Phenyl urea derivative

Abstract

The present invention pertains to a therapeutic agent or preventative agent against diseases involving an orexin receptor, particularly an orexin type-2 receptor, the agent containing a novel compound having a urea skeleton, or a pharmacologically acceptable salt thereof, as an active ingredient. Specifically, the present invention pertains to a therapeutic agent or preventative agent against diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

Description

Phenylurea 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 a novel compound having a urea skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the present invention relates to a therapeutic or preventive agent for diseases such as narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

[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 Document 1).

[0005] International Publication No. 2017 / 135306

[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, R １ is an optionally substituted C６－１０ Aromatic carbocyclic groups, optionally substituted 5- to 10-membered aromatic heterocyclic groups, optionally substituted C ３－６ represents a saturated carbocyclic group, an optionally substituted 4- to 10-membered saturated heterocyclic group, or cyano; １ and L ２ each independently represents a single bond, a methylene (the methylene is one or more of the same or different C １－６ optionally substituted with alkyl), —NR ６ -, -C(=O)-, -OC(=O)-, -SO-, -SO ２ represents -, -S-, or an oxygen atom; ２ represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, C(=O)NR ３ R ４ or C(=O)O-R ５ represents; R ３ , R ４ , R ５ , R ６ are each independently a hydrogen atom or an optionally substituted C １－６ ring E represents an optionally substituted 5- to 10-membered aromatic heterocyclic group or an optionally substituted 4- to 10-membered saturated heterocyclic group; ring G represents 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; and A represents an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt thereof.

[0011] [Section 2] R ２ ~R ６ "Optionally substituted C" １－６ The substitutable substituents in "alkyl" are each independently one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkoxy, or C ３－７ cycloalkyl, and "optionally substituted C １－６The substitutable substituents in "alkoxy" are each independently one or more of the same or different halogen atoms, hydroxy groups, or C ３－７ is cycloalkyl, and R １ C ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a halogen atom, a hydroxy group, C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－６ Alkylamino (the alkyl group in the alkylamino is a halogen atom, a hydroxy group or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), cyano, C １－６ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C ３－７ and 5- to 10-membered aromatic heterocyclic groups (the aromatic heterocyclic groups may contain one or more of the same or different halogen atoms, hydroxy groups, C １－６Alkyl, C １－６ Alkoxy or C ３－７ C of ring E and ring G is one or more substituents selected from the group consisting of C, ... ６－１０ Aromatic carbocyclic groups, 5- to 10-membered aromatic heterocyclic groups, C ３－６ The substitutable substituents in the saturated carbocyclic group and the 4- to 10-membered saturated heterocyclic group are each independently a halogen atom, C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ 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 １－６ Alkyl, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C １－６ 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 １－６ Alkylamino (the alkyl group in the alkylamino is a halogen atom, a hydroxy group or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ 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 １－６ Alkyl, C １－４ Alkoxy or C ３－７ and when there are a plurality of substituents, two of them are C １－６Item 1. The compound of Item 1 or a pharmaceutically acceptable salt thereof, wherein the alkylene groups may be bonded to each other via an alkylene group to form any chemically possible bicyclic structure among fused rings, spiro rings, or bridged rings.

[0012] [Term 3] Formula (2): [In the formula, R ２ represents a hydroxy group, a halogen atom, a cyano group, an optionally substituted C １－４ Alkyl, optionally substituted C １－４ Alkoxy, C(=O)NR ３ R ４ or C(=O)OR ５ represents; R １ , L １ , L ２ , R ３ , R ４ , R ５ Item 3. The compound according to item 1 or 2, wherein the rings E, G, and A are defined as in item 1, or a pharmaceutically acceptable salt thereof.

[0013] [Section 4] R １ is cyano or the following formulas (1a-1) to (1a-6): [In the formula, X １ ~X ６ are each independently a nitrogen atom or CR ａ４ represents; Q １ and Q ２ is an oxygen atom, -NR ａ５ - or a sulfur atom; Q ３ represents CH or a nitrogen atom; 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 １－６ Alkyl, or C １－６ optionally substituted with alkoxy), 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 C３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be optionally substituted with one or more of the same or different halogen atoms, hydroxy groups, or one or more of the same or different halogen atoms). １－６ Alkyl, or C １－６ optionally substituted with alkoxy), cyano, C １－６ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, or C １－６ alkoxy) 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, hydroxy groups, C １－６ Alkyl, or C １－６ Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of:

[0014] [Item 5] Ring G is represented by the following formula (1b-1) to (1b-7): [In the formula, W １ and W ２ are each independently NR ｂ７ , oxygen atom or CR ｂ８ R ｂ９ represents; W ３ , W ４ , W ５ and W ６ are each independently a nitrogen atom or CR ｂ１０ represents; R ｂ１ ~R ｂ１０ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－４ optionally substituted with alkoxy), C １－６Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ a 5- to 10-membered aromatic heterocyclic group (which may be substituted with one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy) or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ substituted with alkoxy), and R ｂ２ and R ｂ３ may be bonded to the same carbon atom if chemically possible; ｂ２ and R ｂ３ is C １－６ and n, m, and p each independently represent an integer of 1 or 2. [Item 6A] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 4, wherein Ring E is any one selected from the following formulae (1c-1) to (1c-4): [In the formula, R ｃ１ , R ｃ２ , R ｃ３ and R ｃ４ are each independently a hydrogen atom, a halogen atom, a cyano, or C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ optionally substituted with alkoxy), C １－６Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ substituted with alkoxy), and R ｃ１ and R ｃ２ may be bonded to the same carbon atom if chemically possible; ｃ１ and R ｃ２ is C １－６ and (c) a fused ring, a spiro ring, or a bridged ring, or a pharmaceutically acceptable salt thereof.

[0015] [Item 6] Ring E is represented by the following formula (1c-1) to (1c-3): [In the formula, R ｃ１ , R ｃ２ and R ｃ３ are each independently a hydrogen atom, a halogen atom, a cyano, or C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ optionally substituted with alkoxy), C １－６ Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ substituted with alkoxy), and R ｃ１ and R ｃ２ may be bonded to the same carbon atom if chemically possible; ｃ１ and R ｃ２ is C １－６ and (c) a fused ring, a spiro ring, or a bridged ring, or a pharmaceutically acceptable salt thereof.

[0016] [Item 7A] Ring E is represented by the following formula (1c-11) to (1c-41): [In the formula, R ｃ４ are each independently a halogen atom, cyano, C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ optionally substituted with alkoxy), C １－６ Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C１－６ Alkyl, or C １－６ Item 6. The compound according to any one of Items 1 to 6A and 6, wherein the compound is any one selected from the group consisting of:

[0017] [Item 7] Ring E is represented by the following formula (1c-11) to (1c-31): [In the formula, R ｃ４ are each independently a halogen atom, cyano, C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ optionally substituted with alkoxy), C １－６ Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ Item 6. The compound according to any one of Items 1 to 6A and 6, wherein the compound is any one selected from the group consisting of:

[0018] [Term 8] Formula (3): [In the formula, R ２ is C optionally substituted with a halogen atom １－６ R represents alkoxy; １ , A, L １ and ring G is as defined in item 1], or a pharmaceutically acceptable salt thereof according to any one of items 1 to 6A, 6, 7A and 7.

[0019] [Section 9] L １ is a single bond, -CH ２ The compound according to any one of Items 1 to 6A, 6, 7A, 7 and 8, wherein R is either - or an oxygen atom, or a pharmaceutically acceptable salt thereof.

[0020] [Section 10] R １ is expressed by the following formulas (1a-1) to (1a-3): [In the formula, X １ ~X ５ are each independently a nitrogen atom or CR ａ４ represents; Q １ and Q ２ each independently represents an oxygen atom or a sulfur atom; ａ１ represents a hydrogen atom, a halogen atom, a cyano, C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, hydroxy groups, or C １－６ optionally substituted with alkoxy) or C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C １－６ R represents an alkyl group, which may be substituted with alkoxy; ａ４ (CR ａ４ If there are multiple R ａ４ are 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 １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C １－６Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C １－６ optionally substituted with alkoxy), C ３－７ Cycloalkoxy (the cycloalkoxy is one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ alkoxy) 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, hydroxy groups, C １－６ Alkyl, or C １－６ or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 9, wherein R represents an integer of 1 to 3, and R represents an integer of 1 to 3, and R represents an integer of 1 to 3.

[0021] [Item 11] Ring G is represented by the following formula (1b-1) to (1b-3): [In the formula, R ｂ１ ~R ｂ３ are each independently a hydrogen atom, C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ optionally substituted with alkoxy), C １－６ Alkoxy (the alkoxy may be substituted with one or more of the same or different halogen atoms), 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C ６－１０ Aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may contain one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy) or C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 10, wherein the compound is any one selected from the group consisting of:

[0022] [Section 12] R ２ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 11, wherein is a halogen atom of F, Cl or Br, and A is an oxygen atom.

[0023] [Section 13] R １ is expressed by the following formula (1a-1): [In the formula, R ａ１ represents a hydrogen atom, a halogen atom, a cyano, C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, hydroxy groups, or C １－６ optionally substituted with alkoxy) or C １－４ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C １－６ 13. The compound according to any one of items 1 to 6A, 6, 7A and 7 to 12, wherein the compound is of the formula: wherein R represents an integer of 1 to 3; and ...

[0024] [Section 14] R １ is expressed by the following formula (1a-2): [In the formula, X １ ~X ３ are each independently a nitrogen atom or CR ａ４ represents; Q １ represents an oxygen atom or a sulfur atom; ａ４ represents the same definition as in item 10; １ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 12, wherein is a single bond.

[0025] [Section 15] R １ However, the following formulas (1a-21) to (1a-25): [In the formula, R ａ４ represents the same meaning as that described in item 10;１ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 12, wherein is a single bond.

[0026] [Section 16] R ａ４ (CR ａ４ If there are multiple R ａ４ are each independently) but 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 １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, or C １－６ alkoxy), 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, hydroxy groups, C １－６ Alkyl, or C １－６ Item 16. The compound according to Item 15, wherein R is 1 or 2, and R is 2 or 3, or a pharmaceutically acceptable salt thereof.

[0027] [Section 17] R １ is expressed by the following formula (1a-3): [In the formula, X ４ and X ５ has the same definition as in item 10; １ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 12, wherein is a single bond.

[0028] [Section 18] R １ However, the following formulas (1a-31) to (1a-34): [In the formula, R ａ４Item 18. The compound according to Item 17, or a pharmaceutically acceptable salt thereof, which is any one selected from the group consisting of:

[0029] [Section 19] R ａ４ (CR ａ４ If there are multiple R ａ４ are each independently) but C １－６ Alkyl (the alkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkoxy or C ３－７ optionally substituted with cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, hydroxy groups, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), C １－６ Alkoxy (the alkoxy may be one or more of the same or different halogen atoms, hydroxy groups, or C １－６ Item 19. The compound according to item 17 or 18, wherein R is 1 or 2, and R is 1 or 2, and R is 2 or 3, or a pharmaceutically acceptable salt thereof.

[0030] [Item 20] Ring G is the following formula (1b-2): [In the formula, R ｂ２ has the same definition as in item 11], or a pharmaceutically acceptable salt thereof according to any one of items 1 to 6A, 6, 7A and 7 to 19.

[0031] [Item 21] Ring G is the following formula (1b-1): [In the formula, R ｂ１ is C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ a 5- to 10-membered aromatic heterocyclic group (which may be substituted with one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６Alkyl, or C １－６ 20. The compound according to any one of Items 1 to 6A, 6, 7A and 7 to 19, wherein the compound is represented by the formula: wherein the formula is an integer of 1 to 15, and the formula is optionally substituted with alkoxy; or a pharmaceutically acceptable salt thereof.

[0032] [Item 22] Ring G is the following formula (1b-3): [In the formula, R ｂ３ is C １－６ Alkyl (the alkyl may be substituted with one or more of the same or different halogen atoms, or C １－６ a 5- to 10-membered aromatic heterocyclic group (which may be substituted with one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ optionally substituted with alkoxy), or C ３－７ Cycloalkyl (the cycloalkyl may be one or more of the same or different halogen atoms, C １－６ Alkyl, or C １－６ 20. The compound according to any one of Items 1 to 6A, 6, 7A and 7 to 19, wherein the compound is represented by the formula: wherein the formula is an integer of 1 to 15, and the formula is optionally substituted with alkoxy; or a pharmaceutically acceptable salt thereof.

[0033] [Item 23] A compound according to Item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: Example 20: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 22: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide Example 44: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 45: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 53: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 54: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 55: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 61: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 67: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 77: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

[0034] [Item 24] A compound according to Item 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: Example 87: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 89: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamide Example 101: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamide Example 115: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 116: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 117: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 118: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 130: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 144: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 147: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

[0035] [Item 25] A pharmaceutical composition comprising the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0036] [Item 26] A therapeutic agent for a disease associated with the orexin type 2 receptor, comprising the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0037] [Item 27] ​​A compound according to any one of Items 1 to 6A, 6, 7A, and 7 to 24, 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, Möbius syndrome, etc.). syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinism-induced obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic obesity) obesity, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, coma and other disorders of consciousness, side effects and complications of anesthesia, sleep disturbances, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorders, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunken syndrome, disorders related to circadian rhythm, fibromyalgia, conditions resulting from poor quality sleep, overeating, compulsive eating disorder, obesity-related disorders, high blood pressure, diabetes Diarrhea, elevated plasma insulin levels and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, 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, sexual and reproductive dysfunction such as reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, and female hirsutism; fetal defects associated with maternal obesity; gastrointestinal motility disorders such as obesity-related gastroesophageal reflux; respiratory disorders such as obesity-related hypoventilation syndrome (Pickwickian syndrome); inflammation such as systemic inflammation of the vascular system; risk of secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy; migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial hot flashes, night sweats, and genital / diseases of the urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cerebral defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, eye injuries, retinopathy, for the treatment of cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesias, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, or traumatic brain injury.

[0038] [Item 28] A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with dementia with Lewy bodies, comprising the compound according to any one of Items 1 to 6A, 6, 7A, and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0039] [Item 29] A therapeutic agent for narcolepsy, comprising the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0040] [Item 30] A therapeutic agent for idiopathic hypersomnia, comprising the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0041] [Item 31] A therapeutic agent for hypersomnia associated with Parkinson's disease, comprising the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0042] [Item 32] A therapeutic agent for hypersomnia associated with dementia with Lewy bodies, comprising the compound according to any one of Items 1 to 6A, 6, 7A, and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0043] [Item 33] 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 6A, 6, 7A, and 7 to 24, or a pharmaceutically acceptable salt thereof.

[0044] [Item 34] Use of the compound according to any one of Items 1 to 6A, 6, 7A and 7 to 24 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.

[0045] [Item 35] A pharmaceutical composition comprising the compound according to any one of Items 1 to 6A, 6, 7A, and 7 to 24, 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.

[0046] [Item 36] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 6A, 6, 7A and 7 to 24 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.

[0047] 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."

[0048] 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.

[0049] Unless otherwise specified in the present specification, the bonding position of a substituent is any chemically possible position. In addition, in the structural formulas in the present specification, wedge-shaped solid and dashed lines represent absolute configurations, and thick solid and dashed lines represent relative configurations.

[0050] "Halogen" includes, for example, fluorine, chlorine, bromine, iodine, etc. Preferably, it is fluorine or chlorine.

[0051] "C １－４"Alkyl" means a straight or branched chain 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.

[0052] "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. １－６ Specific 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.

[0053] "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.

[0054] 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 of a "5- or 6-membered monocyclic aromatic heterocycle" described below, and a "4- to 10-membered saturated heterocycle" described below).

[0055] "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 Preferred examples of "alkoxy" include methoxy, ethoxy, and isopropoxy.

[0056] "C ３－７ "Cycloalkoxy" refers to the same as "C ３－７ It means an oxy group substituted with "cycloalkyl". ３－６ "Cycloalkoxy". ３－７Specific examples of "cycloalkoxy" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Preferred is cyclohexyloxy.

[0057] "C ６－１０ An "aromatic carbocyclic group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ It is also referred to as "aryl." Phenyl is more preferred. ６－１０ Specific examples of the "aromatic carbocyclic group" include phenyl, 1-naphthyl, and 2-naphthyl.

[0058] 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 heterocycle" described below, or a 5- or 6-membered ring within a "4- to 10-membered saturated heterocycle" described below), or a 5- to 7-membered cycloalkyl ring (e.g., cyclopentane, cyclohexane, or cycloheptane).

[0059] The term "5- to 10-membered aromatic heterocyclic group" refers to a monocyclic or polycyclic 5- to 10-membered aromatic heterocyclic 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, and is preferably a "5- or 6-membered monocyclic aromatic heterocyclic group." The term "5- or 6-membered monocyclic aromatic heterocyclic group" refers to a monocyclic 5- or 6-membered aromatic heterocyclic group among "5- to 10-membered aromatic heterocyclic groups."

[0060] 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, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In another embodiment, preferred examples include benzofuranyl (bonding position on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0061] "C ３－６ "Saturated carbocyclic ring" means a monocyclic saturated or partially unsaturated hydrocarbon ring having 3 to 6 carbon atoms. ３－６ Specific examples of the "saturated carbocyclic ring" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene, etc. Preferably, cyclopropane or cyclobutane is used.

[0062] 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, oxetane, thiomorpholine, dioxothiomorpholine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, 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.

[0063] The term "4- to 10-membered saturated heterocyclic group" refers to a substituent in which the above-mentioned "4- to 10-membered saturated heterocycle" is a monovalent group, and the term "4- to 6-membered saturated heterocyclic group" refers to a substituent in which the above-mentioned "4- to 10-membered saturated heterocycle" is a monovalent group. Preferred examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0064] The compounds of the present invention also include various hydrates, solvates and crystalline polymorphs.

[0065] 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.

[0066] In the present invention, "pharmaceutically acceptable salt" refers to an acid addition salt and a base addition salt that are pharmaceutically acceptable. Examples of "pharmaceutically acceptable salt" include, but are not limited to, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, Examples of 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.

[0067] 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.

[0068] 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.

[0069] The dose of the compound of the present invention is appropriately selected depending on the animal to be administered, the administration route, the disease, the age, weight, and symptoms of the patient. For example, in the case of oral administration, the lower limit is 0.01 mg and the upper limit is 10,000 mg per day for an adult, and this amount can be administered once a day or in divided doses.

[0070] The compound of the present invention has agonistic activity against the orexin type 2 receptor. Therefore, it can be a useful preventive or therapeutic agent for diseases associated with the orexin receptor. Specific examples of these diseases include narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, and Hashimoto's encephalopathy), coma, loss of consciousness, obesity ( For example, malignant mast cells, exogenous obesity, hyperinsulinaemic 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, disorders of consciousness such as coma, side effects and complications of anesthesia, sleep disturbances, sleep problems, insomnia, intermittent sleep, nocturnal clonic cramps, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorders, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight syndrome, circadian Rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, sexual and reproductive dysfunction such as reproductive 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, 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.

[0071] 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.

[0072] 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.

[0073]

[0033] The compound of the present invention may be synthesized by a combination of the following synthesis method and known synthesis methods. 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] Production Method 1: Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, the compound represented by formula (1') can be produced, for example, by the following production method. (In the formula, R １ , R ２ , L １ , L ２ , ring G, and A have the same meanings as in item 1.

[0078] Step (1): Compound (1') can be produced by reacting compound (s-1) and compound (s-2) in an appropriate inert solvent under commonly used urea bond-forming conditions. Examples of reaction conditions include triphosgene, 4-nitrophenyl chloroformate, or thiophosgene. Examples of bases used in this reaction 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.

[0079] Production Method 2: Among the compounds represented by formula (1) or pharmaceutically acceptable salts thereof, the compound represented by formula (s-5) can also be produced, for example, by the following production method. (In the formula, R １ , R ２ , L １ , L ２ , and A are the same as in item 1, and R ｂ１ is the same as in item 5, and X is a protecting group for an amino group. Compound (s-3) is a compound in which ring G in Production Method 1 is a protected nitrogen-containing ring, and can be synthesized in the same manner as in step (1) of Production Method 1.

[0080] Step (2): Compound (s-4) can be produced by subjecting compound (s-3) to a reaction in an appropriate inert solvent under commonly used deprotection conditions. Regarding the conditions for this reaction, for example, when X is a Boc group, deprotection can be achieved using an acid. Examples of acids include hydrochloric acid, sulfuric acid, hydrobromic acid, and trifluoroacetic acid. Examples of solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane, 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. When X is a Cbz group or a Bn group, deprotection can be achieved, for example, by catalytic reduction under hydrogenation conditions. A heterogeneous catalyst such as palladium-carbon is used as the catalyst. "Under hydrogenation conditions" refers to a hydrogen atmosphere or the presence of formic acid, ammonium formate, or the like. Examples of solvents include methanol, ethanol, THF, and ethyl acetate. The reaction time is from 30 minutes to 24 hours, and the reaction temperature is from 0° C. to the boiling point of the solvent.

[0081] Step (3): Compound (s-5) can be produced by reacting compound (s-4) in an appropriate inert solvent under commonly used reductive amination conditions. Examples of conditions for this reaction include those using sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc. Examples of acids used in this reaction include acetic acid, etc. Examples of solvents include halogenated carbons such as chloroform and dichloromethane, ether solvents such as diethyl ether, THF, and 1,4-dioxane, 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.

[0082] The present invention will be explained in more detail below with reference to the following examples and experimental examples, but the present invention is not limited to these examples. The names of compounds shown in the following examples and experimental examples do not necessarily conform to the IUPAC nomenclature.

[0083] The following abbreviations may be used herein: CDCl ３ : deuterated chloroform DMSO-d ６ : deuterated dimethyl sulfoxide Rt: retention time min: minute HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate THF: tetrahydrofuran TFA: trifluoroacetic acid DMF: N,N-dimethylformamide Boc: tert-butoxycarbonyl Ns: 2-nitrobenzenesulfonyl group Tf: trifluoromethanesulfonyl group Abs: absolute configuration; the chemical structure of a compound with the abbreviation Abs enclosed in a box indicates that the wedge-shaped bond is represented as the absolute configuration. However, this does not necessarily mean that the chemical structure of a compound without the abbreviation is not represented as the absolute configuration, and this can be determined based on the description of the target compound in this specification, the context, and the common sense of a person skilled in the art. Rac: Racemic compound; refers to a compound that does not exhibit optical rotation due to the presence of equal amounts of two enantiomers.

[0084] In the Reference Examples and Examples, column chromatography and amino chromatography were carried out using silica gel columns and amino columns manufactured by Yamazen Co., Ltd. When purifying using TLC, Silica gel 60F254 (Merck) was used for TLC (silica gel plate), and TLC plate NH (FujiSilysia) was used for TLC (NH silica gel plate).

[0085] 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

[0086] 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.

[0087] LC / MS data for each compound in the Examples and Reference Examples was obtained using one of the following instruments. Method A: Detector: ACQUITY® SQ detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC® 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) Method C: Detector: ACQUITY® SQ detector (Waters) HPLC: ACQUITY UPLC® SYSTEM Column: Waters ACQUITY UPLC® BEH C18 (1.7 μm, 2.1 mm × 30 mm) Method D: Detector: Shimadzu LCMS-2020 Column: Waters ACQUITY UPLC (registered trademark) C18 (1.8 μm, 2.1 mm × 50 mm)

[0088] 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). For each measured value, the measurement conditions used are indicated as either A to D. Method A Solvent: Solution A; 0.06% formic acid / H ２Solution 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 ２ Solution O, B: acetonitrile Gradient conditions: 0.0-1.7 min (linear gradient from 10% B to 99% B) Flow rate: 0.5 mL / min; Detection UV: 220 nm; Temperature: 40°C Method C Solvent: Solution A: 0.05% formic acid / H ２ Solution O, B: acetonitrile Gradient conditions: 0.0-1.3 min (linear gradient from 10% B to 95% B), 1.3-1.5 min (10% B) Flow rate: 0.8 mL / min; UV detection: 220 nm and 254 nm; Temperature: 40°C Method D Solvent: Solution A: 0.1% formic acid / H ２ Solution O, B: 0.1% formic acid / acetonitrile. Gradient conditions: 0.01-4.0 min (linear gradient from 5% B to 99% B), 4.0 min-5.0 min (95% B). Flow rate: 0.5 mL / min; UV detection: 220 nm; temperature: 25°C. Unless otherwise specified below, analysis was performed using Method A.

[0089] Reference Example 1: tert-butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperazine-1-carboxylate Step (i): 4-Nitrophenyl chloroformate (0.073 g) was added to a mixture of compound 1 (0.100 g), diisopropylethylamine (0.047 g), and chloroform (1.8 mL) at 0°C, and the mixture was stirred at that temperature for 1 hour. 4-(4-methylphenyl)piperidine (0.070 g) was added to the reaction mixture 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 ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 2 (0.152 g). LCMS: [M+H] + / Rt(min):479 / 1.27

[0090] Reference Example 2: 2-[4-(propan-2-yl)piperazin-1-yl]aniline

[0091] Step (i): A mixture of compound 3 (1.41 g), potassium carbonate (5.52 g), isopropylpiperazine (1.28 g), and THF (25 mL) was stirred at 50° C. for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was used directly in the next reaction.

[0092] Step (ii): A mixture of compound 4, 10% palladium carbon (1.06 g), and methanol (25 mL) was stirred at room temperature under a hydrogen gas atmosphere for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 5 (1.50 g). LCMS: [M+H] + / Rt(min):220 / 0.35

[0093] Reference Example 3: 4-fluoro-2-[4-(propan-2-yl)piperazin-1-yl]aniline

[0094] Step (i): Using compound 6 (0.159 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 7 was obtained.

[0095] Step (ii): Using the mixture of compound 7, the title compound 8 (0.144 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):238 / 0.39

[0096] Reference Example 4: 2-Methoxy-6-[4-(propan-2-yl)piperazin-1-yl]aniline

[0097] Step (i): Using compound 9 (0.020 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 10 was obtained.

[0098] Step (ii): Using the mixture of compound 10, the title compound 11 (0.019 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):250 / 0.60

[0099] Reference Example 5: 2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]aniline

[0100] Step (i): Using compound 12 (0.159 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 13 was obtained.

[0101] Step (ii): Using the mixture of compound 13, the title compound 14 (0.190 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):238 / 1.16 (Method B)

[0102] Reference Example 6: 3-fluoro-2-[4-(propan-2-yl)piperazin-1-yl]aniline

[0103] Step (i): Using compound 15 (0.477 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 16 was obtained.

[0104] Step (ii): Using the mixture of compound 16, the title compound 17 (0.443 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H]+ / Rt(min):238 / 0.46

[0105] Reference Example 7: 2-methyl-6-[4-(propan-2-yl)piperazin-1-yl]aniline

[0106] Step (i): Using compound 18 (0.310 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 19 was obtained.

[0107] Step (ii): Using the mixture of compound 19, the title compound 20 (0.410 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):234 / 0.61

[0108] Reference Example 8: 2-[4-(propan-2-yl)piperazin-1-yl]-6-(trifluoromethyl)aniline

[0109] Step (i): Using compound 21 (0.209 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 22 was obtained.

[0110] Step (ii): Using the mixture of compound 22, the title compound 23 (0.220 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):288 / 1.50 (Method B)

[0111] Reference Example 9: 2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]aniline

[0112] Step (i): Using compound 24 (4.00 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 25 was obtained.

[0113] Step (ii): To a mixture of compound 25, reduced iron (3.82 g), and methanol (57 mL), 4N aqueous ammonium chloride solution (28.5 mL) was added at 90° C. and stirred at that temperature for 2 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, concentrated under reduced pressure, dissolved in ethyl acetate, and washed with water and saturated brine. 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 26 (4.10 g). LCMS: [M+H] + / Rt(min):254 / 1.33 (Method B)

[0114] Reference Example 10: 2-chloro-6-(4-cyclopropylpiperazin-1-yl)aniline Compound 27 was synthesized according to the method described in Reference Example 9, except that cyclopropylpiperazine was used instead of isopropylpiperazine in step (i) of Reference Example 9. LCMS: [M+H] + / Rt(min):252 / 0.60

[0115] Reference Example 11: 2-bromo-6-[4-(propan-2-yl)piperazin-1-yl]aniline

[0116] Step (i): Using compound 28 (1.50 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 29 was obtained.

[0117] Step (ii): Using the mixture of compound 29, the title compound 30 (1.64 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):298,300 / 0.58

[0118] Reference Example 12: 2-amino-N,N-dimethyl-3-[4-(propan-2-yl)piperazin-1-yl]benzamide

[0119] Step (i): Using compound 31 (0.212 g) and according to a method similar to that of step (i) of Reference Example 2, a mixture of the title compounds 32 was obtained.

[0120] Step (ii): Using the mixture of compound 32, the title compound 33 (0.201 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):291 / 1.07 (Method B)

[0121] Reference Example 13: tert-butyl (2R,5S)-2-(2-aminophenyl)-5-(propan-2-yl)morpholine-4-carboxylate

[0122] Step (i): A mixture of compound 34 (1.00 g), sodium azide (0.533 g), water (10 mL), and ethanol (20 mL) was stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used directly in the next reaction.

[0123] Step (ii): A mixture of crude compound 35, sodium borohydride (0.127 g), and methanol was stirred at 0° C. for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 36 (0.488 g).

[0124] Step (iii): A mixture of compound 36 (0.289 g), 1-bromo-3-methyl-2-butanone (0.641 g), cesium carbonate (1.176 g), and DMF (3 mL) was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 37 (0.402 g). LCMS: [M+H] + / Rt(min):293 / 1.05

[0125] Step (iv): A mixture of compound 37 (0.82 g), triphenylphosphine (0.184 g), and THF (2 mL) was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 38 (0.058 g). LCMS: [M+H] + / Rt(min):249 / 0.54

[0126] Step (v): A mixture of compound 38 (0.059 g), sodium triacetoxyborohydride (0.100 g), and dichloromethane (2 mL) was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 39 (0.049 g). LCMS: [M+H] + / Rt(min):251 / 0.63

[0127] Step (vi): A mixture of compound 39 (0.038 g), di-tert-butyl dicarbonate (0.040 g), N,N-dimethyl-4-aminopyridine (0.001 g), and acetonitrile (2 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was used directly in the next reaction. LCMS: [M+H] + / Rt(min):325 / 1.24

[0128] Step (vii): Using the mixture of compound 40, the title compound 41 (0.036 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):321 / 1.13

[0129] Reference Example 14: Rac-2-[3-methyl-4-(propan-2-yl)piperazin-1-yl]aniline

[0130] Step (i): Using compound 42 (0.282 g) and according to a method similar to that of Reference Example 2, step (i), the title compound 43 was obtained as a crude product.

[0131] Step (ii): A mixture of the crude compound 43, trifluoroacetic acid (1.80 g), and chloroform (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 44 (0.370 g). LCMS: [M+H] + / Rt(min):222 / 1.29 (Method B)

[0132] Step (iii): A mixture of compound 44 (0.221 g), sodium triacetoxyborohydride (0.635 g), acetic acid (0.060 g), acetone (0.058 g), and THF (5 mL) was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was used directly in the next reaction.

[0133] Step (iv): Using the crude product of compound 45, the title compound 46 (0.170 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):234 / 0.48 (Method B)

[0134] Reference Example 15: Rac-2-[2-methyl-4-(propan-2-yl)piperazin-1-yl]aniline

[0135] Step (i): Using compound 47 (0.221 g) and according to a method similar to that of Reference Example 14, step (iii), the title compound 48 was obtained as a crude product.

[0136] Step (ii): Using the crude product of compound 48, the title compound 49 (0.098 g) was obtained according to the same method as in Step (ii) of Reference Example 14. LCMS: [M+H] + / Rt(min):143 / 0.30

[0137] Step (iii): Using compound 49 (0.071 g) and according to a method similar to that of step (i) of Reference Example 2, a crude product of the title compound 50 was obtained.

[0138] Step (iv): Using the crude product of compound 50, the title compound 51 (0.060 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):234 / 0.54

[0139] Reference Example 16: Methyl 2-amino-3-[4-(propan-2-yl)piperazin-1-yl]benzoate

[0140] Step (i): Using compound 52 (0.150 g), a mixture of title compounds 53 was obtained according to the same method as in Step (i) of Reference Example 2. LCMS: [M+H] + / Rt(min):308 / 0.55

[0141] Step (ii): Using the mixture of compound 53, the title compound 54 (0.132 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):278 / 0.58

[0142] Reference Example 17: tert-butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-1,4-diazepane-1-carboxylate

[0143] Step (i): Using compound 55 (1.06 g), the title compound 56 (2.40 g) was obtained according to the same method as in Step (i) of Reference Example 2. LCMS: [M+H] + / Rt(min): 322 / 1.08

[0144] Step (ii): Using compound 56 (2.40 g), the title compound 57 (1.77 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):292 / 0.96

[0145] Step (iii): Using compound 57 (0.095 g), the title compound 58 (0.153 g) was obtained according to the same method as in Step (i) of Reference Example 1. LCMS: [M+H] + / Rt(min):493 / 1.12

[0146] Reference Example 18: tert-Butyl 4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-1,4-diazepane-1-carboxylate Step (i): Using compound 57 (0.104 g) and according to a method similar to that of Reference Example 1, step (i), the title compound 59 (0.154 g) was obtained.

[0147] Reference Example 19: 2-(4-tert-butylpiperazin-1-yl)-6-chloroaniline

[0148] Step (i): Using compound 24 (0.300 g) and according to a method similar to that of step (i) of Reference Example 2, the title compound 60 was obtained as a crude product.

[0149] Step (ii): Using the crude product of compound 60, the title compound 61 (0.315 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):268 / 0.56

[0150] Reference Example 20: 2-[1-(propan-2-yl)piperidin-4-yl]aniline

[0151] Step (i): Compound 62 (5.00 g), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (7.60 g), Pd(dppf)Cl ２ CH ２ Cl ２A mixture of (2.02 g), sodium carbonate (5.25 g), water (25 mL), and 1,4-dioxane (50 mL) was stirred at 110° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 63 (7.51 g). LCMS: [M+H] + / Rt(min):305 / 4.24 (Method D)

[0152] Step (ii): A mixture of compound 63 (7.51 g), 4N hydrochloric acid in dioxane (31 mL), and methanol (150 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 64 (5.13 g). LCMS: [M+H] + / Rt(min):205 / 2.15 (Method D)

[0153] Step (iii): A mixture of compound 64 (2.50 g), sodium triacetoxyborohydride (6.60 g), acetone (0.058 g), and dichloromethane (75 mL) was stirred at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 65 (1.60 g). LCMS: [M+H] + / Rt(min):247 / 2.17 (Method D)

[0154] Step (iv): Using compound 65 (1.60 g), the title compound 66 (0.675 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):219 / 1.85 (Method D)

[0155] Reference Example 21: 2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]aniline

[0156] Step (i): Using compound 28 (0.220 g), the title compound 67 (0.234 g) was obtained according to the same method as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):323 / 2.12 (Method B)

[0157] Step (ii): A mixture of compound 67 (0.230 g), trifluoroacetic acid (1.80 g), and chloroform (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound 68 as a crude product.

[0158] Step (iii): A mixture of crude compound 68, sodium triacetoxyborohydride (0.454 g), acetic acid (0.064 g), acetone (0.166 g), and THF (3 mL) was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 69 (0.150 g). LCMS: [M+H] + / Rt(min):265 / 0.60 (Method B)

[0159] Step (iv): Using compound 69 (0.100 g), the title compound 70 (0.050 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):237 / 0.53 (Method B)

[0160] Reference Example 22: 2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]aniline Step (i): Using compound 69 (0.100 g), the title compound 71 (0.077 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):235 / 0.55 (Method B)

[0161] Reference Example 23: tert-butyl 4-(3-ethoxy-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

[0162] Step (i): A mixture of compound 72 (0.654 g), ethyl iodide (0.702 g), potassium carbonate (1.66 g), and THF (10 mL) was stirred at 50° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 73 (0.621 g).

[0163] Step (ii): Using compound 73 (0.500 g), the title compound 74 (0.558 g) was obtained according to the same method as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):349 / 2.24 (Method B)

[0164] Step (iii): Using compound 74 (0.300 g) and according to a method similar to that of Step (ii) of Reference Example 2, the title compound 75 was obtained as a crude product.

[0165] Step (iv): To a mixture of the crude product of compound 75, diisopropylethylamine (0.278 g), and chloroform (4 mL), triphosgene (0.064 g) was added at 0°C, and the mixture was stirred at that temperature for 1 hour. 4-(4-methylphenyl)piperidine (0.084 g) was added to the reaction mixture 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 ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 76 (0.180 g). LCMS: [M+H] + / Rt(min):522 / 2.35 (Method B)

[0166] Reference Example 24: tert-butyl 4-(2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}-3-[(propan-2-yl)oxy]phenyl)piperidine-1-carboxylate

[0167] Step (i): Using compound 72 (0.654 g) and according to a method similar to that of Reference Example 23, step (i), the title compound 77 (0.522 g) was obtained.

[0168] Step (ii): Using compound 77 (0.520 g), the title compound 78 (0.611 g) was obtained according to the same method as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):363 / 2.30 (Method B)

[0169] Step (iii): Using compound 78 (0.300 g) and according to a method similar to that of Reference Example 2, step (ii), the title compound 79 was obtained as a crude product.

[0170] Step (iv): Using the crude product of compound 79, the title compound 80 (0.299 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):536 / 2.40 (Method B)

[0171] Reference Example 25: tert-butyl 4-(3-chloro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0172] Step (i): Using compound 81 (0.709 g), the title compound 82 (0.502 g) was obtained according to the same method as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):339 / 2.26 (Method B)

[0173] Step (ii): Using compound 82 (0.100 g), the title compound 83 (0.070 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):309 / 2.22 (Method B)

[0174] Step (iii): Using compound 83 (0.070 g), the title compound 84 (0.082 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):511 / 2.27 (Method B)

[0175] Reference Examples 26 to 29 The compounds of Reference Examples 26 to 29 shown in the following table were synthesized according to the method described in Reference Example 25 above, using the corresponding starting compounds instead of 4-(4-methylphenyl)piperidine in step (iii) of Reference Example 25.

[0176] Reference Example 26: tert-butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Reference Example 27: tert-butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Reference Example 28: tert-butyl 4-(3-chloro-2-{[4-methyl-4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Reference Example 29: tert-butyl 4-{3-chloro-2-[(4-cyano-4-methylpiperidine-1-carbonyl)amino]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

[0177] Reference Example 30: tert-Butyl 4-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0178] Step (i): Using compound 67 (0.900 g), the title compound 89 (0.750 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):293 / 2.10 (Method B)

[0179] Step (ii): Using compound 89 (0.100 g), the title compound 90 (0.130 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):494 / 2.27 (Method B)

[0180] Reference Example 31: tert-butyl 4-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

[0181] Step (i): Using compound 67 (0.100 g) and according to a method similar to that of step (ii) of Reference Example 2, the title compound 91 was obtained as a crude product.

[0182] Step (ii): Using the crude product of compound 91, the title compound 92 (0.120 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):496 / 1.22

[0183] Reference Example 32: 2-methoxy-6-[1-(propan-2-yl)piperidin-4-yl]aniline

[0184] Step (i): Using compound 93 (3.00 g) and according to a method similar to that of Reference Example 20, step (i), the title compound 94 (3.78 g) was obtained.

[0185] Step (ii): Using compound 94 (3.78 g), the title compound 95 (2.80 g) was obtained according to the same method as in Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):235 / 2.31 (Method D)

[0186] Step (iii): Using compound 95 (2.80 g), the title compound 96 (2.80 g) was obtained according to the same method as in Step (iii) of Reference Example 20. LCMS: [M+H] + / Rt(min):277 / 2.42 (Method D)

[0187] Step (iv): Using compound 96 (2.00 g), the title compound 97 (1.45 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):249 / 3.57 (Method C)

[0188] Reference Example 33: 2-methoxy-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]aniline Step (i): Using compound 96 (0.350 g), the title compound 98 (0.237 g) was obtained according to a method similar to that of Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):247 / 5.02 (Method D)

[0189] Reference Example 34: tert-butyl 3-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0190] Step (i): Using compound 28 (0.100 g) and the corresponding boronic acid and according to a method similar to that of step (i) of Reference Example 20, the title compound 99 (0.113 g) was obtained. 1 H-NMR (CDCl3) δ: 1.49 (9H, s), 4.20-4.34 (2H, m), 4.35-4.50 (2H, m), 5.90-6.04 (1H, m), 7.08-7.17 (1H, m), 7.17-7.25 (1H, m), 7.42-7.51 (1H, m).

[0191] Step (ii): Using compound 99 (0.111 g), the title compound 100 (0.065 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):279 / 0.99 (Method B)

[0192] Step (iii): Using compound 100 (0.030 g), the title compound 101 (0.030 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H]+ / Rt(min):480 / 2.21(shi) (Method C)

[0193] Reference Example 35: 2-(3,6-dihydro-2H-pyran-4-yl)-6-fluoroaniline

[0194] Step (i): Using compound 28 (0.100 g) and the corresponding boronic acid and according to a method similar to that of step (i) of Reference Example 20, the title compound 102 (0.056 g) was obtained. 1 H-NMR (CDCl3) δ: 2.34-2.42 (2H, m), 3.86-3.92 (2H, m), 4.21-4.27 (2H, m), 5.79-5.86 (1H, m), 7.07-7.13 (1H, m), 7.13-7.21 (1H, m), 7.40-7.50 (1H, m).

[0195] Step (ii): Using compound 102 (0.054 g), the title compound 103 (0.032 g) was obtained according to a method similar to that of Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):194 / 0.70 (Method C)

[0196] Reference Example 36: 2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoroaniline Step (i): Using compound 104 (0.100 g) and the corresponding boronic acid, the title compound 105 (0.007 g) was obtained according to a method similar to that of Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):218 / 0.72 (Method C)

[0197] Reference Example 37: 2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]aniline

[0198] Step (i): Using compound 28 (0.165 g) and the corresponding boronic acid, the title compound 106 (0.110 g) was obtained in the same manner as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):261 / 0.98

[0199] Step (ii): Using compound 106 (0.110 g), the title compound 107 (0.084 g) was obtained according to a method similar to that of Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):231 / 0.64

[0200] Reference Example 38: 2-fluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}aniline

[0201] Step (i): A mixture of compound 108 (0.157 g), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g), diisopropyl azadicarboxylate (0.242 g), triphenylphosphine (0.524 g), and THF (10 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 109 (0.233 g). LCMS: [M+H] + / Rt(min):341 / 2.17 (Method B)

[0202] Step (ii): Using compound 109 (0.100 g) and according to a method similar to that of Step (ii) of Reference Example 21, a crude product of the title compound 110 was obtained.

[0203] Step (iii): Using the crude product of compound 110 and according to a method similar to that of step (iii) of Reference Example 20, the title compound 111 (0.060 g) was obtained.

[0204] Step (iv): Using compound 111 (0.060 g) and according to a method similar to that of Reference Example 2, step (ii), the title compound 112 (0.030 g) was obtained.

[0205] Reference Example 39: Rac-2-chloro-6-{[1-(propan-2-yl)pyrrolidin-3-yl]oxy}aniline

[0123] Using the corresponding starting compounds instead of compound 108 and tert-butyl 4-hydroxypiperidine-1-carboxylate in step (i) of Reference Example 38, the following compound was synthesized according to the method described in Reference Example 38 above.

[0206] Reference Example 40: tert-butyl 3-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenoxy)azetidine-1-carboxylate

[0207] Step (i): A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.30 g), sodium hydride (0.41 g), and THF (21 mL) was stirred at 0°C for 30 minutes, and then compound 24 was added and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 114 (2.06 g). LCMS: [M+H] + / Rt(min):329 / 1.11

[0208] Step (ii): Using compound 114 (1.00 g), the title compound 115 (0.77 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):299 / 1.06

[0209] Step (iii): Using compound 115 (0.060 g), the title compound 116 (0.110 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):533 / 1.08

[0210] Reference Example 41: 2-methoxy-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}aniline

[0211] Step (i): Using compound 117 (0.181 g) and isopropylpiperazine (0.128 g) and according to a method similar to that of Reference Example 20, step (iii), the title compound 118 (0.231 g) was obtained.

[0212] Step (ii): Using compound 118 (0.230 g) and according to a method similar to that of Reference Example 2, step (ii), the title compound 119 (0.140 g) was obtained.

[0213] Reference Example 42: 3-fluoro-4'-(propan-2-yl)[1,1'-biphenyl]-2-amine

[0214] Step (i): Using compound 28 (0.220 g) and the corresponding boronic acid and according to a method similar to that of step (i) of Reference Example 20, the title compound 120 (0.231 g) was obtained.

[0215] Step (ii): Using compound 120 (0.230 g) and according to a method similar to that of Reference Example 2, step (ii), the title compound 121 (0.165 g) was obtained.

[0216] Reference Example 43: tert-butyl 4-(3-chloro-2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

[0217] Step (i): Using compound 81 (0.709 g), the title compound 122 (0.502 g) was obtained according to the same method as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):339 / 2.26 (Method B)

[0218] Step (ii): Using compound 122 (0.10 g), the title compound 123 (0.039 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):311 / 2.21 (Method B)

[0219] Step (iii): Using compound 123 (0.070 g), the title compound 124 (0.084 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):545 / 1.12 (Method C)

[0220] Reference Examples 44 to 45 The following compounds were synthesized according to the method described in Reference Example 43 above, using the corresponding starting compounds instead of 4-(4-methylphenyl)piperidine in step (iii) of Reference Example 43.

[0221] Reference Example 44: tert-butyl 4-(3-chloro-2-{[4-methyl-4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate Reference Example 45: tert-butyl 4-(3-chloro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)piperidine-1-carboxylate

[0222] Reference Example 46: 2-fluoro-6-(6-methylpyridin-3-yl)aniline

[0223] Step (i): Using compound 28 (0.178 g) and the corresponding boronic acid, the title compound 127 (0.198 g) was obtained in the same manner as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):261 / 0.98

[0224] Step (ii): Using compound 127 (0.184 g), the title compound 128 (0.148 g) was obtained according to a method similar to that of Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):231 / 0.64

[0225] Reference Example 47: 2-chloro-6-[6-(propan-2-yl)pyridin-3-yl]aniline

[0226] Step (i): Using compound 81 (0.247 g) and the corresponding boronic acid, the title compound 129 (0.147 g) was obtained according to a method similar to that of step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):277 / 1.07

[0227] Step (ii): Using compound 129 (0.142 g), the title compound 130 (0.130 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):247 / 0.75

[0228] Reference Example 48: 2-fluoro-6-(5-methylpyridin-3-yl)aniline

[0229] Step (i): Using compound 28 (0.143 g) and the corresponding boronic acid, the title compound 131 (0.104 g) was obtained according to a method similar to that of Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):233 / 0.80

[0230] Step (ii): Using compound 131 (0.091 g), the title compound 132 (0.072 g) was obtained according to a method similar to that of Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):203 / 0.53

[0231] Reference Example 49: 2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]aniline Step (i): Using compound 104 (0.248 g) and the corresponding boronic acid, the title compound 133 (0.054 g) was obtained according to a method similar to that of step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):257 / 0.90 (Method C)

[0232] Reference Example 50: 2-fluoro-6-[2-(propan-2-yl)pyrimidin-5-yl]aniline

[0233] Step (i): Using compound 28 (0.100 g) and the corresponding boronic acid, the title compound 134 (0.038 g) was obtained in the same manner as in Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):262 / 0.90 (Method C)

[0234] Step (ii): Using compound 134 (0.036 g) and according to a method similar to that of Reference Example 9, step (ii), the title compound 135 (0.004 g) was obtained. 1 H-NMR (CDCl3) δ: 1.41 (6H, d, J = 6.8 Hz), 3.22-3.37 (1H, m), 3.79 (2H, br), 6.72-6.84 (1H, m), 6.84-6.94 (1H, m), 7.00-7.12 (1H, m), 8.81 (2H, s).

[0235] Reference Example 51: tert-butyl (1S,4S)-5-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0236] Step (i): Using compound 12 (0.324 g), the title compound 136 (0.530 g) was obtained according to the same method as in Step (i) of Reference Example 2. LCMS: [M+H] + / Rt(min):338 / 1.08

[0237] Step (ii): Using compound 136 (0.530 g), the title compound 137 (0.385 g) was obtained according to a method similar to that of Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):308 / 1.01

[0238] Step (iii): Using compound 137 (0.044 g), the title compound 138 (0.080 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):509 / 1.15

[0239] Reference Example 52: tert-butyl (1S,4S)-5-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Step (i): Using compound 137 (0.124 g), the title compound 139 (0.189 g) was obtained according to a method similar to that of Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):541 / 1.01

[0240] Reference Example 53: tert-butyl (1R,4R)-5-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0241] Step (i): Using compound 12 (0.252 g), the title compound 140 (0.410 g) was obtained according to the same method as in Step (i) of Reference Example 2. LCMS: [M+H] + / Rt(min):338 / 1.08

[0242] Step (ii): Using compound 140 (0.404 g), the title compound 141 (0.224 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):308 / 1.01

[0243] Step (iii): Using compound 141 (0.037 g), the title compound 142 (0.080 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):509 / 1.15

[0244] Reference Example 54: tert-butyl (1R,4R)-5-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Step (i): Using compound 141 (0.055 g), the title compound 143 (0.088 g) was obtained according to a method similar to that of Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):541 / 1.01

[0245] Reference Example 55: tert-butyl 3-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0246] Step (i): Using compound 12 (0.382 g) and according to a method similar to that of Reference Example 2, step (i), the title compound 144 (0.575 g) was obtained.

[0247] Step (ii): Using compound 144 (0.563 g), the title compound 145 (0.451 g) was obtained according to the same method as in Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):322 / 1.11

[0248] Step (iii): Using compound 145 (0.111 g), the title compound 146 (0.161 g) was obtained according to a method similar to that of Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):523 / 1.23

[0249] Reference Example 56: tert-butyl 3-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}-3-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step (i): Using compound 145 (0.107 g), the title compound 147 (0.189 g) was obtained according to a method similar to that of Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):556 / 1.12

[0250] Reference Example 57: benzyl 8-(3-fluoro-2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0251] Step (i): Using compound 12 (0.204 g), the title compound 148 (0.338 g) was obtained according to the same method as in Step (i) of Reference Example 2. LCMS: [M+H] + / Rt(min):386 / 1.15

[0252] Step (ii): Using compound 148 (0.307 g), the title compound 149 (0.220 g) was obtained according to a method similar to that of step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):356 / 1.10

[0253] Step (iii): Using compound 149 (0.073 g), the title compound 150 (0.080 g) was obtained according to the same method as in Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):557 / 1.20

[0254] Reference Example 58: Rac-tert-butyl (2R,5S)-2-(2-amino-3-chlorophenyl)-5-(propan-2-yl)morpholine-4-carboxylate

[0255] Step (i): A mixture of compound 151 (3.03 g), manganese dioxide (11.56 g), and chloroform (160 mL) was stirred under reflux for 12 hours. After cooling, the mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 152 (2.59 g). LCMS: [M+H] + / Rt(min):186 / 0.81

[0256] Step (ii): To a mixture of methyltriphenylphosphonyl bromide (3.25 g) and THF (21 mL), a hexane solution of n-butyllithium (1.57 M, 5.35 mL) was added at 0°C and stirred at that temperature for 1 hour. To this mixture, a THF (7 mL) solution of compound 152 (1.30 g) was added dropwise, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride 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 resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 153 (0.756 g).

[0257] Step (iii): A mixture of compound 153 (0.333 g), metachloroperbenzoic acid (0.542 g), and methylene chloride (9 mL) was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by silica gel column chromatography (eluent: chloroform / methanol) to give the title compound 154 (0.141 g).

[0258] Step (iv): A mixture of compound 154 (0.141 g), sodium azide (0.046 g), and acetonitrile (3 mL) was stirred at 40° C. for 3 hours. Water (1 mL) was added and the mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 155 (0.084 g).

[0259] Step (v): A mixture of compound 155 (0.100 g), 1-bromo-3-methylbutan-2-one (0.086 g), cesium carbonate (0.226 g), and acetonitrile (3.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 156 (0.100 g). LCMS: [M+H] + / Rt(min):327 / 1.10

[0260] Step (vi): A mixture of compound 156 (0.100 g), triphenylphosphine (0.097 g), and THF (6 mL) was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (0.098 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was used directly in the next reaction. LCMS: [M+H] + / Rt(min): 285 / 0.69, 285 / 0.74 (Method C)

[0261] Step (vii): The crude product of compound 157, Boc ２ A mixture of 0 (0.067 g) and THF (6 mL) was stirred at room temperature for 16 hours. A mixture of the title compounds (0.55 g) was obtained in the same manner as in Step (ii) of Reference Example 2. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 158 (0.031 g) and the title compound 159 (0.018 g).

[0262] Step (vii): Using compound 158 (0.031 g), the title compound 160 (0.029 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):355 / 1.29

[0263] Reference Example 59: Rac-tert-butyl (2R,5R)-2-(2-amino-3-chlorophenyl)-5-(propan-2-yl)morpholine-4-carboxylate Step (i): Using compound 159 (0.018 g), the title compound 161 (0.011 g) was obtained according to the same method as in Step (ii) of Reference Example 9. LCMS: [M+H] + / Rt(min):355 / 1.29

[0264] Reference Example 60: Rac-6-(4-methylphenyl)-3-azabicyclo[4.1.0]heptane

[0265] Step (i): A mixture of compound 162 (1.42 g), paratolylmagnesium bromide (1 M, 8.52 mL), and THF (20 mL) was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 163 (1.62 g). LCMS: [M+H] + / Rt(min):326 / 1.01

[0266] Step (ii): A mixture of compound 163 (0.742 g), paratoluenesulfonic acid monohydrate (0.217 g), and toluene was stirred at 50° C. for 1 hour. A saturated aqueous solution of sodium bicarbonate 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 resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 164 (0.561 g). LCMS: [M+H] + / Rt(min):308 / 2.23 (Method B)

[0267] Step (iii): A dichloromethane solution (0.8 mL) of compound 164 (0.130 g) was added dropwise to a mixture of diethylzinc (1 M, 2.12 mL), diiodomethane (0.566 g), and dichloromethane (2 mL) at 0°C, followed by stirring at room temperature for 14 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in THF (2.8 mL) and water (2.8 mL). N-methylmorpholine N-oxide (0.114 g) and osmium(VIII) oxide were added, followed by stirring at room temperature for 12 hours. THF (3 mL) and saturated aqueous sodium thiosulfate solution were added to the reaction mixture, followed by stirring at 0°C for 30 minutes. After extraction with ethyl acetate, 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 165 (0.018 g). LCMS: [M+H] + / Rt(min):322 / 2.27 (Method B)

[0268] Step (iv): Using compound 165 (0.017 g), the title compound 166 (0.010 g) was obtained according to a method similar to that of Step (ii) of Reference Example 2. LCMS: [M+H] + / Rt(min):188 / 1.37 (Method B)

[0269] Reference Example 61: 4-(2-fluoro-4-methylphenyl)piperidine

[0270] Step (i): Using compound 167 (0.095 g), the title compound 168 (0.100 g) was obtained according to a method similar to that of Step (i) of Reference Example 20. LCMS: [M+H] + / Rt(min):292 / 2.26 (Method B)

[0271] Step (ii): Using compound 168 (0.100 g) and according to a method similar to that of Reference Example 2, step (ii), the title compound 169 was obtained as a crude product.

[0272] Step (iii): Using the crude product of compound 169, the title compound 170 (0.050 g) was obtained according to the same method as in Step (ii) of Reference Example 14. LCMS: [M+H] + / Rt(min):194 / 0.58

[0273] Reference Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride

[0274] Step (i): To a solution of compound 171 (50.0 g) in ethanol (446 mL), 50% aqueous hydroxylamine solution (132 mL) was added, and the mixture was stirred at 70° C. for 8 hours. After cooling to room temperature, water (892 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The resulting white crystals were collected by filtration, and then suspended and stirred again in water (344 mL) at room temperature for 30 minutes. The resulting white solid was collected by filtration and dried to give the title compound 172 (52.3 g). LCMS: [M+H] + / Rt(min):258 / 0.52 (Method C)

[0275] Step (ii): In an ice bath, triethylamine (142 mL) was slowly added dropwise to a mixture of compound 172 (52.3 g), cyclopropanecarboxylic acid (18.4 g), HATU (85 g), and THF (406 mL), and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (406 mL) was added to the reaction mixture, and the mixture was washed with water (406 mL) and saturated brine (406 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 173 (59.1 g). LCMS: [M+H] + / Rt(min):326 / 0.77 (Method C)

[0276] Step (iii): A mixture of compound 173 (59.1 g), DBU (54.2 mL), and toluene (727 mL) was stirred under reflux for 1 hour. After cooling to room temperature and washing with water (727 mL), the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 174 (54.5 g). LCMS: [M+H] + / Rt(min):308 / 1.11 (Method C)

[0277] Step (iv): Using compound 174 (54.5 g), the title compound 175 (35.3 g) was obtained according to a method similar to that of step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):208 / 0.30 (Method C)

[0278] Reference Examples 63 to 87 The compounds of Reference Examples 63 to 87 shown in the following table were synthesized according to the method described in Reference Example 62 above, using the corresponding starting compounds instead of compound 171 in step (i) and cyclopropanecarboxylic acid in step (ii) in Reference Example 62.

[0279] Reference Example 63: 4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride Reference Example 64: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride Reference Example 65: 4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride Reference Example 66: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride Reference Example 67: 4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine hydrochloride Reference Example 68: 4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride Reference Example 69: 4-Methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride Reference Example 70: 4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 71: 4-Methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride Reference Example 72: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine hydrochloride Reference Example 73: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine hydrochloride Reference Example 74: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine hydrochloride Reference Example 75: rac-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine hydrochloride Reference Example 76: 4-[5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 77: 4-[5-(2,2-dimethylcyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 78: 4-methyl-4-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine hydrochloride Reference Example 79: 4-[5-(1-methoxycyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 80: 4-[5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 81: 4-[5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine hydrochloride Reference Example 82: rac-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride Reference Example 83: rac-4-{5-[(1R,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride Reference Example 84: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride Reference Example 85: 4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride Reference Example 86: 4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride Reference Example 87: 4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine hydrochloride,

[0280] Reference Example 88: 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octane

[0281] Step (i): To a solution of compound 201 (0.100 g) in toluene (0.01 mL), CDI (0.070 g) was added and the mixture was stirred at room temperature for 3 hours. N'-Hydroxycyclopropanecarboximidamide hydrochloride (0.059 mg) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hours. The reaction mixture was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 202 (0.123 g). LCMS: [M+H] + / Rt(min):320 / 1.01 (Method C)

[0282] Step (ii): Using compound 202 (0.121 g), the title compound 203 (0.091 g) was obtained according to a method similar to that of Step (ii) of Reference Example 14. LCMS: [M+H] + / Rt(min):220 / 0.30 (Method C)

[0283] Reference Example 89: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride

[0284] Step (i): To a mixture of compound 204 (900 mg), sodium acetate (650 mg), and methanol (5 mL), hydroxylamine hydrochloride (550 mg) was added and stirred at room temperature for 24 hours. The reaction solution was cooled to 0°C, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give title compound 205 (1.23 g).

[0285] Step (ii): To a mixture of compound 205 (416 mg) and DMF (4 mL), N-chlorosuccinimide (252 mg) was added and stirred for 3 hours. The reaction solution was cooled to 0°C, water (6 mL) was added, and the precipitated solid was filtered and dried to give title compound 206 (326 mg).

[0286] Step (iii): Compound 206 (326 mg) and sodium bicarbonate (198 mg) were added to a mixture of ethynylcyclopropane (117 mg) and toluene (5 mL), and the mixture was stirred at room temperature. After confirming the disappearance of the raw materials, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 207 (348 mg). LCMS: [M+H] + / Rt(min):307 / 1.13

[0287] Step (iv): Using compound 207 (337 mg), the title compound 208 (307 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):207 / 0.49

[0288] Reference Examples 90 to 91 The compounds of Reference Examples 90 to 91 shown in the following table were synthesized according to the method described in Reference Example 89 above, except that the corresponding starting compounds were used instead of ethynylcyclopropane in step (iii) of Reference Example 89.

[0289] Reference Example 90: 4-methyl-4-[5-(propan-2-yl)-1,2-oxazol-3-yl]piperidine Reference Example 91: 4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine

[0290] Reference Example 92: 2-(4-methylpiperidin-4-yl)-1,3-benzoxazole

[0291] Step (i): To a THF solution (30 mL) of compound 211 (1.46 g), isobutyl chloroformate (819 mg) and diisopropylethylamine (3.88 g) were added under ice-cooling, and the mixture was stirred for 1 hour. Then, 2-aminophenol (655 mg) was added under ice-cooling, and the mixture was heated and stirred at 70°C for 6 hours. The reaction solution was directly purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 212 (710 mg). LCMS: [M+H] + / Rt(min):335 / 2.28 (Method B)

[0292] Step (ii): A mixture of compound 212 (204 mg) and acetic acid (1.10 mL) was heated and stirred at 90°C for 2 hours, and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (2 mL), and trifluoromethanesulfonic acid (2.1 mL) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and aqueous sodium bicarbonate solution were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 213 (99 mg). LCMS: [M+H] + / Rt(min):217 / 1.36 (Method B)

[0293] Reference Example 93: 4-(4-chloro-5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride

[0294] Step (i): A DMF solution (3.3 mL) of compound 207 (500 mg) and N-chlorosuccinimide (240 mg) was stirred at room temperature for 3 days. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 214 (434 mg).

[0295] Step (ii): Using compound 214 (200 mg), the title compound 215 (120.1 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):241 / 0.65

[0296] Reference Example 94: 4-(4-chloro-5-methyl-1,2-oxazol-3-yl)-4-methylpiperidine hydrochloride Compound 216 was synthesized according to the method described in Reference Example 93 above, using compound 210 of Reference Example 91 instead of compound 207 in step (i) of Reference Example 93. LCMS: [M+H] + / Rt(min):215 / 0.51

[0297] Reference Example 95: 4-cyclopentyl-4-methylpiperidine hydrochloride

[0298] Step (i): To a mixture of compound 217 (700 mg) and THF (14 mL), lithium diisopropylamide (2 M, 5.18 mL) was added at −78° C., and the mixture was stirred at that temperature for 2 hours. Bromocyclopentane (1.23 mL) and potassium iodide (478 mg) were then added to the reaction mixture, which was then warmed to room temperature and stirred overnight. Water was then added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 218 (468 mg). LCMS: [M+H] + / Rt(min):312 / 1.26

[0299] Step (ii): To a mixture of lithium aluminum hydride (104 mg) and THF (3 mL), a mixture of compound 218 (371 mg) and THF (6 mL) was added under ice cooling, and the mixture was stirred for 4 hours. After confirming the disappearance of the raw materials, water (0.104 mL), 15% aqueous sodium hydroxide solution (0.104 ml), and water (0.312 mL) were added sequentially to the reaction mixture at 0° C. and stirred. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 219 (320 mg). LCMS: [M+H] + / Rt(min):284 / 1.06

[0300] Step (iii): To a mixture of compound 219 (314 mg), triethylamine (0.309 mL), and THF (5 mL), methanesulfonyl chloride (0.104 mL) was added and stirred at room temperature. After confirming the disappearance of the raw materials, water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to give the title compound 220 (290 mg). LCMS: [M+H] + / Rt(min):362 / 1.15

[0301] Step (iv): To a mixture of compound 220 (278 mg) and THF (3 mL), lithium triethylborohydride (0.99 M, 1.55 mL) was added and stirred at room temperature. The reaction mixture was then heated to 70°C. After confirming the disappearance of the raw materials, the mixture was cooled to 0°C and an aqueous ammonium chloride solution was added. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 221 (100 mg). LCMS: [M+H] + / Rt(min):268 / 1.42

[0302] Step (v): Using compound 221 (90 mg), the title compound 222 (58.5 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H]+ / Rt(min):168 / 0.62

[0303] Reference Example 96: 4-methyl-4-(2-methyl-1,3-oxazol-5-yl)piperidine

[0304] Step (i): A toluene solution of LHMDS (1 M, 4.35 mL) was added dropwise to a solution of compound 223 (1.00 g) in THF (10 mL) cooled to -78°C, and the mixture was stirred for 1 hour. Trimethylchlorosilane (0.495 g) was added, and the mixture was warmed to 0°C and stirred for 30 minutes. After cooling to -78°C again, bromine (0.662 g) was added, and the mixture was gradually warmed to room temperature. The reaction mixture was poured into a mixed solution of 10% aqueous sodium hypochlorite solution (7.5 mL) and saturated aqueous ammonium chloride solution (7.5 mL), and extracted with ethyl acetate. The resulting organic layer was evaporated under reduced pressure to give the title compound 224 (1.16 g). LCMS: [M+H] + / Rt(min):321 / 0.94

[0305] Step (ii): A mixture of compound 224 (0.10 g) and acetamide (0.020 g) was stirred at 130° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 225 (0.007 g). LCMS: [M+H] + / Rt(min):281 / 0.97

[0306] Step (iii): Using compound 225 (0.007 g), the title compound 226 (0.005 g) was obtained according to a method similar to that of Step (ii) of Reference Example 14. LCMS: [M+H] + / Rt(min):181 / 0.22

[0307] Reference Example 97: 4-methyl-4-[2-(propan-2-yl)-1,3-oxazol-5-yl]piperidine

[0308] Step (i): Using compound 224 (0.10 g), the title compound 227 (0.012 g) was obtained according to a method similar to that of Step (ii) of Reference Example 96. LCMS: [M+H] + / Rt(min):309 / 1.18

[0309] Step (ii): Using compound 227 (0.011 g), the title compound 228 (0.009 g) was obtained according to a method similar to that of Step (ii) of Reference Example 14. LCMS: [M+H] + / Rt(min):209 / 0.38

[0310] Reference Example 98: 4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine

[0311] Step (i): HATU (686 mg) and diisopropylethylamine (1.15 mL) were added to a mixture of compound 211 (399 mg), cyclopropanecarbohydrazide hydrochloride (269 mg), and DMF (5 mL), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 229 (520 mg). LCMS: [M+H] + / Rt(min):326 / 0.74

[0312] Step (ii): To a mixture of compound 229 (255 mg) and toluene (6 mL), Lawesson's reagent (349 mg) was added, and the mixture was heated and stirred under reflux for 1 hour. After cooling the reaction mixture to 0°C, aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: hexane / ethyl acetate) and then amino silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 230 (102 mg). LCMS: [M+H] + / Rt(min):324 / 1.08

[0313] Step (iii): Using compound 230 (92 mg), the title compound 231 (78 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):224 / 0.45

[0314] Reference Example 99: 4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine hydrochloride

[0315] Step (i): Using compound 211 (718 mg) and 2-amino-1-cyclopropylethan-1-one hydrochloride (400 mg), the title compound 232 (796 mg) was obtained according to a method similar to that of Step (i) of Reference Example 98. LCMS: [M+H] + / Rt(min):325 / 0.83

[0316] Step (ii): To a mixture of compound 232 (127 mg), pyridine (0.063 mL), and toluene (3 mL), Lawesson's reagent (205 mg) was added, and the mixture was heated and stirred under reflux for 14 hours. After cooling the reaction mixture to room temperature, aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 233 (76.3 mg). LCMS: [M+H] + / Rt(min):323 / 1.43

[0317] Step (iii): Using compound 233 (77 mg), the title compound 234 (66.5 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):223 / 0.67

[0318] Reference Example 100: 4-(2-cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine hydrochloride

[0319] Step (i): A methanol solution (6 mL) of compound 224 (531.6 mg) and cyclopropanecarbothioamide (168 mg) was stirred under reflux for 2.5 hours. The resulting mixture was allowed to cool to room temperature, and then saturated aqueous sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 235 (119 mg).

[0320] Step (ii): Using compound 235 (119 mg), the title compound 236 (136.8 mg) was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):223 / 0.57

[0321] Reference Example 101: Ethyl 4-methyl-1-({2-[4-(propan-2-yl)piperazin-1-yl]phenyl}carbamoyl)piperidine-4-carboxylate Step (i): Using compound 5 (0.237 g), the title compound 237 (0.357 g) was obtained according to the same method as in Step (i) of Reference Example 1. LCMS: [M+H] + / Rt(min):417 / 1.61 (Method B)

[0322] Reference Example 102: Ethyl 4-fluoro-1-({2-[4-(propan-2-yl)piperazin-1-yl]phenyl}carbamoyl)piperidine-4-carboxylate Step (i): Using compound 5 (0.179 g), the title compound 238 (0.040 g) was obtained according to the same method as in Step (i) of Reference Example 1. LCMS: [M+H] + / Rt(min):421 / 1.57 (Method B)

[0323] Reference Example 103 tert-Butyl (3aR,5s,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound A-2) and tert-butyl (3aR,5r,6aS)-5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound A-3)

[0324] To a solution of compound A-1 (331 mg) in 1,2-dimethoxyethane (6.7 mL) / ethanol (0.67 mL), p-toluenesulfonylmethyl isocyanide (373 mg) and potassium t-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 the title compounds A-2 (80 mg) and A-3 (59.4 mg). Compound A-2: LCMS: [M+H] + / Rt(min):237 / 0.89 Compound A-3: LCMS: [M+H] + / Rt(min):237 / 0.88

[0325] Reference Examples 104 to 105 The compounds of Reference Examples 104 to 105 shown in the following table were synthesized according to the method described in Reference Example 62 above, using Compound A-2 or A-3 of Reference Example 103 instead of Compound 171 in Step (i) of Reference Example 62.

[0326] Reference Example 104: (3aR,5s,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole Reference Example 105: (3aR,5r,6aS)-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)octahydrocyclopenta[c]pyrrole

[0327] Example 1: N-[2-(4-ethylpiperazin-1-yl)phenyl]-4-(4-methoxyphenyl)piperidine-1-carboxamide Using compound 239 (0.025 g) and compound 240 (0.021 g) and according to a method similar to that of Reference Example 23, step (iv), the title compound (0.031 g) was obtained. 1H-NMR (CDCl3) δ: 1.14 (3H, t, J = 7.2 Hz), 1.59-1.76 (3H, m), 1.94 (2H, d, J = 12.4 Hz), 2.48-2.75 (6H, m), 2.95-3.05 (6H, m), 3.80 (3H, s), 4.28 (2H, d, J = 13.2 Hz), 6.87 (2H, d, J = 7.2 Hz), 6.96 (1H, dt, J = 7.6, 5.6 Hz), 7.12-7.18 (4H, m), 8.22 (1H, dd, J = 8.4, 1.6 Hz), 8.26 (1H, s).

[0328] Examples 2 to 120: The compounds of Examples 2 to 120 shown in the following table were prepared in the same manner as in Example 1, using the corresponding commercially available compounds or compounds described in Reference Examples.

[0329] Example 2: 4-(1,3-benzoxazol-2-yl)-N-[2-(4-ethylpiperazin-1-yl)phenyl]piperidine-1-carboxamide Example 3: 4-(3,5-dimethoxyphenyl)-N-[2-(4-ethylpiperazin-1-yl)phenyl]piperidine-1-carboxamide Example 4: N-[2-(4-ethylpiperazin-1-yl)phenyl]-4-methyl-4-phenylpiperidine-1-carboxamide hydrochloride Example 5: 4-methyl-4-phenyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 6: Example 7: 4-cyano-4-phenyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 8: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 9: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 10: Example 11: N-{3-fluoro-2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 12: 4-methyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 13: 4-methyl-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[3-(pyridin-3-yl)-1,2,Example 14: 6-(4-methylphenyl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxamide Example 15: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(trifluoromethyl)phenyl]piperidine-1-carboxamide Example 16: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide Example 17: Example 18: 4-(4-methylphenyl)-N-{2-methyl-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 19: 4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 20: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 21: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 22: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide Example 23: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,Example 24: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 25: N-{2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 26: Rac-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 27: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-phenoxypiperidine-1-carboxamide Example 28: Rac-4-(4-methylphenyl)-N-{2-[3-methyl-4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 29: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(3-methylphenyl)piperidine-1-carboxamide Example 30: Rac-4-(4-methylphenyl)-N-{2-[2-methyl-4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 31: 4-(4-methylphenyl)-N-{2-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide hydrochloride Example 32: 3-(3-cyclopropyl-1,2,Example 33: N-{2-(dimethylcarbamoyl)-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 34: 4-(4-methylphenyl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]-6-(trifluoromethyl)phenyl}piperidine-1-carboxamide Example 35: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 36: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(pyridin-2-yl)piperidine-1-carboxamide Example 37: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(2-methylphenyl)piperidine-1-carboxamide Example 38: Methyl 2-{[4-(4-methylphenyl)piperidine-1-carbonyl]amino}-3-[4-(propan-2-yl)piperazin-1-yl]benzoate Example 39: N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 40: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[4-(propan-2-yl)phenyl]piperidine-1-carboxamide Example 41: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-8-carboxamide Example 42: N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 43: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 44: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 45: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 46: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-methylpyridin-2-yl)piperidine-1-carboxamide Example 47: N-{2-methoxy-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 48: N-{2-methoxy-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 49: 4-(1,3-Benzoxazol-2-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 50: 4-(1,3-Benzoxazol-2-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 51: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide Example 52: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 53: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 54: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 55: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 56: Example 57: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[2-(3,6-dihydro-2H-pyran-4-yl)-6-fluorophenyl]-4-methylpiperidine-1-carboxamide Example 57: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carbothioamide Example 58: N-[2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluorophenyl]-4-(4-methylphenyl)piperidine-1-carboxamide Example 59: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 60: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 61: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 62: N-(2-fluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}phenyl)-4-(4-methylphenyl)piperidine-1-carboxamide Example 63: N-(2-methoxy-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}phenyl)-4-(4-methylphenyl)piperidine-1-carboxamide Example 64: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carbothioamide Example 65: Example 66: 4-(1,3-benzoxazol-2-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 67: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 68: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-[2-fluoro-6-(6-methylpyridin-3-yl)phenyl]-4-methylpiperidine-1-carboxamide Example 69: N-{2-chloro-6-[6-(propan-2-yl)pyridin-3-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 70: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-[2-fluoro-6-(5-methylpyridin-3-yl)phenyl]-4-methylpiperidine-1-carboxamide Example 71: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-4-methylpiperidine-1-carboxamide hydrochloride Example 72: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[2-(propan-2-yl)pyrimidin-5-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 73: 4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 74: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopentyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 75: 4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 76: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 77: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 78: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 79: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 80: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 81: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide Example 82: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 83: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 84: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine-1-carboxamide Example 85: N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2-oxazol-3-yl)piperidine-1-carboxamide Example 86: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 87: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 88: N-{2-bromo-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 89: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamide Example 90: 4-(4-chloro-5-methyl-1,2-oxazol-3-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 91: 4-cyclopentyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 92: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(2-methyl-1,3-oxazol-5-yl)piperidine-1-carboxamide Example 93: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[2-(propan-2-yl)-1,3-oxazol-5-yl]piperidine-1-carboxamide Example 94: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine-1-carboxamide Example 95: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-fluoropiperidine-1-carboxamide Example 96: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(2-cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine-1-carboxamide Example 97: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide Example 98: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-methylpyrimidin-2-yl)piperidine-1-carboxamide Example 99: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)-1,4-diazepane-1-carboxamide Example 100: N-[2-(4-tert-butylpiperazin-1-yl)-6-chlorophenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 101: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamide Example 102: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine-1-carboxamide Example 103: 4-(4-chloro-5-cyclopropyl-1,2-oxazol-3-yl)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 104: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 105: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(cyclopropylmethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 106: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(2,2-dimethylcyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 107: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 108: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(1-methoxycyclopropyl)-1,2,4-Oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 109: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 110: Rac-N-(2-chloro-6-{[1-(propan-2-yl)pyrrolidin-3-yl]oxy}phenyl)-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 111: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 112: Rac-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 113: N-[2-chloro-6-(4-cyclopropylpiperazin-1-yl)phenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 114: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-[5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxamide Example 115: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 116: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide Example 117: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 118: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide Example 119: N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide Example 120: 4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide,

[0330] Example 121: 4-(4-methylphenyl)-N-[2-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide

[0331] Step (i): Using compound 2 (0.152 g), a crude product of the title compound 242 was obtained according to a method similar to that of Step (ii) of Reference Example 20. LCMS: [M+H] + / Rt(min):208 / 0.30

[0332] Step (ii): Using the crude product of compound 242 and according to a method similar to that of Reference Example 20, step (iii), the title compound 243 (0.202 g) was obtained. 1H-NMR (CDCl3) δ: 1.21 (6H, d, J = 6.1 Hz), 1.62-1.71 (2H, m), 1.84 (2H, m), 2.26 (3H, s), 2.55-2.69 (6H, m), 2.85 (4H, m), 2.95 (2H, m), 4.22 (2H, m), 6.88 (1H, m), 7.03-7.11 (6H, m), 8.14 (1H, m), 8.25 (1H, brs)

[0333] Examples 122 to 160: The compounds of Examples 122 to 160 shown in the table below were prepared in the same manner as in Example 121, using the corresponding commercially available compounds or compounds described in Reference Examples.

[0334] Example 122: N-[2-(4-ethylpiperazin-1-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide Example 123: 4-(4-methylphenyl)-N-[2-(4-methylpiperazin-1-yl)phenyl]piperidine-1-carboxamide Example 124: 4-(4-methylphenyl)-N-{2-[4-(oxolan-3-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Example 125: N-{2-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 126: N-{2-[4-(1-methoxypropan-2-yl)piperazin-1-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 127: N-{2-ethoxy-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 128: N-{2-[1-(butan-2-yl)piperidin-4-yl]-6-ethoxyphenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 129: 4-(4-methylphenyl)-N-{2-[(propan-2-yl)oxy]-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}piperidine-1-carboxamide Example 130: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 131: N-[2-chloro-6-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 132: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 133: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 134: N-{2-fluoro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 135: N-{2-[1-(1,1-difluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 136: N-{2-[1-(1,3-difluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 137: N-{2-fluoro-6-[1-(1-fluoropropan-2-yl)piperidin-4-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 138: N-{2-[1-(1,1-difluoropropan-2-yl)piperidin-4-yl]-6-fluorophenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 139: N-{2-fluoro-6-[1-(propan-2-yl)-2,5-dihydro-1H-pyrrol-3-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 140: N-[2-fluoro-6-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide Example 141: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 142: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 143: N-{2-chloro-6-[1-(1-fluoropropan-2-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 144: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide Example 145: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 146: N-{2-chloro-6-[1-(oxetan-3-yl)piperidin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 147: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 148: N-{2-chloro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide Example 149: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-fluorophenyl}-4-methylpiperidine-1-carboxamide Example 150: N-{2-fluoro-6-[(1S,4S)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 151: N-{2-fluoro-6-[(1R,4R)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 152: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[(1R,4R)-5-(propan-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 153: N-[2-(4-ethyl-1,4-diazepan-1-yl)phenyl]-4-(4-methylphenyl)piperidine-1-carboxamide Example 154: N-{2-fluoro-6-[8-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide Example 155: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[8-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]phenyl}-4-methylpiperidine-1-carboxamide Example 156: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[2-(4-ethyl-1,4-diazepan-1-yl)phenyl]-4-methylpiperidine-1-carboxamide Example 157: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-[2-(4-propyl-1,4-diazepan-1-yl)phenyl]piperidine-1-carboxamide Example 158: N-{2-chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-cyano-4-methylpiperidine-1-carboxamide Example 159: N-[2-chloro-6-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-4-cyano-4-methylpiperidine-1-carboxamide Example 160: N-(2-chloro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}phenyl)-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide,

[0335] Example 161: N-{2-fluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl}-4-(4-methylphenyl)piperidine-1-carboxamide

[0336] Step (i): A mixture of compound 150 (0.079 g), palladium hydroxide (0.020 g), and ethanol (2 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was used directly in the next reaction.

[0337] Step (ii): Using the crude product of compound 244 and according to a method similar to that of Reference Example 20, step (iii), the title compound 245 (0.066 g) was obtained. 1 H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.61 (3H, s), 1.74 (2H, ddd, J = 25.4, 13.1, 4.0 Hz), 1.83-1.96 (6H, m), 2.33 (3H, s), 2.55 (2H, d, J = 9.8 Hz), 2.62-2.76 (4H, m), 3.03 (2H, ddd, J = 13.1, 13.1, 2.2 Hz), 3.60-3.65 (2H, m), 4.29-4.37 (2H, m), 6.17 (1H, s), 6.66 (1H, d, J = 8.3 Hz), 6.77 (1H, dd, J = 8.6, 8.3 Hz), 6.94-7.01 (1H, m), 7.11 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz).

[0338] Example 162: 4-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide hydrochloride

[0339] Step (i): A mixture of (Z)-N'-hydroxyacetimidamide (0.0125 g), sodium hydride (0.0134 g), and THF (1 mL) was stirred under reflux for 2 hours. After cooling to room temperature, compound 237 (0.035 g) from Reference Example 101 was added, and the mixture was stirred under reflux for 5 hours. After cooling to room temperature, water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 246 (0.005 g). LCMS: [M+H] + / Rt(min):427 / 0.70

[0340] Examples 163-164: The compounds of Examples 163-164 shown in the table below were prepared in the same manner as in Example 162, using the corresponding commercially available compounds or compounds described in Reference Examples.

[0341] Example 163: 4-methyl-4-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide hydrochloride Example 164: 4-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide

[0342] Example 165: 4-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-{2-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide Sodium hydroxide (0.027 g) was added to a mixture of compound 237 (0.056 g) from Reference Example 101, THF (0.5 mL), MeOH (0.5 mL), and water (0.5 mL), and the mixture was stirred at 60°C for 1 hour. The mixture was neutralized with 10% aqueous hydrochloric acid and extracted with a chloroform / methanol (4:1) solution. The solvent was concentrated under reduced pressure, and the resulting residue was dissolved in DMF (0.5 mL). Diisopropylethylamine (0.059 mL), acetohydrazine (0.020 g), and HATU (0.128 g) were added, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (0.5 mL). Triphenylphosphine (0.071 g), triethylamine (0.057 mL), and carbon tetrachloride (0.052 mL) were added, and the mixture was stirred under reflux for 7 hours. After cooling, the mixture was concentrated under reduced pressure and the resulting residue was purified by aminosilica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 247 (0.010 g). LCMS: [M+H] + / Rt(min):427 / 1.43

[0343] Example 166: 4-(4-methylphenyl)-N-{2-[(2R,5S)-5-(propan-2-yl)morpholin-2-yl]phenyl}piperidine-1-carboxamide

[0344] Step (i): Using compound 41 (0.036 g), the title compound 248 (0.045 g) was obtained according to a method similar to that of Step (iv) of Reference Example 23. LCMS: [M+H] + / Rt(min):522 / 1.25

[0345] Step (ii): Using compound 248 (0.042 g) and according to a method similar to that of Reference Example 14, step (ii), the title compound 249 (0.031 g) was obtained. 1H-NMR (CDCl3) δ: 0.92 (3H, d, J = 7.0 Hz), 0.97 (3H, d, J = 7.0 Hz), 1.51-1.62 (1H, m), 1.66-1.77 (2H, m), 1.86-1.94 (2H, m), 2.33 (3H, s), 2.53-2.60 (1H, m), 2.67-2.76 (1H, m), 2.95-3.04 (2H, m), 3.07 (1H, dd, J = 12.5, 2.7 Hz), 3.16 (1H, dd, J = 11.3, 11.3 Hz), 3.48 (1H, dd, J = 10.4, 10.4 Hz), 4.09 (1H, dd, J = 11.3, 2.7 Hz), 4.21-4.32 (2H, m), 4.53 (1H, dd, J = 10.4, 3.0 Hz), 6.95 (1H, dd, J = 7.3, 7.3 Hz), 7.06 (1H, d, J = 7.3 Hz), 7.11 (4H, d, J = 8.5 Hz), 7.14 (4H, d, J = 8.5 Hz), 7.27 (1H, dd, J = 7.3, 7.3 Hz), 8.10 (1H, d, J = 8.5 Hz), 8.71 (1H, s).

[0346] Examples 167-168: The compounds of Examples 167-168 shown in the table below were prepared in the same manner as in Example 166, using the corresponding commercially available compounds or compounds described in Reference Examples.

[0347] Example 167: Rac-N-{2-chloro-6-[(2R,5S)-5-(propan-2-yl)morpholin-2-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide Example 168: Rac-N-{2-chloro-6-[(2R,5R)-5-(propan-2-yl)morpholin-2-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[0348] Examples 169-170: Using the compounds described in the corresponding Reference Examples, the compounds of Examples 169-170 shown in the table below were prepared in the same manner as in Example 1.

[0349] Example 169: (3aR,5s,6aS)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide Example 170: (3aR,5r,6aS)-N-{2-chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

[0350] 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 left at room temperature for 2 hours. Orexin A 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) set at 100%.

[0351] Test Results: The orexin type 2 receptor agonism of the compounds obtained in Examples 1 to 168 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 Examples 1 to 168 at 10 μM is shown in the table below as a relative value when the luminescence value upon treatment with Orexin A (100 pM) was set to 100%.

[0352] 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. 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) set at 100%.

[0353] Test Results: The orexin type 2 receptor agonism of the compounds obtained in Examples 169 to 170 was measured, and it was observed that the compounds of the present invention exhibited agonistic activity against the orexin type 2 receptor. The orexin type 2 receptor agonism of the compounds obtained in Examples 169 to 170 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%.

[0354] The compounds of the present invention exhibit strong agonistic activity against orexin receptors and are useful as therapeutic or preventive agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, and the like.

Claims

1. Formula (1): 【Chemical 1】 [wherein, R １ represents an optionally substituted C ６－１０ aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C ３－６ saturated carbocyclic group, an optionally substituted 4- to 10-membered saturated heterocyclic group, or cyano; L １ and L ２ each independently represents a single bond, methylene (the methylene may be substituted with one or more identical or different C １－６ alkyl), -NR ６ -, -C(=O)-, -OC(=O)-, -SO-, -SO ２ -, -S-, or an oxygen atom; R ２ represents a hydrogen atom, a hydroxy group, a halogen atom, cyano, optionally substituted C １－６ alkyl, optionally substituted C １－６ alkoxy, C(=O)NR ３ R ４ or C(=O)O-R ５ ; R ３ 、 R ４ 、 R ５ 、 R ６ each independently represents a hydrogen atom or an optionally substituted C １－６ alkyl; Ring E represents an optionally substituted 5- to 10-membered aromatic heterocyclic group or an optionally substituted 4- to 10-membered saturated heterocyclic group; Ring G represents an optionally substituted C ６－１０ aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C ３－６ saturated carbocyclic group, or an optionally substituted 4- to 10-membered saturated heterocyclic group; A represents an oxygen atom or a sulfur atom] A compound represented by the formula or a pharmaceutically acceptable salt thereof.

2. R ２ to R ６ In the “optionally substituted C １－６ alkyl”, the substitutable substituents are each independently one or more identical or different halogen atoms, hydroxy groups, C １－６ alkoxy, or C ３－７ cycloalkyl, and in the “optionally substituted C １－６ alkoxy”, the substitutable substituents are each independently one or more identical or different halogen atoms, hydroxy groups, or C ３－７ cycloalkyl, R １ of C 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, a hydroxy group, C ６－１０ An aromatic carbocyclic group (the C ６－１０ The aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ Cycloalkyl), C １－６ Alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ Alkoxy or C ３－７ Cycloalkyl), C ３－７ Cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ Cycloalkyl), C １－６ Alkylamino (the alkyl group in the alkylamino may be substituted with a halogen atom, a hydroxy group or C ３－７ Cycloalkyl), C ３－７ Cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ Cycloalkyl), cyano, C １－６ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C ３－７ Cycloalkyl) and a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ Alkyl, C １－６ Alkoxy or C ３－７ Cycloalkyl) and are one or more substituents selected from the group consisting of C of ring E and ring G ６－１０ An aromatic carbocyclic group, a 5- to 10-membered aromatic heterocyclic group, C ３－６ The 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 １－６ 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 １－６ Alkyl, C １－６ Alkoxy or C ３－７ Cycloalkyl), C １－６ Alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, a hydroxy group, or C ３－７ Cycloalkyl), C １－６ Alkylamino (the alkyl group in the alkylamino may be substituted with a halogen atom, 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 １－６ Alkyl, C １－６ 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 １－６ Alkyl, C １－４ Alkoxy or C ３－７ Cycloalkyl), and are one or more substituents selected from the group consisting of, 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. Formula (2): [Chemical 2] [wherein, R ２ represents a hydroxy group, a halogen atom, cyano, an optionally substituted C １－４ alkyl, an optionally substituted C １－４ alkoxy, C(=O)NR ３ R ４ or C(=O)OR ５ ; R １ 、L １ 、L ２ 、R ３ 、R ４ 、R ５ 、ring E, ring G, and A have the same definitions as in claim 1 The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula.

4. R １ is cyano or one of the following formulas (1a-1) to (1a-6): 【Chemical Formula 3】 [wherein, X １ ~X ６ each independently represents a nitrogen atom or CR ａ４ ; Q １ and Q ２ represents an oxygen atom, -NR ａ５ -, or a sulfur atom; Q ３ represents CH or a nitrogen atom; R ａ１ to R ａ５ each independently represents (when there are a plurality of CR ａ４ each R ａ４ also independently represents), a hydrogen atom, a halogen atom, a C ６－１０ aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), a C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－４ alkoxy or C ３－７ cycloalkyl), a C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), cyano, C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy), a C ３－７ cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), or a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy). The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

5. Ring G is represented by the following formula (1b-1) to (1b-7): 【Chemical Formula 4】 [wherein, W １ and W ２ each independently represents NR ｂ７ , an oxygen atom or CR ｂ８ R ｂ９ ; W ３ , W ４ , W ５ and W ６ each independently represents a nitrogen atom or CR ｂ１０ ; R ｂ１ ~R ｂ１０ each independently represents a hydrogen atom, a halogen atom, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－４ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ６－１０ aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), and R ｂ２ and R ｂ３ may be bonded to the same carbon atom if chemically possible; Here, R ｂ２ and R ｂ３ may be bonded via C １－６ alkylene to form any bicyclic structure possible chemically among a condensed ring, a spiro ring, or a bridged ring; n, m and p each independently represent an integer of 1 or 2] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

6. Ring E is represented by the following formula (1c-1) to (1c-4): 【Chemical Formula 5】 [wherein, R ｃ１ 、 R ｃ２ 、 R ｃ３ and R ｃ４ each independently represents a hydrogen atom, a halogen atom, cyano, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ６－１０ aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), and R ｃ１ and R ｃ２ may be bonded to the same carbon atom if chemically possible; Here, R ｃ１ and R ｃ２ may be bonded via C １－６ alkylene to form any bicyclic structure possible chemically among a condensed ring, a spiro ring, or a bridged ring. The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

7. Ring E is represented by the following formula (1c-11) to (1c-41): 【Chemical Formula 6】 [wherein, R ｃ４ each independently represents a halogen atom, cyano, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), C ６－１０ aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy)] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

8. Formula (3): [Chemical Formula 7] [wherein, R ２ represents C which may be substituted with a halogen atom １－６ alkoxy; R １ , A, L １ and ring G have the same definition as in claim 1 The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula.

9. L １ is either a single bond, -CH ２ -, or an oxygen atom, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

10. R １ is represented by the following formulas (1a-1) to (1a-3): 【Chemical 8】 [wherein, X １ to X ５ each independently represents a nitrogen atom or CR ａ４ ; Q １ and Q ２ each independently represents an oxygen atom or a sulfur atom; R ａ１ represents a hydrogen atom, a halogen atom, cyano, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy) or C １－４ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy); R ａ４ is (when there are a plurality of CR ａ４ each R ａ４ is independently), a hydrogen atom, a halogen atom, C ６－１０ an aromatic carbon ring group (the C ６－１０ aromatic carbon ring group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkoxy or C ３－７ cycloalkyl), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy), C ３－７ cycloalkoxy (the cycloalkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, C １－６ alkoxy) or a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy). The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

11. Ring G is represented by the following (1b-1) to (1b-3): 【Chemical Formula 9】 [wherein, R ｂ１ ~R ｂ３ each independently represents a hydrogen atom, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), C ６－１０ aromatic carbocyclic group (the C ６－１０ aromatic carbocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy)] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is any one selected from.

12. R ２ The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is any halogen atom of F, Cl, or Br, and A is an oxygen atom.

13. R １ is represented by the following formula (1a-1): 【Chemical 10】 [wherein, R ａ１ represents a hydrogen atom, a halogen atom, cyano, C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy) or C １－４ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy)] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula.

14. R １ is the following formula (1a-2): 【Chemical Formula 11】 [wherein, X １ ~X ３ each independently represents a nitrogen atom or CR ａ４ ; Q １ represents an oxygen atom or a sulfur atom; R ａ４ has the same definition as in claim 10 represents; L １ The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L is a single bond.

15. R １ is represented by the following formulas (1a-21) to (1a-25): 【Chemical Formula 12】 [wherein, R ａ４ has the same definition as in claim 10] is any one selected from; L １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

16. R ａ４ (When there are a plurality of CR ａ４ , each R ａ４ is independently) is 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, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkoxy or C ３－７ cycloalkyl), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), or a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), which is the compound according to claim 15 or a pharmaceutically acceptable salt thereof.

17. R １ is represented by the following formula (1a-3): 【Chemical 13】 [wherein, X ４ and X ５ are as defined in claim 10] represents; L １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

18. R １ is represented by the following formulas (1a-31) to (1a-34): 【Chemical Formula 14】 [wherein, R ａ４ has the same definition as in claim 10] The compound according to Claim 17, or a pharmaceutically acceptable salt thereof, which is any one selected from.

19. R ａ４ (When there are a plurality of CR ａ４ , each R ａ４ is independently) is C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkoxy or C ３－７ cycloalkyl), C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, hydroxy groups, C １－６ alkyl, or C １－６ alkoxy), C １－６ alkoxy (the alkoxy may be substituted with one or more identical or different halogen atoms, hydroxy groups, or C １－６ alkoxy), the compound according to claim 18 or a pharmaceutically acceptable salt thereof.

20. Ring G is represented by the following formula (1b-2): 【Chemical Formula 15】 [wherein, R ｂ２ has the same definition as in claim 11] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula.

21. Ring G is represented by the following formula (1b-1): 【Chemical Formula 16】 [wherein, R ｂ１ is C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy)] The compound according to Claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula.

22. The ring G is represented by the following formula (1b-3): 【Chemical 17】 [In the formula, R ｂ３ represents C １－６ alkyl (the alkyl may be substituted with one or more identical or different halogen atoms, or C １－６ alkoxy), a 5- to 10-membered aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy), or C ３－７ cycloalkyl (the cycloalkyl may be substituted with one or more identical or different halogen atoms, C １－６ alkyl, or C １－６ alkoxy)] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the formula (1b-3).

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: N-{2-Fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide N-{2-Fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)piperidin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2-oxazol-3-yl)-N-{2-fluoro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethyl-N-{2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}piperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-ethylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-(5-cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide N-{2-Chloro-6-[4-(propan-2-yl)piperazin-1-yl]phenyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide N-{2-Chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxamide N-{2-Chloro-6-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide.

25. A pharmaceutical composition comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

26. A therapeutic agent for a disease involving orexin type 2 receptor, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

27. A compound according to claim 1, 2, 23 or 24, or a pharmaceutically acceptable salt thereof, for use in treating 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, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced 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 of anesthesia, sleep disturbance, sleep problems, insomnia, fragmented sleep, nocturnal intermittent myoclonus, REMSleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, abnormal sleep, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sundowning, diseases related to the circadian rhythm, fibromyalgia, conditions resulting from reduced sleep quality, overeating, binge eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart palpitations, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, reduced fertility, infertility, male hypogonadism, sexual and reproductive function disorders such as female hirsutism, fetal defects related to maternal obesity, gastrointestinal motility diseases such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vasculature, atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, renal cancer, risk of secondary consequences of obesity such as reducing the risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genitals / Therapeutic agents for diseases of the urinary system, diseases related to sexual function or fertility, mood disorders, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cerebral deficits after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle contracture, tremor, epilepsy, disorders associated with muscle spasm, delirium, amnestic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug dependence, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, or traumatic brain injury.

28. A therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

29. A therapeutic agent for narcolepsy, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

30. A therapeutic agent for idiopathic hypersomnia, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

31. A therapeutic agent for hypersomnia associated with Parkinson's disease, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

32. A therapeutic agent for hypersomnia associated with Lewy body dementia, comprising the compound according to claim 1, 2, 23 or 24 or a pharmaceutically acceptable salt thereof.

33. Use of the compound according to claim 1, 2, 23 or 24 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.

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