Bicycloamine carboxamide derivative

Abstract

The present invention relates to a compound represented by formula (1) or a pharmaceutically acceptable salt thereof that has therapeutic and prophylactic effects on diseases in which orexin type 2 receptors participate, specifically, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, etc. [In the formula: R1 and R2 independently represent a hydrogen atom, etc.; R3 and R4 independently represent a hydrogen atom, etc.; R5 represents optionally substituted C1-4 alkyl; -L1-ring G represents -ring G, -CH2-ring G, etc.; R6s independently represent a hydrogen atom, etc.; n is an integer of 1 or 2; ring G represents an optionally substituted C6-10 aromatic carbocyclic group, etc.; A1 represents an oxygen atom, etc.; A2 represents an oxygen atom, etc.; j, k, l and m are independently an integer of 0, 1 or 2; a broken line represents a single or double bond; X represents -CR7-, etc.; R7 represents a hydrogen atom, etc.; and ring E is represented by formula (1a-1), (1a-2) or (1a-3).]

Description

Bicycloaminecarboxamide derivatives

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

[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 primarily present 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 intracerebroventricular administration of orexin peptides improves narcolepsy-like symptoms in transgenic mice with degenerated orexin neurons (Non-Patent Document 2). It has also been reported that knockout (KO) of preproorexin, the precursor protein of orexin, induces narcolepsy-like symptoms (Non-Patent Document 3). Furthermore, it has been shown that orexin concentrations in the cerebrospinal fluid of narcolepsy patients are significantly reduced (Non-Patent Document 4), suggesting that narcolepsy is caused by orexin deficiency. Furthermore, mutations in the orexin type 2 receptor have been reported in dogs with hereditary narcolepsy (Non-Patent Document 5), suggesting the involvement of the orexin type 2 receptor in sleep-wake regulation. Furthermore, it has been shown that narcolepsy-like symptoms are induced in orexin type 2 receptor knockout mice (Non-Patent Document 6), strongly suggesting the involvement of orexin type 2 receptor stimulation in maintaining wakefulness. Given these circumstances, orexin type 2 receptor agonists are expected to be promising therapeutic agents for disorders exhibiting hypersomnia, including narcolepsy.

[0004] In recent years, compounds having orexin type 2 receptor agonism have been reported (Patent Documents 1 and 2).

[0005] International Publication No. 2017 / 135306 International Publication No. 2021 / 107023

[0006] Cell, Vol. 92, pp. 573-585, 1998; Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, pp. 4649-4654, 2004; Cell, Vol. 98, pp. 437-451, 1999; The Lancet, Vol. 355, pp. 39-40, 2000. LANCET, Vol. 355, 39-40, 2000) Cell, Vol. 98, pp. 365-376, 1999 (Cell, Vol. 98, 365-376, 1999) Neuron, Vol. 38, pp. 715-730, 2003 (Neuron, Vol. 38, pp. 715-730, 2003) Brain, Vol. 130, pp. 1577-1585, 2007 (Brain, Vol. 130, pp. 1577-1585, 2007) Neuroscience Letters, Vol. 569, pp. 68-73, 2014 (Neuroscience Letters, Vol. 569, pp. 68-73, 2014)

[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.

[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] [Term 1] Formula (1): [In the formula, R１ and R ２ are each independently a hydrogen atom, a halogen atom, cyano, or —(C═O)NR ３ R ４ , carboxy group, —(C═O)O—R ５ , optionally substituted C １－４ Alkyl or optionally substituted C １－４ represents alkoxy, and R １ and R ２ may be bonded to the same carbon atom if chemically possible, and R １ and R ２ are bonded to different carbon atoms on the ring, １ - ６ may be bonded via an alkylene to form a fused ring or a bridged ring; R ３ and R ４ are each independently a hydrogen atom or an optionally substituted C １－４ represents alkyl; R ５ is an optionally substituted C １－４ represents alkyl; １ -Ring G is -Ring G, -CH ２ -Ring G (the CH ２ is one or more of the same or different C １－６ optionally substituted with alkyl), —NR ６ -Ring G, -C(=O)-Ring G, -OC(=O)-Ring G, -SO-Ring G, -SO ２ -ring G, -S-ring G, or -O-ring G; R ６ represents a hydrogen atom or an optionally substituted C １－４ 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 A represents a saturated carbocyclic group or an optionally substituted 4- to 10-membered saturated heterocyclic group; １ represents an oxygen atom or a sulfur atom; ２ represents an oxygen atom or —NH—; j, k, l, and m are each independently an integer of 0, 1, or 2; the dashed line represents a single bond or a double bond; X is —CR ７represents -, a nitrogen atom, or a carbon atom; ７ represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, or an optionally substituted C １－４ Ring E represents alkyl; and ring E represents the following formula (1a-1), (1a-2), or (1a-3): [In the formula, X １ ~X ８ are each independently a nitrogen atom or —CR ａ４ represents -; Q １ and Q ２ represents an oxygen atom or -NR ａ５ represents -; R ａ１ ~R ａ５ are each independently (CR ａ４ If there are multiple R ａ４ 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 may be substituted with 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 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 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 a 5- to 10-membered aromatic heterocyclic group, and R ａ２ and R ａ３ may be bonded to the same carbon atom if chemically possible; １and X ３ Both are CR ａ４ In the case of two R ａ４ and the carbon atoms bonded to them are both X １ , X ２ and X ３ and optionally forming a 6-membered carbocyclic ring fused with a 5-membered ring constituted by the formula (I) or a pharmaceutically acceptable salt thereof.

[0011] [Section 2] R １ ~R ７ In the "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, or C ３－７ C of ring G is cycloalkyl. 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 may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ optionally substituted with cycloalkyl), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, C １－４ Alkoxy, or C ３－７ optionally substituted with cycloalkyl), C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, 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, C１－４ 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 Item 1. The compound of Item 1 or a pharmaceutically acceptable salt thereof, which may be bonded via an alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridged rings.

[0012] [Section 3] R １ ~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 substitutable substituents in "alkoxy" are each independently one or more of the same or different halogen atoms, 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 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 substituted with 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, C１－４ Alkyl, or C １－４ optionally substituted with alkoxy), and C ３－７ Cycloalkoxy (the cycloalkoxy may be 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 Item 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, which may be bonded via an alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridged rings.

[0013] [Item 4] Ring E is represented by the following formula (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): [In the formula, X １ ~X ５ are each independently a nitrogen atom or —CR ａ４ represents -; R ａ１ ~R ａ４ are each independently (CR ａ４ If there are multiple R ａ４ 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 may be substituted with 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 may be one or more of the same or different halogen atoms, hydroxy groups, or C １－４optionally 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, or C １－４ R represents a 5- to 10-membered aromatic heterocyclic group, which may be substituted with an alkoxy group; ａ２ and R ａ３ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are -CR ａ４ - In the case of two R ａ４ and the carbon atoms to which they are attached are both X １ , X ２ and X ３ Item 4. The compound according to any one of Items 1 to 3, wherein the compound represents a 6-membered carbocyclic ring fused with a 5-membered ring consisting of the formula:

[0014] [Item 5] Ring G is represented by the following formula (1b-1) or (1b-2): [In the formula, W １ and W ３ are each independently a nitrogen atom or —CR ｂ３ represents -; W ２ and W ４ are each independently -NR ｂ４ -, oxygen atom, or -CR ｂ５ R ｂ６ represents -; R ｂ１ ~R ｂ６ are each independently a hydrogen atom, —N(R ｂ７ ) R ｂ８ , C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, C ３－６ 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 halogen atoms), or C １－４ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０The 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 substituted with 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, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy may be 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 bonded to the same carbon atom if chemically possible; ｂ１ and R ｂ２ is C １－６ may be bonded via alkylene to form any chemically feasible bicyclic structure among fused, spiro, or bridged rings; R ｂ７ and R ｂ８ are each independently a hydrogen atom, C １－６ Alkyl (the alkyl may be 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 (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 ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４substituted with alkoxy), wherein R ｂ１ ~R ｂ６ -N (R ｂ７ ) R ｂ８ If R ｂ７ and R ｂ８ and optionally, together with the nitrogen atom to which they are attached, form a 3- to 7-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof.

[0015] [Term 6] Formula (2): [In the formula, R １ and R ２ are each independently 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, hydroxy groups, C １－４ Alkoxy, or C ３－７ cycloalkyl), or C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C ３－７ -L represents a cycloalkyl-substituted group; １ -Ring G is -Ring G, -CH ２ -Ring G (the CH ２ is one or more of the same or different C １－６ optionally substituted with alkyl), —NR ６ -Ring G, -C(=O)-Ring G, -OC(=O)-Ring G, -SO-Ring G, -SO ２ -ring G, -S-ring G, or -O-ring G; R ６ are each independently a hydrogen atom or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ Ring G represents the following formula (1b-1) or (1b-2): [In the formula, W １ and W ３ are each independently a nitrogen atom or —CR ｂ３ represents -; W ２ and W ４are each independently -NR ｂ４ -, oxygen atom, or -CR ｂ５ R ｂ６ represents -; R ｂ１ ~R ｂ６ are each independently a hydrogen atom, —N(R ｂ７ ) R ｂ８ , C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, C ３－６ 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 optionally substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be substituted with 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, C １－４ Alkyl, or C １－４ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy may be 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 bonded to the same carbon atom if chemically possible; ｂ１ and R ｂ２ is C １－６ may be bonded via alkylene to form any chemically feasible bicyclic structure among fused, spiro, or bridged rings; R ｂ７ and R ｂ８ are each independently a hydrogen atom, C １－６Alkyl (the alkyl may be 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 (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 ３－７ 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), wherein R ｂ１ ~R ｂ６ -N (R ｂ７ ) R ｂ８ If R ｂ７ and R ｂ８ may be taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered nitrogen-containing saturated heterocycle; １ represents an oxygen atom or a sulfur atom; j, k, l, and m are each independently an integer of 0, 1, or 2; the dashed line represents a single bond or a double bond; X is -CR ７ represents -, a nitrogen atom, or a carbon atom; ７ is a hydrogen atom, a hydroxy group, a halogen atom, cyano, or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ Ring E represents a group represented by the following formula (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): [In the formula, X １ ~X ５ are each independently a nitrogen atom or —CR ａ４represents -; R ａ１ ~R ａ４ are each independently (CR ａ４ If there are multiple R ａ４ 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 may be substituted with 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 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 ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ alkoxy), or a 5- to 10-membered aromatic heterocyclic group, and R ａ２ and R ａ３ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are -CR ａ４ - In the case of two R ａ４ and the carbon atoms to which they are attached are both X １ , X ２ and X ３ Item 6. The compound according to any one of items 1 to 5, wherein the compound represents a 6-membered carbocyclic ring fused with a 5-membered ring consisting of the formula:

[0016] [Section 7] R １ and R２ are each independently 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, hydroxy groups, C １－４ Alkoxy, or C ３－７ L represents a cycloalkyl group; １ represents a single bond or an oxygen atom; and ring G is represented by the following formula (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ are each independently 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 Item 7. The compound according to item 6, wherein the compound represents: wherein the group is optionally substituted with alkoxy; or a pharmaceutically acceptable salt thereof.

[0017] [Term 8] Formula (3): [In the formula, L １ represents a single bond or an oxygen atom; Ring G is a group represented by the following formula (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ are each independently 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 j, k, l, and m each independently represent an integer of 0, 1, or 2; the dashed line represents a single bond or a double bond; X represents -CR ７ represents -, a nitrogen atom, or a carbon atom; ７ is a hydrogen atom, a hydroxy group, a halogen atom, cyano, or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７Ring E represents a group represented by the following formula (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): [In the formula, X １ ~X ５ are each independently a nitrogen atom or —CR ａ４ represents -; R ａ１ ~R ａ４ are each independently (CR ａ４ If there are multiple R ａ４ 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 may be substituted with 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 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 Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ alkoxy), or a 5- to 10-membered aromatic heterocyclic group, and R ａ２ and R ａ３ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are -CR ａ４ - In the case of two R ａ４ and the carbon atoms to which they are attached are both X １ , X２ and X ３ Item 8. The compound according to any one of Items 1 to 7, wherein the compound represents a 6-membered carbocyclic ring fused with a 5-membered ring consisting of the formula:

[0018] [Term 9] Formula (4): [In the formula, L １ represents a single bond or an oxygen atom; Ring G is a group represented by the following formula (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ are each independently 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 The dashed portion represents a single bond or a double bond; X represents -CR ７ represents -, a nitrogen atom, or a carbon atom; ７ is a hydrogen atom or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ Ring E represents a group represented by the following formula (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): [In the formula, X １ ~X ５ are each independently a nitrogen atom or —CR ａ４ represents -; R ａ１ ~R ａ４ are each independently (CR ａ４ If there are multiple R ａ４ 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 １－４Alkyl (the alkyl may be substituted with 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 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 Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkyl, or C １－４ R represents a 5- to 10-membered aromatic heterocyclic group, which may be substituted with an alkoxy group; ａ２ and R ａ３ may be bonded to the same carbon atom if chemically possible; １ and X ３ Both are -CR ａ４ - In the case of two R ａ４ and the carbon atoms to which they are attached are both X １ , X ２ and X ３ and optionally forming a 6-membered carbocyclic ring fused with a 5-membered ring constituted by the formula:

[0019] [Item 10] Ring E is the above formula (1a-2-1) or (1a-3-1): [wherein, X ４ ~X ５ are each independently a nitrogen atom or —CR ａ４ represents -; R ａ１ ~R ａ４ are each independently (CR ａ４ If there are multiple R ａ４ 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 or C １－４ optionally substituted with alkoxy), C３－７ 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), or C １－４ Item 10. The compound according to Item 9, wherein the alkoxy is optionally substituted with one or more of the same or different halogen atoms, or a pharmaceutically acceptable salt thereof.

[0020] [Item 11] Ring E is represented by the following formula (1a-2-2) or (1a-3-1): [In the formula, R ａ１ ~R ａ３ are each independently 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), or 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 Item 10. The compound according to item 9, wherein the compound represents: wherein the group is optionally substituted with alkoxy; or a pharmaceutically acceptable salt thereof.

[0021] [Term 12] Formula (5): [In the formula, L １ represents a single bond or an oxygen atom; Ring G is a group represented by the following formula (1b-1-1) or (1b-2-1): [In the formula, R ｂ４ 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 R represents an alkyl group, optionally substituted with alkoxy; ７ is a hydrogen atom or C １－４ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－４ Alkoxy, or C ３－７ Ring E represents the following formula (1a-2-2) or (1a-3-1): [In the formula, Rａ１ ~R ａ３ are each independently 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), or 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 Item 12. The compound according to any one of items 1 to 11, wherein the compound is represented by the formula: wherein R represents an integer of 1 to 14, and R represents an integer of 1 to 15, and R represents an integer of 1 to 16, and R represents an integer of 1 to 18, and R represents an integer of 1 to 19, or a pharmaceutically acceptable salt thereof.

[0022] [Item 13] Ring G represents the above formula (1b-1-1), and R ｂ４ C optionally substituted with one or more of the same or different halogen atoms １－４ Item 13. The compound according to Item 12, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0023] [Item 14] Ring G represents the above formula (1b-2-1), and R ｂ４ 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 Item 13. The compound according to item 12, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2, and R is 2 or 3, and R is 3 or 4, and R is 4 or 5.

[0024] [Section 15] R ７ Item 13. The compound or a pharmaceutically acceptable salt thereof according to Item 12, wherein is a hydrogen atom.

[0025] [Item 16] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: Example 1: (3aR,5S,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 2: (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 3: (1R,5S,6R)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide, Example 4: (1R,5S,6S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide, Example 6: (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 7: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 8: (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,Example 9: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 10: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 11: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 12: (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 13: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 14: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 15: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 16: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 17: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 5-A: (1S,6R,8S)-8-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[4.2.0]octane-3-carboxamide, Example 5-B: (1R,6S,8R)-8-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[4.2.0]octane-3-carboxamide, Example 10-A: (3aS,6aR)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 10-B: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 18: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 19: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 20: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 21: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 22: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 23: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 24: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 25: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 26: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 27: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 28: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 29: (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, Example 30: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 31: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 32: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 33: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, Example 34: (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide.

[0026] [Item 17] A pharmaceutical composition comprising the compound according to any one of items 1 to 16, or a pharmaceutically acceptable salt thereof.

[0027] [Item 18] A pharmaceutical composition comprising the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof for use in 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.

[0028] [Item 19] A therapeutic agent for a disease associated with the orexin type 2 receptor, comprising the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof.

[0029] [Item 20] A compound according to any one of Items 1 to 16 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 encephalitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinism-related 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 / Disorders of the urinary system, disorders 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 injuries, 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, 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.

[0030] [Item 21] 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 16 or a pharmaceutically acceptable salt thereof.

[0031] [Item 22] A therapeutic agent for narcolepsy, comprising the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof.

[0032] [Item 23] A therapeutic agent for idiopathic hypersomnia, comprising the compound according to any one of items 1 to 16 or a pharmaceutically acceptable salt thereof.

[0033] [Item 24] A method for treating a disease associated with the orexin type 2 receptor, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof.

[0034] [Item 25] 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 16 or a pharmaceutically acceptable salt thereof.

[0035] [Item 26] The compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with the orexin type 2 receptor.

[0036] [Item 27] ​​The compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of 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] [Item 28] Use of the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for a disease associated with the orexin type 2 receptor.

[0038] [Item 29] Use of the compound according to any one of Items 1 to 16 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.

[0039] [Item 30] A medicine comprising the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof in combination with at least one or more drugs selected from the group consisting of therapeutic drugs for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and narcolepsy syndrome accompanied by narcoleptic symptoms, or drugs classified as therapeutic drugs for Parkinson's disease or dementia with Lewy bodies.

[0040] [Item 31] A medicine comprising the compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof for treating a disease involving the orexin type 2 receptor in combination with at least one or more drugs selected from therapeutic drugs for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and narcolepsy syndrome accompanied by narcoleptic symptoms, or drugs classified as therapeutic drugs for Parkinson's disease or dementia with Lewy bodies.

[0041] 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."

[0042] Furthermore, in the description of substituents in this specification, the term "group" may be omitted in some cases. 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. Furthermore, unless otherwise specified, the description of each group also applies when the group is a part or substituent of another group.

[0043] Unless otherwise specified in the present specification, the bonding position of a substituent is any chemically possible position. In addition, in the structural formulae in the present specification, wedge-shaped solid and dashed lines represent absolute configurations, and thick solid and dashed lines represent relative configurations.

[0044] "Halogen" includes, for example, fluorine, chlorine, bromine, iodine, etc. Preferably, it is fluorine or chlorine.

[0045] "C １－４ "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. １－６ "Alkyl" means a straight or branched chain 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.

[0046] "C １－６ "Alkylene" means a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, which may be straight or branched. １－６ As the "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. １－６Specific examples of "alkylene" include the above-mentioned "C １－４ 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.

[0047] "C ３－７ "Cycloalkyl" means 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.

[0048] 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) the same or different heteroatoms selected from nitrogen, sulfur, or oxygen (for example, a 5- or 6-membered ring among the "4- to 10-membered saturated heterocycles" described below).

[0049] "C １－４ The term "alkoxy" refers to the same as the above "C １－４ means an oxy group substituted with "alkyl" and "C １－６ The term "alkoxy" refers to the same as the above "C １－６ "C" means an oxy group substituted with "alkyl." １－４ Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxy", pentyloxy, hexyloxy, etc. are also included. １－４ Alkoxy" or "C１－６ The "alkoxy" is preferably methoxy, ethoxy or isopropoxy.

[0050] "C ３－７ "Cycloalkoxy" refers to the same as "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.

[0051] "C ６－１０ An "aromatic carbocyclic group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ Also called "aryl". ６－１０ Specific examples of the "aromatic carbocyclic group" include phenyl, 1-naphthyl, 2-naphthyl, etc. Phenyl is more preferred.

[0052] 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).

[0053] 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), which may be the same or different, selected from nitrogen, sulfur, or oxygen. A "5- or 6-membered monocyclic aromatic heterocyclic group" is preferred. 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."

[0054] 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, or a group in which a monocyclic aromatic heterocycle is fused together 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, benzofuranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. In another embodiment, preferred examples include benzofuranyl (bonding position on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0055] "C ３－６ "Saturated carbocycle" 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.

[0056] 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 includes those having a partially unsaturated bond, a partially bridged structure, and a partially spiro-bonded structure. 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- to 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, oxetane, azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, homopiperidine, thiomorpholine, dioxothiomorpholine, hexamethyleneimine, oxazolidine, thiazolidine, oxoimidazolidine, dioxoimidazolidine, oxooxazolidine, dioxooxazolidine, dioxothiazolidine, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, etc. Preferred are pyrrolidine, piperidine, piperazine, and morpholine.Specific examples of bicyclic saturated heterocycles include indoline, isoindoline, dihydropurine, dihydrothiazolopyrimidine, dihydrobenzodioxane, dihydroindazole, dihydropyrrolopyridine, tetrahydroquinoline, decahydroquinoline, tetrahydroisoquinoline, decahydroisoquinoline, tetrahydronaphthyridine, and tetrahydropyridoazepine.

[0057] 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.

[0058] The compounds of the present invention also include various hydrates, solvates and crystalline polymorphs.

[0059] 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.

[0060] The compounds of the present invention include all tautomers, all existing stereoisomers, and mixtures thereof. For example, optically active compounds of the compounds of the present invention can be prepared by using optically active starting materials or by optical resolution of the final racemic compound. Methods for optical resolution include physical separation using an optically active column and chemical separation methods such as fractional crystallization.

[0061] In the present invention, "pharmaceutically acceptable salt" refers to an acid addition salt and a base addition salt that are acceptable for pharmaceutically use. 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 the 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.

[0062] 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.

[0063] 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.

[0064] The dose of the compound of the present invention is appropriately selected depending on the target animal, the administration route, the disease, and 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 per day for an adult, and this amount can be administered once a day or in divided doses.

[0065] The compound of the present invention has agonistic activity against the orexin type 2 receptor. Therefore, it can be a useful therapeutic or preventive agent for diseases in which the orexin type 2 receptor is involved. 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, etc.). acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinism-related obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroidism-related 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 from anesthesia Use and complications, sleep disturbances, sleep problems, insomnia, intermittent sleep, nocturnal clonic cramps, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep paralysis, 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, degenerative diseases Arthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormalities, reduced fertility, infertility, hypogonadism in men, hirsutism in women, and other sexual and reproductive disorders, fetal defects associated with maternal obesity,Reduces the risk of secondary consequences of obesity such as 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, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial hot flashes, night sweats, genital / Disorders of the urinary system, disorders 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 injuries, 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. ,

[0066] The compounds of the present invention have agonistic activity against the orexin type 2 receptor, and therefore may be useful therapeutic or preventive agents for diseases associated with the orexin type 2 receptor. The compounds of the present invention are particularly effective for sleep-wake disorders, and specific examples of such disorders include insomnia disorder, hypersomnia disorder, narcolepsy, narcolepsy with orexin (hypocretin) deficiency without cataplexy, narcolepsy with cataplexy but without orexin (hypocretin) deficiency, autosomal dominant cerebellar ataxia with deafness and narcolepsy, autosomal dominant narcolepsy with obesity and type 2 diabetes, narcolepsy secondary to other medical conditions, breathing-related sleep disorders, circadian rhythm sleep-wake disorders, parasomnias, restless legs syndrome, substance- or medication-induced sleep disorders, other specified insomnia disorders, insomnia disorder not otherwise specified, other specified hypersomnia disorders, hypersomnia disorder not otherwise specified, other specified sleep-wake disorders, and sleep-wake disorders not otherwise specified.

[0067] In the present invention, "prevention" refers to the act of administering the compound of the present invention to a healthy person who has not developed a disease, for example, with the aim of preventing the onset of a disease. "Treatment" refers to the act of administering the compound of the present invention to a person (patient) who has been diagnosed by a doctor as having developed a disease, for example, with the aim of alleviating the disease or symptoms or returning the patient to a state before the onset of the disease. Furthermore, even if the purpose of administration is to prevent the disease or symptoms from worsening, it is still a therapeutic act as long as the patient is the recipient of the administration.

[0068] The compound of the present invention can be used in combination with a therapeutic drug for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, or a therapeutic drug for Parkinson's disease or dementia with Lewy bodies. Examples of therapeutic drugs for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms include amphetamine, methylphenidate, modafinil, armodafinil, sodium oxybate, pitolisant, solriamfetol, etc. Examples of therapeutic agents for Parkinson's disease or dementia with Lewy bodies include levodopa, carbidopa, entacapone, MAOB inhibitors (e.g., zonisamide, selegiline, rasagiline, safinamide, etc.), dopamine receptor agonists (e.g., bromocriptine, pergolide, talipexole, cabergoline, pramipexole, ropinirole, rotigotine, apomorphine, etc.), amantadine, droxidopa, istradefylline, and anticholinergic agents (e.g., trihexyphenidyl, biperiden, etc.).

[0069] The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. The compound of the present invention and the concomitant drug may also be combined. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc.

[0070] The process for producing the compound represented by formula (1) of the present invention will be explained below with reference to examples, but the present invention is not limited to these.

[0071]

[0033] The compound of the present invention may be synthesized by a combination of the following synthesis 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 "pharmaceutically acceptable salts" mentioned above. Note that these reactions are merely illustrative, and the compound of the present invention may also be produced by other appropriate methods based on the knowledge of a person skilled in organic synthetic chemistry.

[0072] 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.

[0073] Examples of the protecting group include ordinary 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 the protecting group for an amino group include tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and tetrahydropyranyl. Examples of the protecting group for a hydroxy group include trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, and methoxymethyl. Examples of the protecting group for an aldehyde group include dialkyl acetal and cyclic alkyl acetal. Examples of the protecting group for a carboxyl group include tert-butyl ester, orthoester, and amide.

[0074] 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.

[0075] Production Method 1: The compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be produced, for example, by the following production method. (In the formula, R １ , R ２ , L １ , j, k, l, m, n, ring G, A １ , the dashed line portion, X, and ring E have the same meanings as in item 1.

[0076] Step (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-forming 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 from -20°C to the boiling point of the solvent.

[0077] In step (1-1), the intermediate product such as an isocyanate may be isolated for subsequent conversion.

[0078] Production Method 2: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-2-1) can be produced, for example, by the following production method. (In the formula, R ７ , Rａ１ , Q ２ , j, k, l, and m have the same meanings as in item 1. １ indicates a suitable protecting group, and the same applies hereinafter even when no explanation is given.)

[0079] Step (2-1): Compound (s-2-4) can be produced by reacting compound (s-2-2) and compound (s-2-3) in an appropriate 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.

[0080] Step (2-2): Compound (s-2-6) can be produced by reacting compound (s-2-4) and compound (s-2-5) in an appropriate inert solvent under commonly used condensation reaction conditions. Examples of conditions for this reaction include those using HATU, DCC, or CDI. A base may be used in this reaction, and examples of the base used include triethylamine and 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 usually about 1 to 24 hours, and the reaction temperature is from −20° C. to the boiling point of the solvent.

[0081] Step (2-3): Compound (s-2-7) can be produced by reacting compound (s-2-6) 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 usually about 1 hour to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0082] Step (2-4): Compound (s-2-1) can be prepared by converting compound (s-2-7) 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.

[0083] Production Method 3: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-3-1) can be produced, for example, by the following production method. (In the formula, R ａ２ , R ａ３ , X ６ , X ７ , X 8 , j, k, l, and m are the same as those in item 1. M represents a metal such as lithium or magnesium halide. Z represents boronic acid, boronic acid ester, BF ３ K., B.F. ３ represents Na, trialkyltin, zinc halide, or a hydrogen atom, and Y represents a halogen.

[0084] The compound (s-3-1) can be synthesized from the compound (s-3-2) through steps (3-1) to (3-3).

[0085] Step (3-1): Compound (s-3-4) can be produced by subjecting compound (s-3-2) and compound (s-3-3) to commonly used conditions for addition reactions to ketones in an appropriate inert solvent, either without additives or in the presence of a Lewis acid. Examples of Lewis acids used in this reaction include zinc(II) chloride, scandium triflate(III), copper(I) chloride, boron trifluoride, boronic acid, and boronate esters. 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 usually about 1 hour to 24 hours, and the reaction temperature is from −78° C. to the boiling point of the solvent.

[0086] Step (3-2): Compound (s-3-5) can be produced by reacting compound (s-3-4) in an appropriate inert solvent under commonly used dehydration reaction conditions. Dehydration reaction conditions include those using a dehydrating agent such as an acid or Burgess reagent, Mitsunobu reaction, or the like, or conditions in which the hydroxyl group is converted to a leaving group (via methanesulfonylation, p-toluenesulfonylation, halogen substitution, or the like) followed by an elimination reaction using a base or the like. 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 the base 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 the inert solvent 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 −78° C. to the boiling point of the solvent.

[0087] Step (3-3): Compound (s-3-1) can be produced using compound (s-3-5) under the same conditions as in step (2-4).

[0088] The compound (s-3-5) can also be synthesized from the compound (s-3-2) via steps (3-4) and (3-5).

[0089] Step (3-4): Compound (s-3-6) can be produced by reacting compound (s-3-2) with a commonly used triflating agent in an appropriate inert solvent in the absence of additives or in the presence of an acid or a base (or in the simultaneous presence of an acid and a base). Examples of triflating agents used in this reaction include trifluoromethanesulfonic anhydride and N-phenylbis(trifluoromethanesulfonimide). Examples of acids used in this reaction include 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 hour to 24 hours, and the reaction temperature is from −78° C. to the boiling point of the solvent.

[0090] Step (3-5): Compound (s-3-5) can be produced by reacting compound (s-3-6) with a palladium catalyst in an appropriate inert solvent in the presence of a palladium catalyst and a phosphine ligand, and optionally in the presence of a base, where Z is a boronic acid, a boronic acid ester, BF ３ K., B.F. ３The compound (s-3-7) is produced by reacting the compound (s-3-7) with a compound represented by Na, trialkyltin, or zinc halide. Compound (s-3-7) may be commercially available, or may be synthesized by a known method or a method similar thereto. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), palladium acetate(0), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Examples of 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 mixed solvents 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.

[0091] The compound (s-3-5) can also be synthesized from the compound (s-3-2) via steps (3-6) and (3-7).

[0092] Step (3-6): Compound (s-3-8) can be produced by subjecting the reaction to commonly used vinyl halide-forming reaction conditions in an appropriate inert solvent. Examples of vinyl halide-forming reaction conditions used in this reaction include those involving the reaction with hydrazine followed by the reaction with tetramethylguanidine and iodine, those involving the reaction with phosphorous acid and bromine in the presence of triethylamine, and those involving the reaction with a chlorinating reagent such as phosphorus pentachloride or phosphorus trichloride. 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 from −78° C. to the boiling point of the solvent.

[0093] Step (3-7): Compound (s-3-5) can be produced using compound (s-3-8) under the same conditions as in step (3-5).

[0094] Production Method 4: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-4-1) can be produced, for example, by the following production method. (In the formula, R ａ２ , R ａ３ , X ６ , X ７ , X ８ , j, k, l and m have the same meanings as in item 1.)

[0095] The compound (s-4-1) can be synthesized from the compound (s-3-5) via steps (4-1) and (4-2), or from the compound (s-3-1) via step (4-3).

[0096] Step (4-1): Compound (s-4-2) can be produced by reacting compound (s-3-5) in an appropriate inert solvent, or, if necessary, under a hydrogen atmosphere, in the absence of additives or in the presence of an acid, under commonly used double bond reduction reaction conditions. Examples of reaction conditions include those using palladium on carbon, palladium (II) hydroxide, or Raney nickel, and those using a hydride reducing agent such as triethylsilane. 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. Examples of inert solvents include halogenated carbons such as chloroform and dichloromethane; ether solvents such as diethyl ether, THF, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ester solvents such as ethyl acetate and methyl acetate; and alcoholic solvents such as methanol and ethanol. 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.

[0097] Step (4-2): Compound (s-4-1) can be produced using compound (s-4-2) under the same conditions as in step (2-4).

[0098] Step (4-3): Compound (s-4-1) can be produced using compound (s-3-1) under the same conditions as in step (4-1).

[0099] Production Method 5: Among the compounds represented by formula (s-1-2), the compound represented by formula (s-5-1) can be produced, for example, by the following production method. (In the formula, R ａ２ , R ａ３ , X ６ , X ７ , X ８ , j, k, l and m are the same as those in item 1. Y represents a halogen.

[0100] The compound (s-5-1) can be synthesized from the compound (s-5-2) via steps (5-1) and (5-2).

[0101] Step (5-1): Compound (s-5-4) is produced by reacting compound (s-5-2) with compound (s-5-3) in a suitable inert solvent in the presence of a palladium catalyst, a phosphine ligand, and a base. Compound (s-5-3) may be commercially purchased or synthesized by a known method or a method analogous thereto. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), palladium acetate(0), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Examples of 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 mixed solvents 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.

[0102] In the step (5-1), when the compound (s-5-3) is a compound that undergoes an aromatic nucleophilic substitution reaction, the compound (s-5-4) can also be synthesized by reacting the compound (s-5-2) with the compound (s-5-3) under the reaction conditions.

[0103] Step (5-2): Compound (s-5-1) can be produced using compound (s-5-4) under the same conditions as in step (2-4).

[0104] The present invention will be explained in more detail below with reference to the following examples, examples, and test examples, but the present invention is not limited to these examples. The names of compounds shown in the following examples and test examples do not necessarily conform to the IUPAC nomenclature.

[0105] In the present specification, the following abbreviations may be used: n-: normal- tert-: tertiary- p-: para- CDCl ３ : deuterated chloroform 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 DMSO: dimethyl sulfoxide Boc: tert-butoxycarbonyl DBU: diazabicycloundecene LDA: lithium diisopropylamide LHMDS: lithium bis(trimethylsilyl)amide

[0106] 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 TLC was used for purification, Silica gel 60F254 (Merck) was used for TLC (silica gel plate), and TLC plate NH (FujiSilysia) was used for TLC (NH silica gel plate).

[0107] The following reactors were 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

[0108] Symbols used in NMR include s for singlet, d for doublet, dd for double doublet, ddd for double double doublet, dddd for 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.

[0109] 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 (registered trademark) SYSTEM Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Method B: Detector: Shimadzu LCMS-2020 Column: Phenomenex Kinetex (C18, 1.7 μm, 2.1 mm × 50 mm)

[0110] The measurement conditions for the high-performance liquid chromatograph mass spectrometer (LC / MS) were as follows, and the observed mass spectrometry value [MS (m / z)] was expressed as [M+H] ＋ The retention time is indicated as Rt (min). Method A Solvent: Solution A; 0.06% formic acid / H ２ Solution O, 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; UV detection: 220 nm and 254 nm; Temperature: 40°C Unless otherwise specified, the LC-MS data shown below are those measured using Method A. Method B Solvent: Solution A: 0.05% TFA / H ２Solution O, B: acetonitrile Gradient conditions: 0.0-1.7 min (linear gradient from 10% B to 99% B), 1.7-1.9 min (99% B), 1.9-3.0 min (10% B); Flow rate: 0.5 mL / min; Detection UV: 254 nm; Temperature: 40°C

[0111] Example 1: (3aR,5S,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

[0112] A chloroform solution (1.4 mL) of the literature-known compound 1 (100 mg) (raw material A) and a chloroform solution (0.4 mL) of triethylamine (160 μL) were added to a chloroform solution (0.4 mL) of triphosgene (38.6 mg) at −20°C, and the mixture was stirred at that temperature for 40 minutes. The reaction mixture was added to a chloroform solution (0.5 mL) of the compound of Reference Example 4 (92 mg) (raw material B) and triethylamine (107 μL) at 0°C, and the mixture was stirred at room temperature for 1 hour. 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 silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 2 (168 mg). 1H-NMR (CDCl3) δ: 1.01 (6H, d, J = 6.0 Hz), 1.17-1.23 (4H, m), 1.23-1.47 (2H, m), 1.60-1.87 (2H, m), 1.89-2.02 (3H, m), 2.10-2.24 (4H, m), 2.33-2.52 (7H, m), 2.69 (1H, sep, J = 6.4 Hz), 2.69-2.81 (2H, m), 2.87-3.00 (2H, m), 3.26 (2H, ddd, J = 20.8, 10.4, 4.0 Hz), 3.40-3.48 (1H, m), 3.62-3.71 (2H, m), 4.04-4.20 (1H, m), 4.28 (1H, d, J = 8.4 Hz).

[0113] Examples 2 to 17: The compounds of Examples 2 to 17 shown in the following table were produced in the same manner as in Example 1, except that compounds known in the literature or compounds of Reference Examples shown in the following table were used as compounds corresponding to the raw materials A and B described in Example 1.

[0114] The names of the compounds in Examples 2 to 4, Examples 6 to 9, and Examples 11 to 17 are listed below. Example 2: (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 3: (1R,5S,6R)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide Example 4: (1R,5S,6S)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide Example 6: (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 7: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 8: (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 9: (3aR,5R,6aS)-N-{(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 11: (3aR,6aS)-N-{(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 12: (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 13: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 14: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 15: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 16: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 17: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

[0115] The compounds of Examples 5 and 10 are diastereomeric mixtures each containing two different diastereomers. These can also be separated by asymmetric synthesis or chiral chromatography. In other words, it can be said that the two diastereomers were essentially synthesized.

[0116] Examples 18 to 34: The compounds of Examples 18 to 34 shown in the table below were produced in the same manner as in Example 1, except that compounds known in the literature 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.

[0117] The names of the compounds of Examples 18 to 34 are listed below. Example 18: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 19: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 20: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 21: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 22: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 23: (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 24: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(3-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 25: (3aR,5R,6aS)-N-{(1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 26: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyrimidin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 27: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(pyridin-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 28: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 29: (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide Example 30: (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 31: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 32: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 33: (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 34: (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,

[0118] Reference Example 1: tert-butyl (3aR,5s,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 2) and tert-butyl (3aR,5r,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 3)

[0119] To a solution of compound 1 (331 mg) in 1,2-dimethoxyethane (6.7 mL) / ethanol (0.67 mL), p-toluenesulfonylmethyl isocyanide (373 mg) and potassium tert-butoxide (396 mg) were added at 0°C, and the mixture was stirred at 40°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give title compound 2 (80 mg) and title compound 3 (59.4 mg). Compound 2: LCMS: [M+H] + / Rt(min):237 / 0.89 Compound 3: LCMS: [M+H] + / Rt(min): 237 / 0.88

[0120] Reference Example 2: tert-Butyl (1S,6R,8S)-8-cyano-3-azabicyclo[4.2.0]octane-3-carboxylate

[0121] Step (i): To a solution of compound 4 (600 mg) in chloroform (7.8 mL), isobutyl chloroformate (352 μL) and triethylamine (393 μL) were added at 0° C. and stirred for 2 hours. Aqueous ammonia was then added to the reaction mixture at 0° C., and the mixture was warmed to room temperature and stirred for 1 hour. 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 resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give compound 5 (372 mg). LCMS: [M+H] + / Rt(min):255 / 0.72

[0122] Step (ii): To a solution of compound 5 (364 mg) and diisopropylethylamine (0.63 mL) in chloroform (6 mL), trifluoromethanesulfonic anhydride (0.27 mL) was added at 0° C., and the mixture was stirred for 1 hour. Water was then 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 resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 6 (320 mg). LCMS: [M+H] + / Rt(min):237 / 0.93

[0123] Reference Example 3: tert-Butyl (3aR,5r,6aS)-5-cyano-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate A solution of compound 2 (2.05 g) in THF (8 mL) was slowly added dropwise to a solution of lithium diisopropylamide (1.09 M in n-hexane, 16 mL) in THF (8 mL) at −78°C, and the mixture was stirred for 1.5 hours. Next, a solution of iodomethane (2.7 mL) in THF (8 mL) was added at −78°C, and the mixture was warmed to 0°C and stirred for 2 hours. 1 M aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was warmed to room temperature and extracted with hexane. The organic layer was washed with water, 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 7 (0.8 g). LCMS: [M+H] + / Rt(min):251 / 0.93

[0124] Reference Example 4: (3aR,5s,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole

[0125] Step (i): To a solution of compound 2 (7.3 g) in ethanol (62 mL), 50% aqueous hydroxylamine solution (20 mL) was added and stirred at 70° C. for 11 hours. After cooling to room temperature, water (120 mL) was added to the reaction mixture, which was then extracted with toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 8 (4.6 g). LCMS: [M+H] + / Rt(min):270 / 0.52

[0126] Step (ii): In an ice bath, triethylamine (3.80 mL) was slowly added dropwise to a mixture of compound 8 (1.47 g), cyclopropanecarboxylic acid (0.493 g), HATU (2.28 g), and THF (11 mL), and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (11 mL) was added to the reaction mixture, and the mixture was washed with water (11 mL) and saturated brine (11 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 compound 9 (3.71 g). LCMS: [M+H] + / Rt(min):338 / 0.82

[0127] Step (iii): A mixture of compound 9 (400 mg), DBU (177 μL), toluene (2.2 mL), and acetonitrile (0.741 mL) was stirred under reflux for 1 hour. After cooling to room temperature and washing with water, the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give compound 10 (106 mg). LCMS: [M+H] + / Rt(min):320 / 1.04

[0128] Step (iv): Trifluoroacetic acid (1.6 mL) was added to a toluene solution (2.8 mL) of compound 10 (880 mg), and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure, and toluene (2.76 mL) / acetonitrile (0.9 mL) and sodium carbonate (2.92 g) were added, followed by stirring for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 11 (690 mg). LCMS: [M+H] + / Rt(min): 220 / 0.39

[0129] Reference Examples 5 to 11: Reference Example 5 shown in the table below was synthesized according to the method described in Reference Example 4 above, using carboxylic acid B shown in the table below instead of cyclopropanecarboxylic acid in step (ii) of Reference Example 4. Furthermore, the compounds of Reference Examples 6 to 11 shown in the table below were synthesized according to the method described in Reference Example 4 above, using the corresponding starting material A and carboxylic acid B instead of the starting material (compound 2) in step (i) and cyclopropanecarboxylic acid in step (ii), respectively.

[0130] The names of the compounds in Reference Examples 5 to 11 are listed below. Reference Example 5: (3aR,5s,6aS)-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}octahydrocyclopenta[c]pyrrole Reference Example 6: (1R,5S,6r)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane monohydrochloride Reference Example 7: (1R,5S,6s)-6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane monohydrochloride Reference Example 8: (1S,6R,8S)-8-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-azabicyclo[4.2.0]octane monohydrochloride Reference Example 9: (3aR,5r,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-methyloctahydrocyclopenta[c]pyrrole Reference Example 10: (3aR,5r,6aS)-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-5-methyloctahydrocyclopenta[c]pyrrole Reference Example 11: (3aR,5r,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole

[0131] Reference Example 12: (3aR,5r,6aS)-5-(4-methylphenyl)octahydrocyclopenta[c]pyrrole

[0132] Step (i): To a solution of compound 12 (326 mg) in 1,2-dimethoxyethane (3.2 mL), 4-methylphenylboronic acid (149 mg), an aqueous potassium carbonate solution (0.456 ml, 2 M), and tetrakistriphenylphosphine palladium (211 mg) were added at room temperature, and the mixture was stirred at 80°C for 11 hours. After cooling to room temperature, water (10 mL) 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 compound 13 (139 mg). LCMS: [M+H] + / Rt(min): 300 / 2.313 (Method B)

[0133] Step (ii): Palladium hydroxide-activated carbon (26.1 mg) was added to a solution of compound 13 (139 mg) in methanol (3.9 mL), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to give compound 14 (98 mg). LCMS: [M+H] + / Rt(min): 302 / 2.346 (Method B)

[0134] Step (iii): To a solution of compound 14 (98 mg) in chloroform (0.33 mL), TFA (0.125 mL) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 3M aqueous sodium hydroxide solution 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 15 (29.5 mg). LCMS: [M+H] + / Rt(min): 202 / 1.481 (Method B)

[0135] Reference Examples 13 to 16: The compounds of Reference Examples 13 to 16 shown in the table below were synthesized according to the method described in Reference Example 12 above, except that the corresponding starting material C was used instead of 4-methylphenylboronic acid in step (i) of Reference Example 12.

[0136] Reference Example 13: (3aR,5r,6aS)-5-(2-methylphenyl)octahydrocyclopenta[c]pyrrole monohydrochloride Reference Example 14: (3aR,5r,6aS)-5-(4-fluorophenyl)octahydrocyclopenta[c]pyrrole monohydrochloride Reference Example 15: (3aR,5r,6aS)-5-(3-fluorophenyl)octahydrocyclopenta[c]pyrrole monohydrochloride Reference Example 16: (3aR,5r,6aS)-5-(2-fluorophenyl)octahydrocyclopenta[c]pyrrole monohydrochloride

[0137] Reference Example 17: (3aR,6aS)-2-(2-fluorophenyl)octahydropyrrolo[3,4-c]pyrrole monohydrochloride

[0138] Step (i): To a solution of compound 16 (413 mg) in toluene (6.8 mL), 1-bromo-2-fluorobenzene (309 mg), sodium tert-butoxide (424 mg), tris(dibenzylideneacetone)dipalladium(0) (129 mg), and di-tert-butyl-2-biphenylphosphine (42.2 mg) were added at room temperature, and the mixture was stirred at 90°C for 30 minutes. After cooling to room temperature, 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 compound 17 (270 mg). LCMS: [M+H] + / Rt(min): 307 / 2.15 (Method B)

[0139] Step (ii): To a solution of compound 17 (305 mg) in chloroform (4 ml), hydrochloric acid (4 M cyclopentylmethyl solution, 1.2 ml) was added and stirred at room temperature for 2.5 hours. The reaction solution was then concentrated to give the title compound 18 (287 mg). LCMS: [M+H] + / Rt(min): 207 / 1.28 (Method B)

[0140] Reference Example 18: (3aR,6aS)-2-(3-fluorophenyl)octahydropyrrolo[3,4-c]pyrrole monohydrochloride The compound of Reference Example 18 shown in the following table was synthesized according to the method described in Reference Example 17 above, except that 1-bromo-3-fluorobenzene was used instead of 1-bromo-2-fluorobenzene in step (i) of Reference Example 17.

[0141] Reference Example 19: (3aR,5r,6aS)-5-(3-methylphenyl)octahydrocyclopenta[c]pyrrole monohydrochloride The compound of Reference Example 19 shown in the following table was synthesized according to the method described in Reference Example 12 above, except that 3-methylphenylboronic acid was used instead of 4-methylphenylboronic acid in step (i) of Reference Example 12.

[0142] Reference Example 20: (3aR,5r,6aS)-5-(pyridin-2-yl)octahydrocyclopenta[c]pyrrole monohydrochloride

[0143] Step (i): To a solution of compound 12 (3.04 g) in 1,4-dioxane (28.4 mL), bis(pinacolato)diboron (2.59 g), potassium acetate (2.51 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (278 mg), and 1,1'-bis(diphenylphosphino)ferrocene (189 mg) were added at room temperature, and the mixture was stirred at 80°C for 8 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give compound 19 (2.82 g). LCMS: [M+H] + / Rt(min): 672 / 1.158

[0144] Step (ii): To a solution of compound 19 (293 mg) in 1,2-dimethoxyethane (3.6 mL), 2-bromopyridine (115 mg), an aqueous potassium carbonate solution (0.728 ml, 2 M), and tetrakistriphenylphosphine palladium (168 mg) were added at room temperature, and the mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give compound 20 (130 mg). LCMS: [M+H] + / Rt(min): 287 / 1.46 (Method B)

[0145] Step (iii): Compound 21 was obtained using compound 20 in the same manner as in step (iii) of Reference Example 12. LCMS: [M+H] + / Rt(min): 289 / 1.49 (Method B)

[0146] Step (iv): Using compound 21, the title compound 22 was obtained in the same manner as in step (ii) of Reference Example 17. LCMS: [M+H] + / Rt(min): 189 / 0.778 (Method B)

[0147] Reference Examples 21 and 22: The compounds of Reference Examples 21 and 22 shown in the table below were synthesized according to the method described in Reference Example 19 above, except that the corresponding starting material D was used instead of 2-bromopyridine in step (ii) of Reference Example 19.

[0148] The names of the compounds of Reference Examples 21 and 22 are listed below. Reference Example 21: (3aR,5r,6aS)-5-(pyrimidin-2-yl)octahydrocyclopenta[c]pyrrole monohydrochloride Reference Example 22: (3aR,5r,6aS)-5-(pyridin-3-yl)octahydrocyclopenta[c]pyrrole monohydrochloride

[0149] Reference Example 23: (3aR,5r,6aS)-5-(5-methyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole monohydrochloride The compound of Reference Example 23 shown in the following table was synthesized according to the method described in Reference Example 4 above, using the compound of Reference Example 1 instead of the starting material (compound 2) in step (i) of Reference Example 4, and acetyl chloride instead of cyclopropanecarboxylic acid and HATU in step (ii).

[0150] Test Example 1: Measurement of orexin type 2 receptor agonist activity. Human orexin type 2 receptor and apoaequorin were transiently expressed in CHO cells, and agonism was evaluated using the amount of calcium influx into the cells upon ligand stimulation. The transiently expressed cells were seeded at 2,000 cells / well in a 384-well plate and cultured for 16 to 22 hours. After returning the plate to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added and the plate was incubated at room temperature for 2 hours. Orexin A (Peptide Institute, Inc., Lot. 671009) or a test compound was then added, and the luminescence of the cells was measured using an FDSS7000 (Hamamatsu Photonics). Orexin A and the test compound were dissolved in DMSO (final concentration 0.1%) and diluted with a buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin type 2 receptor agonism of the test compound was calculated as a relative value, with the luminescence value upon treatment with Orexin A (100 pM) taken as 100%.

[0151] Test Results: The orexin type 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 type 2 receptor. The orexin type 2 receptor agonism of the compounds obtained in the Examples at 10 μM is shown in the table below as a relative value when the luminescence value upon treatment with Orexin A (100 pM) is set to 100%.

[0152] Test Example 2: Measurement of orexin type 2 receptor agonist activity. Human orexin type 2 receptor and apoaequorin were transiently expressed in CHO cells, and agonism was evaluated using the amount of calcium influx into the cells upon ligand stimulation. The transiently expressed cells were seeded at 2,000 cells / well in a 384-well plate and cultured for 16 to 22 hours. After returning the plate to room temperature, Coelenterazine hcp (final concentration: 1 μM) was added and the plate was incubated at room temperature for 2 hours. Orexin A (Peptide Institute, Inc., Lot. 711101) or a test compound was then added, and the luminescence of the cells was measured using an FDSS7000 (Hamamatsu Photonics). Orexin A and the test compound were dissolved in DMSO (final concentration 0.1%) and diluted with a buffer (Hanks, 20 mM HEPES, 0.1% BSA). The orexin type 2 receptor agonism of the test compound was calculated as a relative value, with the luminescence value upon treatment with Orexin A (100 pM) taken as 100%.

[0153] Test Results: The orexin type 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 type 2 receptor. The orexin type 2 receptor agonism of the compounds obtained in the Examples at 10 μM is shown in the table below as a relative value when the luminescence value upon treatment with Orexin A (100 pM) is set to 100%.

[0154] The compounds of the present invention exhibit strong agonistic activity against the orexin type 2 receptor and are useful as therapeutic or preventive agents for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy bodies.

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, R １ and R ２ each independently represents a hydrogen atom, a halogen atom, cyano, -(C=O)NR ３ R ４ , a carboxy group, -(C=O)O-R ５ , optionally substituted C １－４ alkyl, or optionally substituted C １－４ alkoxy, and R １ and R ２ may be bonded to the same carbon atom if chemically possible, and when R １ and R ２ are bonded to another carbon atom on the ring, they may be bonded to each other via C １ - ６ alkylene to form a condensed ring or a bridged ring; R ３ and R ４ Each of these is independently a hydrogen atom or a substituted C １－４ Represents alkyl; R ５ C may be substituted. １－４ Represents alkyl; -L １ -Ring G is -Ring G, -CH ２ -Ring G (the CH ２ One or more identical or different C １－６ (may be substituted with alkyl), -NR ６ -Ring G, -C(=O)-Ring G, -OC(=O)-Ring G, -SO-Ring G, -SO ２ Represents a -ring G, -S-ring G, or -O-ring G; R ６ C is a hydrogen atom or a substituted C １－４ Represents alkyl; n is an integer of 1 or 2; Ring G may be substituted with C ６－１０ Aromatic carbocyclic groups, optionally substituted 5-10 member aromatic heterocyclic groups, optionally substituted C ３－６ Represents a saturated carbocyclic group, or a 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-; j, k, l, and m are each independently integers of 0, 1, or 2; The dashed lines represent single or double bonds; X is -CR ７ - represents a nitrogen atom or a carbon atom; R ７ is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or a substituted C １－４ Represents alkyl; Ring E is given by the following formulas (1a-1), (1a-2), or (1a-3): 【Chemistry 2】 [In the formula, X １ ~X ８ Each is independently a nitrogen atom or -CR ａ４ - represents; Q １ and Q ２ is an oxygen atom or -NR ａ５ - represents; R ａ１ ~R ａ５ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, a hydroxyl group, and C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkyl (the alkyl group comprises one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy contains one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, C １－４ (may be substituted with an alkoxy group), or represent a 5-10 member aromatic heterocyclic group, and R ａ２ and R ａ３ If chemically possible, they may be bonded to the same carbon atom; however, X １ and X ３ All of them are CR ａ４ In this case, two R ａ４ The carbon atoms bonded to them are both X １ , X ２ and X ３ A six-membered carbon ring may be formed by condensation with a five-membered ring composed of the above. [Represents] A compound represented by or a pharmaceutically acceptable salt thereof.

2. R １ ~R ７ In the case of "C which may be substituted", １－４ The substituted substituents in "alkyl" are, independently, one or more identical or different halogen atoms, hydroxyl groups, and C １－４ Alkoxy, or C ３－７ It is a cycloalkyl group, and "may be substituted C １－４ The substituted substituents in "alkoxy" are, independently of each other, one or more identical or different halogen atoms, hydroxyl groups, or C ３－７ It is a cycloalkyl, C of ring G ６－１０ An aromatic carbocyclic group, a 5- to 10-membered aromatic heterocyclic group, C ３－６ Substitutable substituents in a saturated carbocyclic group and a 4- to 10-membered saturated heterocyclic group are each independently a halogen atom, C １－６ Alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, a hydroxy group, C １－４ Alkoxy, or C ３－７ Cycloalkyl), C ６－１０ An aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, a hydroxy group, C １－４ Alkyl, C １－４ Alkoxy, or C ３－７ Cycloalkyl), C １－４ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxy group, or C ３－７ Cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, a hydroxy group, C １－４ Alkyl, C １－４ Alkoxy, or C ３－７ Cycloalkyl), and C ３－７ Cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, a hydroxy group, C １－４ Alkyl, C １－４ Alkoxy or C ３－７ Cycloalkyl), or when there are a plurality of substituents, two of them may be bonded via C １－６ Alkylene to form any bicyclic structure chemically possible among a condensed ring, a spiro ring, or a bridged ring. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ to R ７ In the "optionally substituted C １－４ alkyl", the substitutable substituents are each independently one or more identical or different halogen atoms or C １－４ alkoxy, and in the "optionally substituted C １－４ alkoxy", the substitutable substituents are each independently one or more identical or different halogen atoms, Ring G's C ６－１０ Aromatic carbon ring group, 5-10 member aromatic heterocyclic group, C ３－６ The substituted substituents in saturated carbocyclic groups and saturated heterocyclic groups with 4 to 10 members are, independently of each other, halogen atoms, C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ An aromatic carbocyclic group contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) １－４ Alkyl, or C １－４ (May be substituted with alkoxy), and C ３－７ Cycloalkoxy (the cycloalkoxy contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ One or more substituents selected from the group consisting of (which may be substituted with alkoxys), or if there are multiple substituents, two of them are C １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be bonded via alkylene to form any chemically possible bicyclic structure among a fused ring, a spiro ring, or a crosslinking ring.

4. Ring E is given by the following formulas (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): 【Transformation 3】 [In the formula, X １ ~X ５ Each is independently a nitrogen atom or -CR ａ４ - represents; R ａ１ ~R ａ４ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, a hydroxyl group, and C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkyl (the alkyl group comprises one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy contains one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ R may be substituted with an alkoxy group, or it represents a 5-10 member aromatic heterocyclic group. ａ２ and R ａ３ If chemically possible, they may be bonded to the same carbon atom; however, X １ and X ３ All of them are -CR ａ４ - In this case, two R ａ４ The carbon atoms to which they are bonded are both X １ , X ２ and X ３ A six-membered carbon ring may be formed by condensation with a five-membered ring composed of the above. A compound according to claim 1 or a pharmaceutically acceptable salt thereof that represents the compound described in claim 1.

5. Ring G is given by the following formula (1b-1) or (1b-2): 【Chemistry 4】 [In the formula, W １ and W ３ Each is independently a nitrogen atom or -CR ｂ３ - represents; W ２ and W ４ Each is independent of -NR ｂ４ -, oxygen atom, or -CR ｂ５ R ｂ６ - represents; R ｂ１ ~R ｂ６ Each of these is independently a hydrogen atom, -N(R) ｂ７ ) R ｂ８ , C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms, C) ３－６ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C １－４ The C may be substituted with alkyl, １－４ Alkyl may be substituted with a halogen atom), or C １－４ (May be substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ An aromatic carbocyclic group contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) １－４ Alkyl, or C １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (may be substituted with an alkoxy), and also R ｂ１ and R ｂ２ It may be bonded to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ C １－６ They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings; R ｂ７ and R ｂ８ Each of them is independently a hydrogen atom, C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms, C) １－４ Alkoxy, C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C １－４ The C may be substituted with alkyl, １－４ The alkyl group may be substituted with a halogen atom, or may be substituted with a 5-10 member aromatic heterocyclic group), a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group may contain one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (May be substituted with an alkoxy) Here, R ｂ１ ~R ｂ６ ga-N(R ｂ７ ) R ｂ８ If R ｂ７ and R ｂ８ These may combine to form a 3- to 7-membered nitrogen-containing saturated heterocycle with the nitrogen atom to which they bond. A compound according to claim 1 or a pharmaceutically acceptable salt thereof that represents the compound described in claim 1.

6. Formula (2): 【Transformation 5】 [In the formula, R １ and R ２ These are, independently, a hydrogen atom, a halogen atom, and C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ (May be substituted with a cycloalkyl group), or C １－４ Alkoxy (the alkoxy contains one or more identical or different halogen atoms, hydroxyl groups, or C ３－７ Represents (which may be cycloalkyl substituted); -L １ -Ring G is -Ring G, -CH ２ -Ring G (the CH ２ One or more identical or different C １－６ (may be substituted with alkyl), -NR ６ -Ring G, -C(=O)-Ring G, -OC(=O)-Ring G, -SO-Ring G, -SO ２ Represents a -ring G, -S-ring G, or -O-ring G; R ６ Each of these is independently a hydrogen atom or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); Ring G is given by the following formula (1b-1) or (1b-2): 【Transformation 6】 [In the formula, W １ and W ３ Each is independently a nitrogen atom or -CR ｂ３ - represents; W ２ and W ４ Each is independent of -NR ｂ４ -, oxygen atom, or -CR ｂ５ R ｂ６ - represents; R ｂ１ ~R ｂ６ Each of these is independently a hydrogen atom, -N(R) ｂ７ ) R ｂ８ , C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms, C) ３－６ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C １－４ The C may be substituted with alkyl, １－４ (Alkyl may be substituted with a halogen atom) or C １－４ (May be substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ An aromatic carbocyclic group contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, C) １－４ Alkyl, or C １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy contains one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (may be substituted with an alkoxy), and also R ｂ１ and R ｂ２ It may be bonded to the same carbon atom if chemically possible; Here, R ｂ１ and R ｂ２ C １－６ They may be bonded via alkylene to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridging rings; R ｂ７ and R ｂ８ Each of them is independently a hydrogen atom, C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms, C) １－４ Alkoxy, C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms or C １－４ The C may be substituted with alkyl, １－４ The alkyl group may be substituted with a halogen atom, or may be substituted with a 5-10 member aromatic heterocyclic group), a 5-10 member aromatic heterocyclic group (the aromatic heterocyclic group may contain one or more identical or different halogen atoms, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (May be substituted with an alkoxy) Here, R ｂ１ ~R ｂ６ ga-N(R ｂ７ ) R ｂ８ If R ｂ７ and R ｂ８ These may combine to form a 3- to 7-membered nitrogen-containing saturated heterocycle with the nitrogen atom to which they bond. It represents; A １ represents an oxygen atom or a sulfur atom; j, k, l, and m are each independently integers of 0, 1, or 2; The dashed lines represent single or double bonds; X is -CR ７ - represents a nitrogen atom or a carbon atom; R ７ is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); Ring E is given by the following formulas (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): 【Transformation 7】 [In the formula, X １ ~X ５ Each is independently a nitrogen atom or -CR ａ４ - represents; R ａ１ ~R ａ４ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, a hydroxyl group, and C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkyl (the alkyl group comprises one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with an alkoxy group), or represent a 5-10 member aromatic heterocyclic group, and R ａ２ and R ａ３ If chemically possible, they may be bonded to the same carbon atom; however, X １ and X ３ All of them are -CR ａ４ - In this case, two R ａ４ The carbon atoms to which they are bonded are both X １ , X ２ and X ３ A six-membered carbon ring may be formed by condensation with a five-membered ring composed of the above. A compound according to claim 1 or a pharmaceutically acceptable salt thereof that represents the compound described in claim 1.

7. R １ and R ２ However, each is independent of the hydrogen atom, halogen atom, and C. １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); L １ However, it represents a single bond or an oxygen atom; Ring G is given by the following formulas (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): 【Transformation 8】 [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ Each of these is independently a hydrogen atom or C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy) A compound according to claim 6 or a pharmaceutically acceptable salt thereof that represents the above.

8. Formula (3): 【Chemistry 9】 [In the formula, L １ represents a single bond or an oxygen atom; Ring G is given by the following formulas (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): 【Chemistry 10】 [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ Each of these is independently a hydrogen atom or C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy) It represents; j, k, l, and m are each independently integers of 0, 1, or 2; The dashed lines represent single or double bonds; X is -CR ７ - represents a nitrogen atom or a carbon atom; R ７ is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano, or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); Ring E is given by the following formulas (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): 【Chemistry 11】 [In the formula, X １ ~X ５ Each is independently a nitrogen atom or -CR ａ４ - represents; R ａ１ ~R ａ４ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, a hydroxyl group, and C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkyl (the alkyl group comprises one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy contains one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with an alkoxy group), or represent a 5-10 member aromatic heterocyclic group, and R ａ２ and R ａ３ If chemically possible, they may be bonded to the same carbon atom; however, X １ and X ３ All of them are -CR ａ４ - In this case, two R ａ４ The carbon atoms to which they are bonded are both X １ , X ２ and X ３ A six-membered carbon ring may be formed by condensation with a five-membered ring composed of the above. A compound according to claim 1 or a pharmaceutically acceptable salt thereof that represents the compound described in claim 1.

9. Formula (4): 【Chemistry 12】 [In the formula, L １ represents a single bond or an oxygen atom; Ring G is given by the following formulas (1b-1-1), (1b-2-1), (1b-1-2), or (1b-2-2): 【Chemistry 13】 [In the formula, R ｂ４ , R ｂ７ , and R ｂ８ Each of these is independently a hydrogen atom or C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy) It represents; The dashed lines represent single or double bonds; X is -CR ７ - represents a nitrogen atom or a carbon atom; R ７ is a hydrogen atom or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); Ring E is given by the following formulas (1a-1-1), (1a-2-1), (1a-3-1), (1a-3-2), (1a-3-3), or (1a-3-4): 【Chemistry 14】 [In the formula, X １ ~X ５ Each is independently a nitrogen atom or -CR ａ４ - represents; R ａ１ ~R ａ４ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C ６－１０ Aromatic carbocyclic group (the C ６－１０ Aromatic carbocyclic groups consist of one or more identical or different halogen atoms, a hydroxyl group, and C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), C １－４ Alkyl (the alkyl group comprises one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (may be substituted with alkoxy), cyano, C １－４ Alkoxy (the alkoxy contains one or more identical or different halogen atoms, hydroxyl groups, or C １－４ (May be substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ R may be substituted with an alkoxy group, or it represents a 5-10 member aromatic heterocyclic group. ａ２ and R ａ３ If chemically possible, they may be bonded to the same carbon atom; however, X １ and X ３ All of them are -CR ａ４ - In this case, two R ａ４ The carbon atoms to which they are bonded are both X １ , X ２ and X ３ A six-membered carbon ring may be formed by condensation with a five-membered ring composed of the above. A compound according to claim 1 or a pharmaceutically acceptable salt thereof that represents the compound described in claim 1.

10. Ring E is given by the above formula (1a-2-1) or (1a-3-1): [In the formula, X ４ ~X ５ Each is independently a nitrogen atom or -CR ａ４ - represents; R ａ１ ~R ａ４ Each is independent of (CR ａ４ If there are multiple R ａ４ Each of them is independent of the others): hydrogen atom, halogen atom, C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ (May be substituted with alkoxy), or C １－４ [Represents an alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms)] A compound according to claim 9 or a pharmaceutically acceptable salt thereof that represents the compound.

11. Ring E is given by the following formula (1a-2-2) or (1a-3-1): 【Chemistry 15】 [In the formula, R ａ１ ~R ａ３ These are, independently, a hydrogen atom, a halogen atom, and C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ [May be substituted with an alkoxy] A compound according to claim 9 or a pharmaceutically acceptable salt thereof that represents the compound.

12. Formula (5): 【Chemistry 16】 [In the formula, L １ represents a single bond or an oxygen atom; Ring G is given by the following formula (1b-1-1) or (1b-2-1): 【Chemistry 17】 [In the formula, R ｂ４ is a hydrogen atom or C １－６ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy) It represents; R ７ is a hydrogen atom or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms, a hydroxyl group, C) １－４ Alkoxy, or C ３－７ Represents (which may be substituted with a cycloalkyl group); Ring E is given by the following formula (1a-2-2) or (1a-3-1): [Chemistry 18] [In the formula, R ａ１ ~R ａ３ These are, independently, a hydrogen atom, a halogen atom, and C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ (May be substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl is one or more identical or different halogen atoms, a hydroxyl group, C １－４ Alkyl, or C １－４ [May be substituted with an alkoxy] [Represents] A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [formula].

13. Ring G represents the above formula (1b-1-1), and R ｂ４ However, C may be substituted with one or more identical or different halogen atoms. １－４ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, which is alkyl.

14. Ring G represents the above formula (1b-2-1), and R ｂ４ However, hydrogen atoms or C １－４ Alkyl (the alkyl is one or more identical or different halogen atoms or C) １－４ A compound according to claim 12 or a pharmaceutically acceptable salt thereof, which may be substituted with an alkoxy.

15. R ７ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: (3aR,5S,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (1R,5S,6R)-6-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide, (1R,5S,6S)-6-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-3-azabicyclo[3.1.0]hexane-3-carboxamide, (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazole-3-yl}-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,5S,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(2-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (1S,6R,8S)-8-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-3-azabicyclo[4.2.0]octane-3-carboxamide, (1R,6S,8R)-8-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-3-azabicyclo[4.2.0]octane-3-carboxamide, (3aS,6aR)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-phenyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-phenyl-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(4-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(2-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(pyridine-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(pyrimidine-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(3-fluorophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(4-methylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(3-methylphenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(pyridine-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(pyrimidine-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(pyridine-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-yl]cyclohexyl}-5-(5-methyl-1,2,4-oxadiazole-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazole-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]oxy}cyclohexyl]-5-(5-methyl-1,2,4-oxadiazole-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,5R,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-5-phenylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, (3aR,6aS)-N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidine-3-yl]amino}cyclohexyl]-5-phenylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide.

17. A pharmaceutical composition containing a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition containing a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for the treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

19. A therapeutic agent for diseases involving the orexin type 2 receptor, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

20. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof is contained in narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute Disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell disease, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, plasmacytosis, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM Sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome XSexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female hirsutism, fetal defects associated with gestational obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, respiratory diseases such as obesity hypoventilation syndrome (Pickwick syndrome) and dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of secondary consequences of obesity such as a reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / Disorders of the urinary tract, disorders of sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclophobia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral agenesis, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy It is used to treat cognitive impairment, muscle spasms, tremors, epilepsy, muscle spasm-associated disorders, delirium, amnesia, age-related cognitive decline, schizodeaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced Parkinson's syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless limb syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, or traumatic brain injury.

21. A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

22. A therapeutic agent for narcolepsy comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

23. A therapeutic agent for idiopathic hypersomnia, comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for treating a disease involving the orexin type 2 receptor.

25. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for a disease involving the orexin type 2 receptor.

26. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

27. A pharmaceutical product comprising a combination of a pharmaceutical product containing a compound described in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and at least one drug selected from drugs classified as therapeutic agents for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and narcolepsy syndrome with narcolepsy-like symptoms, or drugs classified as therapeutic agents for Parkinson's disease or Lewy body dementia.

28. A pharmaceutical product comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for treating a disease involving the orexin type 2 receptor in combination with at least one drug selected from drugs classified as therapeutic agents for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and narcolepsy syndrome with narcolepsy-like symptoms, or drugs classified as therapeutic agents for Parkinson's disease or Lewy body dementia.

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