkoxy), and R ｂ１ and R ｂ２ may be attached to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ is C １－６ may be linked via alkylene to form any chemically feasible bicyclic structure including fused, spiro, or bridged rings; R ｂ８ and R ｂ９ are each independently a hydrogen atom, C １－６ Alkyl (the alkyl is one or more of the same or different halogen atoms, C １－４ Alkoxy, C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms or C １－４ may be substituted with alkyl, １－４ alkyl may be substituted with a halogen atom), or a 5- to 10-membered aromatic heterocyclic group), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ a 5- to 10-membered aromatic heterocyclic group (which may be substituted with one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy; Here, R ｂ８ and R ｂ９ may be taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered nitrogen-containing saturated heterocycle. The pharmaceutical composition according to any one of claims 1 to 4, which is any one selected from the group consisting of:

6. Formula (2): 【Chemistry 4】 [In the formula, R １ is represented by the following formulas (1a-1) to (1a-4): 【Transformation 5】 [In the formula, X １ ~X ７ are each independently a nitrogen atom or CR ａ６ represents; Q １ and Q ２ represents an oxygen atom, -NR ａ７ - or a sulfur atom; R ａ１ ~R ａ７ are each independently (CR ａ６ If there are multiple CRs, ａ６ each independently), a hydrogen atom, a halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－６ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ R represents a 5- to 10-membered aromatic heterocyclic group, which may be substituted with an alkoxy group; ａ４ and R ａ５ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are CR ａ６ In the case of ａ６ and R ａ６ The carbon atoms bonded to X １ , X ２ and X ３ may form a 6-membered carbocyclic ring fused with a 5-membered ring composed of q １ is an integer of 1 or 2. any one selected from: L １ and L ２ are each independently a single bond, —CH ２ - or an oxygen atom; R ２ represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or an optionally substituted C １－４ represents alkyl; R ３ and R ４ are each independently a hydrogen atom, a halogen atom, or C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ cycloalkyl), or C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C ３－７ optionally cycloalkyl-substituted), and R ３ and R ４ may be bonded to the same carbon atom if chemically possible, and R ３ and R ４ are bonded to different carbon atoms on the ring, １ - ６ may be linked via an alkylene to form a fused or bridged ring; Ring G is selected from the following (1b-1) to (1b-4): 【Transformation 6】 [In the formula, W １ , W ３ , W ５ , W ６ and W ７ are each independently a nitrogen atom or CR ｂ４ represents; W ２ , W ４ and W ８ is NR ｂ５ , oxygen atom or CR ｂ６ R ｂ７ represents; R ｂ１ ~R ｂ７ are each independently (CR ｂ４ If there are multiple R ｂ４ each independently), a hydrogen atom, C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ substituted with alkoxy), and R ｂ１ and R ｂ２ may be attached to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ is C １－６ They may be bonded via an alkylene to form any chemically feasible bicyclic structure, including fused, spiro, or bridged rings. any one selected from: A １ represents an oxygen atom or a sulfur atom; A ２ represents an oxygen atom or —NH—; A ３ The pharmaceutical composition according to any one of claims 1 to 5, wherein is represented by -CH-, a nitrogen atom, or a carbon atom.

7. R １ However, the following formulas (1a-1), (1a-2) and (1a-3-1): 【Transformation 7】 [In formulas (1a-1), (1a-2) and (1a-3-1), X １ ~X ６ are each independently a nitrogen atom or CR ａ６ represents; Q １ and Q ２ represents an oxygen atom, -NR ａ７ - or a sulfur atom; R ａ１ ~R ａ３ , R ａ６ and R ａ７ are each independently (CR ａ６ If there are multiple R ａ６ each independently), a hydrogen atom, a halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkyl (the alkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ substituted with alkoxy) or a 5- to 10-membered aromatic heterocyclic group; １ and X ３ Both are CR ａ６ In the case of ａ６ and R ａ６ The carbon atoms bonded to X １ , X ２ and X ３ may form a 6-membered carbocyclic ring fused with a 5-membered ring constituted by the following formula: The pharmaceutical composition according to claim 6, which is any one selected from the following:

8. Ring G is the following (1b-1), (1b-2) or (1b-4): 【Transformation 8】 [In the formula, W １ , W ３ , W ５ , W ６ and W ７ are each independently a nitrogen atom or CR ｂ４ represents; W ２ and W ４ is NR ｂ５ or CR ｂ６ R ｂ７ represents; R ｂ１ , R ｂ２ and R ｂ４ ~R ｂ７ are each independently (CR ｂ４ If there are multiple R ｂ４ each independently), a hydrogen atom, C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ substituted with alkoxy), and R ｂ１ and R ｂ２ may be attached to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ is C １－６ They may be bonded via an alkylene to form a bridged bicyclic structure. The pharmaceutical composition according to claim 6 or claim 7, wherein

9. Ring G is the following (1b-1) or (1b-2): 【Chemistry 9】 [In the formula, W １ and W ３ is a nitrogen atom or CR ｂ４ represents; W ２ and W ４ is NR ｂ５ or CR ｂ６ R ｂ７ represents; R ｂ１ , R ｂ２ and R ｂ４ ~R ｂ７ are each independently a hydrogen atom, C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkyl), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－４ Alkyl, or C １－４ substituted with alkoxy), and R ｂ１ and R ｂ２ may be attached to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ is C １－６ They may be bonded via an alkylene to form a bridged bicyclic structure. The pharmaceutical composition according to any one of claims 6 to 8, wherein the pharmaceutical composition is represented by the formula:

10. Formula (3): 【Chemistry 10】 [In the formula, R １ is represented by the following formula (1a-1), (1a-2) or (1a-3-1): 【Chemistry 11】 (In formulas (1a-1), (1a-2) and (1a-3-1), X １ ~X ６ are each independently a nitrogen atom or CR ａ６ represents; Q １ and Q ２ represents an oxygen atom or a sulfur atom; R ａ１ ~R ａ３ and R ａ６ are each independently (CR ａ６ If there are multiple R ａ６ each independently), a hydrogen atom, a halogen atom, C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ and optionally substituted with alkoxy; １ and X ３ Both are CR ａ６ In the case of ａ６ and R ａ６ The carbon atoms bonded to X １ , X ２ and X ３ may form a 6-membered carbocyclic ring fused with a 5-membered ring constituted by It is represented by; L １ and L ２ each independently represents a single bond or an oxygen atom; R ２ is a hydrogen atom, a halogen atom, or C １－４ alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms or hydroxy groups); R ３ and R ４ each independently represents a halogen atom; Ring G is represented by the following formula (1b-1), (1b-2-1), (1b-2-2) or (1b-2-3): 【Chemistry 12】 (In formula (1b-1-1), (1b-2-1), (1b-2-2) or (1b-2-3), R ｂ５ is a hydrogen atom or C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy; A １ represents an oxygen atom or a sulfur atom. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is represented by the formula:

11. R １ is the above formula (1a-2), and R ａ１ is a hydrogen atom, a halogen atom, or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy) or C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, or C １－４ The pharmaceutical composition according to any one of claims 4 to 10, wherein the compound is any one selected from the group consisting of:

12. R １ is the above formula (1a-2), and X ４ and X ５ The pharmaceutical composition according to claim 10 or 11, wherein each of

13. Ring G is represented by the above formula (1b-1-1), and R ｂ５ C optionally substituted with one or more of the same or different halogen atoms １－４ The pharmaceutical composition according to any one of claims 10 to 12, wherein the aryl group is alkyl.

14. Ring G is represented by the above formula (1b-2-1), and R ｂ５ is a hydrogen atom or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, or C １－４ The pharmaceutical composition according to any one of claims 10 to 12, wherein the aryl group is substituted with alkoxy.

15. Formula (4): 【Chemistry 13】 [In the formula, R １ is expressed by the following formula (1a-2-1): 【Chemistry 14】 (In formula (1a-2-1), Q ２ represents an oxygen atom or a sulfur atom; R ａ２ represents a C ３－７ cycloalkyl group (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－４ alkyl, or C １－４ alkoxy) or a cycloalkoxy group (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, C １－４ alkyl, or C １－４ alkoxy).) It is represented by; R ２ is C １－４ represents alkyl; Ring G is represented by the following formula (1b-1-1) or (1b-2-1): 【Chemistry 15】 (In formula (1b-1-1) or (1b-2-1), R ｂ５ represents C １－４ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－４ alkoxy).) represents; L ２ represents a single bond or an oxygen atom.] The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition is represented by the formula:

16. R ａ２ C may be substituted with one or more of the same or different halogens ３－７ is a cycloalkyl group, and R ２ The pharmaceutical composition according to claim 15, wherein is a methyl group.

17. R ａ２ is a cyclopropyl group optionally substituted with one or more of the same or different halogens, and R ２ The pharmaceutical composition according to claim 15 or claim 16, wherein is a methyl group.

18. Ring G is the above formula (1b-2-1), and R ｂ５ The pharmaceutical composition according to any one of claims 15 to 17, wherein is an isopropyl group.

19. Ring G is the above formula (1b-1-1), and R ｂ５ The pharmaceutical composition according to any one of claims 15 to 17, wherein is an isobutyl group.

20. Ring G is the above formula (1b-1-1), and R ｂ５ is an isopropyl group, and L ２ The pharmaceutical composition according to any one of claims 15 to 17, wherein is an oxygen atom.

21. Q ２ The pharmaceutical composition according to any one of claims 15 to 20, wherein is an oxygen atom.

22. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any compound represented by the following compound name or structural formula or a pharmaceutically acceptable salt thereof: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 16】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 17】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [Chemistry 18] 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 19】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 20】 N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide 【Chemistry 21】 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 22】 N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 23】 N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide 【Chemistry 24】 N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide 【Chemistry 25】 rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide 【Chemistry 26】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide. 【Chemistry 27】

23. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any compound represented by the following compound name or structural formula or a pharmaceutically acceptable salt thereof: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemistry 28】 N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide 【Chemistry 29】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Transformation 30】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 31】 N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 32】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide 【Transformation 33】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Transformation 34】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemistry 35】

24. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any compound represented by the following compound name or structural formula or a pharmaceutically acceptable salt thereof: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 36】 N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 37】 N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 38】 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 39】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemistry 40】 N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 41】 N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 42】 N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 43】 N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 44】 N-[(1R,6S)-6-{(3S)-3-[cyclopropyl(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 45】 N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 46】 N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 47】 N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 48】 N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 49】 N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide [Transformation 50] rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 51】 N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 52】 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 53】 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1S,2R,6R)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 【Chemistry 54】 N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 55】 N-[(1R,6S)-6-{4-[(cyclopropylmethyl)(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 56】 N-[(1R,6S)-6-{4-[cyclobutyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 57】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 58】

25. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is any compound represented by the following compound name or structural formula or a pharmaceutically acceptable salt thereof: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 59】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Transformation 60】 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemistry 61】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide 【Transformation 62】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 63】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemistry 64】 N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 65】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide 【Chemical Formula 66】 N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 67】 N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 68】 N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide 【Transformation 69】 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide 【Transformation 70】 N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 71】 N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Chemistry 72】 N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 【Transformation 73】

26. A therapeutic agent for a disease associated with an orexin receptor, comprising the pharmaceutical composition according to any one of claims 1 to 25.

27. A pharmaceutical composition according to any one of claims 1 to 25, comprising a pharmaceutical composition for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome accompanied by excessive daytime sleepiness (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-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity ... For example, malignant mast cells, exogenous obesity, hyperinsulinemia obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid 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, REM Sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunkenness, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, 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, cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, Syndrome X, sexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, and female hirsutism; fetal defects associated with maternal obesity; gastrointestinal motility disorders such as obesity-related gastroesophageal reflux; respiratory disorders such as obesity-related hypoventilation syndrome (Pickwickian syndrome); inflammation such as systemic inflammation of the vascular system; risk of secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy; migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial hot flashes, night sweats, and genital / diseases of the urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cerebral defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, eye injuries, retinopathy, for the treatment of cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesias, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism, Gilles de la Tourette 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, or traumatic brain injury.

28. A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy bodies, comprising the pharmaceutical composition according to any one of claims 1 to 25.

29. Use of the pharmaceutical composition according to any one of claims 1 to 25 for the manufacture of a therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy bodies.