Macrocyclic heterocyclic compounds and their uses

Abstract

This invention provides a heterocyclic compound having orexin type 2 receptor agonist activity. [Solution] Formula (I): JPEG2026090421000074.jpg65163 The compound represented by [formula], or its salt, has orexin type 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for 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 nerve cells scattered throughout the lateral hypothalamus and surrounding areas of the brain, 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 mainly found in the brain, and two subtypes of orexin receptors, type 1 and type 2, are known (Non-Patent Literature 1).

[0003] Orexin-producing nerve cells (orexin nerve cells) are localized near the feeding center, and intracerebroventricular administration of orexin peptides increases food intake. Therefore, orexin was initially noticed as a neuropeptide with feeding regulatory effects. Subsequently, it was reported that canine narcolepsy is caused by a gene mutation in the orexin type 2 receptor (Non-Patent Literature 2), and the role of orexin in sleep-wake regulation also came to attention.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice created by crossing these mice with orexin-overexpressing transgenic mice have revealed that narcolepsy-like symptoms appearing due to orexin neuronal degeneration disappear with sustained orexin expression. Similarly, intracerebroventricular administration of orexin peptide to transgenic mice with degenerated orexin neurons also improved narcolepsy-like symptoms (Non-Patent Literature 3). Furthermore, studies using orexin type 2 receptor knockout mice suggest that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Literature 4, Non-Patent Literature 5). Against this backdrop, orexin type 2 receptor agonists are suggested to be potential treatments for narcolepsy and other sleep disorders characterized by excessive sleepiness (Non-Patent Literature 6).

[0005] Furthermore, it has been suggested that peptide agonists that selectively act on orexin type 2 receptors can improve obesity induced by a high-fat diet in mice (Non-Patent Document 7). Furthermore, intracerebroventricular administration of orexin peptide has been suggested to shorten the time required for general anesthesia in rats (Non-Patent Literature 8). Furthermore, it has been suggested that patients with sleep apnea syndrome have low levels of orexin A in their plasma (Non-Patent Document 9). Furthermore, intracerebroventricular administration of orexin peptide has been suggested to improve memory retention in an accelerated aging model mouse (SAMP8) with cognitive impairment (Non-Patent Literature 10). Furthermore, orexin type 2 receptor agonists have been suggested to be potential treatments for heart failure (Patent Document 1, Non-Patent Document 11). Furthermore, it has been suggested that daytime sleepiness in Parkinson's disease patients is caused by the loss of orexin neurons (Non-Patent Literature 12). Furthermore, since orexin controls bone formation and bone loss, it has been suggested that orexin type 2 receptor agonists could be used to treat diseases related to bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). In addition, since a significant improvement in mortality was observed simply by continuously administering orexin peripherally to septic shock model mice, orexin receptor agonists are suggested to be 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 lethargy, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (for example, Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc., and further as anesthetic antagonists and agents for preventing or treating side effects and complications caused by anesthesia.

[0007] On the other hand, as sulfonamide derivatives, Formula

[0008]

Chemical formula

[0009] (Each symbol in the formula is as described in the literature.) Compounds represented by (Patent Document 4) have been reported.

[0010] In addition, the following compounds have been reported as compounds having orexin type 2 receptor agonist activity. Formula

[0011]

Chemical formula

[0012] (Each symbol in the formula is as described in the literature.) Compounds represented by (Patent Document 5). Formula

[0013] [ka]

[0014] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 6). formula

[0015] [ka]

[0016] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 7). formula

[0017] [ka]

[0018] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 8). formula

[0019] [ka]

[0020] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 9). formula

[0021] [ka]

[0022] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 10). formula

[0023] [ka]

[0024] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 11). formula

[0025] [ka]

[0026] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 12). formula

[0027] [ka]

[0028] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 13). formula

[0029] [ka]

[0030] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 14). formula

[0031] [ka]

[0032] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 15). formula

[0033] [ka]

[0034] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 16). formula

[0035] [ka]

[0036] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 17). formula

[0037] [ka]

[0038] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 18). formula

[0039] [ka]

[0040] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 19). formula

[0041] [ka]

[0042] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 20). formula

[0043] [ka]

[0044] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 21). formula

[0045] [ka]

[0046] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 22). formula

[0047] [ka]

[0048] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 23). formula

[0049] [ka]

[0050] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 24). formula

[0051] [ka]

[0052] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 25).

[0053] The development of novel compounds with orexin type 2 receptor agonist activity is desired. [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] The present invention aims to provide heterocyclic compounds having orexin type 2 receptor agonist activity. [Means for solving the problem]

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

[0058] In other words, the present invention relates to the following: [1] Equation (I):

[0059] [ka]

[0060] [In the formula, Ring A may be substituted with C 6-14 An aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, where Y is a ring atom C or N, where C is bonded to hydrogen or any substituent; X is -O-, -S-, -NR1 -, -CR 2 R 3 -, -O-(CR 2 R 3 )-, -(CR 2 R 3 )-O-, or an optionally substituted C 3-6 cycloalkyl group, where the left part of X is bonded to the ring carbon atom on ring A adjacent to Y and the right part of X is bonded to ring B; R 1 is hydrogen or an optionally substituted C 1-6 alkyl group; R 2 and R 3 are independently hydrogen, halogen, or an optionally substituted C 1-6 alkyl group; Ring B is an optionally substituted C 6-14 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-, -O-C(R 4 R 5 )-, -NR 6 -C(R 4 R 5 )-, -C(R 4 R 5 )-C(R 7 R 8 )-, where the left part of L is bonded to ring B and the right part of L is bonded to the carbonyl group; R 4 and R 5 are independently hydrogen, halogen, or an optionally substituted C 1-6 alkyl group; R 6 is hydrogen or an optionally substituted C 1-6 alkyl group; R 7 and R 8 are independently hydrogen, halogen, or an optionally substituted C 1-6It is an alkyl group; R 4 and R 6 They may, together with the atoms to which they bond, form a substituted, 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R 4 and R 5 , or R 4 and R 7 Together, they form a substituted or substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or a substituted or substituted C, along with the atoms to which they are bonded. 3-10 Forms a cycloalkyl group; R a C 1-6 Alkyl alkyl group, C 3-4 Cycloalkyl groups, or mono- or di-C 1-6 It is an alkylamino group, where C 1-6 Alkyl alkyl group, C 3-4 Cycloalkyl groups, and mono- or di-C13 1-6 The alkylamino groups may be substituted; R b is a hydrogen atom or a halogen atom; and R c [This is a hydrogen atom or a halogen atom;] A compound represented by, or a salt thereof.

[0061] [2] Ring A is

[0062] [ka]

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

[0064] [3] Ring B is as follows:

[0065] [ka]

[0066] (wherein iv is the connection point to L, and iii is the connection point to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d C may be hydrogen, halogen, or halogenated C 1-6 Alkyl alkyl group, C 1-6 Alkoxyl group and C 3-6 Selected independently from cycloalkyl groups; and R 24 C may be hydrogen, halogen, or halogenated C 1-6 Alkyl alkyl groups, and C 3-6 (Selected from cycloalkyl groups.) A compound or salt of the above [1] or [2], selected from the above.

[0067] [4] Ring A is

[0068] [ka]

[0069] (wherein i is the bonding point to the crosslinked methylene, and ii is the bonding point to X; and R 11 and R 12 These are, independently, hydrogen, halogen, or C 1-6 It 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 part of X is bonded to the ring carbon atom on ring A adjacent to Y, and the right part of X is bonded to ring B; R 2 and R 3 are independently hydrogen, halogen, or a C 1-6 alkyl group which may be substituted with 1 to 3 substituents independently selected from halogen and C 1-6 alkyl groups; Ring B is as follows:

[0070]

Chemical formula

[0071] (where iv is the bonding point to L, and iii is the bonding point to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d are selected independently from hydrogen, halogen, a C 1-6 alkyl group which may be halogenated, a C 1-6 alkoxyl group and a C 3-6 cycloalkyl group; R 24 is hydrogen or a C 1-6 alkyl group.) selected from; L is -C(R 4 R 5 )-NR 6 -, -C(R 4 R 5 )-O-, -O-C(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-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R 4 and R 5 However, independently, hydrogen, or C 1-6 It is an alkyl group; R 6 However, C may be hydrogenated or halogenated. 1-6 It is an alkyl group; R 7 and R 8 However, independently, is it hydrogen; or L is -C(R 4 R 5 )-NR 6 -or-NR 6 -C(R 4 R 5 )- When R 4 and R 6 However, along with the atoms to which they bond, halogens and C 1-6 A 3- to 8-membered monocyclic non-aromatic heterocyclic ring may be substituted with one to three substituents independently selected from the alkoxyl group, and R 5 But is it hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )- When R 4 and R 7 However, along with the carbon atoms to which they are bonded, C 3-10 Forms a cycloalkyl group, and R 5 and R 8 However, both are hydrogen; R a However, halogen atoms and C 1-6 The C group may be substituted with one to three substituents independently selected from the alkoxyl group. 1-6 Alkyl alkyl group, C 3-4 Cycloalkyl groups, or mono- or di-C 1-6 It is an alkylamino group; Rb but is a hydrogen atom or a halogen atom; and R c However, it is a hydrogen atom or a halogen atom. The compounds or salts of the above [1], [2], or [3].

[0072] [5] Ring A is a phenyl group which may be further substituted with one or two halogen atoms, where Y is a ring atom C bonded to hydrogen or halogen; X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B contains halogen and C 1-6 A pyridine ring which may be substituted with one, two, or three substituents independently selected from the alkyl group; L is -CH2-NH-, where the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R a However, C may be substituted with one to three halogen atoms. 1-6 Alkyl alkyl group, or C 3-4 It is a cycloalkyl group; R b However, it is a halogen atom; and R c However, it is a halogen atom. The compounds or salts of the above [1], [2], [3], or [4].

[0073] [6] Ring A is a phenyl group which may be further substituted with one or two halogen atoms, where Y is a ring atom C bonded to the halogen; X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B has 1, 2, or 3 C 1-6 A pyridine ring which may be substituted with an alkyl group; L is -CH2-NH-, where the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R a However, C may be substituted with one to three halogen atoms. 1-6 It is an alkyl group; R b However, it is a halogen atom; and R c However, it is a halogen atom. The compounds or salts of the above [1] through [5].

[0074] [7] The compounds are as follows: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propan-2-sulfonamide; A compound selected from the group consisting of the above [1], or a salt thereof, as described above.

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

[10] The pharmaceutical product described in [9] above, which is an orexin type 2 receptor agonist.

[11] The pharmaceuticals described above [9] that are agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, or side effects or complications of anesthesia.

[12] The medicine described above [9] as a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[13] The medicine described above [9] as a preventive or therapeutic agent for narcolepsy.

[0076]

[14] A method for preventing or treating a disease or disorder in a mammal that requires the use of an orexin 2 receptor, comprising administering a therapeutically effective amount of a compound or salt thereof as defined in any one of the above paragraphs [1] to [7] to the mammal in need.

[15] The method described above

[14] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia, 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 described in

[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 disease or disorder is narcolepsy, in the manner described above

[14] ,

[15] , or

[16] .

[0077]

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

[19] A treatment method comprising the treatment of a disease or disorder associated with the orexin type 2 receptor, comprising the compound or salt described in

[18] above.

[20] The compound or salt described in

[19] above, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia, 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 one] The compound or salt described in

[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 described in

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

[0078] [twenty three] Use of any of the compounds defined in [1] through [7] above or a salt thereof in the manufacture of a pharmaceutical product for the treatment of a disease or disorder associated with the orexin type 2 receptor. [twenty four] The use described above

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

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

[26] The use described above

[23] , 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 a preventive or therapeutic agent for narcolepsy.

[0080] [Detailed description of the invention] The definitions of each substituent used in this specification are described in detail below. Unless otherwise specified, each substituent has the following definitions. In this specification, "halogen atoms" include, for example, fluorine, chlorine, bromine, and iodine. In this specification, "C 1-6 Examples of alkyl groups 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 One example is [the character]. In this specification, "C which may be halogenated" 1-6 The alkyl group may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl compounds are examples. Specific examples include 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 2-6Examples of "alkenyl groups" 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 "alkynyl groups" 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 "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In this specification, "C which may be halogenated" 3-10 The "cycloalkyl group" may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Examples include cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of "cycloalkenyl groups" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 Examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16Examples of "aralkyl groups" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0081] In this specification, "C 1-6 Examples of "alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In this specification, "C which may be halogenated" 1-6 The "alkoxy group" may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of alkoxy groups include 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 "cycloalkyloxy groups" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. In this specification, "C 1-6 Examples of alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. In this specification, "C which may be halogenated" 1-6 The alkylthio group may have, for example, 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkylthio groups are examples. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0082] In this specification, "C1-6 Examples of alkyl-carbonyl groups include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanol, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanol. In this specification, "C which may be halogenated" 1-6 The alkyl-carbonyl group may have, for example, 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl-carbonyl groups are examples. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. In this specification, "C 6-14 Examples of "aryl-carbonyl groups" include benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16 Examples of "aralkyl-carbonyl groups" include phenylacetyl and phenylpropionyl. In this specification, "5- to 14-membered aromatic heterocyclic carbonyl group" includes, for example, nicotinoyl, isonicotinoyl, tenoyl, and froyl. In this specification, "3- to 14-membered non-aromatic heterocyclic carbonyl group" refers to, for example, morpholinyl carbonyl, piperidinyl carbonyl, and pyrrolidinyl carbonyl.

[0083] In this specification, "mono- or di-C" refers to a single or di-C. 1-6Examples of alkyl-carbamoyl groups include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. In this specification, "mono- or di-C" refers to a single or di-C. 7-16 Examples of "aralkyl-carbamoyl groups" include benzylcarbamoyl and phenethylcarbamoyl.

[0084] In this specification, "C 1-6 Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In this specification, "C which may be halogenated" 1-6 The alkylsulfonyl group may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples include alkylsulfonyl groups. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 Examples of "arylsulfonyl groups" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0085] In this specification, "substituents" include, for example, halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted sulfamoyl groups, optionally substituted hydroxyl groups, optionally substituted sulfanyl (SH) groups, and optionally substituted silyl groups. In this specification, "hydrocarbon group" (including "hydrocarbon group" in "optionally substituted hydrocarbon group") means, for example, C 1-6 Alkyl 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 group and C 7-16 An example is the aralkyl group.

[0086] In this specification, "optionally substituted hydrocarbon group" refers, for example, to a hydrocarbon group which may have substituents selected from the following substituent group A. [Substituent group A] (1) Halogen atom, (2) Nitro group, (3) Cyano group, (4) Oxo group, (5) Hydroxyl group, (6) C may be halogenated 1-6 Alkoxy group, (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8)C 7-16 Aralkyloxy group (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyl oxy, piperidinyl oxy), (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) 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) C which may be halogenated 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, trifluoromethyl sulfonyloxy), (19)C 1-6 C may be substituted with an alkyl group. 6-14 Aryl sulfonyloxy groups (e.g., phenyl sulfonyloxy, toluene sulfonyloxy), (20) C may be halogenated 1-6 Alkylthio group, (21) 5- to 14-membered aromatic heterocyclic groups, (22) 3- to 14-membered non-aromatic heterocyclic groups, (23) Formyl group, (24) Carboxy group, (25) C may be halogenated 1-6 Alkyl-carbonyl group, (26)C 6-14 Aryl-carbonyl group, (27) 5- to 14-membered aromatic heterocyclic carbonyl group, (28) 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl group, (30)C 6-14 Aryloxycarbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16Aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) Carbamoyl group, (33) Thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl group, (35)C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinyl carbamoyl, piperidinyl carbamoyl), (38) C may be halogenated 1-6 Alkyl sulfonyl group, (39)C 6-14 Aryl sulfonyl group, (40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) C which may be halogenated 1-6 Alkyl sulfinyl group, (42)C 6-14 Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl), (43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (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 group (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino), (48)C 7-16Aralkylamino group (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 group (e.g., N-acetyl-N-methylamino), (52)C 6-14 Aryl-carbonylamino 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 group (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C may be substituted with an alkyl group. 6-14 Aryl sulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) C may be halogenated 1-6 alkyl group, (58)C 2-6 Alkenyl group, (59)C 2-6 Alkynyl group, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl group, and (62)C 6-14 Aryl group.

[0087] The number of substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0088] In this specification, "heterocyclic groups" (including "heterocyclic groups" in "optionally substituted heterocyclic groups") include, for example, (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered heterobridged ring groups, each containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms.

[0089] In this specification, "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") refers to, for example, a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable 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, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, phlopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, imidazopyridinyl, thienopyridinyl, phlopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thia Examples include 8- to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocyclic groups such as zolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, prinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxadinyl.

[0090] In this specification, "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") refers to, for example, a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable examples of the "non-aromatic heterocyclic group" include azilidinyl, oxyranil, thyranil, azetidinil, oxetanil, thietanil, tetrahydrothienyl, tetrahydrofuranil, pyrrolinil, pyrrolidinil, imidazolinil, imidazolidinil, oxazolinil, oxazolidinil, pyrazolinil, pyrazolidinil, thiazolinil, thiazolidinil, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranil, tetrahydrothiopyranil, morpholinil, thiomol Three- to eight-membered monocyclic non-aromatic heterocyclic groups such as folinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azokanyl, and diazokanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hex Examples include 9- to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) non-aromatic heterocyclic groups such as sahydrophenothiazinyl, hexahydrophenoxadinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0091] In this specification, preferred examples of “7- to 10-membered heterocrosslinked ring groups” include quinuclidinyl and 7-azabicyclo[2.2.1]heptanil. In this specification, "nitrogen-containing heterocyclic group" refers to a heterocyclic group that contains at least one nitrogen atom as a ring constituent atom.

[0092] In this specification, "a heterocyclic group which may be substituted" refers, for example, to a heterocyclic group which may have substituents selected from the substituent group A described above. The number of substituents in the "optionally substituted heterocyclic group" is, for example, one to three. If there are two or more substituents, each substituent may be the same or different.

[0093] In this specification, "acyl group" means, for example, "halogen atom, optionally halogenated C 1-6C may have one to three substituents selected from an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, and a carbamoyl group. 1-6 Alkyl 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 groups. 1-6 Examples include formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group, and phosphono group, each of which may have one or two substituents selected from alkyl-amino groups. Other examples of "acyl groups" include hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups, and heterocyclic-sulfinyl groups. Here, a hydrocarbon-sulfonyl group refers to a sulfonyl group to which a hydrocarbon group is attached, a heterocyclic-sulfonyl group refers to a sulfonyl group to which a heterocyclic group is attached, a hydrocarbon-sulfinyl group refers to a sulfinyl group to which a hydrocarbon group is attached, and a heterocyclic-sulfinyl group refers to a sulfinyl group to which a heterocyclic group is attached. Preferred examples of "acyl groups" include formyl groups, carboxyl groups, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10 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 6-14Aryloxycarbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl groups, 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 groups (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 groups (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 groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkyl sulfonyl group, C 6-14 Aryl sulfonyl groups, phosphono groups, and mono- or di-C groups. 1-6Examples include alkylphosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0094] In this specification, "optionally substituted amino group" means, for example, "C which may each have one to three substituents selected from substituent group A." 1-6 Alkyl 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 groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkyl sulfonyl group and C 6-14 An example is an amino group which may have one or two substituents selected from arylsulfonyl groups. Preferred examples of optionally substituted amino groups include amino groups, mono- or di-(which may be halogenated) C 1-6 Alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino group (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino group (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino group (e.g., benzylamino, dibenzylamino), mono- or di-(may be halogenated C) 1-6Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino groups (e.g., benzoylamino), mono- or di-C 7-16 Aalkyl-carbonylamino groups (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino groups (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino groups (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxycarbonylamino groups (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino), carbamoylamino groups, (mono- or di-C) 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C) 7-16 Aalkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Aryl sulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group (e.g., N- Acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 Examples include aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0095] In this specification, "optionally substituted carbamoyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl 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 7-16Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples of carbamoyl groups include those having one or two substituents selected from aralkyl-carbamoyl groups. Preferred examples of carbamoyl groups that may be substituted include carbamoyl groups, 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 groups (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl groups (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-carbamoyl groups (e.g., benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl).

[0096] In this specification, "a thiocarbamoyl group which may be substituted" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl 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 7-16Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples include thiocarbamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Preferred examples of substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl groups (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 groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (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 groups (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl).

[0097] In this specification, "optionally substituted sulfamoyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-Carboni 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 groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples include sulfamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Suitable examples of sulfamoyl groups that may be substituted include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl groups (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl sulfamoyl group (e.g., diallyl sulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl groups (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl groups (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl groups (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-sulfamoyl groups (e.g., benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (e.g., pyridylsulfamoyl).

[0098] In this specification, "optionally substituted hydroxyl group" means, for example, "C which may each have one to three substituents selected from substituent group A."1-6 Alkyl 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 groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkyl sulfonyl group and C 6-14 Examples include hydroxyl groups which may have substituents selected from arylsulfonyl groups. Preferred examples of hydroxyl groups that may be substituted include hydroxyl groups, 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 group (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aalkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6Alkoxy-carbonyloxy groups (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), carbamoyloxy groups, 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 aryl sulfonyloxy groups (e.g., phenylsulfonyloxy).

[0099] In this specification, "optionally substituted sulfanyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl 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 include sulfanyl groups which may have substituents selected from aryl-carbonyl groups and 5- to 14-membered aromatic heterocyclic groups, and halogenated sulfanyl groups. Suitable examples of substituted sulfanyl groups include sulfanyl(-SH) groups and C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio group (e.g., cyclohexylthio), C 6-14 Arylthio group (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio group (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutylylthio, pivaloylthio), C 6-14Examples include aryl-carbonylthio groups (e.g., benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (e.g., pyridylthio), and halogenated thio groups (e.g., pentafluorothio).

[0100] In this specification, "optionally substituted silyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group and C 7-16 Examples include silyl groups which may have one to three substituents selected from the aralkyl group. A suitable example of a silyl group that may be substituted is tri-C 1-6 Examples include alkylsilyl groups (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0101] In this specification, "hydrocarbon ring" means, for example, C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes and C 3-10 Cycloalkenes are one example. In this specification, "C 6-14 Examples of "aromatic hydrocarbon rings" include benzene and naphthalene. In this specification, "C 3-10 Examples of "cycloalkanes" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10 Examples of "cycloalkenes" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In this specification, "heterocycle" refers to, for example, aromatic heterocycles and non-aromatic heterocycles that contain, in addition to carbon atoms, one to four heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring constituent atoms.

[0102] In this specification, "aromatic heterocycle" refers to, for example, a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Preferred 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, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, phlopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyridine, imidazopyrimidine, thienopyrimidine, phlopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxatiin, indole, isoindole, 1H-indazo Examples include 8 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocycles such as phosphate, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carbolin, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0103] In this specification, "non-aromatic heterocycle" refers to, for example, a 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable examples of the "non-aromatic heterocycle" include aziridine, oxirane, thiirane, azetidine, oxetane, thiethane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazolline, pyrazolidine, thiazoline, thiazolidin, tetrahydroisothiazole, tetrahydroxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepan, diazepan, azepine, azocan, diazocan, oxepan, and other 3- to 8-membered monocyclic non-aromatic heterocycles; Examples include 9 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthidine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In this specification, "nitrogen-containing heterocycle" refers to a heterocycle that contains at least one nitrogen atom as a ring constituent atom.

[0104] In this specification, "C3-6 Examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In this specification, "C 3-4 Examples of "cycloalkyl groups" include cyclopropyl and cyclobutyl. In this specification, "mono- or di-C" refers to a single or di-C. 1-6 Examples of alkylamino groups 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 definitions of each symbol in equation (I) are explained in detail below. R a C 1-6 Alkyl alkyl group, C 3-4 Cycloalkyl groups, or mono- or di-C 1-6 It is an alkylamino group, where C 1-6 Alkyl alkyl group, C 3-4 Cycloalkyl groups, and mono- or di-C13 1-6 The alkylamino groups may be substituted. The above "C may be replaced" 1-6 "Alkyl group," "may be substituted mono- or di-C" 1-6 "alkylamino group" and "optionally substituted C" 3-4 Examples of substituents on a "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, each substituent may be the same or different. R a Preferably, (1) C may be substituted 1-6Alkyl groups (e.g., methyl, ethyl, isopropyl), (2) Mono- or di-C may be substituted. 1-6 Alkylamino group (e.g., methylamino, dimethylamino), or (3) C may not be substituted 3-4 Cycloalkyl groups (e.g., cyclopropyl) That is the case. R a Preferably, (1) Halogen atoms (e.g., fluorine atoms) and C 1-6 C may be substituted with one to three substituents independently selected from the alkoxyl group (e.g., methoxy). 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), (2)C 3-4 Cycloalkyl groups (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 Alkylamino group (e.g., methylamino, dimethylamino) That is the case. R a more, (1) C may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1-6 Alkyl alkyl groups (e.g., methyl, ethyl, isopropyl), or (2)C 3-4 Cycloalkyl groups (e.g., cyclopropyl) That is the case. R a Furthermore, C may be substituted with one to three 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 This is a hydrogen atom or a halogen atom (e.g., a fluorine atom). Preferably, R b and R c Together, (1) A hydrogen atom, or (2) It is a halogen atom (e.g., a fluorine atom); or (3)R b and R c One of them is a hydrogen atom, and the other is a halogen atom (e.g., a fluorine atom). more, R b is a halogen atom (e.g., a fluorine atom); and R c These are halogen atoms (e.g., fluorine atoms).

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

[0108] [ka]

[0109] (wherein i is the bonding point to the crosslinked methylene, and ii is the bonding point to X; and R 11 and R 12 These are, independently, hydrogen, halogens (e.g., fluorine atoms), or possibly halogenated C 1-6 It is an alkyl group (e.g., methyl). That is the case. Preferably, R 11 and R 12 These are independently hydrogen, halogens (e.g., fluorine atoms), or C 1-6 It is an alkyl group (e.g., methyl). Comfortable, R 11 is hydrogen or halogen (e.g., fluorine atom), and R 12 It is hydrogen.

[0110] X is -O-, -S-, -NR 1 -, -CR 2 R 3 -, -O-(CR 2 R 3 )-,-(CR 2 R 3 )-O-, or C which may be substituted. 3-6 It is a cycloalkyl group, where the left-hand portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right-hand portion of X is bonded to ring B, where: R 1 is hydrogen, or a substituted C 1-6 It is an alkyl group; and R 2 and R 3 These are independently hydrogen, halogen, or a substituted C 1-6 It is an alkyl group. The above "C may be replaced" 1-6 "alkyl group", and "optionally substituted C3-6 Examples of substituents on 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, each substituent 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 portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B, where R 2 and R 3 These are, independently, hydrogen, halogens (e.g., fluorine atoms), or halogens and C 1-6 The C may be substituted with one to three substituents independently selected from the alkyl group. 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 portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B, where R 2 and R 3 These are independently hydrogen, halogens (e.g., fluorine atoms), or C 1-6 It is an alkyl group (e.g., methyl). More preferably, X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B.

[0111] Ring B may be substituted with C 6-14 An aryl group, or a substituted or otherwise substituted 5- or 6-membered monocyclic aromatic heterocycle. Ring B may have substituents in addition to L and X in formula (I). Examples of substituents include substituents selected from substituent group A described above. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different. Preferably, ring B is (1) C which may be further substituted 6-14 Aryl group (e.g., phenyl), or (2) A further substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) That is the case. More preferably, ring B is (1) Halogen atoms (e.g., chlorine atoms) and C 1-6 A phenyl group which may be substituted with one to three substituents selected from alkyl groups (e.g., methyl), (2)(a) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (b) C may be halogenated 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) It is a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) which may be substituted with one to three substituents selected from (specifically, pyridine has one to three substituents, and thiazole, pyrimidine, and pyrazine have one or two substituents). More preferably, ring B is Halogens (e.g., fluorine atom, chlorine atom) and C 1-6 The pyridine ring may be substituted with one, two, or three substituents independently selected from an alkyl group (e.g., methyl). More preferably, ring B is 1, 2, or 3 C 1-6 It is a pyridine ring that may be substituted with an alkyl group (e.g., methyl). More preferably, ring B is:

[0112] [ka]

[0113] (wherein iv is the connection point to L, and iii is the connection point to X; R 21a , R 21b , R 21d , R 22a , R 22b , R 22c , R 23a , R 23b , R 23c and R 23d This includes hydrogen, halogens (e.g., fluorine atom, chlorine atom, bromine atom), and halogenated C. 1-6 Alkyl groups (e.g., methyl, ethyl, difluoromethyl), C 1-6 Alkoxyl groups (e.g., methoxy) and C 3-6 Selected independently from cycloalkyl groups (e.g., cyclopropyl); R 24 C may be hydrogen, halogen, or halogenated C 1-6 Alkyl alkyl groups, and C 3-6 (Selected from cycloalkyl groups.) They are selected from among them. Comfortable, 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-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R 4 and R 5 These are independently hydrogen, halogen, or a substituted C 1-6 It is an alkyl group; R 6 is hydrogen, or a substituted C 1-6 It is an alkyl group; R 7 and R 8 These are independently hydrogen, halogen, or a substituted C 1-6 It is an alkyl group; or R 4 and R 6 They may, together with the atoms to which they bond, form a substituted, 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R 4 and R 5 , or R 4 and R 7 Together, they form a substituted or substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or a substituted or substituted C, along with the atoms to which they are bonded. 3-10 It forms a cycloalkyl group. The above "C may be replaced" 1-6 "alkyl group," "a substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring," and "a substituted C." 3-10 Examples of substituents on 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, each substituent 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-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R 4 and R 5 These are, independently, hydrogen, or C 1-6 It is an alkyl group (e.g., methyl); R 6 C may be hydrogen or halogenated. 1-6 Alkyl groups (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 )- When R 4 and R 6 These, along with the atoms to which they bond, include halogens (e.g., fluorine atoms) and C 1-6 It forms a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., azetidine ring, pyrrolidine ring) which may be substituted with one to three substituents independently selected from the alkoxyl group (e.g., methoxy), and R 5 is hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )- When R 4 and R 7 C 3-10 Forms a cycloalkyl group (e.g., cyclopropyl), and R 5 and R 8 Both are hydrogen. More preferably, L is -CH2-NH-, where the left portion of L is bonded to ring B and the right portion of L is bonded to the carbonyl group.

[0115] The following compounds are good examples of compound (I): [Compound A] R a but, (1) C may be substituted 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, methoxymethyl), (2) Mono- or di-C may be substituted. 1-6 Alkylamino group (e.g., methylamino, dimethylamino), or (3) C may not be substituted 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) C may be substituted 6-14 Aryl group (e.g., phenyl), or (2) A substituted 5- or 6-membered monocyclic aromatic heterocyclic group Here, Y is a ring atom C or N, where C is bonded to hydrogen or any substituent; Ring B is (1) C may be substituted 6-14 Aryl group (e.g., phenyl), or (2) A substituted 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) and; X (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) C may be substituted 3-6 Cycloalkyl groups Here, the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; R 1 However, hydrogen, or a substituted C 1-6 It is an alkyl group, R 2 and R 3 However, independently, hydrogen, halogens (e.g., fluorine atoms), or substituted C 1-6 It is 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 )- Here, the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; and R 4 and R 5 However, independently, hydrogen, halogen, or substituted C 1-6 It is an alkyl group (e.g., methyl); R 6 However, hydrogen, or a substituted C 1-6 It is an alkyl group (e.g., methyl, difluoroethyl); R7 and R 8 However, independently, hydrogen, halogen, or substituted C 1-6 It is an alkyl group; or R 4 and R 6 Together, they form a substituted, possibly substituted, 3- to 8-membered monocyclic non-aromatic heterocyclic ring with the atoms to which they bond (e.g., halogens (e.g., fluorine atoms) and C 1-6 An azetidine ring or pyrrolidine ring (which may be substituted with one to three substituents independently selected from the alkoxyl group (e.g., methoxy); or R 4 and R 5 , or R 4 and R 7 Together, they form a substituted or substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or a substituted or substituted C, along with the atoms to which they are bonded. 3-10 Forms 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 may be substituted with one to three substituents independently selected from the alkoxyl group (e.g., methoxy). 1-6 alkyl group (Examples: methyl, ethyl, isopropyl) (2)C 3-4 Cycloalkyl groups (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 Alkylamino group (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 which may be further substituted with one or two substituents selected from alkyl groups (e.g., methyl), where Y is a ring atom C bonded to hydrogen or a halogen (e.g., a fluorine atom); Ring B is (1) A phenyl group which may be substituted with one to three substituents selected from halogen atoms (e.g., chlorine atoms), (2) A 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine), where pyridine may be substituted with 1 to 3 substituents, and thiazole, pyrimidine, and pyrazine may be substituted with 1 or 2 substituents, in all cases the substituents are (a) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (b) C may be halogenated 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 (1)-O-, (2)-CR 2 R 3 -, (3)-O-(CR 2 R 3 )-,or (4)-(CR 2 R 3 )-O- Here, the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; R 2 and R 3 However, they became independent, (1) Hydrogen, (2) Halogens (e.g., fluorine atom), or (3) Halogens and C 1-6 The C may be substituted with one to three substituents independently selected from the alkyl group. 1-6 Alkyl group (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 )- Here, the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group. Join; and R 4 and R 5 However, independently (1) Hydrogen, or (2)C 1-6 Alkyl group (e.g., methyl) and; R 6 but, (1) Hydrogen, or (2) C may be halogenated 1-6 Alkyl alkyl groups (e.g., methyl, difluoroethyl) and; R 7 and R 8 However, each is hydrogen; or L is -C(R 4 R 5 )-NR 6 -or-NR 6 -C(R 4 R 5 )- When R4 and R 6 These, along with the atoms to which they bond, include halogens (e.g., fluorine atoms) and C 1-6 It forms a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., azetidine ring or pyrrolidine ring) which may be substituted with one to three substituents independently selected from the alkoxyl group (e.g., methoxy), and R 5 But is it hydrogen; or L is -C(R 4 R 5 )-C(R 7 R 8 )- When 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 However, both are hydrogen. Compound (I).

[0117] [Compound C] Ring A is a phenyl group which may be further substituted with one or two halogen atoms (e.g., fluorine atoms), where Y is a ring atom C bonded to hydrogen or a halogen (e.g., fluorine atoms); X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B contains halogens (e.g., fluorine atom, chlorine atom) and C 1-6 A pyridine ring which may be substituted with one, two, or three substituents independently selected from alkyl (e.g., methyl); L is -CH2-NH-, where the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R a However, C may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1-6 Alkyl alkyl groups (e.g., methyl, ethyl, isopropyl), or C 3-4 It is a cycloalkyl group (e.g., cyclopropyl); R bHowever, halogen atoms (e.g., fluorine atoms); and R c However, halogen atoms (e.g., fluorine atoms) Compound (I).

[0118] [Compound D] Ring A is A phenyl group which may be further substituted with one or two halogen atoms (e.g., fluorine atoms), where Y is a ring atom C bonded to the halogen (e.g., fluorine atom); X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B has 1, 2, or 3 C 1-6 A pyridine ring which may be substituted with an alkyl group (e.g., methyl); L is -CH2-NH-, where the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R a However, C may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1- It is a 6-alkyl group (e.g., methyl); R b However, it is a halogen atom (e.g., a fluorine atom); and R c However, these are halogen atoms (e.g., fluorine atoms). Compound (I).

[0119] [Compound E] Ring A is A phenyl group which may be further substituted with one or two halogen atoms (e.g., fluorine atoms), where Y is a ring atom C bonded to the halogen (e.g., fluorine atom); X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B is

[0120] [ka]

[0121] (In the formula, R 21a , R 22a and R 23a These are, independently, hydrogen or C 1-6 It is an alkyl group (e.g., methyl). And, L is -CH2-NH-, where the left-hand portion of L is bonded to ring B, and the right-hand portion of L is bonded to the carbonyl group; R a However, C may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1-6 It is an alkyl group (e.g., methyl); R b However, it is a halogen atom (e.g., a fluorine atom); and R c However, halogen atoms (e.g., fluorine atoms) Compound (I).

[0122] Specific examples of compound (I) include the compounds described in Examples 1 to 111 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-(meteno)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-(meteno)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-(meteno)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 Tyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propan-2-sulfonamide or a salt thereof (Example 97) That is the case.

[0123] The salt of the compound represented by formula (I) is preferably a pharmacokinetically acceptable salt, and examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. 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, and the like. Suitable examples of salts with basic amino acids include salts with arginine, lysine, and ornithine. Suitable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

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

[0125] The raw materials and reagents used in each step of the following manufacturing method, as well as the resulting compounds, can each form salts. For example, such salts can be formed by the chemical formula (I). Examples include salts similar to those used in mixed foods.

[0126] If the compounds obtained in each step are free compounds, they can be converted to the desired salt by methods known to the public. If the compounds obtained in each step are salts, they can be converted to the desired free form or other types of salts by methods known to the public.

[0127] The compounds obtained in each step can be used directly as a reaction solution or as a crude product in subsequent reactions, or the compounds obtained in each step can be isolated and / or purified from the reaction mixture by known separation methods, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography.

[0128] If the raw materials and reagents for each step are commercially available, the commercially available products can be used as is.

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

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

[0131] In each reaction step, the pressure varies depending on the reagents and solvents used. Unless otherwise specified, the pressure is usually between 1 atmosphere and 20 atmospheres, preferably between 1 atmosphere and 3 atmospheres.

[0132] Microwave synthesis equipment such as the Biotage Initiator+ can be used in each reaction step. The reaction temperature may vary depending on the reagents and solvents 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 solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

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

[0134] Unless otherwise specified, the reactions in each step are carried out without a solvent, or by dissolving or suspending the starting compounds in a suitable solvent. Specific examples of solvents include those described in the examples, or 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: such as dichloromethane and carbon tetrachloride; Nitriles: such as acetonitrile; Sulfoxides: such as dimethyl sulfoxide; Aromatic organic bases: such as pyridine; Acid anhydrides: such as acetic anhydride; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc. Inorganic acids: hydrochloric acid, sulfuric acid, etc. Esters: such as ethyl acetate; Ketones: such as acetone and methyl ethyl ketone; water. The above solvents can be used individually or as a mixture of two or more in appropriate proportions.

[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, may be 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: such as sodium hydride; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. Organolithium compounds: such as n-butyllithium.

[0136] When an acid or acidic catalyst is used in the reaction of each step, for example, the acids and acidic catalysts shown below, or the acids and acidic catalysts described in the examples, may be 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 based on publicly known methods, e.g., Experimental Chemistry Course, 5th Edition, Volumes 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume 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 The process is carried out according to the methods described in Heterocyclic Chemistry III, Vol.1-Vol.14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated under the supervision of Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or according to the methods described in the examples.

[0138] In each step, the functional group protection or deprotection reaction is carried out by methods known to the extent of the invention, for example, "Protective Groups" published by Wiley-Interscience in 2007. The process is carried out according to the methods described in "in Organic Synthesis, 4th Ed." (Theodora W. Greene and Peter GM Wuts) and "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or according to the methods described in the examples. Examples of protecting groups for hydroxyl groups in alcohols and phenolic hydroxyl groups include methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetramethyl ether. Examples include ether-type protecting groups such as dropyranil ether; carboxylic acid ester-type protecting groups such as acetate esters; sulfonic acid ester-type protecting groups such as methanesulfonic acid esters; and carbonate ester-type protecting groups such as tert-butyl carbonate. Examples of protecting groups for the carbonyl group of aldehydes 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 ketones 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 protecting groups for carboxyl groups include ester-type protecting groups such as methyl esters, and amide-type protecting groups such as N,N-dimethylamide. Examples of thiol protecting groups include ether-type protecting groups such as benzyl thioether, and ester-type protecting groups such as thioacetic acid esters, thiocarbonates, and thiocarbamates. 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 using methods known to the extent that acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), etc., or by reduction methods.

[0139] When reduction reactions are carried out in each step, the reducing agents used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and triacetoxyborotetramethylammonium hydride; boranes such as boranetetrahydrofuran complexes; Raney nickel; Raney cobalt; hydrogen; formic acid; and triethylsilane. When reducing carbon-carbon double or triple bonds, methods using catalysts such as palladium-carbon or Lindlar catalysts may be employed.

[0140] In each step of the oxidation reaction, the oxidizing agents 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 complexes; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0141] When radical cyclization reactions are carried out in each step, the radical initiators 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; and benzoyl peroxide. In addition, the radical reaction reagents used include tributylstananne, tritrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0142] When Wittig reactions are performed in each step, examples of Wittig reagents used include alkylidene phosphoranes. Alkylidene phosphoranes can be prepared by known methods, for example, by reacting a phosphonium salt with a strong base.

[0143] When carrying out the Horner-Emmons reaction in each step, the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate, and bases such as alkali metal hydrides and organolithium compounds.

[0144] In each step of the Friedel-Crafts reaction, the reagents used are 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.). Alternatively, organic or inorganic acids can be used instead of Lewis acids, and acid anhydrides such as acetic anhydride can be used instead of acid chlorides.

[0145] In each step of the process, when an aromatic nucleophilic substitution reaction is carried out, the reagents used are a nucleophile (e.g., amines, imidazoles, etc.) and a base (e.g., organic bases, etc.).

[0146] In each step, when a nucleophilic addition reaction using a carbanion, a nucleophilic 1,4-addition reaction using a carbanion (Michael addition reaction), or a nucleophilic substitution reaction using a carbanion is performed, the bases used to generate the carbanion include organolithium compounds, metal alkoxides, inorganic bases, and organic bases.

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

[0148] In each step of the Knoevenagel condensation reaction, the reagents used are compounds having an active methylene group sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and bases (e.g., organic bases, metal alkoxides, inorganic bases).

[0149] In each step of the Vilsmeier-Haack reaction, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide) are used as reagents.

[0150] In each step of the process, when carrying out azidation reactions of alcohols, alkyl halides, and sulfonic acid esters, the azidating agents used include diphenyl phosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, for the azidation reaction of alcohols, methods using diphenyl phosphoryl azide and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) or methods using trimethylsilyl azide and Lewis acid are employed.

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

[0152] In each step of the process, when the Mitsunobu reaction is carried out, azodicarboxylic acid esters (e.g., diethyl azodicarboxylic acid (DEAD), diisopropyl azodicarboxylic acid (DIAD), etc.) and triphenylphosphine are used as reagents.

[0153] In each step of the process, when esterification, amidation, or urea formation reactions are carried out, the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, activated esters, and sulfate esters. Activators of carboxylic acids 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-triazine-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl phosphate azide (DPPA); and benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent). Examples include 2-chloro-1-methylpyridinium iodide (Mukoyama Reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; and combinations thereof. When using carbodiimide coupling agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) can be added to the reaction system.

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

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

[0156] In each step of the process, when a thiocarbonylation reaction is carried out, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, in addition to phosphorus pentasulfide, reagents 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 reagent), etc.) may be used.

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

[0158] When performing the Wohl-Ziegler reaction in each step, the halogenating agent used Examples of such initiators include N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and sulfuryl chloride. Furthermore, the reaction can be accelerated by applying heat, light, or radical initiators such as benzoyl peroxide and azobisisobutyronitrile to the reaction system.

[0159] In each step, when a halogenation reaction of a hydroxyl group is carried out, examples of halogenating agents used include hydrohalic acids and acid halides of inorganic acids. Specifically, for chlorination, examples include hydrochloric acid, thionyl chloride, and phosphorus oxychloride, and for bromination, examples include 48% hydrobromic acid. Alternatively, a method may be used to produce alkyl halides by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide. Or, a method may be used to produce alkyl halides through a two-step reaction that includes converting an alcohol to the corresponding sulfonic acid ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide.

[0160] When carrying out the Arbuzov reaction in each step, the reagents used include alkyl halides such as ethyl bromoacetate, and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0161] When sulfonate esterification reactions are carried out in each step, examples of sulfonylation agents that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and p-toluenesulfonic anhydride.

[0162] In each step of the hydrolysis reaction, an acid or a base is used as the reagent. Furthermore, in the acid hydrolysis reaction of tert-butyl esters, formic acid, triethylsilane, etc., 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 dehydrating agents that can be used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphate.

[0164] PG 1 PG 2 PG 3 , and PG 4 Examples of "protecting groups" include those exemplified as "protecting groups" for amino groups and hydroxyl groups.

[0165]

[0131] LG 1 LG 2 LG 3 LG 4 , and LG 5 Examples of "leaving groups" include halogen atoms and halogenated carbon atoms. 1-6 Alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C may be substituted with alkyl. 6-14 Examples include aryl sulfonyloxy compounds (e.g., benzenesulfonyloxy, toluenesulfonyloxy).

[0166] Compound (I) can be prepared from compounds (1a)-(4a) and (1b)-(4b) according to the method shown in Scheme 1 below. In the formulas, 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 a 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; examples of such phosphine ligands include triphenylphosphine. Furthermore, a base may be added to the reaction; examples of such bases include inorganic bases 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 a 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 readily available commercially or can be produced according to methods known to the public.

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

[0170] [ka]

[0171] Compounds (10a) and (10b) can be produced by coupling compounds (7a) and (7b) with compound (8-1), respectively. Compounds (10a) and (10b) can also be produced by coupling compounds (7a) and (7b) with compound (8-2), respectively. Furthermore, compounds (10a) and (10b) can be produced by coupling compounds (7a) and (7b) with compound (8-3), respectively. Compounds (10a) and (10b) can also be produced by nucleophilic substitution reactions of compounds (7a) and (7b) with compound (9), respectively. R r When is cyano, compounds (13a) and (13b) can be produced by subjecting compounds (7a) and (7b) to a coupling reaction with compound (11). Examples of compound (11) to be used include zinc cyanide. Examples of metal catalysts to be used 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 metal catalysts that can be used include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. R r When is cyano, compounds (10a) and (10b) can be produced by reducing and then protecting compounds (13a) and (13b), respectively. Compounds (1a) and (1b) can be produced by subjecting compounds (10a) and (10b) to deprotection, respectively. R r When is cyano, compounds (1a) and (1b) can be produced by reducing compounds (13a) and (13b), respectively, and then subjecting them to deprotection. r ga-COOR sIn this case, compounds (1a) and (1b) can be produced by hydrolyzing compounds (13a) and (13b), respectively, followed by deprotection.

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

[0173] [ka]

[0174] Compounds (15a) and (15b) can be produced by subjecting compounds (7a) and (7b) to a nucleophilic substitution reaction with compound (14), respectively. Compounds (17a) and (17b) can be produced by subjecting compounds (7a) and (7b) to a Mizoroki-Heck reaction with compound (16), respectively. Compounds (18a) and (18b) can be produced by reducing compounds (17a) and (17b), respectively. Compounds (2a) and (2b) can be produced by deprotecting compounds (15a) and (15b), respectively, followed by hydrolysis. Compounds (2a) and (2b) can also be produced 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 produced by subjecting compounds (7a) and (7b) to deprotection, respectively. Compounds (21a) and (21b) can be produced by subjecting compounds (19a) and (19b) to an amidation reaction with compound (20), respectively. Compounds (3a) and (3b) can be produced by subjecting compounds (21a) and (21b) to deprotection, 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) to the amidation reaction with compound (22), respectively.

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

[0182] [ka]

[0183] Compounds (7aa), (7ba), (13aa), and (13ba) can be produced by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (24). a When is -O-, the compounds (7aa), (7ba), (13aa), and (13ba) can also be produced 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 produced 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 the Sandmeyer reaction. The Sandmeyer reaction is a method known in itself, for example, "Organic Reaction Mechanisms and Essence, Revised Edition" (Hideo Togo, Kodansha), "War The process is carried out according to the methods described in "Application of Nominal Reactions in Abbreviated Organic Synthesis" (translated by Kiyoshi Tomioka, Kagaku Dojin) or the methods 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. In the formula, X b -CR 2 R 3 -and C which may be substituted 3-4 It is a cycloalkyl group, R v R r and -L-COOR t 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. Examples of fluorinating agents that can be 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. In the formula, R w C may be substituted. 1-6 It is an alkyl group, M 2 It is a metal, and the other symbols are as defined above.

[0188] [ka]

[0189] Compound (33) can be produced by methods known to the present day, for example, by the methods described in "WO2020158958", "WO2019027058", or by 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 produced by protecting compound (33). Compounds (29a) and (29b) can be produced by subjecting compounds (34a) and (34b) to a borylation reaction with compound (35). Examples of metal catalysts that can be 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 bases and organic bases. Compounds (23aa) and (23ba) can be produced by subjecting compounds (34a) and (34b) to a substitution reaction with compound (36). Examples of compound (36) used include potassium hydroxide. Examples of metal catalysts used include tris(dibenzylideneacetone)dipalladium(0). Examples of phosphine ligands used include 2-di-tert-butylphosphin-2',4',6'-triisopropylbiphenyl. Compounds (23aa) and (23ba) can be produced by subjecting compounds (29a) and (29b) to an oxidation reaction. Examples of oxidizing agents that can be 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 trifluoromethanesulfonylation agents 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 produced by reducing compounds (39a) and (39b).

[0190] In compound (I) obtained in this manner, the functional groups within the molecule can be converted to desired functional groups by combining known chemical reactions. Examples of such chemical reactions include oxidation reactions, reduction reactions, alkylation reactions, acylation reactions, ureation reactions, hydrolysis reactions, amination reactions, esterification reactions, aryl coupling reactions, and deprotection reactions.

[0191] In the above manufacturing method, if the starting compound has an amino group, carboxyl group, hydroxyl group, carbonyl group, or mercapto group as a substituent, protecting groups commonly used in peptide chemistry, etc., may be introduced to these groups, and the target compound can be obtained by removing the protecting group as needed after the reaction.

[0192] Compound (I) obtained by the above manufacturing method can be isolated and purified by known means, such as solvent extraction, liquid-to-liquid conversion, transsolution, crystallization, recrystallization, chromatography, etc. If compound (I) contains optical isomers, stereoisomers, positional isomers, conformational isomers, and rotational isomers, these are also included as compound (I), and each can be obtained individually by known synthesis and separation methods. For example, if compound (I) contains optical isomers, the optical isomers separated from the compound are also included in compound (I). Here, optical isomers can be produced by methods that are already known. Compound (I) may be crystalline. Crystals of compound (I) (hereinafter sometimes abbreviated as "crystals of the present invention") can be produced by applying a known crystallization method to compound (I) and crystallizing it.

[0193] In this specification, the melting point refers to the melting point measured using, for example, a micromelting point analyzer (Yanaco, MP-500D or Buchi, B-545) or a DSC (Differential Scanning Calorimetry) device (METTLER TOLEDO, DSC1). In general, melting points can vary depending on the measuring instrument, measurement conditions, etc. The crystals described herein may exhibit melting points different from those specified herein, as long as they are within the normal margin of error. The crystals of the present invention exhibit excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), and efficacy), making them extremely useful as pharmaceuticals.

[0194] Compound (I) may also be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by reactions with enzymes or gastric acid under physiological conditions in the body, that is, a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, etc. As a prodrug of compound (I), Compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); The hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated. Compounds (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated); Examples of compounds in which the carboxyl group of compound (I) is esterified or amidized (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-dioxolene-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methyl amidized). These compounds can be produced from compound (I) by methods known in themselves.

[0195] Furthermore, the prodrug of compound (I) may be one that transforms into compound (I) under physiological conditions, as described on pages 163 to 198 of Volume 7, "Development of Pharmaceuticals," published by Hirokawa Shoten in 1990. In this specification, the prodrug may form a salt, and examples of such salts include those represented by the compound shown in formula (I) above. Furthermore, compound (I) is an isotope (e.g., 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) It may also be marked with, etc. Compounds (I) labeled or substituted with isotopes can be used, for example, as tracers (PET tracers) in positron emission tomography (PET), and are useful in fields such as medical diagnosis. Furthermore, compound (I) may be a hydrate, a nonhydrate, a solvate (e.g., an anhydride), or a solvate (e.g., a hydrate). moreover, 1 H 2 Deuterium converters converted to H(D) are also included in compound (I). Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalline salt. Here, a cocrystal or cocrystalline salt means 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). Cocrystals or cocrystalline salts can be produced according to known cocrystallization methods.

[0196] Compound (I) or its prodrug (hereinafter sometimes simply referred to as the "compound of the present invention") can be used as is, or mixed with a pharmacologically acceptable carrier, etc., to form a pharmaceutical composition (also called a pharmaceutical), which can then be used in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys) as a preventive or therapeutic agent for various diseases described later. Herein, pharmacologically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, which are incorporated as excipients, lubricants, binders, and disintegrants in solid formulations; and as solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0197] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, acacia gum, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and Examples include crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Suitable examples of solvents 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 solubilizers 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 stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and polysorbates and polyoxyethylene hydrogenated castor oil. Suitable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of buffering agents include buffers such as phosphates, acetates, carbonates, and citrates. A suitable example of an analgesic is benzyl alcohol. Suitable examples of preservatives include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acid salts. Suitable examples of colorants include water-soluble food tar dyes (e.g., food colorants such as Food Red No. 2 and 3, Food Yellow No. 4 and 5, Food Blue No. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble food tar dyes), and natural pigments (e.g., β-carotene, chlorophyll, red iron oxide). Suitable examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0198] Examples of dosage forms for 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, microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal adhesive films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compounds and pharmaceuticals of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, ophthalmally, intracerebrally, intravaginally, intraperitoneally, within a tumor, proximal to a tumor, etc., and directly to the lesion). These formulations may be controlled-release formulations such as immediate-release formulations or sustained-release formulations (e.g., sustained-release microcapsules).

[0199] Pharmaceutical compositions can be manufactured by methods commonly used in the pharmaceutical technology field, such as those 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 amount of the compound administered, etc., but is, for example, about 0.1 to 100% by weight. When manufacturing oral preparations, coating may be applied as needed for purposes such as masking the taste, enteric coating, or sustained release.

[0200] Examples of coating bases used in coating include sugar coating bases, water-soluble film coating bases, enteric-coated film coating bases, and sustained-release film coating bases. As the sugar coating base, sucrose is used, and one or more of the following may be used in combination: talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. Examples of water-soluble film coating bases include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; 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-coated film coating bases include cellulosic polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, and cellulose acetate phthalate; acrylic acid 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 cellulosic polymers such as ethylcellulose; acrylic acid 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 appropriate proportions. Furthermore, a light-shielding agent such as titanium dioxide or iron(III) oxide may be used during the coating process.

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

[0202] Furthermore, the compounds of the present invention are expected to exhibit excellent central nervous system penetration.

[0203] The compounds of the present invention possess excellent orexin type 2 receptor agonist activity and can treat, prevent, and alleviate the risk of various neurological and psychiatric disorders associated with the orexin type 2 receptor. For example, the compounds of the present invention can be used to treat narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell disease, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, hypoplasma obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep Problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeats. Arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, sexual and reproductive dysfunction such as male hypogonadism and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, and systemic inflammation of the vascular system. The risk of secondary consequences of obesity, such as inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / urinary tract disorders, disorders of sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder Acute neurological and psychiatric disorders such as cerebral malformations after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, muscle spasms and related disorders, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced Parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics,It is useful as a preventative and therapeutic agent for various conditions such as restless limb syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury (TBI).

[0204] In particular, the compounds of the present invention are useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive sleepiness (for example, Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness such as coma, side effects and complications of anesthesia, or as an anesthetic antagonist.

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

[0206] Central hypersomnia (CDH) is characterized by excessive daytime sleepiness in the absence of other sleep disorders and in individuals with established, appropriate, and regular sleep habits. CDH includes narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Inne-Levin syndrome, as well as sleep deprivation syndromes and hypersomnias caused by medical conditions, drugs or substances, or mental states, are also considered central hypersomnias. Assessment of central hypersomnia (CDH) includes sleep studies (polysomnography, PSG) in a sleep laboratory and subsequent multiple sleep latency tests (MSLT). Symptoms associated with narcolepsy include abnormal intrusions of REM sleep characteristics into the waking state. Examples include sleep-related hallucinations, sleep paralysis, or vivid dreams and dream-reality confusion. Such symptoms can occur even in people without sleep disorders. Some people with narcolepsy experience cataplexy (narcolepsy type 1), which is a loss of muscle tone 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 a few seconds to a few minutes. Patients with idiopathic hypersomnia (IDH) often complain of excessive daytime sleepiness, prolonged sleep (more than 10-11 hours each night), and severe difficulty waking up in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH often have long, unrefreshing naps. Another common symptom of IDH is "brain fog," a feeling of cognitive impairment during the day. Kleine-Levin syndrome is a rare disorder of periodic hypersomnia.

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

[0208] Another aspect is the method or use of the above-described aspect, wherein administration of the compound of the present invention reduces daytime sleepiness, reduces instances of loss of muscle control, and / or reduces instances of sleep interruption in a subject. Another aspect is a method or use in which the compound of the present invention is administered in an amount effective in reducing excessive daytime sleepiness in adults with narcolepsy. Another aspect is a method or use in which the compound of the present invention is administered in an amount effective in increasing mean sleep latency. Another aspect is a method or use in which the compound of the present invention is administered in an amount effective in reducing cataplexy events. Another aspect is a method or use in which the compound of the present invention is administered in an amount effective in reducing nocturnal sleep disturbance in a subject.

[0209] The dosage of the compound of the present invention varies depending on the recipient, route of administration, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the usual single dose is 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 "combination drugs"). By combining the compound of the present invention with a co-administered drug, (1) The dosage of the compound of the present invention or the concomitant drug can be reduced compared to when it is administered alone. (2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected. (3) By selecting a co-administered drug with a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a co-administered drug with 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 co-administered drug, excellent effects such as a synergistic effect can be obtained.

[0211] Hereinafter, the use of the compound of the present invention in combination with a co-administered drug will be referred to as the "combination agent of the present invention." When using the combination agent of the present invention, the timing of administration of the compound of the present invention and the combination drug is not limited. The compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the target patient simultaneously or with a time difference. The dosage of the combination drug should be in accordance with clinically used dosages and can be appropriately selected depending on the target patient, route of administration, disease, combination, etc. The administration method of the combination agent of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration methods include: (1) administration of a single formulation obtained by simultaneously formulating the compound of the present invention and the combination drug; (2) simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via the same administration route; (3) administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via the same administration route with a time difference; (4) simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via different administration routes; and (5) administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via different administration routes with a time difference (for example, administration in the order of the compound of the present invention; combination drug, or in the reverse order). The dosage of concomitant drugs can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination agent 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 relative to the total formulation. The content of the concomitant drug in the concomitant formulation 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 relative to the total formulation. The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight of the total formulation, preferably about 10 to 90% by weight. Furthermore, the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.

[0212] Examples of concomitant medications include the following: Narcolepsy medications (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), anti-obesity drugs (amphetamine, benzfetamine, bromocloptin, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, fendimetrazine, fenmethrazine, fenmethrazine, phentermine, Qnexa®, phenylpropanolamine, pramulintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, dimerizine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil) , idebenone, tacrine), antidementia agents (e.g., memantine), inhibitors of β-amyloid protein production, secretion, accumulation, aggregation and / or deposition, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetraline, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamine) (N,N-dimethylamino)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'-methyl Xybiphenyl-4-yl)methoxytetraline, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline [(N)ethyl]tetralin, its optically active derivative, its salt and its hydrate, OM99-2 (International Publication 01 / 00663)), γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (Japanese Patent Publication No. Hei 11-514333), PPI-558 (Japanese Patent Publication No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1)),283-289)), β-amyloid vaccines, β-amyloid-degrading enzymes, etc., brain function activators (e.g., aniracetam, nicergoline), Parkinson's disease treatments [(e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, cergiline, remasemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], amyotrophic lateral sclerosis treatments (e.g., riluzole, neurotrophic factors), treatments for abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CE P-1347), neuronal differentiation and regeneration promoters (e.g., leteprinium, 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]isoindorine, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindorine, 6-[3-(4-isopropylphenyl)-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 compounds, salts, and hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroids (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anticytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), urinary incontinence and frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., (que) (Sildenafil), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatments (e.g., alfacalcidol, calcitriol, elcatonin, salmoncalcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate), parathyroid hormone (PTH), calcium receptor antagonists, insomnia treatments (e.g., benzodiazepine drugs, (non-benzodiazepine drugs, melatonin agonists, orexin receptor antagonists), schizophrenia Symptomatic medications (e.g., typical antipsychotics such as haloperidol; clozapine, olanzapine, lithril) Atypical antipsychotics such as peridone and aripiprazole; drugs that act on metabotropic glutamate receptors or ion channel-coupled glutamate receptors; phosphodiesterase inhibitors), benzodiazepine drugs (chlordiazepoxide, diazepam, potassium clorazepate) (e.g., lorazepam, clonazepam, alprazolam), L-type calcium channel inhibitors (e.g., pregabalin), tricyclic or tetracyclic antidepressants (e.g., imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride), selective serotonin reuptake inhibitors (e.g., fluvoxamine maleate, floxetine hydrochloride, citalopram bromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride), norepinephrine reuptake inhibitors (e.g., leboxetine mesylate), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptyline maleate, 5-HT 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, 5-HT3 antagonists (such as siamemazine), non-cardiac selective β-blockers (such as propranolol hydrochloride and oxyprenolol hydrochloride), histamine H1 antagonists (such as hydroxyzine hydrochloride), CRF antagonists, other anxiolytics (such as meprobamate), tachykinin antagonists (such as MK-869 and saledutant), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3 adrenergic antagonists (such as amibegron hydrochloride), GAT-1 inhibitors (such as thiagabine hydrochloride), N-type calcium channel inhibitors, 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.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzole, phenelzine (e.g., rubamate), cannabinoid CB1 antagonists (e.g., rimonabant), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (e.g., methylphenidate hydrochloride, methamphetamine hydrochloride), drugs for treating alcohol dependence, 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 stroke, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating mood disorders, drugs for treating autonomic nervous system dysfunction, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling, lower limb rest Drugs for treating impotence syndromes, substance addiction, alcohol-related disorders, irritable bowel syndrome, dyslipidemia (such as cholesterol-lowering drugs like statins (pravastatin sodium, atrovastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), abnormal behavior drugs or drugs to suppress wandering tendencies due to dementia (sedatives, anxiolytics, etc.), diabetes drugs, drugs to treat diabetic complications, hypertension drugs, hypotension drugs, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anticancer drugs, etc.

[0213] The above-mentioned concomitant drugs may be used in combination of two or more in appropriate proportions. Furthermore, when applying the compounds of the present invention to the above-mentioned diseases, it is possible to use them in combination with biological agents (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), as well as in combination with gene therapy and non-pharmacological treatments in the field of psychiatry. Antibody drugs and vaccine preparations include, for example, vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, TNFα antibodies, antibodies against other cytokines, amyloid-beta 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 against enzymes and proteins involved in the coagulation and fibrinolysis systems in the blood, and those related to glucose metabolism and insulin resistance. Examples include antibodies or vaccine preparations against the protein in question. In addition, combination therapy with biologics related to growth factors such as GH and IGF is also possible. Examples of gene therapies include those using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylation enzymes; those using DNA decoys such as NFκB decoys; those using antisense; those 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); those using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion (e.g., growth factors such as HGF and VEGF); those using genes related to proteins involved in glucose metabolism and insulin resistance; and antisense against cytokines such as TNF. Non-pharmacological treatments in the field of psychiatry include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy including cognitive behavioral therapy. Furthermore, the compounds of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, kidney regeneration, pancreatic regeneration, and blood vessel regeneration, as well as 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, myocardial cell sheets). [Examples]

[0214] The present invention will be further described in detail by the following examples, test examples, and formulation examples, but these will not limit the present invention, and various changes or modifications may be made without departing from the scope of the present invention. In the following examples, "room temperature" typically refers to approximately 10°C to 35°C. Unless otherwise specified, the ratios of mixed solvents are given as volume ratios. Unless otherwise specified, percentages are given as weight percentages.

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

[0216] 1For 1H NMR analysis, software such as ACD / SpecManager (product name) was used. Proton peaks that are very gradual, such as those of hydroxyl or amino groups, may not be described. MS was measured by LC / MS. ESI or APCI methods were used for ionization. The data shown are experimental values ​​(found). Typically, molecular ion peaks are observed, but fragment ions may also be observed. In the case of salts, typically, the molecular ion peak of the free form or a fragment ion peak is observed.

[0217] The unit of the sample concentration (c) for optical rotation ([α]D) is g / 100mL. Elemental analysis values ​​(Anal.) are listed as both calculated values ​​(Calcd) and measured values ​​(Found). The peaks obtained by powder X-ray diffraction in the examples refer to the peaks measured at room temperature using 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° The degree of crystallinity in the examples was calculated by the Hermans method using powder X-ray diffraction. 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 1H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatography-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 æ:ethyl acetate CH2Cl2: Dichloromethane PE: Petroleum ether MsCl: Methanesulfonyl Chloride CDI: 1,1'-Carbonyldiimidazole BOC2O: Di-tert-butyl dicarbonate PyBOP: Benzotriazole-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(diphenylphosphin)ferrocene]palladium(II) dichloride dichloromethane adduct tBuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G3: Methanesulfonate (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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]meth Sulfonamide

[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 CH2Cl2 (50 mL), TEA (4.27 g) was added. The mixture was heated at 20°C. The mixture was stirred for 30 minutes. Then, MsCl (1.44 g) was slowly added to the mixture at 0°C. The mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. The reaction was quenched with water (50 mL) and stirred for 10 minutes. Next, it was extracted with CH2Cl2 and washed with saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain 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 tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl)amino] Pyrrolidine-1-carboxylate (5.05 g) and bis(pinacolate)diborone (4.44 g) XPhos Pd G3 (493 mg) and potassium acetate (2.29 g) were added to a mixture in 50 mL of Luen. The mixture was stirred under a nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was poured into water and extracted with ELISA. The organic layer was washed with saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (8.75 g). MS: [M-Boc+H] + 381.0

[0221] C) tert-butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl) Mino]pyrrolidine-1-carboxylate 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) Mixture of THF (50 mL) and water (50 mL) contains sodium peroxoborate tetrahydrate (4.48 g) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water and extracted with HCl. The organic layer was washed with saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain the title compound (3.50 g). MS: [M-Boc+H] + 271.1

[0222] D) tert-butyl (2S,3S)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate A solution of tert-butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (2.00 g) in DMA (15 mL) is prepared by adding 6-chloro-5-methyl Tylpicolinonitrile (906 mg) and cesium carbonate (2.64 g) were added. The mixture was then subjected to a nitrogen atmosphere. The mixture was stirred at 80°C under ambient air for 12 hours. The reaction mixture was diluted with water and extracted with toluene. The organic layer was then fermented. The mixture was washed with brine, filtered, and concentrated. The residue was purified by silica gel column chromatography (ÃO / PE) to obtain 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-methylpyridine-2-yl]oxy} Phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (2S,3S)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]phenyl} To a solution of methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (759 mg) in MeOH (10 mL), nickel(II) chloride hexahydrate (371 mg) was added. Then, sodium borohydride (177 mg) was added to the mixture at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was slowly quenched at 0°C with saturated aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH containing 0.3% ammonium hydroxide) to obtain the title compound (371 mg). MS: [M+H] + 491.2

[0224] F) N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl) Methylpyrrolidine-3-ylmethanesulfonamide dihydrochloride 371 mg of tert-butyl (2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate] was stirred in 5 mL of 4 M hydrogen chloride-dioxane at 25°C for 2 hours. The mixture was concentrated under vacuum to obtain 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-(a Xeno)-10,14 (Meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl)methyl]pyrrolidine-3-yl}methanesulfonamide dihydrochloride (410 mg) in DMF (410 mL) CDI (158 mg) and DIPEA (686 mg) were added to the solution. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 12 hours to obtain mixture A. In the same manner as in the synthesis of mixture A, N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl)methyl]pyrrolidine-3-yl}methanesulfonamide dihydrochloride (446 mg) in DMF (450 mL) was used to add CDI (172 mg) Mixture B was obtained by adding DIPEA (746 mg). Mixtures A and B were combined and concentrated under vacuum. The residue was then separated by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% ammonium hydroxide). The compound was purified with aqueous 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-(meteno)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-[(methanes] [ruhonyl)amino]pyrroridine-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 CH2Cl2 (15 mL), TEA (875 mg) was added. 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 under a nitrogen atmosphere at 20°C for 2 hours. The reaction was quenched with water and stirred for 10 minutes. Next, it was extracted with CH2Cl2 and washed with saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Me The compound was purified using OH / CH2Cl2 to obtain 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 tert-butyl(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfate] To a solution of honyl)amino]pyrrolidine-1-carboxylate (970 mg) in toluene (20 mL), bis(pinacorato)diborone (869 mg), XPhos Pd G3 (97 mg), and potassium acetate (448 mg) were added. 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 ethyl acetate. The organic layer was washed with saline solution, dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated to obtain 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-[(meth [Sulfonyl amino]pyrrolidine-1-carboxylate 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-carb To a solution of xylate (1.87 g) in THF (10 mL) and water (10 mL), sodium perborate tetrahydrate (1.39 g) was added at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction was quenched with water and extracted with dimethyl phosphate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and reduced. The solution was concentrated under pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to obtain the title compound (774 mg). MS: [M+Na] + 429.1

[0230] D) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]phenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate 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) containing 6-chloro-5-methylpyridine-2-carbonitrile (318 mg) and cesium carbonate (926 mg). The mixture was stirred under a nitrogen atmosphere at 80°C for 12 hours. The reaction mixture was diluted with water and extracted with toluene. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure. The residue was concentrated using silica gel column chromatography ( Depositphotos / PE). A compound (713 mg) was obtained. 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-methylpyridine-2-yl]oxy} [phenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carb Xylart tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]phenyl} Methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Sodium borohydride (171 mg) was added to a solution of (790 mg) in MeOH (10 mL). 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 at 0°C with aqueous ammonium chloride solution, then extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The title compound (676 mg) was obtained. MS: [M+H] + 527.3

[0232] F) N-{(2S,3R)-2-[(3{[6-(aminomethyl)-3-methylpyridine-2-yl]oxyphenyl) Methyl-4,4-difluoropyrrolidine-3-ylmethanesulfonamide dihydrochloride tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carbbox Stir the mixture of silat (200 mg) and 4 M hydrogen chloride-dioxane (5 mL) at 20°C for 1 hour. The mixture was concentrated to obtain 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-hexahydr Ro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide To a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}phenyl)methyl]-4,4-difluoropyrrolidine-3-yl}methanesulfonamide dihydrochloride (200 mg) in DMF (200 mL), CDI (71 mg) and DIPEA (310 mg) were added. The reaction mixture was then subjected to nitrogen. The mixture was stirred at 25°C for 2 hours under controlled conditions. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with water. The organic layer was then extracted with toluene. The organic layer was washed with saline solution, dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% ammonium hydroxide) / acetonitrile) to obtain 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-hexahy Dro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0235] A) 3-Chloro-2-fluorophenylalanine hydrochloride A mixture of 1-(bromomethyl)-3-chloro-2-fluorobenzene (55.0 g), diethyl acetamidomalonate (56.1 g), and EtOH (400 mL) is mixed with 20% sodium ethoxide ethanol. The solution (88 g) was added at 0°C. The mixture was refluxed for 2 hours and 30 minutes and cooled to room temperature. The material was filtered off, the filtrate was concentrated under reduced pressure, and the 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 treated with isopropanol / diisopropyl alcohol. The compound was washed with a solvent to obtain the title compound (67.1 g). MS: [M+H] + 217.8.

[0236] B) N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine 3-Chloro-2-fluorophenylalanine hydrochloride (67.1 g), 1 M sodium hydroxide aqueous solution Boc2O (63.4 g) was added to a mixture of (528 mL) and DME (480 mL) at room temperature. The mixture was stirred at warm temperature for 2 hours and 30 minutes, then 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 toluene. 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 obtain the title compound (63.8 g). MS: [MH] - 316.0.

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

[0238] D) tert-butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-o Xopropan-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), 60% sodium hydride (10.1 g) was added at 0°C. The mixture was stirred at 0°C for 5 minutes, then at room temperature for 10 minutes. To the reaction mixture, 1-(chloromethyl)-4-methoxybenzene (60.7 g) and tetrabutylammonium iodide (7.16 g) were added at 0°C. The mixture was stirred at room temperature for 2 hours and 30 minutes, then placed in ice water. Pour and extract with toluene. Separate the organic layer and wash with water and saturated saline solution, then remove with anhydrous magnesium sulfate. The mixture was dried with nesium and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain 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 Et2O (500 mL), lithium aluminum hydride (9.30 g) was added gradually at -78°C. The mixture was stirred at -15°C for 1 hour and 30 minutes, and ELISA and 10% aqueous potassium bisulfite solution were sequentially 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 materials were dissolved in ceramic. The material was filtered through a thread, and the filtrate was extracted with dimethyl sulfate. The organic layer was separated and treated with water and saturated saline solution. The sample was washed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain 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), add TMSCl (3.85 g) under an argon atmosphere. It was added at warm temperature. The mixture was stirred at room temperature for 15 minutes, maintaining the internal temperature at approximately 50°C, while ethyl blottery was added. Add 71.9 g of rom(difluoro)acetate dropwise to the mixture at room temperature while stirring vigorously. The mixture was stirred at room temperature for 15 minutes, maintaining an internal temperature of approximately 40°C, and then tert-bronze was added to the mixture. A mixture of til [1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbamate (74.7 g) and THF (100 mL) was added dropwise. The mixture was stirred at warm temperature for 2 hours, then cooled on ice, added to a 5% potassium bisulfite aqueous solution, and extracted with toluene. 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 (toluene / hexane) and then labeled as follows: The target compound (61.6 g) was obtained. MS, found: 490.0.

[0241] G) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methyl] Toxyphenyl)methyl]pyrrolidine-2-one Ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chloro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate (61.6 g) To a mixture of EtOH (160 mL) and DIPEA (4 M CPME solution) (282 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours to concentrate the reaction solution. 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 SiO2. 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 (SiO2 / hexane), and the resulting solid was washed with diisopropyl ether / hexane to obtain the title compound (36.1 g). MS: [M+H] +399.9.

[0242] H) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidine-2-one 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]pyrrolidine-2-one (36.1 g), CH3CN (315 mL), and water (105 mL) To the mixture, cerium(IV) ammonium nitrate (99 g) was added at room temperature. The mixture was stirred at room temperature for 4 hours, then poured into ice water and extracted with pharmaceutically acceptable ammonium compounds. The organic layer was separated and washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane) followed by NH silica gel column chromatography (MeOH / ÃO) to obtain 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-hydroxypyrrolidine-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 ELISA / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of sodium bicarbonate (6.83 g) and THF (190 mL) / water (210 mL) was added, along with a solution of Boc2O (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 SiO2. The organic layer was separated, and washed with water and The mixture was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane) to obtain 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-difluor Ro-3-[(trifluoromethanesulfonyl)oxy]pyrroridine-1-carboxylate tert-butyl 2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydrox To a mixture of cypyrrolidine-1-carboxylate (22.1 g), pyridine (96 g), and Et2O (355 mL), trifluoromethanesulfonic anhydride (51.2 g) was added dropwise under an argon atmosphere at 0°C. The mixture was stirred at room temperature for 2 hours and 30 minutes, poured into ice water, and extracted with phenylacetate / hexane. Organic Separate the layers and wash with 10% citric acid solution, sodium bicarbonate solution, water, and saturated saline solution. The residue was purified, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was scanned using silica gel column chromatography. The title compound (22.4 g) was obtained by purification using matrix (SiO₂ / hexane). 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 CH3CN (265 mL), add tetra-n-butylammonium azide (38.3 g) at room temperature. The mixture was added. The mixture was slowly heated to 80°C, stirred for 1 hour, poured into ice water, and extracted with toluene. 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 (toluene / hexane). The compound was prepared to obtain 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 rac-tert-butyl (2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4- Difluoropyrrolidine-1-carboxylate (16.2 g) and a mixture of THF (200 mL) / water (5 mL) were combined with PPh3 (13.1 g) under an argon atmosphere at room temperature. The mixture was stirred at 55°C for 18 hours. Under ice cooling, the mixture was added to an aqueous sodium bicarbonate solution and extracted with .'' / THF. The organic layer was separated. The mixture was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ÃO / hexane) to obtain the title compound. The by-products were obtained separately. The obtained by-products were mixed with THF (100 mL) / water (10 mL). 3.22 g of a 40% aqueous methaneamine solution was added to the mixture at room temperature. The mixture was stirred at 70°C for 15 hours, poured into water, and extracted with toluene. The organic layer was separated, washed with water and saturated brine, and then anhydrous sulfate was used. The residue was dried with magnesium and concentrated under reduced pressure. The residue was then subjected to NH silica gel column chromatography. The compound was purified with (HCl / hexane) and combined with the title compound obtained above to obtain the title compound (14.6 g). 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 subjected to HPLC (column: chiral PAK IA, 50°F). mmID × 500 mML, 20 μm, Mobile phase: Hexane / ethanol / diethylamine = 800 / 200 / 1) The compound was split to obtain the title compound with the shorter retention time (6.84 g) (column: chiral PAK IA, 4.6 mm ID × 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 tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-diph Luoropyrrolidine-1-carboxylate (20 g) and TEA (22.9 ml) mixed in SiO2 (274 ml) MsCl (4.67 ml) was added to the mixture 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 solution and saline solution, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was solidified and the title compound (22.5 g) was obtained as a triturate with Et2O. 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 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 mixed with 8 M potassium hydroxide aqueous solution (12.7 mL x 2 batches). The mixture was stirred in a pressure reactor at 120°C for 2 hours. The mixture was quenched with 1 M hydrochloric acid and extracted with toluene. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / hexane) and crystallized with IPE-hexane to obtain the title compound (17.0 g). MS: [MH] - 422.9

[0250] P) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-cal Boxilart 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- A mixture of methyl picolinonitrile (2.33 g), Cs2CO3 (9.06 g), and DMF (60 mL) was stirred at 120°C for 5 hours. The mixture was quenched with water and extracted with toluene. 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 (toluene / hexane) to obtain the title compound (5.62 g). MS: [MH] - 539.0

[0251] Q) tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methyl Tylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluor (Lopenylmethyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-cal To a solution of boxilate (5.62 g) and cobalt(II) chloride (2.70 g) in MeOH (120 mL), sodium borohydride (1.967 g) was added at 0°C. The mixture was stirred at room temperature for 1 hour. Next... Then, Boc2O (3.62 mL) was added to the reaction mixture at room temperature and stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent, and SiO2 and aqueous sodium bicarbonate were added to the residue. The insoluble solid was then removed by ceramic. Removed with a thread, and the mixture was extracted with toluene. The organic layer was dried with anhydrous magnesium sulfate and reduced. The solution was concentrated under pressure. The residue was purified by silica gel column chromatography (African-hexane). This yielded the title compound (4.82 g). MS: [M+H] + 645.2

[0252] R) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluor [Methyl (Lopenyl)methyl]-4,4-difluoropyrrolidine-3-yl}methanesulfonamide dihydrochloride A solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (4.82 g) in butyl (50 mL) 4 M hydrogen chloride-acetate (50 mL) was added at room temperature. The mixture was stirred overnight at room temperature. The precipitate was filtered and washed with phenylethylamine 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide Di(N-succinimidyl) carbonate (6.67 g) and DIPEA (33.8 g) THF (dry) (42 Add N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}methanesulfone to the suspension in 00 ml. A solution of naamide dihydrochloride (16.9 g) in DMF (dry) (200 ml) was added dropwise over 60 minutes at 0°C. The mixture was stirred at room temperature for 16 hours and concentrated to a small volume. SiO2 and water were added to the residue and partitioned. The aqueous layer was extracted with toluene. The combined organic layers were washed with water and saline solution, and anhydrous sodium sulfate was extracted. The residue was dried with ammonium and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (HCl / hexane). The resulting residue was then dissolved in HCl (600 ml) and activated Ecosorb C-941 (1 g) was added at 55°C, and the mixture was stirred at 55°C for 1 hour. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was crystallized from EtOH-heptane to obtain the title compound (6.16 g). 1 H 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-hexahy Dro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[0255] A) tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfone] [nyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-diph To a solution of luoropyrrolidine-1-carboxylate (80.0 g x 2 batches) in CH2Cl2 (560 mL x 2 batches), TEA (67.0 g x 2 batches) and ethanesulfonyl chloride (42.0 g x 2 batches) were added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 13 hours. The reaction mixture was poured into water and extracted with CH2Cl2. 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 (siRNA / PE). The compound was prepared to obtain 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-fluorinated [Ro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate Dioxanes (243 mL x 5 batches) 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) 2 M potassium hydroxide aqueous solution (89.0 mL x 5 batches) was added to the mixture in 5 batches. The mixture was degassed three times and purged with nitrogen. The mixture was stirred under reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was poured into water and extracted with alkylammonium sulfate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (¼ / PE) to obtain the title compound (85.0 g). 1 H 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-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-cal Boxilart 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 ethyl acetate. 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 (ethyl acetate / PE) to obtain the title compound (80.0 g). MS: [M+Na] + 577.1

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

[0259] E) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluor [Methyl phenyl(L)methyl]-4,4-difluoropyrrolidine-3-yl}ethanesulfonamide dihydrochloride A mixture of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyrrolidine-2-yl]oxy}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (70.0 g) in 4 M hydrogen chloride-SiO2 (783 mL) under a nitrogen atmosphere. The mixture was stirred at -25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue (67.0 g). Then, the remaining 52.0 g was purified by reverse-phase HPLC (column: Agela C18, mobile phase: 0.4% hydrochloric acid / MeOH). The title compound (26 g) was obtained. 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide 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) contains N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-diph A solution of ruolopyrrolidine-3-ylethanesulfonamide 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 all at once. Finally, the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The solution was reduced to remove THF. The crude product was purified by preparative HPLC (column: Phenomenex Titank C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution / acetonitrile) to obtain the title compound (4.60 g). I obtained it. 1H 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 (1 H, 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-(meteno)pyrrolo[2,1-h][1,9]oxazacycloheptadecin-1-yl]methanesulfonamide

[0262] A) tert-butyl (2S,3S)-2-{[3-({6-[(3-tert-butoxy-3-oxopropa-1-en-1-yl]-3-methylpyridine-2-yl}oxy)phenyl]methyl}-3-[(methanesulfonyl)amino]py Loridine-1-carboxylate tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridine-2-yl)oxy]phenyl} A mixture of methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (495 mg), Pd(OAc)2 (10 mg), and ditert-butyl-(2-phenylphenyl)phosphane (26 mg) in DMF (5 mL) was mixed with tert-butylpropa-2-enoate (640 mg) and TEA (177 mg) 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 ethyl acetate. 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 / ethyl acetate) to obtain 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-methylpyridine-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-ca Luboxylart tert-butyl (2S,3S)-2-{[3-({6-[3-tert-butoxy-3-oxopropa-1-en-1-yl]-3-methylpyridine-2-yl}oxy)phenyl]methyl}-3-[(methanesulfonyl)amino]pyro To a mixture of lysine-1-carboxylate (457 mg) in MeOH (5 mL), 10% palladium carbon (wetted with 55% water, 60 mg) was added 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 obtain the title compound (411 mg). MS: [M+H] + 590.2

[0264] C) 3-{6-[3-({(2S,3S)-3-[(methanesulfonyl)amino]pyrrolidine-2-yl}methyl)phenoxy]-5-methylpyridine-2-yl}propanoic acid tert-butyl (2S,3S)-2-[(3-{[6-(3-tert-butoxy-3-oxopropyl)-3-methylpyrrhizate [Din-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-ca A mixture of ruboxilate (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 obtain 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-(aze (no)-14,18-(meteno)pyrrolo[2,1-h][1,9]oxazacycloheptadecin-1-yl]methanesulfonamide 3-{6-[3-({(2S,3S)-3-[(methanesulfonyl)amino]pyrrolidine-2-yl}methyl)pheno To a solution of 75 mg of xyxy-5-methylpyridine-2-ylpropanoic acid in 750 mL of THF, PyBOP (125 mg) and TEA (81 mg) were added 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 separated by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% ammonia). The compound was purified with an aqueous solution of ammonium hydroxide (Acetonitrile) and then freeze-dried. The resulting residue was further purified using SFC (column: DAICEL CHIRALPAK IG, mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide) to obtain the title compound (14.4 mg). 1H 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-(meteno)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 Benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(methyl Tansulfonyl)amino]pyrrolidine-1-carboxylate (1 g) in toluene (15 mL) To the mixture, bis(pinacolato)diborone (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 for 2 hours under a nitrogen atmosphere. The compound was purified by silica gel column chromatography (SiO / hexane) to obtain 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 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 mixed with sodium peroxoborate tetrahydrate (538 mg) at 0°C. The mixture was stirred at 0°C or room temperature for 1.5 hours. The mixture was quenched with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium thiosulfate solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The residue was washed with siRNA-IPE to obtain the title compound (460 mg). MS: [M+H] + 441.0

[0269] C) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboc Syrah 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 overnight at 100°C under a nitrogen atmosphere. The mixture was quenched at room temperature with aqueous ammonium chloride. The organic layer was then extracted with toluene. The organic layer was separated, washed with water and saline solution, and then anhydrous sodium sulfate was used. The mixture was dried and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (siRNA / hexane) to obtain the title compound (431 mg). MS: [M+H] + 557.1

[0270] D) Benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridine-2-yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamide)pyrrolidine-1-carboxylate te Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluor Lophenylmethyl)-4-fluoro-3-[(methanesulfonyl)amino]pyrrolinidine-1-carbocyanide Sodium borohydride (88 mg) was added at 0°C to a solution of sylate (430.5 mg) and nickel chloride hexahydrate (184 mg) in MeOH (15 mL). The mixture was stirred at the same temperature for 30 minutes. After concentrating the resulting mixture, the residue was analyzed by NH silica gel column chromatography (MeOH / siRNA). The compound was purified to obtain the title compound (312 mg). MS: [M+H] + 561.2

[0271] E) N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidine-3-yl}methanesulfonamide dibromide Benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridine-2-yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamide)pyrrolidine-1-carboxylate (311.5 mg) was mixed with 30% hydrobromide-acetic acid (10 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, and then the solvent was removed twice with toluene. The residue was washed with ELISA and IPE to obtain 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-hexa Hydro-1H,15H-4,8-(azeno)-14,10-(meteno)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-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidine-3-yl}methanesulfonamide hydrobromide (327.0 mg) in DMF (dry) (12.50 mL) was added dropwise over 30 minutes at room temperature. The mixture was stirred under an argon atmosphere at room temperature for 2 hours. 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 overnight at room temperature. After removing THF under reduced pressure, the mixture was quenched with aqueous sodium bicarbonate and extracted with ELISA. The organic layer was separated and divided with saline solution. The mixture was washed, 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 ammonium bicarbonate aqueous solution / acetonitrile) to obtain 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-(meteno)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-fu [Orophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-diph 54.2 g of luoropyrrolidine-1-carboxylate and 26.2 g of sodium bicarbonate were stirred in 550 mL of THF and 275 mL of water. Benzyl chloroformate (23.3 mL) was added at 0°C. The mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with phenylethylamine. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was passed through an NH silica gel pad, eluted with toluene, and concentrated under reduced pressure to obtain the title compound (81.5 g). This product was subjected to 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 Lupyrrolidine-1-carboxylate tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (3.76 g), bis(pinacolato)diborone (2.87 g), and potassium acetate (1.48 g) in toluene (37.7 mL) XPhos Pd G3 (0.319 g) was added to the degassed mixture. The mixture was incubated at 100°C under an argon atmosphere for 5 hours. The mixture was stirred. After cooling, the reaction mixture was purified by silica gel column chromatography (HCl / hexane) to obtain 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), sodium perborate tetrahydrate (1.65 g) was added 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 HCl. The organic layer was then diluted with water and The mixture was washed with saline solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain 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 tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (2.47 g) A mixture of 10% palladium-carbon (wetted with 55% water, 0.243 g) and 10% palladium-carbon in EtOH (25.7 mL) was hydrogenated at room temperature under balloon pressure for 14 hours. The catalyst was filtered off and washed with EtOH and THF. The filtrate was then cooled under reduced pressure. The compound was concentrated to obtain 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-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate tert-butyl (2S,3R)-3-amino-4,4-difluoro-2-[(2-fluoro-3-hydroxypheny Methyl pyrrolidine-1-carboxylate (1.77 g), 6-chloro-5-methyl picolinonitrate A mixture of lyl (0.819 g) and cesium carbonate (3.33 g) in DMF (dry) (17.0 mL) is added to the alcohol. The mixture was stirred at 120°C for 1 hour under a gas atmosphere. After cooling to 0°C, potassium carbonate (0.706 g) and bacon were added. 1.08 ml of chloroformate was added to the mixture. The reaction mixture was heated to room temperature and stirred for 2 hours. The mixture was diluted with toluene and water, and the solution was extracted with toluene. The extract was washed with saline solution. 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 (toluene / hexane) to obtain 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-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (1.63 g) is mixed with tert-butyl (2S,3R)-3-{[(benzyloxy) Rubonyl]amino}-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate (5.13 g) and Cobalt Chloride To a solution of ruth(II) (2.23 g) in MeOH (50 mL), it was slowly added 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, and it The mixture was stirred at room temperature for 1 hour. An aqueous solution of sodium bicarbonate was added to the reaction mixture at room temperature, and the solid was filtered. Removed. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saline solution, and anhydrous sodium sulfate was used. The mixture was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (.'') to obtain the title compound (3.46 g). MS: [MH] - 699.1

[0280] G) Benzyl {(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-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-methylpyridine-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 / ELISA) to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadia [Zacycloheptadecin-16-yl]carbamate A solution of benzyl{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}carbamate (2.51 g) in dry DMF (81 mL) was added over 40 minutes at room temperature to a solution of di(N-succinimidyl) carbonate (1.41 g) and N-methylmorpholine (1.10 mL) in dry THF (2430 mL). After stirring at room temperature for 1 hour, DIPEA (8.57 mL) was added to the reaction mixture. This mixture was left to stand at room temperature for 1.5 hours. The mixture was then stirred 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 siRNA. The organic layer was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-1-one 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]carbamate (8.22 g) and 20% palladium hydroxide-active A mixture of char (400 mg) in MeOH (80 mL) was hydrogenated at room temperature under balloon pressure for 12 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxa Diazacycloheptadecin-16-yl]methanesulfonamide A solution of fluoromethanesulfonyl chloride (0.790 g) in THF (dry) (10 mL) was added at 5°C 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadesin-1-one (2.00 g) in pyridine (10 mL). The mixture was then prepared under a nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 hours. The mixture was then subjected to NH silica gel column chromatography ( Depositphotos / H The compound was purified by xane and MeOH / HCl and silica gel column chromatography (HCl / hexane), and then recrystallized from HCl-heptane to obtain 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-hexahy Dro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[0285] A) tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropane [Sulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-diph A stirred solution of luoropyrrolidine-1-carboxylate (6.2 g) in pyridine (50 mL) contains ice. Cyclopropanesulfonyl chloride (3.64 mL) was added dropwise while cooling in a bath. The mixture was stirred at 50°C for 3 hours. The mixture was quenched with water at room temperature and extracted with toluene. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / hexane) to obtain 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 then converted to ammonium chloride. The solution was acidified with an aqueous solution of ammonium and extracted with ethyl acetate. The organic layer was separated and washed with water and saline solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane) to obtain the title compound (3600 mg). MS: [MH] - 449.0

[0287] C) tert-butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridine-2-yl)oxy]phenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate 5-chloro-6-fluoropicoli 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 (3000 mg) and cesium carbonate (4520 mg) in DMF (dry) (50 mL). Nonitrile (1194 mg) was added at room temperature. The mixture was stirred at 90°C for 1 hour. The mixture was then treated with toluene. The solution was diluted. The organic layer was separated, washed with saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane) and labeled as follows: The target compound (3860 mg) was obtained. MS: [M+CH3CN] + 609.0

[0288] D) tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3- Loropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfone) [nyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (382 mg) is combined with tert-butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridine-2-yl)oxy]phenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (2960 mg) and cobalt(II) chloride (1309 The solution of (mg) in MeOH (60 mL) was added 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 and stirred at room temperature for 1 hour. The solvent was removed by concentration, and siRNA and aqueous sodium bicarbonate were added to the residue. The insoluble solid was removed with Celite, and the mixture was extracted with ethyl acetate. The organic layer was then mixed with anhydrous sulfuric acid. The mixture was dried with magnesium and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (2700 mg). MS: [M+Na] + 713.1

[0289] E) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloropyridine-2-yl]oxy}-2-fluor [Methyl (Lopenyl)methyl]-4,4-difluoropyrrolidine-3-yl}cyclopropanesulfonamide dihydrochloride tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropane sulfonyl To a solution of [Amino]-4,4-difluoropyrrolidine-1-carboxylate (2730 mg) in MeOH (30 mL), 4 M hydrogen chloride-siRNA (19.75 mL) was added at 0°C. After stirring at 0°C for 30 minutes, the mixture was allowed to stand to return to room temperature and stirred overnight. After crude concentration under reduced pressure, siRNA was added and the precipitate was stirred. The sample was collected to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide A solution of di(N-succinimidyl) carbonate (963 mg) and DIPEA (3.94 mL) in THF (dry) (2000 mL) is added to DMF (dry) (30 mL) containing N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3- 2120 mg of loropyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}cyclopropanesulfonamide dihydrochloride was administered dropwise over 5 minutes at room temperature. The mixture was concentrated under reduced pressure, then quenched with an aqueous sodium bicarbonate solution and extracted with dimethyl sulfate. The organic layer was separated, washed twice with saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ÃO / hexane and MeOH / ÃO), and then recrystallized from ÃO-heptane to obtain the title compound (960 mg). 1H 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-(meteno)pyrrolo[1,2-d][1,12,4]dioxazacycloheptadecin-16-yl]methane Sulfonamide

[0292] A) tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridine-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridine-2-yl)oxy]phenyl} A solution of methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1.00 g) in THF (10 mL) was mixed with 60% sodium hydride (97 mg) at 0°C. The mixture was left to stand at 0°C for 0.1 hours. The mixture was stirred, and 2-(chloromethoxy)ethyl](trimethyl)silane (403 mg) was added dropwise. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with water and extracted with toluene. 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 (toluene / PE) to obtain 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-methylpyridine-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl) Ethoxymethylaminopyrrolidine-1-carboxylate tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridine-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 ditert-butyl-[3,6-dimethoxy-2-(2,4,6- [Lyisopropylphenyl]phenyl]phosphan; methanesulfonic acid; palladium; 2-phenyl A mixture of ruaniline (34 mg) in DME (5 mL) was subjected to nitrogen atmosphere and microwave irradiation. The mixture was then heated at 100°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (.''.'' to obtain 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-(meteno)pyrrolo[1,2-d][1,12,4]dioxazacycloheptadecin-16-yl]methanesulfonamide Compound tert-butyl (2S,3S)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methyl A solution of lupyridine-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. The residue obtained in this way (130 mg), PyBOP (215 mg), and TEA (139 mg) in THF (300 mL) The mixture was degassed and purged with nitrogen three times, and then 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 (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-hex Sahydro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[0296] A) tert-butyl (2S,3R)-2-({3-[(6-amino-3-bromo-5-fluoropyridine-2-yl) oxy [C]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Cesium carbonate (1535 mg) was added at room temperature 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-difluoropyridine-2-amine (739 mg) in NMP (7854 μl). 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 ethyl acetate. The organic layer was separated, washed with saline solution, and then... The residue was dried over magnesium hydroxide and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography. The compound was purified with phosphate (siRNA / hexane) to obtain the title compound (792 mg). MS: [M+Na] + 635.0

[0297] B) tert-butyl (2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridine-2-yl) oxy [C]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate DME (5 ml) of tert-butyl (2S,3R)-2-({3-[(6-amino-3-bromo-5-fluoropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (791 mg) and trimethylboroxine (0.541 ml) Potassium carbonate (446 mg) was added to the solution 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 overnight at 90°C. The mixture was filtered. The filtrate was diluted with ethyl acetate and poured into water at room temperature. The organic layer was separated and washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (640 mg). MS: [M+H] + 549.1

[0298] C) tert-butyl (2S,3R)-2-({3-[(6-bromo-5-fluoro-3-methylpyridine-2-yl)oxy [C]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate 196 μl of tert-butyl nitrite was added at room temperature to a solution of tert-butyl(2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridine-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). The mixture was stirred at 60°C for 1.5 hours. ELISA and water were added to the mixture. The precipitate was removed with Celite. The organic layer of the filtrate was then removed. The residue was separated, washed with aqueous sodium thiosulfate solution and saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (RINKAN / hexane). The compound was purified to obtain the title compound (363 mg). MS: [MH] - 611.0

[0299] D) tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-5-butyl Luoro-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (2S,3R)-2-({3-[(6-bromo-5-fluoro-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (363 mg), potassium [[(tert-butoxycarbonyl)amino]methyl [L]trifluoroborate (281 mg), Pd(OAc)2 (13.31 mg), potassium carbonate (164 mg) A mixture of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (48.7 mg) in toluene (2470 μl) and water (494 μl) was stirred overnight at 85°C under an argon atmosphere. Water was added and the mixture was extracted with toluene. The organic layer was separated, washed with saline solution, and anhydrous sulfur The mixture was dried over magnesium oxide and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane) to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide TFA (1 ml) is used to make tert-butyl(2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino] Methyl}-5-fluoro-3-methylpyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (362 mg) It was added at room temperature. The mixture was stirred at room temperature for 30 minutes. After removing the solvent with toluene, The residue was purified by NH silica gel column chromatography (MeOH / Â). The solution of the obtained residue in DMF(dry) (5 mL) was added dropwise over 30 minutes at room temperature to a mixture of di(N-succinimidyl) carbonate (155 mg) and 4-methylmorpholine (0.363 mL) in THF(dry) (180 mL). The mixture was stirred at room temperature for 30 minutes. Then DIPEA (0.961 mL) was added. The mixture was stirred under Ar at 60°C for 30 minutes. The mixture was evaporated. The residue was treated with ÃO. The solution was diluted, poured into water at room temperature, and extracted with siRNA. The organic layer was separated and washed with water and saline solution. The residue was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / hexane). The residue was solidified with ÃO-hexane and the title compound was collected. I obtained (102 mg) of the substance. 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-(meteno)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-(meteno)pyrrolo[1,2-j][1,8,10]oxadi Azacycloheptadecin-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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadesine-16-yl]methanesulfonamide (460 mg) in DMF (5 mL), cesium carbonate (360 mg), sodium iodide (17 mg), and 4-methoxybenzyl chloride (208 mg) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was saline solution. The residue was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain 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-(meteno)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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (463 mg) in DMF (5 mL), add 60% sodium hydride (104 mg) at 0°C and stir the mixture at 0°C under a nitrogen atmosphere for 30 minutes. Mixed. Then iodomethane (367 mg) was added to the mixture and stirred at 60°C for 13 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saline solution and anhydrous sodium sulfate was used. The mixture was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / Â) to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide N-[(15aS,16S)-2,7-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-i In CH2Cl2 (3 mL), 272 mg of N-(4-methoxyphenyl)methyl methanesulfonamide To the mixture, methanesulfonic acid (285 mg) was added at 25°C, and the mixture 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), and most of the acetonitrile was removed. The lyl was removed under reduced pressure, and the remaining solvent was removed by lyophilization to obtain the title compound (136.2 mg). Ta. 1 H 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-hex Sahydro-1H,15H-4,8-(azeno)-14,10-(meteno)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-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)oxy]-2-fluor (Lopenylmethyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-cal A solution of boxilate (328 mg) in THF (4 mL) is prepared with 1 M methylmagnesium bromide-THF (6.07 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. Then, 1 M methyl magnesium was added. Nesium bromide-THF (6.07 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was then cooled to 0°C. The mixture was cooled to [temperature], and MeOH (10 mL) was added dropwise. Then, sodium borohydride (68.9 mg) was added, and the mixture was stirred overnight at room temperature. The mixture was quenched with aqueous ammonium chloride at 0°C. The organic layer was extracted with toluene. The organic layer was separated, washed with saline solution, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (.''.'' to obtain the title compound (238 mg). MS: [M+H] + 559.2

[0307] B) N-{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridine-2-yl]oxy}-2-flu Olophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}methanesulfonamide TFA (2 mL) was added to tert-butyl(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridine-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. After removing the solvent with toluene, the residue was collected in an NH silica gel column. The title compound (175 mg) was obtained by purification using chromatography (MeOH / methoxy). 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (optical isomer) A mixture of di(N-succinimidyl) carbonate (100 mg), DIPEA (0.400 mL), and THF (300 mL) is mixed with N-{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}methanesulfone A solution of mid (175 mg) in DMF (10 mL) was added dropwise at room temperature over 30 minutes. The mixture was then left at room temperature for 1 hour. The mixture was stirred at 60°C overnight. The mixture was evaporated. The residue was diluted with ¼ and left at room temperature. It was poured into water and extracted with toluene. The organic layer was separated, washed with saline solution, and then treated with anhydrous magnesium sulfate. The residue was dried in a microwave oven and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (A / H). The compound was purified by xane HPLC to obtain two fractions. The fraction with lower polarity was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution / acetonitrile) to obtain the title compound (14.3 mg) from the fraction with lower polarity. 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-hexahy Dro-1H,9H,16H-4,8-(azeno)-11,15-(meteno)pyroro[2,1-h][1,9,11]oxadiazasic [Luoctadecine-17-yl]methanesulfonamide

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

[0311] B) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-ca Luboxylart tert-butyl (2S,3R)-2-({3-[(6-chloro-3-methylpyridine-2-yl)methoxy]-2-butyl Olophenyl(methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-ca A mixture of ruboxilate (184.4 mg), zinc cyanide (122.2 mg), and DMF (3 mL) was mixed with Pd(Ph3P)4 (38 mg) at room temperature, and the mixture was stirred at 120°C for 2 hours. The mixture was then quenched with water. The mixture was then extracted with toluene. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) and the title was determined. The compound (184 mg) was obtained. MS: [M+H-(tBu)] + 449.1

[0312] C) tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methyl Tylpyridine-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-2-yl)methoxy]-2-butyl Olophenyl(methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-ca A mixture of ruboxilate (181 mg), cobalt(II) chloride (49.8 mg), and MeOH (3 mL) was mixed with sodium borohydride (42.8 mg) at 0°C, and the mixture was stirred at 0°C for 1 hour. Boc2O (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 ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The solution was concentrated. The residue was purified by NH silica gel column chromatography (Âde / hexane). The title compound (184 mg) was obtained. 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-(meteno)pyrrolo[2,1-h][1,9,11]oxadiazaci Chlooctadecine-17-yl]methanesulfonamide To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridine-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 overnight at room temperature. The solution of the residue in DMF (2 mL) was added at room temperature to a mixture of di(N-succinimidyl) carbonate (27.9 mg), N-methylmorpholine (80 μL), and THF (30 mL). The mixture was stirred at room temperature for 3 hours. DIPEA (157 μL) was added, and the mixture was left at room temperature for 3 hours at 60°C. The mixture was stirred overnight. The mixture was quenched with an aqueous sodium bicarbonate solution and extracted with toluene. The layers were separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was separated by preparative HPLC. (Column: YMC-Actus Triant C18, Mobile phase: 10 mM ammonium bicarbonate aqueous solution / acetonite) It was purified using a toryl (Toryl) ion. Then, the desired fraction was concentrated and crystallized from hexane-ethylethanol. Then, the sample was filtered to obtain 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-(meteno)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) is benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl) A mixture of methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (2.0 g), bis(pinacolato)diborone (3.22 g), and potassium acetate (0.830 g) in toluene (20 mL) was added at room temperature under an argon atmosphere. The mixture was stirred at 100°C under an argon atmosphere for 2 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was collected in a silica gel column. The title compound (2.204 g) was obtained by purification using chromatography (methoxy / hexane). MS: [M+H] + 565.2

[0316] B) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridine-2-yl)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxyl Syrah Pd(dppf)Cl2·CH2Cl2 (141 mg) is used with benzyl (2S,3R,4S)-3-[(ethanesulfonyl)amine]. [4-fluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- A mixture of 972 mg of phenyl(Iyl)phenyl]methyl}pyrrolidine-1-carboxylate, 287 mg of 6-(chloromethyl)-5-methylpicolinonitrile, and 2.58 mL of 2 M aqueous sodium carbonate solution in 9 mL of DME was added and stirred at 120°C for 1 hour under microwave irradiation. siRNA and water were added to the reaction mixture at room temperature, and insoluble matter was filtered off. The organic layer of the filtrate was separated. The aqueous layer was extracted with siRNA. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure. The residue was then analyzed by silica gel column chromatography ( Depositphotos / hexane). The compound was purified to obtain the title compound (713 mg). MS: [M+H] + 569.2

[0317] C) Benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]methyl}- 2-Fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1- Carboxylates Sodium borohydride (118 mg) was added to a mixture of benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridine-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. alkyl and water were added to the reaction mixture at room temperature, and then the insoluble matter was filtered. The filtrate was removed. The organic layer of the filtrate was separated. The aqueous layer was extracted with SiO2. The organic layer was extracted with water and saline solution. The sample was washed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (MeOH / ÃO) to obtain the title compound (128 mg). MS: [M+H] + 573.2

[0318] D) N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]methyl}-2-fluorophenyl)methyl]-4-fluoropyrrolidine-3-yl}ethanesulfonamide A mixture of benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyrrolidine-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (128 mg) and 10% palladium carbon (wetted with 55% water, 23.79 mg) in MeOH (2 mL) was hydrogenated at room temperature under balloon pressure for 3 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 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-hexa Hydro-1H,9H,15H-8,4-(azeno)-10,14-(meteno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide N-{(2S,3R,4S)-2-[(3{[6-(aminomethyl)-3-methylpyridine-2-yl]methyl}-2-full A solution of olophenyl)methyl]-4-fluoropyrrolidine-3-yl}ethanesulfonamide (90 mg) in THF (8 mL) was added at 0°C to a mixture of di(N-succinimidyl) carbonate (52.6 mg) and 4-methylmorpholine (0.027 mL) in THF (42 mL). The mixture was left at 0°C for 1 hour. The mixture was stirred. DIPEA (0.108 mL) was added to the reaction mixture at 0°C. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. siRNA and water were added to the residue at room temperature, and then the organic layer was added. The layers were separated. The aqueous layer was extracted with toluene. The organic layer was washed with water and saline solution, and anhydrous magnesium sulfate was used. The mixture was dried with nesium and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (MeOH / siRNA). The solid was crystallized from siRNA-hexane to obtain the title compound (3.70 mg). I obtained it. 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-hex Sahydro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[0321] A) tert-butyl (2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridine-2-yl) oxy [(Cy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Cesium carbonate (17.07 g) is added to tert-butyl (2S,3R)-3-[(cyclopropanesulfonyl) [Mino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-ca Ruboxylate (11.80 g) and 5-chloro-3,6-difluoropyridine-2-amine (7.76 g) The mixture was added to a solution 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 ethyl acetate, and passed through a Celite pad. The Celite pad was washed with ethyl acetate. The filtrate was poured into water and saline. The mixture was filtered through a Celite pad. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saline. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (12.67 g). MS: [M+H] + 595.1

[0322] B) tert-butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridine-2-yl) oxy [(Cy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl nitrite (3.57 mL) is mixed with tert-butyl(2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropane A mixture of 12.67 g of ruhonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate and 4.28 g of copper[I] bromide in acetonitrile (130 mL) was added at room temperature. The mixture was then heated to 60°C. The mixture was stirred for 1 hour. The mixture was cooled to room temperature. ELISA and water were added to the mixture. The precipitate was removed by passing it through a Celite pad. The filtrate was then mixed with aqueous solution of ELISA and sodium thiosulfate. The mixture was poured at room temperature. The organic layer was separated, washed with water and saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (Â1 / hexane). The solution was purified. The mixture was suspended in 16 mL of residue IPE and stirred overnight at room temperature. The precipitated solid was filtered off. The compound was then 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- (Lolo-5-fluoropyrrolidine-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Toluene (81 g) of tert-butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridine-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). The mixture in (mL) and water (16 mL) was degassed under 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 under a nitrogen atmosphere at 85°C for 4.5 hours. Water and ethyl acetate 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 (ethyl acetate / hexane) to obtain the title compound (2.92 g). MS: [MH] - 707.2

[0324] D) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}cyclopropanesul Honami TFA (20 mL) was added to tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloro-5-fluoropyridine-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. The residue was purified by NH silica gel column chromatography (MeOH / ¼) to obtain 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-he Xahydro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide A mixture of di(N-succinimidyl) carbonate (0.637 g) and DIPEA (3.16 mL) in THF (dry) (900 mL) contains N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyrrolidine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl} A solution of cyclopropanesulfonamide (1.15 g) in DMF (dry) (30 mL) is heated in a chamber over 30 minutes. The mixture was added dropwise at warm temperature. The mixture was stirred overnight at room temperature. The mixture was evaporated to obtain residue A. . In the same manner as the synthesis of residue A, 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- Fluoropyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrheli Using 1.15 g of din-3-yl cyclopropanesulfonamide and 30 mL of dry DMF, Residue B was obtained. Residues A and B were combined, diluted with SiO2, and poured into water at room temperature. The organic layer was separated and diluted with water. The solution was washed with saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Â1 / hexane), and recrystallized from Â1 / hexane. The title compound (1.11 g) was obtained. 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-(meteno)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-methylpyrimidine-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-ca Luboxylart 2,4-dichloro-5-methylpyrimidine (75 μL) was used to treat tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolic acid. Zin-1-carboxylate (250 mg) and potassium carbonate (200 mg) in DMF (dry) (3.0 mL) The solution was added at room temperature. The mixture was stirred overnight at room temperature under an argon atmosphere, then poured into ice water and extracted with siRNA. The organic layer was separated, washed with brine, and dried with anhydrous magnesium sulfate. The mixture was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (246 mg). MS: [M+H] + 551.2

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

[0329] C) tert-butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidine-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidi n-1-carbonyl}pyrrolidine-1-carboxylate HATU (110 mg) is added to N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidine-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-3-yl]methanesulfonamide Hydrochloride (108 mg), (tert-butoxycarbonyl)-L-proline (56 mg), and DIPEA (120 mg) The mixture was added at room temperature to a solution of (μL) THF (dry) (1.0 mL) and DMF (dry) (1.0 mL). 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 continued for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with aqueous sodium bicarbonate solution and saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (116 mg). MS: [M-Boc+H] + 548.2

[0330] D) N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidine-4-yl)oxy]-2-fluorophosphate (Nylmethyl)-4,4-difluoro-1-L-prolylpyrrolidine-3-yl]methanesulfonamide Hydrochloride 4 M hydrogen chloride-siRNA (1.0 mL) is mixed with tert-butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5- Methylpyrimidine-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carbonyl}pyrrolidine-1-carboxylate (115 mg) was added to a solution in THF (1.0 mL) at room temperature. The mixture was stirred under an argon atmosphere at room temperature for 2 hours, and then concentrated to obtain 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-(meteno)dipyrrolo[1,2-g:1',2'-j][1,5,7,10]oxatriazacycloheptadecin-17-yl]methanesulfonamide DIPEA (150 μL) is used to prepare N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidine-4-yl)oxy [104 mg]-2-fluorophenylmethyl)-4,4-difluoro-1-L-prolylpyrrolidine-3-yl]methanesulfonamide hydrochloride was added to a solution in DMF (dry) (2 mL) and acetonitrile (30 mL) at room temperature. The mixture was stirred overnight at 80°C under an argon atmosphere and then concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution / acetonitrile) to obtain 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-hexahy Dro-15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-d][1,12,4]dioxazacyclohept Tadesin-16-yl]methanesulfonamide

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

[0334] B) N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridine-2-yl)oxy]-2-fluoro Nylmethyl)-4,4-difluoropyrrolidine-3-yl]methanesulfonamide hydrochloride tert-butyl (2S,3R)-2-({3-[(3-chloro-6-fluoropyridine-2-yl)oxy]-2-flu Olophenyl(methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-ca A mixture of ruboxilate (381.4 mg) in 4 M hydrogen chloride-CPME (10 mL) was prepared in a dry atmosphere. The mixture was stirred overnight at warm temperature. The mixture was concentrated to obtain the title compound (338 mg). MS: [MH] - 452.9

[0335] C) 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridine-2-yl)oxy]-2-fluoro (Nylmethyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-yl}-2-ol Xoethyl acetate To a solution of N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-3-yl]methanesulfonamide hydrochloride (337.6 mg) in THF (7 mL), TEA (0.288 mL) and acetoxyacetyl chloride (0.081 mL) were added at 0°C. The mixture was stirred at 0°C for 2 hours under a dry atmosphere. The reaction mixture was diluted with ELISA. Next, the mixture was poured into water. The organic layer was separated, washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (Â1 / hexane) to obtain 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-(meteno)pyrrolo[1,2-d][1,12,4]dioxazacyclohe Butadecin-16-yl]methanesulfonamide 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridine-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-yl}-2-oxy A solution of soethyl acetate (309 mg) in THF (20 mL) and EtOH (20 mL) was mixed with 1 M sodium hydroxide aqueous solution (4 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes. It was concentrated under pressure. The residue was diluted with siRNA and then poured into an aqueous solution of ammonium chloride. The layers were separated, washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was analyzed by silica gel column chromatography (RINKAN / hexane) and NH silica gel. The title compound (251 mg) was obtained by purification using column chromatography (siRNA / hexane). 1 H 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacyclooctadecine-17-yl]methanesulfonamide

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

[0339] B) tert-butyl (2S,3S)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]meth [3-(methoxycarbonyl)phenyl]methyl]pyrrolidine-1-carboxylate tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3-[(methanesulfonyl){[2-(t To a solution of dimethylsilyl)ethoxymethylaminopyrrolidine-1-carboxylate (2470 mg) and TEA (0.916 ml) in DMF (10 ml) and MeOH (3 ml), PdCl2(dppf) (321 mg) was added, and the mixture was stirred at 80°C for 6 hours under a carbon monoxide atmosphere. The mixture was quenched with saline solution. Extracted with toluene. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Depositphotos / hexane) and then labeled. A combined solution (630 mg) was obtained. 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 tert-butyl (2S,3S)-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]-2-{[3-(methoxycarbonyl)phenyl]methyl}pyrrolidine-1-carboxylate (630 mg) of THF (dry) in a solution in (5 ml) of 1 M diisobutylaluminum hydride-hexa 2.90 ml of sodium sulfate was added at 0°C. The mixture was stirred at room temperature for 10 minutes. Then, sodium sulfate was added. The decahydrate was added and the mixture was stirred for 2 hours. After filtration and evaporation under reduced pressure, the residue was removed. The result was purified by silica gel column chromatography (alkyl hexane) to obtain the title compound (508). mg was obtained. MS: [M+Na] + 537.2

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

[0342] E) tert-butyl (2S,3S)-2-[(3-{[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridine-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(t [methylsilyl]ethoxy]methyl}amino]pyrrolin-1-carboxylate tert-butyl (2S,3S)-2-[(3-{[(6-bromo-3-methylpyridine-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (437 mg), potassium [[(tert-butoxycarbonyl) A mixture of mino-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 RINKAN. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The compound was purified using Graphy (toluene / hexane) to obtain 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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacyclooctadecine-17-yl]methanesulfonamide tert-butyl (2S,3S)-2-[(3-{[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methyl [Tylpyridine-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2-(to A mixture of dimethylsilyl)ethoxymethylaminopyrrolidine-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 / SiO). The solution of the thus obtained residue in DMF (dry) (1 ml) was mixed with di(N-succinimidyl) carbonate (32.5 mg) and N-methyl Add the mixture of 0.013 ml of rumorpholine and 50 ml of THF (dry) at room temperature, and mix 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 saline solution and extracted with toluene. The organic layer was separated. Washed with saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was separated and HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution / acetate). The compound was purified with tonitrile to obtain 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, ddd, 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-hexahy Dro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propan-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 tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-diph A solution of luoropyrrolidine-1-carboxylate (4.0 g) in CH2Cl2 (22 mL) was placed in a water bath. At ambient temperature, 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (4.1 mL), next Isopropylsulfonyl chloride (1.9 mL) was added. The mixture was stirred at room temperature for 24 hours. A saturated aqueous solution of ammonium chloride was added to the mixture. The organic layer was separated, washed sequentially with aqueous sodium bicarbonate solution and saline solution, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Â1 / heptane) to obtain 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]phenyl Loridine-1-carboxylate To a nitrogen-substituted 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)diborone (798 mg) in toluene (8.4 mL), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (180 mg) was added. The mixture was then substituted with nitrogen and then 80 The mixture was stirred at °C for 16 hours. The mixture was diluted with MeOH, filtered through a Celite pad, and the filtrate was reduced. The solution was concentrated under pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to obtain 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 1:1 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 THF-water (6.2 mL), sodium perborate tetrahydrate (579 mg) was added at room temperature. The mixture was stirred at ambient temperature for 16 hours in an open atmosphere. The mixture was diluted with water, filtered through a fine frit, and the filtrate was extracted with ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / heptane) to obtain the title compound (370 mg). MS: [M+2H(-tBu)] + 397.2.

[0348] D) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-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), 6-chloro-5-methylpicolinonitrile (249 mg) was added. The mixture was stirred at 80°C for 16 hours. The mixture was quenched with water and extracted with ELISA. The organic layer was separated, washed with saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ÃO / heptane) to obtain the title. The compound (226 mg) was obtained. MS: [M+2H(-tBu)] + 513.2.

[0349] E) tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyro Lysine-1-carboxylate Sodium borohydride (45 mg) is added to tert-butyl (2S,3R)-2-({3-[(6-cyano-3-meth Lupyridine-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) were added at 0°C to a solution in MeOH (2.6 mL). The mixture was cooled for 3 hours. Next, the mixture was stirred at room temperature for 3 hours. The reaction was then quenched with a saturated aqueous solution of ammonium chloride and mixed. The mixture was extracted with ethyl acetate. 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 proceeded to the next step without purification. MS: [M+H] + 573.3.

[0350] F) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluor [Lopenylmethyl]-4,4-difluoropyrrolidine-3-yl}propane-2-sulfonamide Hydrochloride A solution of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-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... The compound was then concentrated under reduced pressure to obtain 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-hexa Hydro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propan-2-sulfonamide N,N'-Disuccinimidyl carbonate (76 mg) was administered in three divided doses to a mixture of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}propan-2-sulfonamide dihydrochloride (217 mg) and N-methylmorpholine (0.26 mL) in THF (dry) (380 mL) and DMF (dry) (15 mL). It was then added at room temperature over 5 minutes. The mixture was stirred at room temperature for 4 days, and then concentrated under reduced pressure. Remains are removed using reversed-phase column chromatography (Column: Gemini (registered trademark) NX-C18, Mobile phase: The title compound (83 mg) was purified with 10 mM ammonium bicarbonate aqueous solution (acetonitrile). I got it. 1H 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-hexahy Dro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2-j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[0353] A) tert-butyl N-(6-bromo-5-methylpyridine-2-yl)glycinate 6-bromo-5-methylpyridine-2-amine (11.0 g) was added to a mixture of tert-butyl 2-bromoacetate (12.6 g) and potassium carbonate (16.3 g) in NMP (220 mL). The mixture was stirred at 140°C under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. 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 (ethyl acetate / PE) to obtain the title compound (8.33 g). 1H 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-methylpyridine-2-yl}oxy)-2-fluorophenyl]methyl}3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl N-(6-bromo-5-methylpyridine-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) The mixture was degassed three times and purged with nitrogen, then stirred at 100°C under a nitrogen atmosphere for 12 hours. The solution was cooled to room temperature and diluted with water. The mixture was extracted twice with alkyl hydroxide. The combined organic layers were then separated. The mixture was washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / PE) to obtain the title compound (97.4 mg). . MS: [M+H] + 659.2.

[0355] C) N-{6-[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-2-i [Il(methyl)-2-fluorophenoxy]-5-methylpyridine-2-ylglycine dihydrochloride tert-butyl (2S,3R)-2-{[3-({6-[(2-tert-butoxy-2-oxoethyl)amino]-3-methyl Lupyridine-2-yl}oxy)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (150 mg) of 4 M hydrogen chloride-1,4-dioxa The solution in (12 mL) was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure and then prepared as described in the title. A combined solution (141 mg) was obtained. 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-(meteno)pyrrolo[1,2-j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide HATU (131 mg) and DIPEA (239 μL) are mixed with N-{6-[3-({(2S,3R)-3-[(ethanesulfonyl) [Amino]-4,4-difluoropyrrolidine-2-yl}methyl)-2-fluorophenoxy]-5-methylpyridine-2-yl}glycine dihydrochloride (140 mg) was added to a solution in DMF (140 mL) at room temperature and stirred for 12 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (SiO2, siRNA / PE) to obtain the title compound and a mixture of its isomers. The mixture of isomers was purified by preparative SFC (column: DAICEL CHIRALCEL OJ, mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)) to obtain the title compound (15.7 mg, shorter retention time). 1H 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-He Xahydro-1H,9H,15H-4,8-(azeno)-14,10-(meteno)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-carb Xylart 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-methylpyridine-2-carbonitride (424 mg), Pd(OAc)2 (21 mg), 1,3-bis(2,4,6-trimethylphenyl)imidazole-1-ium A mixture of loride (63 mg) and cesium carbonate (1.19 g) in 1,4-dioxane (30 mL) was stirred at 80°C for 24 hours under a carbon monoxide atmosphere (50 psi). The reaction mixture was concentrated under reduced pressure, and the remaining The residue was purified by silica gel column chromatography (Â1 / PE) to obtain the title compound (337 mg). MS: [M+H] + 567.1.

[0359] B) tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridine-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-carboc Sylate (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 sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The combined organic phase was washed with saline solution and anhydrous sodium sulfate solution was used. The solution was dried with thorium, filtered, and concentrated under reduced pressure. The crude isolate was purified by preparative HPLC (column: Boston Green ODS, mobile phase: 0.2% formic acid aqueous solution / acetonitrile) to obtain the title compound (128 mg). MS: [M+H] + 589.0.

[0360] C) tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl](diflu Oro(methyl)-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-diflu Olopyrrolidine-1-carboxylate Sodium borohydride (82.6 mg) is added to tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methyl Tylpyridine-2-yl)(difluoro)methyl]-2-fluorophenyl}methyl)-3-[(ethanes Rufonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (128 mg) and chloride Nickel(II) hexahydrate (52.3 mg) was added at 0°C to a solution in MeOH (5.0 mL). The reaction mixture was heated to 20°C and stirred for 2 hours. The reaction mixture was quenched with water and extracted three times with toluene. The combined organic phases were washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (98 mg). MS: [M+H] + 593.1.

[0361] D) N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl](difluoro)methyl [L-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl]ethanesulfone Midotri hydrochloride tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoro A solution of lopyrrolidine-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 obtain the title compound (99.5 mg). I obtained it. 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-(meteno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridine-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}ethanesulfone To a suspension of dotri hydrochloride (99.5 mg) in THF (15 mL), add DIPEA (173 μL), then 1,1'- Carbonyldiimidazole (40.2 mg) was added at 0°C. The reaction mixture was heated to 45°C and then nitrogen-neutralized. The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude residue, which was then separated and subjected to preparative HPLC (column: Phenomenex C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution (0.05% hydroxide). The compound was purified with ammonium (containing acetonitrile) to obtain the title compound (26.4 mg). 1 H 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-hexahy Dro-9H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-d][1,4]oxazacyclohepta Decine-16-yl]ethanesulfonamide

[0364] A) (3-methylpyridine-2-yl)methyl acetate (3-methyl-2-pyridyl)methanol (2.0 g) in a solution in THF (40 mL) is mixed with acetic anhydride (2.30 Add pyridine (2.49 mL) and DMAP (199 mg). Stir the mixture at 20°C for 12 hours. The reaction mixture was diluted with water and a saturated aqueous sodium bicarbonate solution, and then with dimethyl carbonate. Extraction was performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / PE) to obtain 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-pyridine-1-ium-2-yl)methyl acetate To a solution of (3-methylpyridine-2-yl)methyl acetate (2.4 g) in CH2Cl2 (50 mL), m-chloroperoxybenzoic acid (4.42 g, 85% purity) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with water and sodium sulfite was added. Quenched with (5 g) and made basic to pH = 8 with saturated sodium bicarbonate solution. Extracted with toluene. The organic layer was anhydrous sodium sulfate. The residue was dried with um, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The title compound (4 g) was obtained by purification with (alkyl acetylene / PE). 1H 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-methylpyridine-2-yl)methyl acetate A mixture of (3-methyl-1-oxide-pyridine-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, made basic to pH = 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / PE) to obtain 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-methylpyridine-2-yl]oxy}acetate (6-chloro-3-methylpyridine-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) Pd2(dba)3 (103 mg) was added to a solution in 5 mL of San 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 ELISA. The organic layer was washed with saline solution. The solution was purified, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / PE) to obtain the title compound (140 mg). MS: [M+H] + 254.2.

[0368] E) tert-butyl {[6-(chloromethyl)-5-methylpyridine-2-yl]oxy}acetate To a solution of tert-butyl {[6-(hydroxymethyl)-5-methylpyridine-2-yl]oxy}acetate (110 mg) in CH2Cl2 (4 mL), thionyl chloride (207 μL) was added. The mixture was stirred at 25°C for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with siRNA. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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-methylpyridine-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate tert-butyl {[6-(chloromethyl)-5-methylpyridine-2-yl]oxy}acetate (80 mg) and tert-butyl(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-butyl Luoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}py Roridine-1-carboxylate (110 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) Potassium carbonate (80.7 mg) and Pd(dppf)Cl2.CH2Cl2 (15.9 mg) were added to the solution under a nitrogen atmosphere. The mixture was stirred under a nitrogen atmosphere at 100°C for 3 hours. The mixture was diluted with water and extracted with Â. The organic layer was washed with saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / PE) to obtain the title compound (120). mg was obtained. MS: [M+H] + 658.3.

[0370] G) [(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-2-i [methyl]-2-fluorophenyl]methyl]-5-methylpyridine-2-yl)oxy]acetic acid dihydrochloride tert-butyl (2S,3R)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyrrhizic acid A solution of 120 mg of din-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate in 5 mL of 4 M hydrogen chloride-1,4-dioxane was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to obtain 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-(meteno)pyrrolo[1,2-d][1,4]oxazacyclohept Tadesin-16-yl]ethanesulfonamide [(6-{[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-2-yl}methyl)-2-fluorophenyl]methyl}-5-methylpyridine-2-yl)oxy]acetic acid dihydrochloride A solution of (45 mg) siRNA in (260 mL) contains dibutyldiphosphonic acid (37.8 mg, 50% purity) Bipyridine (130 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with water and extracted three times with toluene. The combined organic layers were washed with saline solution and anhydrous sodium sulfate was added. The solution was dried with saturates, 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 obtain 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-(meteno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide and N-[(9S,15aS,16R)-17,17,20-triflu Oro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfone Amido

[0373] A) 1-(3-methylpyridine-2-yl)ethenyl trifluoromethanesulfonate To a solution of 1-(3-methyl-2-pyridyl)ethanone (2.0 g) in toluene (50 mL), trifluoromethanesulfonic anhydride (8.35 g) and DIPEA (5.2 mL) were added 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 collected in a silica gel container. The compound was purified by chromatography (¼ / heptane) to obtain 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-fluorinated Ro-3-[1-(3-methylpyridine-2-yl)ethenyl]phenyl}methyl)pyrrolidine-1-carbocyanide Syrah 1-(3-methylpyridine-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) were degassed and purged with nitrogen three times. Then the mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere 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) 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 (620 mg) in EtOH (10 mL) was treated with 10% palladium on carbon (418 mg) under a nitrogen atmosphere and the suspension was degassed and purged with hydrogen three times and then stirred at 25 °C for 16 h under a hydrogen atmosphere (20 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 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 ​​​​​​Loridine-1-carboxylate m-chloroperoxybenzoic acid (118 mg, 85% purity) is used to make tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methylpyridine-2-yl) Ethyl]phenyl}methyl)pyrrolidine-1-carboxylate (280 mg) in CH2Cl2 (20 mL) The solution was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (20 mL) and then washed with saturated sodium carbonate aqueous solution (10 mL). The phases were separated, and the organic layer was washed with saturated sodium thiosulfate aqueous solution (10 mL) and then again with saturated sodium carbonate aqueous solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (260 mg). MS: [M+H] + 558.3.

[0377] E) tert-butyl (2S,3R)-2-({3-[1-(6-cyano-3-methylpyridine-2-yl)ethyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-ca Luboxylart tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-({2-fluoro-3-[1-(3-methyl-1-oxide-pyridine-1-ium-2-yl)ethyl]phenyl}methyl) A solution of lysine-1-carboxylate (260 mg) in 1,2-dichloroethane (5 mL) contains cyanide. Add trimethylsilyl chloride (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 silica The title compound (155 mg) was obtained by purification using gel column chromatography (Â / PE). MS: [M+H] + 567.1.

[0378] F) tert-butyl (2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridine-2-yl]ethyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate Sodium borohydride (120 mg) was slowly added at 0°C to a solution of tert-butyl (2S,3R)-2-({3-[1-(6-cyano-3-methylpyridine-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). The mixture was left to stand at 0°C for 2 hours. The mixture was stirred. The mixture was diluted with CH2Cl2, and the reaction was quenched with water, resulting in a solid precipitate. The solid was filtered off, and the filtrate phase was separated. The organic phase was preserved. The aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (136 mg). MS: [M+H] + 571.2.

[0379] G) N-{(2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridine-2-yl]ethyl}-2-Fur Olophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}ethanesulfonamide trihydrochloride tert-butyl (2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridine-2-yl]ethyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine A solution of n-1-carboxylate (140 mg) in 4 M hydrogen chloride-1,4-dioxane (8 mL) is placed around The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 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-(meteno)pyrrolo[1,2-c][1,3]diazasic Loheptadecin-16-yl]ethanesulfonamide and N-[(9S,15aS,16R)-17,17,20-tri Fluoro-7,9-dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfate Honami A mixture of N-{(2S,3R)-2-[(3-{1-[6-(aminomethyl)-3-methylpyridine-2-yl]ethyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-3-yl}ethanesulfonamide trihydrochloride (122 mg) in DMF (4.5 mL) and THF (105 mL) contains N,N'-disuccinimid 48.5 mg of chlorocarbonate and 138 μL of N-methylmorpholine were added at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was partitioned into CH2Cl2 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 / CH2Cl2). The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 10 mM ammonium bicarbonate aqueous solution (containing 0.05% ammonium hydroxide) / acetonitrile), then purified by SFC column: DAICEL CHIRALCEL OD-H; mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)), Diastereomer A (20 mg, shorter retention time) and diastereomer B (27 mg, longer retention time) The retention time was obtained.

[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 obtain 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)-CO2; isocratic B, 30%) to obtain the other title compound (8.5 mg). 1 H 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]oxaazacyclo heptadecine - 16 - yl]ethanesulfonamide

[0384] A) tert - butyl (2S,3R)-3 - [(ethanesulfonyl)amino]-4,4 - difluoro - 2 - ({2 - flu oro - 3 - [(6 - fluoro - 3 - methylpyridin - 2 - yl)methyl]phenyl}methyl)pyrrolidine - 1 - carboxylate In a 10 mL microwave vial equipped with a stir bar and a rubber septum, tert - but (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-carb Xylate (250 mg), Pd(dppf)Cl2.CH2Cl2 (37 mg), 2-(chloromethyl)-6-fluoro-3-methyl Tyl-pyridine hydrochloride (119 mg), 2 M sodium carbonate aqueous solution (1.0 mL), and 1,2-dimethoxyethane (3.30 mL) were added. The reaction mixture was purged with nitrogen a...

Claims

1. Equation (I) 【Chemistry 1】 [In the formula, Ring A may be substituted with C ６－１４ An aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, where Y is a ring atom C or N, where C is bonded to hydrogen or any substituent; X is -O-, -S-, -NR １ -, -CR ２ R ３ -, -O-(CR ２ R ３ ), -(CR ２ R ３ ), -O-, or an optionally substituted C ３－６ cycloalkyl group, where the left part of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right part of X is bonded to ring B; R １ is hydrogen, or a substituted C １－６ It is an alkyl group; R ２ and R ３ This is independently hydrogen, halogen, or a substituted C １－６ It is an alkyl group; Ring B may be substituted with C ６－１４ An aryl group, or a 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 portion of L is bonded to ring B, and the right portion of L is bonded to the carbonyl group; R ４ and R ５ This is independently hydrogen, halogen, or a substituted C １－６ It is an alkyl group; R ６ is hydrogen, or a substituted C １－６ It is an alkyl group; R ７ and R ８ This is independently hydrogen, halogen, or a substituted C １－６ It is an alkyl group; or R ４ and R ６ They may, together with the atoms to which they bond, form a substituted, 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R ４ and R ５ , or R ４ and R ７ Together, they form a substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or a substituted C, along with the atoms to which they are bonded. ３－１０ Forms a cycloalkyl group; R ａ C １－６ alkyl group, C ３－４ Cycloalkyl groups, or mono- or di-C １－６ It is an alkylamino group, and here, C １－６ alkyl group, C ３－６ Cycloalkyl groups, and mono- or di-C １－６ The alkylamino groups may each be substituted; R ｂ is a hydrogen atom or a halogen atom; and R ｃ is a hydrogen atom or a halogen atom; A compound of or a salt thereof.

2. Ring A is 【Chemistry 2】 (wherein i is a bonding point to the crosslinked methylene, and ii is a bonding point to X; and R １１ and R １２ C is independently hydrogen, halogen, or a halogenated C １－６ It is an alkyl group. It is; The compound according to claim 1, or a salt thereof.

3. Ring B is as follows: 【Transformation 3】 (wherein iv is the connection point to L, and iii is the connection point to X; R ２１ａ , R ２１ｂ , R ２１ｄ , R ２２ａ , R ２２ｂ , R ２２ｃ , R ２３ａ , R ２３ｂ , R ２３ｃ and R ２３ｄ C is hydrogen, halogen, or a halogenated C １－６ alkyl group, C １－６ Alkoxyl group and C ３－６ Selected independently from cycloalkyl groups; and R ２４ C is hydrogen, halogen, or a halogenated C １－６ Alkyl alkyl groups, and C ３－６ (Selected from cycloalkyl groups.) Selected from; The compound according to claim 1, or a salt thereof.

4. Ring A is 【Chemistry 4】 (wherein i is a bonding point to the crosslinked methylene, and ii is a bonding point to X; and R １１ and R １２ These are, independently, hydrogen, halogen, or C １－６ It is an alkyl group. And; X is -O-, -CR ２ R ３ -, -O-(CR ２ R ３ ) - or - (CR ２ R ３ )-O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; R ２ and R ３ However, independently, hydrogen, halogen, or halogen and C １－６ The C group may be substituted with one to three substituents independently selected from the alkyl group. １－６ It is an alkyl group; Ring B is as follows: 【Transformation 5】 (wherein iv is the connection point to L, and iii is the connection point to X; R ２１ａ 、R ２１ｂ 、R ２１ｄ 、R ２２ａ 、R ２２ｂ 、R ２２ｃ 、R ２３ａ 、R ２３ｂ 、R ２３ｃ and R ２３ｄ are independently selected from hydrogen, halogen, a C １－６ alkyl group which may be halogenated, a C １－６ alkoxyl group and a C ３－６ cycloalkyl group; R ２４ is hydrogen or a C １－６ 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 R ５ )-, or-C(R ４ R ５ )-C(R ７ R ８ ) - where the left portion of L is bonded to ring B, and the right portion of L is bonded to the carbonyl group; R ４ and R ５ However, independently, hydrogen, or C １－６ It is an alkyl group; R ６ However, C may be hydrogenated or halogenated. １－６ It is an alkyl group; R ７ and R ８ However, independently, is it hydrogen; or L is -C(R ４ R ５ ) - NR ６ - or - NR ６ -C(R ４ R ５ )- When R ４ and R ６ However, along with the atoms to which they bond, halogens and C １－６ A 3- to 8-membered monocyclic non-aromatic heterocyclic ring may be substituted with one to three substituents independently selected from the alkoxyl group, and R ５ But is it hydrogen; or L is -C(R ４ R ５ )-C(R ７ R ８ )- When R ４ and R ７ However, along with the carbon atoms to which they are bonded, C ３－１０ Forms a cycloalkyl group, and R ５ and R ８ However, both are hydrogen; R ａ However, halogen atoms and C １－６ C may be substituted with one to three substituents independently selected from the alkoxyl group. １－６ alkyl group, C ３－４ Cycloalkyl groups, or mono- or di-C １－６ It is an alkylamino group; R ｂ but is a hydrogen atom or a halogen atom; and R ｃ However, it is either a hydrogen atom or a halogen atom; The compound according to claim 1, or a salt thereof.

5. Ring A is a phenyl group which may be further substituted with one or two halogen atoms, where Y is a ring atom C bonded to hydrogen or halogen; X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B contains halogen and C １－６ A pyridine ring which may be substituted with one, two, or three substituents independently selected from the alkyl group; L is -CH ２ It is -NH-, where the left side of L is bonded to ring B, and the right side of L is bonded to the carbonyl group; R ａ However, C may be substituted with one to three halogen atoms. １－６ alkyl group, or C ３－４ It is a cycloalkyl group; R ｂ However, it is a halogen atom; and R ｃ However, it is a halogen atom; The compound according to claim 1, or a salt thereof.

6. Ring A is a phenyl group which may be further substituted with one or two halogen atoms, where Y is a ring atom C bonded to the halogen; X is -O-, where the left portion of X is bonded to a ring carbon atom on ring A adjacent to Y, and the right portion of X is bonded to ring B; Ring B has 1, 2, or 3 C １－６ A pyridine ring which may be substituted with an alkyl group; L is -CH ２ It is -NH-, where the left side of L is bonded to ring B, and the right side of L is bonded to the carbonyl group; R ａ However, C may be substituted with one to three halogen atoms. １－６ It is an alkyl group; R ｂ However, it is a halogen atom; and R ｃ However, it is a halogen atom; The compound according to claim 1, or a salt thereof.

7. The compounds are as follows: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)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-(meteno)pyrrolo[1,2-j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide; A compound according to claim 1, or a salt thereof, selected from the group consisting of the following.

8. A pharmaceutical composition comprising a compound defined in any one of claims 1 to 7, or a salt thereof, and a pharmacologically acceptable carrier.

9. A pharmaceutical product comprising a compound defined in any one of claims 1 to 7, or a salt thereof.

10. The pharmaceutical product according to claim 9, which is an orexin type 2 receptor agonist.

11. The pharmaceutical product according to claim 9, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, or side effects or complications of anesthesia.

12. The pharmaceutical product according to claim 9, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

13. The pharmaceutical product according to claim 9, which is a preventive or therapeutic agent for narcolepsy.

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

15. The method according to claim 14, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive 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 claim 14, 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 claim 14, wherein the disease or disorder is narcolepsy.

18. A compound as defined in any one of claims 1 to 7, or a salt thereof, for use in therapeutic applications.

19. The compound or salt according to claim 18, wherein the treatment method comprises the treatment of a disease or disorder associated with the orexin type 2 receptor.

20. The compound or salt according to claim 19, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive 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.

21. The compound or salt according to claim 19, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

22. The compound or salt according to claim 19, wherein the disease or disorder is narcolepsy.

23. Use of a compound or salt thereof as defined in any one of claims 1 to 7 in the manufacture of a pharmaceutical product for the treatment of a disease or disorder associated with the orexin type 2 receptor.

24. The use according to claim 23, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive 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.

25. The use according to claim 23, 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 claim 23, wherein the disease or disorder is narcolepsy.

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