Cycloalkyl urea derivatives

Abstract

The present invention relates to a drug for treating or preventing diseases related to orexin receptors, particularly orexin type 2 receptors, comprising a novel compound having a urea structure or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the present invention relates to a drug for treating or preventing narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and the like.

Description

Technical Field

[0001] The present invention relates to a drug for treating or preventing diseases related to orexin receptors, particularly orexin type 2 receptors, comprising a novel compound having a urea structure or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the present invention relates to a drug for treating or preventing narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, and the like. Background Art

[0002] Orexin is a neuropeptide produced particularly in specific neurons distributed throughout the lateral hypothalamus and its adjacent areas. Orexin is an endogenous ligand of the orexin receptor, which is a G-protein coupled receptor mainly present in the brain, and binds to the orexin receptor. It is known that the orexin receptor has two subtypes, type 1 and type 2 (Non-patent reference 1).

[0003] It has been reported that narcolepsy-like symptoms in transgenic mice whose orexin neurons undergo degeneration are improved by intraventricular injection of orexin peptide (Non-patent Reference 2), and that narcolepsy-like symptoms can be induced by knocking out pro-orexin, which is a precursor protein of orexin (Non-patent Reference 3), and furthermore, the orexin concentration in the cerebrospinal fluid of narcolepsy patients is significantly reduced (Non-patent Reference 4). Thus, it has been suggested that narcolepsy can be induced by a deficiency of orexin.

[0004] In addition, it has been reported that there is a mutation of the orexin 2 receptor in dogs suffering from hereditary narcolepsy (non-patent reference 5), which suggests that the orexin 2 receptor is involved in the sleep-wake function. In addition, it was revealed that narcolepsy-like symptoms were induced in orexin 2 receptor KO mice (non-patent reference 6), which strongly suggests that stimulation of the orexin 2 receptor is involved in the sleep-wake function. Thus, orexin 2 receptor agonists are expected to be promising therapies for patients presenting hypersomnia-like symptoms such as narcolepsy.

[0005] Recently, compounds having orexin 2 receptor agonistic action have been reported (Patent Reference 1). Background Art

[0007] (Patent References)

[0008] [Patent Document 1] WO 2017 / 135306

[0009] (Non-patent reference)

[0010] [Non-patent document 1] Cell, Vol. 92, 573-585, 1998

[0011] [Non-patent document 2] Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004

[0012] [Non-patent document 3] Cell, Vol. 98, 437-451, 1999

[0013] [Non-patent document 4] THE LANCET, Vol. 355, 39-40, 2000

[0014] [Non-patent document 5] Cell, Vol. 98, 365-376, 1999

[0015] [Non-patent document 6] Neuron, Vol. 38, pp. 715-730, 2003

[0016] [Non-patent document 7] Brain, Vol. 130, 1577-1585, 2007

[0017] [Non-patent document 8] Neuroscience Letters, Vol. 569, 68-73, 2014. Summary of the invention

[0018] (Technical Issues)

[0019] An object of the present invention may be to provide a drug for treating or preventing diseases associated with orexin type 2 receptor (eg, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, etc.).

[0020] (Solution to the problem)

[0021] The inventors of the present invention have conducted extensive studies to achieve the above object, and have found that a compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, it may be referred to as "the compound of the present invention") has therapeutic and preventive effects on diseases associated with orexin type 2 receptor (e.g., narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, etc.). Based on the novel findings, the present invention has been completed.

[0022] The present invention can be shown as follows.

[0023] (Project A1)

[0024] A compound of formula (1) or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in

[0027] R 1is optionally substituted C 6-10 an aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C 3-6 saturated carbocyclyl, optionally substituted 4- to 10-membered saturated heterocyclyl, or cyano;

[0028] L 1 and L 2 each independently is a single bond, -CH2- or an oxygen atom;

[0029] R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group or an optionally substituted C 1-4 Alkyl; or

[0030] When L 1 When it is a single bond, R 1 and R 2 can be combined together as a spiro ring to form an optionally substituted C 3-6 saturated carbocyclic ring or optionally substituted 4- to 10-membered saturated heterocyclic ring;

[0031] R 3 and R 4 are independently a hydrogen atom, a halogen atom, a cyano group, -(C=O)NR 5 R 6 , carboxyl, -(C=O)OR 7 , optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, where R 3 and R 4 Can be bonded to the same carbon atom if chemically possible; or

[0032] When R 3 and R 4 When bound to different ring carbon atoms, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a fused ring or a bridged ring;

[0033] R 5 To R 7 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-4 alkyl;

[0034] n is an integer of 1 or 2;

[0035] Ring G is optionally substituted C 6-10 an aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C 3-6saturated carbocyclyl or optionally substituted 4- to 10-membered saturated heterocyclyl;

[0036] A 1 is an oxygen atom or a sulfur atom;

[0037] A 2 is an oxygen atom or -NH-;

[0038] A 3 is -CH-, a nitrogen atom or a carbon atom; and

[0039] Bonds accompanied by a dashed line are each independently a single bond or a double bond.

[0040] (Project A2)

[0041] The compound of Item A1 or a pharmaceutically acceptable salt thereof, wherein

[0042] In R 2 -R 7 In the above, "optionally substituted C 1-4 The optional substituents of "alkyl" are the same or different one or more substituents selected from the following: halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl; and “optionally substituted C 1-4 The optional substituents of the "alkoxy" are the same or different one or more substituents selected from the following: halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl;

[0043] In R 1 In the above, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of the "optionally substituted 4- to 10-membered saturated heterocyclic group" and the "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 3-7Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, and C 3-7 cycloalkyl) and a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 cycloalkyl); and

[0044] In ring G, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "optionally substituted 4- to 10-membered saturated heterocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from a halogen atom, a C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C3-7 Cycloalkyl) and C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 or when there are multiple optional substituents, two of them may be C 1-6 The alkylene groups are taken together to form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings.

[0045] (Item A3)

[0046] The compound of item A1 or A2 or a pharmaceutically acceptable salt thereof, wherein

[0047] In R 2 -R 7 In the above, "optionally substituted C 1-4 The optional substituents of the "alkyl" group are the same or different and are one or more substituents selected from the following: halogen atoms and C 1-4 Alkoxy; and “optionally substituted C 1-4 The optional substituents of the "alkoxy" are the same or different one or more substituents selected from the following: halogen atoms and C 1-4 alkyl;

[0048] In R 1 In the above, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "saturated carbocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), cyano, C1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, and C 3-7 cycloalkyl) and a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 cycloalkyl); and

[0049] In ring G, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of the "optionally substituted 4- to 10-membered saturated heterocyclic group" and the "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from the following: a halogen atom, a C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) and C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 or when there are multiple optional substituents, two of them can be C 1-6 The alkylene groups are taken together to form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings.

[0050] (Item A4)

[0051] The compound of any one of Items A1 to A3 or a pharmaceutically acceptable salt thereof, wherein

[0052] R 1Selected from the following formulas (1a-1) to (1a-4):

[0053]

[0054] in

[0055] X 1 -X 7 are independently a nitrogen atom or CR a6 ;

[0056] Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom;

[0057] R a1 -R a7 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein R a4 and R a5 can be bound to the same carbon atom if chemically possible; and when X 1 and X 3 All CR a6 When two R a6Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring of

[0058] q 1 Is an integer of 1 or 2.

[0059] (Item A5)

[0060] The compound of any one of Items A1 to A4 or a pharmaceutically acceptable salt thereof, wherein

[0061] Ring G is selected from the following (1b-1) to (1b-4):

[0062]

[0063] in

[0064] W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ;

[0065] W 2 , W 4 and W 8 YesNR b5 , oxygen atom or CR b6 R b7 ;

[0066] R b1 -R b7 Each independently is (if there are multiple CR b4 , then each R b4 Also independently) a hydrogen atom, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups are taken together to form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings.

[0067] (Item A6)

[0068] The compound of any one of Items A1 to A5 or a pharmaceutically acceptable salt thereof, which has the formula (2):

[0069]

[0070] in

[0071] R 1 Selected from the following formulas (1a-1) to (1a-4):

[0072]

[0073] in

[0074] X 1 -X 7 are independently a nitrogen atom or CR a6 ;

[0075] Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom;

[0076] R a1 -R a7 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C1-4 Alkoxy), C 3-6 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein R a4 and R a5 can be bound to the same carbon atom if chemically possible; and when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring of

[0077] q 1 is an integer of 1 or 2;

[0078] L 1 and L 2 each independently is a single bond, -CH2- or an oxygen atom;

[0079] R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group or an optionally substituted C 1-4 alkyl;

[0080] R 3 and R 4 are independently a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl) or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl); wherein R 3 and R4 can be bound to the same carbon atom if chemically possible; and when R 3 and R 4 When bound to different carbon atoms in the ring, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a fused ring or a bridged ring;

[0081] Ring G is selected from the following (1b-1) to (1b-4):

[0082]

[0083] in

[0084] W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ;

[0085] W 2 , W 4 and W 8 YesNR b5 , oxygen atom or CR b6 R b7 ;

[0086] R b1 -R b7 Each independently is (if there are multiple CR b4 , then each R b4 Also independently) a hydrogen atom, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings;

[0087] A 1 is an oxygen atom or a sulfur atom;

[0088] A 2 is an oxygen atom or -NH-; and

[0089] A 3 It is -CH-, a nitrogen atom or a carbon atom.

[0090] (Item A7)

[0091] The compound of Item A6 or a pharmaceutically acceptable salt thereof, wherein

[0092] R 1 Selected from the following formulas (1a-1), (1a-2) and (1a-3-1):

[0093]

[0094] in

[0095] X 1 -X 6 are independently a nitrogen atom or CR a6 ;

[0096] Q 1 and Q 2 is an oxygen atom, -NR a7 - or a sulfur atom; and

[0097] R a1 -R a3 , R a6 and R a7 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring is fused.

[0098] (Item A8)

[0099] The compound of item A6 or A7 or a pharmaceutically acceptable salt thereof, wherein

[0100] Ring G is selected from the following (1b-1), (1b-2) and (1b-4):

[0101]

[0102] in

[0103] W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ;

[0104] W 2 and W 4 YesNR b5 or CR b6 R b7 ;and

[0105] R b1 , R b2 and R b4 -R b7Each independently is (if there are multiple CR b4 , then each R b4 Also independently) a hydrogen atom, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups are taken together to form a bridged bicyclic structure.

[0106] (Item A9)

[0107] The compound of any one of Items A6 to A8 or a pharmaceutically acceptable salt thereof, wherein

[0108] Ring G is selected from the following (1b-1) and (1b-2):

[0109]

[0110] in

[0111] W 1 and W 3 is a nitrogen atom or CR b4 ;

[0112] W 2 and W 4 YesNR b5 or CR b6 R b7 ;and

[0113] Rb1 , R b2 and R b4 -R b7 are independently hydrogen atoms, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups are taken together to form a bridged bicyclic structure.

[0114] (Item A10)

[0115] The compound of any one of Items A1 to A9 or a pharmaceutically acceptable salt thereof, which has the formula (3):

[0116]

[0117] in

[0118] R 1 It is the following formula (1a-1), (1a-2) or (1a-3-1):

[0119]

[0120] in

[0121] X 1 -X 6 are independently a nitrogen atom or CR a6 ;

[0122] Q 1 and Q 2 is an oxygen atom or a sulfur atom;

[0123] R a1 -R a3 and R a6 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy); wherein when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring is fused;

[0124] L 1 and L 2 each independently is a single bond or an oxygen atom;

[0125] R 2 is a hydrogen atom, a halogen atom, or a C which may be optionally substituted by the same or different one or more substituents. 1-4 Alkyl, wherein the substituent is selected from halogen atoms and hydroxyl groups;

[0126] R 3 and R 4 each independently a halogen atom;

[0127] Ring G is the following (1b-1), (1b-2-1), (1b-2-2) or (1b-2-3):

[0128]

[0129] in

[0130] R b5 is a hydrogen atom or a C which may be optionally substituted by one or more substituents which may be the same or different. 1-6 Alkyl, the substituent is selected from halogen atoms and C 1-4 alkoxy; and

[0131] A 1 It is an oxygen atom or a sulfur atom.

[0132] (Item A11)

[0133] The compound of any one of Items A4 to A10 or a pharmaceutically acceptable salt thereof, wherein

[0134] R 1 is formula (1a-2), and

[0135] R a1 It is a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy) or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 alkyl).

[0136] (Item A12)

[0137] The compound of item A10 or A11 or a pharmaceutically acceptable salt thereof, wherein

[0138] R 1 is formula (1a-2), and

[0139] X 4 and X 5 They are all nitrogen atoms.

[0140] (Item A13)

[0141] The compound of any one of Items A10 to A12 or a pharmaceutically acceptable salt thereof, wherein

[0142] Ring G is of formula (1b-1-1), and

[0143] R b5 is C which may be optionally substituted by one or more halogen atoms which may be the same or different 1-4 alkyl.

[0144] (Item A14)

[0145] The compound of any one of Items A10 to A12 or a pharmaceutically acceptable salt thereof, wherein

[0146] Ring G is of formula (1b-2-1), and

[0147] R b5 is a hydrogen atom, or a C which may be optionally substituted by one or more substituents which may be the same or different. 1-4 Alkyl, the substituent is selected from halogen atoms and C 1-4 Alkoxy.

[0148] (Item A15)

[0149] The compound of any one of Items A1 to A12 or a pharmaceutically acceptable salt thereof, which has the formula (4):

[0150]

[0151] in

[0152] R 1 is the following (1a-2-1):

[0153]

[0154] in

[0155] Q 2 is an oxygen atom or a sulfur atom;

[0156] R a2 It is C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy) or cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy);

[0157] R 2 It is C 1-4 alkyl;

[0158] Ring G is the following (1b-1-1) or (1b-2-1):

[0159]

[0160] in

[0161] R b5is C which may be optionally substituted by one or more substituents which may be the same or different 1-4 Alkyl, the substituent is selected from halogen atoms and C 1-4 alkyl; and

[0162] L 2 It is a single bond or an oxygen atom.

[0163] (Item A16)

[0164] The compound of Item A15 or a pharmaceutically acceptable salt thereof, wherein

[0165] R a2 is C which may be optionally substituted by one or more substituents which may be the same or different 3-7 Cycloalkyl, the substituents are selected from halogen atoms, and

[0166] R 2 It's methyl.

[0167] (Item A17)

[0168] The compound of Item A15 or A16 or a pharmaceutically acceptable salt thereof, wherein

[0169] R a2 is a cyclopropyl group which may be optionally substituted by one or more substituents which are the same or different and which are selected from halogen atoms, and

[0170] R 2 It's methyl.

[0171] (Item A18)

[0172] The compound of any one of Items A15 to A17 or a pharmaceutically acceptable salt thereof, wherein

[0173] Ring G is of formula (1b-2-1), and

[0174] R b8 It is isopropyl.

[0175] (Item A19)

[0176] The compound of any one of Items A15 to A17 or a pharmaceutically acceptable salt thereof, wherein

[0177] Ring G is of formula (1b-1-1),

[0178] R b5 is isopropyl, and

[0179] L 2 It's an oxygen atom.

[0180] (Item A20)

[0181] The compound of any one of Items A15 to A19 or a pharmaceutically acceptable salt thereof, wherein Q 2 It's an oxygen atom.

[0182] (Item A21)

[0183] The compound of Item A1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0184] Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0185]

[0186] Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0187]

[0188] Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0189]

[0190] Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0191]

[0192] Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0193]

[0194] Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0195]

[0196] Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0197]

[0198] Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0199]

[0200] Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0201]

[0202] Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0203]

[0204] Example 79: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide

[0205]

[0206] Example 80: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide

[0207] .

[0208] (Item A22)

[0209] The compound of Item A1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0210] Example 64: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0211]

[0212] Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0213]

[0214] Example 71: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0215]

[0216] Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0217]

[0218] Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0219]

[0220] Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0221]

[0222] Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0223]

[0224] Example 76: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide

[0225] .

[0226] (Item A23)

[0227] A medicament for treating a disease associated with an orexin receptor, comprising a compound according to any one of Items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0228] (Item A24)

[0229] Drugs used to treat the following conditions: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome including excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen Encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperisolating obesity, protoplasmic obesity, pituitary obesity, protoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, fragmented sleep, nocturnal myoclonus, REM sleep disruption, jet lag, jet lag syndrome, shift work sleep disorders, sleep disorders, sleep terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunset syndrome, circadian rhythm-related diseases, fibromyalgia, conditions caused by reduced sleep quality, binge eating disorder, compulsive eating disorders, obesity-related diseases, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, cholelithiasis, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, hypogonadism in males, sexual / reproductive dysfunction such as hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as respiratory distress, inflammation such as systemic vascular inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, secondary risks of obesity such as risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia,Flushing, night sweats, genital / urinary disorders, disorders related to sexual function or fertility, dysthymic disorder, 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 brain defects after heart bypass surgery or heart transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle Convulsion, tremor, epilepsy, disorders related to muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Tourette syndrome, chorea, myoclonus, convulsions, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, brain edema, pain, bone pain, joint pain, toothache, cataplexy or traumatic brain injury, the drug comprising a compound of any one of items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0230] (Item A25)

[0231] A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia, the medicament comprising a compound of any one of Items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0232] (Item A26)

[0233] A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease or hypersomnia associated with Lewy body dementia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Items A1 to A22 or a pharmaceutically acceptable salt thereof.

[0234] (Item A27)

[0235] Use of a compound of any one of items A1 to A22 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome containing narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

[0236] The present invention can also be shown as follows.

[0237] (Item 1)

[0238] A compound of formula (1) or a pharmaceutically acceptable salt thereof:

[0239]

[0240] in

[0241] R 1 is optionally substituted C 6-10 an aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C 3-6 saturated carbocyclyl, optionally substituted 4- to 10-membered saturated heterocyclyl, or cyano;

[0242] L 1 and L 2 are each independently a single bond, a methylene group (which may be optionally replaced by the same or different one or more C 1-4 Alkyl substituted), -NR 8 -, -C(=O)-, -OC(=O)-, -SO-, -SO2-, -S- or an oxygen atom;

[0243] R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group or an optionally substituted C 1-4 Alkyl; or

[0244] When L 1 When it is a single bond, R 1 and R 2 can be combined together as a spiro ring to form an optionally substituted C 3-6 saturated carbocyclic ring or optionally substituted 4- to 10-membered saturated heterocyclic ring;

[0245] R 3 and R 4 are independently a hydrogen atom, a halogen atom, a cyano group, -(C=O)NR 5 R 6 , carboxyl, -(C=O)OR 7 , optionally substituted C 1-4 Alkyl or optionally substituted C 1-4Alkoxy, where R 3 and R 4 Can be bonded to the same carbon atom if chemically possible; or

[0246] When R 3 and R 4 When bound to different ring carbon atoms, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a fused ring or a bridged ring;

[0247] R 5 To R 7 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-4 alkyl;

[0248] R 8 are each independently a hydrogen atom or an optionally substituted C 1-4 alkyl;

[0249] n is an integer of 1, 2, 3 or 4;

[0250] Ring G is optionally substituted C 6-10 an aromatic carbocyclic group, an optionally substituted 5- to 10-membered aromatic heterocyclic group, an optionally substituted C 3-6 saturated carbocyclyl or optionally substituted 4- to 10-membered saturated heterocyclyl;

[0251] A 1 is an oxygen atom or a sulfur atom;

[0252] A 2 is an oxygen atom or -NR 8 -;

[0253] A 3 is -CH-, a nitrogen atom or a carbon atom; and

[0254] Bonds accompanied by a dashed line are each independently a single bond or a double bond.

[0255] (Item 2)

[0256] The compound of item 1 or a pharmaceutically acceptable salt thereof, wherein

[0257] In R 2 -R 8 In the above, "optionally substituted C 1-4 The optional substituents of "alkyl" are the same or different one or more substituents selected from the following: halogen atoms, hydroxyl groups, C 1-4 Alkoxy, C 6-10 Aromatic carbocyclic groups and C 3-7 Cycloalkyl; and “optionally substituted C1-4 The optional substituents of the "alkoxy" are the same or different one or more substituents selected from the following: halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl;

[0258] In R 1 In the above, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "saturated carbocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-6 Alkylamino (the alkyl group may be optionally replaced by a halogen atom, a hydroxyl group or a C 3-7 Cycloalkyl substituted), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, and C 3-7 cycloalkyl) and a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 cycloalkyl); and

[0259] In ring G, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "optionally substituted 4- to 10-membered saturated heterocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from a halogen atom, a C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl), C 1-6 Alkylamino (the alkyl group may be optionally replaced by a halogen atom, a hydroxyl group or a C 3-7 Cycloalkyl substituted), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl) and C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 or when there are multiple optional substituents, two of them may be C 1-6 The alkylene groups are taken together to form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings.

[0260] (Item 3)

[0261] The compound of item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein

[0262] In R 2 -R 7 In the above, "optionally substituted C 1-4 The optional substituents of the "alkyl" group are the same or different and are one or more substituents selected from the following: halogen atoms and C1-4 Alkoxy; and “optionally substituted C 1-4 The optional substituents of the "alkoxy" group are the same or different one or more of the following substituents: halogen atoms and C 1-4 Alkoxy;

[0263] In R 1 In the above, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "saturated carbocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 Cycloalkyl), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, and C 3-7 cycloalkyl) and a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-7 cycloalkyl); and

[0264] In ring G, "optionally substituted C 6-10 "aromatic carbocyclic group", "optionally substituted 5- to 10-membered aromatic heterocyclic group", "optionally substituted C 3-6 The optional substituents of "optionally substituted 4- to 10-membered saturated heterocyclic group" and "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from a halogen atom, a C 1-6Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-6 Alkylamino (the alkyl group may be optionally replaced by a halogen atom, a hydroxyl group or a C 3-7 Cycloalkyl substituted) and C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 or when there are multiple optional substituents, two of them can be C 1-6 The alkylene groups are taken together to form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings.

[0265] (Item 4)

[0266] The compound of any one of items 1 to 3 or a pharmaceutically acceptable salt thereof, wherein

[0267] R 1 Selected from the following formulas (1a-1) to (1a-4):

[0268]

[0269] in

[0270] X 1 -X 7 are independently a nitrogen atom or CR a6 ;

[0271] Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom;

[0272] R a1 -R a7 Each independently is (if there are multiple CR a6 , then each Ra6 also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein R a4 and R a5 can be bound to the same carbon atom if chemically possible; and when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring of

[0273] q 1 Is an integer of 1 or 2.

[0274] (Item 5)

[0275] The compound of any one of items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein

[0276] Ring G is selected from the following (1b-1) to (1b-14):

[0277]

[0278] in

[0279] W1 , W 3 , W 5 , W 6 , W 7 , W 11 , W 12 , W 13 , W 15 , W 16 , W 17 , W 19 and W 25 are independently a nitrogen atom or CR b4 ;

[0280] W 2 , W 4 , W 8 , W 9 , W 10 , W 14 , W 18 , W 20 , W 21 , W 22 , W 23 and W 24 YesNR b5 , oxygen atom or CR b6 R b7 ;

[0281] R b1 -R b7 Each independently is (if there are multiple CR b4 , then each R b4 are also independently) a hydrogen atom, -N(R b8 )R b9 , C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl (the C 1-4 The alkyl group may be substituted with a halogen atom), and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy), a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from fused rings, spiro rings, and bridged rings; and

[0282] R b8 and R b9 are independently hydrogen atoms, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkoxy, C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl (the C 1-4 The alkyl group may be substituted with a halogen atom)), and a 5- to 10-membered aromatic heterocyclic group), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 alkyl), a 5- to 10-membered aromatic heterocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), or C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy); or R b8 and R b9 Together with the nitrogen atom to which they are attached, they may form a 3- to 7-membered nitrogen-containing saturated heterocyclic ring.

[0283] (Item 6)

[0284] The compound of any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, which has the formula (2):

[0285]

[0286] in

[0287] R 1 Selected from the following formulas (1a-1) to (1a-4):

[0288]

[0289] in

[0290] X 1 -X 7 are independently a nitrogen atom or CR a6 ;

[0291] Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom;

[0292] R a1 -R a7 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-6 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein Ra4 and R a5 can be bound to the same carbon atom if chemically possible; and when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring of

[0293] q 1 is an integer of 1 or 2;

[0294] L 1 and L 2 each independently is a single bond, -CH2- or an oxygen atom;

[0295] R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group or an optionally substituted C 1-4 alkyl;

[0296] R 3 and R 4 are independently a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkoxy and C 3-7 Cycloalkyl) or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 3-7 Cycloalkyl); wherein R 3 and R 4 can be bound to the same carbon atom if chemically possible; and when R 3 and R 4 When bound to different carbon atoms in the ring, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a fused ring or a bridged ring;

[0297] Ring G is selected from the following (1b-1) to (1b-4):

[0298]

[0299] in

[0300] W 1 , W 3 , W 5, W 6 and W 7 are independently a nitrogen atom or CR b4 ;

[0301] W 2 , W 4 and W 8 YesNR b5 , oxygen atom or CR b6 R b7 ;

[0302] R b1 -R b7 Each independently is (if there are multiple CR b4 , then each R b4 Also independently) a hydrogen atom, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from fused rings, spiro rings and bridged rings;

[0303] A 1 is an oxygen atom or a sulfur atom;

[0304] A 2 is an oxygen atom or -NH-; and

[0305] A 3 It is -CH-, a nitrogen atom or a carbon atom.

[0306] (Item 7)

[0307] The compound of item 6 or a pharmaceutically acceptable salt thereof, wherein

[0308] R 1 Selected from the following formulas (1a-1), (1a-2) and (1a-3-1):

[0309]

[0310] in

[0311] X 1 -X 6 are independently a nitrogen atom or CR a6 ;

[0312] Q 1 and Q 2 is an oxygen atom, -NR a7 - or a sulfur atom; and

[0313] R a1 -R a3 , R a6 and R a7 Each independently is (if there are multiple CR a6 , then each R a6 Also independently) a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano, C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4alkoxy) or a 5- to 10-membered aromatic heterocyclic group; wherein when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring is fused.

[0314] (Item 8)

[0315] The compound of item 6 or 7 or a pharmaceutically acceptable salt thereof, wherein

[0316] Ring G is selected from the following (1b-1), (1b-2) and (1b-4):

[0317]

[0318] in

[0319] W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ;

[0320] W 2 and W 4 YesNR b5 or CR b6 R b7 ;and

[0321] R b1 , R b2 and R b4 -R b7 Each independently is (if there are multiple CR b4 , then each R b4 Also independently) a hydrogen atom, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C 3-7Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups are taken together to form a bridged bicyclic structure.

[0322] (Item 9)

[0323] The compound of any one of items 6 to 8 or a pharmaceutically acceptable salt thereof, wherein

[0324] Ring G is selected from the following (1b-1) and (1b-2):

[0325]

[0326] in

[0327] W 1 and W 3 is a nitrogen atom or CR b4 ;

[0328] W 2 and W 4 YesNR b5 or CR b6 R b7 ;and

[0329] R b1 , R b2 and R b4 -R b7 are independently hydrogen atoms, C 1-6 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 6-10 Aromatic carbocyclic group (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy), C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkyl), C3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy) or C 3-7 Cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy); wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups are taken together to form a bridged bicyclic structure.

[0330] (Item 10)

[0331] The compound of any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, which has the formula (3):

[0332]

[0333] in

[0334] R 1 It is the following formula (1a-1), (1a-2) or (1a-3-1):

[0335]

[0336] in

[0337] X 1 -X 6 are independently a nitrogen atom or CR a6 ;

[0338] Q 1 and Q 2 is an oxygen atom or a sulfur atom;

[0339] R a1 -R a3 and R a6 Each independently is (if there are multiple CR a6 , then each R a6 also independently) a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups and C 1-4 Alkoxy), C 3-7Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy), cyano or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy); wherein when X 1 and X 3 All CR a6 When two R a6 Together with the carbon atoms to which they are attached, they can form a 6-membered carbon ring, which contains X 1 , X 2 and X 3 The 5-membered ring is fused;

[0340] L 1 and L 2 each independently is a single bond or an oxygen atom;

[0341] R 2 is a hydrogen atom, a halogen atom or a C which may be optionally substituted by the same or different one or more substituents. 1-4 Alkyl, wherein the substituent is selected from halogen atoms and hydroxyl groups;

[0342] R 3 and R 4 each independently a halogen atom;

[0343] Ring G is the following (1b-1), (1b-2-1), (1b-2-2) or (1b-2-3):

[0344]

[0345] in

[0346] R b5 is a hydrogen atom or a C which may be optionally substituted by one or more substituents which may be the same or different. 1-6 Alkyl, the substituent is selected from halogen atoms and C 1-4 alkoxy; and

[0347] A 1 It is an oxygen atom or a sulfur atom.

[0348] (Item 11)

[0349] The compound of any one of items 4 to 10 or a pharmaceutically acceptable salt thereof, wherein

[0350] R 1is formula (1a-2), and

[0351] R a1 It is a hydrogen atom, a halogen atom, a C 1-4 Alkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 Alkoxy), C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, hydroxyl groups, C 1-4 Alkyl and C 1-4 Alkoxy) or C 1-4 Alkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms and C 1-4 alkyl).

[0352] (Item 12)

[0353] The compound of items 10 to 11 or a pharmaceutically acceptable salt thereof, wherein

[0354] R 1 is formula (1a-2), and

[0355] X 4 and X 5 They are all nitrogen atoms.

[0356] (Item 13)

[0357] The compound of any one of items 10 to 12 or a pharmaceutically acceptable salt thereof, wherein

[0358] Ring G is of formula (1b-1-1), and

[0359] R b5 is C which may be optionally substituted by one or more substituents which may be the same or different 1-4 The alkyl group, wherein the substituent is selected from halogen atoms.

[0360] (Item 14)

[0361] The compound of any one of items 10 to 12 or a pharmaceutically acceptable salt thereof, wherein

[0362] Ring G is of formula (1b-2-1), and

[0363] R b5 is a hydrogen atom or a C which may be optionally substituted by one or more substituents which may be the same or different. 1-4 Alkyl, the substituent is selected from halogen atoms and C 1-4 Alkoxy.

[0364] (Item 15)

[0365] The compound of any one of items 1 to 12 or a pharmaceutically acceptable salt thereof, which has the formula (4):

[0366]

[0367] in

[0368] R 1 is the following (1a-2-1):

[0369]

[0370] in

[0371] Q 2 is an oxygen atom or a sulfur atom;

[0372] R a2 It is C 3-7 Cycloalkyl (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 alkoxy) or cycloalkoxy (which may be optionally substituted by the same or different one or more substituents selected from halogen atoms, C 1-4 Alkyl and C 1-4 Alkoxy);

[0373] R 2 It is C 1-4 alkyl;

[0374] Ring G is the following (1b-1-1) or (1b-2-1):

[0375]

[0376] in

[0377] R b5 is C which may be optionally substituted by one or more substituents which may be the same or different 1-4 Alkyl, the substituent is selected from halogen atoms and C 1-4 alkoxy; and

[0378] L 2 It is a single bond or an oxygen atom.

[0379] (Item 16)

[0380] The compound of Item 15 or a pharmaceutically acceptable salt thereof, wherein

[0381] R a2 is C which may be optionally substituted by one or more substituents which may be the same or different 3-7Cycloalkyl, the substituents are selected from halogen atoms, and

[0382] R 2 It's methyl.

[0383] (Item 17)

[0384] The compound of item 15 or 16 or a pharmaceutically acceptable salt thereof, wherein

[0385] R a2 is a cyclopropyl group which may be optionally substituted by one or more substituents which are the same or different and which are selected from halogen atoms, and

[0386] R 2 It's methyl.

[0387] (Item 18)

[0388] The compound of any one of items 15 to 17 or a pharmaceutically acceptable salt thereof, wherein

[0389] Ring G is of formula (1b-2-1), and

[0390] R b5 It is isopropyl.

[0391] (Item 19)

[0392] The compound of any one of items 15 to 17 or a pharmaceutically acceptable salt thereof, wherein

[0393] Ring G is of formula (1b-1-1), and

[0394] R b5 It is isobutyl.

[0395] (Item 20)

[0396] The compound of any one of items 15 to 17 or a pharmaceutically acceptable salt thereof, wherein

[0397] Ring G is of formula (1b-1-1),

[0398] R b5 is isopropyl, and

[0399] L 2 It's an oxygen atom.

[0400] (Item 21)

[0401] The compound of any one of items 15 to 20 or a pharmaceutically acceptable salt thereof, wherein Q 2 It's an oxygen atom.

[0402] (Item 22)

[0403] The compound of Item 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0404] Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0405]

[0406] Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0407]

[0408] Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0409]

[0410] Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0411]

[0412] Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0413]

[0414] Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0415]

[0416] Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0417]

[0418] Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0419]

[0420] Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0421]

[0422] Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0423]

[0424] Example 79: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carbothioamide

[0425]

[0426] Example 80: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide

[0427]

[0428] (Item 23)

[0429] The compound of Item 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0430] Example 64: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0431]

[0432] Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0433]

[0434] Example 71: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0435]

[0436] Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0437]

[0438] Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0439]

[0440] Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0441]

[0442] Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0443]

[0444] Example 76: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide.

[0445]

[0446] (Item 24)

[0447] The compound of Item 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0448] Example 82: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0449]

[0450] Example 95: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0451]

[0452] Example 96: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0453]

[0454] Example 97: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0455]

[0456] Example 99: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0457]

[0458] Example 110: N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0459]

[0460] Example 111: N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0461]

[0462] Example 112: N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0463]

[0464] Example 114: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0465]

[0466] Example 115: N-[(1R,6S)-6-{(3S)-3-[cyclopropyl(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0467]

[0468] Example 128: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0469]

[0470] Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0471]

[0472] Example 136: N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0473]

[0474] Example 137: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0475]

[0476] Example 138: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[0477]

[0478] Example 139: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0479]

[0480] Example 152: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0481]

[0482] Example 156-A: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0483]

[0484] Example 156-B: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1S,2R,6R)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0485]

[0486] Example 157: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0487]

[0488] Example 158: N-[(1R,6S)-6-{4-[(cyclopropylmethyl)(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0489]

[0490] Example 159: N-[(1R,6S)-6-{4-[cyclobutyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0491]

[0492] Example 161: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0493]

[0494] (Item 25)

[0495] The compound of Item 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures:

[0496] Example 83: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0497]

[0498] Example 84: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0499]

[0500] Example 102: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0501]

[0502] Example 103: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0503]

[0504] Example 107: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0505]

[0506] Example 116: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0507]

[0508] Example 118: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0509]

[0510] Example 119: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide

[0511]

[0512] Example 120: N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0513]

[0514] Example 121: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0515]

[0516] Example 122: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[0517]

[0518] Example 126: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide

[0519]

[0520] Example 133: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0521]

[0522] Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0523]

[0524] Example 143: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide.

[0525]

[0526] (Item 26)

[0527] A medicament for treating a disease associated with orexin receptors, comprising the compound of any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0528] (Item 27)

[0529] Drugs used to treat the following conditions: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome including excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen Encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperisolating obesity, protoplasmic obesity, pituitary obesity, protoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, fragmented sleep, nocturnal myoclonus, REM sleep disruption, jet lag, jet lag syndrome, shift work sleep disorders, sleep disorders, sleep terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunset syndrome, circadian rhythm-related diseases, fibromyalgia, conditions caused by reduced sleep quality, binge eating disorder, compulsive eating disorders, obesity-related diseases, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, cholelithiasis, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, hypogonadism in males, sexual / reproductive dysfunction such as hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as respiratory distress, inflammation such as systemic vascular inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, secondary risks of obesity such as risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia,Flushing, night sweats, genital / urinary disorders, disorders related to sexual function or fertility, dysthymic disorder, 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 brain defects after heart bypass surgery or heart transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle Muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Tourette syndrome, chorea, myoclonus, convulsions, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), conduct disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, brain edema, pain, bone pain, joint pain, toothache, cataplexy or traumatic brain injury, the drug comprising any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0530] (Item 28)

[0531] A medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease or hypersomnia associated with Lewy body dementia, the medicament comprising a compound of any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0532] (Item 29)

[0533] A method for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease or hypersomnia associated with Lewy body dementia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of items 1 to 25 or a pharmaceutically acceptable salt thereof.

[0534] (Item 30)

[0535] Use of a compound of any one of items 1 to 25 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome containing narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

[0536] Description of the implementation plan

[0537] Hereinafter, the present invention is explained in more detail. In the description, the number of carbon atoms in the definition of a "substituent" may be indicated as, for example, "C 1-6 The specific definition of "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. In the present specification, a substituent group not accompanied by "optionally substituted" or "substituted" refers to an "unsubstituted" substituent group. For example, "C 1-6 "Alkyl" refers to "unsubstituted C 1-6 alkyl".

[0538] Substituent groups in this specification may sometimes be expressed without the term "group". In the case where "optionally substituted" is used in the definition of a substituent group, the number of substituents is not limited as long as substitution is achievable, i.e., it is one or more. This means that the possible number of substituents is the number of available substitutions on the carbon atoms or carbon / nitrogen atoms that are acceptable for substitution in the substituent group. Unless otherwise noted, the definition of each substituent group also extends to the situation where the substituent group is partially included in another substituent group or the situation where the substituent group is connected to another substituent group.

[0539] Unless otherwise specified, the binding site of a substituent group is not limited as long as the site is available for binding.

[0540] The "halogen" includes, for example, fluorine, chlorine, bromine, iodine, etc. It is preferably fluorine or chlorine.

[0541] “C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, and "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-4 "C alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and "C 1-6 The "alkyl" includes, for example, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and structural isomers thereof, and the above C 1-4 Alkyl. "C 1-6 Alkyl" or "C 1-4Preferred examples of the "alkyl group" include methyl, ethyl, propyl and isopropyl; more preferred are methyl and isopropyl.

[0542] “C 1-6 "Alkylene" refers to a divalent straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkylene" preferably includes "C 1-4 Alkylene", more preferably "C 1-3 Alkylene". "C 1-3 "Alkylene" includes, for example, methylene, ethylene, propylene, trimethylene, etc. "C 1-4 The "alkylene" includes, for example, butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, etc., and in the "C 1-3 Examples are listed in "Alkylene". 1-6 The "alkylene" includes, for example, pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, etc., and in the "C 1-4 Examples are listed in "Alkylene".

[0543] “C 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group (i.e., a saturated hydrocarbon group and a partially unsaturated hydrocarbon group) having 3 to 7 carbon atoms, which preferably includes "C 3-6 Cycloalkyl". "C 3-7 "Cycloalkyl" also includes bridged C 3-7 Cycloalkyl. 3-10 The "cycloalkyl" group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and cycloheptyl.

[0544] “C 3-7 "Cycloalkyl" also includes bicyclic fused rings, wherein "C 3-7 The term "cycloalkyl" is fused to benzene or a 5- or 6-membered ring having one heteroatom selected from nitrogen, sulfur or oxygen atom, or the same or different and two or more (e.g., 2 to 4) heteroatoms thereof (e.g., the 5- or 6-membered ring in the "5- or 6-membered monocyclic heteroaryl" mentioned below and the "4- to 10-membered saturated heterocyclic group" mentioned below).

[0545] “C 1-4 "Alkoxy" refers to the above-mentioned "C 1-4 "C 1-6 "Alkoxy" refers to the above-mentioned "C 1-6 "C 1-4"Alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferably, "C 1-4 "Alkoxy" includes methoxy, ethoxy and isopropoxy.

[0546] “C 3-7 "Cycloalkoxy" refers to 3-7 Cycloalkyl" substituted oxy group, which preferably includes "C 3-6 Cycloalkoxy". "C 3-7 The "cycloalkoxy group" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and preferably cyclohexyloxy.

[0547] “C 6-10 "Aromatic carbocyclic group" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, which is also referred to as "C 6-10 More preferably, it is phenyl. 6-10 The "aromatic carbocyclic group" includes, for example, phenyl, 1-naphthyl and 2-naphthyl.

[0548] “C 6-10 The “aromatic carbocyclic group” also includes a condensed ring in which a “phenyl group” is condensed with a 5- or 6-membered ring having one heteroatom selected from a nitrogen, sulfur or oxygen atom, or the same or different and two or more (e.g., 2 to 4) heteroatoms thereof (e.g., the 5- or 6-membered ring in the “5- or 6-membered monocyclic aromatic heterocyclic group” mentioned below and the “4- to 10-membered saturated heterocyclic group” mentioned below) or a 5- to 7-membered cycloalkyl ring (e.g., cyclopentane, cyclohexane and cycloheptane).

[0549] The “5- to 10-membered aromatic heterocyclic group” refers to a 5- to 10-membered monocyclic or polycyclic aromatic group having, in addition to carbon atoms as ring atoms, one heteroatom selected from nitrogen, sulfur or oxygen atoms or the same or different and two or more (e.g., 2 to 4) heteroatoms thereof, preferably a “5- or 6-membered monocyclic aromatic heterocyclic group”. The “5- or 6-membered monocyclic aromatic heterocyclic group” refers to a 5- or 6-membered monocyclic aromatic group within the “5- to 10-membered aromatic heterocyclic group”.

[0550] The polycyclic aromatic heterocyclic group within the “5- to 10-membered aromatic heterocyclic group” includes, for example, a condensed ring in which the same or different two monocyclic aromatic heterocyclic rings are condensed, or a monocyclic aromatic heterocyclic ring is condensed with an aromatic ring (e.g., benzene) or a non-aromatic ring (e.g., cyclohexane).

[0551] "5- to 10-membered aromatic heterocyclic group" includes, for example, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl. Another embodiment preferably includes benzofuranyl, wherein the binding site is on the heteroaryl (furan) ring, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl.

[0552] “C 3-6 "Saturated carbocycle" refers to a monocyclic saturated or partially unsaturated hydrocarbon group having 3 to 6 carbon atoms. 3-6 The "saturated carbocycle" includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene and cyclohexadiene, and preferably cyclopropane and cyclobutane.

[0553] "4- to 10-membered saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle consisting of 4 to 10 atoms, which, in addition to the carbon atoms as ring atoms, has the same or different and one or more (e.g., 2 to 4, preferably 2 to 3, more preferably 2) heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms. The heterocycle may include partially unsaturated heterocycles, partially bridged heterocycles and partially spiro heterocycles. It is preferably a 5- or 6-membered saturated heterocycle. Bicyclic saturated heterocycles also include fused rings of monocyclic saturated heterocycles and benzene or 5- or 6-membered monocyclic aromatic heterocycles. And, the saturated heterocyclic ring may further contain one or two carbonyl groups, thiocarbonyl groups, sulfinyl groups or sulfonyl groups, that is, the saturated heterocyclic ring includes, for example, cyclic groups such as lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate and cyclic thiocarbamate, wherein the number of atoms constituting the 4- to 10-membered ring (i.e., ring size) or the number of heteroatoms constituting the heterocyclic ring does not count the oxygen atoms in the carbonyl groups, sulfinyl groups and sulfonyl groups, and the sulfur atom in the thiocarbonyl groups. The “4- to 10-membered saturated heterocyclic ring” preferably includes a monocyclic or bicyclic “4- to 8-membered saturated heterocyclic ring”, more preferably a monocyclic “4- to 6-membered saturated heterocyclic ring”, and even more preferably a monocyclic “5- or 6-membered saturated heterocyclic ring”. The “4- to 10-membered saturated heterocycle” includes, for example, piperazine, oxetanyl, azetidinyl, pyranyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, homopiperidinyl, oxetanyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneimino, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydropyridinyl, and preferably pyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. “Bicyclic saturated heterocycle” includes, for example, dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl and tetrahydropyrido-azepanyl.

[0554] The "4- to 6-membered saturated heterocyclic group" refers to a monovalent substituent derived from the "4- to 6-membered saturated heterocyclic ring" belonging to the above-mentioned "4- to 10-membered saturated heterocyclic ring". It preferably includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.

[0555] By adding R b8 and R b9 The “3- to 7-membered nitrogen-containing saturated heterocycle” formed in combination with the nitrogen atom to which they are attached corresponds to the above-mentioned “4- to 10-membered saturated heterocycle” wherein the number of atoms constituting the ring is 3 to 7 and one nitrogen atom is included as an atom constituting the ring other than a carbon atom.

[0556] The compounds of the present invention include various hydrates, solvates and crystal polymorphs thereof.

[0557] By substitution, the compounds of the present invention may include one or more isotopic atoms such as D, 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 35 S. 18 F and 125 I, and such isotopically substituted compounds are also included in the compounds of the present invention.

[0558] As used herein, "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. "Pharmaceutically acceptable salts" include, but are not limited to, for example, acid addition salts such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), lauryl sulfate, malate, ascorbate, mandelate, saccharin, xinafoate, pamoate, cinnamate, adipate, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, polyacrylate and carboxyvinyl polymer; inorganic base addition salts such as lithium, sodium, potassium and calcium salts; organic base addition salts such as morpholine and piperidine; and amino acid addition salts such as aspartate and glutamate.

[0559] The compounds of the present invention can be directly administered orally or parenterally, or administered as suitable preparations such as pharmaceutical products, drugs and pharmaceutical compositions. The preparations thereof may include, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, gel patches, etc., but are not limited thereto. The preparations may be prepared in a known manner with pharmaceutically acceptable additives.

[0560] Additives may be selected for any purpose and include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavoring agents, etc. Specifically, they include, for example, lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, cross-linked carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0561] The dosage of the compound of the present invention should be appropriately determined according to the target animal, administration route, target disease, and age, weight and condition of the patient for administration. For example, in the case of oral administration, a minimum of about 0.01 mg to a maximum of 10000 mg divided into one or several portions can be administered to an adult in one day.

[0562] The compounds of the present invention have agonist activity of orexin receptors. Therefore, the compounds can be drugs for preventing or treating diseases related to orexin receptors. The diseases include, for example, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome including excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome symptoms, Rasmussen encephalitis, Wernicke encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperpancreatic obesity, protoplasmic obesity, pituitary obesity, protoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, fragmented sleep, nocturnal myoclonus, REM sleep disruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunset syndrome, circadian rhythm-related disorders, fibromyalgia, disorders caused by reduced sleep quality, bulimia, compulsive eating disorders, obesity-related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, cholelithiasis, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, heart Vascular disease, sudden death, polycystic ovaries, 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, decreased fertility, infertility, hypogonadism in males, sexual / reproductive dysfunction such as hirsutism in females, fetal defects related to maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as respiratory distress, inflammation such as systemic vascular inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease,Gout, kidney cancer, secondary risks of obesity such as risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / urinary system disorders, disorders related to sexual function or fertility, dysthymic disorder, 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 brain defects after heart bypass surgery or heart transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment , muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Tourette syndrome, chorea, myoclonus, convulsions, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), conduct disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, brain edema, pain, bone pain, joint pain, toothache, cataplexy and traumatic brain injury; and preferably narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease and hypersomnia associated with Lewy body dementia. ,

[0563] Hereinafter, the method for preparing the compound of formula (1) of the present invention is illustrated together with Examples, but the method of the present invention should not be limited to the Examples.

[0564] Preparation method

[0565] The compound of the present invention can be synthesized according to each preparation method shown below or a combination thereof with a known synthesis method.

[0566] Each compound in the following scheme may exist as its salt, wherein the salt includes, for example, the "pharmaceutically acceptable salt" mentioned above. The following scheme is disclosed only as an example, and thus based on the knowledge of those skilled in the art of synthetic organic chemistry, it is also possible to optionally prepare the compounds of the present invention by different methods.

[0567] In each of the preparation methods described below, a protecting group may be used when necessary even if the use of the protecting group is not explicitly described. Also, after a reaction is completed or a series of reactions have been carried out to obtain a desired compound, the protecting group may be deprotected.

[0568] As such a protecting group, for example, general protecting groups described in the following documents can be used: T.W. Greene and PGMWuts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Inc., New York (1999) etc. Examples of amino protecting groups include, for example, tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, tetrahydropyranyl, etc.; examples of hydroxy protecting groups include, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl, etc.; examples of aldehyde protecting groups include, for example, dialkyl acetal, cycloalkyl acetal, etc.; and examples of carboxyl protecting groups include, for example, tert-butyl esters, orthoesters, amides, etc.

[0569] By methods commonly used in synthetic organic chemistry (see, for example, TWGreene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Inc., NewYork (1999) ), or similar methods, can achieve the introduction and elimination of protecting groups.

[0570] Preparation method 1:

[0571] Among the compounds according to formula (1) or pharmaceutically acceptable salts thereof, for example, the compounds of formula (s-1-1) or pharmaceutically acceptable salts thereof can be prepared by the following method, wherein A 3 The compound of formula (1) is a nitrogen atom.

[0572]

[0573] Where R 1 -R 4 , L 1 , L 2 ,n,ring G,A 1 and the bonds accompanied by dashed lines are as defined in item 1.

[0574] Step (1-1):

[0575] Compound (s-1-1) can be prepared by reacting compound (s-1-2) and compound (s-1-3) in a suitable inert solvent under the reaction conditions of a urea-bound formulation. The present reaction conditions include, for example, the use of triphosgene, 4-nitrophenyl chloroformate, 1,1'-carbonyldiimidazole or thiophosgene. A base is used in the present reaction, and the base used herein includes triethylamine and diisopropylethylamine. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0576] In step (1-1), an intermediate such as isocyanate may be isolated and then converted.

[0577] Preparation method 2:

[0578] Among the compounds according to formula (s-1-3), for example, the compound of formula (s-2-1), which is a compound of formula (s-1-3) having no unsaturated bond in the ring, can be prepared by the following method, provided that L 2 is an oxygen atom or -NR 10 -, or L 2 is a single bond and ring G is connected to the cycloalkyl group via the nitrogen atom therein, wherein R 10 Is H or C 1-4 Alkyl, this definition applies below unless otherwise stated.

[0579]

[0580] Where R 3 , R 4 , L 2 , n and ring G are as defined in item 1; P 1 is a suitable protecting group; and LG is a suitable leaving group, said definitions being used below unless otherwise indicated.

[0581] Compound (s-2-1) can be produced from compound (s-2-2) via step (2-1) and step (2-2).

[0582] Step (2-1):

[0583] Compound (s-2-4) can be prepared by reacting compound (s-2-2) and compound (s-2-3) in a suitable inert solvent without an additive or in the presence of an acid or a base. The acid used herein includes, for example, protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as zinc (II) chloride, scandium (III) trifluoromethanesulfonate, cuprous chloride (I), boron trifluoride, boric acid and boric acid esters. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. Inert solvents include halogenated carbon solvents 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 generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0584] Step (2-2):

[0585] Compound (s-2-1) can be prepared by reacting compound (s-2-4) under conventional conditions of nitro reduction in a suitable inert solvent or under a hydrogen atmosphere (if necessary). The present reaction conditions include, for example, the use of iron, zinc, tin (II) chloride, Raney nickel, carbon-supported palladium or palladium (II) hydroxide. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; ester solvents such as ethyl acetate and methyl acetate; and alcohol solvents such as methanol and ethanol. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0586] Compound (s-2-1) can also be produced from compound (s-2-5) via step (2-3) and step (2-4).

[0587] Steps (2-3):

[0588] Compound (s-2-6) can be prepared by reacting compound (s-2-5) and compound (s-2-3) in a suitable inert solvent in the absence of an additive or in the presence of an acid or base under conventional conditions of an aziridine ring-opening reaction. The acid used herein includes, for example, protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as zinc (II) chloride, scandium (III) trifluoromethanesulfonate, cuprous chloride (I), boron trifluoride, boric acid and boric acid esters. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. Inert solvents include halogenated carbon solvents 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 generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0589] Steps (2-4):

[0590] Compound (s-2-1) can be prepared by deprotecting compound (s-2-6) in a known manner (for example, the manner described in the following literature: Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, ed. by RC Larock, VCH publisher Inc., 1989, etc.) or a manner analogous thereto.

[0591] Compound (s-2-1) can also be produced from compound (s-2-7) via step (2-5) to step (2-7) and step (2-4).

[0592] Steps (2-5):

[0593] Compound (s-2-8) can be prepared by reacting compound (s-2-7) and compound (s-2-3) in a suitable inert solvent in the absence of an additive or in the presence of an acid or base under conventional conditions of an epoxide ring-opening reaction. The acid used herein includes, for example, protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as boron trifluoride, zinc (II) chloride, scandium (III) trifluoromethanesulfonate, cuprous chloride (I), boric acid and boric acid esters. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. Inert solvents include halogenated carbon solvents 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 generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0594] Steps (2-6):

[0595] By reacting compound (s-2-8) in a suitable inert solvent under the conventional conditions of the conversion reaction from hydroxyl to leaving group, compound (s-2-9) can be prepared. This reaction condition includes, for example, using methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride. Base is used in this reaction, and the base used in this article includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyl lithium and isopropyl magnesium chloride; and metal amide reagents such as LDA and LHMDS. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0596] Steps (2-7):

[0597] In the presence of compound (s-2-9), P 1Compound (s-2-6) can be prepared in a general nucleophilic substitution reaction of NH2 and a base. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyl lithium and isopropyl magnesium chloride; and metal amide reagents such as LDA and LHMDS. The solvent used herein includes halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0598] Step (2-6) and step (2-7) can be carried out as one step without isolating the intermediate. Also, step (2-6) and step (2-7) can be carried out as one step under Mitsunobu reaction conditions.

[0599] Preparation method 3-1:

[0600] Among the compounds according to formula (s-2-1), for example, a compound of formula (s-3-1) can also be prepared by the following method, which is a compound of formula (s-2-1) wherein L 2 is a single bond and ring G is bonded to the cycloalkyl group via the nitrogen atom therein.

[0601]

[0602] Where R 3 , R 4 , n and ring G are as defined in item 1.

[0603] Compound (s-3-1) can be produced from compound (s-2-2) via step (3-1) to step (3-3).

[0604] Step (3-1):

[0605] Compound (s-3-2) can be prepared in a similar manner to step (2-1) using compound (s-2-2) and ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation).

[0606] Step (3-2):

[0607] Compound (s-3-3) can be prepared by using compound (s-3-2) in the formation of a nitrogen-containing heterocyclic ring. For example, compound (s-3-2) can be prepared by reacting compound (s-3-3) with N-benzyl-bis(2-chloroethyl)amine, followed by deprotection and alkylation, where ring G is piperazine.

[0608] Step (3-3):

[0609] Compound (s-3-1) can be prepared using compound (s-3-3) in a similar manner to step (2-2).

[0610] Compound (s-3-1) can also be produced from compound (s-2-5) via step (3-4) to step (3-6).

[0611] Steps (3-4):

[0612] Compound (s-3-4) can be prepared in a similar manner to step (2-3) using compound (s-2-5) and ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation).

[0613] Steps (3-5):

[0614] Compound (s-3-5) can be prepared using compound (s-3-4) in a similar manner to step (3-2).

[0615] Steps (3-6):

[0616] Compound (s-3-1) can be prepared by deprotecting compound (s-3-5) in a similar manner to step (2-4).

[0617] Preparation method 3-2:

[0618] For example, the compound according to formula (s-3-1) can also be prepared by the following method.

[0619]

[0620] Where R 3 , R 4 , n and ring G are as defined in item 1.

[0621] Compound (s-3-1) can be produced from compound (s-3-6) via step (3-7) and step (3-8).

[0622] Steps (3-7):

[0623] Compound (s-3-6) is compound (s-2-9) in Preparation Method 2, wherein L2 is a single bond and ring G is connected to the cycloalkyl group via the nitrogen atom therein. Compound (s-3-7) can be prepared by using compound (s-3-6) and a conventional base as an intramolecular reaction in a general nucleophilic substitution reaction such as step (2-7). Compound (s-3-7) can be used in the next step without isolation.

[0624] Steps (3-8):

[0625] Compound (s-3-1) can be prepared in a general ring-opening reaction using compound (s-3-7) and ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation).

[0626] Preparation method 4:

[0627] Among the compounds according to formula (s-2-1), for example, the compound of formula (s-4-1) can also be prepared by the following method, which is wherein L 2 Is O or NR 10 A compound of formula (s-2-1).

[0628]

[0629] Where R 3 , R 4 , n and ring G are as defined in item 1; and Y is O or NR 10 , said definitions apply below unless otherwise indicated.

[0630] Compound (s-4-1) can be produced from compound (s-2-2) via step (4-1) to step (4-3).

[0631] Step (4-1):

[0632] Compound (s-4-2) can be prepared by reacting compound (s-2-2) with YH2 or a reagent equivalent to YH2 in a manner similar to step (2-1), wherein the reagent equivalent to YH2 includes a protected reagent P 2 YH (which is deprotected after the addition reaction), where P 2 are suitable protecting groups and said definitions apply below unless otherwise stated.

[0633] Step (4-2):

[0634] Compound (s-4-3) can be prepared using compound (s-4-2), ring G with a leaving group and a base in a general nucleophilic substitution reaction or an aromatic nucleophilic substitution reaction. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyl lithium and isopropyl magnesium chloride; and metal amide reagents such as LDA and LHMDS. The solvent used herein includes halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0635] Step (4-3):

[0636] Compound (s-4-1) can be prepared using compound (s-4-3) in a similar manner to step (2-2).

[0637] Compound (s-4-1) can also be produced from compound (s-2-5) via step (4-4) to step (4-6).

[0638] Step (4-4):

[0639] Compound (s-4-4) can be prepared by reacting compound (s-2-5) with YH2 or a reagent equivalent to YH2 in a manner similar to step (2-3), wherein the reagent equivalent to YH2 includes a protected reagent P 2 YH (which is deprotected after the addition reaction).

[0640] Steps (4-5):

[0641] Compound (s-4-5) can be prepared using compound (s-4-4) in a similar manner to step (4-2).

[0642] Steps (4-6):

[0643] Compound (s-4-1) can be prepared by deprotecting compound (s-4-5) in a similar manner to step (2-4).

[0644] Preparation method 5:

[0645] For example, the compound of formula (s-2-5) can also be produced by the following method.

[0646]

[0647] Where R 3 , R4 and n is as defined in item 1.

[0648] Compound (s-2-5) can be produced from compound (s-5-1) via step (5-1) to step (5-4).

[0649] Step (5-1):

[0650] Compound (s-2-7) can be prepared by reacting compound (s-5-1) in a suitable inert solvent under the normal conditions of epoxide formation. This reaction condition includes, for example, using an oxidant such as hydrogen peroxide solution, mCPBA, tert-butyl hydroperoxide and ozone. In this reaction, metal catalysts such as V, Mo, Al, Ti, Fe, Ta, Zr, Nb, W and Re can be used when appropriate. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0651] Step (5-2):

[0652] In a suitable inert solvent, in a manner similar to step (2-5), compound (s-2-7) and P are reacted with 1 NH2 can prepare compound (s-5-2).

[0653] Step (5-2) can be accomplished in a method comprising the steps of reacting compound (s-2-7) with ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation), and then reacting the compound (s-2-7) with a protecting group P 1 Protect the product.

[0654] Step (5-3):

[0655] Compound (s-5-3) can be prepared using compound (s-5-2) in a suitable inert solvent in a similar manner to step (2-6).

[0656] Step (5-4):

[0657] Compound (s-2-5) can be prepared by reacting compound (s-5-3) under conventional conditions of intramolecular cyclization reaction in a suitable inert solvent in the presence of a base. The base used herein includes, for example, organic bases such as triethylamine, diisopropylethylamine and DBU; inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate; metal alkoxides such as potassium tert-butoxide; organometallic reagents such as n-butyl lithium and isopropyl magnesium chloride; and metal amination reagents such as LDA and LHMDS. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0658] Step (5-3) and step (5-4) can be carried out in one step without isolating the intermediate. Also, step (5-3) and step (5-4) can be carried out in one step under Mitsunobu reaction conditions.

[0659] Compound (s-2-5) can also be produced from compound (s-5-1) via step (5-5).

[0660] Step (5-5):

[0661] Compound (s-2-5) can be prepared by reacting compound (s-5-1) in a suitable inert solvent under conventional conditions for aziridine ring formation reaction. The reaction conditions include, for example, using P in the presence of a metal catalyst. 1 NH2 and oxidizing agents such as iodophenyl, and the use of hydroxylamine derivatives P 1 N(H)O-LG and metal catalysts.

[0662] Preparation method 6:

[0663] Among the compounds according to formula (s-1-1), the compound of formula (s-6-1) having an unsaturated bond in the ring can be prepared, for example, by the following method.

[0664]

[0665] Where R 3 , R 4 , L 2 , n and ring G are as defined in item 1; Z is boronic acid, boronic ester, BF3K, BF3Na, trialkyltin, zinc halide or hydrogen atom; and X is halogen.

[0666] Compound (s-6-1) can be prepared from compound (s-6-6) via step (6-7). Also, compound (s-6-6) can be prepared from compound (s-6-2) via step (6-1) to step (6-3) or via step (6-4) to step (6-6).

[0667] Step (6-1):

[0668] Compound (s-6-4) can be prepared by reacting compound (s-6-2) with compound (s-6-3) (wherein Z is boronic acid, boronic acid ester, BF3K, BF3Na, trialkyltin or zinc halide) in the presence of a palladium catalyst and a phosphine ligand, and optionally in the presence of a base in a suitable inert solvent, wherein L 2 is a single bond or a methylene group, which may be optionally replaced by the same or different one or more C 1-4 Alkyl substitution.Compound (s-6-3) is commercially available, or can be prepared according to a known method or a method similar thereto.The palladium catalyst used herein includes, for example, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), palladium acetate (0), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II).

[0669] The phosphine ligand used herein includes, for example, o-tolylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANT-Phos) and bis((2-diphenylphosphino)phenyl)ether (DPE-Phos). The base used herein includes, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide and potassium hydroxide. The inert solvent includes, for example, 1,4-dioxane, THF, 1,2-dimethoxyethane, acetonitrile, water, and a mixture thereof. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0670] Alternatively, compound (s-6-4) can be prepared by reacting compound (s-6-2) with compound (s-6-3) (wherein Z is a hydrogen atom) in the presence of a palladium catalyst, a phosphine ligand and a base in a suitable inert solvent, wherein L 2 Is O or NR 10 .

[0671] Step (6-2):

[0672] Compound (s-6-5) can be prepared using compound (s-6-4) in a similar manner to step (2-6).

[0673] Step (6-3):

[0674] In a similar manner to step (2-7), compound (s-6-5) and P 1 NH2 can prepare compound (s-6-6).

[0675] Step (6-3) can be carried out in a method comprising the steps of: reacting compound (s-6-5) with ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation), and then reacting the compound (s-6-5) with a protecting group P 1 Protect the product.

[0676] Step (6-2) and step (6-3) can be carried out in one step without isolating the intermediate. Also, step (6-2) and step (6-3) can be carried out in one step under Mitsunobu reaction conditions.

[0677] Step (6-4):

[0678] Compound (s-6-7) can be prepared using compound (s-6-2) in a similar manner to step (6-2).

[0679] Step (6-5):

[0680] Compound (s-6-8) can be prepared using compound (s-6-7) in a similar manner to step (6-3).

[0681] Step (6-5) can be carried out in a method comprising the steps of reacting compound (s-6-7) with ammonia or a reagent equivalent to ammonia, wherein the reagent equivalent to ammonia includes a protected amine reagent (which is deprotected after amination) and an azide inducing agent (which is reduced after azidation), and then reacting the compound (s-6-7) with a protecting group P 1 Protect the product.

[0682] Step (6-4) and step (6-5) can be carried out as one step without isolating the intermediate. Also, step (6-4) and step (6-5) can be carried out as one step under Mitsunobu reaction conditions.

[0683] Step (6-6):

[0684] Compound (s-6-6) can be prepared using compound (s-6-8) in a similar manner to step (6-1).

[0685] Steps (6-7):

[0686] Compound (s-6-1) can be prepared by deprotecting compound (s-6-6) in a similar manner to step (2-4).

[0687] Preparation method 7:

[0688] Among the compounds according to formula (s-1-1), the compound of formula (s-7-1) having no unsaturated bond in the ring can be prepared, for example, by the following method.

[0689]

[0690] Where R 1 -R 4 , L 1 , L 2 , n, ring G and A 1 As defined in item 1.

[0691] Compound (s-7-1) can be prepared from compound (s-7-4) via step (7-6). Also, compound (s-7-4) can be prepared from compound (s-5-3) via step (7-1) to step (7-3) or from compound (s-2-5) via step (7-4) and step (7-5).

[0692] Step (7-1):

[0693] Compound (s-7-2) can be prepared by deprotecting compound (s-5-3) in a similar manner to step (2-4).

[0694] Step (7-2):

[0695] Compound (s-7-3) can be prepared by using compound (s-7-2) and compound (s-1-2) in a urea formation similar to step (1-1). In this step, the hydroxyl group may be protected and deprotected, if necessary.

[0696] Step (7-3):

[0697] Compound (s-7-4) can be prepared using compound (s-7-3) in a similar manner to step (5-3) and step (5-4).

[0698] Step (7-4):

[0699] Compound (s-7-5) can be prepared by deprotecting compound (s-2-5) in a similar manner to step (2-4).

[0700] Step (7-5):

[0701] Compound (s-7-4) can be prepared by using compound (s-7-5) and compound (s-1-2) in the same manner as in step (1-1) to form urea.

[0702] Step (7-6):

[0703] Compound (s-7-1) can be prepared by using compound (s-7-4) and compound (s-2-3) in a similar manner to step (2-3) through an aziridine ring-opening reaction.

[0704] Preparation method 8:

[0705] The compound of formula (s-1-1) can also be produced from compound (s-8-1) via step (8-1) to step (8-3).

[0706]

[0707] Where R 1 -R 4 , L 1 , L 2 ,n,ring G,A 1 and the bonds accompanied by dashed lines are as defined in item 1.

[0708] Step (8-1):

[0709] Compound (s-8-2) can be prepared by reacting compound (s-8-1) under conventional conditions of acyl azide formation in a suitable inert solvent. The present reaction conditions include, for example, using diphenylphosphoryl azide, or converting a carboxylic acid into its acyl halide, and then azidating the acyl halide with a metal azide. Inert solvents include ether solvents such as ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene, ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0710] Step (8-2):

[0711] Compound (s-8-3) can be prepared by reacting compound (s-8-2) under Curtius rearrangement reaction conditions in a suitable inert solvent. Compound (s-8-2) used herein may be an unisolated product from the previous step.

[0712] Step (8-3):

[0713] Compound (s-1-1) can be prepared by reacting compound (s-8-3) and compound (s-1-2) in a suitable inert solvent under conventional conditions of addition reaction. Compound (s-8-3) used herein may be an unisolated product from the previous step.

[0714] Preparation method 9:

[0715] Among the compounds according to formula (s-8-1), the compound of formula (s-9-1) having no unsaturated bond in the ring can be prepared, for example, by the following method.

[0716]

[0717] Where R 3 , R 4 , L 2 , n and ring G are as defined in item 1; and P 3 is a suitable protecting group or C 1-3 Alkyl, this definition applies below unless otherwise stated.

[0718] Compound (s-9-1) can be produced from compound (s-9-2) via step (9-1) and step (9-2).

[0719] Step (9-1):

[0720] Compound (s-9-3) can be prepared in a similar manner to step (2-1) using compound (s-9-2) and compound (s-2-3).

[0721] Step (9-2):

[0722] Compound (s-9-1) can be prepared by subjecting compound (s-9-3) to general conditions for hydrolysis or deprotection.

[0723] Compound (s-9-1) can be produced from compound (s-2-9) via step (9-3) and step (9-4).

[0724] Step (9-3):

[0725] Compound (s-9-4) can be prepared using compound (s-2-9) and metal cyanide in a similar manner to step (2-7).

[0726] Step (9-4):

[0727] Compound (s-9-1) can be prepared by reacting compound (s-9-4) in a suitable inert solvent under general conditions of hydrolysis.

[0728] Preparation method 10:

[0729] Among the compounds according to formula (s-8-1), the compound of formula (s-10-1) having an unsaturated bond in the ring can be prepared, for example, by the following method.

[0730]

[0731] Where R 3 , R 4 , L 2 , n and ring G are as defined in item 1; Z is boronic acid, boronic ester, BF3K, BF3Na, trialkyltin, zinc halide or hydrogen atom; and X is halogen.

[0732] Compound (s-10-1) can be prepared from compound (s-10-2) via step (10-2). Compound (s-10-2) can also be prepared from compound (s-6-5) via step (10-1), or from compound (s-6-7) via step (10-3) and step (10-4).

[0733] Step (10-1):

[0734] Compound (s-10-2) can be prepared using compound (s-6-5) and metal cyanide in a similar manner to step (2-7).

[0735] Step (10-2):

[0736] Compound (s-10-1) can be prepared by reacting compound (s-10-2) in a suitable inert solvent under general conditions of hydrolysis.

[0737] Step (10-3):

[0738] Compound (s-10-3) can be prepared using compound (s-6-7) and metal cyanide in a similar manner to step (10-1).

[0739] Step (10-4):

[0740] Compound (s-10-2) can be prepared using compound (s-10-3) and compound (s-6-3) in a similar manner to step (6-1).

[0741] Preparation method 11:

[0742] Among the compounds according to formula (1) or pharmaceutically acceptable salts thereof, the compound of formula (s-11-1) can be prepared, for example, by the following method, wherein A 3 is a compound of formula (1) wherein: is a carbon atom, or a pharmaceutically acceptable salt thereof.

[0743]

[0744] Where R 1 -R 4 , L 1 , L 2 , n, ring G and the bonds accompanied by dashed lines are as defined in item 1.

[0745] Step (11-1):

[0746] Compound (s-11-1) can be prepared by reacting compound (s-11-2) and compound (s-1-3) in a suitable inert solvent under conventional conditions for amide bond-forming reaction. The reaction conditions include, for example, the use of a condensing agent and a base, and the condensing agent used herein includes, for example, carbodiimides such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diphenylphosphoryl azide (DPPA), diethylphosphorocyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrahydroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (HATU). The base used in this article includes organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBU, pyridine and dimethylaminopyridine. Inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform; ether solvents such as ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used in this article.

[0747] Compound (s-11-1) can also be produced from compound (s-11-2) via step (11-2) and step (11-3).

[0748] Step (11-2):

[0749] Compound (s-11-3) can be prepared by reacting compound (s-11-2) in a suitable inert solvent under the conventional conditions of the acyl halide formation reaction. The present reaction conditions include, for example, using a halogenating agent, and the halogenating agent used herein includes, for example, thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus tribromide and phosphorus pentachloride. Inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform; ether solvents such as ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0750] Step (11-3):

[0751] Compound (s-11-1) can be prepared by reacting compound (s-11-3) and compound (s-1-3) in a suitable inert solvent in the presence of a base. The base used herein includes organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBU, pyridine and dimethylaminopyridine; and inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate. Inert solvents include halogenated hydrocarbon solvents such as dichloromethane and chloroform; ether solvents such as ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0752] Preparation method 12:

[0753] Among the compounds according to formula (1) or pharmaceutically acceptable salts thereof, the compound of formula (s-12-1) can be prepared, for example, by the following method: 2 is a compound of formula (1) wherein is an oxygen atom, or a pharmaceutically acceptable salt thereof.

[0754]

[0755] Where R 1 -R 4 , L 1 , L 2 ,n,ring G,A 1and the bonds accompanied by dashed lines are as defined in item 1.

[0756] Step (12-1):

[0757] Compound (s-12-1) can be prepared by reacting compound (s-1-2) and compound (s-12-2) in a suitable inert solvent under the conventional conditions of carbamate formation reaction. The present reaction conditions include, for example, the use of triphosgene, 4-nitrophenyl chloroformate or thiophosgene. A base is used in the present reaction, and the base used herein includes triethylamine and diisopropylethylamine. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0758] In the method for producing compound (s-2-8), compound (s-12-2) having no unsaturated bond in the ring is produced. Also, in the method for producing compound (s-6-4), compound (s-12-2) having an unsaturated bond in the ring is produced.

[0759] Preparation method 13:

[0760] Among the compounds according to formula (s-1-2), the compound of formula (s-13-1) can be prepared, for example, by the following method.

[0761]

[0762] Where R 2 As defined in Item 1, R a1 and Q 2 As defined in item 4; and P 4 are suitable protecting groups and said definitions apply below unless otherwise stated.

[0763] Step (13-1):

[0764] Compound (s-13-4) can be prepared by reacting compound (s-13-2) and compound (s-13-3) in a suitable inert solvent under conventional conditions of addition reaction. Inert solvents include halocarbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; alcohol solvents such as methanol and ethanol; and water. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20°C to the boiling point of the solvent used herein.

[0765] Step (13-2):

[0766] Compound (s-13-6) can be prepared by reacting compound (s-13-4) and compound (s-13-5) under the conventional conditions of condensation reaction in a suitable inert solvent. The present reaction conditions include, for example, using HATU, DCC or CDI. A base is used in the present reaction, and the base used herein includes triethylamine and diisopropylethylamine. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0767] Step (13-3):

[0768] Compound (s-13-7) can be prepared by reacting compound (s-13-6) in a suitable inert solvent under the conventional conditions of dehydration reaction. In this reaction, bases such as triethylamine and DBU can be used when appropriate. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0769] Step (13-4):

[0770] Compound (s-13-1) can be prepared by deprotecting compound (s-13-7) in a known manner (for example, the manner described in the following literature: Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, ed. by RC Larock, VCH publisher Inc., 1989, etc.) or a manner analogous thereto.

[0771] Preparation method 14:

[0772] Among the compounds according to formula (s-1-2), for example, a compound of formula (s-14-1) can also be prepared by the following method, which is a compound of formula (s-1-2) wherein L 1 is a single bond and R 1 is an optionally substituted 5-membered aromatic heterocyclic group.

[0773]

[0774] Where R 2 As defined in Item 1, X 4 and R a1 As defined in item 4.

[0775] Compound (s-14-1) can be produced from compound (s-14-2) via step (14-1) to step (14-3).

[0776] Step (14-1):

[0777] Compound (s-14-3) can be prepared by reacting compound (s-14-2) in a suitable inert solvent under the normal conditions of chlorination reaction. The present reaction conditions include, for example, using chlorine, N-succinimide and trimethylbenzyl tetrachloroammonium iodate. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide; water; and mixtures thereof. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0778] Step (14-2):

[0779] By reacting compound (s-14-3) and compound (s-14-4) in a suitable inert solvent under the conventional conditions of 1,3-dipolar cycloaddition reaction, compound (s-14-5) can be prepared. This reaction condition includes, for example, using a base, and the base used herein includes inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide and potassium fluoride; and organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline and NMM. Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0780] Step (14-3):

[0781] Compound (s-14-1) can be prepared using compound (s-14-5) in a similar manner to step (13-4).

[0782] Preparation method 15:

[0783] Among the compounds according to formula (s-1-2), the compound of formula (s-15-1) can be prepared, for example, by the following method.

[0784]

[0785] Where R 2 As defined in Item 1, X 1 -X 3 , Q 1 and R a6 As defined in item 4.

[0786] Step (15-1):

[0787] Compound (s-15-4) can be prepared by reacting compound (s-15-2) and compound (s-15-3) in a suitable inert solvent under a condensation reaction such as step (13-2).

[0788] Step (15-2):

[0789] Compound (s-15-5) can be prepared by reacting Compound (s-15-4) in a suitable inert solvent under conventional conditions of dehydration reaction or under cyclization conditions after treatment with Lawesson's reagent or the like.

[0790] Step (15-3):

[0791] Compound (s-15-1) can be prepared using compound (s-15-5) in a similar manner to step (13-4).

[0792] Preparation method 16:

[0793] Among the compounds according to formula (s-1-2), for example, a compound of formula (s-16-5) or a compound of formula (s-16-8) can be prepared by the following method, which is a compound of formula (s-1-2) wherein L 1 is a single bond and R 1 is optionally substituted C 6-10 An aromatic carbocyclic group or an optionally substituted 5- to 10-membered aromatic heterocyclic group.

[0794]

[0795] Where R 1 and R 2 as defined in item 1; Z is as exemplified in the following step (16-1); and X is halogen.

[0796] Compound (s-16-5) can be produced from compound (s-16-1) via step (16-1) to step (16-3).

[0797] Step (16-1):

[0798] Compound (s-16-3) can be prepared by coupling compound (s-16-1) with an organic boron compound (e.g., Z is B(OH)2, etc.), an organic zinc compound (e.g., Z is ZnCl, etc.), an alkenyl compound, an alkynyl compound, a hydroxy compound (e.g., Z is OH, etc.), an amine compound (e.g., Z is NH2, etc.) or a metal cyanide (e.g., Z is CuCN, etc.) in the presence of a base and a metal catalyst. The base used herein includes inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide and potassium fluoride; and organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline and NMM. Sometimes, depending on the coupling type, no base is used. The metal catalyst used herein includes, for example, bis(tri-tert-butylphosphine)palladium, bis(tri-o-tolylphosphine)palladium dichloride, bis(tri-o-tolylphosphine)palladium, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium dichloride, bis(tri-o-tolylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and PEPPSITM.IPr((1,3-bis(2,6-diisopropylphenyl)imidazolylidene) (3-chloropyridyl)palladium dichloride (II)). Palladium acetate or palladium chloride can be used herein, and the ligand described in Palladium reagents and catalysts, John Wiley & Sons Inc. (2004) or similar ligands can also be used to replace the acetate in palladium acetate or the chloride in palladium chloride. The solvent used herein includes, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide; water; and mixtures thereof. The reaction temperature should be determined according to the starting compound to be used, and it is generally about 0°C to about 250°C, preferably about 20°C to about 200°C. The reaction time is generally 30 minutes to 48 hours, preferably 1 to 24 hours.

[0799] Step (16-2):

[0800] By reacting compound (s-16-3) in a suitable inert solvent under the conventional conditions of olefin reduction reaction, and if necessary under a hydrogen atmosphere, compound (s-16-4) can be prepared. The present reaction conditions include, for example, using a reducing agent such as palladium on carbon, palladium hydroxide (II), platinum on carbon, platinum oxide (IV), Raney nickel, ruthenium carbon and tris (triphenylphosphine) rhodium chloride (I). Inert solvents include halogenated carbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; aromatic solvents such as benzene, toluene and xylene; alcohol solvents such as methanol and ethanol; and ester solvents such as ethyl acetate and methyl acetate. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0801] Step (16-3):

[0802] Compound (s-16-5) can be prepared using compound (s-16-4) in a similar manner to step (13-4).

[0803] Compound (s-16-8) can be produced from compound (s-16-1) via step (16-1) and step (16-4) to step (16-6).

[0804] Step (16-4):

[0805] By reacting compound (s-16-3), an alkylating agent R in a suitable inert solvent under alkylation reaction conditions. 2 -X and a base reaction can prepare compound (s-16-6). The base used herein includes LDA, LHMDS and n-butyl lithium. Inert solvents include ether solvents such as diethyl ether, THF and 1,4-dioxane; and aromatic solvents such as benzene, toluene and xylene. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0806] Step (16-5):

[0807] Compound (s-16-7) can be prepared by reacting compound (s-16-6) in a suitable inert solvent in a similar manner to step (16-2), wherein the reducing agent may include sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

[0808] Step (16-6):

[0809] Compound (s-16-8) can be prepared using compound (s-16-7) in a similar manner to step (13-4).

[0810] Preparation method 17:

[0811] Among the compounds according to formula (s-1-2), the compound of formula (s-17-1) can be prepared, for example, by the following method.

[0812]

[0813] Where R 1 As defined in item 1, and R 8 It is C 1-3 alkyl.

[0814] Step (17-1):

[0815] By reacting compound (s-17-2) and an alkylating agent R in a suitable inert solvent under the conditions of the alkylation reaction as in step (16-4), 1 -X (wherein X is a halogen) reaction can prepare compound (s-17-3).

[0816] Step (17-2):

[0817] Compound (s-17-4) can be prepared by reacting compound (s-17-3) in a suitable inert solvent under the conventional conditions of a reduction reaction. The present reaction conditions include, for example, using LAH or DIBAL. Inert solvents include halocarbon solvents such as chloroform and dichloromethane; ether solvents such as ether, THF and 1,4-dioxane; and aromatic solvents such as benzene, toluene and xylene. The reaction time is generally about 1 hour to 24 hours, and the reaction temperature is -20 ° C to the boiling point of the solvent used herein.

[0818] Step (17-3):

[0819] Compound (s-17-5) can be prepared by reacting compound (s-17-4) in a suitable inert solvent under Barton-McCombie deoxygenation conditions.

[0820] Step (17-4):

[0821] Compound (s-17-1) can be prepared using compound (s-17-5) in a similar manner to step (13-4). Example

[0822] The present invention is explained in more detail below by referring to reference examples, examples and tests; however, the technical scope of the present invention should not be limited thereto. It should be understood that the names of the compounds used in the following reference examples and examples do not necessarily follow the IUPAC nomenclature.

[0823] In this specification, the abbreviations shown below may be used.

[0824] CDCl3: deuterated chloroform

[0825] DMSO-d6: deuterated dimethyl sulfoxide

[0826] Rt: retention time

[0827] min: minutes

[0828] HATU: O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0829] DCC: N,N'-Dicyclohexylcarbodiimide

[0830] CDI: Carbonyldiimidazole

[0831] THF: Tetrahydrofuran

[0832] TFA: trifluoroacetic acid

[0833] DMF: N,N-dimethylformamide

[0834] DMSO: dimethyl sulfoxide

[0835] CPME: Cyclopentyl Methyl Ether

[0836] Boc: tert-Butoxycarbonyl

[0837] Ns: 2-nitrobenzenesulfonyl

[0838] Tf: trifluoromethanesulfonyl

[0839] DBU: Diazabicycloundecene

[0840] DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

[0841] LDA: Lithium diisopropylamide

[0842] LHMDS: Lithium bis(trimethylsilyl)amide

[0843] mCPBA: meta-chloroperbenzoic acid

[0844] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0845] NMM: N-methylmorpholine

[0846] LAH: Lithium Aluminum Hydride

[0847] DIBAL: Diisobutylaluminum hydride

[0848] Abs: Absolute configuration; each chemical structure of a compound described with the Abs symbol surrounded by a box is shown in an absolute configuration with a wedge-shaped bond. However, not all compounds without the Abs symbol are shown in a non-absolute configuration, that is, the configuration should be appropriately judged with or without the Abs symbol based on the disclosure of the subject compound in this specification and its context, and the technical knowledge of the technician.

[0849] In the column chromatography used in Reference Example and Example and amino chromatography, silica gel column and amino column manufactured by YAMAZEN CORPORATION were used. The TLC (silica gel plate) used in the TLC purification was silica gel 60F254 (Merck), and the TLC (NH silica gel plate) used therein was TLC plate NH (Fuji Silysia).

[0850] In Reference Examples and Examples, the reactor shown below was used. The physicochemical data described in Reference Examples and Examples were obtained using the following equipment.

[0851] Microwave reactor: Biotage AB Initiator

[0852] 1 H-NMR: JEOL JNM-AL400; JEOL JNM-ECS400; Brucker AVANCE 400Spectrometer

[0853] The symbols used in NMR are defined as follows, s: singlet, d: doublet, dd: double of doublets, ddd: double of doublets of doublets, dddd: double of doublets of doublets of doublets, t: triplet, td: triplet of doublets, q: quartet, m: multiplet, br: broad singlet or multiplet, and J: coupling constant.

[0854] LC / MS data of each compound in Examples and Reference Examples were obtained using any of the following equipments.

[0855] Method A

[0856] Testing equipment: ACQUITY TM SQ detector (Waters Corporation)

[0857] HPLC: ACQUITY TM UPLC SYSTEM

[0858] Column: Waters ACQUITY TMUPLC BEH C18 (1.7 μm, 2.1 mm×30 mm)

[0859] Method B

[0860] Detection equipment: Shimadzu LCMS-2020

[0861] Column: Phenomenex Kinetex (C18, 1.7 μm, 2.1 mm × 50 mm)

[0862] Method C

[0863] Testing equipment: ACQUITY TM SQ detector (Waters Corporation)

[0864] HPLC: ACQUITY TM UPLC SYSTEM

[0865] Column: Waters ACQUITY TM UPLC BEH C18 (1.7 μm, 2.1 mm×30 mm)

[0866] High performance liquid chromatography mass spectrometer; LC / MS measurement conditions are as follows, where the observed [MS (m / z)] is expressed as [M+H] + denoted by , and retention time is denoted by Rt (min). Each measured MS value shown in the working examples is accompanied by any of A to D, which are the measurement methods used in actual measurements.

[0867] Method A

[0868] Solvent: A; 0.06% formic acid / H2O, B; 0.06% formic acid / acetonitrile

[0869] Gradient conditions: 0.0-1.3 min (linear gradient from B 2% to B 96%)

[0870] Flow rate: 0.8 mL / min; UV detection: 220 nm and 254 nm; Temperature: 40°C

[0871] Hereinafter, the LC-MS data shown below were measured by Method A unless otherwise specified.

[0872] Method B

[0873] Solvent: A; 0.05% TFA / H2O, B; acetonitrile

[0874] Gradient conditions: 0.0-1.7 min (linear gradient from B 10% to B 99%)

[0875] Flow rate: 0.5 mL / min; UV detection: 220 nm; Temperature: 40°C

[0876] Method C

[0877] Solvent: A; 0.05% formic acid / H2O, B; acetonitrile

[0878] Gradient conditions: 0.0-1.3 min (linear gradient from B 10% to B 95%) 1.3-1.5 min (B 10%)

[0879] Flow rate: 0.8 mL / min; UV detection: 220 nm and 254 nm; Temperature: 40°C

[0880] Embodiment 1:

[0881] rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide

[0882]

[0883] To a mixture of Reference Example 1 (211 mg) (Material A), triethylamine (0.391 mL) and chloroform (3 mL) was added 4-nitrophenyl chloroformate (208 mg) at 0°C, and the mixture was stirred at the same temperature for 40 minutes. 4-(4-methylphenyl)piperidine hydrochloride (238 mg) (Material B) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (346 mg).

[0884] 1H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.04-1.11 (1H, m), 1.12-1.40 (3H, m), 1.58-1.71 (3H, m), 1.76-1.93 (4H, m), 2.27 (1H, dd, J = 10.4,3.6 Hz), 2.32 (3H, s), 2.35-2.54 (6H, m), 2.54-2.65 (3H, m), 2.65-2.75 (2H,m), 2.78-2.91 (2H, m), 3.25-3.33 (1H, m), 4.08-4.19 (2H, m), 5.76 (1H, s), 7.09 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz).

[0885] Embodiments 2 to 16:

[0886] The compounds of Examples 2 to 16 shown in the following table were prepared in the same manner as in Example 1 by using commercially available compounds corresponding to Material A and Material B described in Example 1 or Reference Example compounds.

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893] The chemical names of Examples 2 to 16 are listed below.

[0894] Example 2: Racemic-N-[(1R,2S)-2-(4-ethylpiperazin-1-yl)cyclohexyl]-4-(4-methylphenyl)piperidine-1-carboxamide

[0895] Example 3: rac-4-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide

[0896] Example 4: Racemic-N-{(1R,2S,6S)-2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide

[0897] Example 5: rac-4-(4-methylphenyl)-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclopentyl}piperidine-1-carboxamide

[0898] Example 6: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methyl-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclopentyl}piperidine-1-carboxamide

[0899] Example 7: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2S)-3,3-difluoro-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0900] Example 8: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(4-methylphenyl)piperidine-1-carboxamide

[0901] Example 9: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[0902] Example 10: 4-Methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[0903] Example 11: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine-1-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[0904] Example 12: 4-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine-1-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[0905] Example 13: 4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-4-methylpiperidine-1-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[0906] Example 14: (1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxylate

[0907] Example 15: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-4-methyl-N-{2-[6-(propan-2-yl)pyridin-3-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide

[0908] Example 16: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{2-[6-(propan-2-yl)pyridin-3-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide

[0909] Embodiment 17:

[0910] rac-N-[(1S,2S)-2-(4-ethylpiperazin-1-yl)cyclohexyl]-4-(4-methylphenyl)piperidine-1-carboxamide

[0911]

[0912] To a mixture of Reference Example 2 (73.7 mg), sodium acetate (18.9 mg), acetaldehyde (0.054 mL) and dichloromethane (2 mL) was added sodium triacetoxyborohydride (122 mg) at 0°C, and the mixture was warmed to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the obtained residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (24 mg).

[0913] 1H-NMR (CDCl3) δ: 1.02-1.12 (1H, m), 1.07 (3H, t, J = 7.3 Hz), 1.14-1.41 (3H, m), 1.57-1.71 (3H, m), 1.75-1.96 (5H, m), 2.16-2.78 (15H, m), 2.78-2.90 (2H, m), 3.24-3.39 (1H, m), 4.05-4.18 (2H, m), 5.72 (1H, s), 7.09 (2H,d, J = 7.9 Hz), 7.12 (2H, d, J = 7.9 Hz).

[0914] Embodiment 18:

[0915] rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{2-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]cyclohex-2-en-1-yl}piperidine-1-carboxamide

[0916]

[0917] To a solution of Reference Example 13 (13.5 mg) in chloroform (2 mL) was added a hydrogen chloride / acetic acid solution (4M, 0.198 mL), and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, the reaction mixture was concentrated in vacuo. Sodium acetate (8.66 mg), acetone (0.058 mL) and chloroform (2 mL) were added to the obtained residue. Sodium triacetoxyborohydride (33.6 mg) was added to the mixture at 0°C, and the mixture was warmed to room temperature and stirred. After the reaction was completed, water was added to the reaction mixture at ice temperature, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (10 mg).

[0918] 1H-NMR (CDCl3) δ: 1.07 (6H, d, J = 6.1 Hz), 1.17-1.22 (4H, m), 1.23-1.32 (2H, m), 1.29 (3H, s), 1.43-1.66 (3H, m), 1.91-1.98 (1H, m), 2.08-2.26(6H, m), 2.26-2.41 (1H, m), 2.50 (1H, ddd, J = 11.2, 7.2, 4.8 Hz), 2.63-2.76(2H, m), 2.97-3.13 (3H, m), 3.13-3.23 (1H, m), 3.52-3.63 (2H, m), 4.43 (1H,d, J = 7.3 Hz), 4.63-4.69 (1H, m), 5.78-5.84 (1H, m), 5.85-5.91 (1H, m).

[0919] Embodiment 19:

[0920] rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0921]

[0922] Triphosgene (27.1 mg) was added to a mixture of Reference Example 14 (84.6 mg) (Material A), triethylamine (0.318 mL) and chloroform (2 mL) at 0°C, and the mixture was stirred at the same temperature for 40 minutes. Reference Example 8 (66.7 mg) (Material B) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound (99.1 mg).

[0923] 1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 6.0 Hz), 1.01 (3H, d, J = 6.0 Hz), 1.17-1.22 (4H, m), 1.23-1.30 (1H, m), 1.30-1.48 (2H, m), 1.31 (3H, s), 1.57-1.70 (2H, m), 1.75-1.84 (1H, m), 1.89-1.97 (1H, m), 2.10-2.27 (4H, m), 2.32-2.53 (7H, m), 2.53-2.64 (1H, m), 2.68-2.78 (2H, m), 3.08 (1H, ddd, J = 13.6,10.7, 3.1 Hz), 3.16 (1H, ddd, J = 13.6, 10.7, 3.1 Hz), 3.66 (1H, ddd, J =13.6, 4.7, 4.1 Hz), 3.77 (1H, ddd, J = 13.6, 4.7, 4.1 Hz), 4.10-4.21 (1H, m), 4.54 (1H, d, J = 7.3 Hz).

[0924] Embodiments 20 to 76:

[0925] The compounds of Examples 20 to 76 shown in the following table were prepared in the same manner as in Example 19 by using commercially available compounds corresponding to Material A and Material B described in Example 19 or Reference Example compounds.

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949] The chemical names of Examples 20 to 76 are listed below.

[0950] Example 20: rac-4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0951] Example 21: rac-4-(1,3-benzoxazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0952] Example 22: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0953] Example 23: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0954] Example 24: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0955] Example 25: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0956] Example 26: rac-4-cyclopentyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0957] Example 27: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)piperidine-1-carboxamide

[0958] Example 28: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[0959] Example 29: rac-4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0960] Example 30: rac-4-(4,4-difluorocyclohexyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0961] Example 31: rac-4-(5-cyclopropyl-1,2,4-thiadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0962] Example 32: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(pyridin-2-yl)piperidine-1-carboxamide

[0963] Example 33: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-8-azaspiro[4.5]decane-8-carboxamide

[0964] Example 34: rac-4-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0965] Example 35: rac-4-cyclohexyl-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}piperidine-1-carboxamide

[0966] Example 36: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(pyrimidin-2-yl)piperidine-1-carboxamide

[0967] Example 37: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-hydroxy-4-(pyridin-2-yl)piperidine-1-carboxamide

[0968] Example 38: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-phenylpiperidine-1-carboxamide

[0969] Example 39: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-phenylpiperidine-1-carboxamide

[0970] Example 40: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-hydroxy-4-phenylpiperidine-1-carboxamide

[0971] Example 41: rac-4-(4-chlorophenyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-hydroxypiperidine-1-carboxamide

[0972] Example 42: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-[(pyridin-2-yl)oxy]piperidine-1-carboxamide

[0973] Example 43: 4-(5-cyclopropyl-1,2,4-thiadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0974] Example 44: 4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0975] Example 45: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methoxy-1,2,4-thiadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[0976] Example 46: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-fluoro-4-(pyridin-2-yl)piperidine-1-carboxamide

[0977] Example 47: rac-4-(2-cyclopropyl-1,3-thiazol-4-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0978] Example 48: rac-4-(5-cyclopropyl-1,3-thiazol-2-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0979] Example 49: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0980] Example 50: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methylpyridin-2-yl)piperidine-1-carboxamide

[0981] Example 51: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(3-fluoro-5-methylpyridin-2-yl)piperidine-1-carboxamide

[0982] Example 52: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-fluoropyridin-2-yl)piperidine-1-carboxamide

[0983] Example 53: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methoxypyridin-2-yl)piperidine-1-carboxamide

[0984] Example 54: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(5-methylpyrimidin-2-yl)piperidine-1-carboxamide

[0985] Example 55: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-[5-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide

[0986] Example 56: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-(2-fluoro-4-methylphenyl)-4-methylpiperidine-1-carboxamide

[0987] Example 57: 4-[5-(Cyclopropyloxy)-1,2,4-thiadiazol-3-yl]-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0988] Example 58: rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0989] Example 59: rac-4-[4-(difluoromethyl)phenyl]-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0990] Example 60: 4-(2-Cyano-4-methylphenyl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0991] Example 61: N-{(1R,6S)-2,2-difluoro-6-[6-(propan-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0992] Example 62: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0993] Example 63: N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0994] Example 64: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[0995] Example 65: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[0996] Example 66: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[0997] Example 67: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[0998] Example 68: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[0999] Example 69: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[1000] Example 70: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-[5-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxamide

[1001] Example 71: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1002] Example 72: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1003] Example 73: N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1004] Example 74: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[1005] Example 75: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1006] Example 76: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide

[1007] Embodiment 77:

[1008] rac-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4'-methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxamide

[1009]

[1010] To a solution of 4-(4-methylphenyl)-cyclohex-1-ene-carboxylic acid (64.3 mg) in chloroform (2 mL) was added oxalyl chloride (0.036 mL) and DMF (5 μL), and the mixture was stirred at room temperature for 3 hours. Then, the reaction solution was concentrated in vacuo, and chloroform (2 mL), triethylamine (0.120 mL) and Reference Example 14 (53.3 mg) were added to the reaction residue. The mixture was stirred. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (55.6 mg).

[1011] 1 H-NMR (CDCl3) δ: 1.02 (6H, d, J = 6.7 Hz), 1.23-1.50 (2H, m), 1.71-1.91 (4H, m), 1.93-2.11 (2H, m), 2.13-2.68 (14H, m), 2.69-2.89 (4H, m), 4.27-4.44 (1H, m), 5.68-5.77 (1H, m), 6.67-6.77 (1H, m), 7.09-7.20 (4H, m).

[1012] Embodiment 78:

[1013] 4'-Methyl-1,2,3,6-tetrahydro[1,1'-biphenyl]-4-carboxylic acid rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl ester

[1014] By using Reference Example 6 instead of Reference Example 14 in Example 77, the compound of Example 78 shown in the following table was prepared in the same manner as in Example 77.

[1015]

[1016] Embodiment 79:

[1017] rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide

[1018]

[1019] To a mixture of Reference Example 14 (10.0 mg) (Material A), N,N-diisopropylamine (0.034 mL) and chloroform (0.2 mL) was added thiophosgene (4.40 mg) at 0°C, and the mixture was stirred at the same temperature for 40 minutes. Reference Example 8 (66.7 mg) (Material B) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for one hour. The mixture was directly purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (9.6 mg).

[1020] 1 H-NMR (CDCl3) δ: 1.02 (6H, d, J = 5.6 Hz), 1.14-1.27 (4H, m), 1.27-1.50 (2H, m), 1.50-1.91 (8H, m), 1.91-2.04 (1H, m), 2.08-2.24 (2H, m), 2.24-2.35 (2H, m), 2.35-2.55 (5H, m), 2.55-2.70 (2H, m), 2.79-3.00 (2H, m), 3.33(1H, t, J = 11.2 Hz), 3.49 (1H, t, J = 11.2 Hz), 4.16 (1H, d, J = 12.8 Hz), 4.49 (1H, d, J = 12.8 Hz), 5.02-5.26 (1H, m), 5.42 (1H, d, J = 8.0 Hz).

[1021] Embodiment 80:

[1022] 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide

[1023] The compounds of Example 80 shown in the following table were prepared in the same manner as in Example 79 by using Reference Example 15 (corresponding to Material A in Example 79) and Reference Example 8 (corresponding to Material B in Example 79).

[1024]

[1025] Embodiment 81:

[1026] rac-4-(4-methylphenyl)-N-[(1S,4R)-3-{[4-(propan-2-yl)piperazin-1-yl]methyl}bicyclo[2.2.1]heptane-2-yl]piperidine-1-carboxamide

[1027]

[1028] TFA (0.057 ml) was added to a solution of Reference Example 40 (20 mg) in chloroform (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for one hour. The reaction solution was concentrated in vacuo, and the obtained residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate). The obtained residue was dissolved in chloroform (0.284 mL). N, N-diisopropylethylamine (36.8 mg) and triphosgene (8.4 mg) were added to the solution at 0°C, and the mixture was stirred at the same temperature for one hour. Then, 4-(4-methylphenyl)piperidine (0.057 mL) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was directly purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (8 mg).

[1029] 1 H-NMR (CDCl3) δ: 1.24 (6H, d, J = 7.3 Hz), 1.31-1.49 (7H, m), 1.54-1.67 (4H, m), 1.84 (2H, m), 2.24 (1H, m), 2.32 (3H, s), 2.63 (2H, m), 2.80-2.99 (4H, m), 3.06-3.49 (8H, m), 4.05-4.14 (3H, m), 7.07-7.13 (4H, m).

[1030] Examples 82 - 156:

[1031] The compounds of Examples 82 to 156 shown in the following table were prepared in the same manner as in Example 19 by using commercially available compounds corresponding to Material A and Material B described in Example 19 or Reference Example compounds.

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059] The chemical names of Examples 82 to 155 are listed below.

[1060] Example 82: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1061] Example 83: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1062] Example 84: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1063] Example 85: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[1064] Example 86: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1065] Example 87: N-[(1R,6S)-2,2-difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1066] Example 88: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1067] Example 89: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1068] Example 90: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1069] Example 91: N-[(1R,6S)-6-{benzyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1070] Example 92: N-[(1R,6S)-2,2-difluoro-6-{[2-(propan-2-yl)pyrimidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1071] Example 93: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1072] Example 94: N-{(1R,6S)-2,2-difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1073] Example 95: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1074] Example 96: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1075] Example 97: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[1076] Example 98: N-[(1R,6S)-2,2-difluoro-6-{[(1R,3S,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1077] Example 99: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1078] Example 100: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8R)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1079] Example 101: N-[(1R,6S)-2,2-difluoro-6-{4-[(propan-2-yl)oxy]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1080] Example 102: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1081] Example 103: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide

[1082] Example 104: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,8S)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1083] Example 105: N-[(1R,6S)-2,2-difluoro-6-{[(1R,3R,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1084] Example 106: N-[(1R,6S)-2,2-difluoro-6-{[(1R,5S,6S)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1085] Example 107: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1086] Example 108: N-[(1R,6S)-2,2-difluoro-6-{[(3R,4R)-4-methoxy-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1087] Example 109: N-[(1R,6S)-2,2-difluoro-6-{[4-methyl-1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1088] Example 110: N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1089] Example 111: N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1090] Example 112: N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1091] Example 113: N-[(1R,6S)-2,2-difluoro-6-{methyl[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1092] Example 114: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1093] Example 115: N-[(1R,6S)-6-{(3S)-3-[cyclopropyl(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1094] Example 116: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide

[1095] Example 117: N-[(1R,6R)-2,2-difluoro-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1096] Example 118: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1097] Example 119: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide

[1098] Example 120: N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1099] Example 121: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1100] Example 122: N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[1101] Example 123: N-[(1R,6S)-2,2-difluoro-6-{methyl[1-(propan-2-yl)piperidin-4-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1102] Example 124: N-{(1R,6S)-2,2-difluoro-6-[4-(pyrrolidin-1-yl)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1103] Example 125: N-{(1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1104] Example 126: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide

[1105] Example 127: N-{(1R,6S)-2,2-difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decan-8-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1106] Example 128: N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1107] Example 129: N-{(1R,6S)-6-[4-(diethylamino)piperidin-1-yl]-2,2-difluorocyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1108] Example 130: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide

[1109] Example 131: N-[(1R,6S)-2,2-difluoro-6-{4-methyl-4-[methyl(propan-2-yl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1110] Example 132: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazine-1-carbonyl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1111] Example 133: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1112] Example 134: N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1113] Example 135: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1114] Example 136: N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1115] Example 137: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1116] Example 138: N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide

[1117] Example 139: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[1118] Example 140: N-{(1R,6S)-2,2-difluoro-6-[4-(methyl{[1-(trifluoromethyl)cyclopropyl]methyl}amino)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1119] Example 141: N-[(1R,6S)-6-{(1R,3R,5S)-3-[(cyclopropylmethyl)(methyl)amino]-8-azabicyclo[3.2.1]octan-8-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1120] Example 142: N-[(1R,6S)-6-{(1R,3S,5S)-3-[(cyclopropylmethyl)(methyl)amino]-8-azabicyclo[3.2.1]octan-8-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1121] Example 143: N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1122] Example 144: N-[(1R,6S)-6-{(4S)-4-[(cyclopropylmethyl)(methyl)amino]azepan-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1123] Example 145: N-[(1R,6S)-6-{(4R)-4-[(cyclopropylmethyl)(methyl)amino]azepan-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1124] Example 146: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N,4-dimethylpiperidine-1-carboxamide

[1125] Example 147: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[1126] Example 148: N-[(1R,6S)-2,2-difluoro-6-{3-[methyl(propan-2-yl)amino]azetidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1127] Example 149: N-[(1R,6S)-6-{3-[(cyclopropylmethyl)(methyl)amino]azetidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1128] Example 150: N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1129] Example 151: rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-N-{(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cycloheptyl}piperidine-1-carboxamide

[1130] Example 152: N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1131] Example 153: (1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carbonyl)amino]cyclohexyl 4-(propan-2-yl)piperazine-1-carboxylate

[1132] Example 154: N-[(1S,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]sulfanyl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1133] Example 155: N-{(1S,6S)-2,2-difluoro-6-[1-(propan-2-yl)piperidine-4-sulfonyl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide.

[1134] The compound of Reference Example 124 described above, which is a mixture of diastereomers, and the intermediates for preparing the compound can be obtained as individual enantiomers by optical resolution using chiral column chromatography or by crystallization using an acid having a chiral center. In addition, by using an optically active epoxide as a starting material, the compound of Reference Example 124 as an individual enantiomer can also be prepared. Thus, when Reference Example 124 as the starting material A is further identified by separation or asymmetric synthesis, the diastereomer mixture of Example 156 can be prepared as each diastereomer.

[1135] Additionally, the compound of Example 156 can be obtained as a single enantiomer as a mixture of diastereomers by optical resolution using chiral column chromatography or by crystallization with an acid having a chiral center. Thus, the two diastereomers of Example 156 can be separated into their individual diastereomers.

[1136] The compound of Example 156 is a diastereomeric mixture comprising two different diastereomers. These diastereomers can be separated by their method or by optical resolution using chiral column chromatography. This means that essentially two different diastereomers are prepared.

[1137] serial number Chemical structures of diastereomers Chemical name 156-A #timg# 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 156-B #timg# 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1S,2R,6R)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide

[1138] Examples 157 - 160:

[1139] The compounds of Examples 157 to 160 shown in the following table were prepared according to the method in Example 17 by using the compound of Reference Example 80 and each appropriate commercially available aldehyde or ketone compound.

[1140]

[1141]

[1142] The chemical names of Examples 157 to 160 are listed below.

[1143] Example 157: N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1144] Example 158: N-[(1R,6S)-6-{4-[(cyclopropylmethyl)(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1145] Example 159: N-[(1R,6S)-6-{4-[cyclobutyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1146] Example 160: N-[(1R,6S)-6-{4-[ethyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1147] Example 161:

[1148] N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1149]

[1150] To a mixture of reference example 90 (175 mg) and ethanol (1.3 mL) was added palladium on carbon (6.4 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere. After the reaction was terminated by LC-MS, the reaction mixture was filtered with Celite and concentrated in vacuo. Then, the resulting residue was purified by HPLC (eluent: acetonitrile / water / TFA) to obtain the title compound (44.1 mg).

[1151] 1 H-NMR (CDCl3) δ: 1.03-1.31 (2H, m), 1.13 (6H, d, J = 6.0 Hz), 1.34(3H, s), 1.38-1.88 (13H, m), 1.91-2.23 (3H, m), 2.27 (2H, d, J = 13.2 Hz),2.33-2.42 (1H, m), 2.42-2.54 (1H, m), 2.95-3.21 (2H, m), 3.32-3.54 (1H, brs),3.58-3.80 (2H, m), 3.91-4.08 (1H, m), 4.65 (1H, d, J = 9.2 Hz), 4.93 (1H,dddd, J = 63.6, 6.4, 6.4, 4.0 Hz).

[1152] Reference Example 1:

[1153] rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1154]

[1155] Step (i):

[1156] In a mixture of compound 1 (1.13 g) and dichloromethane (2 mL) was added 1-isopropylpiperazine (1.14 g) at room temperature, and the mixture was stirred for 17 hours. After the reaction was terminated as judged by the consumption of the starting material, ether was added to the reaction mixture. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to produce a crude product. The crude product obtained was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 2 (1.82 g).

[1157] LCMS: [M+H] + / Rt (min): 256 / 0.48

[1158] Step (ii):

[1159] Palladium / carbon (0.95 g) was added to a mixture of compound 2 (1.14 g), acetic acid (2.04 mL) and ethanol (15 mL) at room temperature, and the mixture was stirred for 18 hours under a hydrogen atmosphere. After the reaction was terminated by LC-MS, the reaction mixture was filtered with Celite and concentrated in a vacuum. The residue obtained was then purified by amino silica gel column chromatography (eluent: chloroform) to obtain title compound 3 (0.370 g).

[1160] LCMS: [M+H] + / Rt (min): 226 / 0.31

[1161] Reference Example 2:

[1162] 4-(4-Methylphenyl)-N-[(1S,2S)-2-(piperazin-1-yl)cyclohexyl]piperidine-1-carboxamide dihydrochloride

[1163]

[1164] Step (i):

[1165] The title compound 4 (1.28 g) was prepared in the same manner as in step (i) in Reference Example 1 by using Compound 1 (1.17 g) and 1-Boc-piperazine (1.72 g).

[1166] Step (ii):

[1167] To a solution of compound 4 (593 mg) in ethanol (9 mL) was added palladium hydroxide (266 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere. After the reaction was judged to be terminated by LC-MS, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to obtain the title compound 5 (560 mg).

[1168] Step (iii):

[1169] To a mixture of compound 5 (370 mg), triethylamine (0.91 mL) and dichloromethane (5 mL) was added 4-nitrophenyl chloroformate (316 mg) at 0°C, and the mixture was stirred for 2 hours. Then, 4-(4-methylphenyl)piperidine (297 mg) was added to the reaction mixture at 0°C, and stirring was continued at room temperature. After the reaction was terminated as judged by the consumption of the reaction intermediate, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 6 (435 mg).

[1170] Step (iv):

[1171] To a mixture of compound 6 (430 mg) and chloroform (3 mL) was added hydrogen chloride / dioxane solution (4 M, 2.22 mL) at 0° C., and the mixture was stirred for 16 hours. Then, the reaction mixture was concentrated in vacuo to give the title compound 7 (310 mg).

[1172] LCMS: [M+H] + / Rt (min): 385 / 0.71

[1173] Reference Example 3:

[1174] rac-(1R,2S)-2-(4-ethylpiperazin-1-yl)cyclohexane-1-amine

[1175]

[1176] Step (i):

[1177] To a mixture of compound 8 (312 mg) and acetic acid (5 mL) was added platinum (IV) oxide (86 mg), and the mixture was stirred at 70 ° C under a hydrogen atmosphere for 6 hours. Then, the reaction mixture was filtered with Celite, and the filtrate was concentrated in a vacuum to produce a crude product. The crude product obtained was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain title compound 9 (9 mg).

[1178] LCMS: [M+H] + / Rt (min): 212 / 0.15

[1179] Reference Example 4:

[1180] rac-(1R,2S,6S)-2-methoxy-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine trihydrochloride

[1181]

[1182] Step (i):

[1183] The title compound 11 (424 mg) was prepared in the same manner as in step (i) in Reference Example 3 by using Compound 10 (407 mg).

[1184] LCMS: [M+H] + / Rt (min): 146 / 0.15

[1185] Step (ii):

[1186] In a mixture of compound 11 (424 mg), triethylamine (1.22 mL) and acetonitrile (10 mL), Boc2O (765 mg) was added at room temperature, and the mixture was stirred at room temperature. After the reaction was terminated by LC-MS, 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 in vacuo, and the residue obtained was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain title compound 12 (310 mg).

[1187] LCMS: [M+H] + / Rt (min): 246 / 0.78

[1188] Step (iii):

[1189] To a mixture of compound 12 (141 mg), triethylamine (0.160 mL) and THF (3 mL) was added ethanesulfonyl chloride (0.160 mL) at ice temperature, and the mixture was warmed to room temperature and continued to stir. After the reaction was terminated by LC-MS, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 13 (180 mg).

[1190] LCMS: [M+H] + / Rt (min): 338 / 0.86

[1191] Step (iv):

[1192] Potassium carbonate (76 mg) was added to a mixture of compound 13 (155 mg), 1-isopropylpiperazine (236 mg) and 1,4-dioxane (4 mL) at room temperature, and the mixture was stirred for 13 hours while heating with a microwave apparatus at 150 ° C. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 14 (17 mg).

[1193] LCMS: [M+H] + / Rt (min): 356 / 0.81

[1194] Step (v):

[1195] The title compound 15 (16.8 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 14 (16.3 mg).

[1196] LCMS: [M+H] + / Rt (min): 256 / 0.32

[1197] Reference Example 5:

[1198] rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cyclopentan-1-amine

[1199]

[1200] Step (i):

[1201] To a mixture of compound 16 (315 mg), triethylamine (0.289 mL) and THF (5 mL), ethanesulfonyl chloride (0.15 mL) was added, and the mixture was stirred at room temperature for 15 hours. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain title compound 17 (140 mg).

[1202] LCMS: [M+H] + / Rt (min): 231 / 0.44

[1203] Step (ii):

[1204] Sodium azide (77 mg) was added to a mixture of compound 17 (136 mg) and DMF (4 mL), and the mixture was stirred at 80 ° C for 3.5 hours. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 18 (137 mg).

[1205] LCMS: [M+H] + / Rt (min): 238 / 0.42

[1206] Step (iii):

[1207] Palladium / carbon (202 mg) was added to a mixture of compound 18 (42.4 mg), hydrogen chloride / ethyl acetate solution (4.0 M, 0.711 mL) and ethanol (2.8 mL), and the mixture was stirred for 8 hours under a hydrogen atmosphere. After the reaction was terminated by LC-MS, methanol and sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was filtered with Celite and extracted with chloroform / methanol (6 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in a vacuum, and the residue obtained was then purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain title compound 19 (98.7 mg).

[1208] LCMS: [M+H] + / Rt (min): 212 / 0.15

[1209] Reference Example 6:

[1210] Rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-ol

[1211]

[1212] Step (i):

[1213] 1-isopropylpiperazine (723 mg) was added to a mixture of compound 20 (688 mg) and ethanol (20 mL) at room temperature, and the mixture was stirred for 9 hours while heating at 80°C. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 21 (830 mg).

[1214] LCMS: [M+H] + / Rt (min): 263 / 0.35

[1215] Reference Example 7:

[1216] rac-(1R,2S)-3,3-difluoro-2-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1217]

[1218] Step (i):

[1219] Oxalyl chloride (0.075 mL) was added to a mixture of DMSO (0.081 mL) and dichloromethane (2 mL) at -78 ° C, and the mixture was stirred for 20 minutes. Then, a solution of compound 21 (150 mL) in dichloromethane (2 mL) was added to the reaction mixture, and the mixture was further stirred at -78 ° C for 30 minutes. Triethylamine (0.398 mL) was added to the reaction mixture, and the mixture was warmed to 0 ° C. Then, the mixture was stirred for 30 minutes, and sodium borohydride was added thereto. The mixture was stirred for 30 minutes. In addition, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue obtained was then purified by silica gel column chromatography (eluent: chloroform / methanol) to obtain title compound 22 (27 mg).

[1220] LCMS: [M+H] + / Rt (min): 263 / 0.38

[1221] Step (ii):

[1222] To a mixture of compound 22 (27 mg), triethylamine (0.029 mL) and THF (2 mL), ethanesulfonyl chloride (0.015 mL) was added, and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 23 (23 mg).

[1223] LCMS: [M+H] + / Rt (min): 354 / 0.65

[1224] Step (iii):

[1225] The title compound 24 (16.0 mg) was prepared in the same manner as in step (ii) in Reference Example 5 by using Compound 23 (23.4 mg).

[1226] LCMS: [M+H] + / Rt (min): 288 / 0.60

[1227] Step (iv):

[1228] Triphenylphosphine (25.6 mg) was added to a mixture of compound 24 (14 mg), THF (1 mL) and water (1 mL) at room temperature, and the mixture was stirred for 4.5 hours while heating at 50 ° C. Then, the reaction mixture was cooled to room temperature, and aqueous hydrochloric acid solution was added thereto. The mixture was washed with ethyl acetate, and aqueous sodium bicarbonate solution was added to the water layer. The obtained mixture was extracted with chloroform / methanol (3 / 1). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the title compound 25 (7.8 mg).

[1229] LCMS: [M+H] + / Rt (min): 262 / 0.31

[1230] Reference Example 8:

[1231] 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride

[1232]

[1233] Step (i):

[1234] To a solution of compound 26 (50.0 g) in ethanol (446 mL) was added 50% hydroxylamine aqueous solution (132 mL), and the mixture was stirred at 70 ° C for 8 hours. The reaction mixture was cooled to room temperature, and water (892 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The precipitated white crystals were collected on a filter, the obtained crystals were suspended in water (344 mL) again, and the suspension was stirred at room temperature for 30 minutes. The precipitated white solid was collected on a filter and dried to obtain the title compound 27 (52.3 g).

[1235] LCMS: [M+H] + / Rt (min): 258 / 0.52 (Method C)

[1236] Step (ii):

[1237] In an ice bath, triethylamine (142 mL) was slowly added dropwise to a mixture of compound 27 (52.3 g), cyclopropanecarboxylic acid (18.4 g), HATU (85 g) and THF (406 mL), and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (406 mL) was added to the reaction mixture, and the mixture was washed with water (406 mL) and brine (406 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 28 (59.1 g).

[1238] LCMS: [M+H] + / Rt (min): 326 / 0.77 (Method C)

[1239] Step (iii):

[1240] A mixture of compound 28 (59.1 g), DBU (54.2 mL) and toluene (727 mL) was stirred under reflux for one hour. The reaction mixture was cooled to room temperature and washed with water (727 mL). The organic layer was concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 29 (54.5 g).

[1241] LCMS: [M+H] + / Rt (min): 308 / 1.11

[1242] Step (iv):

[1243] The title compound 30 (35.3 g) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 29 (54.5 g).

[1244] LCMS: [M+H] + / Rt (min): 208 / 0.30 (Method C)

[1245] Reference Examples 9 to 12'

[1246] The compounds of Reference Examples 9 to 12' shown in the following table were prepared according to the method in Reference Example 8 above by using each appropriate starting compound in place of cyclopropanecarboxylic acid at step (ii) in Reference Example 8.

[1247]

[1248]

[1249] Reference Example 9: 4-(5-ethyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride

[1250] Reference Example 10: 4-[5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl]-4-methylpiperidine monohydrochloride

[1251] Reference Example 11: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine monohydrochloride

[1252] Reference Example 12: 4-Methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine monohydrochloride

[1253] Reference Example 12': 4-Methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine monohydrochloride

[1254] Reference Example 13:

[1255] 4-(6-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carbonyl]amino}cyclohex-1-en-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1256]

[1257] Step (i):

[1258] Sodium borohydride (51.4 mg) was added to a mixture of compound 35 (192 mg), cerium (III) chloride heptahydrate (309 mg) and methanol (3 mL) at ice temperature, and the mixture was stirred at the same temperature for 3 hours. Sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (6 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain title compound 36 (120 mg).

[1259] LCMS: [M+H] + / Rt (min): 280 / 0.97

[1260] Step (ii):

[1261] To a mixture of compound 36 (115 mg), triethylamine (0.143 mL) and THF (2 mL) was added ethanesulfonyl chloride (0.058 mL) at ice temperature, and the mixture was stirred for 30 minutes. Then, sodium azide (107 mg) was added to the reaction solution. The mixture was warmed to room temperature, and the mixture was then stirred. After the reaction was terminated as judged by the consumption of the reaction intermediate, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 37 (80 mg).

[1262] LCMS: [M+H] + / Rt (min): 305 / 1.25

[1263] Step (iii)

[1264] The title compound 38 (35 mg) was prepared in the same manner as in step (iv) in Reference Example 7 by using Compound 37 (73 mg).

[1265] LCMS: [M+H] + / Rt (min): 279 / 0.74

[1266] Step (iv)

[1267] The title compound 39 (14.0 mg) was prepared in the same manner as in step (iii) in Reference Example 2 by using Compound 38 (14.4 mg).

[1268] LCMS: [M+H] + / Rt (min): 512 / 1.14

[1269] Reference Example 14:

[1270] rac-(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine trihydrochloride

[1271]

[1272] Step (i):

[1273] The title compound 41 (1.59 g) was prepared in the same manner as in step (ii) in Reference Example 4 by using Compound 40 (1.69 g).

[1274] LCMS: [M+H] + / Rt (min): 252 / 0.73

[1275] Step (ii):

[1276] Potassium tert-butoxide (1.01 g) was added to a mixture of compound 41 (1.5 g) and THF (30 mL) at ice temperature, and the mixture was stirred at the same temperature for 20 minutes. Then, tosyl chloride (1.37 g) was added to the reaction mixture at ice temperature, and the reaction mixture was further stirred for 2.5 hours. Water was added to the reaction mixture at ice temperature, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in 1,4-dioxane (30 mL), and tosyl chloride (1.37 g) was added to the solution at ice temperature. The solution was heated to 100 ° C and stirred for 30 minutes. The reaction solution was cooled to room temperature, and an aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with chloroform / ethanol (3 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 42 (1.09 g).

[1277] LCMS: [M+H] + / Rt (min): 234 / 1.01

[1278] Step (iii):

[1279] A mixture of compound 42 (1.09 g), 1-isopropylpiperazine (0.899 g) and ethanol (10 mL) was stirred for 8 hours while heating with a microwave apparatus at 120° C. Then, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 43 (1.32 g).

[1280] LCMS: [M+H] + / Rt (min): 362 / 0.74

[1281] Step (iv):

[1282] The title compound 44 (1.40 g) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 43 (1.31 g).

[1283] LCMS: [M+H] + / Rt (min): 262 / 0.19

[1284] Reference Examples 15 to 17

[1285] The compounds of Reference Examples 15 to 17 shown in the following table were prepared according to the method in Reference Example 14 above by using an optically active isomer of Compound 40 (as material A) instead of Compound 40 at step (i) in Reference Example 14 and using each appropriate starting compound (as material B) instead of 1-isopropylpiperazine at step (iii) in Reference Example 14.

[1286]

[1287] Reference Example 15: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine trihydrochloride

[1288] Reference Example 15': (1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1289] Reference Example 16: (1R,6S)-2,2-Difluoro-6-[6-(propan-2-yl)-3,6-diazabicyclo[3.1.1]heptane-3-yl]cyclohexane-1-amine

[1290] Reference Example 17: (1R,6S)-2,2-Difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexane-1-amine

[1291] Reference Example 18:

[1292] (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1293]

[1294] Step (i):

[1295] 2-nitrobenzenesulfonyl chloride (10.5 g) was added to a mixture of compound 48 (5.94 g), sodium bicarbonate (13.2 g) and THF (131 mL) at room temperature, and the mixture was stirred at the same temperature for 16 hours. Sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in THF (131 mL), and triethylamine (11 mL) and methanesulfonyl chloride (3.67 mL) were added to the solution at ice temperature. The mixture was stirred. After the reaction was terminated by judging the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in acetonitrile (393 mL), and potassium carbonate (16.3 mg) was added to the solution. The mixture was stirred for one hour while being heated at 80°C. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 49 (9.25 g).

[1296] LCMS: [M+H] + / Rt (min): 319 / 0.94

[1297] Step (ii):

[1298] A mixture of compound 49 (7.1 g), 1-isopropylpiperazine (3.56 mL) and toluene (22.3 mL) was stirred for one hour while heating at 110° C. After the reaction was terminated as judged by the consumption of the starting material, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound 50 (9.79 g).

[1299] LCMS: [M+H] + / Rt (min): 447 / 0.68

[1300] Step (iii):

[1301] Sodium hydride (55%, 0.215 g) was added to a mixture of thiophenol (0.530 mL) and toluene (11.2 mL) at ice temperature, and the mixture was warmed to room temperature and stirred for 10 minutes. Then, a solution of compound 50 (1g) in toluene (9 mL) was added to the reaction mixture, and the mixture was stirred while heating at 60°C. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was cooled to 0°C, and a 40% aqueous sodium hydroxide solution was added to the reaction mixture. The mixture was extracted with toluene. 5 M hydrochloric acid was added to the organic layer at ice temperature, and the water layer was extracted from the mixture. A 40% aqueous sodium hydroxide solution was added to the obtained water layer, and the obtained mixture was extracted with toluene again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 51 (0.47 g).

[1302] LCMS: [M+H] + / Rt (min): 262 / 0.17

[1303] Reference Example 19:

[1304] 2-(4-Methylpiperidin-4-yl)-4,5,6,7-tetrahydro-1,3-benzoxazole

[1305]

[1306] Step (i):

[1307] A mixture of compound 52 (120 mg), 2-chlorocyclohexanone (68.9 mg) and DMF (1.5 mL) was stirred for 11 hours while heating at 130 ° C with a microwave apparatus. Then, hydrogen chloride / 1,4-dioxane solution (0.25 mL) was added to the reaction solution, and the mixture was stirred for 6 hours while heating at 130 ° C with a microwave apparatus. The reaction solution was concentrated in a vacuum, and the obtained residue was dissolved in ethanol. 15% sodium hydroxide aqueous solution (2 mL) was added to the solution, and the mixture was stirred for 3 hours while heating at 150 ° C with a microwave apparatus. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in a vacuum, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 53 (14 mg).

[1308] LCMS: [M+H] + / Rt (min): 221 / 0.57

[1309] Reference Example 20:

[1310] 4-(5-Cyclopropyl-1,2-oxazol-3-yl)-4-methylpiperidine monohydrochloride

[1311]

[1312] Step (i):

[1313] To a mixture of compound 54 (900 mg), sodium acetate (650 mg) and methanol (5 mL) was added hydroxylamine hydrochloride (550 mg), and the mixture was stirred at room temperature for 24 hours. The reaction solution was cooled to 0 ° C, and water was added thereto. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound 55 (1.23 g).

[1314] Step (ii):

[1315] To a mixture of compound 55 (416 mg) and DMF (4 mL) was added N-chlorosuccinimide (252 mg), and the mixture was stirred for 3 hours. The reaction solution was cooled to 0°C, and water (6 mL) was added thereto. The precipitated solid was collected on a filter and dried to obtain the title compound 56 (326 mg).

[1316] Step (iii):

[1317] Compound 56 (326 mg) and sodium bicarbonate (198 mg) were added to a mixture of ethynylcyclopropane (117 mg) and toluene (5 mL), and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, 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 in vacuo. Then, the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 57 (348 mg).

[1318] LCMS: [M+H] + / Rt (min): 307 / 1.13

[1319] Step (iv):

[1320] The title compound 58 (307 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 57 (337 mg).

[1321] LCMS: [M+H] + / Rt (min): 207 / 0.49

[1322] Reference Example 21

[1323] 2-(4-Methylpiperidin-4-yl)-1,3-benzoxazole

[1324]

[1325] Step (i):

[1326] Isobutyl chloroformate (819 mg) and diisopropylethylamine (3.88 g) were added to a solution of compound 59 (1.46 g) in THF (30 mL) at ice temperature, and the mixture was stirred for one hour. 2-Aminophenol (655 mg) was added to the reaction mixture at ice temperature, and the mixture was stirred for 6 hours while heating at 70°C. The reaction solution was directly purified by amino silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 60 (710 mg).

[1327] LCMS: [M+H] + / Rt (min): 335 / 2.28 (Method B)

[1328] Step (ii):

[1329] The mixture of compound 60 (204 mg) and acetic acid (1.10 mL) was stirred for 2 hours while heating at 90 ° C, and concentrated in vacuo. The obtained residue was dissolved in chloroform (2 mL), and trifluoromethanesulfonic acid (2.1 mL) was added to the solution. The mixture was stirred at room temperature for one hour. The reaction solution was concentrated in a vacuum, and ethyl acetate and sodium bicarbonate aqueous solution were added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in a vacuum, and the obtained residue was then purified by amino silica gel column chromatography (eluent: ethyl acetate / hexane) to produce title compound 61 (99 mg).

[1330] LCMS: [M+H] + / Rt (min): 217 / 1.36 (Method B)

[1331] Reference Example 22

[1332] 4-Cyclopentyl-4-methylpiperidine monohydrochloride

[1333]

[1334] Step (i):

[1335] To a mixture of compound 62 (700 mg) and THF (14 mL) was added lithium diisopropylamide (2M, 5.18 mL) at -78 ° C, and the mixture was stirred at the same temperature for 2 hours. Bromocyclopentane (1.23 mL) and potassium iodide (478 mg) were added to the reaction mixture, and the mixture was warmed to room temperature. The mixture was stirred overnight, and water was then added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain title compound 63 (468 mg).

[1336] LCMS: [M+H] + / Rt (min): 312 / 1.26

[1337] Step (ii):

[1338] Compound 63 (371 mg) and THF (6 mL) were added to a mixture of lithium aluminum hydride (104 mg) and THF (3 mL) at ice temperature, and the mixture was stirred for 4 hours. After the reaction was terminated as judged by the consumption of the starting material, water (0.104 mL), 15% aqueous sodium hydroxide solution (0.104 mL), and then water (0.312 mL) were added to the reaction mixture at 0°C, and the mixture was stirred. The reaction mixture was filtered. The filtrate was concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound 64 (320 mg).

[1339] LCMS: [M+H] + / Rt (min): 284 / 1.06

[1340] Step (iii):

[1341] Methanesulfonyl chloride (0.104 mL) was added to a mixture of compound 64 (314 mg), triethylamine (0.309 mL) and THF (5 mL), and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue obtained was then purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain title compound 65 (290 mg).

[1342] LCMS: [M+H] + / Rt (min): 362 / 1.15

[1343] Step (iv):

[1344] To a mixture of compound 65 (278 mg) and THF (3 mL) was added lithium triethylborohydride (0.99 M, 1.55 mL), and the mixture was stirred at room temperature. Then, the reaction solution was heated to 70°C. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was cooled to 0°C, and an aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Then, the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 66 (100 mg).

[1345] LCMS: [M+H] + / Rt (min): 268 / 1.42

[1346] Step (v):

[1347] The title compound 67 (58.5 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using compound 66 (90 mg).

[1348] LCMS: [M+H] + / Rt (min): 168 / 0.62

[1349] Reference Example 23:

[1350] 4-(4,4-Difluorocyclohexyl)-4-methylpiperidine monohydrochloride

[1351] By using 1,1-difluoro-4-iodocyclohexane instead of bromocyclopentane at step (i) in Reference Example 22, the compound of Reference Example 23 shown in the following table was prepared according to the method in Reference Example 22 above.

[1352]

[1353] Reference Example 24:

[1354] 4-(5-Cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methylpiperidine monohydrochloride

[1355]

[1356] Step (i):

[1357] To a mixture of compound 59 (399 mg), cyclopropanecarbohydrazide hydrochloride (269 mg) and DMF (5 mL), HATU (686 mg) and diisopropylethylamine (1.15 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain title compound 69 (520 mg).

[1358] LCMS: [M+H] + / Rt (min): 326 / 0.74

[1359] Step (ii):

[1360] To a mixture of compound 69 (255 mg) and toluene (6 mL) was added Lawesson's reagent (349 mg), and the mixture was stirred under reflux for one hour. The reaction solution was cooled to 0°C, and an aqueous sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate), and then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 70 (102 mg).

[1361] LCMS: [M+H] + / Rt (min): 324 / 1.08

[1362] Step (iii):

[1363] The title compound 71 (78 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 70 (92 mg).

[1364] LCMS: [M+H] + / Rt (min): 224 / 0.45

[1365] Reference Example 25:

[1366] 4-(5-Cyclopropyl-1,3-thiazol-2-yl)-4-methylpiperidine monohydrochloride

[1367]

[1368] Step (i):

[1369] The title compound 72 (796 mg) was prepared in the same manner as in step (i) in Reference Example 24 by using Compound 59 (718 mg) and 2-amino-1-cyclopropylethan-1-one hydrochloride (400 mg).

[1370] LCMS: [M+H] + / Rt (min): 325 / 0.83

[1371] Step (ii):

[1372] To a mixture of compound 72 (127 mg), pyridine (0.063 mL) and toluene (3 mL) was added Lawesson's reagent (205 mg), and the mixture was stirred at reflux for 14 hours. The reaction solution was cooled to room temperature, and then an aqueous sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 73 (76.3 mg).

[1373] LCMS: [M+H] + / Rt (min): 323 / 1.43

[1374] Step (iii):

[1375] The title compound 74 (66.5 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 73 (77 mg).

[1376] LCMS: [M+H] + / Rt (min): 223 / 0.67

[1377] Reference Example 26:

[1378] 4-(2-Cyclopropyl-1,3-thiazol-4-yl)-4-methylpiperidine monohydrochloride

[1379]

[1380] Step (i):

[1381] A solution of compound 75 (532 mg) and cyclopropanethiocarboxamide (168 mg) in methanol (6 mL) was stirred under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and then a saturated sodium bicarbonate aqueous solution was added to the reaction mixture. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 76 (119 mg).

[1382] Step (ii):

[1383] The title compound 77 (137 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 76 (119 mg).

[1384] LCMS: [M+H] + / Rt (min): 223 / 0.572

[1385] Reference Example 27:

[1386] 4-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-4-methylpiperidine dihydrochloride

[1387]

[1388] Step (i):

[1389] The title compound 78 (648 mg) was prepared in the same manner as in step (i) in Reference Example 24 by using Compound 59 (611 mg) and cyclopropylhydrazine hydrochloride (300 mg).

[1390] LCMS: [M+H] + / Rt (min): 298 / 0.80

[1391] Step (ii):

[1392] A mixture of compound 78 (374 mg), ammonium formate (1.43 g) and trimethyl orthoformate (2.78 mL) was stirred while heating at 100°C. After the reaction was completed, the reaction solution was concentrated. Water was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 79 (163 mg).

[1393] LCMS: [M+H] + / Rt (min): 307 / 0.89

[1394] Step (iii):

[1395] The title compound 80 (142 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 79 (144 mg).

[1396] LCMS: [M+H] + / Rt (min): 207 / 0.39

[1397] Reference Example 28:

[1398] 4-(5-Cyclopropyl-1,2,4-thiadiazol-3-yl)-4-methylpiperidine

[1399]

[1400] Step (i):

[1401] To a solution of compound 27 (1.04 g) in THF (15 mL) was added thiocarbonyl imidazole (0.864 mg) at ice temperature, and the mixture was stirred at room temperature. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was cooled to 0°C, and water was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo.

[1402] The obtained residue was dissolved in THF (15 mL), and boron trifluoride-ether complex (1.52 mL) was added to the solution at 0°C. The mixture was warmed to room temperature under stirring. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate).

[1403] To the solution of the purified compound in THF (15 mL) was added hydrogen chloride / dioxane solution (4 M, 5.05 mL) at 0°C, and the mixture was warmed to room temperature and stirred. After the reaction was completed, the reaction solution was concentrated in vacuo, and the obtained residue was dissolved in THF (15 mL). Triethylamine (3.38 ml) and 2-nitrobenzenesulfonyl chloride (0.985 g) were added to the solution, and the mixture was stirred at room temperature. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 81 (627 mg).

[1404] LCMS: [M+H] + / Rt (min): 385 / 0.93

[1405] Step (ii):

[1406] Phosphorus oxychloride (0.572 mL) was added to a mixture of compound 81 (590 mg), pyridine (0.248 mL) and toluene (7 mL), and the mixture was stirred under reflux. After the reaction was completed, the reaction solution was added to an aqueous sodium bicarbonate solution at 0°C, and the mixture was filtered. The filtrate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 82 (432 mg).

[1407] LCMS: [M+H] + / Rt (min): 403 / 1.21

[1408] Step (iii):

[1409] To a mixture of compound 82 (210 mg), cyclopropylzinc (II) bromide (0.5 M, 3.13 mL) and THF (2 mL) was added tetrakis (triphenylphosphine) palladium (0) (30.1 mg), and the mixture was stirred at 60 ° C for 1.5 hours. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 83 (84 mg).

[1410] LCMS: [M+H] + / Rt (min): 409 / 1.24

[1411] Step (iv):

[1412] Potassium carbonate (145 mg) was added to a mixture of compound 83 (71.4 mg), 1-dodecanethiol (0.251 mL) and acetonitrile (3 mL), and the mixture was stirred at 80°C. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform / methanol (6 / 1). The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate => chloroform / methanol) to obtain the title compound 84 (38 mg).

[1413] LCMS: [M+H]+ / Rt (min): 224 / 0.52

[1414] Reference Example 29:

[1415] 4-(5-Methoxy-1,2,4-thiadiazol-3-yl)-4-methylpiperidine

[1416]

[1417] Step (i):

[1418] To a solution of compound 82 (119 mg) in methanol (2 mL) was added sodium methoxide (28%, 285 mg), and the mixture was stirred at room temperature. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was concentrated in vacuo to obtain the title compound 85 (97.1 mg).

[1419] LCMS: [M+H] + / Rt (min): 399 / 1.18

[1420] Step (ii):

[1421] The title compound 86 (14.9 mg) was prepared in the same manner as in step (iv) in Reference Example 28 by using Compound 85 (91.6 mg).

[1422] LCMS: [M+H] + / Rt (min): 214 / 0.48

[1423] Reference Example 30:

[1424] 4-[5-(Cyclopropyloxy)-1,2,4-thiadiazol-3-yl]-4-methylpiperidine

[1425] By using cyclopropanol and sodium hydride instead of sodium methoxide at step (i) in Reference Example 29, the compound of Reference Example 30 shown in the following table was prepared according to the method in the above Reference Example 29.

[1426]

[1427] Reference Example 31:

[1428] 2-[(4-Methylpiperidin-4-yl)oxy]pyridine monohydrochloride

[1429]

[1430] Step (i):

[1431] To a solution of compound 88 (183 mg) in DMF (2 mL) was added sodium hydride (55%, 48.2 mg) at ice temperature, and the mixture was stirred for 20 minutes. 2-Fluoropyridine (0.109 mL) was added to the reaction mixture, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was cooled to 0°C. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 89 (18 mg).

[1432] LCMS: [M+H] + / Rt (min): 293 / 1.29

[1433] Step (ii):

[1434] The title compound 90 (13.2 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 89 (14.7 mg).

[1435] LCMS: [M+H] + / Rt (min): 193 / 0.48

[1436] Reference Example 32:

[1437] 4-(2-Fluoro-4-methylphenyl)-4-methylpiperidine

[1438]

[1439] Step (i):

[1440] To a mixture of compound 91 (211 mg), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (274 mg), potassium carbonate (386 mg), 1,2-dimethoxymethane (4 mL) and water (1 mL) was added dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (45.6 mg) at room temperature, and the mixture was heated under reflux. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 92 (32 mg).

[1441] LCMS: [M+H] + / Rt (min): 206 / 0.51

[1442] Step (ii):

[1443] To a solution of compound 92 (137 mg) in THF (3 mL) was added n-butyl lithium solution (1.57 M, 0.68 mL) at -18 °C, and the mixture was further cooled to -50 °C. Dimethyl sulfate was added dropwise to the reaction solution, and the mixture was stirred at -50 °C for one hour. Aqueous ammonia was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to produce a residue.

[1444] The obtained residue was dissolved in methanol (3 mL), and sodium borohydride (80 mg) was added to the solution at ice temperature. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 93 (32 mg).

[1445] LCMS: [M+H] + / Rt (min): 222 / 0.63

[1446] Step (iii):

[1447] To a solution of compound 93 (30.4 mg) in 1,2-dichloroethane (3 mL) was added 1-chloroethyl chloroformate (0.045 mL) at room temperature, and the mixture was heated under reflux. The reaction solution was concentrated in a vacuum, and chloroform and aqueous sodium hydroxide solution were added to the obtained residue. The mixture was stirred at room temperature and then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in a vacuum, and the obtained residue was then purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 94 (22 mg).

[1448] LCMS: [M+H] + / Rt (min): 208 / 0.66

[1449] Reference Example 33:

[1450] 4-[4-(Difluoromethyl)phenyl]-4-methylpiperidine monohydrochloride

[1451]

[1452] Step (i):

[1453] To a solution of compound 95 (490 mg) in THF (6 mL) was added n-butyllithium solution (1.57 M, 1.15 mL) at -78°C, and the mixture was stirred for 30 minutes. DMF (0.535 mL) was added to the reaction solution, and the mixture was warmed to 0°C. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 96 (256 mg).

[1454] LCMS: [M+H] + / Rt (min): 304 / 1.10

[1455] Step (ii):

[1456] Deoxo-Fluor (R) (0.285 mL) was added to a solution of compound 96 (157 mg) in dichloromethane (2 mL) at ice temperature, and the mixture was then stirred at room temperature. After the reaction was completed, the reaction solution was added to an aqueous sodium bicarbonate solution in an ice bath, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 97 (110 mg).

[1457] LCMS: [M+H] + / Rt (min): 326 / 1.20

[1458] Step (iii):

[1459] The title compound 98 (84.5 mg) was prepared in the same manner as in step (iv) in Reference Example 2 by using compound 97 (104.8 mg).

[1460] LCMS: [M+H] + / Rt (min): 226 / 0.60

[1461] Reference Example 34:

[1462] 5-Methyl-2-(4-methylpiperidin-4-yl)benzonitrile

[1463]

[1464] Step (i):

[1465] To a mixture of compound 99 (267 mg) and m-cresol (1.20 mL) was added trifluoromethanesulfonic acid (1.01 mL), and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was added to an aqueous sodium bicarbonate solution at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 100 (388 mg).

[1466] LCMS: [M+H] + / Rt (min): 278 / 1.01

[1467] Step (ii):

[1468] To a mixture of compound 100 (113 mg), potassium carbonate (169 mg) and THF (4 mL) was added N-phenylbis(trifluoromethanesulfonimide) (175 mg), and the mixture was stirred while heating at 120° C. with a microwave apparatus. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 101 (138 mg).

[1469] LCMS: [M+H] + / Rt (min): 410 / 1.26

[1470] Step (iii):

[1471] The title compound 102 (40.8 mg) was prepared in the same manner as in step (iii) in Reference Example 28 by using compound 101 (130 mg) and zinc cyanide (55.8 mg).

[1472] LCMS: [M+H] + / Rt (min): 287 / 1.07

[1473] Step (iv):

[1474] Potassium hydroxide (78 mg) was added to a solution of compound 102 (40 mg) in 2-propanol (3 ml) at room temperature, and the mixture was then stirred while heating at 110° C. with a microwave apparatus. After the reaction was completed, water was added to the reaction solution. The mixture was extracted with chloroform / ethanol (4 / 1). The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 103 (20.6 mg).

[1475] LCMS: [M+H] + / Rt (min): 215 / 0.57

[1476] Reference Example 35:

[1477] (3S,4S)-4-Fluoro-1-(propan-2-yl)pyrrolidin-3-ol

[1478]

[1479] Step (i):

[1480] To a solution of compound 104 (500 mg) in chloroform (2 mL) was added hydrogen chloride / 1,4-dioxane (4 M, 6 mL) at 0°C, and the mixture was warmed to room temperature and stirred. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was concentrated in vacuo. The obtained residue was dissolved in chloroform (2 mL). Acetone (1.79 mL), sodium acetate (200 mg) and sodium triacetoxyborohydride (1.03 g) were added to the solution at 0°C, and the mixture was warmed to room temperature and stirred. After the reaction was completed, an aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform / methanol (5 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 105 (348 mg).

[1481] LCMS: [M+H] + / Rt (min): 148 / 0.17

[1482] Reference Example 36:

[1483] (3R)-4,4-Difluoro-1-(propan-2-yl)pyrrolidin-3-ol

[1484] The compounds of Reference Example 36 shown in the following table were prepared according to the method in the above-mentioned Reference Example 35 by using appropriate starting compounds in place of Compound 104 at step (i) in Reference Example 35.

[1485]

[1486] Reference Example 37:

[1487] (1R,6S)-2,2-Difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1488]

[1489] Step (i):

[1490] A mixture of compound 49 (1.5 g), (S)-1-isopropylpyrrolidin-3-ol (0.792 mg) and NMP (1 mL) was stirred while heating at 150° C. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was directly purified by silica gel column chromatography (eluent: chloroform / methanol / triethylamine) and then by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 106 (1.03 g).

[1491] LCMS: [M+H] + / Rt (min): 448 / 0.78

[1492] Step (ii):

[1493] The title compound 107 (43 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 106 (100 mg).

[1494] LCMS: [M+H] + / Rt (min): 263 / 0.22

[1495] Reference Examples 38 to 40:

[1496] The compounds of Reference Examples 38 to 40 shown in the following table were prepared according to the method in the above-mentioned Reference Example 37 by using each appropriate starting compound in place of (S)-1-isopropylpyrrolidin-3-ol at step (i) in Reference Example 37.

[1497]

[1498] Reference Example 38: (1R,6S)-2,2-Difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1499] Reference Example 39: (1R,6S)-2,2-Difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1500] Reference Example 40: (1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexane-1-amine

[1501] Reference Example 41:

[1502] 3-Fluoro-5-methyl-2-(piperidin-4-yl)pyridine

[1503]

[1504] Step (i):

[1505] The title compound 109 (90.5 mg) was prepared in the same manner as in step (i) in Reference Example 32 by using Compound 108 (72.4 mg) and 1-benzyloxycarbonyl-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

[1506] LCMS: [M+H] + / Rt (min): 327 / 1.04 (Method C)

[1507] Step (ii):

[1508] To a solution of compound 109 (88.0 mg) in ethyl acetate (1.5 mL) was added palladium / carbon (88.0 mg), and the mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound 110 (22.2 mg).

[1509] LCMS: [M+H] + / Rt (min): 195 / 0.35 (Method C)

[1510] Reference Example 42:

[1511] (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-ol

[1512]

[1513] Step (i):

[1514] To a solution of compound 111 (300 mg) and sodium bicarbonate (634 mg) in ethanol (10 mL) was added N-benzyl-N,N-bis(2-chloroethyl)amine hydrochloride (586 mg), and the mixture was stirred while heating at 120° C. with a microwave apparatus. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 112 (398 mg).

[1515] LCMS: [M+H] + / Rt (min): 311 / 0.46

[1516] Step (ii):

[1517] The title compound 113 (289 mg) was prepared in the same manner as in step (ii) in Reference Example 2 by using Compound 112 (389 mg).

[1518] LCMS: [M+H] + / Rt (min): 221 / 0.16

[1519] Step (iii):

[1520] To a mixture of compound 113 (389 mg), acetone (1.73 mL) and dichloromethane (6 mL) was added sodium triacetoxyborohydride (1.5 g) at 0°C, and the mixture was warmed to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 114 (255 mg).

[1521] LCMS: [M+H] + / Rt (min): 263 / 0.36

[1522] Reference Example 43:

[1523] tert-Butyl [(1S,4R)-3-{[4-(Propan-2-yl)piperazin-1-yl]methyl}bicyclo[2.2.1]heptane-2-yl]carbamate

[1524]

[1525] Step (i):

[1526] To a mixture of compound 115 (239 mg), 1-isopropylaziridine (128 mg), acetic acid (0.086 mL) and THF (2.5 mL) was added sodium triacetoxyborohydride (635 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Sodium bicarbonate aqueous solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 116 (310 mg).

[1527] LCMS: [M+H] + / Rt (min): 352 / 1.35 (Method B)

[1528] Reference Example 44:

[1529] rac-2-[6-(propan-2-yl)pyridin-3-yl]cyclohex-2-en-1-amine

[1530]

[1531] Step (i):

[1532] To a mixture of compound 117 (350 mg), 6-isopropylpyridin-3-yl borate (273 mg), cesium carbonate (1.28 g), 1,4-dioxane (5 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (129 mg) at room temperature, and the mixture was stirred at 90°C for 3 hours. Water was added to the reaction mixture at 0°C, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 118 (168 mg).

[1533] Step (ii) to step (iv):

[1534] The title compound 121 (29.7 mg) was prepared in the same manner as steps (i) to (iii) in Reference Example 13 by using Compound 118 (68.2 mg).

[1535] LCMS: [M+H] + / Rt (min): 217 / 0.39

[1536] Reference Example 45:

[1537] N-Methyl-N-[(1-methylcyclopropyl)methyl]piperidin-4-amine

[1538]

[1539] Step (i):

[1540] To a solution of tert-butyl 4-(methylamino)piperidine-1-carboxylate (584 mg), 1-methylcyclopropane-1-carboxylic acid (300 mg) and triethylamine (0.76 mL) in DMF (4 mL) was added HATU (1.24 g), and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 123 (926 mg).

[1541] Step (ii):

[1542] To a solution of compound 123 (806 mg) in chloroform (4.5 mL) was added hydrochloric acid (5M in CPME, 2.7 mL) at 0° C., and the reaction solution was warmed to room temperature and stirred. After the reaction was completed, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 124 (477 mg).

[1543] Step (iii):

[1544] The title compound 125 (203 mg) was prepared in the same manner as in step (ii) in Reference Example 22 by using Compound 124 (413 mg).

[1545] LCMS: [M+H] + / Rt (min): 183 / 0.15

[1546] Reference Examples 46-47

[1547] The compounds of Reference Examples 46-47 shown in the following table were prepared according to the method in the above-mentioned Reference Example 45 by using each appropriate starting compound in place of 1-methylcyclopropane-1-carboxylic acid at step (i) in Reference Example 45.

[1548]

[1549] Reference Example 46: N-[(1-Fluorocyclopropyl)methyl]-N-methylpiperidin-4-amine

[1550] Reference Example 47: N-Methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidin-4-amine

[1551] Reference Example 48: (3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-ol

[1552]

[1553] Step (i):

[1554] The title compound 127 (196 mg) was prepared in the same manner as in step (i) in Reference Example 45 by using (S)-3-pyrrolidinol (103 mg) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (200 mg).

[1555] Step (ii):

[1556] The title compound 128 (87.2 mg) was prepared in the same manner as in step (iii) in Reference Example 45 by using Compound 127 (184 mg).

[1557] LCMS: [M+H] + / Rt (min): 210 / 0.30

[1558] Reference Example 49:

[1559] (1R,3S,5S)-N-(Cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine

[1560]

[1561] Step (i):

[1562] The title compound 130 (178 mg) was prepared in the same manner as in step (iii) in Reference Example 42 by using Compound 129 (146 mg) and cyclopropane-carbaldehyde (170 mg).

[1563] Step (ii):

[1564] The title compound 131 (106 mg) was prepared in the same manner as in step (ii) in Reference Example 45 by using Compound 130 (166 mg).

[1565] LCMS: [M+H]+ / Rt (min): 195 / 0.14

[1566] Reference Examples 50-52

[1567] The compounds of Reference Examples 50 to 52 shown in the following table were prepared according to the method in the above-mentioned Reference Example 49 by using each appropriate starting compound in place of Compound 129 at step (i) in Reference Example 49.

[1568]

[1569] Reference Example 50: (1R,3R,5S)-N-(Cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine

[1570] Reference Example 51: (4S)-N-(Cyclopropylmethyl)-N-methylazepan-4-amine

[1571] Reference Example 52: (4R)-N-(Cyclopropylmethyl)-N-methylazepan-4-amine

[1572] Reference Example 53:

[1573] (1R,3S,5S)-8-(Propan-2-yl)-8-azabicyclo[3.2.1]octan-3-ol

[1574]

[1575] Step (i):

[1576] The title compound was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 132 (3 g).

[1577] Step (ii):

[1578] The title compound 134 (1.98 g) was prepared in the same manner as in step (iii) in Reference Example 42 by using compound 133 and acetone (1.3 g).

[1579] LCMS: [M+H] + / Rt (min): 170 / 0.15

[1580] Reference Examples 54-57

[1581] The compounds of Reference Examples 54 to 57 shown in the following table were prepared according to the method in the above-mentioned Reference Example 53 by using each appropriate starting compound in place of Compound 132 at step (i) in Reference Example 53.

[1582]

[1583]

[1584] Reference Example 54: (1R,5S,8R)-3-(Propan-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

[1585] Reference Example 55: (1R,5S,8S)-3-(Propan-2-yl)-3-azabicyclo[3.2.1]octan-8-ol

[1586] Reference Example 56: (1R,3R,5S)-8-(Propan-2-yl)-8-azabicyclo[3.2.1]octan-3-ol

[1587] Reference Example 57: (1R,5S,6S)-3-(Propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-ol

[1588] Reference Examples 58 - 79

[1589] The compounds of Reference Examples 58 to 79 shown in the following table were prepared according to the method in the above-mentioned Reference Example 18 by using each appropriate starting compound in place of 1-isopropylpiperazine at step (ii) in Reference Example 18.

[1590]

[1591]

[1592]

[1593]

[1594] Reference Example 58: (1S,6R)-2,2-Difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1595] Reference Example 59: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidin-1-amine

[1596] Reference Example 60: (1R,6S)-2,2-Difluoro-6-{4-[(propan-2-yl)oxy]piperidin-1-yl}cyclohexane-1-amine

[1597] Reference Example 61: (1R,6S)-2,2-Difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1598] Reference Example 62: (1R,6S)-2,2-Difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1599] Reference Example 63: (1S,2R)-3,3-difluoro-N 1 -Methyl-N 1 -[1-(Propan-2-yl)piperidin-4-yl]cyclohexane-1,2-diamine

[1600] Reference Example 64: (1R,6S)-2,2-Difluoro-6-[4-(pyrrolidin-1-yl)piperidin-1-yl]cyclohexane-1-amine

[1601] Reference Example 65: (1R,6S)-2,2-difluoro-6-[5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]cyclohexane-1-amine

[1602] Reference Example 66: (1R,6S)-2,2-Difluoro-6-[2-(propan-2-yl)-2,8-diazaspiro[4.5]decan-8-yl]cyclohexane-1-amine

[1603] Reference Example 67: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,N-diethylpiperidin-4-amine

[1604] Reference Example 68: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N,4-dimethyl-N-(propan-2-yl)piperidin-4-amine

[1605] Reference Example 69: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-[(1-methylcyclopropyl)methyl]piperidin-4-amine

[1606] Reference Example 70: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-[(1-fluorocyclopropyl)methyl]-N-methylpiperidin-4-amine

[1607] Reference Example 71: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-{[1-(trifluoromethyl)cyclopropyl]methyl}piperidin-4-amine

[1608] Reference Example 72: (1R,3R,5S)-8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine

[1609] Reference Example 73: (1R,3S,5S)-8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methyl-8-azabicyclo[3.2.1]octan-3-amine

[1610] Reference Example 74: (4S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazepan-4-amine

[1611] Reference Example 75: (4R)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazepan-4-amine

[1612] Reference Example 76: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)azetidin-3-amine

[1613] Reference Example 77: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylazetidine-3-amine

[1614] Reference Example 78: (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexane-1-amine

[1615] Reference Example 79: tert-Butyl {1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]piperidin-4-yl}methylcarbamate

[1616] Reference Example 80:

[1617] N-{(1R,6S)-2,2-difluoro-6-[4-(methylamino)piperidin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide

[1618]

[1619] Step (i):

[1620] The title compound 136 (2.92 g) was prepared in the same manner as in Example 19 by using the compound of Reference Example 79 (2.61 g).

[1621] Step (ii):

[1622] To a solution of compound 136 (2.92 g) in toluene (24 ml), TFA (5.56 g) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated in a vacuum, the obtained residue was dissolved in water, and aqueous sodium bicarbonate solution was added to the solution. The mixture was extracted with chloroform, and the organic layer was concentrated in a vacuum to obtain title compound 137 (2.38 g).

[1623] LCMS: [M+H] + / Rt (min): 499 / 0.49 (Method C)

[1624] Reference Example 81:

[1625] (1S,2R)-3,3-difluoro-N 1 -Methyl-N 1 -[(3S)-1-(Propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine

[1626]

[1627] Step (i):

[1628] Compound 138 (2.61 g) was prepared in the same manner as in step (ii) in Reference Example 18 by using tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate instead of 1-isopropylpiperazine at step (ii) in Reference Example 18.

[1629] Step (ii):

[1630] The title compound 139 (2.59 g) was prepared in the same manner as in step (iv) in Reference Example 2 by using Compound 138 (2.61 g).

[1631] Step (iii):

[1632] The title compound 140 (1.97 g) was prepared in the same manner as in step (iii) in Reference Example 42 by using compound 139 (2.59 g) and acetone (3.87 mL).

[1633] Step (iv):

[1634] The title compound 141 (925 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 140 (1.97 g).

[1635] LCMS: [M+H] + / Rt (min): 276 / 0.15

[1636] Reference Examples 82 - 88

[1637] The compounds of Reference Examples 82 to 88 shown in the following table were prepared in the same manner as in Reference Example 81 by using an appropriate starting compound (material A) instead of tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate at step (i) in Reference Example 81 and using each appropriate starting compound (material B) instead of acetone at step (iii) in Reference Example 81.

[1638]

[1639]

[1640] Reference Example 82: (3R)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)pyrrolidin-1-amine

[1641] Reference Example 83: (1S,2R)-3,3-difluoro-N 1 -Methyl-N 1 -[(3R)-1-(Propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine

[1642] Reference Example 84: 1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(propan-2-yl)piperidin-4-amine

[1643] Reference Example 85: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-cyclopropyl-N-methylpyrrolidin-1-amine

[1644] Reference Example 86: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-methyl-N-(2-methylpropyl)pyrrolidin-1-amine

[1645] Reference Example 87: (3S)-1-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-N-(cyclopropylmethyl)-N-methylpyrrolidin-1-amine

[1646] Reference Example 88: (1S,6S)-2,2-Difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]sulfanyl}cyclohexane-1-amine

[1647] Reference Example 89:

[1648] (1S,2R)-N 1 -Benzyl-3,3-difluoro-N 1 -[(3S)-1-(Propan-2-yl)pyrrolidin-3-yl]cyclohexane-1,2-diamine

[1649]

[1650] Step (i):

[1651] Compound 142 (2.19 g) was prepared in the same manner as in step (ii) in Reference Example 18 by using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate instead of 1-isopropylpiperazine at step (ii) in Reference Example 18.

[1652] Step (ii):

[1653] The title compound 143 (240 mg) was prepared in the same manner as in step (iii) in Reference Example 42 by using Compound 142 (990 mg) and benzaldehyde (312 mg).

[1654] Step (iii):

[1655] The title compound 144 (161 mg) was prepared in the same manner as in step (ii) and step (iii) in Reference Example 81 by using Compound 143 (235 mg).

[1656] Step (iv):

[1657] The title compound 145 (87.4 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 144 (158 mg).

[1658] LCMS: [M+H] + / Rt (min): 352 / 0.42 (Method C)

[1659] Reference Example 90:

[1660] Benzyl {(1S,2R)-3,3-difluoro-2-[(4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carbonyl)amino]cyclohexyl}[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]carbamate

[1661]

[1662] Step (i):

[1663] To a solution of compound 142 (680 mg) in a mixture of dioxane and water (10 mL / 3.3 mL) was added benzyl chloroformate (345 mg) and sodium acetate (116 mg) at 0°C, and the reaction solution was refluxed for 2 hours. After the reaction was completed, the reaction solution was extracted with chloroform. The organic layer was concentrated in vacuo to obtain the title compound 146 (530 mg).

[1664] Step (ii):

[1665] The title compound 147 (256 mg) was prepared in the same manner as in step (ii) and step (iii) in Reference Example 81 by using Compound 146 (530 mg).

[1666] Step (iii):

[1667] The title compound 148 (137 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 147 (254 mg).

[1668] Step (iv):

[1669] The title compound 149 (175 mg) was prepared in the same manner as in Example 19 by using Compound 148 (135 mg).

[1670] LCMS: [M+H] + / Rt (min): 647 / 0.79 (Method C)

[1671] Reference Example 91:

[1672] (1R,6S)-2,2-Difluoro-6-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]cyclohexane-1-amine

[1673]

[1674] Step (i):

[1675] Sodium cyanide (495 mg) and lithium perchlorate (67 mg) were added to a solution of compound 49 (2.01 g) in acetonitrile (12.6 ml), and the reaction solution was refluxed for 3 hours. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 150 (2.05 g).

[1676] Step (ii):

[1677] The title compound 151 (1.88 g) was prepared in the same manner as in step (i) in Reference Example 8 by using Compound 150 (2.04 g).

[1678] Step (iii):

[1679] The title compound 152 (89.7 mg) was prepared in the same manner as in step (ii) and step (iii) in Reference Example 8 by using compound 151 (200 mg) and isobutyric acid (53.6 mg).

[1680] Step (iv):

[1681] The title compound 153 (41.5 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 152 (87.7 mg).

[1682] LCMS: [M+H] + / Rt (min): 246 / 0.37 (Method C)

[1683] Reference Example 92:

[1684] (1R,6S)-2,2-Difluoro-6-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]cyclohexane-1-amine

[1685]

[1686] Step (i):

[1687] To a solution of compound 49 (1.6 g) in a mixture of acetonitrile and water (23 mL / 2.5 mL) was added sodium azide (490 mg), and the reaction solution was heated at 70°C for 1.5 hours. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 154 (1.78 g).

[1688] Step (ii):

[1689] To a solution of compound 154 (550 mg) in a mixture of methanol and THF (11.4 mL / 2.3 mL / 4 mL), sodium ascorbate (30.2 mg), tris(2-benzimidazolylmethyl)amine (46.5 mg) and 3-methylbut-1-yne (156 mg) were added. A solution of copper sulfate (18.2 mg) in water (3.8 mL) was added to the reaction solution, and the reaction mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was filtered with Celite and concentrated in vacuo. Then, the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 155 (353 mg).

[1690] Step (iii):

[1691] The title compound 156 (168 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 155 (353 mg).

[1692] LCMS: [M+H] + / Rt (min): 245 / 0.42

[1693] Reference Example 93:

[1694] (1R,6S)-2,2-Difluoro-6-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]cyclohexane-1-amine

[1695] The compound of Reference Example 93 shown in the following table was prepared according to the method in the above-mentioned Reference Example 92 by using 4-methylpent-1-yne instead of 3-methylbut-1-yne at step (ii) in Reference Example 92.

[1696]

[1697] Reference Example 94:

[1698] [(1S,2R)-2-Amino-3,3-difluorocyclohexyl][4-(propan-2-yl)piperazin-1-yl]methanone

[1699]

[1700] Step (i):

[1701] To a solution of compound 150 (555 mg) in DMSO (6 mL) was added aqueous hydrochloric acid (9 mL), and the reaction solution was heated at 120° C. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound 157 (600 mg).

[1702] Step (ii):

[1703] 1-isopropylpiperazine (234 mg), triethylamine (308 mg) and HATU (753 mg) were added to a solution of compound 157 (476 mg) in DMF (1.5 mL), and the reaction solution was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 158 (610 mg).

[1704] LCMS: [M+H] + / Rt (min): 475 / 0.59

[1705] Step (iii):

[1706] The title compound 159 (180 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 158 (605 mg).

[1707] LCMS: [M+H] + / Rt (min): 290 / 0.16

[1708] Reference Example 95:

[1709] (1R,6R)-2,2-Difluoro-6-{[4-(propan-2-yl)piperazin-1-yl]methyl}cyclohexane-1-amine

[1710]

[1711] Step (i):

[1712] The title compound 160 (112 mg) was prepared in the same manner as in step (ii) in Reference Example 22 by using Compound 159 (171 mg).

[1713] LCMS: [M+H] + / Rt (min): 276 / 0.24

[1714] Reference Examples 96 - 114:

[1715] The compounds of Reference Examples shown in the following table were prepared according to the method in the above-mentioned Reference Example 37 by using each appropriate starting compound in place of (S)-1-isopropylpyrrolidin-3-ol at step (i) in Reference Example 37.

[1716]

[1717]

[1718]

[1719]

[1720] Reference Example 96: (1R,6S)-2,2-Difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexane-1-amine

[1721] Reference Example 97: (1R,6S)-2,2-Difluoro-6-{[3-(propan-2-yl)-1,2,4-thiadiazol-5-yl]oxy}cyclohexane-1-amine

[1722] Reference Example 98: (1R,6S)-2,2-Difluoro-6-{[1-(propan-2-yl)-1H-pyrazol-4-yl]oxy}cyclohexane-1-amine

[1723] Reference Example 99: (1R,6S)-2,2-Difluoro-6-{[1-(propan-2-yl)azetidin-3-yl]oxy}cyclohexane-1-amine

[1724] Reference Example 100: (1R,6S)-2,2-Difluoro-6-{[(1R,3S,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexane-1-amine

[1725] Reference Example 101: (1R,6S)-2,2-Difluoro-6-{[(1R,5S,8R)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexane-1-amine

[1726] Reference Example 102: (1R,6S)-2,2-Difluoro-6-{[(1R,5S,8S)-3-(propan-2-yl)-3-azabicyclo[3.2.1]octan-8-yl]oxy}cyclohexane-1-amine

[1727] Reference Example 103: (1R,6S)-2,2-Difluoro-6-{[(1R,3R,5S)-8-(propan-2-yl)-8-azabicyclo[3.2.1]octan-3-yl]oxy}cyclohexane-1-amine

[1728] Reference Example 104: (1R,6S)-2,2-Difluoro-6-{[(1R,5S,6S)-3-(propan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl]oxy}cyclohexane-1-amine

[1729] Reference Example 105: (1R,6S)-2,2-Difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1730] Reference Example 106: (1R,6S)-2,2-Difluoro-6-{[(3R,4R)-4-methoxy-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1731] Reference Example 107: (1R,6S)-2,2-Difluoro-6-{[4-methyl-1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexane-1-amine

[1732] Reference Example 108: (1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexane-1-amine

[1733] Reference Example 109: (1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexane-1-amine

[1734] Reference Example 110: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexane-1-amine

[1735] Reference Example 111: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexane-1-amine

[1736] Reference Example 112: (1R,6S)-2,2-Difluoro-6-{[(3S)-1-{[1-(trifluoromethyl)cyclopropyl]methyl}pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1737] Reference Example 113: (1R,6S)-2,2-Difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexane-1-amine

[1738] Reference Example 114: (1R,6S)-2,2-difluoro-6-({(3S)-1-[(3-methyloxetan-3-yl)methyl]pyrrolidin-3-yl}oxy)cyclohexane-1-amine

[1739] Reference Examples 115 - 118

[1740] The compounds of Reference Examples 115 to 118 shown in the following table were prepared in the same manner as in Reference Example 8 by using an appropriate starting compound (material A) instead of compound 26 at step (i) in Reference Example 8 and using each appropriate starting compound (material B) instead of cyclopropanecarboxylic acid at step (iii) in Reference Example 8.

[1741]

[1742] Reference Example 115: 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine

[1743] Reference Example 116: 4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine

[1744] Reference Example 117: 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine monohydrochloride

[1745] Reference Example 118: 4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine

[1746] Reference Example 119:

[1747] (1R,6S)-2,2-Difluoro-6-{[2-(propan-2-yl)pyrimidin-4-yl]oxy}cyclohexane-1-amine

[1748]

[1749] Step (i):

[1750] To a solution of compound 161 (148 mg) known in the literature in THF (3 ml) was added sodium hydride (55%, 30 mg) and then 4-chloro-2-(propane-2-yl)pyrimidine at 0°C. The reaction solution was warmed to room temperature and stirred. After the reaction was completed, water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 162 (209 mg).

[1751] Step (ii):

[1752] To a solution of compound 162 (113 mg) in ethyl acetate (2 mL) was added palladium hydroxide (17 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere. After the reaction was terminated as judged by LC-MS, the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound 163 (33.5 mg).

[1753] LCMS: [M+H] + / Rt (min): 272 / 0.47

[1754] Reference Example 120:

[1755] (1R,6S)-2,2-Difluoro-N-methyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1756]

[1757] Step (i):

[1758] To a solution of compound 50 (173 mg) in DMF (3 mL) was added cesium carbonate (253 mg) and iodomethane (72 mg) at 0°C, and the reaction mixture was then warmed to room temperature and stirred. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 164 (159 mg).

[1759] Step (ii):

[1760] The title compound 165 (71 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 164 (134 mg).

[1761] LCMS: [M+H]+ / Rt (min): 276 / 0.15

[1762] Reference Example 121:

[1763] rac-(1S,6S)-2,2-dimethyl-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1764]

[1765] Step (i):

[1766] To a solution of compound 166 (283 mg) in 2-propanol (8 ml) was added aqueous ammonia (6 g) and the reaction mixture was refluxed. After the reaction was terminated as judged by the consumption of the starting material, the reaction solution was concentrated in vacuo for use in the next step.

[1767] Step (ii):

[1768] The title compound 168 (64.3 mg) was prepared in the same manner as in step (i) in Reference Example 18 by using Compound 167.

[1769] Step (iii):

[1770] The title compound 169 (102 mg) was prepared in the same manner as in step (ii) in Reference Example 18 by using Compound 168 (60.8 mg).

[1771] Step (iv):

[1772] The title compound 170 (40.2 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 169 (102 mg).

[1773] LCMS: [M+H] + / Rt (min): 254 / 0.43

[1774] Reference Example 122:

[1775] rac-(1S,2S)-2-[4-(propan-2-yl)piperazin-1-yl]cycloheptane-1-amine

[1776] The compounds of Reference Examples shown in the following table were prepared according to the method in the above-mentioned Reference Example 120 by using 8-oxabicyclo[5.1.0]octane instead of Compound 166 at step (i) in Reference Example 120.

[1777]

[1778] Reference Example 123:

[1779] rac-(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1780]

[1781] Step (i):

[1782] A solution of compound 171 (403 mg) and tetra-n-butylammonium dihydrogen trifluoride (1.78 g) in toluene (1 mL) was heated at 150° C. using a microwave apparatus. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 172 (323 mg).

[1783] Step (ii):

[1784] Compound 172 (457 mg) was dissolved in THF (4.1 mL). Triethylamine (1.13 mL) and methanesulfonyl chloride (0.318 mL) were added to the solution at ice temperature, and the reaction mixture was stirred. After the reaction was terminated as determined by the consumption of the starting material, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 173 (578 mg).

[1785] Step (iii):

[1786] To a solution of compound 173 (571 mg) in ethanol (3.5 mL) was added palladium hydroxide (20%, 133 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered with Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 174 (400 mg).

[1787] Step (iv):

[1788] Compound 174 (176 mg) was dissolved in 1,4-dioxane (3.5 mL). DBU (0.25 mL) was added to the solution, and the reaction mixture was stirred at 85 ° C. After the reaction was terminated as determined by the consumption of the starting material, the reaction mixture was then reacted in the same manner as step (i) in reference example 121, and mesylated in the same manner as step (ii) of this example. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title compound 175 (86 mg).

[1789] Step (v):

[1790] The title compound 176 (92.8 mg) was prepared by using compound 175 (86 mg) according to the cyclization conditions of step (ii) in Reference Example 121, followed by the same manner as in step (ii) in Reference Example 18.

[1791] Step (vi):

[1792] The title compound 177 (35.1 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 176 (86.1 mg).

[1793] LCMS: [M+H] + / Rt (min): 244 / 0.19

[1794] Reference Example 124:

[1795] rac-(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexane-1-amine

[1796]

[1797] Step (i):

[1798] The title compound 179 (953 mg) was prepared in the same manner as in step (i) in Reference Example 123 by using Compound 178 (929 mg).

[1799] Step (ii):

[1800] Compound 179 (283 mg) was dissolved in chloroform (6 mL). Pyridine (0.51 mL) and trifluoromethanesulfonic anhydride (0.256 mL) were added to the solution at ice temperature, and the reaction mixture was stirred. After the reaction was terminated as judged by the consumption of the starting material, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 180 (424 mg).

[1801] Step (iii):

[1802] Sodium azide (229 mg) was added to a solution of compound 180 (418 mg) in DMF (4 mL), and the reaction solution was stirred at room temperature. After the reaction was completed, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 181 (102 mg).

[1803] Step (iv):

[1804] Palladium hydroxide (20%, 58 mg) was added to a solution of compound 181 (102 mg) in ethanol (2 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere. The reaction mixture was filtered with Celite, and the filtrate was concentrated in a vacuum. The obtained residue was dissolved in ethanol (2 mL) again, and aqueous hydrogen chloride solution (cyclopentylmethyl solution, 5M, 0.327 mL) and palladium on carbon (10%, 71 mg) were added thereto. The mixture was stirred under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered with Celite, and the filtrate was concentrated in a vacuum to obtain title compound 182 (76.8 mg).

[1805] Step (v):

[1806] The title compound 183 (69 mg) was prepared in the same manner as in step (i) and step (ii) in Reference Example 18 by using Compound 182 (103 mg).

[1807] Step (vi):

[1808] The title compound 184 (34.3 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 183 (72 mg).

[1809] LCMS: [M+H]+ / Rt (min): 244 / 0.14

[1810] Reference Example 125:

[1811] (1S,2R)-2-Amino-3,3-difluorocyclohexyl 4-(propan-2-yl)piperazine-1-carboxylate

[1812]

[1813] Step (i):

[1814] To a solution of compound 185, known in the literature, in acetonitrile (3 mL) was added Boc2O (238 mg), and the reaction solution was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound 186 (216 mg).

[1815] Step (ii):

[1816] The title compound 187 (118 mg) was prepared in the same manner as in step (iii) of Reference Example 2 using compound 186 (95.7 mg).

[1817] Step (iii):

[1818] The title compound 188 (99.7 mg) was prepared in the same manner as in step (iv) of Reference Example 2 using compound 187 (118 mg).

[1819] LCMS: [M+H] + / Rt (min): 306 / 0.25

[1820] Reference Example 126:

[1821] N-{(1S,6S)-2,2-Difluoro-6-[1-(propan-2-yl)piperidine-4-sulfonyl]cyclohexyl}-4-nitrobenzenesulfonamide

[1822] [Chemical Formula 1]

[1823]

[1824] Step (i):

[1825] The title compound 189 (402 mg) was prepared in the same manner as in step (ii) in Reference Example 18 by using Compound 49 (399 mg) and tert-butyl 4-sulfanylpiperidine-1-carboxylate (300 mg).

[1826] Step (ii):

[1827] To a solution of compound 189 (210 mg) in chloroform (2 mL) was added m-CPBA (242 mg), and the reaction solution was stirred at room temperature. After the reaction was completed, an aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the resulting residue was then purified by amino silica gel column chromatography (eluent: chloroform / methanol) to obtain the title compound 190 (250 mg).

[1828] Step (iii):

[1829] The title compound 191 (223 mg) was prepared in the same manner as in step (i) and step (ii) in Reference Example 53 by using compound 190 (250 mg).

[1830] Step (iv):

[1831] The title compound 192 (102 mg) was prepared in the same manner as in step (iii) in Reference Example 18 by using Compound 191 (223 mg).

[1832] LCMS: [M+H] + / Rt (min): 325 / 0.21

[1833] Study 1: Evaluation of agonist activity at orexin receptor type 2

[1834] Human orexin receptor type 2 and apoaequorin were transiently expressed in CHO cells, and agonist activity was evaluated based on intracellular calcium mobilization under ligand stimulation. Human orexin receptor type 2 and apoaequorin transiently expressed in CHO cells were seeded on 384-well plates with 2,000 cells / well, and then incubated for 16-22 hours. After the plate was restored to room temperature, coelenterazine hcp (final concentration: 1 μM) was added to the plate, and the plate was left to stand at room temperature for 2 hours. Then, orexin A (PEPTIDE INSTITUTE, INC., lot number 641114) or each test compound was added to the plate, and the luminescence of the cell was measured with FDSS7000 (Hamamatsu Photonics KK), wherein orexin A and each test compound were dissolved in DMSO (final concentration: 0.1%), and diluted with buffer (Hanks, 20 mM HEPES, 0.1% BSA). The agonist activity (E-max) of each test compound on orexin receptor type 2 was calculated as the relative luminescence percentage of the luminescence (100%) of orexin A (100 pM).

[1835] result:

[1836] The agonist activity of each compound obtained in the examples on orexin receptor type 2 was evaluated, and the results showed that the compounds of the present invention have agonist activity on orexin receptor type 2. The agonist activity (E-max) of each example compound is shown in the following table as the relative luminescence percentage of the luminescence (100%) of orexin A (100 pM).

[1837]

[1838]

[1839] Study 2: Evaluation of agonist activity at orexin receptor type 2

[1840] Human orexin receptor type 2 and apoaequorin were transiently expressed in CHO cells, and agonist activity was evaluated based on intracellular calcium mobilization under ligand stimulation. Human orexin receptor type 2 and apoaequorin transiently expressed in CHO cells were seeded on 384-well plates with 2,000 cells / well, and then incubated for 16-22 hours. After the plate was restored to room temperature, coelenterazine hcp (final concentration: 1 μM) was added to the plate, and the plate was left to stand at room temperature for 2 hours. Then, orexin A (PEPTIDE INSTITUTE, INC., lot number 671009) or each test compound was added to the plate, and the luminescence of the cell was measured with FDSS7000 (Hamamatsu Photonics KK), wherein orexin A and each test compound were dissolved in DMSO (final concentration: 0.1%), and diluted with buffer (Hanks, 20 mM HEPES, 0.1% BSA). The agonist activity (E-max) of each test compound on orexin receptor type 2 was calculated as the relative luminescence percentage of the luminescence (100%) of orexin A (100 pM).

[1841] result:

[1842] The agonist activity of each compound obtained in the examples on orexin receptor type 2 was evaluated, and the results showed that the compounds of the present invention have agonist activity on orexin receptor type 2. The agonist activity (E-max) of each example compound is shown in the following table as the relative luminescence percentage of the luminescence (100%) of orexin A (100 pM).

[1843]

[1844] Industrial Applicability

[1845] The compounds of the present invention exhibit potent agonist activity on orexin receptors, and thus they are useful as drug...

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: in R 1 is an optionally substituted C6 aromatic carbocyclic group, an optionally substituted 5- to 6-membered aromatic heterocyclic group or an optionally substituted C 3-6 Saturated carbocyclic group; L 1 is a single bond, -S-, or an oxygen atom; L 2 is a single bond, methylene, -NR 8 -, OC(=O)-, -SO2-, -S- or an oxygen atom; R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, or a C 1-4 alkyl; R 3 and R 4 are independently a hydrogen atom, a halogen atom, a C 1-4 Alkyl or C 1-4 Alkoxy, where R 3 and R 4 Can be bonded to the same carbon atom if chemically possible; or When R 3 and R 4 When bound to different ring carbon atoms, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a bridged ring; R 8 are independently hydrogen atoms, C 1-4 Alkyl or C 6-10 Aromatic carbocyclic substituted C 1-4 alkyl; n is an integer of 1, 2 or 3; Ring G is an optionally substituted 5- to 6-membered aromatic heterocyclic group or an optionally substituted 4- to 10-membered saturated heterocyclic group; A 1 is an oxygen atom or a sulfur atom; A 2 is an oxygen atom or -NR 8 -; A 3 is a nitrogen atom; and The bonds accompanied by dashes are each independently single or double bonds, In R 1 In the present invention, "optionally substituted C6 aromatic carbocyclic group", "optionally substituted 5- to 6-membered aromatic heterocyclic group" and "optionally substituted C 3-6 The optional substituents of the "saturated carbocyclic group" are each independently at least one substituent selected from the following: a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkoxy, cyano, and C 1-4 Alkoxy; In R 1 In the C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 alkyl; and In ring G, the optional substituents of the "optionally substituted 5- to 6-membered aromatic heterocyclic group" and the "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from a halogen atom, a C 1-6 Alkyl, C 1-4 Alkoxy, C 1-6 Alkylamino, and C 3-7 Cycloalkoxy; or when there are multiple optional substituents, two of them can be C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from spirocyclic and bridged rings, In ring G, the C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 3-7 Cycloalkyl; said C 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 Alkyl; the C 1-6 The alkyl group of the alkylamino group is optionally replaced by C 3-7 Cycloalkyl substitution; the C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein In R 1 In the present invention, "optionally substituted C6 aromatic carbocyclic group", "optionally substituted 5- to 6-membered aromatic heterocyclic group", and "optionally substituted C 3-6 The optional substituents of the "saturated carbocyclic group" are each independently at least one substituent selected from a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group, C 1-4 Alkyl, C 3-7 Cycloalkyl, cyano, and C 1-4 Alkoxy; In R 1 In the C 1-4 The alkyl group is optionally substituted with the same or different one or more substituents selected from halogen atoms; and In ring G, the optional substituents of the "optionally substituted 5- to 6-membered aromatic heterocyclic group" and the "optionally substituted 4- to 10-membered saturated heterocyclic group" are each independently at least one substituent selected from a halogen atom, a C 1-6 Alkyl, C 1-4 Alkoxy, C 1-6 Alkylamino and C 3-7 Cycloalkoxy; or when there are multiple optional substituents, two of them can be C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from spirocyclic and bridged rings, In ring G, the C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 Alkyl; the C 1-6 The alkyl group of the alkylamino group is optionally replaced by C 3-7 Cycloalkyl substitution; the C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following formulas (1a-1) to (1a-4): in X 1 -X 7 are independently a nitrogen atom or CR a6 ; Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom; R a1 -R a7 are independently a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group, C 1-4 Alkyl, C 3-7 Cycloalkyl, cyano, C 1-4 Alkoxy, or C 3-7 Cycloalkoxy; wherein R a4 and R a5 Can be bonded to the same carbon atom if chemically possible; If there are multiple CR a6 , then each R a6 Also independently the above groups; said C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms, and C 1-4 alkyl; and q 1 Is an integer of 1 or 2.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ring G is selected from the following (1b-1) to (1b-14): in W 1 , W 3 , W 5 , W 6 , W 7 , W 11 , W 12 , W 13 , W 15 , W 16 , W 17 , W 19 and W 25 are independently a nitrogen atom or CR b4 ; W 2 、W 4 、W 8 、W 9 、W 10 、W 14 、W 18 、W 20 、W 21 、W 22 、W 23 and W 24 are NR b5 、an oxygen atom or CR b6 R b7 ; R b1 -R b7 are independently hydrogen atoms, C 1-6 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkoxy; wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from spirocyclic and bridged rings; If there are multiple CR b4 , then each R b4 Also independently the above groups; said C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 3-7 Cycloalkyl; said C 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 Alkyl; the C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the formula (2): in R 1 Selected from the following formulas (1a-1) to (1a-4): in X 1 -X 7 are independently a nitrogen atom or CR a6 ; Q 1 and Q 2 is an oxygen atom, -NR a7 - or sulfur atom; R a1 -R a7 are independently a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group, C 1-4 Alkyl, C 3-6 Cycloalkyl, cyano, C 1-4 Alkoxy, or C 3-7 Cycloalkoxy, the C 3-6 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 Alkyl; wherein R a4 and R a5 Can be bonded to the same carbon atom if chemically possible; If there are multiple CR a6 , then each R a6 Also independently the above groups; said C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-6 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 alkyl; and q 1 is an integer of 1 or 2; L 1 is a single bond or oxygen atom; L 2 is a single bond, -CH2-, or an oxygen atom; R 2 is a hydrogen atom, a hydroxyl group, a halogen atom, or a C 1-4 alkyl; R 3 and R 4 are independently a hydrogen atom, a halogen atom, a C 1-4 Alkyl or C 1-4 Alkoxy; wherein R 3 and R 4 can be bound to the same carbon atom if chemically possible; and when R 3 and R 4 When bound to different carbon atoms in the ring, R 3 and R 4 Can be obtained through C 1-6 The alkylene groups together form a bridged ring; Ring G is selected from the following (1b-1) to (1b-4): in W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ; W 2 , W 4 and W 8 YesNR b5 , oxygen atom or CR b6 R b7 ; R b1 -R b7 are independently hydrogen atoms, C 1-6 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkoxy; wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a chemically possible bicyclic structure selected from spirocyclic and bridged rings; If there are multiple CR b4 , then each R b4 Also independently the above groups; said C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 Alkyl; the C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl; A 1 is an oxygen atom or a sulfur atom; A 2 is an oxygen atom or -NH-; and A 3 It's a nitrogen atom.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the following formulas (1a-1), (1a-2) and (1a-3-1): in X 1 -X 6 are independently a nitrogen atom or CR a6 ; Q 1 and Q 2 is an oxygen atom, -NR a7 - or a sulfur atom; and R a1 -R a3 , R a6 and R a7 are independently a hydrogen atom, a halogen atom, a C 6-10 Aromatic carbocyclic group, C 1-4 Alkyl, C 3-7 Cycloalkyl, cyano, C 1-4 Alkoxy, or C 3-7 Cycloalkoxy, If there are multiple CR a6 , then each R a6 Also independently the above groups; The C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms, and C 1-4 alkyl.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Ring G is selected from the following (1b-1), (1b-2) and (1b-4): in W 1 , W 3 , W 5 , W 6 and W 7 are independently a nitrogen atom or CR b4 ; W 2 and W 4 YesNR b5 or CR b6 R b7 ;and R b1 , R b2 and R b4 -R b7 are independently hydrogen atoms, C 1-6 Alkyl, C 1-4 Alkoxy, or C 3-7 Cycloalkoxy; or R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a bridged bicyclic structure, If there are multiple CR b4 , then each R b4 Also independently the above groups; The C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 alkyl; The C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl.

8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Ring G is selected from the following (1b-1) and (1b-2): in W 1 and W 3 is a nitrogen atom or CR b4 ; W 2 and W 4 YesNR b5 or CR b6 R b7 ;and R b1 , R b2 and R b4 -R b7 are independently hydrogen atoms, C 1-6 Alkyl, C 1-4 Alkoxy or C 3-7 Cycloalkoxy; wherein R b1 and R b2 Can be bound to the same carbon atom if chemically possible; or R b1 and R b2 Can be obtained through C 1-6 The alkylene groups together form a bridged bicyclic structure, The C 1-6 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 1-4 The alkoxy group is optionally substituted by one or more substituents which may be the same or different and which are selected from the group consisting of C 1-4 alkyl; The C 3-7 Cycloalkoxy is optionally substituted by the same or different one or more substituents selected from C 1-4 alkyl.

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the formula (3): in R 1 It is the following formula (1a-1), (1a-2) or (1a-3-1): in X 1 -X 6 are independently a nitrogen atom or CR a6 ; Q 1 and Q 2 is an oxygen atom or a sulfur atom; R a1 -R a3 and R a6 are independently a hydrogen atom, a halogen atom, a C 1-4 Alkyl, C 3-7 Cycloalkyl, cyano or C 1-4 Alkoxy; if there are multiple CR a6 , then each R a6 Also independently the above groups; said C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 alkyl; L 1 and L 2 each independently is a single bond or an oxygen atom; R 2 is a hydrogen atom, a halogen atom or a C 1-4 alkyl, R 3 and R 4 each independently a halogen atom; Ring G is the following (1b-1), (1b-2-1), (1b-2-2) or (1b-2-3): in R b5 is a hydrogen atom or a C optionally substituted by one or more substituents which may be the same or different 1-6 An alkyl group, wherein the substituent is selected from halogen atoms; and A 1 It is an oxygen atom or a sulfur atom.

10. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is formula (1a-2), and R a1 It is a hydrogen atom, a halogen atom, a C 1-4 Alkyl, C 3-7 Cycloalkyl or C 1-4 Alkoxy, The C 1-4 The alkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms; 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 alkyl.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is formula (1a-2), and X 4 and X 5 They are all nitrogen atoms.

12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein Ring G is of formula (1b-1-1), and R b5 is C optionally substituted by the same or different one or more halogen atoms 1-4 alkyl.

13. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein Ring G is of formula (1b-2-1), and R b5 is a hydrogen atom or a C optionally substituted by one or more substituents which may be the same or different 1-4 The alkyl group, wherein the substituent is selected from halogen atoms.

14. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the formula (4): in R 1 is the following (1a-2-1): in Q 2 is an oxygen atom or a sulfur atom; R a2 It is C 3-7 Cycloalkyl or C 3-7 Cycloalkoxy; the C 3-7 The cycloalkyl group is optionally substituted by one or more substituents which may be the same or different and which are selected from halogen atoms and C 1-4 alkyl; R 2 It is C 1-4 alkyl; Ring G is the following (1b-1-1) or (1b-2-1): in R b5 is C optionally substituted by one or more substituents which may be the same or different 1-4 An alkyl group, wherein the substituent is selected from halogen atoms; and L 2 It is a single bond or an oxygen atom.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R a2 is C which may be optionally substituted by one or more substituents which may be the same or different 3-7 Cycloalkyl, the substituents are selected from halogen atoms, and R 2 It's methyl.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R a2 is cyclopropyl, and R 2 It's methyl.

17. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Ring G is of formula (1b-2-1), and R b5 It is isopropyl.

18. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Ring G is of formula (1b-1-1), and R b5 It is isobutyl.

19. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Ring G is of formula (1b-1-1), R b5 is isopropyl, and L 2 It's an oxygen atom.

20. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein Q 2 It's an oxygen atom.

21. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures: 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide 4-(5-cyclopropyl-1,2-oxazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[3-(propan-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1S,2R)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-thiocarboxamide 22. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures: 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-(4-methylphenyl)piperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3R)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methyl-4-{5-[(1R,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-4-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3R)-4,4-difluoro-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide 23. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures: N-{(1S,6R)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1R,2R)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{methyl[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[(2S)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[(2R)-2-methyl-4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{(3R)-3-[methyl(propan-2-yl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{(3S)-3-[Cyclopropyl(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{(3S)-3-[methyl(2-methylpropyl)amino]pyrrolidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-(4-{[(1-fluorocyclopropyl)methyl](methyl)amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{(3S)-3-[(cyclopropylmethyl)(methyl)amino]pyrrolidin-1-yl}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide rac-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-{(1R,2R,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide N-{(1R,6S)-2,2-difluoro-6-[4-(propan-2-yl)-1,4-diazepan-1-yl]cyclohexyl}-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1R,2S,6S)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide 4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-N-{(1S,2R,6R)-2-fluoro-6-[4-(propan-2-yl)piperazin-1-yl]cyclohexyl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{4-[methyl(2-methylpropyl)amino]piperidin-1-yl}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{4-[(Cyclopropylmethyl)(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{4-[Cyclobutyl(methyl)amino]piperidin-1-yl}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]amino}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 24. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following compound names or structures: N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[1-(propan-2-yl)piperidin-4-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide 4-(5-cyclobutyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-ethyl-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{[(3S)-1-(Cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{[(3S)-1-(2,2-dimethylpropyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-6-{[(3S)-1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}-2,2-difluorocyclohexyl]-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methylpiperidine-1-carboxamide 4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-methylcyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-({(3S)-1-[(1-fluorocyclopropyl)methyl]pyrrolidin-3-yl}oxy)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-(4-{methyl[(1-methylcyclopropyl)methyl]amino}piperidin-1-yl)cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide N-[(1R,6S)-2,2-difluoro-6-{[(3S)-1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl]oxy}cyclohexyl]-4-{5-[(1S,2S)-2-fluorocyclopropyl]-1,2,4-oxadiazol-3-yl}-4-methylpiperidine-1-carboxamide 25. Use of the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with orexin receptors.

26. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating narcolepsy, idiopathic hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Lewy body dementia, hypersomnia syndrome including excessive daytime sleepiness, loss of consciousness, obesity, insulin resistance syndrome, Alzheimer's disease, impaired consciousness, side effects or complications caused by anesthesia, sleep disorders, insomnia, fragmented sleep, nocturnal myoclonus, rapid eye movement sleep disruption, jet lag, jet lag syndrome, parasomnia, night terrors, depression, major depression, sleepwalking, enuresis , Alzheimer's Sunset Syndrome, Circadian Rhythm-Related Disorders, Fibromyalgia, Conditions Caused by Reduced Sleep Quality, Binge Eating Disorder, Compulsive Eating Disorders, Obesity-Related Disorders, Hypertension, Diabetes, Elevated Plasma Insulin Levels / 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 Disease, Sudden Death, Polycystic Ovaries, Craniopharyngioma, Fröhlich Syndrome, Growth Hormone Deficiency, Normal Variant Short Stature, Turner Syndrome, Children Suffering from Acute Lymphoblastic Leukemia, Syndrome X, Reproductive hormone abnormalities, decreased fertility, infertility, hypogonadism in men, sexual / reproductive dysfunction, fetal defects related to maternal obesity, gastrointestinal motility disorders, Pickwick syndrome, respiratory diseases, inflammation, atherosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, secondary risk of obesity, migraine, headache, neuropathic pain, psychosis, schizophrenia, facial flushing, night sweats, genital / urinary system diseases, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder disorders, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, eye injury, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Tourette syndrome, chorea, myoclonus, convulsions, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), conduct disorders, 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.

27. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating narcolepsy, idiopathic hypersomnia, sleep apnea syndrome, narcolepsy syndrome including narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, or hypersomnia associated with Lewy body dementia.

28. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating coma, narcolepsy-bulimia syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis or Hashimoto's encephalopathy.

29. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating malignant mast cells, exogenous obesity, hyperisolative obesity, protoplasmic obesity, pituitary obesity, protoplasmic obesity, hypothyroid obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, gonadal obesity, systemic mastocytosis, primary obesity or centripetal obesity.

30. Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating hirsutism in women, obesity-related gastroesophageal reflux, respiratory distress, systemic vascular inflammation, risk of left ventricular hypertrophy, or brain defects occurring after cardiac bypass surgery or heart transplantation.

31. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a sleep disorder.

32. The use according to claim 31, wherein the sleep disorder is a sleep disorder of shift workers.

33. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating sleep problems.

34. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hypersomnia.

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