Macrocyclic heterocyclic compounds and their uses

Abstract

The present invention provides heterocyclic compounds having orexin type 2 receptor agonist activity. Formula (I): JPEG0007821946000071.jpg65163 (wherein each symbol is as defined in the specification.) The compound represented by the formula (I) or a salt thereof has orexin type 2 receptor agonist activity and is useful as an agent for the prophylaxis or treatment of narcolepsy.

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds, particularly heterocyclic compounds having orexin type 2 receptor agonist activity.

[0002] BACKGROUND OF THE INVENTION Orexin is a neuropeptide specifically produced by certain neurons scattered throughout the lateral hypothalamus and its surrounding areas, and consists of two subtypes: orexin A and orexin B. Both orexin A and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors found primarily in the brain, and two subtypes of orexin receptors, type 1 and type 2, are known (Non-Patent Document 1).

[0003] Orexin-producing neurons (orexin neurons) are localized near the feeding center, and intracerebroventricular administration of orexin peptides increases food intake. Therefore, when orexin was first discovered, it attracted attention as a neuropeptide with an appetite-regulating effect. However, it was later reported that canine narcolepsy is caused by a genetic mutation in the orexin type 2 receptor (Non-patent Document 2), and the role of orexin in regulating sleep and wakefulness also began to attract attention.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice, which were crossbred with transgenic mice overexpressing orexin, have demonstrated that sustained expression of orexin eliminates narcolepsy-like symptoms caused by degeneration of orexin neurons. Similarly, intracerebroventricular administration of orexin peptides to transgenic mice with degenerated orexin neurons also improved narcolepsy-like symptoms (Non-Patent Document 3). Furthermore, studies of orexin type 2 receptor knockout mice suggest that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Documents 4 and 5). Based on these findings, orexin type 2 receptor agonists have been suggested as potential therapeutic agents for narcolepsy and other sleep disorders characterized by hypersomnia (Non-Patent Document 6).

[0005] It has also been suggested that a peptide agonist that selectively acts on the orexin type 2 receptor ameliorates obesity induced by a high-fat diet in mice (Non-Patent Document 7). It has also been suggested that intracerebroventricular administration of orexin peptides shortens the time of general anesthesia in rats (Non-Patent Document 8). It has also been suggested that patients with sleep apnea syndrome have low plasma orexin A concentration levels (Non-Patent Document 9). It has also been suggested that intracerebroventricular administration of orexin peptides improves memory retention in senescence-accelerated mouse model (SAMP8) with cognitive impairment (Non-Patent Document 10). Furthermore, it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11). It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by loss of orexin neurons (Non-Patent Document 12). Furthermore, orexin regulates bone formation and bone loss, and it has been suggested that orexin type 2 receptor agonists could be used to treat diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). Furthermore, a significant improvement in mortality rate was observed in a mouse model of septic shock simply by continuous peripheral administration of orexin, suggesting that orexin receptor agonists are useful for the prevention or treatment of sepsis, severe sepsis, and septic shock (Patent Document 3).

[0006] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be useful as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, and the like, as well as anesthetic antagonists and agents for preventing or treating side effects and complications caused by anesthesia.

[0007] On the other hand, sulfonamide derivatives include: formula

[0008] [ka]

[0009] (The symbols in the formula are as described in the literature.) A compound represented by the following formula (Patent Document 4) has been reported.

[0010] Furthermore, the following compounds have been reported to have orexin type 2 receptor agonist activity. formula

[0011] [ka]

[0012] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 5). formula

[0013] [ka]

[0014] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 6). formula

[0015] [ka]

[0016] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 7). formula

[0017] [ka]

[0018] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 8). formula

[0019] [ka]

[0020] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 9). formula

[0021] [ka]

[0022] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 10). formula

[0023] [ka]

[0024] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 11). formula

[0025] [ka]

[0026] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 12). formula

[0027] [ka]

[0028] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 13). formula

[0029] [ka]

[0030] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 14). formula

[0031] [ka]

[0032] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 15). formula

[0033] [ka]

[0034] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 16). formula

[0035] [ka]

[0036] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 17). formula

[0037] [ka]

[0038] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 18). formula

[0039] [ka]

[0040] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 19). formula

[0041] [ka]

[0042] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 20). formula

[0043] [ka]

[0044] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 21). formula

[0045] [ka]

[0046] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 22). formula

[0047] [ka]

[0048] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 23). formula

[0049] [ka]

[0050] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 24). formula

[0051] [ka]

[0052] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 25).

[0053] There is a need for the development of novel compounds that have orexin type 2 receptor agonist activity. [Prior art documents] [Patent documents]

[0054] [Patent Document 1] WO2015 / 073707A1 [Patent Document 2] WO2015 / 048091A1 [Patent Document 3] WO2015 / 147240A1 [Patent Document 4] WO2012 / 137982A9 [Patent Document 5] WO2017 / 135306A1 [Patent Document 6] WO2018 / 164191A1 [Patent Document 7] WO2018 / 164192A1 [Patent Document 8] WO2019 / 027003A1 [Patent Document 9] WO2019 / 027058A1 [Patent Document 10] WO2020 / 004536A1 [Patent Document 11] WO2020 / 004537A1 [Patent Document 12] WO2020 / 122092A1 [Patent Document 13] WO2020 / 122093A1 [Patent Document 14] WO2020 / 158958A1 [Patent Document 15] WO2020 / 167701A1 [Patent Document 16] WO2020 / 167706A1 [Patent Document 17] WO2021 / 106975A1 [Patent Document 18] WO2021 / 108628A1

Patent document 19

Patent document 20

Patent document 21

Patent document 22

Patent document 23

Patent document 24

Patent document 25

Non-licensed literature

[0055] [Non-licensed document 1] Cell, Vol. 92, 573-585, 1998 [Non-licensed document 2] Cell, Vol. 98, 365-376, 1999 [Non-licensed document 3] Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

[0056] An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0057] The present inventors have found that a compound represented by the following formula (I) or a salt thereof (also referred to as compound (I) in this specification) has orexin type 2 receptor agonist activity, and as a result of further research, have completed the present invention.

[0058] That is, the present invention relates to the following. [1] Formula (I):

[0059] [ka]

[0060] [In the formula, Ring A is an optionally substituted C 6-14 an aryl group or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, wherein Y is a ring atom C or N, wherein the C is bonded to a hydrogen atom or an optional substituent; X is -O-, -S-, or -NR1 -, -CR 2 R 3 -, -O-(CR 2 R 3 )-, -(CR 2 R 3 )-O-, or optionally substituted C 3-6 a cycloalkyl group, wherein the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y, and the right moiety of X is attached to ring B; R 1 is hydrogen or optionally substituted C 1-6 is an alkyl group; R 2 and R 3 are independently hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group; Ring B is an optionally substituted C 6-14 an aryl group or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; L is -C(R 4 R 5 )-NR 6 -, -C(R 4 R 5 )-O-, -OC(R 4 R 5 )-, -NR 6 -C(R 4 R 5 )-, -C(R 4 R 5 )-C(R 7 R 8 )-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R 4 and R 5 are independently hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group; R 6 is hydrogen or optionally substituted C 1-6 is an alkyl group; R 7 and R 8 are independently hydrogen, halogen, or optionally substituted C 1-6is an alkyl group; R 4 and R 6 taken together with the atom to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R 4 and R 5 , or R 4 and R 7 taken together with the atom to which they are attached, form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C 3-10 Forms a cycloalkyl group; R a is C 1-6 Alkyl group, C 3-4 Cycloalkyl group, or mono- or di-C 1-6 alkylamino group, where C 1-6 Alkyl group, C 3-4 Cycloalkyl groups, and mono- or di-C 1-6 Each alkylamino group may be optionally substituted; R b is a hydrogen atom or a halogen atom; and R c is a hydrogen atom or a halogen atom; A compound represented by the formula (I) or a salt thereof.

[0061] [2] Ring A is

[0062] [ka]

[0063] wherein i is the point of attachment to the bridging methylene and ii is the point of attachment to X; and R 11 and R 12 are independently hydrogen, halogen, or optionally halogenated C 1-6 is an alkyl group. The compound or salt of [1] above,

[0064] [3] Ring B is:

[0065] [ka]

[0066] wherein iv is the point of attachment to L and iii is the point of attachment to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d is hydrogen, halogen, optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxyl groups and C 3-6 independently selected from cycloalkyl groups; and R 24 is hydrogen, halogen, optionally halogenated C 1-6 Alkyl groups, and C 3-6 cycloalkyl groups. The compound or salt of [1] or [2] above, selected from:

[0067] [4] Ring A is

[0068] [ka]

[0069] wherein i is the point of attachment to the bridging methylene and ii is the point of attachment to X; and R 11 and R 12 are independently hydrogen, halogen, or C 1-6 is an alkyl group. and; X is -O-, -CR2 R 3 -, -O-(CR 2 R 3 )-, or -(CR 2 R 3 )-O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; R 2 and R 3 are independently hydrogen, halogen, or halogen and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkyl groups 1-6 is an alkyl group; Ring B is:

[0070] [ka]

[0071] wherein iv is the point of attachment to L and iii is the point of attachment to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d is hydrogen, halogen, optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxyl groups and C 3-6 independently selected from cycloalkyl groups; R 24 is hydrogen or C 1-6 is an alkyl group. Selected from; L is -C(R 4 R 5 )-NR 6 -, -C(R 4 R 5 )-O-, -OC(R 4 R 5 )-, -NR 6 -C(R 4 R5 )-, or -C(R 4 R 5 )-C(R 7 R 8 )-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R 4 and R 5 are independently hydrogen or C 1-6 is an alkyl group; R 6 is hydrogen or optionally halogenated C 1-6 is an alkyl group; R 7 and R 8 are independently hydrogen; or L is -C(R 4 R 5 )-NR 6 -or-NR 6 -C(R 4 R 5 )-, R 4 and R 6 However, along with the atoms to which they are attached, halogens and C 1-6 forming a 3- to 8-membered monocyclic non-aromatic heterocyclic ring optionally substituted by 1 to 3 substituents independently selected from alkoxyl groups, and R 5 is hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )-, R 4 and R 7 together with the carbon atoms to which they are attached, C 3-10 Forming a cycloalkyl group, and R 5 and R 8 are both hydrogen; R a However, halogen atoms and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxyl groups 1-6 Alkyl group, C 3-4 Cycloalkyl group, or mono- or di-C 1-6 is an alkylamino group; R b is a hydrogen atom or a halogen atom; and R c is a hydrogen atom or a halogen atom; A compound or salt of the above [1], [2], or [3].

[0072] [5] Ring A is a phenyl group optionally further substituted with 1 to 2 halogen atoms, where Y is a ring atom C bonded to hydrogen or a halogen; X is -O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B is halogen and C 1-6 a pyridine ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl groups; L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R a C optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl group, or C 3-4 is a cycloalkyl group; R b is a halogen atom; and R c is a halogen atom, The compound or salt of [1], [2], [3] or [4] above.

[0073] [6] Ring A is a phenyl group optionally further substituted with 1 to 2 halogen atoms, where Y is a ring atom C bonded to the halogen; X is -O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B may contain 1, 2 or 3 C 1-6 a pyridine ring optionally substituted with an alkyl group; L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R a C optionally substituted with 1 to 3 halogen atoms 1-6 is an alkyl group; R b is a halogen atom; and R c is a halogen atom, The compounds or salts of [1] to [5] above.

[0074] [7] The compound is: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide; 1-Fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; and N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide; The compound according to the above [1], or a salt thereof, selected from the group consisting of:

[0075] [8] A pharmaceutical composition comprising a compound defined in any one of the above [1] to [7] or a salt thereof, and a pharmacologically acceptable carrier. [9] A pharmaceutical composition comprising a compound defined in any one of the above [1] to [7] or a salt thereof.

[10] The pharmaceutical agent according to the above-mentioned [9], which is an orexin type 2 receptor agonist.

[11] The pharmaceutical agent according to [9] above, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, or side effects or complications caused by anesthesia.

[12] The pharmaceutical agent according to the above-mentioned [9], which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[13] The pharmaceutical agent according to the above-mentioned [9], which is a preventive or therapeutic agent for narcolepsy.

[0076]

[14] A method for preventing or treating a disease or disorder associated with the orexin type 2 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound defined in any one of the above items [1] to [7] or a salt thereof.

[15] The method according to

[14] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications of anesthesia.

[16] The method according to

[14] or

[15] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

[17] The method according to any one of the above

[14] ,

[15] , or

[16] , wherein the disease or disorder is narcolepsy.

[0077]

[18] A compound as defined in any of [1] to [7] above, or a salt thereof, for use in therapy.

[19] The compound or salt according to

[18] above, wherein the therapeutic method comprises treating a disease or disorder associated with the orexin type 2 receptor.

[20] The compound or salt according to

[19] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness, and side effects or complications of anesthesia. [twenty one] The compound or salt according to

[19] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. [twenty two] The compound or salt according to

[19] above, wherein the disease or disorder is narcolepsy.

[0078] [twenty three] Use of a compound or a salt thereof as defined in any one of [1] to [7] above in the manufacture of a medicament for the treatment of a disease or disorder associated with the orexin type 2 receptor. [twenty four] The use according to

[23] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications of anesthesia. [twenty five] The use according to

[23] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

[26] The use according to

[23] above, wherein the disease or disorder is narcolepsy. [Effects of the Invention]

[0079] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for the prevention or treatment of narcolepsy.

[0080] [Detailed Description of the Invention] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. As used herein, "optionally halogenated C 1-6 The "alkyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkyl groups, such as methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. In this specification, "C 2-6 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. In this specification, "C 2-6 Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. In this specification, "C 3-10 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. As used herein, "optionally halogenated C 3-10 The "cycloalkyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples include cycloalkyl groups, such as cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl. In this specification, "C 7-16 Examples of the "aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0081] In this specification, "C 1-6Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. As used herein, "optionally halogenated C 1-6 The "alkoxy group" includes, for example, a C alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkoxy groups, such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. As used herein, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, a C alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0082] In this specification, "C 1-6Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. As used herein, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, a C alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of alkyl-carbonyl groups include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl and 2-naphthoyl. In this specification, "C 7-16 Examples of the "aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl. As used herein, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0033] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0083] As used herein, "mono- or di-C 1-6Examples of the "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 Examples of the "aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0084] In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. As used herein, "optionally halogenated C 1-6 The alkylsulfonyl group includes, for example, a C alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkylsulfonyl groups, such as methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0085] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups and C 7-16 Examples include aralkyl groups.

[0086] In the present specification, examples of the "optionally substituted hydrocarbon group" include hydrocarbon groups which may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (11)C 1-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) Optionally halogenated C 1-6 alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 alkyl-carbonyl groups, (26)C 6-14 aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 alkoxy-carbonyl groups, (30)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 alkyl-carbamoyl groups, (35)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (36) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16aralkylamino groups (e.g., benzylamino), (49) formylamino group, (50)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 arylcarbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (57) Optionally halogenated C 1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C 2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0087] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0088] In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0089] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0090] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, and the like. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as diisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrobenzo[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydro ... and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0091] In the present specification, suitable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" that contain at least one nitrogen atom as a ring-constituting atom.

[0092] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0093] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C, each of which may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Aralkyl groups, 5- to 14-membered aromatic heterocyclic groups, 3- to 14-membered non-aromatic heterocyclic groups, amino groups, and mono- or di-C 1-6 Examples of the alkyl-amino group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which may have "1 or 2 substituents selected from an alkyl-amino group." The term "acyl group" also includes hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups and heterocyclic-sulfinyl groups. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C3-10 Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), NC 1-6 Alkyl-N',N'-di-C 1-6 Alkylhydrazine-carbonyl group, thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, and mono- or di-C 1-6 Examples include alkylphosphono groups (eg, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0094] As used herein, examples of the "optionally substituted amino group" include "amino groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an amino group which may have one or two substituents selected from an arylsulfonyl group. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6Alkenylamino group (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino group (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), and (C 1-6 Alkyl)(C 6-14 and aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0095] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and carbamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0096] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and a thiocarbamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Suitable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples thereof include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl), and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0097] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which optionally has 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and a sulfamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Suitable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0098] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from Substituent Group A, each of which may have 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups. Suitable examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy groups (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), and C 6-14 Examples include arylsulfonyloxy groups (eg, phenylsulfonyloxy).

[0099] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from Substituent Group A, each of which may have 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Examples thereof include a sulfanyl group which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, and a halogenated sulfanyl group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C3-10 Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0100] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0101] As used herein, the term "hydrocarbon ring" refers to, for example, C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes and C 3-10 Cycloalkenes are examples. In this specification, "C 6-14 Examples of the "aromatic hydrocarbon ring" include benzene and naphthalene. In this specification, "C 3-10 "Cycloalkanes" include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10"Cycloalkenes" include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. As used herein, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0102] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidin and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzophenone, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0103] As used herein, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples thereof include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the term "nitrogen-containing heterocycle" includes "heterocycles" that contain at least one nitrogen atom as a ring-constituting atom.

[0104] In this specification, "C 3-6 Examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-4 Examples of the "cycloalkyl group" include cyclopropyl and cyclobutyl. As used herein, "mono- or di-C 1-6 Examples of the "alkylamino group" include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neo-pentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, and 2-ethylbutylamino.

[0105] The definition of each symbol in formula (I) is explained in detail below. R a is C 1-6 Alkyl group, C 3-4 Cycloalkyl group, or mono- or di-C 1-6 alkylamino group, where C 1-6 Alkyl group, C 3-4 Cycloalkyl groups, and mono- or di-C 1-6 Each alkylamino group may be optionally substituted. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted mono- or di-C 1-6 "Alkylamino group" and "Optionally substituted C 3-4 Examples of the substituent of the "cycloalkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. R a is preferably (1) optionally substituted C 1-6alkyl groups (e.g., methyl, ethyl, isopropyl); (2) optionally substituted mono- or di-C 1-6 an alkylamino group (e.g., methylamino, dimethylamino), or (3) optionally substituted C 3-4 Cycloalkyl groups (e.g., cyclopropyl) is. R a is preferably (1) Halogen atoms (e.g., fluorine atoms) and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxyl groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (2) C 3-4 a cycloalkyl group (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, dimethylamino) is. R a is more preferably (1) C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl), or (2) C 3-4 Cycloalkyl groups (e.g., cyclopropyl) is. R a is even more preferably C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 It is an alkyl group (e.g., methyl).

[0106] R b is a hydrogen atom or a halogen atom (e.g., a fluorine atom); and R c is a hydrogen atom or a halogen atom (e.g., a fluorine atom). Preferably, R b and R c are both (1) a hydrogen atom, or (2) a halogen atom (e.g., a fluorine atom); or (3)R b and R c One of the groups is a hydrogen atom and the other is a halogen atom (eg, a fluorine atom). More preferably, R b is a halogen atom (e.g., a fluorine atom); and R c is a halogen atom (e.g., a fluorine atom).

[0107] Ring A is an optionally substituted C 6-14 An aryl group (e.g., phenyl), or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, wherein Y is a ring atom C or N, where the C is bonded to a hydrogen atom or an optional substituent. Ring A may have a substituent in addition to the -CH2-pyrrolidine ring and X in formula (I). Examples of the substituent include those selected from the above-mentioned substituent group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. Ring A is preferably (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 alkyl groups (e.g., methyl); wherein Y is a ring atom C bonded to a hydrogen atom or a halogen atom (eg, a fluorine atom). Ring A is more preferably a phenyl group which may be further substituted with 1 or 2 halogen atoms (e.g., fluorine atoms), where Y is a ring atom C which is bonded to hydrogen or a halogen atom (e.g., fluorine atom). Ring A is more preferably a phenyl group which may be further substituted with 1 or 2 halogen atoms (e.g., fluorine atoms), where Y is a ring atom C which bonds to a halogen (e.g., fluorine atom). Preferably, ring A is

[0108] [ka]

[0109] wherein i is the point of attachment to the bridging methylene and ii is the point of attachment to X; and R 11 and R 12 are independently hydrogen, halogen (e.g., fluorine atom), or optionally halogenated C 1-6 It is an alkyl group (e.g., methyl). is. Preferably, R 11 and R 12 are independently hydrogen, halogen (e.g., fluorine atom), or C 1-6 It is an alkyl group (e.g., methyl). More preferably, R 11 is hydrogen or halogen (e.g., fluorine atom), and R 12 is hydrogen.

[0110] X is -O-, -S-, or -NR 1 -, -CR 2 R 3 -, -O-(CR 2 R 3 )-, -(CR 2 R 3 )-O-, or optionally substituted C 3-6 is a cycloalkyl group, wherein the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y, and the right moiety of X is attached to ring B, wherein: R 1 is hydrogen or optionally substituted C 1-6 is an alkyl group; and R 2 and R 3 are independently hydrogen, halogen, or optionally substituted C 1-6 It is an alkyl group. The above "Optionally substituted C 1-6 "Alkyl group", and "Optionally substituted C 3-6Examples of the substituent of the "cycloalkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. Preferably, X is -O-, -CR 2 R 3 -, -O-(CR 2 R 3 )-, or -(CR 2 R 3 )-O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B, where R 2 and R 3 are independently hydrogen, halogen (e.g., fluorine atom), or halogen and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkyl groups 1-6 It is an alkyl group (e.g., methyl). Preferably, X is -O-, -CR 2 R 3 -, -O-(CR 2 R 3 )-, or -(CR 2 R 3 )-O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B, where R 2 and R 3 are independently hydrogen, halogen (e.g., fluorine atom), or C 1-6 It is an alkyl group (e.g., methyl). More preferably, X is —O—, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B.

[0111] Ring B is an optionally substituted C 6-14 It is an aryl group or an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle. Ring B may have a substituent in addition to L and X in formula (I). Examples of the substituent include those selected from the above-mentioned substituent group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. Preferably, ring B is (1) Optionally further substituted C 6-14 an aryl group (e.g., phenyl), or (2) Optionally further substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) is. More preferably, ring B is (1) Halogen atoms (e.g., chlorine atoms) and C 1-6 a phenyl group optionally substituted by 1 to 3 substituents selected from alkyl groups (e.g., methyl), (2) (a) Halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms), (b) optionally halogenated C 1-6 alkyl groups (e.g., methyl, ethyl, difluoromethyl); (c)C 3-6 cycloalkyl groups (e.g., cyclopropyl), and (d)C 1-6 Alkoxy groups (e.g., methoxy) and a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) optionally substituted by 1 to 3 substituents selected from the group consisting of (specifically, 1 to 3 substituents for pyridine, and 1 or 2 substituents for thiazole, pyrimidine, and pyrazine). More preferably, ring B is Halogens (e.g., fluorine atoms, chlorine atoms) and C 1-6 It is a pyridine ring which may be substituted with 1, 2 or 3 substituents independently selected from alkyl groups (eg, methyl). More preferably, ring B is 1, 2 or 3 Cs 1-6 It is a pyridine ring which may be substituted with an alkyl group (eg, methyl). More preferably, ring B is:

[0112] [ka]

[0113] wherein iv is the point of attachment to L and iii is the point of attachment to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d is hydrogen, halogen (e.g., fluorine atom, chlorine atom, bromine atom), optionally halogenated C 1-6 Alkyl groups (e.g., methyl, ethyl, difluoromethyl), C 1-6 Alkoxyl groups (e.g., methoxy) and C 3-6 independently selected from cycloalkyl groups (e.g., cyclopropyl); R 24 is hydrogen, halogen, optionally halogenated C 1-6 Alkyl groups, and C 3-6 cycloalkyl groups. Selected from. More preferably, R 24 is hydrogen or C 1-6 It is an alkyl group.

[0114] L is -C(R 4 R 5 )-NR 6 -, -C(R 4 R 5 )-O-, -OC(R 4 R 5 )-, -NR 6 -C(R 4 R 5 )-, -C(R 4 R 5 )-C(R 7 R 8)-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R 4 and R 5 are independently hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group; R 6 is hydrogen or optionally substituted C 1-6 is an alkyl group; R 7 and R 8 are independently hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group; or R 4 and R 6 taken together with the atom to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R 4 and R 5 , or R 4 and R 7 taken together with the atom to which they are attached, form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C 3-10 Forms a cycloalkyl group. The above "Optionally substituted C 1-6 "alkyl group," "optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring," and "optionally substituted C 3-10 Examples of the substituent of the "cycloalkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different. Preferably, L is -C(R 4 R 5 )-NR 6 -, -C(R 4 R 5 )-O-, -OC(R 4 R 5 )-, -NR 6 -C(R 4 R 5)-, or -C(R 4 R 5 )-C(R 7 R 8 )-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R 4 and R 5 are independently hydrogen or C 1-6 an alkyl group (e.g., methyl); R 6 is hydrogen or optionally halogenated C 1-6 an alkyl group (e.g., methyl, difluoroethyl); R 7 and R 8 are both hydrogen; or L is -C(R 4 R 5 )-NR 6 -or-NR 6 -C(R 4 R 5 )-, R 4 and R 6 together with the atoms to which they are attached, halogens (e.g., fluorine atoms) and C 1-6 forming a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., azetidine ring, pyrrolidine ring) optionally substituted by 1 to 3 substituents independently selected from alkoxyl groups (e.g., methoxy), and R 5 is hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )-, R 4 and R 7 along with the carbon atoms to which they are attached, C 3-10 Forms a cycloalkyl group (e.g., cyclopropyl), and R 5 and R 8 are both hydrogen. More preferably, L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group.

[0115] Suitable examples of compound (I) include the following compounds: [Compound A] R a but, (1) optionally substituted C 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, methoxymethyl); (2) optionally substituted mono- or di-C 1-6 an alkylamino group (e.g., methylamino, dimethylamino), or (3) optionally substituted C 3-4 Cycloalkyl groups (e.g., cyclopropyl) and; R b but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine atoms) and; R c but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine atoms) and; Ring A is (1) optionally substituted C 6-14 an aryl group (e.g., phenyl), or (2) An optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group wherein Y is a ring atom C or N, where C is bonded to a hydrogen or an optional substituent; Ring B is (1) optionally substituted C 6-14 an aryl group (e.g., phenyl), or (2) Optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) and; X is, (1)-O-, (2)-S-, (3)-NR 1 -, (4)-CR 2 R 3-, (5)-O-(CR 2 R 3 )-, (6)-(CR 2 R 3 )-O-, or (7) optionally substituted C 3-6 cycloalkyl group wherein the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y, and the right moiety of X is attached to ring B; R 1 is hydrogen or optionally substituted C 1-6 is an alkyl group, R 2 and R 3 are independently hydrogen, halogen (e.g., fluorine atom), or optionally substituted C 1-6 an alkyl group (e.g., methyl); L, (1)-C(R 4 R 5 )-NR 6 -, (2)-C(R 4 R 5 )-O-, (3)-OC(R 4 R 5 )-, (4)-NR 6 -C(R 4 R 5 )-, (5)-C(R 4 R 5 )-C(R 7 R 8 )- wherein the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; and R 4 and R 5 are independently hydrogen, halogen, or optionally substituted C 1-6 an alkyl group (e.g., methyl); R 6 is hydrogen or optionally substituted C 1-6 an alkyl group (e.g., methyl, difluoroethyl); R7 and R 8 are independently hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group; or R 4 and R 6 together with the atom to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., halogen (e.g., fluorine atom) and C 1-6 an azetidine ring or a pyrrolidine ring optionally substituted with 1 to 3 substituents independently selected from alkoxyl groups (e.g., methoxy); or R 4 and R 5 , or R 4 and R 7 taken together with the atom to which they are attached, form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C 3-10 Forming a cycloalkyl group (e.g., cyclopropyl), Compound (I).

[0116] [Compound B] R a but, (1) Halogen atoms (e.g., fluorine atoms) and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxyl groups (e.g., methoxy) 1-6 alkyl groups (e.g., methyl, ethyl, isopropyl); (2) C 3-4 a cycloalkyl group (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, dimethylamino) and; R b but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine atoms) and; R c but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine atoms) and; Ring A is Halogen atoms (e.g., fluorine atoms) and C 1-6 a phenyl group optionally further substituted by 1 or 2 substituents selected from alkyl groups (e.g., methyl), wherein Y is a ring atom C bonded to hydrogen or halogen (e.g., a fluorine atom); Ring B is (1) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a chlorine atom), (2) 5- or 6-membered monocyclic aromatic heterocyclic groups (e.g., thiazole, pyridine, pyrimidine, pyrazine), where pyridine is optionally substituted with 1 to 3 substituents, and thiazole, pyrimidine, and pyrazine are optionally substituted with 1 or 2 substituents, in all cases the substituents are (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), (b) optionally halogenated C 1-6 alkyl groups (e.g., methyl, ethyl, difluoromethyl); (c)C 3-6 cycloalkyl groups (e.g., cyclopropyl), and (d)C 1-6 Alkoxy groups (e.g., methoxy) Selected from; X is, (1)-O-, (2)-CR 2 R 3 -, (3)-O-(CR 2 R 3 )-,or (4)-(CR 2 R 3 )-O- wherein the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y, and the right moiety of X is attached to ring B; R 2 and R 3 But independently, (1) Hydrogen, (2) halogen (e.g., fluorine atom), or (3) Halogens and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkyl groups 1-6 Alkyl groups (e.g., methyl) and; L, (1)-C(R 4 R 5 )-NR 6 -, (2)-C(R 4 R 5 )-O-, (3)-OC(R 4 R 5 )-, (4)-NR 6 -C(R 4 R 5 )-, (5)-C(R 4 R 5 )-C(R 7 R 8 )- wherein the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; and R 4 and R 5 But independently (1) hydrogen, or (2) C 1-6 Alkyl groups (e.g., methyl) and; R 6 but, (1) hydrogen, or (2) Optionally halogenated C 1-6 Alkyl groups (e.g., methyl, difluoroethyl) and; R 7 and R 8 are each hydrogen; or L is -C(R 4 R 5 )-NR 6 -or-NR 6 -C(R 4 R 5 )-, R 4 and R6 together with the atoms to which they are attached, halogens (e.g., fluorine atoms) and C 1-6 forming a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., an azetidine ring or a pyrrolidine ring) optionally substituted by 1 to 3 substituents independently selected from alkoxyl groups (e.g., methoxy), and R 5 is hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )-, R 4 and R 7 However, along with the atoms to which they are bonded, C 3-10 Forms a cycloalkyl group (e.g., cyclopropyl), and R 5 and R 8 are both hydrogen atoms. Compound (I).

[0117] [Compound C] Ring A is a phenyl group optionally further substituted with 1 or 2 halogen atoms (e.g., fluorine atoms), wherein Y is a ring atom C bonded to hydrogen or a halogen atom (e.g., fluorine atom); X is -O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B is halogen (e.g., fluorine atom, chlorine atom) and C 1-6 a pyridine ring optionally substituted with 1, 2, or 3 substituents independently selected from alkyl (e.g., methyl); L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R a C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), or C 3-4 a cycloalkyl group (e.g., cyclopropyl); R b is a halogen atom (e.g., a fluorine atom); and Rc is a halogen atom (e.g., a fluorine atom), Compound (I).

[0118] [Compound D] Ring A is a phenyl group optionally further substituted with 1 or 2 halogen atoms (e.g., fluorine atoms), wherein Y is a ring atom C bonded to a halogen atom (e.g., fluorine atom); X is -O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B may contain 1, 2 or 3 C 1-6 a pyridine ring optionally substituted with an alkyl group (e.g., methyl); L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R a C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl); R b is a halogen atom (e.g., a fluorine atom); and R c is a halogen atom (e.g., a fluorine atom). Compound (I).

[0119] [Compound E] Ring A is a phenyl group optionally further substituted with 1 or 2 halogen atoms (e.g., fluorine atoms), wherein Y is a ring atom C bonded to a halogen atom (e.g., fluorine atom); X is -O-, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B is

[0120] [ka]

[0121] (In the formula, R 21a , R 22a and R 23a are independently hydrogen or C 1-6 Alkyl (e.g., methyl). and L is -CH2-NH-, where the left moiety of L is attached to ring B and the right moiety of L is attached to the carbonyl group; R a C optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 an alkyl group (e.g., methyl); R b is a halogen atom (e.g., a fluorine atom); and R c is a halogen atom (e.g., a fluorine atom), Compound (I).

[0122] Specific examples of Compound (I) include the compounds of Examples 1 to 111 described below. Specifically, compound (I) is preferably N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 2); N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 4); N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide or a salt thereof (Example 5); 1-fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 19); N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide or a salt thereof (Example 22); N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 36); N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide or a salt thereof (Example 58); or N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide or a salt thereof (Example 97) is.

[0123] As the salt of the compound represented by formula (I), a pharmacologically acceptable salt is preferred, and examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0124] The method for producing the compound of the present invention is explained below.

[0125] The starting compounds and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt, such as the salt of the compound represented by formula (I).

[0126] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. When the compound obtained in each step is a salt, it can be converted into the desired free form or another type of salt by a method known per se.

[0127] The compound obtained in each step can be used in the next reaction directly as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture according to a known separation method, for example, concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, or the like.

[0128] When the raw material compounds and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0129] In the reaction of each step, the reaction time varies depending on the reagents and solvent used, and unless otherwise specified, the reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0130] In the reactions of each step, the reaction temperature varies depending on the reagents and solvents used, and unless otherwise specified, the reaction temperature is usually from -78°C to 300°C, preferably from -78°C to 150°C.

[0131] In the reaction of each step, the pressure varies depending on the reagents and solvents used, and unless otherwise specified, the pressure is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0132] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator+ can be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0133] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in the amount of the solvent.

[0134] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending the raw material compounds in an appropriate solvent. Specific examples of the solvent include those described in the Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents can be used alone or in combination of two or more in an appropriate ratio.

[0135] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples are used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0136] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples are used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0137] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or in accordance with the method described in the Examples.

[0138] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene and Peter G.M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (P.J. Kocienski), published by Thieme in 2004, or the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of thiol-protecting groups include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or the like, or a reduction method.

[0139] When a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar's catalyst can be used.

[0140] In the oxidation reactions carried out in each step, examples of oxidizing agents that can be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0141] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0142] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0143] When the Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0144] When a Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.) is used as a reagent. Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0145] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0146] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0147] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0148] In each step, when a Knoevenagel condensation reaction is carried out, a compound having an active methylene group sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0149] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0150] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the azidation reaction of alcohols, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilyl azide and a Lewis acid is employed.

[0151] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include aldehydes such as paraformaldehyde and acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0152] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0153] When an esterification reaction, amidation reaction, or urea reaction is performed in each step, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. Examples of carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-Chloro-1-methyl-pyridinium iodide (Mukaiyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be added to the reaction system.

[0154] When a coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases.

[0155] When a carbonylation reaction is carried out in each step, examples of the carbonylating agent to be used include 1,1-carbonyldiimidazole (CDI), triphosgene, di(N-succinimidyl)carbonate (DSC), etc. Furthermore, a base may be added to the reaction, and examples of such a base include inorganic bases and organic bases.

[0156] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent)) may be used in addition to diphosphorus pentasulfide.

[0157] When a sulfonylation reaction is carried out in each step, examples of the sulfonylating agent to be used include sulfonyl chloride, sulfamoyl chloride, etc. Furthermore, a base may be added to the reaction, and examples of such a base include inorganic bases and organic bases.

[0158] When the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent used include N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by providing the reaction system with a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile.

[0159] When a halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent used include hydrohalic acids and acid halides of inorganic acids. Specific examples of chlorination include hydrochloric acid, thionyl chloride, and phosphorus oxychloride, and examples of bromination include 48% hydrobromic acid. Alternatively, a method for producing alkyl halides by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method for producing alkyl halides via a two-step reaction including converting the alcohol to the corresponding sulfonic acid ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide may be used.

[0160] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite.

[0161] When a sulfonate esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0162] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. In addition, for the acid hydrolysis reaction of a tert-butyl ester, formic acid, triethylsilane, or the like may be added to reductively trap the by-product tert-butyl cation.

[0163] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0164] PG 1 , P.G. 2 , P.G. 3 , and P.G. 4 Examples of the "protecting group" include those exemplified as the "protecting group" for an amino group and a hydroxy group.

[0165]

[0131] LG 1 , L.G. 2 , L.G. 3 , L.G. 4 , and L.G. 5 Examples of the "leaving group" include a halogen atom, an optionally halogenated C 1-6 Alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl 6-14 Examples thereof include arylsulfonyloxy (eg, benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0166] Compound (I) can be prepared from compounds (1a)-(4a) and (1b)-(4b) according to the method shown in Scheme 1 below, where the symbols are as defined above.

[0167] [ka]

[0168]

[0001] Compound (I) can be produced by subjecting compound (1a) to a carbonylation reaction. Compound (I) can be produced by subjecting compound (2a) to an amidation reaction. Compound (I) can be produced by subjecting compound (3a) to a nucleophilic substitution reaction. Compound (I) can be produced by subjecting compound (4a) to the Mizoroki-Heck reaction followed by reduction. Examples of metal catalysts used in the Mizoroki-Heck reaction include palladium compounds such as palladium(II) acetate. A phosphine ligand may also be added to the reaction, such as triphenylphosphine. A base may also be added to the reaction, such as inorganic and organic bases. Compound (5) can be produced by subjecting compound (1a) to a carbonylation reaction. Compound (5) can be produced by subjecting compound (2a) to an amidation reaction. Compound (5) can be produced by subjecting compound (3a) to a nucleophilic substitution reaction. Compound (5) can be produced by subjecting compound (4a) to the Mizoroki-Heck reaction, followed by reduction. Compound (I) can be produced by deprotecting compound (5) and then subjecting it to a sulfonylation reaction with compound (6). Compound (6) is a readily available commercial product, or can be produced by a method known per se.

[0169] Compounds (1a) and (1b) can be prepared from compounds (7a) and (7b), respectively, according to the method shown in Scheme 2 below. r is cyano or -COOR s and R s may be substituted C 1-6 is an alkyl group, and M 1is a metal, and the other symbols are as defined above.

[0170] [ka]

[0171] Compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b), respectively, to a coupling reaction with compound (8-1). Compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b), respectively, to a coupling reaction with compound (8-2). Compounds (10a) and (10b) can also be produced by subjecting compounds (7a) and (7b), respectively, to a coupling reaction with compound (8-3). Compounds (10a) and (10b) can also be produced by subjecting compounds (7a) and (7b), respectively, to a nucleophilic substitution reaction with compound (9). R r When is cyano, compounds (13a) and (13b) can be produced by coupling compounds (7a) and (7b) with compound (11). Examples of compounds (11) include zinc cyanide. Examples of metal catalysts include tetrakis(triphenylphosphine)palladium(0). R r Ga-COOR s In this case, compounds (13a) and (13b) can also be produced by subjecting compounds (7a) and (7b) to a coupling reaction with carbon monoxide and compound (12). Examples of the metal catalyst used include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. R r When is cyano, compounds (10a) and (10b) can be prepared by subjecting compounds (13a) and (13b), respectively, to reduction and subsequent protection. Compounds (1a) and (1b) can be prepared by deprotecting compounds (10a) and (10b), respectively. R r When R is cyano, compounds (1a) and (1b) can be prepared by reducing compounds (13a) and (13b), respectively, followed by deprotection. r Ga-COOR s In this case, compounds (1a) and (1b) can be prepared by subjecting compounds (13a) and (13b), respectively, to hydrolysis and subsequent deprotection.

[0172] Compounds (2a) and (2b) can be prepared from compounds (7a) and (7b), respectively, according to the method shown in Scheme 3 below. t may be substituted C 1-6 is an alkyl group, and the other symbols are as defined above.

[0173] [ka]

[0174] Compounds (15a) and (15b) can be prepared by subjecting compounds (7a) and (7b), respectively, to a nucleophilic substitution reaction with compound (14). Compounds (17a) and (17b) can be produced by subjecting compounds (7a) and (7b), respectively, to the Mizoroki-Heck reaction with compound (16). Compounds (18a) and (18b) can be prepared by subjecting compounds (17a) and (17b), respectively, to reduction. Compounds (2a) and (2b) can be prepared by deprotecting compounds (15a) and (15b), respectively, followed by hydrolysis. Compounds (2a) and (2b) can also be prepared by deprotecting compounds (18a) and (18b), respectively, followed by hydrolysis.

[0175] Compounds (3a) and (3b) can be prepared from compounds (7a) and (7b), respectively, according to the method shown in Scheme 4 below.

[0176] [ka]

[0177] Compounds (19a) and (19b) can be prepared by deprotecting compounds (7a) and (7b), respectively. Compounds (21a) and (21b) can be produced by subjecting compounds (19a) and (19b), respectively, to an amidation reaction with compound (20). Compounds (3a) and (3b) can be prepared by deprotecting compounds (21a) and (21b), respectively.

[0178] Compounds (4a) and (4b) can be prepared from compounds (19a) and (19b), respectively, according to the method shown in Scheme 5 below.

[0179] [ka]

[0180] Compounds (4a) and (4b) can be produced by subjecting compounds (19a) and (19b), respectively, to an amidation reaction with compound (22).

[0181] Compounds (7aa), (7ba), (13aa), and (13ba) can be prepared from compounds (23a) and (23b) according to the method shown in Scheme 6 below, where X a -O-, -S-, -NR 1 -,-(CR 2 R 3 )-O- and R u is R r and L.G. 2and the other symbols are as defined above.

[0182] [ka]

[0183] Compounds (7aa), (7ba), (13aa), and (13ba) can be prepared by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (24). a When is —O—, compounds (7aa), (7ba), (13aa), and (13ba) can also be prepared by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (25). Compounds (28a) and (28b) can be produced by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (26). a When is —O—, compounds (28a) and (28b) can also be prepared by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (27). Compounds (7aa) and (7ba) can be produced by subjecting compounds (28a) and (28b) to a Sandmeyer reaction. The Sandmeyer reaction can be carried out according to a method known per se, such as the method described in "Organic Name Reactions: Reaction Mechanism and Essence, Revised Edition" (Hideo Togo, Kodansha) or "Application of Name Reactions in Strategic Organic Synthesis" (translated by Kiyoshi Tomioka, Kagaku Dojin), or the method described in the Examples.

[0184] Compounds (13ab), (13bb), (15ab), and (15bb) can be prepared from compounds (29a) and (29b) according to the method shown in Scheme 7 below. b -CR 2 R 3 - and optionally substituted C 3-4 is a cycloalkyl group, and R v is R r and -L-COOR tand the other symbols are as defined above.

[0185] [ka]

[0186] Compounds (13ab), (13bb), (15ab), and (15bb) can be produced by subjecting compounds (29a) and (29b) to a coupling reaction with compound (30). Compounds (32a) and (32b) can be produced by subjecting compounds (29a) and (29b) to a coupling reaction with carbon monoxide and compound (31). Compounds (13ab), (13bb), (15ab), and (15bb) can be produced by subjecting compounds (32a) and (32b) to a fluorination reaction. Fluorinating agents used include (diethylamino)sulfur trifluoride and bis(2-methoxyethyl)aminosulfur trifluoride.

[0187] Compounds 23aa, 23ba, 23ab, and 23bb can be prepared from compound 33 according to the method shown in Scheme 8 below, where R w may be substituted C 1-6 is an alkyl group, and M 2 is a metal, and the other symbols are as defined above.

[0188] [ka]

[0189] Compound (33) can be produced according to a method known per se, for example, the methods described in "WO2020158958" and "WO2019027058", or the methods described in the Examples. Compound (34a) can be produced by subjecting compound (33) to a sulfonylation reaction with compound (6). Compound (34b) can be prepared by subjecting compound (33) to protection. Compounds (29a) and (29b) can be produced by subjecting compounds (34a) and (34b) to a borylation reaction with compound (35). Examples of the metal catalyst used include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. A base may also be added to the reaction, and examples of such bases include inorganic and organic bases. Compounds (23aa) and (23ba) can be produced by subjecting compounds (34a) and (34b) to a substitution reaction with compound (36). Potassium hydroxide and the like can be used as the compound (36). Tris(dibenzylideneacetone)dipalladium(0) and the like can be used as the metal catalyst. 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl and the like can be used as the phosphine ligand. Compounds (23aa) and (23ba) can be produced by subjecting compounds (29a) and (29b) to an oxidation reaction. Examples of the oxidizing agent used include sodium peroxoborate tetrahydrate and sodium perborate tetrahydrate. Compounds (37a) and (37b) can be produced by subjecting compounds (23aa) and (23ba) to trifluoromethanesulfonylation. Examples of the trifluoromethanesulfonylation agent used include trifluoromethanesulfonic anhydride. Compounds (39a) and (39b) can be produced by subjecting compounds (37a) and (37b) to a coupling reaction with carbon monoxide and compound (38). Compounds (23ab) and (23bb) can be prepared by subjecting compounds (39a) and (39b) to reduction.

[0190] In the compound (I) thus obtained, the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0191] In the above-mentioned production methods, when the starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group, or a mercapto group as a substituent, a protecting group commonly used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0192] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means, such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, and the like. When compound (I) contains optical isomers, stereoisomers, positional isomers, conformational isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I). Here, the optical isomers can be produced by methods known per se. Compound (I) may be crystalline. The crystals of Compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing Compound (I) using a crystallization method known per se.

[0193] In this specification, the melting point refers to the melting point measured using, for example, a micromelting point analyzer (Yanaco, MP-500D model or Buchi, B-545 model) or a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1). Generally, the melting point may vary depending on the measuring instrument, measuring conditions, etc. The crystals in this specification may be crystals that exhibit a melting point different from that described in this specification, as long as it is within the normal error range. The crystals of the present invention have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), pharmacological efficacy), and are extremely useful as pharmaceuticals.

[0194] Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, or the like. Prodrugs of compound (I) include: a compound in which the amino group of compound (I) has been acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); Examples include compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidized). These compounds can be produced from compound (I) by methods known per se.

[0195] Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Hirokawa Shoten, 1990, Vol. 7, Molecular Design, pp. 163 to 198. In the present specification, the prodrug may be in the form of a salt, and examples of such salts include those exemplified as salts of the compound represented by formula (I) above. Compound (I) may also contain isotopes (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 I) or the like. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) for use in positron emission tomography (PET), and is useful in fields such as medical diagnosis. Furthermore, Compound (I) may be a hydrate, a non-hydrate, a non-solvate (eg, anhydrous), or a solvate (eg, hydrate). moreover, 1 H 2 Deuterium-converted compounds converted to H(D) are also encompassed by Compound (I). Furthermore, Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared by a known cocrystallization method.

[0196] Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) can be used as a prophylactic or therapeutic agent for various diseases described below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys) either as such or in the form of a pharmaceutical composition (also referred to as a medicine) by mixing it with a pharmacologically acceptable carrier or the like. Here, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are used as pharmacologically acceptable carriers, and are incorporated as excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. Furthermore, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can also be used as needed.

[0197] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose. Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Suitable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate. Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Suitable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. A suitable example of a soothing agent is benzyl alcohol. Suitable examples of the preservative include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acids. Suitable examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.

[0198] Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), capsules (including soft capsules and microcapsules), pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal patch films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compound of the present invention and the medicament of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, subcutaneously, intraorgan, intranasally, intradermally, by eye drop, intracerebrally, intravaginally, intraperitoneally, inside a tumor, in the vicinity of a tumor, or directly to a lesion). These formulations may be immediate release formulations or controlled release formulations such as sustained release formulations (eg, sustained release microcapsules).

[0199] The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical formulation, for example, a method described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight. When producing oral preparations, coating may be carried out as necessary for the purposes of taste masking, enteric coating or sustained release.

[0200] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination. Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L (Eudragit L (trade name)), methacrylic acid copolymer LD (Eudragit L-30D55 ​​(trade name)), and methacrylic acid copolymer S (Eudragit S (trade name)); and natural products such as shellac. Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)). The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Furthermore, a light-shielding agent such as titanium oxide or iron sesquioxide may be used during coating.

[0201] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent or diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0202] Furthermore, the compounds of the present invention are expected to have excellent central nervous system transfer properties.

[0203] The compound of the present invention has excellent orexin type 2 receptor agonist activity and can treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor. The compound of the present invention can be used to treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor, for example, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, U-12 encephalitis, and other conditions. Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications from anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms convulsions, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunkenness, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, Cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormalities, sexual and reproductive dysfunction such as reduced fertility, infertility, male hypogonadism, and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity-hypoventilation syndrome (Pickwickian syndrome),Reduces the risk of respiratory disorders such as shortness of breath, inflammation such as systemic inflammation of the vascular system, secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flashes, night sweats, genital / urinary system disorders, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cerebral defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, and spinal cord trauma. The compounds are useful as preventive or therapeutic agents for various diseases, such as head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury (TBI). ,

[0204] In particular, the compound of the present invention is useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, side effects and complications caused by anesthesia, and the like, or as an anesthetic antagonist.

[0205] In some embodiments, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness, and side effects or complications of anesthesia. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy.

[0206] Central hypersomnia (CDH) is characterized by excessive daytime sleepiness in the absence of other sleep disorders and despite the establishment of adequate and regular sleep habits. Central hypersomnia (CDH) includes narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Kleine-Levin syndrome and insufficient sleep syndromes or hypersomnia caused by medical conditions, drugs or substances, or psychiatric conditions are also considered central hypersomnia. Evaluation of CDH includes sleep testing in a sleep laboratory (polysomnography, PSG) followed by multiple sleep latency testing (MSLT). Symptoms associated with narcolepsy include abnormal intrusions of REM sleep characteristics into wakefulness, such as sleep-related hallucinations, sleep paralysis, or vivid dreams and confusion between dreams and reality. These symptoms can occur even in people without a sleep disorder. Some people with narcolepsy experience cataplexy (narcolepsy type 1), a loss of muscle tone that is triggered by emotions, typically laughter or anticipation. Cataplexy can be generalized or partial and does not involve loss of consciousness. This muscle weakness usually improves within seconds to minutes. Patients with idiopathic hypersomnia (IDH) often complain of excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours of sleep per night), and severe difficulty waking in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH often take long, unrefreshing naps. Another common symptom of IDH is "brain fog," a feeling of daytime cognitive clouding. Kleine-Levin syndrome is a rare disorder of periodic hypersomnia.

[0207] One aspect of the disclosure is a method of treating a subject having one or more central hypersomnias (CDH), comprising administering to the subject a compound of the invention. Another aspect of the present disclosure is the use of a compound of the present invention for the manufacture of a medicament for the treatment of one or more central hypersomnias (CDH) in a subject. Another aspect of the present disclosure is a compound of the present invention for use in treating one or more central hypersomnias (CDH) in a subject. Another embodiment is the method or use of the previous embodiment, wherein the subject has narcolepsy. In one embodiment, the subject has been diagnosed with narcolepsy type 1. In another embodiment, the subject has been diagnosed with narcolepsy type 2. In yet another embodiment, the subject has been diagnosed with idiopathic hypersomnia.

[0208] Another embodiment is a method or use of any of the preceding embodiments, wherein administering a compound of the invention reduces daytime sleepiness, reduces instances of loss of muscle control, and / or reduces instances of sleep disruption in a subject. Another aspect is a method or use wherein a compound of the invention is administered in an amount effective to reduce excessive daytime sleepiness in adults with narcolepsy. Another aspect is the method or use, wherein a compound of the invention is administered in an amount effective to increase mean sleep latency. Another aspect is a method or use, wherein a compound of the invention is administered in an amount effective to reduce cataplexy events. Another aspect is a method or use, wherein a compound of the invention is administered in an amount effective to reduce nocturnal sleep disruption in a subject.

[0209] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose is usually about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, and more preferably 0.5 to 20 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

[0210] The compound of the present invention can be used in combination with other drugs (hereinafter abbreviated as concomitant drugs). By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to when the compound of the present invention or a concomitant drug is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the patient's symptoms (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0211] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as the "concomitant drug of the present invention." When using the combination drug of the present invention, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may be administered to a subject simultaneously or at staggered times. The dosage of the concomitant drug may be in accordance with the dosage used clinically and can be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes with a time lag (e.g., administration in the order of the compound of the present invention and the concomitant drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage, and the mixing ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination drug of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight of the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total weight of the formulation. Furthermore, when the compound of the present invention and the concomitant drug are formulated separately, the contents may be similar.

[0212] Concomitant medications include, for example, the following: narcolepsy medications (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromocloptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), antidementia drugs (e.g., memantine), inhibitors of beta-amyloid protein production, secretion, accumulation, aggregation and / or deposition, beta-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4 -biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, their optically active forms, their salts and their hydrates,OM99-2 (International Publication No. 01 / 00663)), gamma-secretase inhibitors, beta-amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP Patent Publication No. Hei 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem.J.(1999),340(1),283-289)), beta-amyloid vaccines, beta-amyloid degrading enzymes, etc., brain function enhancers (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-dopa , bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline (remacemide), riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), Neuronal differentiation and regeneration promoters (e.g., leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, propylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active forms, salts, hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors,MAP kinase inhibitors), drugs for treating urinary incontinence and frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil citrate), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), drugs for treating osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, salmon calciton nin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for treating insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), drugs for treating schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole) drugs acting on metabotropic glutamate receptors or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin Reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT, 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective beta-blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, beta3-adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel blockers, type 2 carbonic anhydrase inhibitors, NM DA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), drugs for treating bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, phenelzine sulfate ... benzodiazepines (e.g., benzodiazepines), cannabinoid CB1 antagonists (e.g., rimonabant), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (e.g., methylphenidate hydrochloride, methamphetamine hydrochloride), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating dysthymia, drugs for treating autonomic nervous system disorders, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling, and drugs for treating leg immobility drugs for treating impotence syndrome, drugs for treating substance dependence, drugs for treating alcohol-related diseases, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wanderlust due to dementia (sedatives, anti-anxiety drugs, etc.), drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating high blood pressure, drugs for treating low blood pressure, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0213] The above concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. Furthermore, when the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in combination with a biological product (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, or a vaccine preparation), and can also be used in combination with a gene therapy or the like, or with a drug-free psychiatric therapy. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, TNFα antibodies, antibodies against other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in the blood coagulation and fibrinolysis systems, antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance, etc. In addition, they can also be used in combination with biological preparations related to growth factors such as GH and IGF. Examples of gene therapy methods include therapies using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes; treatments using DNA decoys such as NFκB decoys; treatments using antisense; treatments using genes related to enzymes and proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion, and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids); treatments using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion and the like (e.g., growth factors such as HGF and VEGF); treatments using genes related to proteins involved in glucose metabolism and insulin resistance; and antisense against cytokines such as TNF. Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy, including cognitive behavioral therapy. Furthermore, the compound of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, cardiomyocyte sheets). [Example]

[0214] The present invention will be explained in more detail by the following examples, test examples and formulation examples, but these do not limit the present invention, and various changes or modifications can be made without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to a temperature of about 10° C. to about 35° C. The ratio of mixed solvents is by volume unless otherwise specified. % is by weight unless otherwise specified.

[0215] Unless otherwise specified, elution in column chromatography in the examples was carried out under observation by TLC (thin layer chromatography). In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used in column chromatography was used as the eluent. A UV detector was used for detection. In silica gel column chromatography, the abbreviation NH indicates the use of aminopropylsilane-bonded silica gel, and the abbreviation Diol indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high-performance liquid chromatography), the abbreviation C18 indicates the use of octadecyl-bonded silica gel. Unless otherwise specified, the ratio of elution solvents is expressed by volume.

[0216] 1H NMR analysis was performed using ACD / SpecManager (trade name) software. Peaks with very gentle proton peaks, such as those of hydroxyl or amino groups, may not be recorded. MS was measured using LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0217] The unit of sample concentration (c) for the optical rotation ([α]D) is g / 100 mL. Elemental analysis values ​​(Anal.) are reported as calculated values ​​(Calcd) and found values ​​(Found). In the examples, the peaks measured by powder X-ray diffraction are those measured at room temperature using an Ultima IV (Rigaku Corporation) with CuKα radiation as the radiation source. The measurement conditions are as follows: Voltage / Current: 40kV / 50mA Scan speed: 6° / min 2-theta scan range: 2-35° In the examples, the crystallinity measured by powder X-ray diffraction was calculated by the Hermans method. The following abbreviations are used in the following examples: mp: melting point MS: Mass spectrum M: Molar concentration CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph-mass spectrometer ESI: Electrospray Ionization APCI: atmospheric pressure chemical ionization Et2O: Diethyl ether DIPEA: Diisopropylethylamine IPE: Diisopropyl ether CPME: Cyclopentyl methyl ether NMP: N-methyl-2-pyrrolidone TFA: Trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) TEA: Triethylamine MeOH: Methanol EtOH: ethanol EtOAc: ethyl acetate CH2Cl2: Dichloromethane PE: Petroleum ether MsCl: methanesulfonyl chloride CDI: 1,1'-carbonyldiimidazole BOC2O: Di-tert-butyl dicarbonate PyBOP: Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Pd(Ph3P)4: Tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2: Palladium(II) acetate Pd(dppf)Cl2·CH2Cl2:[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G3: Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) SFC: Supercritical Fluid Chromatography

[0218] Example 1 N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0219] A) tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (5.00 g) in CHCl (50 mL) was added TEA (4.27 g). The mixture was stirred at 20°C for 30 minutes. Then, MsCl (1.44 g) was slowly added to the mixture at 0°C. The mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (50 mL) and stirred for 10 minutes. It was then extracted with CHCl and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH) to give the title compound (5.05 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.05 (9H, s), 1.20-1.35 (2H, m), 1.82-1.92 (1H, m), 2.07-2.15 (1H, m), 2.30-2.40 (1H, m), 2.84-2.91 (2H, m), 2.94 (3H, s), 3.80-3.90 (1H, m), 7.14-7.18 (1H, m), 7.20-7.25 (1H, m), 7.35-7.40 (2H, m), 7.50-7.56 (1H, m).

[0220] B) tert-Butyl (2S,3S)-3-[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.05 g) and bis(pinacolato)diboron (4.44 g) in toluene (50 mL) was added XPhos Pd G3 (493 mg) and potassium acetate (2.29 g). The mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (8.75 g). MS: [M-Boc+H] + 381.0

[0221] C) tert-Butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3S)-3-[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (5.60 g) in THF (50 mL) and water (50 mL) was added sodium perborate tetrahydrate (4.48 g). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH) to give the title compound (3.50 g). MS: [M-Boc+H] + 271.1

[0222] D) tert-Butyl (2S,3S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (2.00 g) in DMA (15 mL) was added 6-chloro-5-methylpicolinonitrile (906 mg) and cesium carbonate (2.64 g). The mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (759 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.08-1.33 (9H, m), 1.80-1.91 (1H, m), 2.00-2.13 (1H, m), 2.37 (3H, s), 2.87 (3H, s), 3.12-3.30 (4H, m), 3.80-3.92 (1H, m), 4.02-4.11 (1H, m), 6.92-7.21 (3H, m), 7.33 (1H, t, J = 8.0 Hz), 7.41-7.55 (1H, m), 7.68 (1H, d, J = 7.2 Hz), 7.90-7.97 (1H, m).

[0223] E) tert-Butyl (2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (759 mg) in MeOH (10 mL) was added nickel(II) chloride hexahydrate (371 mg). Sodium borohydride (177 mg) was then added to the mixture at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction was slowly quenched with saturated aqueous ammonium chloride at 0° C. and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0.3% ammonium hydroxide in CHCl / MeOH) to give the title compound (371 mg). MS: [M+H] + 491.2

[0224] F) N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]pyrrolidin-3-yl}methanesulfonamide dihydrochloride tert-Butyl (2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (371 mg) in 4 M hydrogen chloride-dioxane (5 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo to give the title compound (446 mg). MS: [M+H] + 391.1

[0225] G) N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14 (metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a solution of N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]pyrrolidin-3-yl}methanesulfonamide dihydrochloride (410 mg) in DMF (410 mL) was added CDI (158 mg) and DIPEA (686 mg). The reaction mixture was stirred at 25° C. under a nitrogen atmosphere for 12 hours to obtain mixture A. In a similar manner to the synthesis of mixture A, N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]pyrrolidin-3-yl}methanesulfonamide dihydrochloride (446 mg) in DMF (450 mL) was added CDI (172 mg) and DIPEA (746 mg) to obtain mixture B. Mixtures A and B were combined and concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonium hydroxide solution / acetonitrile) to obtain the title compound (230 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.71-1.85 (1H, m), 2.02-2.12 (1H, m), 2.26 (3H, s), 2.76-2.87 (3H, m), 3.01 (3H, s), 3.06-3.15 (1H, m), 3.75-3.86 (2H, m), 4.19-4.27 (1H, m), 4.43-4.53 (1H, m), 6.00 (1H, dd, J = 9.6, 3.6 Hz), 6.86-6.92 (2H, m), 7.10-7.14 (1H, m), 7.17-7.25 (2H, m), 7.55-7.67 (2H, m).

[0226] Example 2 N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0227] A) tert-butyl (2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (1.00 g) in CHCl (15 mL) was added TEA (875 mg). The mixture was stirred at 20°C for 30 minutes. Then, MsCl (400 mg) was slowly added to the mixture at 0°C. The mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water and stirred for 10 minutes. It was then extracted with CHCl and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CHCl) to give the title compound (1.07 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.06 (9H, s), 2.90 (2H, dd, J = 13.6, 4.4 Hz), 2.99 (3H, s), 3.75-3.85 (2H, m), 4.27-4.32 (1H, m), 4.47-4.56 (1H, m), 7.19 (1H, s), 7.20-7.40 (3H, m), 8.17 (1H, d, J = 9.6 Hz).

[0228] B) tert-Butyl (2S,3R)-4,4-difluoro-3-[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (970 mg) in toluene (20 mL) was added bis(pinacolato)diboron (869 mg), XPhos Pd G3 (97 mg), and potassium acetate (448 mg). The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.87 g). MS: [M+Na] + 539.1

[0229] C) tert-Butyl (2S,3R)-4,4-difluoro-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-4,4-difluoro-3-[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (1.87 g) in THF (10 mL) and water (10 mL) was added sodium perborate tetrahydrate (1.39 g) at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CHCl) to give the title compound (774 mg). MS: [M+Na] + 429.1

[0230] D) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]phenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (770 mg) in DMA (10 mL) was added 6-chloro-5-methyl-pyridine-2-carbonitrile (318 mg) and cesium carbonate (926 mg). The mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (713 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.05-1.14 (9H, m), 2.37 (3H, s), 2.56-2.64 (1H, m), 2.70-2.81 (1H, m), 2.87-2.97 (3H, m), 3.70-3.91 (2H, m), 4.29-4.38 (1H, m), 4.41-4.59 (1H, m), 6.95-7.20 (3H, m), 7.23-7.42 (1H, m), 7.69 (1H, d, J = 7.6 Hz), 7.94 (1H, dd, J = 7.2, 0.8 Hz), 8.05-8.20 (1H, m).

[0231] E) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]phenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (790 mg) in MeOH (10 mL) was added sodium borohydride (171 mg). Nickel(II) chloride hexahydrate (359 mg) was then added to the mixture at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction was slowly quenched with aqueous ammonium chloride at 0° C., then extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (676 mg). MS: [M+H] + 527.3

[0232] F) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride A mixture of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (200 mg) and 4 M hydrogen chloride-dioxane (5 mL) was stirred at 20° C. for 1 hour. The mixture was concentrated to give the title compound (200 mg). MS: [M+H] + 427.1

[0233] G) N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride (200 mg) in DMF (200 mL) was added CDI (71 mg) and DIPEA (310 mg). The reaction mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) to give the title compound (13.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 2.27 (3H, s), 2.54-2.63 (1H, m), 2.84 (1H, dd, J = 13.6, 4.4 Hz), 3.08 (3H, s), 3.60-3.72 (1H, m), 3.75-3.90 (2H, m), 4.27-4.44 (2H, m), 4.55-4.62 (1H, m), 6.32 (1H, dd, J = 9.2, 2.8 Hz), 6.85-6.92 (2H, m), 7.03 (1H, d, J = 7.2 Hz), 7.18 (1H, s), 7.23 (1H, t, J = 8.0 Hz), 7.56 (1H, d, J = 7.6 Hz), 7.74 (1H, brs).

[0234] Example 4 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0235] A) 3-chloro-2-fluorophenylalanine hydrochloride To a mixture of 1-(bromomethyl)-3-chloro-2-fluorobenzene (55.0 g), diethyl acetamidomalonate (56.1 g), and EtOH (400 mL) was added 20% sodium ethoxide in ethanol (88 g) at 0°C. The mixture was refluxed for 2 hours and 30 minutes and then cooled to room temperature. Impurities were removed by filtration, the filtrate was concentrated under reduced pressure, and a mixture of the residue and 6 M hydrochloric acid (500 mL) was refluxed for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with isopropanol / diisopropyl ether to give the title compound (67.1 g). MS: [M+H] + 217.8.

[0236] B) N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine To a mixture of 3-chloro-2-fluorophenylalanine hydrochloride (67.1 g), 1 M aqueous sodium hydroxide solution (528 mL), and DME (480 mL) was added BocO (63.4 g) at room temperature. The mixture was stirred at room temperature for 2 hours and 30 minutes and poured into ice water. The mixture was made basic with 1 M aqueous sodium hydroxide solution, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether / hexane to give the title compound (63.8 g). MS: [MH] - 316.0.

[0237] C) tert-Butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate To a mixture of N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine (63.8 g), N-methoxymethanamine hydrochloride (21.5 g), HOBt (29.8 g), TEA (44.7 g), and DMF (425 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (46.2 g) at 0°C. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was added to aqueous sodium bicarbonate and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether / hexane to give the title compound (70.0 g). MS, found: 260.9.

[0238] D) tert-Butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-methoxybenzyl)carbamate To a mixture of tert-butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (70.0 g) and DMF (390 mL) was added 60% sodium hydride (10.1 g) at 0°C. The mixture was stirred at 0°C for 5 minutes and then at room temperature for 10 minutes. 1-(chloromethyl)-4-methoxybenzene (60.7 g) and tetrabutylammonium iodide (7.16 g) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for 2 hours and 30 minutes, poured into ice water, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (90.7 g). MS: [M+H] + 481.1.

[0239] E) tert-butyl [1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbamate To a mixture of tert-butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-methoxybenzyl)carbamate (90.7 g) and EtO (500 mL) was added lithium aluminum hydride (9.30 g) portionwise at −78°C. The mixture was stirred at −15°C for 1 hour and 30 minutes, and EtOAc and 10% aqueous potassium hydrogen sulfite solution were added dropwise to the reaction mixture at −78°C. The mixture was stirred at room temperature for 15 minutes, and water was added to the mixture. Insoluble matter was removed by filtration through Celite, and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (74.7 g). MS: [MH] - 420.0.

[0240] F) Ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chloro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate To a mixture of zinc (37.0 g) and THF (500 mL) was added TMSCl (3.85 g) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 15 minutes, and then ethyl bromo(difluoro)acetate (71.9 g) was added dropwise to the mixture at room temperature with vigorous stirring while maintaining the internal temperature at approximately 50°C. The mixture was stirred at room temperature for 15 minutes, and then a mixture of tert-butyl [1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbamate (74.7 g) and THF (100 mL) was added dropwise to the mixture while maintaining the internal temperature at approximately 40°C. The mixture was stirred at room temperature for 2 hours, added to 5% aqueous potassium bisulfite solution under ice cooling, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (61.6 g). MS, found: 490.0.

[0241] G) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one To a mixture of ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chloro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate (61.6 g) and EtOH (160 mL) was added 4 M hydrogen chloride solution in CPME (282 mL) at room temperature. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated. To the resulting residue, EtOH (360 mL) and DIPEA (43.8 g) were added. The mixture was stirred at 70°C for 1 hour and 30 minutes. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane), and the resulting solid was washed with diisopropyl ether / hexane to give the title compound (36.1 g). MS: [M+H] + 399.9.

[0242] H) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2-one To a mixture of 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one (36.1 g), CHCN (315 mL), and water (105 mL) was added ammonium cerium(IV) nitrate (99 g) at room temperature. The mixture was stirred at room temperature for 4 hours, poured into ice water, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by NH silica gel column chromatography (MeOH / EtOAc) to afford the title compound (22.7 g). MS: [MH] - 278.0.

[0243] I) tert-Butyl 2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-carboxylate To a mixture of 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2-one (22.7 g) and THF (350 mL), 1 M borane-THF complex THF solution (284 mL) was added dropwise at room temperature. The mixture was slowly heated to 60°C and stirred for 4 hours. Water was added dropwise to the mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. 1 M hydrochloric acid (500 mL) was added to the residue, and the mixture was vigorously stirred at 60°C for 1 hour and 30 minutes. The mixture was slowly added to 1 M aqueous sodium hydroxide solution under ice-cooling. The mixture was made basic with potassium carbonate, saturated with salt, and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the resulting residue, sodium bicarbonate (6.83 g), and THF (190 mL) / water (210 mL) was added a solution of BocO (19.5 g) in THF (20 mL) at room temperature. The mixture was vigorously stirred at room temperature for 15 hours, poured into water, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (22.2 g). MS, found: 265.9.

[0244] J) rac-tert-butyl (2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate To a mixture of tert-butyl 2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-carboxylate (22.1 g), pyridine (96 g), and EtO (355 mL) was added dropwise trifluoromethanesulfonic anhydride (51.2 g) at 0 °C under an argon atmosphere. The mixture was stirred at room temperature for 2 hours and 30 minutes, poured into ice water, and extracted with EtOAc / hexane. The organic layer was separated, washed with 10% aqueous citric acid, aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (22.4 g). MS, found: 397.9.

[0245] K) rac-tert-butyl (2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate To a mixture of rac-tert-butyl (2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate (22.4 g) and CHCN (265 mL) was added tetra-n-butylammonium azide (38.3 g) at room temperature. The mixture was slowly heated to 80 °C and stirred for 1 hour. It was then poured into ice water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (16.2 g). MS, found: 290.9.

[0246] L) rac-tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate To a mixture of rac-tert-butyl (2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (16.2 g) and THF (200 mL) / water (5 mL) was added PPh3 (13.1 g) at room temperature under an argon atmosphere. The mixture was stirred at 55°C for 18 hours, added to aqueous sodium bicarbonate solution under ice cooling, and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound and a by-product, respectively. To a mixture of the by-product and THF (100 mL) / water (10 mL), 40% aqueous methanamine solution (3.22 g) was added at room temperature. The mixture was stirred at 70°C for 15 hours, poured into water, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (Et0Ac / hexane) to give the title compound (14.6 g) combined with the title compound obtained above. MS, found: 308.9.

[0247] M) tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate Rac-tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (14.6 g) was separated by HPLC (column: Chiral PAK IA, 50 mmID×500 mmL, 20 μm, mobile phase: hexane / ethanol / diethylamine = 800 / 200 / 1) to give the title compound (6.84 g) with a shorter retention time (column: Chiral PAK IA, 4.6 mmID×250 mmL, 5 μm, mobile phase: hexane / ethanol / diethylamine = 800 / 200 / 1). MS, found: 309.1.

[0248] N) tert-Butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (20 g), TEA (22.9 ml) in EtOAc (274 ml) was added MsCl (4.67 ml) at 0°C. The mixture was stirred at room temperature for 1 hour. Aqueous ammonium chloride solution was added to the mixture. The organic layer was separated, washed with aqueous sodium bicarbonate and brine, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was solidified and triturated with EtO to give the title compound (22.5 g). MS: [MH] - 441.0

[0249] O) tert-Butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (15 g x 2 batches), Pd2(dba)3 (1.55 g x 2 batches), and tBuXPhos (2.88 g x 2 batches) in DME (135 mL x 2 batches) was added 8 M aqueous potassium hydroxide solution (12.7 mL x 2 batches). The mixture was stirred at 120 °C in a medium pressure reactor for 2 hours. The mixture was quenched with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and crystallized from IPE-hexane to give the title compound (17.0 g). MS: [MH] - 422.9

[0250] P) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.9 g), 6-chloro-5-methylpicolinonitrile (2.33 g), CsCO (9.06 g), and DMF (60 mL) was stirred at 120 °C for 5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (5.62 g). MS: [MH] - 539.0

[0251] Q) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.62 g) and cobalt(II) chloride (2.70 g) in MeOH (120 mL) was added sodium borohydride (1.967 g) at 0° C. The mixture was stirred at room temperature for 1 hour. Then, BocO (3.62 mL) was added to the reaction mixture at room temperature, and it was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent, and EtOAc and aqueous sodium bicarbonate solution were added to the residue. The insoluble solid was removed through Celite, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (4.82 g). MS: [M+H] + 645.2

[0252] R) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (4.82 g) in EtOAc (50 mL) was added 4 M hydrogen chloride-EtOAc (50 mL) at room temperature. The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with EtOAc to obtain the title compound (3.85 g). MS: [M+H] + 445.1

[0253] S) N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a suspension of di(N-succinimidyl) carbonate (6.67 g) and DIPEA (33.8 g) in dry THF (4200 ml) was added dropwise a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride (16.9 g) in dry DMF (200 ml) at 0° C. over 60 minutes. The mixture was stirred at room temperature for 16 hours and concentrated to a small volume. EtOAc and water were added to the residue, and the mixture was partitioned. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane). To a solution of the residue thus obtained in EtOAc (600 ml), activated carbon Ecosorb C-941 (1 g) was added at 55°C, and the mixture was stirred at 55°C for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from EtOH-heptane to give the title compound (6.16 g). 1H NMR (400 MHz, DMSO-d6) δ 2.30 (3H, s), 2.65 (1H, br d, J = 12.7 Hz), 2.76-2.87 (1H, m), 3.11 (3H, s), 3.60 (1H, br d, J = 14.7 Hz), 3.68-3.88 (2H, m), 4.27-4.48 (2H, m), 4.52-4.62 (1H, m), 6.14 (1H, br d, J = 8.6 Hz), 6.85 (1H, d, J = 7.1 Hz), 6.96-7.03 (1H, m), 7.07 (1H, t, J = 7.7 Hz), 7.11-7.18 (1H, m), 7.48-7.61 (1H, m), 8.17 (1H, d, J = 9.5 Hz)

[0254] Example 5 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[0255] A) tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (80.0 g x 2 batches) in CHCl (560 mL x 2 batches) was added TEA (67.0 g x 2 batches) and ethanesulfonyl chloride (42.0 g x 2 batches) at 0 °C. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 13 hours. The reaction mixture was poured into water and extracted with CHCl. ​​The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (184 g). MS: [M-Boc+H] + 357.1

[0256] B) tert-Butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (27.0 g x 5 batches), Pd2(dba)3 (16.0 g x 5 batches), and tBuXPhos (8.00 g x 5 batches) in dioxane (243 mL x 5 batches) was added 2 M aqueous potassium hydroxide solution (89.0 mL x 5 batches). The mixture was degassed and purged with nitrogen three times. The mixture was stirred under reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (85.0 g). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (9H, s), 1.27 (3H, t, J = 7.2 Hz), 2.93 (1H, d, J = 13.6 Hz), 3.07-3.18 (3H, m), 3.63-3.76 (1H, m), 3.83-3.96 (1H, m), 4.31 (1H, d, J = 8.4 Hz), 4.42-4.57 (1H, m), 6.56-6.63 (1H, m), 6.83 (2H, t, J = 6.8 Hz), 8.18 (1H, d, J = 9.2 Hz), 9.65 (1H, s)

[0257] C) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (80.0 g), 6-chloro-5-methylpicolinonitrile (42.0 g), and cesium carbonate (119 g) in DMA (560 mL) was stirred at 120 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (80.0 g). MS: [M+Na] + 577.1

[0258] D) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (36.1 g x 2 batches) in MeOH (252 mL x 2 batches) were added nickel(II) chloride hexahydrate (16.0 g x 2 batches) and sodium borohydride (7.00 g x 2 batches) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched with aqueous ammonium chloride solution at 0°C. The mixture was then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (70.0 g). MS: [M+H] + 559.3

[0259] E) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide dihydrochloride A mixture of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (70.0 g) in 4 M hydrogen chloride-EtOAc (783 mL) was stirred at 25° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue (67.0 g). The residue (52.0 g) was then purified by reverse-phase HPLC (column: Agela C18, mobile phase: 0.4% hydrochloric acid / MeOH) to give the title compound (26 g). MS: [M+H] + 459.0

[0260] F) N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide To a mixture of di(N-succinimidyl)carbonate (2.00 g x 6 batches) and 4-methylmorpholine (4.00 g x 6 batches) in THF (4.11 L x 6 batches), a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide dihydrochloride (4.00 g x 6 batches) in DMF (58.0 mL x 6 batches) was added dropwise at 25°C for 30 minutes. Then, DIPEA (8.00 g x 6 batches) was added in one portion. Finally, the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The crude product was purified by preparative HPLC (column: Phenomenex Titank C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution / acetonitrile) to give the title compound (4.60 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 2.61-2.69 (1H, m), 2.78-2.89 (1H, m), 3.16-3.21 (2H, m), 3.60 (1H, d, J = 14.4 Hz), 3.70-3.86 (2H, m), 4.24-4.45 (2H, m), 4.52 (1H, t, J = 9.6 Hz), 6.14 (1H, d, J = 8.8 Hz), 6.85 (1H, d, J = 7.2 Hz), 6.96-7.16 (3H, m), 7.55 (1H, d, J = 7.2 Hz), 8.16 (1H, s).

[0261] Example 7 N-[(1S,19aS)-11-methyl-5-oxo-2,3,6,7,19,19a-hexahydro-1H,5H-8,12-(azeno)-14,18-(metheno)pyrrolo[2,1-h][1,9]oxaazacycloheptadecin-1-yl]methanesulfonamide

[0262] A) tert-Butyl (2S,3S)-2-{[3-({6-[(3-tert-butoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}oxy)phenyl]methyl}-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (495 mg), Pd(OAc)2 (10 mg), and di-tert-butyl-(2-phenylphenyl)phosphane (26 mg) in DMF (5 mL), tert-butyl prop-2-enoate (640 mg) and TEA (177 mg) were added at 25°C, and the mixture was stirred at 120°C under a nitrogen atmosphere for 13 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc) to afford the title compound (457 mg). MS: [M+H] + 588.2

[0263] B) tert-Butyl (2S,3S)-2-[(3-{[6-(3-tert-butoxy-3-oxopropyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3S)-2-{[3-({6-[3-tert-butoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}oxy)phenyl]methyl}-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (457 mg) in MeOH (5 mL) was added 10% palladium on carbon (55% wet with water, 60 mg) at 25° C. The mixture was stirred under a hydrogen atmosphere at 25° C. for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (411 mg). MS: [M+H] + 590.2

[0264] C) 3-{6-[3-({(2S,3S)-3-[(methanesulfonyl)amino]pyrrolidin-2-yl}methyl)phenoxy]-5-methylpyridin-2-yl}propanoic acid A mixture of tert-butyl (2S,3S)-2-[(3-{[6-(3-tert-butoxy-3-oxopropyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (67 mg) in 4 M hydrogen chloride-dioxane (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (48 mg). MS: [M+H] + 434.2

[0265] D) N-[(1S,19aS)-11-methyl-5-oxo-2,3,6,7,19,19a-hexahydro-1H,5H-8,12-(azeno)-14,18-(metheno)pyrrolo[2,1-h][1,9]oxaazacycloheptadecin-1-yl]methanesulfonamide To a solution of 3-{6-[3-({(2S,3S)-3-[(methanesulfonyl)amino]pyrrolidin-2-yl}methyl)phenoxy]-5-methylpyridin-2-yl}propanoic acid (75 mg) in THF (750 mL) were added PyBOP (125 mg) and TEA (81 mg) at 25° C., and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonia hydroxide solution / acetonitrile) and then lyophilized. The residue thus obtained was further purified by SFC (column: DAICEL CHIRALPAK IG, mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide) to give the title compound (14.4 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.69-1.83 (1H, m), 2.01-2.09 (1H, m), 2.20-2.34 (4H, m), 2.66-2.76 (1H, m), 2.81-2.91 (3H, m), 3.01 (3H, s), 3.16-3.29 (2H, m), 3.39-3.45 (1H, m), 3.74-3.86 (1H, m), 4.30-4.39 (1H, m), 6.85-6.96 (3H, m), 7.10-7.16 (1H, m), 7.19-7.28 (1H, m), 7.55 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 4.0 Hz).

[0266] Example 10 N-[(15aS,16R,17S)-17,20-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0267] A) Benzyl (2S,3R,4S)-4-fluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1 g) in toluene (15 mL), bis(pinacolato)diboron (0.830 g), potassium acetate (0.428 g), and XPhos Pd G3 (0.092 g) were added at room temperature. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (0.961 g). MS: [M+H] + 551.2

[0268] B) Benzyl (2S,3R,4S)-4-fluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of benzyl (2S,3R,4S)-4-fluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (962.5 mg) in THF (5.0 mL) and water (5.0 mL) was added sodium perborate tetrahydrate (538 mg) at 0°C. The mixture was stirred at 0°C to room temperature for 1.5 hours. The mixture was quenched with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated, washed with aqueous sodium thiosulfate, water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was washed with EtOAc-IPE to give the title compound (460 mg). MS: [M+H] + 441.0

[0269] C) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate A mixture of benzyl (2S,3R,4S)-4-fluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (500 mg), 6-chloro-5-methylpicolinonitrile (217 mg), and cesium carbonate (462 mg) in DMA (3 mL) was stirred at 100°C overnight under a nitrogen atmosphere. The mixture was quenched with aqueous ammonium chloride at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to afford the title compound (431 mg). MS: [M+H] + 557.1

[0270] D) Benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridin-2-yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamido)pyrrolidine-1-carboxylate To a solution of benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (430.5 mg) and nickel chloride hexahydrate (184 mg) in MeOH (15 mL) was added sodium borohydride (88 mg) at 0° C. The mixture was stirred at the same temperature for 30 minutes. The resulting mixture was concentrated, and the residue was purified by NH silica gel column chromatography (MeOH / EtOAc) to give the title compound (312 mg). MS: [M+H] + 561.2

[0271] E) N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}methanesulfonamide dihydrobromide To benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridin-2-yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamido)pyrrolidine-1-carboxylate (311.5 mg) was added 30% hydrogen bromide-acetic acid (10 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, and then the solvent was co-evaporated with toluene twice. The residue was washed with EtOAc and IPE to give the title compound (378 mg). MS: [M+H] + 427.1

[0272] F) N-[(15aS,16R,17S)-17,20-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a solution of CDI (99 mg) and DIPEA (0.582 mL) in THF(dry) (250 mL), N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}methanesulfonamide dihydrobromide (327.0 mg) in DMF(dry) (12.50 mL) was added dropwise at room temperature over 30 minutes. The mixture was stirred at room temperature for 2 hours under an argon atmosphere. After removing THF under reduced pressure, THF(dry) (250 mL) and DMF(dry) (12.5 mL) were added to the residue. The mixture was stirred at room temperature overnight. After removing THF under reduced pressure, the mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the title compound (42.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ 2.26-2.34 (3H, m), 2.68 (1H, br d, J = 12.6 Hz), 2.97 (1H, br t, J = 12.8 Hz), 3.09 (3H, s), 3.49-3.75 (3H, m), 3.86-4.03 (1H, m), 4.35-4.46 (2H, m), 5.28 (1H, dt, J = 56.6, 4.6 Hz), 6.00 (1H, br d, J = 8.8 Hz), 6.83 (1H, d, J = 7.2 Hz), 6.90-7.17 (3H, m), 7.54 (1H, d, J = 7.0 Hz), 7.74 (1H, d, J = 8.4 Hz).

[0273] Example 19 1-Fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0274] A) tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate To a stirred mixture of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (54.2 g) and sodium bicarbonate (26.2 g) in THF (550 mL) and water (275 mL) was added benzyl chloroformate (23.3 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was passed through a pad of NH silica gel, eluted with EtOAc, and concentrated under reduced pressure to give the title compound (81.5 g). This product was used in the next reaction without further purification. MS: [MH] - 496.9

[0275] B) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate To a degassed mixture of tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (3.76 g), bis(pinacolato)diboron (2.87 g), and potassium acetate (1.48 g) in toluene (37.7 mL) was added XPhos Pd G3 (0.319 g). The mixture was stirred at 100 °C under an argon atmosphere for 5 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (3.17 g). MS: [MH] - 589.2

[0276] C) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (3.17 g) in THF (26.8 mL) and water (26.8 mL) was added sodium perborate tetrahydrate (1.65 g) at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was acidified with 1 M hydrochloric acid at 0°C (pH = 3-4) and extracted with EtOAc. The organic layer was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.47 g). MS: [MH] - 479.1

[0277] D) tert-Butyl (2S,3R)-3-amino-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (2.47 g) and 10% palladium on carbon (55% water-wet, 0.243 g) in EtOH (25.7 mL) was hydrogenated under balloon pressure at room temperature for 14 hours. The catalyst was removed by filtration and washed with EtOH and THF. The filtrate was concentrated under reduced pressure to give the title compound (1.77 g). MS: [MH] - 345.0

[0278] E) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-3-amino-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (1.77 g), 6-chloro-5-methylpicolinonitrile (0.819 g), and cesium carbonate (3.33 g) in dry DMF (17.0 mL) was stirred at 120 °C for 1 hour under an argon atmosphere. After cooling to 0 °C, potassium carbonate (0.706 g) and benzyl chloroformate (1.08 ml) were added to the mixture. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with EtOAc and water, and the solution was extracted with EtOAc. The extract was washed with brine. The solution was passed through NH silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.88 g). MS: [MH] - 595.1

[0279] F) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (1.63 g) was slowly added to a solution of tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate (5.13 g) and cobalt(II) chloride (2.23 g) in MeOH (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Di-t-butyl dicarbonate (2.99 mL) was added to the reaction mixture at 0° C., which was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction mixture at room temperature, and the solid was removed by filtration. The filtrate was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (3.46 g). MS: [MH] - 699.1

[0280] G) Benzyl {(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}carbamate TFA (9.0 mL) was added to tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate (4.51 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. It was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (MeOH / EtOAc) to give the title compound (3.00 g). MS: [M+H] + 501.1

[0281] H) Benzyl [(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]carbamate A solution of benzyl {(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}carbamate (2.51 g) in DMF (dry) (81 mL) was added to a solution of di(N-succinimidyl) carbonate (1.41 g) and N-methylmorpholine (1.10 mL) in THF (dry) (2430 mL) at room temperature over 40 minutes. After stirring for 1 hour at room temperature, DIPEA (8.57 mL) was added to the reaction mixture, which was stirred at room temperature for 1.5 hours and then at 70°C for 2 hours. The solvent was removed under reduced pressure. Water was added to the residue, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (2.08 g). MS: [M+H] + 527.2

[0282] I) (15aS,16R)-16-amino-17,17,20-trifluoro-7-methyl-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-1-one A mixture of benzyl [(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]carbamate (8.22 g) and 20% palladium hydroxide on activated carbon (400 mg) in MeOH (80 mL) was hydrogenated under balloon pressure at room temperature for 12 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (5.38 g). MS: [M+H] + 393.1

[0283] J) 1-Fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide A solution of fluoromethanesulfonyl chloride (0.790 g) in dry THF (10 mL) was added to a solution of (15aS,16R)-16-amino-17,17,20-trifluoro-7-methyl-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-1-one (2.00 g) in pyridine (10 mL) at 5 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The mixture was purified by NH silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) and silica gel column chromatography (EtOAc / hexane), followed by recrystallization from EtOAc-heptane to give the title compound (1.76 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.30 (3H, s), 2.62-2.69 (1H, m), 2.79-2.88 (1H, m), 3.56-3.64 (1H, m), 3.71-3.88 (2H, m), 4.29-4.46 (2H, m), 4.50-4.58 (1H, m), 5.41-5.66 (2H, m), 6.14-6.19 (1H, m), 6.85 (1H, d, J = 7.2 Hz), 6.97-7.12 (3H, m), 7.53-7.56 (1H, m), 8.79-8.94 (1H, m).

[0284] Example 22 N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[0285] A) tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a stirred solution of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (6.2 g) in pyridine (50 mL) was added dropwise cyclopropanesulfonyl chloride (3.64 mL) while cooling in an ice bath. The mixture was stirred at 50°C for 3 hours. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.00 g). MS: [MH] - 467.9

[0286] B) tert-Butyl (2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (5000 mg), potassium hydroxide (1795 mg), Pd2dba3 (488 mg), tBuXPhos (906 mg), DME (6 mL), and water (2 mL) was heated at 120 °C for 1 hour under microwave irradiation. The mixture was acidified with aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (3600 mg). MS: [MH] - 449.0

[0287] C) tert-Butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridin-2-yl)oxy]phenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (3000 mg) and cesium carbonate (4520 mg) in dry DMF (50 mL) was added 5-chloro-6-fluoropicolinonitrile (1194 mg) at room temperature. The mixture was stirred at 90°C for 1 hour. The mixture was diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (3860 mg). MS: [M+CH3CN] + 609.0

[0288] D) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (382 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridin-2-yl)oxy]phenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (2960 mg) and cobalt(II) chloride (1309 mg) in MeOH (60 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Then, di-t-butyl dicarbonate (1.756 mL) was added to the reaction mixture at room temperature, which was stirred at room temperature for 1 hour. The solvent was removed by concentration, and EtOAc and aqueous sodium bicarbonate were added to the residue. The insoluble solid was removed through Celite, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2700 mg). MS: [M+Na] + 713.1

[0289] E) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide dihydrochloride To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (2730 mg) in MeOH (30 mL) was added 4 M hydrogen chloride-EtOAc (19.75 mL) at 0° C. After stirring at 0° C. for 30 minutes, the mixture was allowed to warm to room temperature and stirred overnight. After crude concentration under reduced pressure, EtOAc was added and the precipitate was collected to give the title compound (2120 mg). MS: [M+H] + 491.0

[0290] F) N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide To a solution of di(N-succinimidyl) carbonate (963 mg) and DIPEA (3.94 mL) in dry THF (2000 mL) was added N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide dihydrochloride (2120 mg) in dry DMF (30 mL) at room temperature over 5 minutes. After concentration under reduced pressure, the mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) and then recrystallized from EtOAc-heptane to give the title compound (960 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.98-1.10 (4H, m), 2.65-2.95 (3H, m), 3.60-3.92 (3H, m), 4.23-4.49 (2H, m), 4.49-4.62 (1H, m), 6.26 (1H, br d, J = 9.0 Hz), 6.99-7.13 (3H, m), 7.15-7.25 (1H, m), 7.90 (1H, d, J = 7.9 Hz), 8.22 (1H, br d, J = 9.0 Hz).

[0291] Example 33 N-[(15aS,16S)-7-methyl-1-oxo-1,2,15a,16,17,18-hexahydro-15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,12,4]dioxaazacycloheptadecin-16-yl]methanesulfonamide

[0292] A) tert-Butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1.00 g) in THF (10 mL) was added 60% sodium hydride (97 mg) at 0° C. The mixture was stirred at 0° C. for 0.1 hours, and 2-(chloromethoxy)ethyl](trimethyl)silane (403 mg) was added dropwise to the mixture. The mixture was stirred at 20° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (0.98 g). 1 H NMR (400 MHz, DMSO-d6) δ -0.02 (9H, s), 0.80-0.88 (2H, m), 1.02-1.15 (9H, m), 1.20-1.25 (2H, m), 2.05-2.34 (5H, m), 2.75-2.94 (1H, m), 3.06 (3H, s), 3.36-3.58 (3H, m), 4.02-4.26 (2H, m), 4.40-4.82 (2H, m), 6.78-7.20 (4H, m), 7.24-7.36 (1H, m), 7.68-7.90 (1H, m).

[0293] B) tert-Butyl (2S,3S)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (500 mg), tert-butyl hydroxyacetate (211 mg), 2-(di-t-butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (19 mg), cesium carbonate (520 mg), and di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane; methanesulfonic acid; palladium; and 2-phenylaniline (34 mg) in DME (5 mL) was heated at 100°C under nitrogen atmosphere and microwave irradiation for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (260 mg). MS: [M+H] + 722.3

[0294] C) N-[(15aS,16S)-7-methyl-1-oxo-1,2,15a,16,17,18-hexahydro-15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,12,4]dioxaazacycloheptadecin-16-yl]methanesulfonamide A solution of the compound tert-butyl (2S,3S)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (210 mg) in 4 M hydrogen chloride-dioxane (4.20 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure. A mixture of the thus obtained residue (130 mg), PyBOP (215 mg), and TEA (139 mg) in THF (300 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 25° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) and then purified by SFC (column: DAICEL CHIRALPAK AD, mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)) to obtain the title compound (3.9 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.65-1.81 (1H, m), 1.99-2.06 (1H, m), 2.19 (3H, s), 2.81-2.87 (1H, m), 3.01 (3H, s), 3.06-3.12 (1H, m), 3.16-3.18 (2H, m), 3.79-3.87 (1H, m), 4.24-4.46 (2H, m), 4.05-4.68 (1H, m), 6.55 (1H, d, J = 8.0 Hz), 6.87 (1H, s), 6.94-6.97 (1H, m), 7.18-7.30 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 5.6 Hz).

[0295] Example 36 N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0296] A) tert-butyl (2S,3R)-2-({3-[(6-amino-3-bromo-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Cesium carbonate (1535 mg) was added to a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1000 mg) and 5-bromo-3,6-difluoropyridin-2-amine (739 mg) in NMP (7854 μL) at room temperature. The mixture was stirred at 150°C under microwave irradiation for 5.5 hours. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (792 mg). MS: [M+Na] + 635.0

[0297] B) tert-Butyl (2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-({3-[(6-amino-3-bromo-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (791 mg) and trimethylboroxine (0.541 ml) in DME (5 ml) was added potassium carbonate (446 mg) at room temperature. The mixture was stirred at room temperature for 10 minutes. PdCl2(dppf) (94 mg) was added at room temperature. The mixture was heated at 90 °C overnight. The mixture was filtered. The filtrate was diluted with EtOAc and poured into water at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (640 mg). MS: [M+H] + 549.1

[0298] C) tert-Butyl (2S,3R)-2-({3-[(6-bromo-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Tert-butyl nitrite (196 μL) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (639 mg) and copper[I] bromide (234 mg) in acetonitrile (5824 μL) at room temperature. The mixture was stirred at 60° C. for 1.5 hours. EtOAc and water were added to the mixture. The precipitate was removed through Celite. The organic layer of the filtrate was separated, washed with aqueous sodium thiosulfate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (363 mg). MS: [MH] - 611.0

[0299] D) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-2-({3-[(6-bromo-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (363 mg), potassium [[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (281 mg), Pd(OAc) (13.31 mg), potassium carbonate (164 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (48.7 mg) in toluene (2470 μL) and water (494 μL) was stirred at 85°C overnight under an argon atmosphere. Water was added, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (362 mg). MS: [M+Na] + 685.2

[0300] E) N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide TFA (1 ml) was added to tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (362 mg) at room temperature. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated using toluene, and the residue was purified by NH silica gel column chromatography (MeOH / EtOAc). A solution of the residue thus obtained in DMF (5 mL) was added dropwise to a mixture of di(N-succinimidyl) carbonate (155 mg) and 4-methylmorpholine (0.363 mL) in THF (dry) (180 mL) at room temperature over 30 minutes. The mixture was stirred at room temperature for 30 minutes. Then DIPEA (0.961 mL) was added. The mixture was stirred at 60° C. under Ar for 30 minutes. The mixture was evaporated. The residue was diluted with EtOAc, poured into water at room temperature, and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was solidified with EtOAc-hexane to give the title compound (102 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.32 (3H, s), 2.65 (1H, br d, J = 13.2 Hz), 2.73-2.90 (1H, m), 3.11 (3H, s), 3.60-3.95 (3H, m), 4.19-4.47 (2H, m), 4.50-4.62 (1H, m), 6.20 (1H, br d, J = 9.0 Hz), 6.94-7.24 (3H, m), 7.58 (1H, dd, J = 9.4, 0.8 Hz), 8.18 (1H, d, J = 9.4 Hz).

[0301] Example 40 N-[(15aS,16S)-2,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0302] A) N-[(4-methoxyphenyl)methyl]-N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a solution of N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (460 mg) in DMF (5 mL) was added cesium carbonate (360 mg), sodium iodide (17 mg), and 4-methoxybenzyl chloride (208 mg), and the mixture was stirred at 80 °C for 15 h under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH) to give the title compound (463 mg). MS: [M+H] + 537.5

[0303] B) N-[(15aS,16S)-2,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide To a mixture of N-[(4-methoxyphenyl)methyl]-N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (463 mg) in DMF (5 mL) was added 60% sodium hydride (104 mg) at 0°C, and the mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. Iodomethane (367 mg) was then added to the mixture, which was stirred at 60°C for 13 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc) to give the title compound (302 mg). MS: [M+H] + 551.1

[0304] C) N-[(15aS,16S)-2,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a mixture of N-[(15aS,16S)-2,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide (272 mg) in CHCl (3 mL) was added methanesulfonic acid (285 mg) at 25° C., which was then stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonium hydroxide solution / acetonitrile), most of the acetonitrile was removed under reduced pressure, and the remaining solvent was removed by lyophilization to obtain the title compound (136.2 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.90-2.01 (1H, m), 2.15-2.25 (1H, m), 2.78 (3H, s), 2.41 (3H, s), 2.55-2.65 (1H, m), 2.85-2.95 (1H, m), 2.99 (3H, s), 3.05-3.16 (1H, m), 3.35-3.45 (1H, m), 3.70-3.85 (1H, m), 3.90-4.00 (1H, m), 4.45-4.55 (1H, m), 4.65-4.75 (1H, m), 6.80-6.90 (2H, m), 6.97 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.24 (1H, t, J = 8.0 Hz), 7.47 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 7.6 Hz).

[0305] Example 51 N-[(15aS,16R)-17,17,20-trifluoro-3,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (optical isomer)

[0306] A) tert-Butyl (2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (328 mg) in THF (4 mL) was added dropwise 1 M methylmagnesium bromide-THF (6.07 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. Then, 1 M methylmagnesium bromide-THF (6.07 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0° C., and MeOH (10 mL) was added dropwise. Then, sodium borohydride (68.9 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous ammonium chloride at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) to give the title compound (238 mg). MS: [M+H] + 559.2

[0307] B) N-{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide TFA (2 mL) was added to tert-butyl (2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (238 mg) in a flask at room temperature. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated using toluene, and the residue was purified by NH silica gel column chromatography (MeOH / EtOAc) to give the title compound (175 mg). MS: [M+H] + 459.2

[0308] C) N-[(15aS,16R)-17,17,20-trifluoro-3,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (optical isomer) To a mixture of di(N-succinimidyl) carbonate (100 mg), DIPEA (0.400 mL), and THF (300 mL), a solution of N-{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide (175 mg) in DMF (10 mL) was added dropwise over 30 minutes at room temperature. The mixture was stirred at room temperature for 1 hour and at 60°C overnight. The mixture was evaporated. The residue was diluted with EtOAc, poured into water at room temperature, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give two fractions. The less polar fraction was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the title compound (14.3 mg) from the less polar fraction. 1 H NMR (300 MHz, DMSO-d6) δ 1.05 (3H, br s), 2.29 (3H, s), 2.71-2.93 (2H, m), 3.16 (3H, s), 3.40-3.69 (1H, m), 3.98-4.37 (2H, m), 4.43-4.74 (2H, m), 5.57-5.78 (1H, m), 6.88 (1H, d, J = 7.3 Hz), 7.07-7.26 (3H, m), 7.56 (1H, dd, J = 7.4, 0.8 Hz), 8.29 (1H, br d, J = 8.4 Hz).

[0309] Example 54 N-[(16aS,17R)-18,18,21-trifluoro-7-methyl-1-oxo-2,3,16a,17,18,19-hexahydro-1H,9H,16H-4,8-(azeno)-11,15-(metheno)pyrrolo[2,1-h][1,9,11]oxadiazacyclooctadecin-17-yl]methanesulfonamide

[0310] A) tert-Butyl (2S,3R)-2-({3-[(6-chloro-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (444 mg), cesium carbonate (1.1 g), and DMF (8 mL) was added a solution of 6-chloro-2-(chloromethyl)-3-methylpyridine (222 mg) in DMF (1 mL) at room temperature, and the mixture was stirred at 50°C for 2 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (494 mg). MS: [M+H] + 564.2

[0311] B) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-2-({3-[(6-chloro-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (184.4 mg), zinc cyanide (122.2 mg), and DMF (3 mL) was added Pd(PhP) (38 mg) at room temperature, and the mixture was stirred at 120° C. for 2 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (184 mg). MS: [M+H-(tBu)] + 449.1

[0312] C) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (181 mg), cobalt(II) chloride (49.8 mg), and MeOH (3 mL) was added sodium borohydride (42.8 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hour. BocO (0.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to afford the title compound (184 mg). MS: [M+H] + 659.3

[0313] D) N-[(16aS,17R)-18,18,21-trifluoro-7-methyl-1-oxo-2,3,16a,17,18,19-hexahydro-1H,9H,16H-4,8-(azeno)-11,15-(metheno)pyrrolo[2,1-h][1,9,11]oxadiazacyclooctadecin-17-yl]methanesulfonamide To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (58.5 mg) in MeOH (1 mL), 4 M hydrogen chloride-CPME (0.2 mL) was added at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. A solution of the residue in DMF (2 mL) was added to a mixture of di(N-succinimidyl)carbonate (27.9 mg), N-methylmorpholine (80 μL), and THF (30 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. DIPEA (157 μL) was added, and the mixture was stirred at room temperature for 3 hours and at 60° C. overnight. The mixture was quenched with aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile). The desired fraction was then concentrated, crystallized from hexane-EtOAc, and collected by filtration to give the title compound (6.2 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.15-2.46 (6H, m), 2.75-3.03 (1H, m), 3.09 (3H, s), 3.70-4.64 (5H, m), 5.11-5.75 (2H, m), 6.37-6.85 (3H, m), 6.86-7.13 (1H, m), 7.37-7.58 (1H, m), 8.04-8.38 (1H, m).

[0314] Example 56 N-[(15aS,16R,17S)-17,20-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-8,4-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[0315] A) Benzyl (2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate XPhos Pd G3 (0.179 g) was added to a mixture of benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (2.0 g), bis(pinacolato)diboron (3.22 g), and potassium acetate (0.830 g) in toluene (20 mL) at room temperature under an argon atmosphere. The mixture was stirred at 100°C under an argon atmosphere for 2 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (2.204 g). MS: [M+H] + 565.2

[0316] B) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate Pd(dppf)Cl2·CHCl2 (141 mg) was added to a mixture of benzyl (2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (972 mg), 6-(chloromethyl)-5-methylpicolinonitrile (287 mg), and 2 M aqueous sodium carbonate (2.58 mL) in DME (9 mL) and stirred at 120 °C for 1 h under microwave irradiation. EtOAc and water were added to the reaction mixture at room temperature, and the insoluble material was removed by filtration. The organic layer of the filtrate was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (713 mg). MS: [M+H] + 569.2

[0317] C) Benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate Sodium borohydride (118 mg) was added to a mixture of benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (356 mg) and cobalt(II) chloride (163 mg) in MeOH (3 mL) at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 5 hours under an argon atmosphere. EtOAc and water were added to the reaction mixture at room temperature, and the insoluble matter was removed by filtration. The organic layer of the filtrate was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (MeOH / EtOAc) to afford the title compound (128 mg). MS: [M+H] + 573.2

[0318] D) N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide A mixture of benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (128 mg) and 10% palladium on carbon (55% water-wet, 23.79 mg) in MeOH (2 mL) was hydrogenated under balloon pressure at room temperature for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (90 mg). MS: [M+H] + 439.1

[0319] E) N-[(15aS,16R,17S)-17,20-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-8,4-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide A solution of N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide (90 mg) in THF (8 mL) was added to a mixture of di(N-succinimidyl)carbonate (52.6 mg) and 4-methylmorpholine (0.027 mL) in THF (42 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. DIPEA (0.108 mL) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc and water were added to the residue at room temperature, and the organic layer was then separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (MeOH / EtOAc). The solid was crystallized from EtOAc-hexane to give the title compound (3.70 mg). 1 H NMR (400 MHz, CDCl3) δ 1.41-1.52 (3H, m), 2.32-2.43 (3H, m), 2.59-2.79 (1H, m), 3.07-3.25 (2H, m), 3.36-3.77 (2H, m), 3.84-4.25 (4H, m), 4.26-4.71 (3H, m), 4.96 (1H, br d, J = 9.4 Hz), 5.08-5.32 (1H, m), 6.37 (1H, br s), 6.78-6.92 (1H, m), 6.93-7.22 (3H, m), 7.29-7.44 (1H, m).

[0320] Example 58 N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[0321] A) tert-butyl (2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Cesium carbonate (17.07 g) was added to a solution of tert-butyl (2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (11.80 g) and 5-chloro-3,6-difluoropyridin-2-amine (7.76 g) in NMP (131 mL) at room temperature. The mixture was stirred at 150° C. for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc, and passed through a Celite pad. The Celite pad was washed with EtOAc. The filtrate was poured into water and brine. The mixture was filtered through a Celite pad. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (12.67 g). MS: [M+H] + 595.1

[0322] B) tert-Butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Tert-butyl nitrite (3.57 mL) was added to a mixture of tert-butyl (2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (12.67 g) and copper[I] bromide (4.28 g) in acetonitrile (130 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature. EtOAc and water were added to the mixture. The precipitate was removed by filtration through a Celite pad. The filtrate was poured into EtOAc and aqueous sodium thiosulfate at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was suspended in IPE (16 mL), and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with IPE, and dried under reduced pressure to obtain the title compound (8.07 g). MS: [MH] - 658.0

[0323] C) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (8.07 g), potassium [[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (3.48 g), and potassium carbonate (3.39 g) in toluene (81 mL) and water (16 mL) was degassed with nitrogen for 10 minutes. 2-Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (2.011 g) and Pd(OAc)2 (0.550 g) were added at room temperature. The mixture was stirred at 85 °C under a nitrogen atmosphere for 4.5 hours. Water and EtOAc were added at room temperature, and the mixture was filtered through a Celite pad. The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (2.92 g). MS: [MH] - 707.2

[0324] D) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide TFA (20 mL) was added to tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (3.813 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was evaporated, and the residue was purified by NH silica gel column chromatography (MeOH / EtOAc) to give the title compound (2.351 g). MS: [M+H] + 509.0

[0325] E) N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide To a mixture of di(N-succinimidyl) carbonate (0.637 g) and DIPEA (3.16 mL) in dry THF (900 mL) was added a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide (1.15 g) in dry DMF (30 mL) at room temperature over 30 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to give residue A. Residue B was obtained in the same manner as in the synthesis of residue A using di(N-succinimidyl) carbonate (0.637 g), DIPEA (3.16 mL), THF(dry) (900 mL), N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide (1.15 g), and DMF(dry) (30 mL). Residues A and B were combined, diluted with EtOAc, and poured into water at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and recrystallized from EtOAc-hexane to give the title compound (1.11 g). 1H NMR (400 MHz, CDCl3) δ 1.02-1.38 (4H, m), 2.52-2.63 (1H, m), 2.75-2.86 (1H, m), 2.91-3.02 (1H, m), 3.77-3.98 (2H, m), 3.99-4.24 (2H, m), 4.26-4.44 (1H, m), 4.46-4.71 (1H, m), 4.72-4.88 (1H, m), 4.93 (1H, br d, J = 10.0 Hz), 7.03-7.11 (1H, m), 7.11-7.22 (2H, m), 7.48 (1H, d, J = 7.7 Hz).

[0326] Example 59 N-[(16aS,17R,21aS)-18,18,22-trifluoro-8-methyl-21-oxo-2,3,16a,17,18,19,21,21a-octahydro-1H,16H-5,9-(azeno)-11,15-(metheno)dipyrrolo[1,2-g:1',2'-j][1,5,7,10]oxatriazacycloheptadecin-17-yl]methanesulfonamide

[0327] A) tert-Butyl (2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate 2,4-Dichloro-5-methylpyrimidine (75 μL) was added to a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (250 mg) and potassium carbonate (200 mg) in dry DMF (3.0 mL) at room temperature. The mixture was stirred overnight under an argon atmosphere, then poured into ice water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (246 mg). MS: [M+H] + 551.2

[0328] B) N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride 4 M hydrogen chloride-EtOAc (1.0 mL) was added to a solution of tert-butyl (2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (122 mg) in THF (1.0 mL) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours, and then concentrated to give the title compound (108 mg). MS: [M+H] + 451.1

[0329] C) tert-Butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carbonyl}pyrrolidine-1-carboxylate HATU (110 mg) was added to a solution of N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (108 mg), (tert-butoxycarbonyl)-L-proline (56 mg), and DIPEA (120 μL) in THF (dry) (1.0 mL) and DMF (dry) (1.0 mL) at room temperature. The mixture was stirred overnight at room temperature under an argon atmosphere. HATU (40 mg), DIPEA (60 μL), and (tert-butoxycarbonyl)-L-proline (25 mg) were added, and stirring was continued for 5 hours. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to afford the title compound (116 mg). MS: [M-Boc+H] + 548.2

[0330] D) N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-1-L-prolylpyrrolidin-3-yl]methanesulfonamide hydrochloride 4 M hydrogen chloride-EtOAc (1.0 mL) was added to a solution of tert-butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carbonyl}pyrrolidine-1-carboxylate (115 mg) in THF (1.0 mL) at room temperature. The mixture was stirred at room temperature under an argon atmosphere for 2 hours, and then concentrated to give the title compound (104 mg). MS: [M+H] + 548.3

[0331] E) N-[(16aS,17R,21aS)-18,18,22-trifluoro-8-methyl-21-oxo-2,3,16a,17,18,19,21,21a-octahydro-1H,16H-5,9-(azeno)-11,15-(metheno)dipyrrolo[1,2-g:1',2'-j][1,5,7,10]oxatriazacycloheptadecin-17-yl]methanesulfonamide DIPEA (150 μL) was added to a solution of N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-1-L-prolylpyrrolidin-3-yl]methanesulfonamide hydrochloride (104 mg) in DMF (dry) (2 mL) and acetonitrile (30 mL) at room temperature. The mixture was stirred at 80° C. under an argon atmosphere overnight and then concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution / acetonitrile) to give the title compound (33.6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.71-1.96 (3H, m), 2.18 (3H, s), 2.24-2.34 (1H, m), 2.73 (1H, br d, J = 11.7 Hz), 2.87-2.99 (1H, m), 3.11 (3H, s), 3.34-3.53 (2H, m), 3.97-4.18 (3H, m), 4.44-4.64 (2H, m), 6.94-7.06 (2H, m), 7.21 (1H, t, J = 6.1 Hz), 8.15 (1H, s), 8.19-8.34 (1H, m).

[0332] Example 62 N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-1,2,15a,16,17,18-hexahydro-15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-d][1,12,4]dioxaazacycloheptadecin-16-yl]methanesulfonamide

[0333] A) tert-butyl (2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (424 mg) in DMF (3 mL) was added 3-chloro-2,6-difluoropyridine (150 mg) and cesium carbonate (652 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere for 1 hour. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (381 mg). MS: [MH] - 552.0

[0334] B) N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride A mixture of tert-butyl (2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (381.4 mg) in 4 M hydrogen chloride-CPME (10 mL) was stirred at room temperature under a dry atmosphere overnight. The mixture was concentrated to give the title compound (338 mg). MS: [MH] - 452.9

[0335] C) 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidin-1-yl}-2-oxoethyl acetate To a solution of N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (337.6 mg) in THF (7 mL) was added TEA (0.288 mL) and acetoxyacetyl chloride (0.081 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours under a dry atmosphere. The reaction mixture was diluted with EtOAc and then poured into water. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (309 mg). MS: [M+H] + 554.1

[0336] D) N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-1,2,15a,16,17,18-hexahydro-15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-d][1,12,4]dioxaazacycloheptadecin-16-yl]methanesulfonamide To a solution of 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidin-1-yl}-2-oxoethyl acetate (309 mg) in THF (20 mL) and EtOH (20 mL) was added 1 M aqueous sodium hydroxide solution (4 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and then poured into aqueous ammonium chloride solution. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane) to give the title compound (251 mg). 1H NMR (300 MHz, DMSO-d6) δ 2.65-2.99 (2H, m), 3.07-3.16 (3H, m), 3.57-3.76 (1H, m), 4.09-4.23 (1H, m), 4.26-4.55 (3H, m), 4.56-4.69 (1H, m), 6.61-6.73 (1H, m), 7.05-7.32 (3H, m), 7.86-8.00 (1H, m), 8.26 (1H, br s).

[0337] Example 68 N-[(16aS,17S)-7-methyl-1-oxo-2,3,16a,17,18,19-hexahydro-1H,10H,16H-4,8-(azeno)-11,15-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacyclooctadecin-17-yl]methanesulfonamide

[0338] A) tert-Butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (2000 mg) in dry DMF (15 ml) was added 60% sodium hydride (240 mg), and the reaction mixture was stirred for 5 minutes at room temperature. Next, 2-(chloromethoxy)ethyl](trimethyl)silane (0.980 ml) was added, and the reaction mixture was stirred for 2 hours at room temperature. The mixture was quenched with aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (2470 mg). MS: [M+Na] + 587.0

[0339] B) tert-Butyl (2S,3S)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]-2-{[3-(methoxycarbonyl)phenyl]methyl}pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (2470 mg) and TEA (0.916 ml) in DMF (10 ml) and MeOH (3 ml) was added PdCl2(dppf) (321 mg), and the mixture was stirred at 80 °C under a carbon monoxide atmosphere for 6 hours. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (630 mg). MS: [M+Na] + 565.2

[0340] C) tert-Butyl (2S,3S)-2-{[3-(hydroxymethyl)phenyl]methyl}-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]-2-{[3-(methoxycarbonyl)phenyl]methyl}pyrrolidine-1-carboxylate (630 mg) in dry THF (5 ml) was added 1 M diisobutylaluminum hydride-hexane (2.90 ml) at 0°C. The mixture was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate was then added, and the mixture was stirred for 2 hours. After filtration and evaporation under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (508 mg). MS: [M+Na] + 537.2

[0341] D) tert-Butyl (2S,3S)-2-[(3-{[(6-bromo-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3S)-2-{[3-(hydroxymethyl)phenyl]methyl}-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (508 mg) in dry DMF (5 ml) was added 60% sodium hydride (47.4 mg) at room temperature. The mixture was stirred at room temperature for 10 minutes under an argon atmosphere. Next, 6-bromo-2-fluoro-3-methylpyridine (281 mg) was added to the solution, and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (437 mg). MS: [M+Na] + 706.2

[0342] E) tert-Butyl (2S,3S)-2-[(3-{[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3S)-2-[(3-{[(6-bromo-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (437 mg), potassium [[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (303 mg), Pd(OAc)2 (14.33 mg), potassium carbonate (176 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (52.4 mg) in toluene (2659 μL) and water (532 μL) was stirred at 85°C for 4 hours under an argon atmosphere. Water was added, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (281 mg). MS: [M+H] + 736.3

[0343] F) N-[(16aS,17S)-7-methyl-1-oxo-2,3,16a,17,18,19-hexahydro-1H,10H,16H-4,8-(azeno)-11,15-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacyclooctadecin-17-yl]methanesulfonamide A mixture of tert-butyl (2S,3S)-2-[(3-{[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (281 mg) in TFA (1 mL) was stirred at room temperature for 10 minutes. After evaporation, the residue was purified by NH silica gel column chromatography (MeOH / EtOAc). A solution of the residue thus obtained in DMF (1 mL) was added to a mixture of di(N-succinimidyl) carbonate (32.5 mg), N-methylmorpholine (0.013 mL), and THF (dry) (50 mL) at room temperature, and the mixture was stirred overnight at room temperature. DIPEA (0.201 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the title compound (6.1 mg). 1 H NMR (300 MHz, CDCl3) δ 1.75-1.90 (1H, m), 2.20 (3H, s), 2.26-2.47 (2H, m), 3.06 (3H, s), 3.16-3.32 (2H, m), 3.80-4.08 (3H, m), 4.35 (1H, dd, J = 10.3, 6.9, 3.2 Hz), 4.51 (1H, dd, J = 16.0, 6.2 Hz), 4.87 (2H, br dd, J = 6.0, 3.0 Hz), 5.26 (1H, d, J = 12.4 Hz), 5.45 (1H, d, J = 12.4 Hz), 6.53 (1H, d, J = 7.5 Hz), 6.91-7.01 (1H, m), 7.09-7.17 (2H, m), 7.21-7.25 (1H, m), 7.48 (1H, s).

[0344] Example 97 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide

[0345] A) tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (4.0 g) in CHCl (22 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.1 mL) followed by isopropylsulfonyl chloride (1.9 mL) in a water bath at ambient temperature. The mixture was stirred at room temperature for 24 hours. Saturated aqueous ammonium chloride was added to the mixture. The organic layer was separated, washed successively with aqueous sodium bicarbonate and brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to give the title compound (3.1 g). MS: [M+2H(-tBu)] + 415.2

[0346] B) tert-butyl (2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate To a nitrogen-purged mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (987 mg), potassium acetate (411 mg), and bis(pinacolato)diboron (798 mg) in toluene (8.4 mL) was added (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (180 mg). The mixture was purged with nitrogen and then stirred at 80 °C for 16 hours. The mixture was diluted with MeOH and filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to give the title compound (882 mg). MS: [M+2H(-tBu)] + 507.2.

[0347] C) tert-Butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (882 mg) in 1:1 THF-water (6.2 mL) was added sodium perborate tetrahydrate (579 mg) at room temperature. The mixture was stirred open to air at ambient temperature for 16 hours. The mixture was diluted with water and filtered through a fine frit, and the filtrate was extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to afford the title compound (370 mg). MS: [M+2H(-tBu)] + 397.2.

[0348] D) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (370 mg) and cesium carbonate (534 mg) in DMA (3 ml) was added 6-chloro-5-methylpicolinonitrile (249 mg). The mixture was stirred at 80°C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to afford the title compound (226 mg). MS: [M+2H(-tBu)] + 513.2.

[0349] E) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate Sodium borohydride (45 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (226 mg) and nickel(II) chloride hexahydrate (94 mg) in MeOH (2.6 mL) at 0° C. The mixture was cooled and stirred for 3 hours and then at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue, containing the title compound (230 mg), was carried forward without purification. MS: [M+H] + 573.3.

[0350] F) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}propane-2-sulfonamide dihydrochloride A solution of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (228 mg) in 4 M hydrogen chloride-1,4-dioxane (4.9 mL) was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and then concentrated under reduced pressure to give the title compound (225 mg). MS: [M+H] + 473.2.

[0351] G) N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide N,N'-Disuccinimidyl carbonate (76 mg) was added in three portions to a mixture of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}propane-2-sulfonamide dihydrochloride (217 mg) and N-methylmorpholine (0.26 mL) in dry THF (380 mL) and dry DMF (15 mL) at room temperature over 5 minutes. The mixture was stirred at room temperature for 4 days and then concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column: Gemini® NX-C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile) to give the title compound (83 mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (6H, app dd, J = 6.8, 4.5 Hz), 2.31 (3H, s), 2.65 (1H, app br d, J = 13.6 Hz), 2.86 (1H, app t, J = 12.6 Hz), 3.26-3.30 (1H, m), 3.60 (1H, br d, J = 14.18 Hz), 3.69-3.91 (2H, m), 4.24-4.46 (2H, m), 4.46-4.55 (1H, m), 6.14 (1H, br d, J = 8.7 Hz), 6.86 (1H, d, J = 7.28 Hz), 6.97-7.04 (1H, m), 7.05-7.13 (2H, m), 7.55 (1H, d, J = 7.3 Hz), 8.11 (1H, d, J = 9.8 Hz).

[0352] Example 99 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[0353] A) tert-butyl N-(6-bromo-5-methylpyridin-2-yl)glycinate To a mixture of tert-butyl 2-bromoacetate (12.6 g) and potassium carbonate (16.3 g) in NMP (220 mL) was added 6-bromo-5-methyl-pyridin-2-amine (11.0 g). The mixture was stirred at 140° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (8.33 g). 1 H NMR (400 MHz, CDCl3) δ ppm 1.48 (9H, s), 2.22 (3H, s), 3.98 (2H, s), 4.96 (1H, br s), 6.32 (1H, d, J = 8.2 Hz), 7.23 (1H, d, J=8.07 Hz).

[0354] B) tert-Butyl (2S,3R)-2-{[3-({6-[(2-tert-butoxy-2-oxoethyl)amino]-3-methylpyridin-2-yl}oxy)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl N-(6-bromo-5-methylpyridin-2-yl)glycinate (206 mg), tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (200 mg), copper iodide (17.4 mg), pyridine-2-carboxylic acid (22.5 mg), and potassium triphosphate (242 mg) in DMSO (4 mL) was degassed and purged with nitrogen three times and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature and diluted with water. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (97.4 mg). MS: [M+H] + 659.2.

[0355] C) N-{6-[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenoxy]-5-methylpyridin-2-yl}glycine dihydrochloride A solution of tert-butyl (2S,3R)-2-{[3-({6-[(2-tert-butoxy-2-oxoethyl)amino]-3-methylpyridin-2-yl}oxy)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (150 mg) in 4 M hydrogen chloride-1,4-dioxane (12 mL) was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (141 mg). MS: [M+H] + 503.0.

[0356] D) N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide HATU (131 mg) and DIPEA (239 μL) were added to a solution of N-{6-[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenoxy]-5-methylpyridin-2-yl}glycine dihydrochloride (140 mg) in DMF (140 mL) at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (SiO, EtOAc / PE) to give the title compound and a mixture of its isomers. The mixture of isomers was purified by preparative SFC (column: DAICEL CHIRALCEL OJ, mobile phase: CO / EtOH (containing 0.1% ammonium hydroxide)) to give the title compound (15.7 mg, shorter retention time). 1 H NMR (400 MHz, CDCl3) δ ppm 1.42-1.53 ​​(3H, m), 2.18-2.29 (3H, m), 2.72-3.28 (5H, m), 3.61-3.96 (2H, m), 4.00-4.38 (3H, m), 4.44-4.64 (1H, m), 4.96-5.22 (1H, m), 6.06-6.29 (1H, m), 6.95-7.18 (3H, m), 7.26 (1H, br s).

[0357] Example 100 N-[(15aS,16R)-9,9,17,17,20-pentafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[0358] A) tert-butyl (2S,3R)-2-{[3-(6-cyano-3-methylpyridine-2-carbonyl)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (1.0 g), 6-bromo-5-methyl-pyridine-2-carbonitrile (424 mg), Pd(OAc) (21 mg), 1,3-bis(2,4,6-trimethylphenyl)imidazol-1-ium chloride (63 mg), and cesium carbonate (1.19 g) in 1,4-dioxane (30 mL) was stirred at 80° C. under carbon monoxide (50 psi) for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (337 mg). MS: [M+H] + 567.1.

[0359] B) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)(difluoro)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-Butyl (2S,3R)-2-{[3-(6-cyano-3-methylpyridine-2-carbonyl)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (234 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (4.55 g) were combined in a reaction vessel and stirred at 65° C. for 24 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude isolate was purified by preparative HPLC (column: Boston Green ODS, mobile phase: 0.2% aqueous formic acid / acetonitrile) to give the title compound (128 mg). MS: [M+H] + 589.0.

[0360] C) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (82.6 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)(difluoro)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (128 mg) and nickel(II) chloride hexahydrate (52.3 mg) in MeOH (5.0 mL) at 0° C. The reaction mixture was warmed to 20° C. and stirred for 2 hours. The reaction mixture was quenched with water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (98 mg). MS: [M+H] + 593.1.

[0361] D) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide trihydrochloride A solution of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (98 mg) in 4 M hydrogen chloride-1,4-dioxane (5.4 mL) was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound (99.5 mg). MS: [M+H] + 493.0.

[0362] E) N-[(15aS,16R)-9,9,17,17,20-pentafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide To a suspension of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide trihydrochloride (99.5 mg) in THF (15 mL) was added DIPEA (173 μL) followed by 1,1′-carbonyldiimidazole (40.2 mg) at 0° C. The reaction mixture was heated to 45° C. and stirred at that temperature for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (column: Phenomenex C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) to give the title compound (26.4 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (3H, dt, J = 12.0, 7.3 Hz), 2.64 (3H, br d, J = 11.4 Hz), 2.78-3.01 (1H, m), 3.08-3.28 (2H, m), 3.34-3.61 (1H, m), 3.69-4.15 (2H, m), 4.18-4.85 (4H, m), 5.13-5.83 (2H, m), 7.10-7.24 (2H, m), 7.38-7.68 (3H, m).

[0363] Example 102 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-1,2,15a,16,17,18-hexahydro-9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,4]oxaazacycloheptadecin-16-yl]ethanesulfonamide

[0364] A) (3-Methylpyridin-2-yl)methyl acetate To a solution of (3-methyl-2-pyridyl)methanol (2.0 g) in THF (40 mL) were added acetic anhydride (2.30 mL), pyridine (2.49 mL), and DMAP (199 mg). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with water and saturated aqueous sodium bicarbonate solution, and then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (2.4 g). 1 H NMR (400 MHz, CDCl3) δ ppm 2.13 (3H, s), 2.36 (3H, s), 5.23 (2H, s), 7.17 (1H, dd, J = 7.6, 4.8 Hz), 7.49 (1H, d, J = 7.0 Hz), 8.44 (1H, d, J = 4.1 Hz).

[0365] B) (3-methyl-1-oxide-pyridin-1-ium-2-yl)methyl acetate To a solution of (3-methylpyridin-2-yl)methyl acetate (2.4 g) in CH2Cl2 (50 mL) was added m-chloroperoxybenzoic acid (4.42 g, 85% purity). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water and added sodium sulfite. The mixture was quenched with (5 g) and basified with saturated aqueous sodium bicarbonate to pH = 8. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (4 g). 1 H NMR (400 MHz, MeOH-d4) δ ppm 2.09 (3H, s), 2.50 (3H, s), 5.47 (2H, s), 7.43-7.51 (2H, m), 8.27 (1H, d, J = 6.2 Hz).

[0366] C) (6-chloro-3-methylpyridin-2-yl)methyl acetate A mixture of (3-methyl-1-oxide-pyridin-1-ium-2-yl)methyl acetate (2 g) and phosphoryl chloride (10 mL) was stirred at 90° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, basified with saturated aqueous sodium bicarbonate to pH = 8, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (600 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 2.13 (3H, s), 2.34 (3H, s), 5.18 (2H, s), 7.22 (1H, d, J = 8.0 Hz), 7.37-7.48 (1H, m).

[0367] D) tert-Butyl {[6-(hydroxymethyl)-5-methylpyridin-2-yl]oxy}acetate To a solution of (6-chloro-3-methylpyridin-2-yl)methyl acetate (400 mg), tert-butyl 2-hydroxyacetate (297 mg), cesium carbonate (1.10 g), and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (268 mg) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (103 mg) under a nitrogen atmosphere. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (140 mg). MS: [M+H] + 254.2.

[0368] E) tert-Butyl {[6-(chloromethyl)-5-methylpyridin-2-yl]oxy}acetate To a solution of tert-butyl {[6-(hydroxymethyl)-5-methylpyridin-2-yl]oxy}acetate (110 mg) in CHCl (4 mL) was added thionyl chloride (207 μL). The mixture was stirred at 25° C. for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (80 mg). MS: [M+H] + 272.2.

[0369] F) tert-Butyl (2S,3R)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl {[6-(chloromethyl)-5-methylpyridin-2-yl]oxy}acetate (80 mg) and tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (110 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) was added potassium carbonate (80.7 mg) and Pd(dppf)Cl2.CHCl2 (15.9 mg) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (120 mg). MS: [M+H] + 658.3.

[0370] G) [(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]acetic acid dihydrochloride A solution of tert-butyl (2S,3R)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (120 mg) in 4 M hydrogen chloride-1,4-dioxane (5 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give the title compound (95 mg). MS: [M+H] + 502.3.

[0371] H) N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-1,2,15a,16,17,18-hexahydro-9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,4]oxazacycloheptadecin-16-yl]ethanesulfonamide To a solution of [(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]acetic acid dihydrochloride (45 mg) in EtOAc (260 mL) were added dibutyldiphosphonic acid (37.8 mg, 50% purity) and pyridine (130 mL). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched by adding water and extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, mobile phase: 0.1% TFA aqueous solution / acetonitrile) to give the title compound (20.5 mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (3H, t, J = 7.3 Hz), 2.37 (3H, s), 2.62 (1H, br d, J = 14.2 Hz), 2.94 (1H, br t, J = 12.9 Hz), 3.14-3.23 (2H, m), 3.93 (1H, s), 4.08-4.44 (4H, m), 4.47-4.55 (2H, m), 4.59-4.67 (1H, m), 6.47-6.56 (1H, m), 6.83-6.91 (1H, m), 6.92-6.99 (1H, m), 7.05-7.10 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 8.23-8.30 (1H, m).

[0372] Examples 105 and 106 N-[(9R,15aS,16R)-17,17,20-trifluoro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide and and N-[(9S,15aS,16R)-17,17,20-trifluoro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[0373] A) 1-(3-methylpyridin-2-yl)ethenyl trifluoromethanesulfonate To a solution of 1-(3-methyl-2-pyridyl)ethanone (2.0 g) in toluene (50 mL) was added trifluoromethanesulfonic anhydride (8.35 g) and DIPEA (5.2 mL) at 0° C. The mixture was heated to 45° C. and stirred at that temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to give the title compound (1.01 g). MS: [M+H] + 268.0.

[0374] B) tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methylpyridin-2-yl)ethenyl]phenyl}methyl)pyrrolidine-1-carboxylate A mixture of 1-(3-methylpyridin-2-yl)ethenyl trifluoromethanesulfonate (509 mg), tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (500 mg), Pd(PPh3)4 (211 mg), sodium carbonate (193 mg) in 1,4-dioxane (10 mL) and water (3 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C under a nitrogen atmosphere for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to afford the title compound (650 mg). MS: [M+H] + 540.3.

[0375] C) tert-Butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methylpyridin-2-yl)ethyl]phenyl}methyl)pyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methylpyridin-2-yl)ethenyl]phenyl}methyl)pyrrolidine-1-carboxylate (620 mg) in EtOH (10 mL) was added 10% palladium on carbon (418 mg) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times, then stirred under a hydrogen atmosphere (20 psi) at 25° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (630 mg). MS: [M+H] + 542.3.

[0376] D) tert-Butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methyl-1-oxide-pyridin-1-ium-2-yl)ethyl]phenyl}methyl)pyrrolidine-1-carboxylate m-Chloroperoxybenzoic acid (118 mg, 85% purity) was added to a solution of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methylpyridin-2-yl)ethyl]phenyl}methyl)pyrrolidine-1-carboxylate (280 mg) in CHCl (20 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with CHCl (20 mL) and then washed with saturated aqueous sodium carbonate (10 mL). The phases were separated, and the organic layer was washed with saturated aqueous sodium thiosulfate (10 mL) and then again with saturated aqueous sodium carbonate (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (260 mg). MS: [M+H] + 558.3.

[0377] E) tert-Butyl (2S,3R)-2-({3-[1-(6-cyano-3-methylpyridin-2-yl)ethyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methyl-1-oxide-pyridin-1-ium-2-yl)ethyl]phenyl}methyl)pyrrolidine-1-carboxylate (260 mg) in 1,2-dichloroethane (5 mL) was added trimethylsilyl cyanide (91 μL) and N,N-dimethylcarbamoyl chloride (77.9 mg). The mixture was stirred at 80° C. for 5 hours and then concentrated under reduced pressure. The crude isolate was purified by silica gel column chromatography (EtOAc / PE) to afford the title compound (155 mg). MS: [M+H] + 567.1.

[0378] F) tert-Butyl (2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridin-2-yl]ethyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (120 mg) was slowly added to a solution of tert-butyl (2S,3R)-2-({3-[1-(6-cyano-3-methylpyridin-2-yl)ethyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (135 mg) and nickel(II) chloride hexahydrate (45.3 mg) in MeOH (12 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with CHCl, and the reaction was quenched with water, resulting in the precipitation of a solid. The solid was removed by filtration, and the phases of the filtrate were separated. The organic phase was saved. The aqueous layer was extracted three times with CHCl. ​​The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (136 mg). MS: [M+H] + 571.2.

[0379] G) N-{(2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridin-2-yl]ethyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide trihydrochloride A solution of tert-butyl (2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridin-2-yl]ethyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (140 mg) in 4 M hydrogen chloride-1,4-dioxane (8 mL) was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (122 mg). MS: [M+H] +471.2.

[0380] H) N-[(9R,15aS,16R)-17,17,20-trifluoro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide and and N-[(9S,15aS,16R)-17,17,20-trifluoro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide To a mixture of N-{(2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridin-2-yl]ethyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide trihydrochloride (122 mg) in DMF (4.5 mL) and THF (105 mL) was added N,N'-disuccinimidyl carbonate (48.5 mg) and N-methylmorpholine (138 μL) at room temperature. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was partitioned between CHCl and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude isolate was purified by silica gel column chromatography (MeOH / CHCl). The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 10 mM aqueous ammonium bicarbonate (containing 0.05% ammonium hydroxide) / acetonitrile), followed by SFC column: DAICEL CHIRALCEL OD-H; mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)) to give diastereomer A (20 mg, shorter retention time) and diastereomer B (27 mg, longer retention time).

[0381] Diastereomer A (20 mg) was further purified by SFC (column: DAICEL CHIRALCEL OD-H; mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)) to give one of the title compounds (9.5 mg, 96% purity). 1 H NMR (400MHz, CDCl3) δ ppm 1.29-1.43 (3H, m), 1.64 (3H, br d, J = 5.2 Hz), 2.27-2.48 (3H, m), 2.66 (1H, br d, J = 12.8 Hz), 2.95 (1H, br t, J = 12.0 Hz), 3.02-3.21 (2H, m), 3.73-4.43 (5H, m), 4.44-4.59 (1H, m), 4.59-4.76 (1H, m), 4.80-4.96 (1H, m), 6.73 (1H, br d, J = 7.6 Hz), 6.79-7.01 (2H, m), 7.05-7.14 (1H, m), 7.23-7.39 (1H, m).

[0382] Diastereomer B (27 mg) was further purified by SFC (column: DAICEL CHIRALPAK AD (250x30 mm x 10 μm); mobile phase: ethanol (containing 0.1% ammonium hydroxide)-CO; isocratic B, 30%) to give the other title compound (8.5 mg). 1H NMR (400MHz, CDCl3) δ ppm 1.39 (3H, t, J = 7.2 Hz), 1.65-1.82 (3H, m), 2.32-2.48 (4H, m), 3.03-3.19 (2H, m), 3.3- 3.52 (2H, m), 3.99 (1H, br d, J = 16.8 Hz), 4.12-4.34 (2H, m), 4.42 (1H, br dd, J = 16.8, 4.0 Hz), 4.57-4.74 (1H, m), 4.81-5.00 (2H, m), 6.53 (1H, br s), 6.77-6.95 (3H, m), 7.32 (1H, d, J = 7.8 Hz).

[0383] Example 111 N-[(2S,15aS,16R)-17,17,20-trifluoro-2,7-dimethyl-1-oxo-1,2,15a,16,17,18-hexahydro-9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,4]oxaazacycloheptadecin-16-yl]ethanesulfonamide

[0384] A) tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[(6-fluoro-3-methylpyridin-2-yl)methyl]phenyl}methyl)pyrrolidine-1-carboxylate A 10 mL microwave vial equipped with a stir bar and rubber septum was charged with tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (250 mg), Pd(dppf)Cl.CHCl (37 mg), 2-(chloromethyl)-6-fluoro-3-methyl-pyridine hydrochloride (119 mg), 2 M aqueous sodium carbonate (1.0 mL), and 1,2-dimethoxyethane (3.30 mL). The reaction mixture was purged with nitrogen, and the rubber septum was replaced with a crimp cap. The reaction mixture was heated in a microwave reactor at 100 °C for 1 h. The reaction mixture was diluted with water and then extracted twice with CHCl. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The crude isolate was purified by silica gel column chromatography (EtOAc / heptane) to afford the title compound (219 mg). MS: [M+H] + 546.5.

[0385] B) ((2S)-2-[(6-{[3-({(2S,3R)-1-(tert-butoxycarbonyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]propanoic acid 60% Sodium hydride (29 mg) was added in portions to a stirred solution of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[(6-fluoro-3-methylpyridin-2-yl)methyl]phenyl}methyl)pyrrolidine-1-carboxylate (134 mg) and tert-butyl (S)-2-hydroxypropanoate (72 mg) in THF (dry) (1.0 mL) at room temperature. The reaction mixture was then heated at 50° C. for 3 hours. tert-Butyl (S)-2-hydroxypropanoate (72 mg) and 60% sodium hydride (29 mg) were added to the mixture, and the mixture was stirred at 50° C. for 2 hours. tert-Butyl (S)-2-hydroxypropanoate (72 mg) and 60% sodium hydride (29 mg) were added to the mixture, and the mixture was stirred at 50 °C for another 2 hours. The reaction mixture was cooled to room temperature. The reaction was quenched by adding water, and 1 M hydrochloric acid was added until the pH was 3. The mixture was extracted twice with CHCl, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (column: Gemini NX-C18, mobile phase: 0.05% TFA aqueous solution / acetonitrile) to give the title compound (65 mg). MS: [M+H] + 616.5.

[0386] C) (2S)-2-[(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]propanoic acid dihydrochloride A solution of ((2S)-2-[(6-{[3-({(2S,3R)-1-(tert-butoxycarbonyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]propanoic acid (65 mg) in 4 M hydrogen chloride-1,4-dioxane (0.50 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the title compound (50 mg). MS: [M+H] + 516.3.

[0387] D) N-[(2S,15aS,16R)-17,17,20-trifluoro-2,7-dimethyl-1-oxo-1,2,15a,16,17,18-hexahydro-9H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-d][1,4]oxaazacycloheptadecin-16-yl]ethanesulfonamide A solution of (2S)-2-[(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]propanoic acid dihydrochloride (50 mg) in DMF (5.0 mL) was added dropwise over 15 minutes to a solution of HATU (39 mg) and DIPEA (89 μL) in DMF (25 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated to dryness, and the residue was purified by reverse-phase preparative HPLC (Gemini® NX-C18, mobile phase: 0.05% TFA aqueous solution / acetonitrile). The isolated product (TFA salt) was dissolved in MeOH and passed through an Agilent Technologies StratoSphere SPE PL-HCO3 MP Resin cartridge to remove TFA. The filtrate was concentrated under reduced pressure to give the title compound (5 mg). 1H NMR (400 MHz, MeOH-d4) δ ppm 1.41 (3H, t, J = 7.3Hz), 1.47 (3H, d, J = 6.8 Hz), 2.38 (3H, s), 2.69-2.86 (1H, m), 3.09-3.24 (3H, m), 3.90 (1H, dd, J = 14.0, 1.6 Hz), 4.07 (1H, d, J = 14.1 Hz), 4.25-4.39 (3H, m), 4.70-4.81 (2H, m), 6.44 (1H, d, J = 8.3 Hz), 6.82-6.92 (2H, m), 7.06-7.13 (1H, m), 7.37 (1H, d, J = 8.3 Hz).

[0388] The example compounds are shown in the following tables. In these tables, MS represents the observed molecular ion (measured value). The compounds described in Examples 3, 6, 8, 9, 11-18, 20, 21, 23-32, 34, 35, 37-39, 41-50, 52, 53, 55, 57, 60, 61, 63-67, 69-96, 98, 101, 103, 104, and 107-110 were synthesized using the same reactions and purification methods as those described in the above examples.

[0389] [Table 1-1]

[0390] [Table 1-2]

[0391] [Table 1-3]

[0392] [Table 1-4]

[0393] [Table 1-5]

[0394] Table 1-6

[0395] Table 1-7

[0396] Table 1-8

[0397] Table 1-9

[0398] Table 1-10

[0399] Table 1-11

[0400] Table 1-12

[0401] Table 1-13

[0402] Table 1-14

[0403] Table 1-15

[0404] Table 1-16

[0405] Table 1-17

[0406] Table 1-18

[0407] Table 1-19

[0408] Table 1-20

[0409] Table 1-21

[0410] Table 1-22

[0411] Table 1-23

[0412] Table 1-24

[0413] Table 1-25

[0414] Test Example 1: Obtaining cells stably expressing human orexin type 2 receptor (hOX2R) To obtain cell clones stably expressing human orexin type 2 receptor, human orexin type 2 (residues 1-444, NCBI reference sequence: AK314279) was constructed in the pcDNA3.1(+) vector (Invitrogen) and expressed in mammalian cells. This plasmid DNA was transfected into CHO-K1 cells by electroporation, and stable clones were obtained by limiting dilution using G418 resistance as a selection marker.

[0415] Test Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells overexpressing human OX2 receptor were seeded at 10,000 cells / well in a 384-well black clear-bottom plate (BD Falcon) and incubated at room temperature for 30 minutes, followed by incubation at 37°C and 5% CO2 for 1 day. After removing the cell plate medium, 30 μL / well of assay buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4AM (Dojindo Laboratories), 0.08% Pluronic F127 (Dojindo Laboratories), 1.25 mM probenecid (Dojindo Laboratories)) was added. The plates were incubated at 37°C for 30 minutes in a 5% CO2 incubator, followed by another 30 minutes at room temperature. Test compounds diluted in assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) were added at 10 μL / well, and fl...

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, Ring A is a phenyl group optionally further substituted with 1 to 2 halogen atoms, where Y is a ring atom C bonded to hydrogen or a halogen; X is —O—, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B is a pyridine ring optionally substituted by 1, 2 or 3 substituents independently selected from halogen and a C 1-6 alkyl group; L is —CH 2 —NH—, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R ａ is a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms or a C 3-4 cycloalkyl group; R ｂ is a halogen atom; and R ｃ is a halogen atom; or a salt thereof.

2. Ring A is a phenyl group optionally further substituted with 1 to 2 halogen atoms, wherein Y is a ring atom C bonded to the halogen; X is —O—, where the left moiety of X is attached to a ring carbon atom on ring A adjacent to Y and the right moiety of X is attached to ring B; Ring B may contain 1, 2 or 3 C １－６ a pyridine ring optionally substituted with an alkyl group; L is -CH ２ -NH-, where the left moiety of L is attached to Ring B and the right moiety of L is attached to the carbonyl group; R ａ C optionally substituted with 1 to 3 halogen atoms １－６ is an alkyl group; R ｂ is a halogen atom; and R ｃ is a halogen atom; The compound of claim 1, or a salt thereof.

3. The compound is: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide; 1-fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; and N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide; 2. The compound of claim 1, or a salt thereof, selected from the group consisting of:

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