Cycloalkylurea derivative

Abstract

To provide a therapeutic or preventive agent for a disease in which an orexin type 2 receptor is involved, the agent comprising, as an active ingredient, a novel compound possessing a urea skeleton or a pharmaceutically acceptable salt thereof.SOLUTION: A compound has a structure represented by the following formula. [In the formula, ring G represents an optionally substituted C6-10 aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C3-6 saturated carbocyclic group, or an optionally substituted 4- to 10-membered saturated heterocyclic group; A1 represents an oxygen atom or a sulfur atom; A2 represents an oxygen atom or -NR8-; A3 represents -CH-, a nitrogen atom, or a carbon atom; and R8 represents a hydrogen atom or an optionally substituted C1-4 alkyl.]SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Orexin is a neuropeptide specifically produced in certain neurons scattered throughout the lateral hypothalamus and its surrounding areas. Orexin is an endogenous ligand for orexin receptors, which are G protein-coupled receptors present primarily in the brain, and binds to these receptors. Two subtypes of orexin receptors, type 1 and type 2, are known (Non-Patent Document 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 peptides (Non-Patent Document 2), and that narcolepsy-like symptoms are induced by knockout of preproorexin, the precursor protein of orexin (Non-Patent Document 3).Furthermore, it has been revealed that the orexin concentration in the cerebrospinal fluid of narcolepsy patients is significantly reduced (Non-Patent Document 4), suggesting that narcolepsy is caused by a deficiency of orexin. Furthermore, mutations in the orexin 2 receptor have been reported in dogs with hereditary narcolepsy (Non-Patent Document 5), suggesting the involvement of the orexin 2 receptor in sleep and wakefulness. Furthermore, it has been revealed that narcolepsy-like symptoms are induced in orexin 2 receptor knockout mice (Non-Patent Document 6), strongly suggesting the involvement of orexin 2 receptor stimulation in the maintenance of wakefulness. Against this background, orexin 2 receptor agonists are expected to be promising treatments for diseases presenting with hypersomnia symptoms, including narcolepsy.

[0004] In recent years, compounds having orexin 2 receptor agonism 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.92,573-585,1998 [Non-patent document 2] Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, pp. 4649-4654, 2004 (Proc. Natl. Acad. Sci. USA, Vol. 101, pp. 4649-4654, 2004) [Non-patent document 3] Cell, Vol. 98, pp. 437-451, 1999 [Non-patent document 4] THE LANCET,Vol.355,39-40,2000 [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.130,1577-1585,2007 [Non-patent document 8] Neuroscience Letters, Vol. 569, pp. 68-73, 2014 Summary of the Invention [Problem to be solved by the invention]

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

[0008] As a result of extensive investigations, the present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "the compound of the present invention") has therapeutic and preventive effects on diseases in which the orexin type 2 receptor is involved, specifically diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome, and have completed the present invention.

[0009] That is, the present invention is as follows.

[0010] [Section A1] Formula (1): [ka] [In the formula, R 1 may be 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, —CH—, or an oxygen atom; R 2 is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or an optionally substituted C1-4 represents alkyl; Also L 1 If 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, a cyano group, or —(C═O)NR 5 R 6 , carboxy group, -(C=O)OR 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, they may be bonded to each other via a C1-6 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; n is an integer of 1 or 2; 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 -NH-; A 3 represents -CH-, a nitrogen atom or a carbon atom; The dashed lines represent single or double bonds. or a pharmaceutically acceptable salt thereof.

[0011] [Section A2] 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, hydroxy groups, C 1-4 Alkoxy, 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 contain one or more of the same or different halogen atoms, hydroxyl 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 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 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 1-4Alkoxy (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 cycloalkyl) and 5-10-membered aromatic heterocyclic group (the aromatic heterocyclic ring 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 aryl C 6-10 The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 optionally substituted with cycloalkyl), C 1-4 Alkoxy (the alkoxy can be 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 3-7 Cycloalkyl (the cycloalkyl 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), 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 1-4Alkoxy or C 3-7 and when there are multiple 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 compound of item A1 or a pharmaceutically acceptable salt thereof.

[0012] [Section A3] 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 and "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 contain one or more of the same or different halogen atoms, hydroxyl 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 may be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7optionally 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 cycloalkyl) and 5-10-membered aromatic heterocyclic group (the aromatic heterocyclic ring 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 may be one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 optionally substituted with alkoxy), 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 1-6may be bonded via an alkylene to form any chemically feasible bicyclic structure among fused, spiro or bridged rings; The compound according to item A1 or A2, or a pharmaceutically acceptable salt thereof.

[0013] [Section A4] R 1 However, the following equations (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 are each independently a nitrogen atom or CR a6 represents; Q 1 and Q 2 is 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 contain one or more of the same or different halogen atoms, hydroxyl 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 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), cyano, C 1-4 Alkoxy (the alkoxy can 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), C3-7 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; provided that X 1 and X 3 Both are CR a6 In the case of R 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 compound according to any one of items A1 to A3, which is any one selected from the following, or a pharmaceutically acceptable salt thereof.

[0014] [Section A5] Ring G is one of the following (1b-1) to (1b-4): [ka] [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), hydrogen atom, C 1-6Alkyl (the alkyl may contain 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 may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 and may be bonded via an alkylene to form any chemically feasible bicyclic structure among fused, spiro, or bridged rings. The compound or a pharmaceutically acceptable salt thereof according to any one of items A1 to A4.

[0015] [Section A6] Formula (2): [ka] [In the formula, R 1 is expressed by the following equations (1a-1) to (1a-4): [ka] [In the formula, X1 ~X 7 are each independently a nitrogen atom or CR a6 represents; Q 1 and Q 2 is 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 contain one or more of the same or different halogen atoms, hydroxyl 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 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), cyano, C 1-4 Alkoxy (the alkoxy can 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 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; provided that X 1 and X 3 Both are CR a6 In the case of R a6 and R a6 The carbon atoms bonded to X1 , 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 each independently represents a single bond, —CH—, or an oxygen atom; R 2 is 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 optionally substituted with cycloalkyl), or C 1-4 Alkoxy (the alkoxy can be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 3-7 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, they may be bonded to each other via a C1-6 alkylene to form a fused or bridged ring; Ring G is one of the following (1b-1) to (1b-4): [ka] [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 , W4 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), hydrogen atom, C 1-6 Alkyl (the alkyl may contain 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 may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 and may be bonded via an alkylene to form any chemically feasible bicyclic structure among 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-; A3 The compound according to any one of items A1 to A5, wherein is represented by -CH-, a nitrogen atom, or a carbon atom, or a pharmaceutically acceptable salt thereof.

[0016] [Section A7] R 1 However, the following formulas (1a-1), (1a-2), and (1a-3-1): [ka] [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 is 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), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, hydroxyl 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 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), cyano, C 1-4 Alkoxy (the alkoxy can be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C1-4 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 R 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: The compound according to item A6, or a pharmaceutically acceptable salt thereof, which is any one selected from the following:

[0017] [Section A8] Ring G is the following (1b-1), (1b-2), or (1b-4): [ka] [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), hydrogen atom, C 1-6 Alkyl (the alkyl may contain one or more of the same or different halogen atoms, or C 1-4 optionally substituted with alkoxy), C6-10 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 may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 They may be linked via an alkylene to form a bridged bicyclic structure. The compound according to item A6 or A7, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0018] [Section A9] Ring G is the following (1b-1) or (1b-2): [ka] [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 contain 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 may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 They may be linked via an alkylene to form a bridged bicyclic structure. The compound according to any one of items A6 to A8, which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0019] [Section A10] Formula (3): [ka] [In the formula, R 1 is represented by the following formula (1a-1), (1a-2), or (1a-3-1): [ka] (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), hydrogen atom, halogen atom, C 1-4 Alkyl (the alkyl may contain 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 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), cyano, C 1-4 Alkoxy (the alkoxy can be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 1-4 substituted with alkoxy; 1 and X 3 Both are CR a6 In the case of R 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 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); R3 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): [ka] (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 contain one or more of the same or different halogen atoms, or C 1-4 alkoxy); A 1 represents an oxygen atom or a sulfur atom. The compound according to any one of items A1 to A9, which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0020] [Section A11] R 1 is the above formula (1a-2), and R a1 However, hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl may contain one or more of the same or different halogen atoms, or C 1-4 optionally substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 1-4 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 compound according to any one of items A4 to A10, or a pharmaceutically acceptable salt thereof, wherein the compound represents any one selected from the group consisting of:

[0021] [Section A12] R 1 is the above formula (1a-2), and X 4 and X 5The compound or pharmaceutically acceptable salt thereof according to item A10 or A11, wherein each of the groups represented by the formula (I) is a nitrogen atom.

[0022] [Section A13] Ring G is represented by the above formula (1b-1-1), and R b5 C which may be substituted with one or more of the same or different halogen atoms 1-4 The compound or pharmaceutically acceptable salt thereof according to any one of items A10 to A12, wherein the group is alkyl.

[0023] [Section A14] 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 contain one or more of the same or different halogen atoms, or C 1-4 The compound according to any one of items A10 to A12, wherein R is 1 or 2, and R is 2 or 3, and R is 3 or 4, and R is 4 or 5, and R is 5 or 6, and R is 6 or 7, and R is 7 or 8.

[0024] [Section A15] Formula (4): [ka] [In the formula, R 1 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 is C 3-7 Cycloalkyl groups (the cycloalkyl groups may be one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 alkoxy) or cycloalkoxy group (the cycloalkoxy may be substituted with one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 ) which may be substituted with alkoxy. Represented by; R 2 is C 1-4 represents alkyl; Ring G is represented by the following formula (1b-1) or (1b-2-1): [ka] (In formula (1b-1-1) or (1b-2-1), R b5 is C 1-4 Alkyl (the alkyl may contain one or more of the same or different halogen atoms, or C 1-4 It represents a group which may be substituted with alkyl. represents; L 2 represents a single bond or an oxygen atom.] The compound according to any one of items A1 to A12, which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0025] [Section A16] 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 compound of item A15, wherein is a methyl group, or a pharmaceutically acceptable salt thereof.

[0026] [Section A17] R a2 is a cyclopropyl group optionally substituted with one or more of the same or different halogens, and R 2 The compound or a pharmaceutically acceptable salt thereof according to item A15 or A16, wherein is a methyl group.

[0027] [Section A18] Ring G is the above formula (1b-2-1), and R b8 The compound or a pharmaceutically acceptable salt thereof according to any one of items A15 to A17, wherein is an isopropyl group.

[0028] [Section A19] Ring G is the above formula (1b-1-1), and Rb5 is an isopropyl group, and L 2 The compound or pharmaceutically acceptable salt thereof according to any one of items A15 to A17, wherein is an oxygen atom.

[0029] [Section A20] Q 2 The compound or pharmaceutically acceptable salt thereof according to any one of items A15 to A19, wherein is an oxygen atom.

[0030] [Section A21] A compound according to Item A1, which is represented by the following compound name or structural formula, 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)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide [ka] Example 23: 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 [ka] Example 24: 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 [ka] Example 25: 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 [ka] Example 62: 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 [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)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 68: 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 [ka] Example 69: 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 [ka] Example 79: 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 [ka] Example 80: 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. [ka]

[0031] [Section A22] A compound according to Item A1, which is represented by the following compound name or structural formula, or a pharmaceutically acceptable salt thereof. Example 64: 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 [ka] Example 67: 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 [ka] Example 71: 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 [ka] Example 72: 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 [ka] Example 73: 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 [ka] Example 74: 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 [ka] Example 75: 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 [ka] Example 76: 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 [ka]

[0032] [Section A23] A therapeutic agent for a disease associated with an orexin receptor, comprising the compound according to any one of items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0033] [Section A24] A compound according to any one of items A1 to A22 or a pharmaceutically acceptable salt thereof, for use in 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 (e.g., cerebrovascular disease, encephalopathy ... For example, malignant mast cells, exogenous obesity, hyperinsulinaemic obesity, hyperplasmocytosis, pituitary obesity, hypoplasmocytosis, 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, coma and other disorders of consciousness, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorders, 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 levels 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 hormonal abnormalities, decreased fertility, infertility, male hypogonadism, and female hirsutism; fetal defects associated with maternal obesity; gastrointestinal motility disorders such as obesity-related gastroesophageal reflux; obesity-hypoventilation syndrome (Pickwickian syndrome); respiratory disorders such as dyspnea; inflammation such as systemic inflammation of the vascular system; risk of secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy; migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, 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 attacks, 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 damage, retinopathy, To treat cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug dependence, 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.

[0034] [Section A25] 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 compound according to any one of items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0035] [Section A26] A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy bodies, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0036] [Section A27] Use of the compound according to any one of items A1 to A22 or a pharmaceutically acceptable salt thereof 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.

[0037] The present invention also provides the following:

[0038] [Section 1] Formula (1): [ka] [In the formula, R 1 may be 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 represents -, -C(=O)-, -OC(=O)-, -SO-, -SO2-, -S-, or an oxygen atom; R 2 is a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or an optionally substituted C 1-4 represents alkyl; Also L 1If 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, a cyano group, or —(C═O)NR 5 R 6 , carboxy group, -(C=O)OR 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 is 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. or a pharmaceutically acceptable salt thereof.

[0039] [Section 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 contain one or more of the same or different halogen atoms, hydroxyl 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 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 1-6 Alkylamino (the alkyl group in the alkylamino is not a halogen, a hydroxyl group, C 3-7optionally 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 cycloalkyl) and 5-10-membered aromatic heterocyclic group (the aromatic heterocyclic ring 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 aryl C 6-10 The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 optionally substituted with cycloalkyl), C 1-4 Alkoxy (the alkoxy can be 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 not a halogen, a hydroxyl group, C3-7 optionally substituted with cycloalkyl), C 3-7 Cycloalkyl (the cycloalkyl 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), 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 multiple 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; Item 1. The compound of Item 1 or a pharmaceutically acceptable salt thereof.

[0040] [Section 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 and "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 contain one or more of the same or different halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7optionally 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 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), 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 cycloalkyl) and 5-10-membered aromatic heterocyclic group (the aromatic heterocyclic ring 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 3-7Cycloalkyl (the cycloalkyl 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 1-6 Alkylamino (the alkyl group in the alkylamino is not a halogen, a hydroxyl group, 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; Item 1 or 2, a compound or a pharmaceutically acceptable salt thereof.

[0041] [Section 4] R 1 However, the following equations (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 are each independently a nitrogen atom or CR a6 represents; Q 1 and Q 2 is 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 contain one or more of the same or different halogen atoms, hydroxyl groups, C 1-4 Alkyl or C 1-4 optionally substituted with alkoxy), C1-4 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 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), cyano, C 1-4 Alkoxy (the alkoxy can 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 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; provided that X 1 and X 3 Both are CR a6 In the case of R 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. 4. The compound according to any one of items 1 to 3, which is any one selected from the group consisting of:

[0042] [Section 5] Ring G is one of the following (1b-1) to (1b-4): [ka] [In the formula, W 1 , W 3 , W5 , 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 The 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 alkoxy), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may contain one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4optionally 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 may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 may be linked via alkylene to form any chemically feasible bicyclic structure among 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 The alkyl may be substituted with a halogen atom, or may be substituted with 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 alkyl), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may contain one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 optionally substituted with alkoxy), or C 3-7Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 1-4 which may be substituted by alkoxy; where 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. Item 5. The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof.

[0043] [Section 6] Formula (2): [ka] [In the formula, R 1 is expressed by the following equations (1a-1) to (1a-4): [ka] [In the formula, X 1 ~X 7 are each independently a nitrogen atom or CR a6 represents; Q 1 and Q 2 is 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 contain one or more of the same or different halogen atoms, hydroxyl 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 1-4optionally substituted with alkoxy), C 3-6 Cycloalkyl (the cycloalkyl 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), cyano, C 1-4 Alkoxy (the alkoxy can 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 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; provided that X 1 and X 3 Both are CR a6 In the case of R 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 each independently represents a single bond, —CH—, or an oxygen atom; R 2 is 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 3-7optionally substituted with cycloalkyl), or C 1-4 Alkoxy (the alkoxy can be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 3-7 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, they may be bonded to each other via a C1-6 alkylene to form a fused or bridged ring; Ring G is one of the following (1b-1) to (1b-4): [ka] [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), hydrogen atom, C 1-6 Alkyl (the alkyl may contain 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 1-4optionally substituted with alkyl), C 3-7 Cycloalkyl (the cycloalkyl may be 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 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 and may be bonded via an alkylene to form any chemically feasible bicyclic structure among 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 6. The compound according to any one of items 1 to 5, wherein is represented by -CH-, a nitrogen atom or a carbon atom, or a pharmaceutically acceptable salt thereof.

[0044] [Section 7] R 1 However, the following formulas (1a-1), (1a-2), and (1a-3-1): [ka] [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 is an oxygen atom, -NR a7 - or a sulfur atom; R a1 ~R a3 , Ra6 and R a7 are each independently (CR a6 If there are multiple R a6 (each independently), hydrogen atom, halogen atom, C 6-10 Aromatic carbocyclic group (the C 6-10 The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, hydroxyl 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 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), cyano, C 1-4 Alkoxy (the alkoxy can 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 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 R 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: Item 7. The compound according to item 6, or a pharmaceutically acceptable salt thereof, which is any one selected from the following:

[0045] [Section 8] Ring G is the following (1b-1), (1b-2), or (1b-4): [ka] [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), hydrogen atom, C 1-6 Alkyl (the alkyl may contain 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 may be 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 alkoxy), and R b1 and R b2may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 They may be linked via an alkylene to form a bridged bicyclic structure. Item 8. The compound according to item 6 or 7, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0046] [Section 9] Ring G is the following (1b-1) or (1b-2): [ka] [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 contain 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 may be one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 optionally substituted with alkoxy), or C 3-7Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 alkoxy), and R b1 and R b2 may be attached to the same carbon atom if chemically possible; where R b1 and R b2 is C 1-6 They may be linked via an alkylene to form a bridged bicyclic structure. Item 9. The compound according to any one of items 6 to 8, which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0047] [Section 10] Formula (3): [ka] [In the formula, R 1 is represented by the following formula (1a-1), (1a-2), or (1a-3-1): [ka] (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), hydrogen atom, halogen atom, C 1-4 Alkyl (the alkyl may contain 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 may be one or more of the same or different halogen atoms, hydroxy groups, C1-4 Alkyl or C 1-4 optionally substituted with alkoxy), cyano, C 1-4 Alkoxy (the alkoxy can be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 1-4 substituted with alkoxy; 1 and X 3 Both are CR a6 In the case of R 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 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): [ka] (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 contain one or more of the same or different halogen atoms, or C 1-4 alkoxy); A 1 represents an oxygen atom or a sulfur atom. Item 10. The compound according to any one of items 1 to 9, represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0048] [Section 11] R 1 is the above formula (1a-2), and R a1 However, hydrogen atoms, halogen atoms, C 1-4 Alkyl (the alkyl may contain one or more of the same or different halogen atoms, or C 1-4 optionally substituted with alkoxy), C 3-7 Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C 1-4 Alkyl or C 1-4 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 Item 11. The compound according to any one of items 4 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound represents any one selected from the group consisting of:

[0049] [Section 12] R 1 is the above formula (1a-2), and X 4 and X 5 Item 12. The compound or pharmaceutically acceptable salt thereof according to item 10 or 11, wherein each of

[0050] [Section 13] Ring G is represented by the above formula (1b-1-1), and R b5 C which may be substituted with one or more of the same or different halogen atoms 1-4 13. The compound or a pharmaceutically acceptable salt thereof according to any one of items 10 to 12, wherein R is alkyl.

[0051] [Section 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 contain one or more of the same or different halogen atoms, or C 1-4 13. The compound according to any one of items 10 to 12, wherein R is 1 or 2, and R is 2 or 3, and R is 3 or 4, and R is 4 or 5, and R is 5 or 6. The compound according to item 10 to 12, wherein R is 1 or 2, and R is 2 or 3, and R is 3 or 4, and R is 4 or 5, and R is 2 or 3, and R is

[0052] [Section 15] Formula (4): [ka] [In the formula, R 1 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 is C 3-7 Cycloalkyl groups (the cycloalkyl groups may be one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 alkoxy) or cycloalkoxy group (the cycloalkoxy may be substituted with one or more of the same or different halogen atoms, C 1-4 Alkyl or C 1-4 ) which may be substituted with alkoxy. 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): [ka] (In formula (1b-1-1) or (1b-2-1), R b5 is C 1-4 Alkyl (the alkyl may contain one or more of the same or different halogen atoms, or C 1-4 ) which may be substituted with alkoxy. represents; L 2 represents a single bond or an oxygen atom.] Item 13. The compound according to any one of items 1 to 12, which is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0053] [Section 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 Item 16. The compound of item 15, wherein is a methyl group, or a pharmaceutically acceptable salt thereof.

[0054] [Section 17] R a2 is a cyclopropyl group optionally substituted with one or more of the same or different halogens, and R 2 Item 17. The compound or a pharmaceutically acceptable salt thereof according to item 15 or 16, wherein is a methyl group.

[0055] [Section 18] Ring G is the above formula (1b-2-1), and R b5 18. The compound or a pharmaceutically acceptable salt thereof according to any one of items 15 to 17, wherein is an isopropyl group.

[0056] [Section 19] Ring G is the above formula (1b-1-1), and R b5 18. The compound or a pharmaceutically acceptable salt thereof according to any one of items 15 to 17, wherein is an isobutyl group.

[0057] [Section 20] Ring G is the above formula (1b-1-1), and R b5 is an isopropyl group, and L 2 18. The compound or a pharmaceutically acceptable salt thereof according to any one of items 15 to 17, wherein is an oxygen atom.

[0058] [Section 21] Q 2 21. The compound or pharmaceutically acceptable salt thereof according to any one of items 15 to 20, wherein is an oxygen atom.

[0059] [Section 22] Item 1. The compound or pharmaceutically acceptable salt thereof according to Item 1, which is represented by the following compound name or structural formula: Example 22: 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 [ka] Example 23: 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 [ka] Example 24: 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 [ka] Example 25: 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 [ka] Example 62: 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 [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)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 68: 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 [ka] Example 69: 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 [ka] Example 79: 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 [ka] Example 80: 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. [ka]

[0060] [Section 23] Item 1. The compound or pharmaceutically acceptable salt thereof according to Item 1, which is represented by the following compound name or structural formula: Example 64: 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 [ka] Example 67: 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 [ka] Example 71: 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 [ka] Example 72: 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 [ka] Example 73: 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 [ka] Example 74: 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 [ka] Example 75: 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 [ka] Example 76: 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 [ka]

[0061] [Section 24] Item 1. The compound or pharmaceutically acceptable salt thereof according to Item 1, which is represented by the following compound name or structural formula: Example 82: 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 [ka] Example 95: 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 [ka] Example 96: 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 [ka] Example 97: 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 [ka] Example 99: 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 [ka] Example 110: 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 [ka] Example 111: 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 [ka] Example 112: 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 [ka] Example 114: 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 [ka] Example 115: 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 [ka] Example 128: 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 [ka] Example 134: 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 [ka] Example 136: 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 [ka] Example 137: 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 [ka] Example 138: 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 [ka] Example 139: 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 [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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide [ka] Example 156-A: 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 [ka] Example 156-B: 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 [ka] Example 157: 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 [ka] Example 158: 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 [ka] Example 159: 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 [ka] Example 161: 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 [ka]

[0062] [Section 25] Item 1. The compound or pharmaceutically acceptable salt thereof according to Item 1, which is represented by the following compound name or structural formula: Example 83: 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 [ka] Example 84: 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 [ka] Example 102: 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 [ka] Example 103: 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 [ka] Example 107: 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 [ka] Example 116: 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 [ka] Example 118: 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 [ka] Example 119: 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 [ka] Example 120: 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 [ka] Example 121: 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 [ka] Example 122: 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 [ka] Example 126: 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 [ka] Example 133: 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 [ka] Example 134: 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 [ka] Example 143: 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 [ka]

[0063] [Section 26] 26. A therapeutic agent for a disease associated with an orexin receptor, comprising the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0064] [Section 27] Item 26. A compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof, for use in 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 (e.g., cerebrovascular disease, encephalopathy ... For example, malignant mast cells, exogenous obesity, hyperinsulinaemic obesity, hyperplasmocytosis, pituitary obesity, hypoplasmocytosis, 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, coma and other disorders of consciousness, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorders, 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 levels 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 hormonal abnormalities, decreased fertility, infertility, male hypogonadism, and female hirsutism; fetal defects associated with maternal obesity; gastrointestinal motility disorders such as obesity-related gastroesophageal reflux; obesity-hypoventilation syndrome (Pickwickian syndrome); respiratory disorders such as dyspnea; inflammation such as systemic inflammation of the vascular system; risk of secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy; migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, 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 attacks, 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 damage, retinopathy, To treat cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug dependence, 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.

[0065] [Section 28] Item 26. 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 compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0066] [Section 29] A method for treating 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 administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0067] [Section 30] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 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. DETAILED DESCRIPTION OF THE INVENTION

[0068] The present invention will be described in more detail below. In the present specification, the number of carbon atoms in the definition of "substituent" is, for example, "C 1-6 " It may also be written as "C 1-6 The term "alkyl" is synonymous with alkyl having 1 to 6 carbon atoms. In this specification, when a substituent is not specifically designated with the term "optionally substituted" or "substituted", it means an "unsubstituted" substituent. For example, "C 1-6 "Alkyl" means "unsubstituted C 1-6 It means "alkyl."

[0069] In addition, in the description of substituents in this specification, the term "group" may be omitted. In addition, when defined as "optionally substituted," the number of substituents when present is not particularly limited as long as substitution is possible, and may be one or more. In other words, this indicates that the group may be substituted with the number of substituents that can be substituted on the substitutable carbon atoms, or the carbon atoms and nitrogen atoms, in the corresponding group. In addition, unless otherwise specified, the description of each group also applies when the group is a part or substituent of another group.

[0070] Unless otherwise specified in the present specification, the bonding position of a substituent may be any chemically possible position.

[0071] "Halogen" includes, for example, fluorine, chlorine, bromine, iodine, etc. Preferably, it is fluorine or chlorine.

[0072] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, and "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-4 Specific examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-6 In addition to the above, specific examples of "alkyl" include pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and structural isomers thereof. 1-6 Alkyl" or "C 1-4 As the "alkyl", methyl, ethyl, propyl and isopropyl are preferred, and methyl and isopropyl are more preferred.

[0073] "C 1-6 "Alkylene" means a linear or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 As "alkylene", preferably "C 1-4 alkylene", and more preferably "C 1-3 "C alkylene" is an example. 1-3 Specific examples of "alkylene" include methylene, ethylene, propylene, trimethylene, etc. 1-4 Specific examples of "alkylene" include the above-mentioned "C 1-3 In addition to the specific examples of "alkylene," butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, etc. are also included. 1-6 Specific examples of "alkylene" include the above-mentioned "C1-4 In addition to the specific examples of "alkylene," examples include pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, and the like.

[0074] "C 3-7 The term "cycloalkyl" refers to a cyclic non-aromatic hydrocarbon group (saturated hydrocarbon group and partially unsaturated hydrocarbon group) having 3 to 7 carbon atoms. 3-6 "Cycloalkyl". 3-7 "Cycloalkyl" also includes bridged groups. 3-7 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and the like.

[0075] Said “C 3-7 "Cycloalkyl" includes "C 3-7 Also encompassed are bicyclic groups formed by condensing "cycloalkyl" with a benzene ring or a 5- or 6-membered ring containing one, or two or more (e.g., 2 to 4) identical or different heteroatoms selected from nitrogen, sulfur, or oxygen (for example, a 5- or 6-membered ring of a "5- or 6-membered monocyclic heteroaryl" described below, and a "4- to 10-membered saturated heterocycle" described below).

[0076] "C 1-4 "Alkoxy" refers to the above "C 1-4 means an oxy group substituted with "alkyl" and "C 1-4 "Alkoxy" refers to the above "C 1-4 "C" means 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.

[0077] "C 3-7 "Cycloalkoxy" refers to the above "C 3-7 It means an oxy group substituted with "cycloalkyl". 3-6 "Cycloalkoxy". 3-7 Specific examples of "cycloalkoxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Preferred is cyclohexyloxy.

[0078] "C 6-10 An "aromatic carbocyclic group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 It is also referred to as "aryl." Phenyl is more preferred. 6-10 Specific examples of the "aromatic carbocyclic group" include phenyl, 1-naphthyl, and 2-naphthyl.

[0079] Said “C 6-10 The term "aromatic carbocyclic group" also encompasses groups formed by condensing "phenyl" with a 5- or 6-membered ring containing one, or two or more (e.g., 2 to 4), the same or different, heteroatoms selected from nitrogen, sulfur, or oxygen (e.g., a "5- or 6-membered monocyclic aromatic heterocyclic group" described below, or a 5- or 6-membered ring of a "4- to 10-membered saturated heterocycle" described below), or a 5- to 7-membered cycloalkyl ring (e.g., cyclopentane, cyclohexane, or cycloheptane).

[0080] The term "5- to 10-membered aromatic heterocyclic group" refers to a monocyclic or polycyclic 5- to 10-membered aromatic group containing, in addition to carbon atoms constituting the ring, one heteroatom or two or more (e.g., 2 to 4), the same or different, selected from nitrogen, sulfur, and oxygen, and is preferably a "5- or 6-membered monocyclic aromatic heterocyclic group." The term "5- or 6-membered monocyclic aromatic heterocyclic group" refers to a monocyclic 5- or 6-membered aromatic group among "5- to 10-membered aromatic heterocyclic groups."

[0081] Specific examples of the polycyclic aromatic heterocyclic group in the "5- to 10-membered aromatic heterocyclic group" include a group in which two identical or different monocyclic aromatic heterocycles are fused together, and a group in which a monocyclic aromatic heterocycle is fused with an aromatic ring (e.g., benzene) or a non-aromatic ring (e.g., cyclohexane). Specific examples of the "5- to 10-membered aromatic heterocyclic group" include pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In another embodiment, preferred examples include benzofuranyl (the bonding position is on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0082] "C 3-6 "Saturated carbocyclic ring" means a monocyclic saturated or partially unsaturated hydrocarbon ring having 3 to 6 carbon atoms. 3-6 Specific examples of the "saturated carbocyclic ring" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene, etc. Preferably, cyclopropane or cyclobutane is used.

[0083] The term "4- to 10-membered saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle composed of 4 to 10 atoms, containing, in addition to carbon atoms, one or two or more (e.g., 2 to 4, preferably 2 to 3, more preferably 2) identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms. This term includes those having a partially unsaturated bond, a partially bridged structure, and a partially spiro-substituted heterocycle. A 5- or 6-membered saturated heterocycle is preferred. Bicyclic saturated heterocycles also include those formed by condensing a monocyclic saturated heterocycle with benzene or a monocyclic 5- or 6-membered aromatic heterocycle. The saturated heterocycle may contain one or two carbonyls, thiocarbonyls, sulfinyls, or sulfonyls. Examples of such saturated heterocycles include lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates. Here, the oxygen atom of carbonyl, sulfinyl, and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number of members (ring size) and the number of heteroatoms constituting the ring. The "4-10-membered saturated heterocycle" preferably includes a monocyclic or bicyclic "4- to 8-membered saturated heterocycle", more preferably a monocyclic "4- to 6-membered saturated heterocycle", and even more preferably a monocyclic "5- or 6-membered saturated heterocycle". Specific examples of the "4- to 10-membered saturated heterocycle" include piperazine, oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, homopiperidinyl, oxetanyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, etc. Preferred are pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.Specific examples of bicyclic saturated heterocycles include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, and tetrahydropyridazepinyl.

[0084] The "4- to 6-membered saturated heterocyclic group" refers to a substituent in which the "4- to 6-membered saturated heterocyclic ring" is a monovalent group among the above-mentioned "4- to 10-membered saturated heterocyclic rings." Preferred examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl. R b8 and R b9 and , taken together with the nitrogen atom to which they are bonded, form a "3- to 7-membered nitrogen-containing saturated heterocycle" which has 3 to 7 atoms constituting the ring of the above "4- to 10-membered saturated heterocycle" and contains one nitrogen atom in addition to carbon atoms constituting the ring.

[0085] The compounds of the present invention also include various hydrates, solvates and crystalline polymorphs.

[0086] The compounds of the present invention may also contain isotopes (e.g., D, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 35 S, 18 F, 125 I, etc.), and these compounds are also included in the compounds of the present invention.

[0087] In the present invention, "pharmaceutically acceptable salt" refers to an acid addition salt and a base addition salt that are pharmaceutically acceptable. Examples of "pharmaceutically acceptable salt" include, but are not limited to, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, Examples of acid addition salts include xinafoate, pamoate, cinnamate, adipate, cysteine ​​salt, N-acetylcysteine ​​salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer salt; 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.

[0088] The compound of the present invention can be administered orally or parenterally, either directly or in the form of a formulation, medicament, or pharmaceutical composition using an appropriate dosage form. Specific examples of these dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. These formulations can be produced by known methods using additives commonly used as pharmaceutical additives.

[0089] These additives may include, depending on the purpose, excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavors, etc. Specific examples of these additives include, but are not limited to, 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, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0090] The dose of the compound of the present invention is appropriately selected depending on the animal to be administered, the administration route, the disease, the age, weight and symptoms of the patient. For example, in the case of oral administration, 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 divided doses.

[0091] The compound of the present invention has agonistic activity against orexin receptors. Therefore, it can be a useful preventive or therapeutic agent for diseases associated with 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 dementia with Lewy bodies, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with 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, and Hashimoto's encephalopathy), coma, loss of consciousness, obesity ( For example, malignant mast cells, exogenous obesity, hyperinsulinaemic obesity, hyperplasmocytosis, pituitary obesity, hypoplasmocytosis, 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, coma and other disorders of consciousness, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorders, 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 levels 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 hormonal abnormalities, decreased fertility, infertility, male hypogonadism, and female hirsutism; fetal defects associated with maternal obesity; gastrointestinal motility disorders such as obesity-related gastroesophageal reflux; obesity-hypoventilation syndrome (Pickwickian syndrome); respiratory disorders such as dyspnea; inflammation such as systemic inflammation of the vascular system; risk of secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy; migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flashes, night sweats, and genital / Disorders of the urinary system, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, 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 damage, retinopathy , cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced 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, and traumatic brain injury. Preferred examples include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy bodies.

[0092] The production method of the compound represented by formula (1) of the present invention will be explained below with examples, but the present invention is not limited to these.

[0093] Manufacturing method The compound of the present invention may be synthesized by a combination of the following production method and a known synthesis method. The compounds in the reaction schemes may each form a salt, and examples of such salts include those similar to the above-mentioned "pharmaceutically acceptable salts." Note that these reactions are merely illustrative, and the compounds of the present invention may also be produced by other appropriate methods based on the knowledge of those skilled in organic synthetic chemistry.

[0094] In each of the production methods described below, even if the use of a protecting group is not specifically specified, when a functional group that requires protection is present, the functional group may be protected as necessary, and the target product may be obtained by deprotecting the functional group after completion of the reaction or after performing a series of reactions.

[0095] Examples of the protecting group include conventional protecting groups described in the literature (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 3rd Ed., John Wiley and Sons, Inc., New York (1999)). More specifically, examples of protecting groups for amino groups include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and tetrahydropyranyl. Examples of protecting groups for hydroxy groups include trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, and methoxymethyl. Examples of protecting groups for aldehyde groups include dialkyl acetals and cyclic alkyl acetals. Examples of protecting groups for carboxyl groups include tert-butyl esters, orthoesters, and amides.

[0096] Introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 3rd Ed., John Wiley and Sons, Inc., New York (1999)) or a method similar thereto.

[0097] Manufacturing method 1: Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, A 3 The compound represented by formula (s-1-1) or a pharmaceutically acceptable salt thereof, in which is a nitrogen atom, can be produced, for example, by the following production method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 , and the dashed line part are the same as in item 1.)

[0098] Process (1-1): Compound (s-1-1) can be produced by reacting compound (s-1-2) and compound (s-1-3) in an appropriate inert solvent under commonly used urea bond formation conditions. Examples of reaction conditions include triphosgene, 4-nitrophenyl chloroformate, 1,1'-carbonyldiimidazole, or thiophosgene. A base is used in this reaction, and examples of the base include triethylamine and diisopropylethylamine. 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 about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0099] In step (1-1), the intermediate isocyanate or the like may be isolated for subsequent conversion.

[0100] Manufacturing method 2: Among the compounds represented by formula (s-1-3), the compound represented by formula (s-2-1) having no unsaturated bond in the ring can be produced, for example, by the following production method. (However, L 2 is an oxygen atom or -NR 10 -compound or L 2 is a single bond and ring G is linked to cycloalkyl via a nitrogen atom. 10 is H or C 1-4 The same applies hereinafter unless otherwise specified.) [ka] (In the formula, R 3 , R 4 , L 2 , n, ring G, and the dashed line portion are the same as in item 1. 1 represents a suitable protecting group, and LG represents a suitable leaving group, and the same applies hereinafter unless otherwise specified.)

[0101] Compound (s-2-1) can be synthesized from compound (s-2-2) via steps (2-1) and (2-2).

[0102] Process (2-1): Compound (s-2-4) can be produced by reacting compound (s-2-2) with compound (s-2-3) in an appropriate inert solvent without additives or in the presence of an acid or 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, and Lewis acids such as zinc(II) chloride, scandium triflate(III), copper(I) chloride, boron trifluoride, boronic acid, and boronate esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as potassium tert-butoxide; 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.

[0103] Process (2-2): Compound (s-2-1) can be produced by reacting compound (s-2-4) in an appropriate 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 on carbon, and palladium(II) hydroxide. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane; ethers such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters such as ethyl acetate and methyl acetate; and alcohols such as methanol and ethanol. The reaction time is typically about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0104] Compound (s-2-1) can also be synthesized from compound (s-2-5) via steps (2-3) and (2-4).

[0105] Process (2-3): Compound (s-2-6) can be produced by subjecting compound (s-2-5) and compound (s-2-3) to conventional aziridine ring-opening reaction conditions in an appropriate inert solvent, either without additives or in the presence of an acid or 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 boronate esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as potassium tert-butoxide; 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.

[0106] Process (2-4): Compound (s-2-1) can be prepared by converting compound (s-2-6) into a compound (s-2-2) by a known method (e.g., Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformations, RC Laroque et al., VCH Publishers Inc., 1989, etc.) to remove the protecting groups.

[0107] The compound (s-2-1) can also be synthesized from the compound (s-2-7) via steps (2-5) to (2-7) and step (2-4).

[0108] Process (2-5): Compound (s-2-8) can be produced by subjecting compound (s-2-7) and compound (s-2-3) to conventional epoxide ring-opening reaction conditions in an appropriate inert solvent, either without additives or in the presence of an acid or 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, and Lewis acids such as boron trifluoride, zinc(II) chloride, scandium triflate(III), copper(I) chloride, boronic acid, and boronate esters. Examples of bases used in this reaction include organic bases such as triethylamine, diisopropylethylamine, and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as potassium tert-butoxide; 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.

[0109] Process (2-6): Compound (s-2-9) can be produced by subjecting compound (s-2-8) to commonly used conditions for converting a hydroxyl group to a leaving group in an appropriate inert solvent. Examples of reaction conditions include those using methanesulfonyl chloride, paratoluenesulfonyl chloride, or trifluoromethanesulfonyl chloride. A base is also used in this reaction. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, or DBU; inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate; metal alkoxides such as potassium tert-butoxide; 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 usually about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0110] Process (2-7): Compound (s-2-6) is a compound (s-2-9) and P 1 The synthesis can be carried out using NH2 and a base under standard nucleophilic substitution reaction 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, or potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyllithium or isopropylmagnesium chloride; and metal amide reagents such as LDA or LHMDS. Examples of solvents used include halogenated carbons such as chloroform and dichloromethane; ethers such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; and esters such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0111] Steps (2-6) and (2-7) may be carried out in one step without isolating the intermediate, or by using the Mitsunobu reaction conditions, step (2-6) and step (2-7) may be carried out in one step.

[0112] Manufacturing method 3-1: Among the compounds represented by formula (s-2-1), L 2 The compound represented by formula (s-3-1) in which is a single bond and ring G is linked to cycloalkyl via a nitrogen atom can also be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , n, and the ring G are synonymous with term 1.)

[0113] The compound (s-3-1) can be produced from the compound (s-2-2) via steps (3-1) to (3-3).

[0114] Process (3-1): Compound (s-3-2) can be produced by reacting compound (s-2-2) with ammonia or a reagent equivalent to ammonia (including a case where compound (s-2-2) is reacted with a protected amine reagent followed by a deprotection reaction, or a case where compound (s-2-2) is reacted with an azide-introducing reagent followed by conversion to an amino group by a reduction reaction) under conditions similar to those in step (2-1).

[0115] Process (3-2): Compound (s-3-3) can be produced by a reaction step of forming a nitrogen-containing heterocycle using compound (s-3-2). For example, when ring G is piperazine, it can be produced by reacting with N-benzyl-bis(2-chloroethyl)amine, followed by deprotection and alkylation.

[0116] Process (3-3): The compound (s-3-1) can be produced using the compound (s-3-3) under the same conditions as in the step (2-2).

[0117] The compound (s-3-1) can also be synthesized from the compound (s-2-5) via steps (3-4) to (3-6).

[0118] Process (3-4): Compound (s-3-4) can be produced by reacting compound (s-2-5) with ammonia or a reagent equivalent to ammonia (including a case where compound (s-2-5) is reacted with a protected amine reagent followed by a deprotection reaction, or a case where compound (s-2-5) is reacted with an azide-introducing reagent followed by conversion to an amino group by a reduction reaction) under the same conditions as in step (2-3).

[0119] Process (3-5): The compound (s-3-5) can be synthesized using the compound (s-3-4) by a reaction process similar to that in step (3-2).

[0120] 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).

[0121] Manufacturing method 3-2: The compound represented by formula (s-3-1) can also be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , n, and the ring G are synonymous with term 1.)

[0122] Compound (s-3-1) can be produced from compound (s-3-6) via steps (3-7) and (3-8).

[0123] Process (3-7): Compound (s-3-6) is the compound (s-2-9) shown in Production Method 2, which is L 2is a single bond and the G ring is linked to a cycloalkyl via a nitrogen atom. Compound (s-3-7) can be synthesized by reacting compound (s-3-6) with a commonly used base under general intramolecular nucleophilic substitution reaction conditions similar to those in step (2-7). Compound (s-3-7) may be used in the next reaction without isolation.

[0124] 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 a reagent equivalent to ammonia (including the case of reacting compound (s-3-7) with a protected amine reagent followed by a deprotection reaction, or the case of reacting compound (s-3-7) with an azide-introducing reagent followed by conversion to an amino group by a reduction reaction).

[0125] 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, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , n, and ring G have the same meaning as in item 1. Y is O or NR 10 (The same applies below even if there is no explanation.)

[0126] The compound (s-4-1) can be synthesized from the compound (s-2-2) via steps (4-1) to (4-3).

[0127] Process (4-1): Compound (s-4-2) can be prepared by the reaction of YH2 or an equivalent reagent (protected reagent P 2 YH, followed by deprotection: 2 represents a suitable protecting group, and this applies hereinafter even if there is no explanation.) under the same conditions as in step (2-1) to react compound (s-2-2).

[0128] 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 standard nucleophilic substitution reaction conditions or aromatic nucleophilic substitution reaction 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, or potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyllithium or isopropylmagnesium chloride; and metal amide reagents such as LDA or LHMDS. Examples of solvents used include halogenated carbons such as chloroform and dichloromethane; ethers such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; and esters such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0129] Process (4-3): The compound (s-4-1) can be produced using the compound (s-4-3) under the same conditions as in the step (2-2).

[0130] The compound (s-4-1) can also be synthesized from the compound (s-2-5) via steps (4-4) to (4-6).

[0131] Process (4-4): Compound (s-4-4) can be produced by reacting compound (s-2-5) with YH2 or an equivalent reagent (including the case of reacting with a protected reagent P2YH, followed by a deprotection reaction) under the same conditions as in step (2-3).

[0132] Process (4-5): The compound (s-4-5) can be synthesized using the compound (s-4-4) by a reaction process similar to that in step (4-2).

[0133] 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).

[0134] Manufacturing method 5: The compound represented by formula (s-2-5) can be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , and n are synonymous with term 1.)

[0135] The compound (s-2-5) can be synthesized from the compound (s-5-1) via steps (5-1) to (5-4).

[0136] 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 an oxidizing agent such as aqueous hydrogen peroxide, mCPBA, tert-butyl hydroperoxide, or oxone. If necessary, a metal catalyst containing V, Mo, Al, Ti, Fe, Ta, Zr, Nb, W, Re, or the like may be added to this reaction. 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 is from -20°C to the boiling point of the solvent.

[0137] Process (5-2): Compound (s-5-2) can be synthesized by subjecting compound (s-2-7) and P1NH2 to the same conditions as in step (2-5) in an appropriate inert solvent.

[0138] In step (5-2), compound (s-2-7) is reacted with ammonia or a reagent equivalent to ammonia (including a case where a deprotection reaction is carried out after reaction with a protected amine reagent, or a case where an azide-introducing reagent is reacted with compound (s-2-7) and then converted to an amino group by a reduction reaction), followed by the addition of a protecting group P 1 It can also be synthesized under conditions where the compound is protected with

[0139] Process (5-3): Compound (s-5-3) can be produced by subjecting compound (s-5-2) to the same conditions as in step (2-6) in a suitable inert solvent.

[0140] Process (5-4): Compound (s-2-5) can be produced by subjecting compound (s-5-3) to commonly used intramolecular cyclization conditions in a suitable inert solvent in the presence of a base. Examples of the base 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 potassium tert-butoxide; 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 about 1 to 24 hours, and the reaction temperature is between −20°C and the boiling point of the solvent.

[0141] Steps (5-3) and (5-4) may be carried out in one step without isolating the intermediate, or by using the Mitsunobu reaction conditions, step (5-3) and step (5-4) may be carried out in one step.

[0142] Compound (s-2-5) can also be synthesized from compound (s-5-1) via step (5-5).

[0143] 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. 1 The oxidizing conditions using NH2 and iodosylbenzene under metal catalyst and the hydroxylamine derivative P 1 These include conditions using N(H)O-LG and a metal catalyst.

[0144] Manufacturing method 6: Among the compounds represented by formula (s-1-1), the compound represented by formula (s-6-1) having an unsaturated bond in the ring can be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , L 2 , n, and ring G are the same as defined in item 1. Z represents boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin, zinc halide, or a hydrogen atom, and X represents a halogen.

[0145] Compound (s-6-1) can be synthesized from compound (s-6-6) via step (6-7), and 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).

[0146] Process (6-1): Among compounds (s-6-4), L 2 is a single bond or methylene (the methylene is one or more of the same or different C 1-4The compound (s-6-2) is optionally substituted with alkyl, and is produced by reacting the compound (s-6-2) with a compound (s-6-3) in which Z is boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin, or zinc halide in a suitable inert solvent in the presence of a palladium catalyst and a phosphine ligand, and optionally in the presence of a base. Compound (s-6-3) can be commercially purchased or synthesized by a known method or a method analogous thereto. Examples of the palladium catalyst 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 the phosphine ligand 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 the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc. Examples of the inert solvent include 1,4-dioxane, THF, 1,2-dimethoxyethane, acetonitrile, water, and mixtures thereof. The reaction time is usually about 1 hour to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0147] In addition, among compounds (s-6-4), L 2 is O or NR 10 The compound represented by the formula (s-6-2) can also be produced by reacting the compound (s-6-2) with the compound (s-6-3) in which Z is a hydrogen atom in the presence of a palladium catalyst, a phosphine ligand, and a base in a suitable inert solvent.

[0148] Process (6-2): Compound (s-6-5) can be produced using compound (s-6-4) under the same conditions as in step (2-6).

[0149] Process (6-3): Compound (s-6-6) is a compound (s-6-5) and P 1 It can be produced by subjecting NH2 to the same conditions as in step (2-7).

[0150] In step (6-3), compound (s-6-5) is reacted with ammonia or a reagent equivalent to ammonia (including a case where a deprotection reaction is carried out after reaction with a protected amine reagent, or a case where an azide-introducing reagent is reacted with the compound (s-6-5) and then converted to an amino group by a reduction reaction), followed by the addition of a protecting group P 1 The condition for protection may be

[0151] Steps (6-2) and (6-3) may be carried out in one step without isolating the intermediate, or by using the Mitsunobu reaction conditions, step (6-2) and step (6-3) may be carried out in one step.

[0152] Process (6-4): Compound (s-6-7) can be produced using compound (s-6-2) under the same conditions as in step (6-2).

[0153] Process (6-5): Compound (s-6-8) can be produced using compound (s-6-7) under the same conditions as in step (6-3).

[0154] In step (6-5), compound (s-6-7) is reacted with ammonia or a reagent equivalent to ammonia (including a case where a deprotection reaction is performed after reaction with a protected amine reagent, or a case where an azide-introducing reagent is reacted with the compound (s-6-7) and then converted to an amino group by a reduction reaction), followed by the addition of a protecting group P 1 The condition for protection may be

[0155] Steps (6-4) and (6-5) may be carried out in one step without isolating the intermediate, or by using the Mitsunobu reaction conditions, step (6-4) and step (6-5) may be carried out in one step.

[0156] Process (6-6): Compound (s-6-6) can be produced using compound (s-6-8) under the same conditions as in step (6-1).

[0157] 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).

[0158] Manufacturing method 7: Among the compounds represented by formula (s-1-1), the compound represented by formula (s-7-1) which does not have an unsaturated bond in the ring can also be produced, for example, by the following production method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 , n, ring G, and A 1 is equivalent to term 1.)

[0159] Compound (s-7-1) can be synthesized from compound (s-7-4) via step (7-6), and compound (s-7-4) can 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).

[0160] 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).

[0161] Process (7-2): Compound (s-7-3) can be produced using compound (s-7-2) and compound (s-1-2) under the same urea-forming conditions as in step (1-1). In this step, protection and deprotection of the hydroxyl group may be carried out if necessary.

[0162] Process (7-3): Compound (s-7-4) can be produced using compound (s-7-3) through steps similar to steps (5-3) and (5-4).

[0163] 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).

[0164] Process (7-5): Compound (s-7-4) can be produced using compound (s-7-5) and compound (s-1-2) under the same urea-forming conditions as in step (1-1).

[0165] Process (7-6): Compound (s-7-1) can be produced using compound (s-7-4) and compound (s-2-3) under the same aziridine ring-opening reaction conditions as in step (2-3).

[0166] Manufacturing method 8: The compound represented by formula (s-1-1) can also be produced from compound (s-8-1) through steps (8-1) to (8-3). [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 , and the dashed line part are the same as in item 1.)

[0167] Process (8-1): Compound (s-8-2) can be prepared by reacting compound (s-8-1) in an appropriate inert solvent under commonly used acyl azide-forming conditions. Examples of suitable reaction conditions include the use of diphenylphosphoryl azide or the conversion to an acid halide followed by the reaction with a metal azide. Examples of suitable inert solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; esters 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 is between -20°C and the boiling point of the solvent.

[0168] Process (8-2): Compound (s-8-3) can be prepared by reacting compound (s-8-2) in a suitable inert solvent under commonly used Curtius rearrangement conditions, and compound (s-8-2) used here does not need to be isolated from the previous step.

[0169] Process (8-3): Compound (s-1-1) can be produced by reacting compound (s-8-3) with 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.

[0170] Manufacturing method 9: Among the compounds (s-8-1), the compound represented by formula (s-9-1) which does not have an unsaturated bond in the ring can be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , L 2 , n, and the ring G are the same as in item 1. 3is a suitable protecting group or C 1-3 The same applies hereinafter unless otherwise specified.)

[0171] Compound (s-9-1) can be synthesized from compound (s-9-2) via steps (9-1) and (9-2).

[0172] 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).

[0173] Process (9-2): Compound (s-9-1) can be produced by subjecting compound (s-9-3) to general hydrolysis conditions or deprotection conditions.

[0174] Compound (s-9-1) can be synthesized from compound (s-2-9) via steps (9-3) and (9-4).

[0175] Process (9-3): The compound (s-9-4) can be produced by subjecting the compound (s-2-9) and a metal cyanide to the same conditions as in the step (2-7).

[0176] Process (9-4): Compound (s-9-1) can be produced by reacting compound (s-9-4) in a suitable inert solvent under commonly used hydrolysis conditions.

[0177] Manufacturing method 10: Among the compounds (s-8-1), the compound represented by formula (s-10-1) having an unsaturated bond in the ring can be produced, for example, by the following production method. [ka] (In the formula, R 3 , R 4 , L 2, n, and ring G are the same as defined in item 1. Z represents boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin, zinc halide, or a hydrogen atom, and X represents a halogen.

[0178] Compound (s-10-1) can be synthesized from compound (s-10-2) via step (10-2), and compound (s-10-2) can be synthesized from compound (s-6-5) via step (10-1) or from compound (s-6-7) via steps (10-3) and (10-4).

[0179] 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).

[0180] Process (10-2): Compound (s-10-1) can be produced by reacting compound (s-10-2) in a suitable inert solvent under commonly used hydrolysis conditions.

[0181] 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).

[0182] 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).

[0183] Manufacturing method 11: Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, A 3 The compound of formula (s-11-1) or a pharmaceutically acceptable salt thereof, in which is represented by a carbon atom, can be produced, for example, by the following production method. [ka] (In the formula, R 1~R 4 , L 1 , L 2 , n, ring G, and the dashed line are the same as in item 1.)

[0184] Process (11-1): Compound (s-11-1) can be produced by reacting compound (s-11-2) and compound (s-1-3) in a suitable inert solvent under commonly used amide bond forming conditions. The reaction conditions include those using a condensing agent and a base. Examples of the condensing agent 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 of suitable bases include organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBU, pyridine, and dimethylaminopyridine. Examples of suitable 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 typically about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0185] Compound (s-11-1) can also be synthesized from compound (s-11-2) via steps (11-2) and (11-3).

[0186] Process (11-2): Compound (s-11-3) can be synthesized by subjecting compound (s-11-2) to commonly used acid halide-forming conditions in an appropriate 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. Examples of suitable 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 is between -20°C and the boiling point of the solvent.

[0187] Process (11-3): Compound (s-11-1) can be obtained by reacting compound (s-11-3) with compound (s-1-3) in the presence of a base in an appropriate inert solvent. Examples of the base 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 the inert solvent 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 is from -20°C to the boiling point of the solvent.

[0188] Manufacturing method 12: Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, A 2The compound represented by formula (s-12-1) or a pharmaceutically acceptable salt thereof, in which represents an oxygen atom, can be produced, for example, by the following production method. [ka] (In the formula, R 1 ~R 4 , L 1 , L 2 ,n,ring G,A 1 , and the dashed line part are the same as in item 1.)

[0189] Process (12-1): Compound (s-12-1) can be produced by reacting compound (s-1-2) and compound (s-12-2) in an appropriate inert solvent under commonly used carbamate-forming conditions. Examples of reaction conditions include triphosgene, 4-nitrophenyl chloroformate, or thiophosgene. A base is used in this reaction, and examples of the base include triethylamine and diisopropylethylamine. 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 about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0190] Among the compounds represented by formula (s-12-2), if they do not have an unsaturated bond in the ring, the production method is the same as that for compound (s-2-8).If they have an unsaturated bond in the ring, the production method is the same as that for compound (s-6-4).

[0191] Manufacturing method 13: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-13-1) can be produced, for example, by the following production method. [ka] (In the formula, R2 is synonymous with term 1. R a1 and Q 2 is the same as Item 4. Also, P 4 indicates an appropriate protecting group, and the same applies hereinafter unless otherwise specified.)

[0192] Process (13-1): Compound (s-13-4) can be produced by reacting compound (s-13-2) and compound (s-13-3) in a suitable inert solvent under commonly used addition reaction conditions. 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 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.

[0193] Process (13-2): Compound (s-13-6) can be produced by reacting compound (s-13-4) and compound (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, and examples of the base include triethylamine or diisopropylethylamine. Examples of 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 is between -20°C and the boiling point of the solvent.

[0194] Process (13-3): Compound (s-13-7) can be prepared by subjecting compound (s-13-6) to a reaction in an appropriate inert solvent under commonly used dehydration reaction conditions. This reaction may optionally be carried out in the presence of a base such as triethylamine or DBU. 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 about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0195] Process (13-4): Compound (s-13-1) can be prepared by converting compound (s-13-7) into a compound (s-13-2) by a known method (e.g., Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformations, RC Laroque et al., VCH Publishers Inc., 1989, etc.) to remove the protecting groups.

[0196] Manufacturing method 14: Among the compounds represented by formula (s-1-2), L 1 is a single bond and R 1 The compound represented by formula (s-14-1), in which is an optionally substituted 5-membered aromatic heterocyclic group, can be produced, for example, by the following production method. [ka] (In the formula, R 2 is synonymous with term 1, and X 4 and R a1 is equivalent to Term 4.)

[0197] The compound (s-14-1) can be synthesized from the compound (s-14-2) through steps (14-1) to (14-3).

[0198] Process (14-1): Compound (s-14-3) can be produced by reacting compound (s-14-2) in an appropriate inert solvent under commonly used chlorination reaction conditions. Examples of reaction conditions include those using chlorine, N-chlorosuccinimide, or benzyltrimethylammonium tetrachloroiodate. 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; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; water; or a mixture thereof. The reaction time is typically about 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0199] Process (14-2): Compound (s-14-5) can be produced by reacting compound (s-14-3) with compound (s-14-4) in an appropriate inert solvent under commonly used 1,3-dipolar cyclization reaction conditions. Examples of conditions for this reaction include conditions using a base. Examples of the base 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, and organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, and NMM. 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.

[0200] Process (14-3): Compound (s-14-1) can be produced using compound (s-14-5) in the same manner as in step (13-4).

[0201] Manufacturing method 15: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-15-1) can be produced, for example, by the following production method. [ka] (In the formula, R 2 is synonymous with term 1, and X 1 ~X 3 , Q 1 and R a6 is equivalent to Term 4.)

[0202] Process (15-1): Compound (s-15-4) can be produced by reacting compound (s-15-2) and compound (s-15-3) in an appropriate inert solvent under the same condensation reaction conditions as in step (13-2).

[0203] Process (15-2): Compound (s-15-5) can be produced by subjecting compound (s-15-4) to a reaction under commonly used dehydration reaction conditions in an appropriate inert solvent, or under cyclization reaction conditions after treatment with Lawesson's reagent or the like.

[0204] Process (15-3): Compound (s-15-1) can be produced using compound (s-15-5) in the same manner as in step (13-4).

[0205] Manufacturing method 16: Among the compounds represented by formula (s-1-2), L 1 is a single bond and R 1 optionally substituted C 6-10The compound represented by formula (s-16-5), which is an aromatic carbocyclic group, or the compound represented by formula (s-16-8), which is an optionally substituted 5- to 10-membered aromatic heterocyclic group, can be produced, for example, by the following production method. [ka] (In the formula, R 1 and R 2 has the same meaning as in item 1. Z is exemplified in the following step (16-1). X is a halogen.

[0206] The compound (s-16-5) can be synthesized from the compound (s-16-1) through steps (16-1) to (16-3).

[0207] Process (16-1): Compound (s-16-1) can be subjected to various coupling reactions in the presence of a base and a metal catalyst with an organoboron compound (e.g., when Z is B(OH)), an organozinc compound (e.g., when Z is ZnCl), an alkenyl compound, an alkynyl compound, a hydroxy compound (e.g., when Z is OH), an amine compound (e.g., when Z is NH), or a metal cyanide (e.g., CuCN). Examples of 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, as well as organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, and NMM. Depending on the type of coupling, a base may not be used. Examples of metal catalysts that can be used include bis(tris(tert-butylphosphine)palladium, bis(tris(o-tolylphosphine)dichloropalladium, bis(tris(o-tolylphosphine)palladium, tetrakistriphenylphosphinepalladium, dichloropalladium (acetonitrile), bis(tris(o-tolylphosphine)dichloropalladium, (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium, and PEPPSI™ IPr ((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride). For palladium acetate or palladium chloride, appropriate ligands can be selected from those listed in "Palladium Reagents and Catalysts," John Wiley & Sons Inc. (2004)" or their related ligands.Examples of solvents that can be used include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; water; and 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.

[0208] Process (16-2): Compound (s-16-4) can be prepared by subjecting compound (s-16-3) to a reaction in an appropriate inert solvent, or, if necessary, under a hydrogen atmosphere, under commonly used alkene reduction reaction conditions. Examples of reaction conditions include those using reducing agents such as palladium on carbon, palladium(II) hydroxide, platinum on carbon, platinum(IV) oxide, Raney nickel, ruthenium on carbon, and chlorotris(triphenylphosphine)rhodium(I). Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane; ethers such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol and ethanol; and esters such as ethyl acetate and methyl acetate. The reaction time is typically about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0209] Process (16-3): Compound (s-16-5) can be produced using compound (s-16-4) in the same manner as in step (13-4).

[0210] The compound (s-16-8) can be synthesized from the compound (s-16-1) via steps (16-1) and (16-4) to (16-6).

[0211] Process (16-4): Compound (s-16-6) can be prepared by alkylation reaction of compound (s-16-3), alkylating agent R 2 It can be produced by reacting -X with a base. Examples of bases that can be used in this reaction include LDA, LHMDS, and n-butyllithium. Examples of inert solvents include 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 usually about 1 to 24 hours, and the reaction temperature is between -20°C and the boiling point of the solvent.

[0212] 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) (except that sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride may be used as the reducing agent).

[0213] Process (16-6): Compound (s-16-8) can be produced using compound (s-16-7) in the same manner as in step (13-4).

[0214] Manufacturing method 17: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-17-1) can be produced, for example, by the following production method. [ka] (In the formula, R 1 is synonymous with term 1. R 8 is C 1-3 represents alkyl.

[0215] Process (17-1): Compound (s-17-3) can be prepared by alkylation of compound (s-17-2) and alkylating agent R in a suitable inert solvent under the same alkylation reaction conditions as in step (16-4). 1 -X (X represents a halogen) to produce the compound.

[0216] Process (17-2): Compound (s-17-4) can be produced by reacting compound (s-17-3) in an appropriate inert solvent under commonly used reduction reaction conditions. Examples of conditions for this reaction 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 is from -20°C to the boiling point of the solvent.

[0217] Process (17-3): Compound (s-17-5) can be prepared by reacting compound (s-17-4) under Barton-McCombie deoxygenation conditions in a suitable inert solvent.

[0218] Process (17-4): Compound (s-17-1) can be produced using compound (s-17-5) in the same manner as in step (13-4). [Example]

[0219] The present invention will be explained in more detail below with reference to the following examples, examples, and experimental examples, but the present invention is not limited to these examples. The names of compounds shown in the following examples and experimental examples do not necessarily conform to the IUPAC nomenclature.

[0220] The following abbreviations may be used in this specification: 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]non-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 chemical structure of a compound marked with the abbreviation Abs enclosed in a box indicates that the wedge-shaped bond is represented as the absolute configuration. However, this does not necessarily mean that the chemical structure of a compound without this abbreviation does not represent the absolute configuration, and this can be determined based on the description of the subject compound in this specification, the context, and the common sense of a person skilled in the art.

[0221] In the Reference Examples and Examples, column chromatography and amino chromatography were carried out using silica gel columns and amino columns manufactured by Yamazen Co., Ltd. When purifying using TLC, Silica gel 60F254 (Merck) was used for TLC (silica gel plate), and TLC plate NH (FujiSilysia) was used for TLC (NH silica gel plate).

[0222] 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

[0223] The symbols used in NMR are s for singlet, d for doublet, dd for double doublet, ddd for double double doublet, dddd for double double double double doublet, t for triplet, td for triplet doublet, q for quartet, m for multiplet, br for broad singlet or multiplet, and J for coupling constant.

[0224] LC / MS data for each compound in the Examples and Reference Examples was obtained using one of the following instruments. Method A Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC® 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 Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm × 30 mm)

[0225] The measurement conditions for the high-performance liquid chromatography mass spectrometer (LC / MS) were as follows. The observed mass spectrometry values ​​[MS (m / z)] were calculated as [M+H]. + The retention time is indicated as Rt (min). For each measured value, the measurement conditions used are indicated as one of A to D. Method A Solvent: Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / acetonitrile Gradient conditions: 0.0-1.3 min (linear gradient from 2% B to 96% B) Flow rate: 0.8 mL / min; detection UV: 220 nm and 254 nm; temperature: 40℃ Hereinafter, LC-MS data shown are those measured by Method A unless otherwise specified. Method B Solvent: Solution A: 0.05% TFA / H2O, Solution B: acetonitrile Gradient conditions: 0.0-1.7 min (linear gradient from 10% B to 99% B) Flow rate: 0.5 mL / min; UV detection: 220 nm; Temperature: 40°C Method C Solvent: Solution A: 0.05% formic acid / H2O, Solution B: acetonitrile Gradient conditions: 0.0-1.3 min (linear gradient from 10% B to 95% B), 1.3-1.5 min (10% B) Flow rate: 0.8 mL / min; detection UV: 220 nm and 254 nm; temperature: 40℃

[0226] Example 1: rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide [ka] To a mixture of Reference Example 1 (211 mg) (raw material A), triethylamine (0.391 mL), and chloroform (3 mL) was added 4-nitrophenyl chloroformate (208 mg) at 0°C and stirred at that 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, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0227] Examples 2 to 16: The compounds of Examples 2 to 16 shown in the table below were produced in the same manner as in Example 1, except that the commercially available compounds or compounds of Reference Examples shown in the table below were used as compounds corresponding to the raw materials A and B described in Example 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0228] The names of the compounds in 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-oxadiazol-3-yl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide Example 4: rac-N-{(1R,2S,6S)-2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 5: rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-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)piperazin-1-yl]cyclopentyl}piperidine-1-carboxamide Example 7: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2S)-3,3-difluoro-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 8: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 9: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxylate Example 10: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate Example 11: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxylate Example 12: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxylate Example 13: rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-4-methylpiperidine-1-carboxylate Example 14: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2,4-oxadiazol-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)pyridin-3-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide Example 16: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{2-[6-(propan-2-yl)pyridin-3-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide

[0229] Example 17: rac-N-[(1S,2S)-2-(4-ethylpiperazin-1-yl)cyclohexyl]-4-(4-methylphenyl)piperidine-1-carboxamide [ka] To a mixture of Reference Example 2 (73.7 mg), sodium acetate (18.9 mg), acetaldehyde (0.054 ml), and dichloromethane (2 ml) was added sodium borohydride triacetate (122 mg) at 0°C, and the mixture was warmed to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0230] Example 18: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{2-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide [ka] A hydrogen chloride / acetic acid solution (4 M, 0.198 mL) was added to a chloroform solution (2 mL) of Reference Example 13 (13.5 mg), and the mixture was stirred at room temperature. After confirming the disappearance of the starting materials, the mixture was concentrated under reduced pressure, and sodium acetate (8.66 mg), acetone (0.058 mL), and chloroform (2 mL) were added. Sodium triacetate borohydride (33.6 mg) was added at 0°C, and the mixture was warmed to room temperature and stirred. After completion of the reaction, water was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0231] Example 19: 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-carboxamide [ka] To a mixture of Reference Example 14 (84.6 mg) (raw material A), triethylamine (0.318 mL), and chloroform (2 mL), triphosgene (27.1 mg) was added at 0°C and stirred at that 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, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give 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).

[0232] Examples 20 to 76: Examples 20 to 76 shown in the table below were produced in the same manner as in Example 19, using commercially available compounds or reference examples shown 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]

[0233] The names of the compounds in 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)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 21: rac-4-(1,3-benzoxazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-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)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 23: 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 Example 24: 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 Example 25: 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 Example 26: rac-4-cyclopentyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 27: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)piperidine-1-carboxamide Example 28: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 29: rac-4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-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)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 31: rac-4-(5-cyclopropyl-1,2,4-thiadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 32: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(pyridin-2-yl)piperidine-1-carboxamide Example 33: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-8-azaspiro[4.5]decane-8-carboxamide Example 34: rac-4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 35: rac-4-cyclohexyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide Example 36: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(pyrimidin-2-yl)piperidine-1-carboxamide Example 37: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-hydroxy-4-(pyridin-2-yl)piperidine-1-carboxamide Example 38: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-phenylpiperidine-1-carboxamide Example 39: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-phenylpiperidine-1-carboxamide Example 40: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-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)piperazin-1-yl]cyclohexyl}-4-hydroxypiperidine-1-carboxamide Example 42: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-[(pyridin-2-yl)oxy]piperidine-1-carboxamide Example 43: 4-(5-cyclopropyl-1,2,4-thiadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 44: 4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 45: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methoxy-1,2,4-thiadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 46: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-fluoro-4-(pyridin-2-yl)piperidine-1-carboxamide Example 47: rac-4-(2-cyclopropyl-1,3-thiazol-4-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 48: rac-4-(5-cyclopropyl-1,3-thiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 49: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-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)piperazin-1-yl]cyclohexyl}-4-(5-methylpyridin-2-yl)piperidine-1-carboxamide Example 51: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(3-fluoro-5-methylpyridin-2-yl)piperidine-1-carboxamide Example 52: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-fluoropyridin-2-yl)piperidine-1-carboxamide Example 53: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methoxypyridin-2-yl)piperidine-1-carboxamide Example 54: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methylpyrimidin-2-yl)piperidine-1-carboxamide Example 55: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-[5-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide Example 56: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(2-fluoro-4-methylphenyl)-4-methylpiperidine-1-carboxamide Example 57: 4-[5-(cyclopropyloxy)-1,2,4-thiadiazol-3-yl]-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 58: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-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)piperazin-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)piperazin-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-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 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-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-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)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 67: 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 Example 68: 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 Example 69: 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 Example 70: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 71: 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 Example 72: 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 Example 73: 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 Example 74: 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 Example 75: 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 Example 76: 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

[0234] Example 77: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4'-methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxamide [ka] Oxalyl chloride (0.036 mL) and DMF (5 μL) were added to a chloroform solution (2 mL) of 4-(4-methylphenyl)-cyclohex-1-ene-carboxylic acid (64.3 mg), 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 stirred. After completion of the reaction, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0235] Example 78: rac-(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4'-methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxylate The compound of Example 78 shown in the following table was prepared in the same manner as in Example 77, except that Reference Example 6 was used instead of Reference Example 14 in Example 77. [Table 3]

[0236] Example 79: 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 [ka] To a mixture of Reference Example 14 (10.0 mg) (starting material A), N,N-diisopropylamine (0.034 mL), and chloroform (0.2 mL), thiophosgene (4.40 mg) was added at 0° C. and stirred at that temperature for 40 minutes. Reference Example 8 (66.7 mg) (starting material B) was added to the reaction mixture at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was purified directly by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0237] Example 80: 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 The compound of Example 80 shown in the following table was prepared in the same manner as in Example 79, except that Reference Example 15 was used as the raw material A in Example 79 and Reference Example 8 was used as the raw material B in Example 79. [Table 4]

[0238] Example 81: rac-4-(4-methylphenyl)-N-[(1S,4R)-3-{[4-(propan-2-yl)piperazin-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 stirred at that 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-diisopropylethylamine (36.8 mg) and triphosgene (8.4 mg) were added at 0°C, followed by stirring at that temperature for 1 hour. 4-(4-methylphenyl)piperidine (0.057 mL) was then added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified directly by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give 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).

[0239] Examples 82 to 156: Examples 82 to 156 shown in the table below were produced in the same manner as in Example 19, using commercially available compounds or reference examples shown in the table below as compounds corresponding to raw materials A and B described in Example 19. [Table 5] TIFF2025179148000162.tif245167 TIFF2025179148000163.tif217169 TIFF2025179148000164.tif219169 TIFF2025179148000165.tif203167 TIFF2025179148000166.tif212169 TIFF2025179148000167.tif213167 TIFF2025179148000168.tif238167 TIFF2025179148000169.tif203167 TIFF2025179148000170.tif219169 TIFF2025179148000171.tif223169 TIFF2025179148000172.tif197167 TIFF2025179148000173.tif240167 TIFF2025179148000174.tif202169 TIFF2025179148000175.tif204167 TIFF2025179148000176.tif198167 TIFF2025179148000177.tif204169 TIFF2025179148000178.tif213169 TIFF2025179148000179.tif222169 TIFF2025179148000180.tif197169 TIFF2025179148000181.tif203167 TIFF2025179148000182.tif209167 TIFF2025179148000183.tif198167 TIFF2025179148000184.tif171167

[0240] The compound names of Examples 82 to 155 are listed below. Example 82: 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 Example 83: 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 Example 84: 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 Example 85: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 86: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 87: N-[(1R,6S)-2,2-difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 88: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 89: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 90: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide Example 91: N-[(1R,6S)-6-{benzyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 92: N-[(1R,6S)-2,2-difluoro-6-{[2-(propan-2-yl)pyrimidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 93: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 94: N-{(1R,6S)-2,2-difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 95: 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 Example 96: 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 Example 97: 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 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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 99: 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 Example 100: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8r)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 101: N-[(1R,6S)-2,2-difluoro-6-{4-[(propan-2-yl)oxy]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 102: 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 Example 103: 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 Example 104: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8s)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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]octan-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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]hexan-6-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 107: 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 Example 108: N-[(1R,6S)-2,2-difluoro-6-{[(3R,4R)-4-methoxy-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 Example 109: N-[(1R,6S)-2,2-difluoro-6-{[4-methyl-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 Example 110: 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 Example 111: 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 Example 112: 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 Example 113: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3R)-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 Example 114: 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 Example 115: 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 Example 116: 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 Example 117: N-[(1R,6R)-2,2-difluoro-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 118: 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 Example 119: 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 Example 120: 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 Example 121: 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 Example 122: 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 Example 123: N-[(1R,6S)-2,2-difluoro-6-{methyl[1-(propan-2-yl)piperidin-4-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 124: N-{(1R,6S)-2,2-difluoro-6-[4-(pyrrolidin-1-yl)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 125: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 126: 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 Example 127: N-{(1R,6S)-2,2-difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decan-8-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 128: 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 Example 129: N-{(1R,6S)-6-[4-(diethylamino)piperidin-1-yl]-2,2-difluorocyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 130: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-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]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 133: 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 Example 134: 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 Example 135: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 136: 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 Example 137: 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 Example 138: 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 Example 139: 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 Example 140: N-{(1R,6S)-2,2-difluoro-6-[4-(methyl{[1-(trifluoromethyl)cyclopropyl]methyl}amino)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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-oxadiazol-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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 143: 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 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-oxadiazol-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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 146: 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}-N,4-dimethylpiperidine-1-carboxamide Example 147: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide Example 148: N-[(1R,6S)-2,2-difluoro-6-{3-[methyl(propan-2-yl)amino]azetidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 149: N-[(1R,6S)-6-{3-[(cyclopropylmethyl)(methyl)amino]azetidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 150: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 151: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 153: (1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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)piperidin-4-yl]sulfanyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-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-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0241] The compound of Reference Example 124, which is a diastereomeric mixture, or an intermediate leading up to its synthesis can be obtained as a single enantiomer by, for example, optical resolution by chiral column chromatography or crystallization with an acid having an asymmetric center. 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, Reference Example 124 can be further identified by preparative separation or asymmetric synthesis, and each diastereomer of the diastereomeric mixture of the compound of Example 156 can be optionally produced and identified.

[0242] Furthermore, the compound of Example 156, which is a diastereomeric mixture, can be separated into single enantiomers 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 separated and identified.

[0243] The compound of Example 156 is a diastereomeric mixture containing two different diastereomers. As described above, these can be prepared separately or separated by chiral chromatography. In other words, the two diastereomers can be essentially synthesized. [Table 6]

[0244] Examples 157-160: The compounds of Examples 157 to 160 shown in the following table were prepared in the same manner as in Example 17 using the compound of Reference Example 80 and the corresponding commercially available aldehyde or ketone. [Table 7]

[0245] The compound names of Examples 157 to 160 are listed below. Example 157: 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 Example 158: 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 Example 159: 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 Example 160: N-[(1R,6S)-6-{4-[ethyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0246] Example 161: 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 [ka] Palladium carbon (6.4 mg) was added to a mixture of Reference Example 90 (175 mg) and ethanol (1.3 mL) 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. The residue was purified by HPLC (eluent: acetonitrile / water / TFA) to give 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).

[0247] Reference example 1: rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0248] Process (i): To a mixture of compound 1 (1.13 g) and dichloromethane (2 mL) was added 1-isopropylpiperazine (1.14 g) at room temperature and stirred for 17 hours. After confirming the disappearance of the raw materials, diethyl ether was added to the reaction mixture, and the precipitate was removed by filtration. 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

[0249] Step (ii): To a mixture of compound 2 (1.14 g), acetic acid (2.04 mL), and ethanol (15 mL) was added palladium on 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 and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform) to give the title compound 3 (0.370 g). LCMS: [M+H] + / Rt (min): 226 / 0.31

[0250] Reference example 2: rac-4-(4-methylphenyl)-N-[(1S,2S)-2-(piperazin-1-yl)cyclohexyl]piperidine-1-carboxamide dihydrochloride [ka]

[0251] Process (i): Using compound 1 (1.17 g) and 1-Boc-piperazine (1.72 g), the title compound 4 (1.28 g) was obtained according to a method similar to that of Reference Example 1, step (i).

[0252] Step (ii): Palladium hydroxide (266 mg) was added to a solution (9 mL) of compound 4 (593 mg) in ethanol 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 give the title compound 5 (560 mg).

[0253] Step (iii): To a mixed solution of compound 5 (370 mg), triethylamine (0.91 mL), and dichloromethane (5 mL), 4-nitrophenyl chloroformate (316 mg) was added 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 and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 6 (435 mg).

[0254] Step (iv): To a mixed solution of compound 6 (430 mg) and chloroform (3 mL), a hydrogen chloride / dioxane solution (4 M, 2.22 mL) was added at 0° C. and stirred for 16 hours, after which the reaction mixture was concentrated under reduced pressure to give the title compound 7 (310 mg). LCMS: [M+H] + / Rt (min): 385 / 0.71

[0255] Reference example 3: rac-(1R,2S)-2-(4-ethylpiperazin-1-yl)cyclohexan-1-amine [ka] Process (i): To a mixture of compound 8 (312 mg) and acetic acid (5 mL), platinum(IV) oxide (86 mg) was added and the mixture was 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 a crude product. The obtained 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

[0256] Reference example 4: rac-(1R,2S,6S)-2-Methoxy-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine trihydrochloride [ka]

[0257] Process (i): Compound 10 (407 mg) was used according to a method similar to that of Step (i) of Reference Example 3 to give the title compound 11 (424 mg). LCMS: [M+H] + / Rt (min): 146 / 0.15

[0258] Step (ii): To a mixture of compound 11 (424 mg), triethylamine (1.22 mL), and acetonitrile (10 mL) was added BocO (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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 12 (310 mg). LCMS: [M+H] + / Rt (min): 246 / 0.78

[0259] Step (iii): To a mixture of compound 12 (141 mg), triethylamine (0.160 mL), and THF (3 mL), ethanesulfonyl chloride (0.160 mL) was added under ice cooling, and the mixture was warmed 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 13 (180 mg). LCMS: [M+H] + / Rt (min): 338 / 0.86

[0260] Step (iv): To a mixture of compound 13 (155 mg), 1-isopropylpiperazine (236 mg), and 1,4-dioxane (4 mL) was added potassium carbonate (76 mg) at room temperature and stirred at 150°C for 13 hours under microwave irradiation. Water was then added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 14 (17 mg). LCMS: [M+H] + / Rt (min): 356 / 0.81

[0261] Process (v): Compound 14 (16.3 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 15 (16.8 mg). LCMS: [M+H] + / Rt (min): 256 / 0.32

[0262] Reference example 5: rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclopentan-1-amine [ka]

[0263] Process (i): To a mixture of compound 16 (315 mg), triethylamine (0.289 mL), and THF (5 mL), ethanesulfonyl chloride (0.15 mL) was added and the mixture was stirred at room temperature for 15 hours. After confirming the disappearance of the raw 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. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 17 (140 mg). LCMS: [M+H] + / Rt (min): 231 / 0.44

[0264] 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 raw materials, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 18 (137 mg). LCMS: [M+H] + / Rt (min): 238 / 0.42

[0265] Step (iii): Palladium carbon (202 mg) was added to a mixture of compound 18 (42.4 mg), hydrochloric acid / ethyl acetate solution (4.0 M, 0.711 mL), and ethanol (2.8 mL), and the mixture was stirred under a hydrogen atmosphere for 8 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was mixed with methanol and aqueous sodium bicarbonate, filtered through Celite, and extracted with a chloroform / methanol (6 / 1) solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give the title compound 19 (98.7 mg). LCMS: [M+H] + / Rt (min): 212 / 0.15

[0266] Reference example 6: rac-(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-ol [ka] Process (i): To a mixture of compound 20 (688 mg) and ethanol (20 mL) was added 1-isopropylpiperazine (723 mg) at room temperature, and the mixture was heated to 80° C. and stirred for 9 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 21 (830 mg). LCMS: [M+H] + / Rt (min): 263 / 0.35

[0267] Reference example 7: rac-(1R,2S)-3,3-Difluoro-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0268] Process (i): Oxalyl chloride (0.075 mL) was added to a mixture of DMSO (0.081 mL) and dichloromethane (2 mL) at -78°C, followed by stirring for 20 minutes. A solution of compound 21 (150 mL) in dichloromethane (2 mL) was then added, followed by stirring at -78°C for an additional 30 minutes. Triethylamine (0.398 mL) was added, and the mixture was warmed to 0°C and stirred for 30 minutes. Sodium borohydride was then added and stirred for 30 minutes. Water was then added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 22 (27 mg). LCMS: [M+H] + / Rt (min): 263 / 0.38

[0269] Step (ii): Ethanesulfonyl chloride (0.015 mL) was added to a mixture of compound 22 (27 mg), triethylamine (0.029 mL), and THF (2 mL), and the mixture was stirred at room temperature. After confirming the disappearance of the raw materials, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give the title compound 23 (23 mg). LCMS: [M+H] + / Rt (min): 354 / 0.65

[0270] Step (iii): Compound 23 (23.4 mg) was used according to a method similar to that of Step (ii) of Reference Example 5 to give the title compound 24 (16.0 mg). LCMS: [M+H] + / Rt (min): 288 / 0.60

[0271] Step (iv): To a mixture of compound 24 (14 mg), THF (1 mL), and water (1 mL), triphenylphosphine (25.6 mg) was added at room temperature, heated to 50°C, and stirred for 4.5 hours. After cooling to room temperature, aqueous hydrochloric acid was added and the mixture was washed with ethyl acetate. After that, aqueous sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with chloroform / methanol (3 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 25 (7.8 mg). LCMS: [M+H] + / Rt (min): 262 / 0.31

[0272] Reference example 8: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride [ka]

[0273] Process (i): To a solution of compound 26 (50.0 g) in ethanol (446 mL) was added 50% aqueous hydroxylamine solution (132 mL) 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 collected by filtration and then suspended and stirred again in water (344 mL) at room temperature for 30 minutes. The resulting white solid was collected by filtration and dried to give the title compound 27 (52.3 g). LCMS: [M+H] + / Rt (min): 258 / 0.52(Method C)

[0274] Step (ii): 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) in an ice bath, and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (406 mL) was added to the reaction mixture, which was then washed with water (406 mL) and saturated brine (406 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 28 (59.1 g). LCMS: [M+H] + / Rt (min): 326 / 0.77(Method C)

[0275] Step (iii): A mixture of compound 28 (59.1 g), DBU (54.2 mL), and toluene (727 mL) was stirred under reflux for 1 hour. After cooling to room temperature and washing with water (727 mL), the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 29 (54.5 g). LCMS: [M+H] + / Rt (min): 308 / 1.11

[0276] Step (iv): Compound 29 (54.5 g) was used according to the same method as in Step (iv) of Reference Example 2 to give the title compound 30 (35.3 g). LCMS: [M+H] + / Rt (min): 208 / 0.30(Method C)

[0277] Reference example 9~12' The compounds of Reference Examples 9 to 12′ shown in the following table were synthesized according to the method described in Reference Example 8 above, using the corresponding starting compounds instead of cyclopropanecarboxylic acid in step (ii) of Reference Example 8. [Table 8]

[0278] Reference Example 9: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride Reference Example 10: 4-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine monohydrochloride Reference Example 11: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine monohydrochloride Reference Example 12: 4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine monohydrochloride Reference Example 12': 4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine monohydrochloride

[0279] Reference example 13: rac-tert-butyl 4-(6-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}cyclohex-1-en-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0280] Process (i): To a mixture of compound 35 (192 mg), cerium(III) chloride heptahydrate (309 mg), and methanol (3 mL) was added sodium borohydride (51.4 mg) under ice-cooling and stirred at the same temperature for 3 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (6 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 36 (120 mg). LCMS: [M+H] + / Rt (min): 280 / 0.97

[0281] Step (ii): Ethanesulfonyl chloride (0.058 mL) was added to a mixture of compound 36 (115 mg), triethylamine (0.143 mL), and THF (2 mL) under ice-cooling and stirred for 30 minutes. Sodium azide (107 mg) was then added to the reaction mixture, and the mixture was warmed to room temperature and 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 37 (80 mg). LCMS: [M+H] + / Rt (min): 305 / 1.25

[0282] Process (iii) Compound 37 (73 mg) was used according to a method similar to that in Step (iv) of Reference Example 7 to give the title compound 38 (35 mg). LCMS: [M+H] + / Rt (min): 279 / 0.74

[0283] Process (iv) Compound 38 (14.4 mg) was used according to a method similar to that in Step (iii) of Reference Example 2 to give the title compound 39 (14.0 mg). LCMS: [M+H] + / Rt (min): 512 / 1.14

[0284] Reference example 14: rac-(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine trihydrochloride [ka]

[0285] Process (i): Using compound 40 (1.69 g) and according to a method similar to that in step (ii) of Reference Example 4, the title compound 41 (1.59 g) was obtained. LCMS: [M+H] + / Rt (min): 252 / 0.73

[0286] Step (ii): To a mixture of compound 41 (1.5 g) and THF (30 mL), potassium tert-butoxide (1.01 g) was added under ice-cooling and stirred at the same temperature for 20 minutes. Tosyl chloride (1.37 g) was then added under ice-cooling and stirred for an additional 2.5 hours. Water was then added to the reaction mixture under ice-cooling and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 42 (1.09 g). LCMS: [M+H] + / Rt (min): 234 / 1.01

[0287] 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. for 8 hours under microwave irradiation. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 43 (1.32 g). LCMS: [M+H] + / Rt (min): 362 / 0.74

[0288] Step (iv): Using compound 43 (1.31 g) and according to a method similar to that in step (iv) of Reference Example 2, the title compound 44 (1.40 g) was obtained. LCMS: [M+H] + / Rt (min): 262 / 0.19

[0289] Reference examples 15~17 The compounds of Reference Examples 15 to 17 shown in the following table were synthesized according to the method described in Reference Example 14 above, except that an optically active form of compound 40 (raw material A) was used instead of compound 40 in step (i) of Reference Example 14, and the corresponding raw material compound (raw material B) was used instead of 1-isopropylpiperazine in step (iii). [Table 9]

[0290] Reference Example 15: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine trihydrochloride Reference Example 15': (1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine Reference Example 16: (1R,6S)-2,2-difluoro-6-[6-(propan-2-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl]cyclohexan-1-amine Reference Example 17: (1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexan-1-amine

[0291] Reference example 18: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0292] Process (i): To a mixture of compound 48 (5.94 g), sodium bicarbonate (13.2 g), and THF (131 mL) was added 2-nitrobenzenesulfonyl chloride (10.5 g) at room temperature and stirred at that temperature for 16 hours. Aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and 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 the disappearance of the raw materials, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and 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. Thereafter, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 49 (9.25 g). LCMS: [M+H] + / Rt (min): 319 / 0.94

[0293] Step (ii): A mixture of compound 49 (7.1 g), 1-isopropylpiperazine (3.56 mL), and toluene (22.3 mL) was heated and stirred for 1 hour at 110° C. After confirming the disappearance of the raw materials, the mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 50 (9.79 g). LCMS: [M+H] + / Rt (min): 447 / 0.68

[0294] Step (iii): Sodium hydride (55%, 0.215 g) was added to a mixture of benzenethiol (0.530 mL) and toluene (11.2 mL) under ice cooling, and the mixture was stirred for 10 minutes while warming 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 raw materials, the reaction mixture was cooled to 0 °C, 40% aqueous sodium hydroxide was added, and the mixture was extracted with toluene. 5 M hydrochloric acid was added to the organic layer under ice cooling, and the mixture was extracted with the aqueous layer. 40% aqueous sodium hydroxide was added to the resulting aqueous layer, and the mixture was extracted again with toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 51 (0.47 g). LCMS: [M+H] + / Rt (min): 262 / 0.17

[0295] Reference example 19: 2-(4-methylpiperidin-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 for 11 hours under microwave irradiation. Hydrogen chloride / 1,4-dioxane solution (0.25 mL) was then added to the reaction mixture, and the mixture was heated and stirred at 130°C for 6 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure, dissolved in ethanol, and 15% aqueous sodium hydroxide solution (2 mL) was added. The mixture was heated and stirred at 150°C for 3 hours under microwave irradiation. Water was added 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 purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 53 (14 mg). LCMS: [M+H] + / Rt (min): 221 / 0.57

[0296] Reference example 20: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine monohydrochloride [ka]

[0297] Process (i): To a mixture of compound 54 (900 mg), sodium acetate (650 mg), and methanol (5 mL), hydroxylamine hydrochloride (550 mg) was added 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 concentrated under reduced pressure to give the title compound 55 (1.23 g).

[0298] Step (ii): To a mixture of compound 55 (416 mg) and DMF (4 mL), N-chlorosuccinimide (252 mg) was added 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 give the title compound 56 (326 mg).

[0299] Step (iii): Compound 56 (326 mg) and sodium bicarbonate (198 mg) were added to a mixture of ethynylcyclopropane (117 mg) and toluene (5 mL), and the mixture was stirred at room temperature. After confirming the disappearance of the raw materials, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 57 (348 mg). LCMS: [M+H] + / Rt (min): 307 / 1.13

[0300] Step (iv): Compound 57 (337 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 58 (307 mg). LCMS: [M+H] + / Rt (min): 207 / 0.49

[0301] Reference example 21 2-(4-methylpiperidin-4-yl)-1,3-benzoxazole [ka]

[0302] Process (i): To a solution of compound 59 (1.46 g) in THF (30 mL), isobutyl chloroformate (819 mg) and diisopropylethylamine (3.88 g) were added under ice-cooling and stirred for 1 hour. 2-Aminophenol (655 mg) was then added under ice-cooling, and the mixture was 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 give the title compound 60 (710 mg). LCMS: [M+H] + / Rt (min): 335 / 2.28(Method B)

[0303] 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), and trifluoromethanesulfonic acid (2.1 mL) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and aqueous sodium bicarbonate solution were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 61 (99 mg). LCMS: [M+H] + / Rt (min): 217 / 1.36(Method B)

[0304] Reference example 22 4-Cyclopentyl-4-methylpiperidine monohydrochloride [ka]

[0305] Process (i): To a mixture of compound 62 (700 mg) and THF (14 mL), lithium diisopropylamide (2 M, 5.18 mL) was added at -78 °C and stirred at that temperature for 2 hours. Bromocyclopentane (1.23 mL) and potassium iodide (478 mg) were then added to the reaction mixture, which was then warmed to room temperature and stirred overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 63 (468 mg). LCMS: [M+H] + / Rt (min): 312 / 1.26

[0306] Step (ii): A mixture of compound 63 (371 mg) and THF (6 mL) was added to a mixture of lithium aluminum hydride (104 mg) and THF (3 mL) under ice cooling and stirred for 4 hours. After confirming the disappearance of the raw materials, water (0.104 mL), 15% aqueous sodium hydroxide solution (0.104 mL), and water (0.312 mL) were added sequentially 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 purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 64 (320 mg). LCMS: [M+H] + / Rt (min): 284 / 1.06

[0307] Step (iii): To a mixture of compound 64 (314 mg), triethylamine (0.309 mL), and THF (5 mL), methanesulfonyl chloride (0.104 mL) was added and stirred at room temperature. After confirming the disappearance of the raw 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. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 65 (290 mg). LCMS: [M+H] + / Rt (min): 362 / 1.15

[0308] Step (iv): To a mixture of compound 65 (278 mg) and THF (3 mL), lithium triethylborohydride (0.99 M, 1.55 mL) was added and stirred at room temperature. The reaction mixture was then heated to 70 °C. After confirming the disappearance of the raw materials, the mixture was cooled to 0 °C and an aqueous ammonium chloride solution was added. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 66 (100 mg). LCMS: [M+H] + / Rt (min): 268 / 1.42

[0309] Process (v): Compound 66 (90 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 67 (58.5 mg). LCMS: [M+H] + / Rt (min): 168 / 0.62

[0310] Reference example 23: 4-(4,4-Difluorocyclohexyl)-4-methylpiperidine monohydrochloride The compound of Reference Example 23 shown in the following table was synthesized according to the method described in Reference Example 22 above, except that 1,1-difluoro-4-iodocyclohexane was used instead of bromocyclopentane in step (i) of Reference Example 22. [Table 10]

[0311] Reference example 24: 4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine monohydrochloride [ka]

[0312] Process (i): To a mixture of compound 59 (399 mg), cyclopropanecarbohydrazide hydrochloride (269 mg), and DMF (5 mL), HATU (686 mg) and diisopropylethylamine (1.15 mL) were added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was 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 (eluent: hexane / ethyl acetate) to give the title compound 69 (520 mg). LCMS: [M+H] + / Rt (min): 326 / 0.74

[0313] Step (ii): To a mixture of compound 69 (255 mg) and toluene (6 mL), Lawesson's reagent (349 mg) was added and the mixture was 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 (eluent: hexane / ethyl acetate) followed by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 70 (102 mg). LCMS: [M+H] + / Rt (min): 324 / 1.08

[0314] Step (iii): Compound 70 (92 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 71 (78 mg). LCMS: [M+H] + / Rt (min): 224 / 0.45

[0315] Reference example 25: 4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine monohydrochloride [ka]

[0316] Process (i): Using compound 59 (718 mg) and 2-amino-1-cyclopropylethan-1-one hydrochloride (400 mg), and according to a method similar to that of Step (i) of Reference Example 24, the title compound 72 (796 mg) was obtained. LCMS: [M+H] + / Rt (min): 325 / 0.83

[0317] Step (ii): To a mixture of compound 72 (127 mg), pyridine (0.063 mL), and toluene (3 mL), Lawesson's reagent (205 mg) was added and the mixture was heated and stirred under reflux for 14 hours. After cooling 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 (eluent: hexane / ethyl acetate) to give the title compound 73 (76.3 mg). LCMS: [M+H] + / Rt (min): 323 / 1.43

[0318] Step (iii): Compound 73 (77 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 74 (66.5 mg). LCMS: [M+H] + / Rt (min): 223 / 0.67

[0319] Reference example 26: 4-(2-cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine monohydrochloride [ka]

[0320] Process (i): A solution of compound 75 (532 mg) and cyclopropanecarbothioamide (168 mg) in methanol (6 mL) was stirred under reflux for 2.5 hours. The resulting mixture was allowed to cool to room temperature, and then saturated aqueous sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 76 (119 mg).

[0321] Step (ii): Using compound 76 (119 mg) and according to a method similar to that in step (iv) of Reference Example 2, the title compound 77 (137 mg) was obtained. LCMS: [M+H] + / Rt (min): 223 / 0.572

[0322] Reference example 27: 4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-4-methylpiperidine dihydrochloride [ka]

[0323] Process (i): Using compound 59 (611 mg) and cyclopropylhydrazine hydrochloride (300 mg), and according to a method similar to that of step (i) of Reference Example 24, the title compound 78 (648 mg) was obtained. LCMS: [M+H] + / Rt (min): 298 / 0.80

[0324] 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 completion of the reaction, the reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 79 (163 mg). LCMS: [M+H] + / Rt (min): 307 / 0.89

[0325] Step (iii): Using compound 79 (144 mg) and according to a method similar to that in step (iv) of Reference Example 2, the title compound 80 (142 mg) was obtained. LCMS: [M+H] + / Rt (min): 207 / 0.39

[0326] Reference example 28: 4-(5-cyclopropyl-1,2,4-thiadiazol-3-yl)-4-methylpiperidine [ka]

[0327] Process (i): To a solution (15 mL) of compound 27 (1.04 g) in THF, thiocarbonylimidazole (0.864 mg) was added under ice-cooling and the mixture was stirred at room temperature. After the raw materials disappeared, 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 resulting 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 warmed to room temperature with stirring. After the reaction was completed, aqueous sodium bicarbonate solution was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate). A hydrogen chloride / dioxane solution (4 M, 5.05 mL) was added to a THF solution (15 mL) of the purified compound at 0°C, and the mixture was warmed to room temperature and stirred. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in THF (15 mL). Triethylamine (3.38 mL) and 2-nitrobenzenesulfonyl chloride (0.985 g) were then added, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 81 (627 mg). LCMS: [M+H] + / Rt (min): 385 / 0.93

[0328] Step (ii): Phosphoryl chloride (0.572 mL) was added to a mixture of compound 81 (590 mg), pyridine (0.248 mL), and toluene (7 mL), and the mixture was heated to reflux. After completion of the reaction, the reaction solution was added to an aqueous sodium bicarbonate solution cooled to 0°C, filtered, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 82 (432 mg). LCMS: [M+H] + / Rt (min): 403 / 1.21

[0329] Step (iii): To a mixture of compound 82 (210 mg), cyclopropylzinc(II) bromide (0.5 M, 3.13 mL), and THF (2 mL), tetrakis(triphenylphosphine)palladium(0) (30.1 mg) was added and the mixture was stirred at 60°C for 1.5 hours. After the reaction was completed, aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 83 (84 mg). LCMS: [M+H] + / Rt (min): 409 / 1.24

[0330] Step (iv): Potassium carbonate (145 mg) was added to a mixture of compound 83 (71.4 mg), 1-dodecanethiol (0.251 mL), and acetonitrile (3 mL) and stirred at 80°C. After the reaction was completed, water was added to the reaction mixture and extracted with chloroform / methanol (6 / 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate → chloroform / methanol) to give the title compound 84 (38 mg). LCMS: [M+H] + / Rt (min): 224 / 0.52

[0331] Reference example 29: 4-(5-Methoxy-1,2,4-thiadiazol-3-yl)-4-methylpiperidine [ka]

[0332] Process (i): To a solution of compound 82 (119 mg) in methanol (2 mL), sodium methoxide (28%, 285 mg) was added and the mixture was stirred at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted with chloroform and concentrated under reduced pressure to give the title compound 85 (97.1 mg). LCMS: [M+H] + / Rt (min): 399 / 1.18

[0333] Step (ii): Compound 85 (91.6 mg) was used according to a method similar to that of Step (iv) of Reference Example 28 to give the title compound 86 (14.9 mg). LCMS: [M+H] + / Rt (min): 214 / 0.48

[0334] Reference example 30: 4-[5-(cyclopropyloxy)-1,2,4-thiadiazol-3-yl]-4-methylpiperidine The compound of Reference Example 30 shown in the following table was synthesized according to the method described in Reference Example 29 above, except that cyclopropyl alcohol and sodium hydride were used instead of methoxysodium in step (i) of Reference Example 29. [Table 11]

[0335] Reference example 31: 2-[(4-methylpiperidin-4-yl)oxy]pyridine monohydrochloride [ka]

[0336] Process (i): Sodium hydride (55%, 48.2 mg) was added to a DMF solution (2 mL) of compound 88 (183 mg) under ice-cooling and stirred for 20 minutes. 2-Fluoropyridine (0.109 mL) was then added and stirred at room temperature. After the reaction was completed, 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 89 (18 mg). LCMS: [M+H] + / Rt (min): 293 / 1.29

[0337] Step (ii): Compound 89 (14.7 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 90 (13.2 mg). LCMS: [M+H] + / Rt (min): 193 / 0.48

[0338] Reference example 32: 4-(2-fluoro-4-methylphenyl)-4-methylpiperidine [ka]

[0339] Process (i): To a mixture of 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), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (45.6 mg) was added at room temperature, followed by heating to reflux. After completion of the reaction, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 92 (32 mg). LCMS: [M+H] + / Rt (min): 206 / 0.51

[0340] 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 solution was further cooled to -50°C. Dimethyl sulfate was slowly added dropwise to the reaction solution, and the mixture was stirred at -50°C for 1 hour. Aqueous ammonia was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a residue. The resulting residue was dissolved in methanol (3 mL), and sodium borohydride (80 mg) was added under ice-cooling. After the reaction was completed, aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 93 (32 mg). LCMS: [M+H] + / Rt (min): 222 / 0.63

[0341] Step (iii): To a solution of compound 93 (30.4 mg) in 1,2-dichloroethane (3 mL), 1-chloroethyl chloroformate (0.045 mL) was added at room temperature and the mixture was heated to reflux. The reaction mixture was concentrated under reduced pressure, and chloroform and aqueous sodium hydroxide were added. The mixture was stirred at room temperature and then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give the title compound 94 (22 mg). LCMS: [M+H] + / Rt (min): 208 / 0.66

[0342] Reference example 33: 4-[4-(difluoromethyl)phenyl]-4-methylpiperidine monohydrochloride [ka]

[0343] 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 completed, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 96 (256 mg). LCMS: [M+H] + / Rt (min): 304 / 1.10

[0344] Step (ii): Deoxo-Fluor® (0.285 mL) was added to a dichloromethane solution (2 mL) of compound 96 (157 mg) under ice-cooling, followed by stirring at room temperature. After completion of the reaction, the reaction solution was added to an ice-cooled aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 97 (110 mg). LCMS: [M+H] + / Rt (min): 326 / 1.20

[0345] Step (iii): Compound 97 (104.8 mg) was used according to a method similar to that of Step (iv) of Reference Example 2 to give the title compound 98 (84.5 mg). LCMS: [M+H] + / Rt (min): 226 / 0.60

[0346] Reference example 34: 5-Methyl-2-(4-methylpiperidin-4-yl)benzonitrile [ka]

[0347] Process (i): To a mixture of compound 99 (267 mg) and m-cresol (1.20 mL), trifluoromethanesulfonic acid (1.01 mL) was added and stirred at room temperature. After completion of the reaction, the reaction solution was added to an aqueous solution of sodium bicarbonate cooled to 0°C and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 100 (388 mg). LCMS: [M+H] + / Rt (min): 278 / 1.01

[0348] Step (ii): N-phenylbis(trifluoromethanesulfonimide) (175 mg) was added to a mixture of compound 100 (113 mg), potassium carbonate (169 mg), and THF (4 mL), and the mixture was heated and stirred at 120°C under microwave irradiation. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 101 (138 mg). LCMS: [M+H] + / Rt (min): 410 / 1.26

[0349] Step (iii): Using compound 101 (130 mg) and zinc cyanide (55.8 mg), and according to a method similar to that of step (iii) of Reference Example 28, the title compound 102 (40.8 mg) was obtained. LCMS: [M+H] + / Rt (min): 287 / 1.07

[0350] Step (iv): To a solution (3 ml) of compound 102 (40 mg) in 2-propanol, potassium hydroxide (78 mg) was added at room temperature, followed by stirring at 110°C under microwave irradiation. After completion of the reaction, water was added to the reaction solution, followed by extraction with chloroform / ethanol (4 / 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give the title compound 103 (20.6 mg). LCMS: [M+H] + / Rt (min): 215 / 0.57

[0351] Reference example 35: (3S,4S)-4-Fluoro-1-(propan-2-yl)pyrrolidin-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 warmed to room temperature and stirred. After confirming the disappearance of the raw materials, 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. The mixture was warmed to room temperature and stirred. After the reaction was completed, 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 and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 105 (348 mg). LCMS: [M+H] + / Rt (min): 148 / 0.17

[0352] Reference example 36: (3R)-4,4-Difluoro-1-(propan-2-yl)pyrrolidin-3-ol The compounds of Reference Example 36 shown in the following table were synthesized according to the method described in Reference Example 35 above, using the corresponding starting compounds instead of compound 104 in step (i) of Reference Example 35. [Table 12]

[0353] Reference example 37: (1R,6S)-2,2-Difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine [ka]

[0354] Process (i): A mixture of compound 49 (1.5 g), (S)-1-isopropylpyrrolidin-3-ol (0.792 mg), and NMP (1 mL) was heated and stirred at 150° C. After confirming the disappearance of the raw materials, the reaction mixture was purified directly by silica gel column chromatography (eluent: chloroform / methanol / triethylamine) and then by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to obtain title compound 106 (1.03 g). LCMS: [M+H] + / Rt (min): 448 / 0.78

[0355] Step (ii): Using compound 106 (100 mg) and according to a method similar to that in step (iii) of Reference Example 18, the title compound 107 (43 mg) was obtained. LCMS: [M+H] + / Rt (min): 263 / 0.22

[0356] Reference examples 38~40: The compound of Reference Example 38 shown in the table below was synthesized according to the method described in Reference Example 37 above, using the corresponding starting material compound instead of (S)-1-isopropylpyrrolidin-3-ol in step (i) of Reference Example 37. [Table 13]

[0357] Reference Example 38: (1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 39: (1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 40: (1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexan-1-amine

[0358] Reference example 41: 3-Fluoro-5-methyl-2-(piperidin-4-yl)pyridine [ka]

[0359] Process (i): 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 and according to a method similar to that in step (i) of Reference Example 32, the title compound 109 (90.5 mg) was obtained. LCMS: [M+H] + / Rt (min): 327 / 1.04(Method C)

[0360] Step (ii): Palladium carbon (88.0 mg) was added to a solution of compound 109 (88.0 mg) in ethyl acetate (1.5 mL), 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 give title compound 110 (22.2 mg). LCMS: [M+H] + / Rt (min): 195 / 0.35(Method C)

[0361] Reference example 42: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-ol [ka]

[0362] Process (i): N-benzyl-N,N-bis(2-chloroethyl)amine hydrochloride (586 mg) was added to a solution (10 mL) of compound 111 (300 mg) and sodium bicarbonate (634 mg) in ethanol, and the mixture was heated and stirred at 120°C under microwave irradiation. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 112 (398 mg). LCMS: [M+H] + / Rt (min): 311 / 0.46

[0363] Step (ii): Using compound 112 (389 mg) and according to a method similar to that in step (ii) of Reference Example 2, the title compound 113 (289 mg) was obtained. LCMS: [M+H] + / Rt (min): 221 / 0.16

[0364] Step (iii): To a mixture of compound 113 (389 mg), acetone (1.73 mL), and dichloromethane (6 mL), sodium borohydride triacetate (1.5 g) was added at 0°C, and the mixture was warmed to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 114 (255 mg). LCMS: [M+H] + / Rt (min): 263 / 0.36

[0365] Reference example 43: tert-Butyl [(1S,4R)-3-{[4-(propan-2-yl)piperazin-1-yl]methyl}bicyclo[2.2.1]heptan-2-yl]carbamate [ka] Process (i): To a mixture of compound 115 (239 mg), 1-isopropylaziridine (128 mg), acetic acid (0.086 mL), and THF (2.5 mL) was added sodium triacetate borohydride (635 mg) at room temperature and stirred at that temperature for 3 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 116 (310 mg). LCMS: [M+H] + / Rt (min): 352 / 1.35(Method B)

[0366] Reference example 44: rac-2-[6-(propan-2-yl)pyridin-3-yl]cyclohex-2-en-1-amine [ka]

[0367] Process (i): To a mixture of compound 117 (350 mg), 6-isopropylpyridin-3-ylboronic acid (273 mg), cesium carbonate (1.28 g), 1,4-dioxane (5 mL), and water (1 mL) was added [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 the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 118 (168 mg).

[0368] Step (ii)~Step (iv): Using compound 118 (68.2 mg) and according to a method similar to that of steps (i) to (iii) of Reference Example 13, the title compound 121 (29.7 mg) was obtained. LCMS: [M+H] + / Rt (min): 217 / 0.39

[0369] Reference example 45: N-Methyl-N-[(1-methylcyclopropyl)methyl]piperidin-4-amine [ka]

[0370] Process (i): HATU (1.24 g) was added to a DMF solution (4 ml) of tert-butyl 4-(methylamino)piperidine-1-carboxylate (584 mg), 1-methylcyclopropane-1-carboxylic acid (300 mg), and triethylamine (0.76 ml), and the reaction mixture was stirred at room temperature. After completion of the reaction, 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. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 123 (926 mg).

[0371] Step (ii): To a solution of compound 123 (806 mg) in chloroform (4.5 ml), hydrochloric acid (CPME solution, 5 M, 2.7 ml) was added at 0°C, and the reaction mixture was warmed to room temperature and stirred. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to obtain title compound 124 (477 mg).

[0372] Step (iii): Compound 124 (413 mg) was used according to a method similar to that of Step (ii) of Reference Example 22 to give the title compound 125 (203 mg). LCMS: [M+H] + / Rt (min):183 / 0.15

[0373] Reference examples 46~47 The compounds of Reference Examples 46 to 47 shown in the following table were synthesized according to the method described in Reference Example 45 above, using the corresponding starting compounds instead of 1-methylcyclopropane-1-carboxylic acid in step (i) of Reference Example 45. [Table 14]

[0374] Reference Example 46: N-[(1-fluorocyclopropyl)methyl]-N-methylpiperidin-4-amine Reference Example 47: N-methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidin-4-amine

[0375] Reference Example 48: (3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-ol [ka]

[0376] 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 according to a method similar to that of Step (i) of Reference Example 45.

[0377] Step (ii): Using compound 127 (184 mg) and according to a method similar to that in step (iii) of Reference Example 45, the title compound 128 (87.2 mg) was obtained. LCMS: [M+H] + / Rt (min):210 / 0.30

[0378] Reference example 49: (1R,3s,5S)-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine [ka]

[0379] Process (i): Using compound 129 (146 mg) and cyclopropanecarbaldehyde (170 mg), and according to a method similar to that in step (iii) of Reference Example 42, the title compound 130 (178 mg) was obtained.

[0380] Step (ii): Using compound 130 (166 mg) and according to a method similar to that in step (ii) of Reference Example 45, the title compound 131 (106 mg) was obtained. LCMS: [M+H] + / Rt (min): 195 / 0.14 Reference examples 50~52 The compounds of Reference Examples 50 to 52 shown in the following table were synthesized according to the method described in Reference Example 49 above, using the corresponding starting compounds instead of compound 129 in step (i) of Reference Example 49. [Table 15]

[0381] Reference Example 50: (1R,3r,5S)-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine Reference Example 51: (4S)-N-(cyclopropylmethyl)-N-methylazepan-4-amine Reference Example 52: (4R)-N-(cyclopropylmethyl)-N-methylazepan-4-amine

[0382] Reference example 53: (1R,3s,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-ol [ka]

[0383] Process (i): The title compound was obtained using compound 132 (3 g) according to a method similar to that in Step (iv) of Reference Example 2. Step (ii): Using compound 133 and acetone (1.3 g), and according to a method similar to that of Step (iii) of Reference Example 42, the title compound 134 (1.98 g) was obtained. LCMS: [M+H] + / Rt (min): 170 / 0.15

[0384] Reference examples 54~57 The compounds of Reference Examples 54 to 57 shown in the following table were synthesized according to the method described in Reference Example 53 above, using the corresponding starting compounds instead of compound 132 in step (i) of Reference Example 53. [Table 16]

[0385] Reference Example 54: (1R,5S,8r)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-ol Reference Example 55: (1R,5S,8s)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-ol Reference Example 56: (1R,3r,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-ol Reference Example 57: (1R,5S,6s)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexan-6-ol

[0386] Reference examples 58~79 The compounds of Reference Examples 58 to 79 shown in the following table were synthesized according to the method described in Reference Example 18 above, using the corresponding starting compounds instead of 1-isopropylpiperazine in step (ii) of Reference Example 18. [Table 17] TIFF2025179148000233.tif224169 TIFF2025179148000234.tif219167 TIFF2025179148000235.tif213167 TIFF2025179148000236.tif87169

[0387] Reference Example 58: (1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine Reference Example 59: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidin-3-amine Reference Example 60: (1R,6S)-2,2-difluoro-6-{4-[(propan-2-yl)oxy]piperidin-1-yl}cyclohexan-1-amine Reference Example 61: (1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine Reference Example 62: (1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine Reference Example 63: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[1-(propan-2-yl)piperidin-4-yl]cyclohexane-1,2-diamine Reference Example 64: (1R,6S)-2,2-difluoro-6-[4-(pyrrolidin-1-yl)piperidin-1-yl]cyclohexan-1-amine Reference Example 65: (1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]cyclohexan-1-amine Reference Example 66: (1R,6S)-2,2-difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decan-8-yl]cyclohexan-1-amine Reference Example 67: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,N-diethylpiperidin-4-amine Reference Example 68: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,4-dimethyl-N-(propan-2-yl)piperidin-4-amine Reference Example 69: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-[(1-methylcyclopropyl)methyl]piperidin-4-amine Reference Example 70: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-[(1-fluorocyclopropyl)methyl]-N-methylpiperidin-4-amine Reference Example 71: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidin-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]octan-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]octan-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)azetidin-3-amine Reference Example 77: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazetidin-3-amine Reference Example 78: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexan-1-amine Reference Example 79: tert-butyl {1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]piperidin-4-yl}methylcarbamate

[0388] Reference example 80: N-{(1R,6S)-2,2-difluoro-6-[4-(methylamino)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide [ka]

[0389] Process (i): Using the compound of Reference Example 79 (2.61 g) and according to the same method as in Example 19, the title compound 136 (2.92 g) was obtained.

[0390] Step (ii): To a solution of compound 136 (2.92 g) in toluene (24 ml), 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, and an aqueous solution of sodium bicarbonate was added. The mixture was extracted with chloroform, and the organic layer was concentrated to give title compound 137 (2.38 g). LCMS: [M+H] + / Rt (min):499 / 0.49 (Method C)

[0391] Reference example 81: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine [ka]

[0392] Process (i): Compound 138 (2.61 g) was synthesized according to the method described in Step (ii) of Reference Example 18, using tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate instead of 1-isopropylpiperazine in Step (ii) of Reference Example 18.

[0393] Step (ii): Using compound 138 (2.61 g) and according to a method similar to that of Reference Example 2, step (iv), the title compound 139 (2.59 g) was obtained.

[0394] Step (iii): Using compound 139 (2.59 g) and acetone (3.87 ml), and according to a method similar to that of Step (iii) of Reference Example 42, the title compound 140 (1.97 g) was obtained.

[0395] Step (iv): Using compound 140 (1.97 g) and according to a method similar to that of Step (iii) of Reference Example 18, the title compound 141 (925 mg) was obtained. LCMS: [M+H] + / Rt (min):276 / 0.15

[0396] Reference examples 82~88 The compounds of Reference Examples 82 to 88 shown in the following table were synthesized according to the method described in Reference Example 81, except that the corresponding starting material (starting material A) was used instead of tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate in step (i) of Reference Example 81, and the corresponding starting material compound (starting material B) was used instead of acetone in step (iii). [Table 18] TIFF2025179148000240.tif123169

[0397] Reference Example 82: (3R)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidin-3-amine Reference Example 83: (1S,2R)-3,3-difluoro-N 1 -methyl-N 1 -[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine Reference Example 84: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)piperidin-4-amine Reference Example 85: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-cyclopropyl-N-methylpyrrolidin-3-amine Reference Example 86: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(2-methylpropyl)pyrrolidin-3-amine Reference Example 87: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylpyrrolidin-3-amine Reference Example 88: (1S,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]sulfanyl}cyclohexan-1-amine

[0398] Reference example 89: (1S,2R)-N 1 -benzyl-3,3-difluoro-N 1 -[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine [ka]

[0399] Process (i): Compound 142 (2.19 g) was synthesized according to the method described in Step (ii) of Reference Example 18, except that tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate was used instead of 1-isopropylpiperazine in Step (ii) of Reference Example 18.

[0400] Step (ii): Using compound 142 (990 mg) and benzaldehyde (312 mg), and according to a method similar to that in step (iii) of Reference Example 42, the title compound 143 (240 mg) was obtained.

[0401] Step (iii): Compound 143 (235 mg) was used according to the same procedures as in Step (ii) and Step (iii) of Reference Example 81 to give the title compound 144 (161 mg).

[0402] Step (iv): Compound 144 (158 mg) was used according to a method similar to that of Step (iii) of Reference Example 18 to give the title compound 145 (87.4 mg). LCMS: [M+H] + / Rt (min): 352 / 0.42 (Method C)

[0403] Reference example 90: Benzyl {(1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carbonyl)amino]cyclohexyl}[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]carbamate [ka]

[0404] Process (i): To a solution of compound 142 (680 mg) in dioxane / water (10 ml / 3.3 ml), 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 completion of the reaction, extraction was performed with chloroform, and the organic layer was concentrated to give title compound 146 (530 mg).

[0405] Step (ii): Using compound 146 (530 mg) and according to methods similar to those in steps (ii) and (iii) of Reference Example 81, the title compound 147 (256 mg) was obtained.

[0406] Step (iii): Using compound 147 (254 mg) and according to a method similar to that in step (iii) of Reference Example 18, the title compound 148 (137 mg) was obtained.

[0407] Step (iv): Compound 148 (135 mg) was used according to the same method as in Example 19 to give the title compound 149 (175 mg). LCMS: [M+H] + / Rt (min):647 / 0.79 (Method C)

[0408] Reference example 91: (1R,6S)-2,2-Difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexan-1-amine [ka]

[0409] Process (i): A solution of compound 49 (2.01 g) in acetonitrile (12.6 ml) was added with sodium cyanide (495 mg) and lithium perchlorate (67 mg), and the reaction mixture was heated to reflux for 3 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 150 (2.05 g).

[0410] Step (ii): Using compound 150 (2.04 g) and according to a method similar to that of step (i) of Reference Example 8, the title compound 151 (1.88 g) was obtained.

[0411] Step (iii): Using compound 151 (200 mg) and isobutyric acid (53.6 mg), the title compound 152 (89.7 mg) was obtained according to a method similar to that in step (ii) and step (iii) of Reference Example 8.

[0412] Step (iv): Using compound 152 (87.7 mg) and according to a method similar to that in step (iii) of Reference Example 18, the title compound 153 (41.5 mg) was obtained. LCMS: [M+H] + / Rt (min):246 / 0.37 (Method C)

[0413] Reference example 92: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]cyclohexan-1-amine [ka]

[0414] Process (i): Sodium azide (490 mg) was added to a solution of compound 49 (1.6 g) in acetonitrile / water (23 ml / 2.5 ml), and the reaction mixture was heated to 70°C for 1.5 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 154 (1.78 g).

[0415] Step (ii): To a solution of compound 154 (550 mg) in a methanol / THF mixture (11.4 ml / 2.3 ml / 4 ml), sodium ascorbate (30.2 mg), tris(2-benzimidazolylmethyl)amine (46.5 mg), and 3-methylbut-1-yne (156 mg) were added. Then, an aqueous solution (3.8 ml) of copper sulfate (18.2 mg) was added to the reaction mixture, and the reaction mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 155 (353 mg).

[0416] Step (iii): Compound 155 (353 mg) was used according to a method similar to that of Step (iii) of Reference Example 18 to give the title compound 156 (168 mg). LCMS: [M+H] + / Rt (min):245 / 0.42

[0417] Reference example 93: (1R,6S)-2,2-Difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]cyclohexan-1-amine The compound of Reference Example 93 shown in the following table was synthesized according to the method described in Reference Example 92 above, except that 4-methylpent-1-yne was used instead of 3-methylbut-1-yne in step (ii) of Reference Example 92. [Table 19]

[0418] Reference example 94: [(1S,2R)-2-Amino-3,3-difluorocyclohexyl][4-(propan-2-yl)piperazin-1-yl]methanone [ka]

[0419] Process (i): A reaction mixture of compound 150 (555 mg) in DMSO (6 ml) and aqueous hydrochloric acid (9 ml) was heated to 120°C. After completion of the reaction, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give title compound 157 (600 mg).

[0420] Step (ii): To a DMF solution (1.5 ml) of compound 157 (476 mg), 1-isopropylpiperazine (234 mg), triethylamine (308 mg), and HATU (753 mg) were added, and the reaction mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give title compound 158 (610 mg). LCMS: [M+H] + / Rt (min): 475 / 0.59

[0421] Step (iii): Compound 158 (605 mg) was used according to a method similar to that of Step (iii) of Reference Example 18 to give the title compound 159 (180 mg). LCMS: [M+H] + / Rt (min): 290 / 0.16

[0422] Reference example 95: (1R,6R)-2,2-Difluoro-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}cyclohexan-1-amine [ka]

[0423] Process (i): Using compound 159 (171 mg) and according to a method similar to that in step (ii) of Reference Example 22, the title compound 160 (112 mg) was obtained. LCMS: [M+H] + / Rt (min): 276 / 0.24

[0424] Reference examples 96~114: The compounds of Reference Examples shown in the following table were synthesized according to the method described in Reference Example 37 above, using the corresponding starting compounds instead of (S)-1-isopropylpyrrolidin-3-ol in step (i) of Reference Example 37. [Table 20] TIFF2025179148000249.tif214169 TIFF2025179148000250.tif219169 TIFF2025179148000251.tif182169

[0425] Reference Example 96: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexan-1-amine Reference Example 97: (1R,6S)-2,2-difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]oxy}cyclohexan-1-amine Reference Example 98: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexan-1-amine Reference Example 99: (1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}cyclohexan-1-amine Reference Example 100: (1R,6S)-2,2-difluoro-6-{[(1R,3s,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexan-1-amine Reference Example 101: (1R,6S)-2,2-difluoro-6-{[(1R,5S,8r)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexan-1-amine Reference Example 102: (1R,6S)-2,2-difluoro-6-{[(1R,5S,8s)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexan-1-amine Reference Example 103: (1R,6S)-2,2-difluoro-6-{[(1R,3r,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexan-1-amine Reference Example 104: (1R,6S)-2,2-difluoro-6-{[(1R,5S,6s)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]oxy}cyclohexan-1-amine Reference Example 105: (1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 106: (1R,6S)-2,2-difluoro-6-{[(3R,4R)-4-methoxy-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 107: (1R,6S)-2,2-difluoro-6-{[4-methyl-1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexan-1-amine Reference Example 108: (1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexan-1-amine Reference Example 109: (1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexane-1-amine Reference Example 110: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexan-1-amine Reference Example 111: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexan-1-amine Reference Example 112: (1R,6S)-2,2-difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 113: (1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexan-1-amine Reference Example 114: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidin-3-yl}oxy)cyclohexan-1-amine

[0426] Reference examples 115~118 The compounds of Reference Examples 115 to 118 shown in the table below were synthesized in the same manner as in Reference Example 8 above, except that the corresponding raw material (raw material A) was used instead of compound 26 in step (i) of Reference Example 8, and the corresponding raw material compound (raw material B) was used instead of cyclopropanecarboxylic acid in step (iii). [Table 21]

[0427] Reference Example 115: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine Reference Example 116: 4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine Reference Example 117: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride Reference Example 118: 4-Ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine

[0428] Reference example 119: (1R,6S)-2,2-Difluoro-6-{[2-(propan-2-yl)pyrimidin-4-yl]oxy}cyclohexan-1-amine [ka]

[0429] Process (i): Sodium hydride (55%, 30 mg) was added to a THF solution (3 ml) of the literature-known compound 161 (148 mg) at 0°C, followed by the addition of 4-chloro-2-(propan-2-yl)pyrimidine. The reaction mixture was warmed to room temperature and stirred. After completion of the reaction, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 162 (209 mg).

[0430] Step (ii): Palladium hydroxide (17 mg) was added to a solution of compound 162 (113 mg) in ethyl acetate (2 mL) 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 give title compound 163 (33.5 mg). LCMS: [M+H] + / Rt (min): 272 / 0.47

[0431] Reference example 120: (1R,6S)-2,2-Difluoro-N-methyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0432] Process (i): Cesium carbonate (253 mg) and methyl iodide (72 mg) were added to a DMF solution (3 ml) of compound 50 (173 mg) at 0°C, and the reaction mixture was then warmed to room temperature and stirred. After completion of the reaction, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 164 (159 mg).

[0433] Step (ii): Using compound 164 (134 mg) and according to a method similar to that in Step (iii) of Reference Example 18, the title compound 165 (71 mg) was obtained. LCMS: [M+H] + / Rt (min): 276 / 0.15

[0434] Reference example 121: rac-(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0435] Process (i): Aqueous ammonia (6 g) was added to a solution of compound 166 (283 mg) in 2-propanol (8 ml), and the mixture was heated under reflux. After the raw materials disappeared, the reaction solution was concentrated and used in the subsequent reaction.

[0436] Step (ii): Using compound 167 and according to a method similar to that of step (i) of Reference Example 18, the title compound 168 (64.3 mg) was obtained.

[0437] Step (iii): Using compound 168 (60.8 mg) and according to a method similar to that in Step (ii) of Reference Example 18, the title compound 169 (102 mg) was obtained.

[0438] Step (iv): Using compound 169 (102 mg) and according to a method similar to that in Step (iii) of Reference Example 18, the title compound 170 (40.2 mg) was obtained. LCMS: [M+H] + / Rt (min): 254 / 0.43

[0439] Reference example 122: rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cycloheptan-1-amine The compounds of Reference Examples shown in the following table were synthesized according to the method described in Reference Example 120 above, except that 8-oxabicyclo[5.1.0]octane was used instead of compound 166 in step (i) of Reference Example 120. [Table 22]

[0440] Reference example 123: rac-(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0441] Process (i): A toluene solution (1 ml) of compound 171 (403 mg) and tetrabutylammonium dihydrogen trifluoride (1.78 g) was heated to 150 °C under microwave irradiation. After completion of the reaction, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 172 (323 mg).

[0442] 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 stirred. After confirming the disappearance of the raw materials, 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. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 173 (578 mg).

[0443] Step (iii): Palladium hydroxide (20%, 133 mg) was added to a solution (3.5 mL) of compound 173 (571 mg) in ethanol at room temperature, and the mixture was stirred under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 174 (400 mg).

[0444] Step (iv): Compound 174 (176 mg) was dissolved in 1,4-dioxane (3.5 mL), DBU (0.25 mL) was added, and the mixture was heated and stirred at 85°C. After confirming the disappearance of the raw materials, the mixture was subjected to the conditions up to methanesulfonylation in step (i) and step (ii) of Reference Example 121. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give title compound 175 (86 mg).

[0445] Process (v): Using compound 175 (86 mg), the title compound 176 (92.8 mg) was obtained according to the same conditions for the cyclization reaction of step (ii) of Reference Example 121 and the same method as in step (ii) of Reference Example 18.

[0446] Process (vi): Using compound 176 (86.1 mg) and according to a method similar to the conditions of step (iii) of Reference Example 18, the title compound 177 (35.1 mg) was obtained. LCMS: [M+H] + / Rt (min): 244 / 0.19

[0447] Reference example 124: rac-(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexan-1-amine [ka]

[0448] Process (i): Using compound 178 (929 mg) and according to a method similar to that of step (i) of Reference Example 123, the title compound 179 (953 mg) was obtained.

[0449] Step (ii): Compound 179 (283 mg) was dissolved in chloroform (6 mL), and pyridine (0.51 mL) and trifluoromethanesulfonic anhydride (0.256 mL) were added under ice-cooling and stirred. After confirming the disappearance of the raw materials, aqueous sodium bicarbonate solution was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 180 (424 mg).

[0450] 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 completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 181 (102 mg).

[0451] Step (iv): Palladium hydroxide (20%, 58 mg) was added to a solution of compound 181 (102 mg) in ethanol (2 mL) at room temperature and stirred under a hydrogen atmosphere. The reaction mixture was filtered through Celite, concentrated, and then redissolved in ethanol (2 mL). Hydrogen chloride solution (cyclopentylmethyl solution, 5 M, 0.327 mL) and palladium carbon (10%, 71 mg) were added and stirred under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under reduced pressure to give title compound 182 (76.8 mg).

[0452] Process (v): Compound 182 (103 mg) was used according to the same procedures as in Step (i) and Step (ii) of Reference Example 18 to give the title compound 183 (69 mg).

[0453] Process (vi): Compound 183 (72 mg) was used according to a method similar to that in Step (iii) of Reference Example 18 to give the title compound 184 (34.3 mg). LCMS: [M+H] + / Rt (min): 244 / 0.14

[0454] Reference example 125: (1S,2R)-2-Amino-3,3-difluorocyclohexyl 4-(propan-2-yl)piperazine-1-carboxylate [ka]

[0455] Process (i): To a solution (3 ml) of the literature-known compound 185 in acetonitrile, BocO (238 mg) was added, and the reaction mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 186 (216 mg).

[0456] Step (ii): Using compound 186 (95.7 mg) and according to a method similar to that in Step (iii) of Reference Example 2, the title compound 187 (118 mg) was obtained.

[0457] Step (iii): Using compound 187 (118 mg) and according to a method similar to that of Reference Example 2, step (iv), the title compound 188 (99.7 mg) was obtained. LCMS: [M+H] + / Rt (min): 306 / 0.25

[0458] Reference example 126: N-{(1S,6S)-2,2-difluoro-6-[1-(propan-2-yl)piperidine-4-sulfonyl]cyclohexyl}-4-nitrobenzene-1-sulfonamide [ka]

[0459] Process (i): Using compound 49 (399 mg) and tert-butyl 4-sulfanylpiperidine-1-carboxylate (300 mg), and according to a method similar to that in step (ii) of Reference Example 18, the title compound 189 (402 mg) was obtained.

[0460] Step (ii): To a chloroform solution (2 ml) of compound 189 (210 mg), m-CPBA (242 mg) was added, and the reaction mixture was stirred at room temperature. After completion of the reaction, aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: chloroform / methanol) to give the title compound 190 (250 mg).

[0461] Step (iii): Compound 190 (250 mg) was used according to the same procedures as in Step (i) and Step (ii) of Reference Example 53 to give the title compound 191 (223 mg).

[0462] Step (iv): Compound 191 (223 mg) was used according to a method similar to that in Reference Example 18 (iii) to give the title compound 192 (102 mg). LCMS: [M+H] + / Rt (min): 325 / 0.21

[0463] Test Example 1: Measurement of orexin type 2 receptor agonist activity Human orexin 2 receptor and apoaequorin were transiently expressed in CHO cells, and their agonism was assessed using the amount of calcium influx into cells upon ligand stimulation. Transiently expressed cells were seeded at 2,000 cells / well in a 384-well plate and cultured for 16–22 hours. After the plate was returned to room temperature, coelenterazine hcp (final concentration: 1 μM) was added and incubated at room temperature for 2 hours. Orexin A (Peptide Institute, Inc., Lot. 641114) or test compounds were then added, and cell luminescence was measured using an FDSS7000 (Hamamatsu Photonics). Orexin A and test compounds were dissolved in DMSO (final concentration: 0.1%) and diluted in buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin 2 receptor agonism (E-max) of the test compounds was calculated relative to the luminescence value following Orexin A (100 pM), which was defined as 100%.

[0464] Test results: The orexin 2 receptor agonism of the compounds obtained in the examples was measured, and it was observed that the compounds of the present invention exhibited agonistic activity on the orexin 2 receptor. The orexin 2 receptor agonism (E-max) of the compounds obtained in the examples is shown in the table below as a relative value when the luminescence value upon treatment with Orexin A (100 pM) was set to 100%. [Table 23]

[0465] Test Example 2: Measurement of orexin type 2 receptor agonist activity Human orexin 2 receptor and apoaequorin were transiently expressed in CHO cells, and their agonism was assessed using the amount of calcium influx into cells upon ligand stimulation. Transiently expressed cells were seeded at 2,000 cells / well in a 384-well plate and cultured for 16–22 hours. After the plate was returned to room temperature, coelenterazine hcp (final concentration: 1 μM) was added and incubated at room temperature for 2 hours. Orexin A (Peptide Institute, Inc., Lot. 671009) or test compounds were then added, and cell luminescence was measured using an FDSS7000 (Hamamatsu Photonics). Orexin A and test compounds were dissolved in DMSO (final concentration: 0.1%) and diluted in buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin 2 receptor agonism (E-max) of the test compounds was calculated relative to the luminescence value following Orexin A (100 pM), which was defined as 100%.

[0466] Test results: The orexin 2 receptor agonism of the compounds obtained in the examples was measured, and it was observed that the compounds of the present invention exhibited agonistic activity on the orexin 2 receptor. The orexin 2 receptor agonism (E-max) of the compounds obtained in the examples is shown in the table below as a relative value when the luminescence value upon treatment with Orexin A (100 pM) was set to 100%. [Table 24] [Industrial Applicability]

[0467] The compounds of the present invention exhibit strong agonistic activity against orexin receptors and are useful as therapeutic or preventive agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, and the like.

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. 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 not a halogen, a hydroxyl 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 aryl 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 not a halogen, a hydroxyl 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; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

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 not a halogen, a hydroxyl group, 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; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

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 is 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 compound according to any one of claims 1 to 3, which is any one selected from the following, or a pharmaceutically acceptable salt thereof.

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. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is 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 is 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 compound according to any one of claims 1 to 5, wherein is represented by -CH-, a nitrogen atom or a carbon atom, or a pharmaceutically acceptable salt thereof.

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 is 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:

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, 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.

8. The compound according to claim 6 or 7, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

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 compound according to any one of claims 6 to 8, wherein the compound is represented by the following formula (1): or a pharmaceutically acceptable salt thereof.

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 compound according to any one of claims 1 to 9, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

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 compound according to any one of claims 4 to 10, or a pharmaceutically acceptable salt thereof, 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 12. The compound or pharmaceutically acceptable salt thereof 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 compound according to any one of claims 10 to 12, which is alkyl, or a pharmaceutically acceptable salt thereof.

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 13. The compound according to any one of claims 10 to 12, wherein R is 1 or 2, and R is 2 or 3, and R is 3 or 4, and R is 4 or 5, and R is 5 or 6.

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 compound according to any one of claims 1 to 12, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

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 compound of claim 15, or a pharmaceutically acceptable salt thereof, 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 17. The compound or pharmaceutically acceptable salt thereof according to claim 15 or 16, wherein is a methyl group.

18. Ring G is the above formula (1b-2-1), and R ｂ５ The compound or pharmaceutically acceptable salt thereof 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 compound or pharmaceutically acceptable salt thereof 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 compound or pharmaceutically acceptable salt thereof according to any one of claims 15 to 17, wherein is an oxygen atom.

21. Q ２ The compound or pharmaceutically acceptable salt thereof according to any one of claims 15 to 20, wherein is an oxygen atom.

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the following compound name or structural formula: 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 compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the following compound name or structural formula: 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 compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the following compound name or structural formula: 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 compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the following compound name or structural formula: 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 compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

27. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, for use in 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 (e.g., cerebrovascular disease, encephalopathy ... 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 compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

29. A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy bodies, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

30. Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof 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.

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