Heterocyclic compound

Abstract

The present invention provides a heterocyclic compound having orexin type 2 receptor agonist activity. A compound represented by formula (I): wherein each symbol is as described in the specification, or a salt thereof, useful as an agent for preventing or treating narcolepsy.

Description

[0001] This application is a divisional application of Chinese patent application No. 202380083827.0 (filed on October 30, 2023, entitled "Heterocyclic Compound"). Technical Field

[0002] This invention relates to heterocyclic compounds, particularly heterocyclic compounds with orexin type 2 receptor agonist activity. Background of the Invention Orexin is a neuropeptide specifically produced by specific neurons sparsely distributed in and around the lateral hypothalamus, and consists of two subtypes: orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptor, a G protein-coupled receptor mainly found in the brain, and two subtypes of the orexin receptor, type 1 and type 2, are known (Non-Patent Literature 1).

[0003] Because the neurons that produce orexin (orexin neurons) are located near the feeding center, and intraventricular administration of orexin peptides leads to increased food intake, orexin initially attracted attention as a neuropeptide that regulates feeding behavior. However, since then, it has been reported that narcolepsy in dogs is caused by genetic variations in the orexin type 2 receptor (Non-Patent Literature 2), and the role of orexin in controlling sleep and wakefulness has also been studied.

[0004] Studies using transgenic mice with degenerated orexin neurons and double-transgenic mice obtained by crossing these mice with transgenic mice that overexpress orexin have shown that narcolepsy-like symptoms caused by orexin neuron degeneration disappear due to sustained orexin expression. Similarly, when orexin peptides were administered into the ventricles of transgenic mice with degenerated orexin neurons, an improvement in narcolepsy-like symptoms was observed (Non-Patent Literature 3). Studies on orexin type 2 receptor knockout mice have shown that orexin type 2 receptors are important for maintaining wakefulness (Non-Patent Literature 4, Non-Patent Literature 5). This background suggests that orexin type 2 receptor agonists could be a treatment for narcolepsy or other sleep disorders exhibiting excessive sleepiness (Non-Patent Literature 6).

[0005] In addition, it has been shown that peptide agonists that selectively act on orexin type 2 receptors improve obesity in mice caused by a high-fat diet (Non-Patent Literature 7).

[0006] In addition, it has been shown that intraventricular administration of orexin peptides shortens the duration of general anesthesia in rats (Non-Patent Literature 8).

[0007] In addition, it has been shown that patients with sleep apnea syndrome exhibit lower plasma orexin A concentrations (Non-Patent Literature 9).

[0008] In addition, it has been shown that intracerebroventricular administration of orexin peptides improves memory retention in mice with accelerated aging and cognitive impairment (SAMP8) (Non-Patent Literature 10).

[0009] In addition, it has been shown that orexin type 2 receptor agonists will become a treatment for heart failure (Patent Document 1, Non-Patent Document 11).

[0010] In addition, it has been shown that daytime sleepiness in patients with Parkinson's disease is caused by orexin neurasthenia (Non-Patent Literature 12).

[0011] In addition, it is shown that orexin regulates bone formation and bone loss, and that orexin type 2 receptor agonists will become a treatment for diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2).

[0012] In addition, it has been shown that orexin receptor agonists can be used for the prevention or treatment of sepsis, severe sepsis and septic shock, because mortality can be significantly improved simply by continuous peripheral administration of orexin to mice in a septic shock model (Patent Document 3).

[0013] Therefore, compounds with orexin type 2 receptor agonist activity are expected to be used as therapeutics for the following conditions: narcolepsy, idiopathic hypersomnia, excessive sleep, sleep apnea syndrome, disturbances of consciousness (such as coma), narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc. Furthermore, orexin type 2 receptor agonists can be used as anesthetic antagonists or as preventative or therapeutic agents for anesthetic-induced side effects and complications.

[0014] As sulfonamide derivatives, compounds represented by the following formula have been reported. , Each of these symbols is as described in the document (Patent Document 4).

[0015] In addition, the following compounds have been reported as orexin type 2 receptor agonist activities.

[0016] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 5).

[0017] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 6).

[0018] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 7).

[0019] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 8).

[0020] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 9).

[0021] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 10).

[0022] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 11).

[0023] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 12).

[0024] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 13).

[0025] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 14).

[0026] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 15).

[0027] Compounds represented by the following formula , Each of these symbols is as described in the document (Patent Document 16).

[0028] Compounds represented by the following formula Each of these symbols is as described in the document (Patent Document 17).

[0029] However, these compounds are considered inadequate in terms of activity, pharmacokinetics, or safety, and there is still a desire to develop compounds with orexin type 2 receptor agonist activity.

[0030] [List of References] [Patent Literature] [Patent Document 1] WO 2015 / 073707 A1 [Patent Document 2] WO 2015 / 048091 A1 [Patent Document 3] WO 2015 / 147240 A1 [Patent Document 4] WO 2012 / 137982 A9 [Patent Document 5] WO 2017 / 135306 A1 [Patent Document 6] WO 2018 / 164191 A1 [Patent Document 7] WO 2018 / 164192 A1 [Patent Document 8] WO 2019 / 027003 A1 [Patent Document 9] WO 2019 / 027058 A1 [Patent Document 10] WO 2020 / 004536 A1 [Patent Document 11] WO 2020 / 004537 A1 [Patent Document 12] WO 2020 / 122092 A1 [Patent Document 13] WO 2020 / 122093 A1 [Patent Document 14] WO 2020 / 158958 A1 [Patent Document 15] WO 2020 / 167701 A1 [Patent Document 16] WO 2020 / 167706 A1 [Patent Document 17] WO 2021 / 106975 A1 [Non-patent literature] [Non-patent literature 1] Cell, Vol. 92, 573-585, 1998) [Non-patent literature 2] Cell, Vol. 98, 365-376, 1999) [Non-Patent Literature 3] Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004) [Non-patent literature 4] Cell, Vol. 98, 437-451, 1999) [Non-Patent Literature 5] Neuron, Vol. 38, 715-730, 2003) [Non-Patent Literature 6] CNS Drugs, Vol. 27, pp. 83-90, 2013 [Non-patent literature 7] Cell Metabolism, Vol. 9, 64-76, 2009) [Non-Patent Reference 8] Neuroscience, Vol. 121, 855-863, 2003) [Non-Patent Literature 9] Respiration, Vol. 71, 575-579, 2004) [Non-Patent Literature 10] Peptides, Vol. 23, 1683-1688, 2002) [Non-patent literature 11] Journal of the American College of Cardiology. Vol. 66, 2015, pp. 2522-2533) [Non-Patent Literature 12] Brain. Vol. 130, 2007, pp. 1586-1595) Summary of the Invention

[0031] [The problem this invention aims to solve] The purpose of this invention is to provide heterocyclic compounds with orexin type 2 receptor agonist activity.

[0032] [Problem-solving methods] The inventors have discovered that compounds represented by formula (I) or salts thereof (sometimes referred to as compound (I) in this specification) possess orexin type 2 receptor agonist activity. This invention has been completed through further research.

[0033] Therefore, the present invention provides the following.

[0034] [1] A compound represented by formula (I): (I) in X 1 It is NR8 or CR 9 ; X 2 It is O, NR 10 Or S; X 3 and X 4 Both are C or X 3 and X 4 One of them is N and the other is C; X 5 It is CR 11 Or N; X 6 It is CR 12 ; X 7 It is CR 13 Or N; X 8 It is CR 14 Or N; X 9 It is CR 2 Or N; X 10 It is CR 15 Or N; R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino; R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 alkyl, or When r is 0, then R 2 and R 3 They can combine together to form bonds, or When X 10 It is CR 15 When, then R 3 Can be used with R 15 They come together to form bonds; R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 5 It is a 4-, 5-, or 6-membered monocyclic group that can be optionally substituted; R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl; m is 0 or 1; q is 1 or 2; r is 0 or 1; R 9 R 11 R 12 and R 13 Each is an independent hydrogen atom, with optional substitutions of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 8 and R 10 Each of them does not exist independently, or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 Alkyl; and R 14 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 alkyl; R 15 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 alkyl, or R 15 Can be used with R 3 They come together to form bonds; Or its salt.

[0035] [2] According to the compound in [1] above, where m is 0; q is 1; and r is 0; Or its salt.

[0036] [3] According to the compound in [1] above, where m is 1; q is 1; and r is 0; Or its salt.

[0037] [4] According to the compound in [1] above, where m is 0; q is 1; and r is 1; Or its salt.

[0038] [5] According to the compound in [1] above, where m is 0; q is 2; and r is 0; Or its salt.

[0039] [6] According to the compound in [1] above, wherein X 1 It is NR 8 , where R 8 It does not exist; X 2 It is O; X 3 and X 4 Both are C; X 5 It is CR11 Or N, where R 11 It is a hydrogen atom; X 6 It is CR 12 , where R 12 It is a hydrogen atom, C 1-6 Alkyl or halogen atom; and X 7 It is CR 13 , where R 13 It is a hydrogen atom or a halogen atom; Or its salt.

[0040] [7] According to the compound in [1] above, wherein X 8 It is N; X 9 It is CR 2 , where R 2 It is a hydrogen atom, or when r is 0, then R 2 Can be used with R 3 They come together to form bonds; and X 10 It is N; Or its salt.

[0041] [8] According to the compound in [1] above, wherein R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6 alkyl: (i) Halogen atoms, (ii) C 1-6 alkoxy groups, and (iii) C 3-6 cycloalkyl, (2) C 3-10 cycloalkyl, or (3) Single or double C 1-6 Alkylamino; R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 alkyl, or When r is 0, then R 2 and R 3 They can combine together to form bonds, or When X 10 It is CR 15 When, then R 3 With R 15 They come together to form bonds; R 4 It is a hydrogen atom, C1-6 Alkyl, C 1-6 alkoxy or hydroxyl groups; R 5 It is phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, pyridyl, piperidinyl, or cyclobutyl, any of which may optionally be independently selected from C10 or C20. 1-6 Alkyl group, halogen atom, halogen group (C 1-6 )alkyl and C 1-6 Substitution of alkoxy groups; R 6 and R 7 Each is independently a hydrogen atom, a halogen atom, or a carbon atom. 1-6 alkyl; X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (viii) X 1 It is CR 9 X2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; X 8 X 9 X 10 m, q, and r are selected to form a ring system, which is one of the following: (i) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; (ii) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 1, q is 1, and r is 0; (iii) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 1; (iv) X 8 It is N, X 9 It is N, X 10 It is CR 15 m is 0, q is 1, and r is 0; (v) X 8 It is CR 14 X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; and (vi) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 0, q is 2, and r is 0; R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl group, halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl (C1-6 )alkoxy, halogen (C 1-6 )alkyl, halogen (C 1-6 )alkoxy, C 1-6 Alkoxy (C 1-6 )alkyl, azahexacyclic butyl, C 1-6 Alkoxy, hydroxyl and hydroxyl (C 1-6 )alkyl; and R 14 It is a hydrogen atom, a halogen atom, or a carbon atom. 1-6 Alkyl; and R 15 With R 3 They come together to form bonds; Or its salt.

[0042] [9] According to the compounds in [1] above, the partial structures represented by the following formula are: Each symbol is defined as described above [1]. It is one of the partial structures represented by the following formula: , , , , , and , Each of these symbols is defined as described above in [1].

[0043]

[10] According to the compound of [1] above, wherein the compound is represented by formula (Ia): (Ia) in R 1 It is C 1-6 Alkyl, C 3-10 cycloalkyl or mono-C 1-6 Alkylamino; r is 0 or 1; R 2 and R 3 Each is an independent hydrogen atom, or When r is 0, then R 2 and R 3 They can combine together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is optionally substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is an independent hydrogen atom or a halogen atom; X 5 It is CH or N; and R 12 and R 13 Each is an independent hydrogen atom, C 1-6 Alkyl or halogen atom; Or its salt.

[0044]

[11] According to the compound in

[10] above, wherein R 1 It is C 1-6 alkyl; r is 0 or 1; R 2 and R 3 Each is a hydrogen atom, or When r is 0, then R 2 and R 3 They can combine together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that has been substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is a halogen atom; X 5 It is CH; and R 12 and R 13 Each is an independent hydrogen atom or a halogen atom; Or its salt.

[0045]

[12] According to the compound of [1] above, wherein the compound is represented by formula (Ib): (Ib) in R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino; R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 alkyl, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 5 It is a 5- or 6-membered monocyclic group that can be optionally substituted; R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl; m is 0 or 1; q is 1 or 2; X 1 It is NR 8 or CR 9 ; X 2 It is O, NR 10 Or S; X 3 and X 4 Both are C or X 3 and X 4 One of them is N and the other is C; X 5 It is CR 11 Or N; X 6 It is CR 12 ; X 7 It is CR 13 Or N; R 9 R 11 R 12 and R 13 Each is an independent hydrogen atom, with optional substitutions of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 alkoxy or hydroxyl; and R 8 and R 10 Each of them does not exist independently, or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 alkyl; Or its salt.

[0046] [12a] According to the compound of

[12] above, wherein R 2 and R 3 Each is a hydrogen atom; or a salt thereof.

[0047] [12b] According to the compound of

[12] above, wherein R 2 and R 3 They come together to form bonds; or their salts.

[0048] [12c] According to the compound of

[12] above, wherein m is 0; and q is 1; or a salt thereof.

[0049] [12d] According to the above

[12] compound (I), where m is 1; and q is 1; or a salt thereof.

[0050] [12e] According to the compound of

[12] above, wherein R 1 It is C 1-6 Alkyl group; or its salt.

[0051] [12f] According to the compound in

[12] above, wherein X 1 It is NR 8 And R 8 It does not exist; X 2 It is O; X 3 and X 4 Both are C; X 5 It is CH or N; X 6 It is CR 12 And R 12 It is a hydrogen atom, C 1-6 Alkyl or halogen atom; and X 7 It is CR 13 And R 13 It is a hydrogen atom or a halogen atom; Or its salt.

[0052]

[13] According to the compound in

[12] above, wherein R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6 alkyl: (i) Halogen atoms, (ii) C 1-6 alkoxy groups, and (iii) C 3-6 cycloalkyl, (2) C 3-10 cycloalkyl, or (3) Single or double C 1-6 Alkylamino; R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 Alkyl, or R 2 and R 3 They come together to form bonds; R4 It is a hydrogen atom, C 1-6 Alkyl, C 1-6 alkoxy or hydroxyl groups; R 5 It is phenyl, pyrazolyl, furanyl, thiophenyl, or thiazolyl, any of which may optionally be selected independently by one or more C14 groups. 1-6 Alkyl group, halogen atom, halogen group (C 1-6 )alkyl and C 1-6 Substitution of alkoxy groups; m is 0 or 1; q is 1 or 2; R 6 and R 7 Each is independently a hydrogen atom, a halogen atom, or a carbon atom. 1-6 alkyl; X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X6 It is CR 12 And X 7 It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (viii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;and R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl group, halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl (C 1-6 )alkoxy, halogen (C 1-6 )alkyl, halogen (C 1-6 )alkoxy, C 1-6 Alkoxy (C 1-6 )alkyl, azahexacyclic butyl, C 1-6 Alkoxy, hydroxyl and hydroxyl (C 1-6 )alkyl; Or its salt.

[0053]

[14] According to the compound of [1] above, wherein the compound is represented by formula (Ic): (Ic) in R 1 It is C 1-6 Alkyl or mono-C 1-6 Alkylamino; R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is optionally substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is an independent hydrogen atom or a halogen atom; X 5 It is CH or N; and R 12 and R 13Each is an independent hydrogen atom, C 1-6 Alkyl or halogen atom; Or its salt.

[0054]

[15] According to the compound described in

[14] above, wherein R 1 It is C 1-6 alkyl; R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that has been substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is a halogen atom; X 5 It is CH; and R 12 and R 13 Each is an independent hydrogen atom or a halogen atom; Or its salt.

[0055]

[16] According to the compounds of [1] above, wherein the compounds are selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; Or its salt.

[0056]

[17] An agent comprising a compound or a salt thereof as defined in any one of [1] to

[16] above.

[0057]

[18] According to the above

[17] , the agent is an orexin type 2 receptor agonist.

[0058]

[19] According to the above

[17] , the agent is an agent for the prevention or treatment of the following diseases: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disorder of consciousness, or side effects and complications caused by anesthesia.

[0059]

[20] According to the above

[17] , the agent is an agent for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

[0060]

[21] According to the above

[17] , the medicine is used to prevent or treat narcolepsy.

[0061]

[22] A method for preventing or treating diseases or conditions associated with orexin type 2 receptors in mammals in need, the method comprising administering to the mammal a therapeutically effective amount of a compound or a salt thereof as defined in any one of [1] to

[16] above.

[0062]

[23] According to the method described in

[22] above, the disease or condition is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications caused by anesthesia.

[0063]

[24] According to the method described in

[22] above, the disease or condition is selected from narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

[0064]

[25] According to the method described in

[22] above, the disease or condition is narcolepsy.

[0065]

[26] A compound or salt thereof as defined in any of [1] to

[16] above, said compound or salt thereof is used in a therapeutic manner.

[0066]

[27] According to the compound or salt of

[26] above, said therapy includes treating diseases or conditions associated with orexin type 2 receptor.

[0067]

[28] According to the compound or salt of

[27] above, the disease or condition is selected from the group consisting of: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications of anesthesia.

[0068]

[29] According to the compound or salt of

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

[0069]

[30] According to the compound or salt of

[27] above, wherein the disease or condition is narcolepsy.

[0070]

[31] Use of a compound or salt thereof as defined in any one of [1] to

[16] above as a medicament for treating diseases or conditions associated with orexin type 2 receptor.

[0071]

[32] According to the use described above

[31] , the disease or condition is selected from the group consisting of: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disorder of consciousness, and side effects and complications caused by anesthesia.

[0072]

[33] According to the use described in

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

[0073]

[34] According to the use described in

[31] above, the disease or condition described is narcolepsy.

[0074] [Function of the Invention] The compounds of the present invention have orexin type 2 receptor agonist activity and can be used as agents for the prevention or treatment of certain diseases, such as narcolepsy. Detailed Implementation

[0075] The following describes in detail the definition of each substituent used in this specification. Unless otherwise stated, each substituent has the following definition.

[0076] In this specification, examples of "halogen atoms" include fluorine, chlorine, bromine, and iodine.

[0077] In this specification, "C" 1-6 Examples of "alkyl" 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.

[0078] In this specification, "optionally halogenated C" 1-6 Examples of "alkyl" include C atoms that optionally have 1 to 7, preferably 1 to 5, more preferably 1 to 3 halogen atoms. 1-6Alkyl groups. Specific examples include methyl, chloromethyl, 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.

[0079] In this specification, "halogenated C" 1-6 Examples of "alkyl" include the aforementioned "optionally halogenated C". 1-6 "Halogenated C" in "alkyl" 1-6 alkyl".

[0080] In this specification, "C" 2-6 Examples of "alkenyl" include vinyl, 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.

[0081] In this specification, "C" 2-6 Examples of "alkynyl" include ethynyl, 1-propynyl, 2-propynyl, 2-methyl-1-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-3-pentenyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl.

[0082] In this specification, "C" 2-6 Examples of "alkynyl" 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.

[0083] In this specification, "C" 3-10 Examples of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0084] In this specification, "optionally halogenated C" 3-10 Examples of "cycloalkyl" include C16 groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10Cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0085] In this specification, "C" 3-10 Examples of "cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0086] In this specification, "C" 7-16 Examples of "aryl" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0087] In this specification, "C" 1-6 Examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0088] In this specification, "optionally halogenated C" 1-6 Examples of "alkoxy" include C atoms that optionally have 1 to 7, preferably 1 to 5, more preferably 1 to 3 halogen atoms. 1-6 Alkyl groups. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, and hexoxy.

[0089] In this specification, "halogenated C" 1-6 Examples of "alkoxy" include the aforementioned "optionally halogenated C". 1-6 The "halogenated C" in "alkoxy" 1-6 Alkyl groups.

[0090] In this specification, "C" 3-10 Examples of “cycloalkoxy” include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptoxy, and cyclooctoxy.

[0091] In this specification, "C" 1-6 Examples of "alkylthio" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0092] In this specification, "optionally halogenated C" 1-6 Examples of "alkylthio" include C groups that optionally have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkylthio. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0093] In this specification, "C" 1-6 Examples of "alkyl-carbonyl" include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl, and heptanoyl.

[0094] In this specification, "optionally halogenated C" 1-6 Examples of "alkyl-carbonyl" include C groups that optionally have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl-carbonyl. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0095] In this specification, "C" 1-6 Examples of "alkoxy-carbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, and hexoxycarbonyl.

[0096] In this specification, "C" 6-14 Examples of "aryl-carbonyl" include benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0097] In this specification, "C" 7-16 Examples of "aralkyl-carbonyl" include phenylacetyl and phenylpropionyl.

[0098] Examples of “5- to 14-membered aromatic heterocyclic carbonyl groups” in this specification include nicotinyl, isonicotinyl, thiophenecarboxyl, and furanoyl.

[0099] Examples of “3- to 14-membered non-aromatic heterocyclic carbonyl groups” in this specification include morpholinocarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0100] In this specification, "single or dual C" 1-6 Examples of "alkyl-carbamoyl" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0101] In this specification, "optionally replaced single or double C" 1-6 Examples of "alkylamino" include those having one or two C2Cs. 1-6 Alkyl groups with amino groups. The C group of an amino group. 1-6 The alkyl moiety may optionally have one or two substituents selected from the following: C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aryl-carbamoyl, C 1-6 alkylsulfonyl and C 6-14 The arylsulfonyl group each optionally has 1 to 3 substituents selected from substituent group A.

[0102] In this specification, examples of "optionally substituted amino groups" include those that optionally have the following amino groups: "1 or 2 substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aryl-carbamoyl, C 1-6 alkylsulfonyl and C 6-14 "Arylsulfonyl group, each optionally having 1 to 3 substituents selected from substituent group A".

[0103] Preferred examples of optionally substituted amino groups include amino groups, mono- or di-(optionally halogenated C42-) amino groups, and mono- or di-(halogenated C42-) amino groups. 1-6 Alkyl)amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino (e.g., phenylamino), mono- or di-C 7-16 Arylamino (e.g., benzylamino, diphenylmethylamino), mono- or di-(optionally halogenated C) 1-6 Alkyl)-carbonylamino (e.g., acetylamino, propionylamino), single or two C 6-14 aryl-carbonylamino (e.g., benzoylamino), single or two C 7-16Arylalkyl-carbonylamino (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclic carbonylamino (e.g., nicotinylamino, isonicotinylamino), mono- or di-3- to 14-membered non-aromatic heterocyclic carbonylamino (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (e.g., pyridylamino), carbamoylamino, (single or dicarbonyl) 1-6 alkyl-carbamoyl)amino (e.g., methylcarbamoylamino), (single or dicarbonyl) 7-16 Arylalkyl-carbamoyl)amino (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 Aryl-carbonyl)amino (e.g., N-benzoyl-N-methylamino).

[0104] In this specification, "hydroxyl" refers to -OH. In this specification, "hydroxyl" and "hydroxyl" are the same.

[0105] In this specification, examples of "quaternary, quinary, or hexacyclic monocyclic groups" include those selected from C as described herein. 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 4-, 5-, or 6-membered monocyclic groups of aryl and heterocyclic groups (e.g., aromatic heterocyclic or non-aromatic heterocyclic groups).

[0106] In this specification, "C" 6-14 Examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthrayl, 2-anthrayl, and 9-anthrayl.

[0107] In this specification, examples of "heterocycles" include aromatic heterocycles and non-aromatic heterocycles, each containing one to four (e.g., one, two, three, or four) heteroatoms selected from nitrogen, sulfur, oxygen, and combinations thereof as cyclic atoms other than carbon atoms.

[0108] In this specification, examples of "aromatic heterocycles" include 5- to 14-membered (preferably 5- to 10-membered, more preferably 5- to 6-membered) aromatic heterocycles, wherein the heterocycle contains 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen and combinations thereof as cyclizing atoms other than carbon atoms. Examples of "aromatic heterocycles" 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, tetraazole, triazine, etc.; and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles, such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzo[…]. Triazole, imidazopyridine, thienopyridine, furanopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furanopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxazine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazolin, cinnamoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, pheoxazine, etc.

[0109] In this specification, examples of "non-aromatic heterocycles" include 3- to 14-membered (preferably 4- to 10-membered, more preferably 5- to 6-membered) non-aromatic heterocycles, wherein the heterocycle contains 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen and combinations thereof as cyclizing atoms other than carbon atoms. Examples of "non-aromatic heterocycles" include 3- to 8-membered monocyclic non-aromatic heterocycles, such as azirropropane, oxacyclopropane, thiohexacyclopropane, azirrobutane, oxacyclobutane, thiohexacyclobutane, tetrahydrothiophene, tetrahydrofuran, pyrrololine, pyrrolidine, imidazoline, imidazoline, oxazoline, oxazoline, pyrazolidine, pyrazoline, pyrazolidine, thiazoline, thiazoline, tetrahydroisothiazolidine, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiaran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiaran, morpholine, thiomorpholine, azirroheptane, diazirroheptane, azirroheptane, azirroheptane, diazirrooctane. Oxyheptanes, etc.; and 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycles, such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinazine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoheptatriene, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenothiazine, tetrahydrophthalazine, tetrahydronaphthoidine, tetrahydroquinazolinoline, tetrahydrocarbazole, tetrahydro-β-carbine, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthium, octahydroisoquinoline, etc.

[0110] In this specification, examples of “3- to 7-membered nitrogen-containing heterocycles” include 3- to 7-membered “heterocyclic groups” as described herein that contain at least one (e.g., 1, 2, 3, etc.) nitrogen atom as a cyclizing atom.

[0111] In this specification, examples of "acyl" include formyl, carboxyl, carbamoyl, thiocarbamoyl, sulfinyl, sulfonyl, aminosulfonyl, and phosphonyl, each optionally having "one or two substituents selected from: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, C 7-16 Aryl group, 5- to 14-membered aromatic heterocyclic group, and 3- to 14-membered non-aromatic heterocyclic group, each optionally having 1 to 3 C atoms selected from halogen atoms, optionally halogenated. 1-6 Substituents of alkoxy, hydroxy, nitro, cyano, amino, and carbamoyl groups.

[0112] Examples of "acyl" also include hydrocarbon sulfonyl, heterocyclic sulfonyl, hydrocarbon sulfinyl, and heterocyclic sulfinyl.

[0113] Here, alkyl-sulfonyl means sulfonyl group with alkyl group bond, heterocyclic sulfonyl means sulfonyl group with heterocyclic group bond, alkyl-sulfinyl means sulfinyl group with alkyl group bond, and heterocyclic sulfinyl means sulfinyl group with heterocyclic group bond.

[0114] Examples of "acyl" groups include formyl, carboxyl, and C. 1-6 alkyl-carbonyl, C 2-6 Alkenyl-carbonyl (e.g., crotonyl), C 3-10 Cycloalkyl-carbonyl (e.g., cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyl, cycloheptane carbonyl), C 3-10 Cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 Aryloxy-carbonyl (e.g., phenoxycarbonyl, naphthoxycarbonyl), C 7-16 Aryl alkoxy-carbonyl (e.g., benzyl oxycarbonyl, phenethoxycarbonyl), carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl, 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl), thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), single or two C 2-6 Alkenyl-thiocarbamoyl (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), single or two C 6-14 aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), single or two C 7-16 Aryl-thiocarbamoyl (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridyl thiocarbamoyl), sulfinyl, C 1-6 Alkyl sulfinyl (e.g., methyl sulfinyl, ethyl sulfinyl), sulfonyl, C 1-6 alkylsulfonyl, C 6-14arylsulfonyl, phosphonyl and mono- or di-C 1-6 Alkylphosphonoyl (e.g., dimethylphosphonoyl, diethylphosphonoyl, diisopropylphosphonoyl, dibutylphosphonoyl).

[0115] Examples of “5- to 14-membered aromatic heterocyclic carbonyl groups” in this specification include nicotinyl, isonicotinyl, thiophenecarboxyl, and furanoyl.

[0116] Examples of “3- to 14-membered non-aromatic heterocyclic carbonyl groups” in this specification include morpholinocarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0117] In this specification, examples of "optionally substituted carbamoyl groups" include those optionally having the following carbamoyl groups: "1 or 2 substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl groups, each optionally having 1 to 3 substituents selected from substituent group A.

[0118] Preferred examples of optionally substituted carbamoyl groups include carbamoyl groups, mono- or di-C groups. 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), single or two C 6-14 Aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl (e.g., acetylcarbamoyl, propionylcarbamoyl), single or two C 6-14 Aryl-carbonyl-carbamoyl (e.g., benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl).

[0119] In this specification, examples of "optionally substituted thiocarbamoyl group" include those optionally having the following thiocarbamoyl group: "1 or 2 substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl groups, each optionally having 1 to 3 substituents selected from substituent group A.

[0120] Preferred examples of optionally substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C groups. 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), single or two C 2-6 Alkenyl-thiocarbamoyl (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), single or two C 6-14 aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), single or two C 7-16 Aryl-thiocarbamoyl (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), single or two C 1-6 Alkyl-carbonyl-thiocarbamoyl (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), single or two C 6-14 Aryl-carbonyl-thiocarbamoyl (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridylthiocarbamoyl).

[0121] In this specification, examples of "optionally substituted aminosulfonyl groups" include those optionally having the following aminosulfonyl groups: "1 or 2 substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl groups, each optionally having 1 to 3 substituents selected from substituent group A.

[0122] Preferred examples of optionally substituted aminosulfonyl groups include aminosulfonyl groups, mono- or di-C groups. 1-6 Alkyl-aminosulfonyl (e.g., methylaminosulfonyl, ethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl), mono- or di-C 2-6 Alkenyl-aminosulfonyl (e.g., diallylaminosulfonyl), mono- or di-C 3-10 Cycloalkyl-aminosulfonyl (e.g., cyclopropylaminosulfonyl, cyclohexylaminosulfonyl), mono- or di-C 6-14 aryl-aminosulfonyl (e.g., phenylaminosulfonyl), mono- or di-C 7-16 Aryl alkyl-aminosulfonyl (e.g., benzyl aminosulfonyl, phenylethyl aminosulfonyl), mono- or di-C 1-6 Alkyl-carbonyl-aminosulfonyl (e.g., acetylaminosulfonyl, propionylaminosulfonyl), single or two C 6-14 Aryl-carbonyl-aminosulfonyl (e.g., benzoylaminosulfonyl) and 5- to 14-membered aromatic heterocyclic aminosulfonyl (e.g., pyridylaminosulfonyl).

[0123] In this specification, examples of "optionally substituted hydroxyl groups" include those that optionally have the following hydroxyl groups: "substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic groups, carbamoyl, single or two-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aryl-carbamoyl, C 1-6 alkylsulfonyl and C 6-14 "Arylsulfonyl group, each optionally having 1 to 3 substituents selected from substituent group A".

[0124] Preferred examples of optionally substituted hydroxyl groups include hydroxyl, C 1-6 Alkoxy, C 2-6 Enyloxy groups (e.g., allyloxy, 2-butenoxy, 2-pentenoxy, 3-hexenoxy), C 3-10 Cycloalkoxy (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), C 7-16 Aryl alkoxy groups (e.g., benzyl oxy, phenylethoxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propionyloxy, butyryloxy, isobutyryloxy, neopentyloxy), C 6-14 aryl-carbonyloxy (e.g., benzoyloxy), C 7-16 Arylalkyl-carbonyloxy (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy (e.g., nicotinyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy (e.g., pyridinoxy), carbamoyloxy, C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy), C 7-16 Arylalkyl-carbamoyloxy (e.g., benzylcarbamoyloxy), C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy) and C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy).

[0125] In this specification, examples of "optionally substituted thioalkyl" include thioalkyl groups that optionally have the following substituents: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 "Aryl-carbonyl and 5- to 14-membered aromatic heterocyclic groups, each optionally having 1 to 3 substituents selected from substituent group A", and a thioalkyl halide.

[0126] Preferred examples of optionally substituted thioalkyl groups include thioalkyl (-SH) groups, C 1-6 Alkylthio, C 2-6 Enyl thiols (e.g., allyl thiols, 2-butenyl thiols, 2-pentenyl thiols, 3-hexenyl thiols), C 3-10 Cycloalkylthio (e.g., cyclohexylthio), C 6-14 Aryl thiols (e.g., phenylthiols, naphthiols), C 7-16Aryl thiols (e.g., benzyl thiols, phenylethyl thiols), C 1-6 Alkyl-carbonyl thio groups (e.g., acetyl thio, propionyl thio, butyryl thio, isobutyryl thio, neopentyl thio), C 6-14 Aryl-carbonyl thio (e.g., benzoyl thio), 5- to 14-membered aromatic heterocyclic thio groups (e.g., pyridinyl thio), and halogenated thio groups (e.g., pentafluorothio).

[0127] In this specification, examples of "optionally substituted silicon-based" include silicon-based materials that optionally have the following: "1 to 3 substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl and C 7-16 Aryl alkyl groups, each optionally having 1 to 3 substituents selected from substituent group A.

[0128] Preferred examples of silicon-based alternatives include three-C. 1-6 Alkylsilyl (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0129] In this specification, examples of "hydrocarbon rings" include C 6-14 Aromatic hydrocarbon rings, C 3-10 Cycloalkanes and C 3-10 Cyclic olefins.

[0130] In this specification, "single or dual C" 7-16 Examples of "aralkyl-carbamoyl" include benzylcarbamoyl and phenylethylcarbamoyl.

[0131] In this specification, "C" 1-6 Examples of "alkylsulfonyl" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0132] In this specification, "optionally halogenated C" 1-6 Examples of "alkylsulfonyl" include C groups that optionally have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl sulfonyl groups. Specific examples include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, pentyl sulfonyl, and hexyl sulfonyl.

[0133] In this specification, "C" 6-14 Examples of "arylsulfonyl" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0134] In this specification, examples of "hydrocarbon group" (including "hydrocarbon group" of "optionally substituted hydrocarbon group") include C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl and C 7-16 Aryl alkyl group.

[0135] In this specification, examples of “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridged heterocyclic groups, each containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as cyclizing atoms other than carbon atoms.

[0136] In this specification, examples of "aromatic heterocyclic groups" (including "5- to 14-membered aromatic heterocyclic groups") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as cyclic atoms other than carbon atoms.

[0137] Preferred examples of "aromatic heterocyclic groups" include 5- or 6-membered monocyclic aromatic heterocyclic groups, such as thienyl, furanyl, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups, such as benzothienyl, benzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzo[…]. Triazolyl, imidazopyridyl, thiophene-pyridyl, furan-pyridyl, pyrrolopyridyl, pyrazololopyridyl, oxazololopyridyl, thiazopyridyl, imidazopyrazinyl, imidazopyrimidyl, thiophene-pyrimidyl, furan-pyrimidyl, pyrrolopyrimidyl, pyrazololopyrimidyl, oxazololopyrimidyl, thiazopyrimidyl, pyrazololotriazinyl, naphtho[2,3-b]thiopheneyl, phenoxazinyl, indoleyl, isoindoleyl, 1H-inzolyl, purinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, quinoxolinyl, quinazolinyl, cyclolinyl, carbazoyl, β-carolinyl, phenanthidyl, acridineyl, phenazinyl, phenthiazinyl, phenoxazinyl, etc.

[0138] In this specification, examples of "non-aromatic heterocyclic groups" (including "3- to 14-membered non-aromatic heterocyclic groups") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups, wherein the heterocyclic group contains 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms as cyclic atoms other than carbon atoms.

[0139] Preferred examples of "non-aromatic heterocyclic groups" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups, such as azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrothiophene, tetrahydrofuranyl, pyrrolinyl, pyrrolylyl, imidazolinyl, imidazolinyl, oxazolinyl, oxazolinyl, pyrazolelinyl, pyrazoleyl, thiazolinyl, thiazolinyl, tetrahydroisothiazolinyl, tetrahydrooxazolinyl, tetrahydroisooxazolinyl, piperidinyl, piperazine, tetrahydropyridinyl, dihydropyridinyl, dihydrothiaranyl, tetrahydropyrimidinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, thiomorpholinyl, azirroheptanyl, diazirroheptanyl, azirroheptantrienyl, oxacycloheptanyl, and azirroheptanyl. Heterocyclic octyl groups, diazacyclic octyl groups, etc.; and 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thiophenyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinazinyl, indololinyl, etc. Isoindoline, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzozaheptatrienyl, tetrahydroquinoxalinyl, tetrahydrophenanthridine, hexahydrophenthiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthidyl, tetrahydroquinazolinyl, tetrahydrobenzolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbazolyl, tetrahydroacridyl, tetrahydrophenazinyl, tetrahydrothioxanyl, octahydroisoquinolinyl, etc.

[0140] In this specification, preferred examples of “7- to 10-membered bridged heterocyclic groups” include quinine cycloyl groups and 7-azabicyclo[2.2.1]heptyl groups.

[0141] In this specification, examples of "nitrogen-containing heterocyclic groups" include "heterocyclic groups" that contain at least one nitrogen atom as a cyclic atom.

[0142] In this specification, examples of "optionally substituted heterocyclic groups" include heterocyclic groups that optionally have one or more substituents selected from the substituent group A above.

[0143] The number of substituents in "optionally substituted heterocyclic groups" is, for example, one to three. When the number of substituents is two or more, the individual substituents may be the same or different.

[0144] In this specification, "C" 6-14Examples of "aromatic hydrocarbon rings" include benzene and naphthalene.

[0145] In this specification, "C" 3-10 Examples of "cycloalkanes" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0146] In this specification, "C" 3-10 Examples of "cycloolefins" include cyclopropylene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[0147] In this specification, examples of "nitrogen-containing heterocycles" include heterocycles selected from "heterocycles" that contain at least one nitrogen atom as a cyclizing atom.

[0148] In this specification, examples of "4- to 6-membered heterocyclic groups" include aromatic or non-aromatic 4- to 6-membered heterocyclic groups. Specific examples include oxobutyl, furanyl, pyrazolyl, pyridyl, and pyrimidinyl groups.

[0149] In this specification, examples of "ring" include "hydrocarbon ring" and "heterocyclic ring".

[0150] In this specification, certain portions may be “optionally substituted”, meaning that the group may optionally have one or more substituents selected from substituent group A below.

[0151] [Substituted base set A] (1) Halogen atom, (2) Nitro, (3) Cyano group, (4) Oxide group, (5) Hydroxyl group, (6) Optional halogenated C 1-6 Alkoxy (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 Aryl alkoxy groups (e.g., benzyl alkoxy groups), (9) 5- to 14-membered aromatic heterocyclic groups (e.g., pyridinoxy groups), (10) 3- to 14-membered non-aromatic heterocyclic groups (e.g., tetrahydropyranoxy, morpholinoxy, piperidinoxy), (11) C 1-6 Alkyl-carbonyl groups (e.g., acetoxy, propionyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C 1-6Alkyl-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl), (14) Single or double C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) C 6-14 Aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) 5- to 14-membered aromatic heterocyclic carbonyl groups (e.g., nicotinoxy groups), (17) 3- to 14-membered non-aromatic heterocyclic carbonyl groups (e.g., morpholinyl carbonyl group, piperidinyl carbonyl group), (18) C of optional geohalogenation 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) Optional location C 1-6 Alkyl-substituted C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) C of optional geohalogenation 1-6 Alkylthio, (21) Aromatic heterocyclic groups ranging from 5 to 14 yuan, (22) 3- to 14-membered non-aromatic heterocyclic groups, (23) Formyl group, (24) Carboxyl group, (25) C of optional geohalogenation 1-6 alkyl-carbonyl, (26) C 6-14 aryl-carbonyl, (27) 5- to 14-membered aromatic heterocyclic carbonyl groups, (28) 3- to 14-membered non-aromatic heterocyclic carbonyl groups, (29) C 1-6 alkoxy-carbonyl, (30) C 6-14 Aryloxy-carbonyl (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl), (31) C 7-16 Aryl alkoxy-carbonyl (e.g., benzyloxycarbonyl, phenethoxycarbonyl), (32) Carbamoyl group, (33) Thiocarbamoyl, (34) Single or double C 1-6 Alkyl-carbamoyl, (35) C6-14 Aryl-carbamoyl (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., morpholinocarbamoyl, piperidinylcarbamoyl), (38) C of optional geohalogenation 1-6 alkylsulfonyl, (39) C 6-14 arylsulfonyl, (40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl, (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., pyridyl sulfinyl, thienyl sulfinyl), (44) Amino, (45) Single or double C 1-6 Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) Single or double C 6-14 Arylamino (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino groups), (48) C 7-16 Arylamino (e.g., benzylamino), (49) Formylamino, (50) C 1-6 Alkyl-carbonylamino (e.g., acetylamino, propionylamino, butyrylamino), (51) (C 1-6 Alkyl)(C 1-6 (alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino), (52) C 6-14 Aryl-carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53) C 1-6Alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) C 7-16 Arylalkoxy-carbonylamino (e.g., benzyloxycarbonylamino), (55) C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino), (56) Optional land cover C 1-6 Alkyl-substituted C 6-14 Arylsulfonylamino (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) C of optional geohalogenation 1-6 alkyl, (58) C 2-6 alkenyl, (59) C 2-6 alkynyl group, (60) C 3-10 cycloalkyl, (61) C 3-10 Cycloalkenyl, and (62) C 6-14 Aryl.

[0152] In some respects, examples of "substituents" include 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 aminosulfonyl groups, optionally substituted hydroxyl groups, optionally substituted thioalkyl (SH) groups, and optionally substituted silyl groups.

[0153] The number of substituents is, for example, 1 to 5 (e.g., 1, 2, 3, 4 or 5), preferably 1 to 3 (e.g., 1, 2 or 3). When the number of substituents is two or more, the substituents may be the same or different.

[0154] The definition of each symbol in compound (I) is explained in detail.

[0155] R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino.

[0156] In some respects, R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6Alkyl groups (e.g., methyl, ethyl): (i) Halogen atoms (e.g., fluorine atoms), (ii) C 1-6 Alkyl groups (e.g., methoxy groups), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl groups), (2) C 3-10 Cycloalkyl (e.g., cyclopropyl), or (3) Single or double C 1-6 Alkylamino (e.g., methylamino, dimethylamino).

[0157] In some respects, R 1 It is C 1-6 Alkyl (e.g., methyl, ethyl), C 3-10 cycloalkyl (preferably C) 3-6 Cycloalkyl groups (e.g., cyclopropyl) or mono-C 1-6 Alkylamino (e.g., methylamino).

[0158] In some respects, R 1 It is C 1-6 Alkyl (e.g., methyl, ethyl) or single C 1-6 Alkylamino (e.g., methylamino).

[0159] In some respects, R 1 It is C 1-6 Alkyl (e.g., methyl, ethyl).

[0160] R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 Alkyl group. Or, when r is 0, then R 2 and R 3 They can combine together to form bonds. Or, when X 10 It is R 15 When, then R 3 Can be used with R 15 They come together to form bonds.

[0161] In some respects, R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl), or when r is 0, then R 2 and R 3 They can combine together to form bonds, or when X 10 It is R 15 When, then R 3 With R 15 They come together to form bonds.

[0162] In some respects, R 2 and R 3 Each is a hydrogen atom, or when r is 0, then R 2 and R 3 They can combine together to form bonds, or when X 10 It is R 15 When, then R 3 With R 15 They come together to form bonds.

[0163] In some respects, in X 10 When R is N, 2 and R 3 Each is an independent hydrogen atom, or when r is 0, then R 2 and R 3 They can combine together to form bonds.

[0164] In some respects, in X 10 When R is N, 2 and R 3 Each is a hydrogen atom, or when r is 0, then R 2 and R 3 They can combine together to form bonds.

[0165] In R 2 and R 3 When they combine to form bonds, they contain X 8 X 9 and X 10 The ring includes the connection to R 2 and R 3 The double bonds between carbon atoms.

[0166] R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 Alkyl or hydroxyl groups.

[0167] In some respects, R 4 It is a hydrogen atom, C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl (e.g., ethoxy) or hydroxyl.

[0168] In some respects, R 4 It is a hydrogen atom.

[0169] R 5 It is a 4-, 5-, or 6-membered monocyclic group that can be optionally substituted.

[0170] In some respects, R 5It is phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, pyridyl, piperidinyl, or cyclobutyl, any of which is optionally selected independently by one or more (e.g., 1, 2, 3, etc.) from C. 1-6 Alkyl groups (e.g., methyl), halogen atoms (e.g., fluorine atoms, chlorine atoms), halogen groups (C... 1-6 )alkyl (e.g., trifluoromethyl) and C 1-6 Substituents of alkoxy groups (e.g., methoxy groups).

[0171] In some respects, R 5 It is a phenyl group that is optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms).

[0172] In some respects, R 5 It is a phenyl group that is substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms).

[0173] In some respects, R 5 It is a phenyl group that has been substituted with 2 or 3 fluorine atoms (e.g., 2,6-substituted or 2,4,6-substituted).

[0174] In some respects, R 5 It is a phenyl group that has been substituted with three fluorine atoms (e.g., 2,4,6-substituted).

[0175] R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl.

[0176] In some respects, R 6 and R 7 Each is independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a carbon atom. 1-6 Alkyl (e.g., methyl).

[0177] In some respects, R 6 and R 7 Each is independently a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0178] In some respects, R 6 and R 7 Each is a hydrogen atom, or each is a halogen atom (e.g., a fluorine atom).

[0179] In some respects, R 6 and R 7 Each is a halogen atom (e.g., a fluorine atom).

[0180] The subscript "m" together with "q" is 0 (forming a 5- or 6-element ring) or 1 (forming a 6- or 7-element ring).

[0181] The subscript "q" together with "m" is 1 (forming a 5- or 6-element ring) or 2 (forming a 6- or 7-element ring).

[0182] In some respects, m is 0; and q is 1, to form a 5-membered ring.

[0183] In some respects, m is 1; and q is 1, to form a 6-membered ring.

[0184] The subscript "r" is 0 (forming a 5-membered ring) or 1 (forming a 6-membered ring).

[0185] In some respects, the combination of m, q, and r is: m is 0; q is 1; and r is 0.

[0186] In some respects, the combination of m, q, and r is: m is 1; q is 1; and r is 0.

[0187] In some respects, the combination of m, q, and r is: m is 0; q is 1; and r is 1.

[0188] In some respects, the combination of m, q, and r is: m is 0; q is 2; and r is 0.

[0189] X 1 It is NR 8 or CR 9 , where R 8 It does not exist (i.e., =N-), or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 Alkyl, and R 9 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 Alkyl or hydroxyl groups.

[0190] In some respects, X 1 It is NR 8 , where R 8 It does not exist (i.e., =N-), or C 1-6 Alkyl (e.g., methyl).

[0191] In some respects, X 1 It is NR 8 , where R 8 It does not exist (i.e., =N-).

[0192] In some respects, X 1 It is CR 9 , where R 9 It is a hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl).

[0193] X 2 It is O, NR 10 Or S, where R 10 It does not exist (i.e., =N-), or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 alkyl.

[0194] In some respects, X 2 It is O.

[0195] In some respects, X 2 It is NR 10 , where R 10 It does not exist, or it is C. 1-6 Alkyl (e.g., methyl).

[0196] In some respects, X 2 It is S.

[0197] X 3 and X 4 (i) Both are C, or (ii) X 3 and X 4 One of them is N and the other is C.

[0198] In some respects, X 3 and X 4 Both are C.

[0199] In some respects, X 3 It is N, and X 4 It's C.

[0200] In some respects, X 3 It is C, and X 4 It is N.

[0201] X 5 It is CR 11 Or N, where R 11 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 Alkyl or hydroxyl groups.

[0202] In some respects, X 5 It is N.

[0203] In some respects, X 5 It is CR 11 , where R 11 It is a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a carbon atom. 1-6 Alkyl (e.g., methyl).

[0204] In some respects, X 5 It is CR 11 Or N, where R 11 It is a hydrogen atom.

[0205] X 6 It is CR 12 , where R 12 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 Alkyl or hydroxyl groups.

[0206] In some respects, R 12 It is a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl (C 1-6 )alkoxy groups (e.g., cyclopropylmethoxy), halogen groups (C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), halogen groups (C... 1-6 )alkoxy groups (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy (C 1-6 alkyl (e.g., methoxymethyl), aziridine, C 1-6 Alkyl groups (e.g., methoxy, ethoxy), hydroxyl groups, or hydroxyl groups (C) 1-6 alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl); In some respects, R 12 It is a hydrogen atom, C 1-6 Alkyl (e.g., methyl) or halogen atom (e.g., chlorine or fluorine).

[0207] In some respects, R 12 It is a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0208] X 7 It is CR 13 Or N, where R 13 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 Alkyl or hydroxyl groups.

[0209] In some respects, X 7 It is N.

[0210] In some respects, X 7 It is CR 13 , where R 13 It is a hydrogen atom or a halogen atom (e.g., a fluorine atom, a chlorine atom).

[0211] In some respects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a cyclic system, which is pyrazolopyridine, 1,2-benzoxazole, indazole, imidazopyridine, 1,2-benzothiazole, [1,2]oxazolo[4,5-c]pyridine, isoxazolo[5,4-b]pyridine or isothiazolo[5,4-b]pyridine.

[0212] In these respects, R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl (C 1-6 )alkoxy groups (e.g., cyclopropylmethoxy), halogen groups (C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), halogen groups (C... 1-6 )alkoxy groups (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy (C 1-6 alkyl (e.g., methoxymethyl), aziridine, C 1-6 Alkyl groups (e.g., methoxy, ethoxy), hydroxyl groups, and hydroxyl groups (C) 1-6 alkyl (e.g., hydroxymethyl, 2-hydroxyethyl); and R 8 and R 10 They do not exist independently (i.e., =N-), or are selected from hydrogen atoms and C atoms. 1-6 Alkyl (e.g., methyl).

[0213] In some respects, X 1 It is NR 8 , where R 8 It does not exist (i.e., =N-); X 2 It is O; X 3 and X 4Both are C; X 5 It is CR 11 Or N, where R 11 It is a hydrogen atom; X 6 It is CR 12 , where R 12 It is a hydrogen atom, C 1-6 Alkyl (e.g., methyl) or halogen atom (e.g., chlorine or fluorine); and X 7 It is CR 13 , where R 13 It is a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0214] In some respects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR12 And X 7 It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl (e.g., methyl), X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (viii) X1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 .

[0215] In some respects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 .

[0216] In some respects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7 Selected to form a ring system, where (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 .

[0217] In some respects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7 Selected to form a ring system, where (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CH, X 6 It is CR 12 And X 7 It is CR 13 .

[0218] In these respects, R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl (C 1-6 )alkoxy groups (e.g., cyclopropylmethoxy), halogen groups (C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), halogen groups (C... 1-6 )alkoxy groups (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy (C 1-6 alkyl (e.g., methoxymethyl), aziridine, C 1-6 Alkyl groups (e.g., methoxy, ethoxy), hydroxyl groups, and hydroxyl groups (C) 1-6 alkyl (e.g., hydroxymethyl, 2-hydroxyethyl).

[0219] X 8 It is CR 14 Or N, where R 14 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 alkyl.

[0220] In some respects, X 8 It is N.

[0221] In some respects, X 8 It is CR 14 , where R 14 It is a hydrogen atom.

[0222] X 9 It is CR 2 Or N, where R 2 It is a hydrogen atom or an optionally substituted C 1-6 Alkyl, or when r is 0, then R 2 Can be used with R 3 They come together to form bonds.

[0223] In some respects, X 9 It is CR 2 , where R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl), or when r is 0, then R 2 Can be used with R 3 They come together to form bonds.

[0224] In some respects, X 9 It is CR 2 , where R 2 It is a hydrogen atom, or when r is 0, then R 2 Can be used with R 3 They come together to form bonds.

[0225] In some respects, X 9 It is CR 2 , where R 2 It is a hydrogen atom.

[0226] In some respects, X 9 It is CR 2 r is 0, and R 2 With R 3 They come together to form bonds.

[0227] In some respects, X 9 It is N.

[0228] X 10 It is CR 15 Or N, where R 15 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 Alkyl, or R 15 Can be used with R 3 They come together to form bonds.

[0229] In some respects, X 10 It is N.

[0230] In some respects, X 10 It is CR 15 , where R 15 With R 3 They come together to form bonds.

[0231] In some respects, X 8 It is N; X 9 It is CR 2 , where R 2 It is a hydrogen atom, or when r is 0, then R 2 Can be used with R 3 Together they form bonds; and X 10 It is N.

[0232] In some respects, X 8 It is N; X 9 It is CR 2 , where R 2 It is a hydrogen atom; and X 10 It is N.

[0233] In some respects, X 8 It is N; X 9 It is CR 2 Where r is 0 and R2 is equal to R 3 Together they form bonds; and X 10 It is N.

[0234] In some respects, X 8 X 9 X 10 m, q, and r are selected to form a ring system, which is one of the following: (i) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; (ii) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 1, q is 1, and r is 0; (iii) X 8 It is N, X 9 It is CR 2 X 10It is N, m is 0, q is 1, and r is 1; (iv) X 8 It is N, X 9 It is N, X 10 It is CR 15 m is 0, q is 1, and r is 0; (v) X 8 It is CR 14 X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; and (vi) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 0, q is 2, and r is 0.

[0235] In some respects, X 8 X 9 X 10 m, q, and r are selected to form a ring system, which is one of the following: (i) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; and (iii) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 1.

[0236] In these respects, R 2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl), or when r is 0, then R 2 Can be used with R 3 They come together to form bonds; R 14 It is a hydrogen atom, a halogen atom, or a carbon atom. 1-6 Alkyl; and R 15 With R 3 They come together to form bonds; In some respects, the partial structure is represented by the following formula: Each symbol is defined as described above. It is one of the partial structures represented by the following formula: , , , , , and , Each symbol is defined as described above.

[0237] In some aspects of compound (I), R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6 Alkyl groups (e.g., methyl, ethyl): (i) Halogen atoms (e.g., fluorine atoms), (ii) C 1-6 Alkyl groups (e.g., methoxy groups), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl groups), (2) C 3-10 Cycloalkyl (e.g., cyclopropyl), or (3) Single or double C 1-6 Alkylamino (e.g., methylamino, dimethylamino); R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl), or When r is 0, then R 2 and R 3 They can combine together to form bonds, or When X 10 It is CR 15 When, then R 3 With R 15 They come together to form bonds; R 4 It is a hydrogen atom, C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl (e.g., ethoxy) or hydroxyl; R 5 It is phenyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, pyridyl, piperidinyl, or cyclobutyl, any of which is optionally selected independently by one or more (e.g., 1, 2, 3, etc.) from C. 1-6 Alkyl groups (e.g., methyl), halogen atoms (e.g., fluorine atoms, chlorine atoms), halogen groups (C... 1-6 )alkyl (e.g., trifluoromethyl) and C 1-6 Substituents of alkoxy groups (e.g., methoxy groups); R 6 and R 7Each is independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a carbon atom. 1-6 Alkyl groups (e.g., methyl groups); X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl (e.g., methyl), X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (viii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; X 8X 9 X 10 m, q, and r are selected to form a ring system, which is one of the following: (i) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; (ii) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 1, q is 1, and r is 0; (iii) X 8 It is N, X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 1; (iv) X 8 It is N, X 9 It is N, X 10 It is CR 15 m is 0, q is 1, and r is 0; (v) X 8 It is CR 14 X 9 It is CR 2 X 10 It is N, m is 0, q is 1, and r is 0; and (vi) X 8 It is N, X 9 It is CR 2 X 10 The expression is N, m is 0, q is 2, and r is 0; R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl (C 1-6 )alkoxy groups (e.g., cyclopropylmethoxy), halogen groups (C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), halogen groups (C... 1-6 )alkoxy groups (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy (C 1-6 alkyl (e.g., methoxymethyl), aziridine, C 1-6Alkyl groups (e.g., methoxy, ethoxy), hydroxyl groups, and hydroxyl groups (C) 1-6 alkyl (e.g., hydroxymethyl, 2-hydroxyethyl); and R 14 It is a hydrogen atom; and R 15 With R 3 They come together to form bonds.

[0238] In some respects, compound (I) is represented by formula (Ia): (Ia) in R 1 It is C 1-6 Alkyl (e.g., methyl, ethyl), C 3-10 cycloalkyl (preferably C) 3-6 Cycloalkyl groups (e.g., cyclopropyl) or mono-C 1-6 Alkylamino (e.g., methylamino); r is 0 or 1; R 2 and R 3 Each is an independent hydrogen atom, or When r is 0, then R 2 and R 3 They can combine together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 Each is independently a hydrogen atom or a halogen atom (e.g., a fluorine atom); X 5 It is CH or N; and R 12 and R 13 Each is an independent hydrogen atom, C 1-6 Alkyl (e.g., methyl) or halogen atom (e.g., fluorine atom, chlorine atom); Or its salts (sometimes referred to as compound (Ia)).

[0239] In some aspects of compound (Ia), R 1 It is C 1-6 Alkyl groups (e.g., methyl, ethyl); r is 0 or 1; R 2 and R 3 Each is a hydrogen atom, or When r is 0, then R2 and R 3 They can combine together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 Each is a halogen atom (e.g., a fluorine atom); X 5 It is CH; and R 12 and R 13 Each is independently a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0240] In some respects, compound (I) is represented by formula (Ib): (Ib) in R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino; R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 alkyl, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 5 It is a 5- or 6-membered monocyclic group that can be optionally substituted; R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl; m is 0 or 1; q is 1 or 2; X 1 It is NR 8 or CR 9 ; X 2 It is O, NR 10 Or S; X 3 and X4 Both are C or X 3 and X 4 One of them is N and the other is C; X 5 It is CR 11 Or N; X 6 It is CR 12 ; X 7 It is CR 13 Or N; R 9 R 11 R 12 and R 13 Each is an independent hydrogen atom, with optional substitutions of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 alkoxy or hydroxyl; and R 8 and R 10 Each of them does not exist independently, or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 alkyl; Or its salts (sometimes referred to as compound (Ib)).

[0241] In some aspects of compound (Ib), R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6 Alkyl groups (e.g., methyl, ethyl): (i) Halogen atoms (e.g., fluorine atoms), (ii) C 1-6 Alkyl groups (e.g., methoxy groups), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl groups), (2) C 3-10 Cycloalkyl (e.g., cyclopropyl), or (3) Single or double C 1-6 Alkylamino (e.g., methylamino, dimethylamino); R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 Alkyl (e.g., methyl), or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom, C 1-6Alkyl (e.g., methyl), C 1-6 Alkyl (e.g., ethoxy) or hydroxyl; R 5 It is phenyl, pyrazolyl, furanyl, thiophenyl, or thiazolyl, any of which may optionally be independently selected from C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-6 Alkyl groups (e.g., methyl), halogen atoms (e.g., fluorine atoms, chlorine atoms), halogen groups (C... 1-6 )alkyl (e.g., trifluoromethyl) and C 1-6 Substituents of alkoxy groups (e.g., methoxy groups); m is 0 or 1; q is 1 or 2; R 6 and R 7 Each is independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a carbon atom. 1-6 Alkyl groups (e.g., methyl groups); X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl (e.g., methyl), X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X7 It is CR 13 ;as well as (viii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;and R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl (C 1-6 )alkoxy groups (e.g., cyclopropylmethoxy), halogen groups (C 1-6 alkyl groups (e.g., difluoromethyl, trifluoromethyl), halogen groups (C... 1-6 )alkoxy groups (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy (C 1-6 alkyl (e.g., methoxymethyl), aziridine, C 1-6 Alkyl groups (e.g., methoxy, ethoxy), hydroxyl groups, and hydroxyl groups (C) 1-6 alkyl (e.g., hydroxymethyl, 2-hydroxyethyl).

[0242] In some respects, compound (I) is represented by formula (Ic): (Ic) in R 1 It is C 1-6 Alkyl (e.g., methyl, ethyl) or single C 1-6 Alkylamino (e.g., methylamino); R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5It is a phenyl group that is optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 Each is independently a hydrogen atom or a halogen atom (e.g., a fluorine atom); X 5 It is CH or N; and R 12 and R 13 Each is an independent hydrogen atom, C 1-6 Alkyl (e.g., methyl) or halogen atom (e.g., fluorine atom, chlorine atom); Or its salts (sometimes called compounds (Ic)).

[0243] In some aspects of compound (Ic), R 1 It is C 1-6 Alkyl groups (e.g., methyl, ethyl); R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 Each is a halogen atom (e.g., a fluorine atom); X 5 It is CH; and R 12 and R 13 Each is independently a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0244] Exemplary examples of compounds (I) (including compounds (Ia), (Ib) and (Ic)) include the examples and the compounds listed in Table 1.

[0245] In some aspects, this disclosure provides a compound selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; Or its salt.

[0246] In some aspects, this disclosure provides a compound that is N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide or a salt thereof.

[0247] In some aspects, this disclosure provides a compound that is N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0248] In some aspects, this disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide or a salt thereof.

[0249] In some aspects, this disclosure provides a compound that is N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide or a salt thereof.

[0250] In some aspects, this disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0251] In some aspects, this disclosure provides a compound that is N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0252] In some aspects, this disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0253] In some aspects, this disclosure provides a compound that is N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0254] In some aspects, this disclosure provides a compound that is N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0255] In some aspects, this disclosure provides a compound that is N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0256] In some aspects, this disclosure provides a compound that is N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide or a salt thereof.

[0257] As a salt of the compound represented by formula (I), a pharmacologically acceptable salt is preferred, and examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc.

[0258] Examples of salts with inorganic bases include alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; aluminum and ammonium salts.

[0259] Examples of salts with organic bases include those with trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, etc. N , N - Salts of diphenylmethylethylenediamine, etc.

[0260] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0261] Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0262] Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0263] The method for producing the compounds of the present invention is explained below.

[0264] The starting material compounds and reagents used in each step of the following production method, as well as the resulting compounds, may each be in the form of salts, and examples of such salts include those similar to salts of compounds represented by formula (I).

[0265] When the compound obtained in each step is in its free form, it can be converted into the target salt using known methods. When the compound obtained in each step is a salt, it can be converted into the target free form or other salts using known methods.

[0266] The compounds obtained in each step can be used directly as a reaction mixture or as a crude product in the next reaction. Alternatively, the compounds obtained in each step can be separated and purified from the reaction mixture using known methods, such as separation techniques including concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, column chromatography, etc.

[0267] When the raw material compounds and / or reagents used in each step are commercially available, commercially available products can also be used directly.

[0268] In each step of the reaction, the reaction time varies depending on the type of reagent and solvent used. Generally, unless otherwise specified, the reaction time is from 1 minute to 48 hours, preferably from 10 minutes to 8 hours.

[0269] In each step of the reaction, the reaction temperature varies depending on the type of reagent and solvent used. Generally, unless otherwise specified, the reaction temperature is from -78°C to 300°C, preferably from -78°C to 150°C.

[0270] In each step of the reaction, the pressure varies depending on the type of reagent and solvent used. Generally, unless otherwise specified, the pressure is from 1 atm to 20 atm, preferably from 1 atm to 3 atm.

[0271] Each step of the reaction can be performed using a microwave synthesizer, such as the Initiator+ manufactured by Biotage. Although the reaction temperature varies depending on the type of reagents and solvents used, it is generally from room temperature to 300°C, preferably from 50°C to 250°C, unless otherwise specified. Although the reaction time varies depending on the type of reagents and solvents used, it is generally from 1 minute to 48 hours, preferably from 1 minute to 8 hours, unless otherwise specified.

[0272] In each reaction step, unless otherwise specified, the amount of reagent used relative to the substrate is 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents. When the reagent is used as a catalyst, the amount of reagent used relative to the substrate is 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents. When the reagent is used as a reaction solvent, the reagent is used in solvent-level amounts.

[0273] Unless otherwise stated, each reaction step is carried out in a solvent-free environment or by dissolving or suspending the starting compound in a suitable solvent. Examples of solvents include those described in the examples and the following: Alcohols: methanol, ethanol, tert-butanol, 2-methoxyethanol, etc.; Ethers: Diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amide: N , N -Dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: Acetonitrile, etc.; Sulfoxides: such as dimethyl sulfoxide; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: such as ethyl acetate; Ketones: acetone, methyl ethyl ketone, etc.; and water.

[0274] The solvents described above may be used alone or in appropriate proportions as a mixture of two or more of them.

[0275] When a base is used in each step of the reaction, examples include those described in the examples and the following bases: Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc. Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amine compounds: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazane, etc.; and Organic lithium: n-Butyllithium, etc.

[0276] When an acid or acid catalyst is used in each step of the reaction, examples include those described in the examples, as well as the following acids and acid catalysts: 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 ferric chloride, etc.

[0277] Unless otherwise stated, the reactions in each step are performed according to known methods, for example, Jikken Kagaku Kouza, 5th ed., Volumes 13-19 (edited by the Chemical Society of Japan); Shin Jikken Kagaku Kouza, Volumes 14-15 (edited by the Chemical Society of Japan); Fine Organic Chemistry, 2nd revised edition (LF Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, revised edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES, Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Volumes 1-14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Chemistry. The methods described in or in the examples of Synthesis (Kiyoshi Tomioka, Kagakudojin translation); Comprehensive Organic Transformations (VCHPublishers Inc.), 1989, etc.

[0278] In each step, the protection or deprotection reaction of the functional groups is carried out according to known methods, such as those described in "Protective Groups in Organic Synthesis, 4th Ed", Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter GM Wuts); "Protecting Groups 3rd Ed." Thieme, 2004 (PJ Kocienski), or the methods described in the examples.

[0279] Examples of protecting groups for hydroxyl groups of alcohols and phenolic hydroxyl groups include, for example, ether-type protecting groups such as methoxymethyl ether, anisole, tert-butyldimethylsilyl ether, tetrahydropyranyl ether, etc.; carboxylic acid ester-type protecting groups such as acetate, etc.; sulfonate-type protecting groups such as methanesulfonate, etc.; and carbonate-type protecting groups such as tert-butyl carbonate, etc.

[0280] Examples of protecting groups for the carbonyl group of aldehydes include, for example, acetal-type protecting groups, such as dimethyl acetal; and cyclic acetal-type protecting groups, such as 1,3-dioxane.

[0281] Examples of protecting groups for the carbonyl group of ketones include, for example, ketal protecting groups such as dimethyl ketal; cyclic ketal protecting groups such as 1,3-dioxane; oxime protecting groups such as O-methyl oxime; and hydrazone protecting groups such as N,N-dimethylhydrazone.

[0282] Examples of protecting groups for carboxyl groups include, for example, ester-type protecting groups, such as methyl esters; and amide-type protecting groups, such as N,N-dimethylamides.

[0283] Examples of protecting groups for thiols include, for example, ether-type protecting groups, such as benzyl sulfide; and ester-type protecting groups, such as thioacetate, thiocarbonate, thiocarbamate, etc.

[0284] Examples of protecting groups for amino and aromatic heterocycles (such as imidazole, pyrrole, indole, etc.) include, for example, urethane-type protecting groups, such as benzoyl carbamate; amide-type protecting groups, such as acetamide; alkylamine-type protecting groups, such as N-triphenylmethylamine; and sulfonamide-type protecting groups, such as methanesulfonamide.

[0285] Protecting groups can be removed using known methods, such as by employing acids, bases, ultraviolet light, hydrazine, phenylhydrazine, etc. N Methods and reduction methods for sodium methyl dithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), etc.

[0286] Examples of reducing agents used in each step of the reduction reaction include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride, etc.; boranes such as boranetetrahydrofuran complexes, etc.; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; and so on. When reducing carbon-carbon double or triple bonds, catalysts such as palladium-carbon or Lindlar's catalysts can be used.

[0287] Examples of oxidants used when performing oxidation reactions in each step include, for example, peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide, etc.; perchlorates such as tetrabutylammonium perchlorate, etc.; chlorates such as sodium chlorate, etc.; chlorites such as sodium chlorite, etc.; periodates such as sodium periodate, etc.; high-valent iodine reagents such as iodobenzoylbenzene, etc.; manganese-containing reagents such as manganese dioxide, potassium permanganate, etc.; lead such as lead tetraacetate, etc.; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent, etc.; halogen compounds, such as... N 1,3-bromosuccinimide (NBS), etc.; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

[0288] Examples of radical initiators used in the radical cyclization reaction at each step 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. Examples of radical reagents used include tributyltinane, tris(trimethylsilyl)silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0289] Examples of Wittig reagents used when performing the Wittig reaction in each step include alkylphosphines. Alkylphosphines can be prepared by known methods, for example, by reacting a phosphonium salt with a strong base.

[0290] Examples of reagents used when performing the Horner-Emmons reaction in each step include phosphonoacetates, such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases, such as alkali metal hydrides and organolithium compounds.

[0291] When performing the Friedel-Crafts reaction in each step, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin, etc.) is used as a reagent. Alternatively, an organic or inorganic acid as described herein can be used instead of a Lewis acid, and an acid anhydride, such as acetic anhydride, can be used instead of an acid chloride.

[0292] When an aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (e.g., amine, imidazole, etc.) and a base (e.g., organic base, etc.) are used as reagents.

[0293] Examples of bases used to generate carbanions include organolithium compounds, metal alkoxides, inorganic bases, and organic bases, when the carbanion undergoes nucleophilic addition, nucleophilic 1,4-addition (Michael addition reaction), or nucleophilic substitution in each step.

[0294] Examples of Grignard reagents used when performing a Grignard reaction in each step include aryl magnesium halides, such as phenyl magnesium bromide, and alkyl magnesium halides, such as methyl magnesium bromide. Grignard reagents can be prepared by methods known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in diethyl ether or tetrahydrofuran as a solvent.

[0295] When the Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base, each as described herein) are used as reagents.

[0296] When performing the Vilsmeier-Haack reaction in each step, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide, etc.) are used as reagents.

[0297] Examples of azidizing agents used when performing the azidation reaction of alcohols, alkyl halides, or sulfonates in each step include diphenylphosphohydrazine (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the azidation reaction of alcohols, methods using diphenylphosphohydrazine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), methods using trimethylsilyl azide and Lewis acids, etc., are employed.

[0298] Examples of reducing agents used when reductive amination is performed in each step include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of carbonyl compounds used include paraformaldehyde; aldehydes, such as acetaldehyde; and ketones, such as cyclohexanone. When the substrate is a carbonyl compound, examples of amines used include ammonia; primary amines, such as methylamine; secondary amines, such as dimethylamine; and so on.

[0299] When performing the Mitsunobu reaction in each step, azodicarbonate (e.g., diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0300] Examples of reagents used when performing esterification, amidation, or urea formation reactions in each step include acyl halides, such as acid chlorides, acid bromides, etc.; activated carboxylic acids, such as acid anhydrides; activated esters; sulfates; and so on. Examples of activators of carboxylic acids include carbodiimide condensers, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine condensers, such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium n-hydrate (DMT-MM); carbonate condensers, such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoazide (DPPA); benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl halides of formic acid, such as ethyl chloroformate; and O-(7-azabenzotriazol-1-yl)- N , N , N' , N' -Tetramethylureaium (HATU); sulfuric acid; combinations thereof, etc. When using carbodiimide condensing agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), etc., can be added to the reaction system.

[0301] Examples of metal catalysts used in the coupling reaction at each step include palladium compounds such as palladium(II) acetate, tetra(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(diphenylmethyleneacetone)dipalladium(O), 1,1'-bis(diphenylphosphino)ferrocene palladium(II); nickel compounds such as tetra(triphenylphosphine)nickel(O); rhodium compounds such as tris(triphenylphosphine)rhodium(III); cobalt compounds; copper compounds such as copper oxide, copper iodide(I); and platinum compounds. Additionally, a base may be added to the reaction system, and examples include inorganic bases as described herein.

[0302] Phosphorus pentasulfide is typically used as the sulfoxocarbonylating agent when the sulfoxocarbonylation reaction is carried out in each step. Alternatively, reagents having the structure of 1,3,2,4-dithiaphosphonane-2,4-disulfide (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphonane-2,4-disulfide (Lawsson reagent)) can be used instead of phosphorus pentasulfide.

[0303] Examples of halogenating agents used in each step of the Wohl-Ziegler reaction include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and thioyl chloride. Additionally, the reaction can be accelerated by adding free radical initiators such as heat, light, benzoyl peroxide, and azobisisobutyronitrile.

[0304] Examples of halogenating agents used when performing the halogenation reaction of the hydroxyl group in each step include acid halides of hydrohalic acids and inorganic acids, specifically hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., for chlorination, and 48% hydrobromic acid, etc., for bromination. Alternatively, alkyl halides can be produced by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide. Or, a two-step method can be used to produce alkyl halides, comprising converting the alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride, or sodium iodide.

[0305] Examples of reagents used when carrying out the Arbuzov reaction in each step include alkyl halides, such as ethyl bromoacetate; and phosphites, such as triethyl phosphite and tri(isopropyl) phosphite.

[0306] Examples of sulfonating agents used when performing sulfonation reactions in each step include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.

[0307] When hydrolysis is carried out in each step, an acid or base is used as a reagent. For the acid hydrolysis of tert-butyl ester, formic acid, triethylsilane, etc., can be added to reduce and capture the byproduct tert-butyl cation.

[0308] Examples of dehydrating agents used when the dehydration reaction is carried out in each step include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, etc. N , N '-Dicyclohexylcarbodiimide, alumina, polyphosphate, etc.

[0309] The compound (7) used in process 2 below can be generated from compound (1) according to the method shown in process 1 below. In the formula, P 1 and P 2 Each is either a protecting group or a hydrogen atom, LG 1 It is a leaving base, R 16 C is arbitrarily replaced 1-6 Alkyl or optionally substituted C 6-14 Aryl, and other symbols as defined above. P 1 Examples of “protecting groups” include those exemplified as “protecting groups of amino and aromatic heterocycles (such as imidazole, pyrrole, indole, etc.)”.

[0310] P 2 Examples of “protecting groups” include those exemplified as “protecting groups of hydroxyl groups of alcohols, etc.”

[0311] LG 1 Examples of "leaving groups" include halogen atoms, optionally halogenated C atoms, and other halogenated C atoms. 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), optionally C 1-6 Alkyl-substituted C 6-14 Arylsulfonyloxy (e.g., benzenesulfonyloxy, toluenesulfonyloxy), etc.

[0312] Compound (1) is readily available commercially or can be produced by methods known per se.

[0313] Compound (3) can be produced by sulfonating compound (1) with compound (2). Examples of compound (2) used include sulfonyl chloride, aminosulfonyl chloride, etc. Compound (2) is readily available commercially or can be produced by methods known per se.

[0314] Compound (7) can, for example, be made by making X 8 It is produced by the condensation reaction of compound (5) with compound (6)-1 or compound (6)-2, which contains nitrogen atoms. Compound (6)-1 and compound (6)-2 are readily available commercially or can be produced by methods known per se.

[0315] Compound (I) can be generated from compound (7) according to the method shown in process 2 below. In the formula, R 17 C is arbitrarily replaced 1-6 Alkyl or optionally substituted C 6-14 Aryl, and other symbols as defined above. Compound (8) can be produced by sulfonating compound (7). Examples of sulfonating agents used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.

[0316] Compound (9) can, for example, by making R in it 4 It is produced by the oxidation reaction of a compound (7) containing hydrogen atoms.

[0317] Compound (I) can be produced, for example, by subjecting compound (8) to a nucleophilic substitution reaction in the presence of a base. Examples of bases used include inorganic bases, organic bases, alkali metal hydrides, etc.

[0318] Where X 9 It is CR 2 r is 0, and R 2 and R 3 Compound (I) that forms bonds together can be produced, for example, by subjecting compound (9) to a dehydration reaction.

[0319] Where X 10 It is CR 15 And R 3 and R 15 Compound (I) that forms bonds together can be produced, for example, by subjecting compound (9) to a dehydration reaction.

[0320] In compound (I), intramolecular functional groups can also be transformed into target functional groups through combinations of known chemical reactions. Examples of chemical reactions include oxidation, reduction, alkylation, acylation, ureation, hydrolysis, amination, esterification, aryl coupling, and deprotection reactions.

[0321] In the production method, when the starting compound has amino, carboxyl, hydroxyl, carbonyl or thiol groups as substituents, protecting groups commonly used in peptide chemistry can be introduced into these groups, and if necessary, the target compound can be obtained by removing the protecting groups after the reaction.

[0322] Compound (I) can be separated and purified by known methods, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography, etc.

[0323] When compound (I) contains optical isomers, stereoisomers, regioisomers, or rotational isomers, these compounds are also included in compound (I), and each can be obtained as a single product by synthesis or separation methods. For example, when compound (I) contains optical isomers, the optical isomers separated from said compound are also included in compound (I).

[0324] Optical isomers can be produced using known methods.

[0325] Compound (I) can be a crystal.

[0326] Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallizing compound (I) using known crystallization methods.

[0327] In this specification, melting point means, for example, the melting point measured by a micro melting point apparatus (Yanako, MP-500D or Buchi, B-545), a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1), etc.

[0328] Generally, melting point can vary depending on the measuring device, measuring conditions, etc. The crystal in this specification may be a crystal with a melting point different from the value described in this specification, as long as the difference is within the general error range.

[0329] The crystals of the present invention are excellent in terms of physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and are particularly suitable for use as pharmaceuticals.

[0330] Compound (I) can be used as a prodrug. A prodrug of compound (I) refers to a compound that is converted into compound (I) of the present invention under physiological conditions in vivo via reactions with enzymes, gastric acid, etc. For example, a prodrug of compound (I) may be a compound that is converted into compound (I) of the present invention in the presence of enzymes through oxidation, reduction, hydrolysis, etc., or a compound that is converted into compound (I) of the present invention via hydrolysis with gastric acid, etc.

[0331] The prodrug of compound (I) may be: Compounds obtained by acylation, alkylation or phosphorylation of the amino group in compound (I) (e.g., compounds obtained by eicosanoylation, alanineylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation, neopentyloxymethylation and tert-butylation of the amino group in compound (I)); Compounds obtained by acylation, alkylation, phosphorylation, or borylation of the hydroxyl group in compound (I) (e.g., compounds obtained by acetylation, palmitoylation, propionylation, neopentanoylation, succinylation, fumarylation, alanineylation, dimethylaminomethyl carbonylation, etc., of the hydroxyl group in compound (I)); or Compounds obtained by esterification or amidation of the carboxyl group in compound (I) (e.g., compounds obtained by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, neopentyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthaloyl esterification, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, and methylamidation of the carboxyl group in compound (I).

[0332] Any of these compounds can be produced from compound (I) by known methods.

[0333] The prodrug of compound (I) can also be a prodrug that is converted into compound (I) under physiological conditions, such as... IYAKUHIN no KAIHATSU Those described in (Development of Pharmaceuticals), Volume 7, Design of Molecules, pp. 163-198, published by HIROKAWA SHOTEN (1990).

[0334] In this specification, the prodrug may form a salt, and as such a salt, those exemplified as salts of compounds represented by the above formula (I) may be mentioned.

[0335] Compound (I) can be made using isotopes (e.g., 3 H, 13 C 14 C 18 F, 35 S, 125 I) etc. are marked.

[0336] The isotopically labeled or substituted compound (I) can be used as a tracer for, for example, positron emission tomography (PET) (PET tracer), and can also be used in the field of medical diagnostics, etc.

[0337] In addition, compound (I) can be a hydrate or a nonhydrate, or a nonsolvent (e.g., an acid anhydride), or a solvate (e.g., a hydrate).

[0338] Compound (I) also includes 1 H is converted to 2 The deuterium transformation form of H(D).

[0339] Furthermore, compound (I) can be a pharmaceutically acceptable eutectic or eutectic salt. A eutectic or eutectic salt refers to a crystalline substance at room temperature composed of two or more specific solids, each with different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Eutectic or eutectic salts can be produced by known co-crystallization methods.

[0340] The compound (I) or its prodrug (hereinafter sometimes simply referred to as the compound of the present invention) may be used as is or by mixing with a pharmacologically acceptable carrier, etc., in the form of a pharmaceutical composition (also called a pharmaceutical agent) for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys) as an agent for the prevention or treatment of the following diseases.

[0341] Various organic or inorganic carrier substances commonly used as preparation materials can be used as pharmacologically acceptable carriers. These substances are incorporated as excipients, lubricants, binders, and disintegrants in solid dosage forms; or as solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents in liquid dosage forms; and so on; and, where necessary, formulation additives such as preservatives, antioxidants, colorants, sweeteners, etc., can be added.

[0342] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatin starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, light anhydrous silicate, synthetic aluminum silicate, and magnesium aluminum metasilicate.

[0343] Examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0344] Examples of adhesives include gelatin starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0345] Examples of disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silica, and low-substituted hydroxypropyl cellulose.

[0346] Examples of solvents include water for injection, physiological saline, Ringer's solution, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

[0347] Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzoyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0348] Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzyl chloride, glyceryl monostearate, etc.; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.; polysorbate; and polyoxyethylene hydrogenated castor oil.

[0349] Examples of isotonic agents include sodium chloride, glycerol, D-mannitol, D-sorbitol, and glucose.

[0350] Examples of buffers include phosphates, acetates, carbonates, citrates, and other buffers.

[0351] Examples of soothing agents include benzyl alcohol.

[0352] Examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenylethanol, dehydroacetic acid, and sorbic acid.

[0353] Examples of antioxidants include sulfites and ascorbic acid salts.

[0354] Examples of colorants include aqueous food tar pigments (e.g., food colorings such as Food Coloring Red 2 and 3, Food Coloring Yellow 4 and 5, Food Coloring Blue 1 and 2, and similar food colorings), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned aqueous food tar pigments), natural dyes (e.g., β-carotene, chlorophyll, iron oxide red), etc.

[0355] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizate, aspartame, and stevia.

[0356] Examples of dosage forms for the above-described pharmaceutical compositions include oral formulations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets), capsules (including soft capsules, microcapsules), pills, granules, powders, tablets, syrups, liquids, emulsions, suspensions, aerosols, films (e.g., orally disintegrating films, orally adhesive films), etc.; and parenteral formulations such as injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion), external formulations (e.g., transdermal absorption formulations, ointments, lotions, adhesive formulations), suppositories (e.g., rectal suppositories, vaginal suppositories), granules, nasal formulations, pulmonary formulations (inhalants), eye drops, etc. The compounds and pharmaceutical agents of the present invention can be safely administered orally or parenterously (e.g., rectal, intravenous, intraarterial, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, infusion, intracerebral, intravaginal, intraperitoneal, intratumoral, proximal tumor administration, and administration to the lesion).

[0357] These formulations can be controlled-release formulations (e.g., sustained-release microcapsules), such as immediate-release formulations, sustained-release formulations, etc.

[0358] The pharmaceutical composition can be produced according to methods conventionally used in the field of pharmaceutical formulation, such as those described in the Japanese Pharmacopoeia.

[0359] Although the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dosage, etc. of the compound of the present invention, the content is, for example, from about 0.1 wt% to 100 wt%.

[0360] When producing oral formulations, coating may be applied as necessary for purposes such as taste masking, enteric coagulation, and / or sustainability.

[0361] Examples of coating matrices used for coating include sugar coating matrices, water-soluble membrane coating matrices, enteric membrane coating matrices, and sustained-release membrane coating matrices.

[0362] As a sugar coating matrix, sucrose can be used, and one or more of the following can be used in combination: talc and precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc.

[0363] Examples of water-soluble film coating matrices include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; and polysaccharides such as pullulan, etc.

[0364] Examples of enteric coating matrices include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, carboxymethyl ethyl cellulose, and cellulose acetate; acrylic polymers such as copolymer of methacrylic acid L [Eudragit L (trade name)], copolymer of methacrylic acid LD [Eudragit L-30D-55 (trade name)], and copolymer of methacrylic acid S [Eudragit S (trade name)]; and naturally occurring substances such as shellac.

[0365] Examples of sustained-release membrane coating matrices include cellulose polymers, such as ethyl cellulose; and acrylic polymers, such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)], etc.

[0366] Two or more of the above-mentioned coating substrates can be used in a mixture in appropriate proportions. Additionally, for example, opaque agents such as titanium dioxide or iron oxide red can be used during coating.

[0367] Because the compounds of the present invention exhibit low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and fewer side effects, the compounds can be used as preventive, therapeutic, or diagnostic agents for various diseases in mammals (e.g., humans, cattle, horses, dogs, cats, monkeys, mice, rats).

[0368] The compounds of the present invention have excellent orexin type 2 receptor agonist activity and can treat, prevent or improve the risk of various neurological and psychiatric diseases associated with orexin type 2 receptor. The compounds of this invention can be used as agents for the prevention or treatment of various diseases, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Klein-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 diffuse encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, and Hashimoto's encephalopathy. encephalopathy, coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinemia, protoplasmic hyperplasia, pituitary obesity, hypoplastic obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, diet-induced obesity, hypogonadism, generalized mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disturbances of consciousness (such as coma), side effects and complications of anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep disturbance, jet lag, jet lag syndrome, sleep disorders of alternating workers, sleep disorders, night terrors, depression, major depressive disorder, somnambulism, enuresis, sleep disorders, Alzheimer's dusk Dusk), diseases related to circadian rhythms, fibromyalgia, disorders caused by poor sleep quality, overeating, obsessive-compulsive eating disorders, obesity-related diseases, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, hyperlipidemia, high blood lipids, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, gallstones, heart disease, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary artery disease, cardiovascular disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Froelich's syndromeThis includes conditions such as growth hormone deficiency, normal-mutant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual and reproductive dysfunctions (such as hirsutism in women), fetal defects associated with maternal obesity, gastrointestinal motility disorders (such as obesity-related gastroesophageal reflux), and obesity-related hypoventilation syndrome (Pickwick syndrome). Syndrome), respiratory diseases (such as shortness of breath), inflammation (such as systemic inflammation of the vascular system), arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of secondary outcomes of obesity (such as reduced risk of left ventricular hypertrophy), migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, reproductive / urinary system disorders, disorders related to sexual function or fertility, depressed mood disorder, bipolar disorder, type I bipolar disorder, type II bipolar disorder, cyclothymic disorder, acute stress disorder, fear of empty rooms, 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 brain defects after coronary artery bypass surgery and transplantation), stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease. Diseases, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, conditions related to muscle spasms, delirium, amnesia, age-related cognitive decline, affective schizophrenia, paranoia, drug addiction, motor disability, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Jill-do-La Tourette's syndrome, chorea, myoclonus, tic disorders, restless legs syndrome, dystonia, motor disability, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, sudden collapse, and traumatic brain injury.

[0369] In particular, the compounds of the present invention can be used as agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, disturbances of consciousness (such as coma), side effects and complications caused by anesthesia, or as anesthetic antagonists.

[0370] In some respects, the compounds of the present invention can be used as agents for the prevention or treatment of the following diseases: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, altered consciousness, and side effects and complications caused by anesthesia.

[0371] In some respects, the compounds of the present invention can be used as agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, excessive sleep, or sleep apnea syndrome.

[0372] In some respects, the compounds of the present invention can be used as agents for the prevention or treatment of narcolepsy.

[0373] Central narcolepsy (CDH) is characterized by excessive daytime sleepiness in the absence of other sleep disorders, despite a history of adequate and regular sleep patterns. CDH includes type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia. Klein-Levin syndrome, as well as sleep deprivation syndromes and hypersomnia caused by medical conditions, drugs, substances, or mental illnesses, are also considered central narcolepsy. Evaluation of CDH involves sleep testing (multichannel sleep recording, PSG) in a sleep laboratory, followed by multiple sleep latency tests (MSLT).

[0374] Symptoms associated with narcolepsy involve abnormal REM sleep features intruding into the waking state: for example, sleep-related hallucinations, sleep paralysis or vivid dreams, and confusion between dreams and reality. These symptoms can also occur in people without sleep disorders.

[0375] Some people with narcolepsy also experience cataplexy (type 1 narcolepsy), a loss of muscle tone triggered by emotions (usually laughter or anticipation). Cataplexy can be generalized or partial and is unrelated to any loss of consciousness. This muscle weakness usually improves within seconds to minutes.

[0376] Patients with idiopathic hypersomnia (IDH) typically describe excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours per night), and severe difficulty arousing in the morning (sleep inertia). In contrast to narcolepsy, IDH patients typically describe prolonged daytime naps and lethargy. Another common symptom of IDH is "brain fog," a feeling of cognitive confusion during the day. Klein-Levin syndrome is a rare form of periodic hypersomnia.

[0377] One aspect of this disclosure is a method for treating a subject suffering from one or more types of central narcolepsy (CDH), the method comprising administering the compound of the present invention to the subject.

[0378] Another aspect of this disclosure is the use of the compounds of the present invention in the manufacture of an agent for treating one or more types of central narcolepsy (CDH) in a subject.

[0379] Another aspect of this disclosure is the compounds of the present invention for treating one or more types of central narcolepsy (CDH) in a subject.

[0380] Another aspect is the method or use of the preceding aspect, wherein the subject suffers from narcolepsy. In one aspect, the subject has been diagnosed with type 1 narcolepsy. In another aspect, the subject has been diagnosed with type 2 narcolepsy. In yet another aspect, the subject has been diagnosed with idiopathic hypersomnia.

[0381] Another aspect is the method or use of the prior aspect, wherein applying the compound of the present invention reduces daytime sleepiness, reduces loss of muscle control, and / or reduces sleep disruption in the subject.

[0382] Another aspect is a method or use in which the compound of the invention is applied in an amount that effectively reduces excessive daytime sleepiness in adults suffering from narcolepsy.

[0383] Another aspect is a method or use in which the compound of the invention is applied in an amount that effectively increases the average sleep latency.

[0384] Another aspect is a method or use in which the compound of the invention is applied in an amount that effectively reduces sudden collapse events.

[0385] Another aspect is a method or use in which the compound of the invention is applied in an amount that effectively reduces nighttime sleep disruption in the subject.

[0386] Although the dosage of the compounds of the present invention varies depending on the subject, route of administration, target disease, symptoms, etc., for example, when the compounds of the present invention are administered orally or parenterally to adult patients, the dosage of the compounds is, for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose, and more preferably 0.5 to 20 mg / kg body weight per dose. This amount is ideally administered in 1 to 3 doses per day.

[0387] The compounds of this invention can be used in combination with other drugs (hereinafter referred to as concomitant drugs).

[0388] Excellent effects can be achieved by combining the compounds of the present invention with concomitant drugs, for example, (1) Compared with the application of the compounds of the present invention alone or in combination with other drugs, the dosage can be reduced. (2) Drugs that can be combined with the compounds of the present invention can be selected according to the patient's condition (mild, severe, etc.). (3) By selecting concomitant drugs with different effects and mechanisms of action than the compounds of the present invention, the treatment period can be extended. (4) By selecting concomitant drugs with different effects and mechanisms of action than the compounds of the present invention, sustained therapeutic effects can be designed. (5) By using the compounds of the present invention in combination with accompanying drugs, a synergistic effect can be provided.

[0389] In this specification, the compounds of the present invention used in combination with accompanying drugs are referred to as "combinations of the present invention".

[0390] When using the combination formulation of the present invention, the administration time of the compounds and concomitant drugs is not limited, and the compounds or pharmaceutical compositions thereof, or the concomitant drugs or pharmaceutical compositions thereof, may be administered to the subject simultaneously or at different times. The dosage of the concomitant drug may be determined according to clinically used dosages and may be appropriately selected depending on the subject, route of administration, disease, combination, etc.

[0391] The administration mode of the combination formulation and accompanying medicine of the present invention is not particularly limited, and the compounds and accompanying medicine of the present invention need only be combined during administration. Examples of such administration modes include the following: (1) Administration of a single formulation obtained by simultaneously treating the compound of the present invention and a concomitant drug. (2) Two formulations of the independently produced compound of the present invention and a concomitant drug are administered simultaneously via the same route of administration. (3) Two formulations of the independently produced compound of the present invention and the accompanying drug are administered in an alternating manner via the same route of administration. (4) The two formulations of the independently produced compound of the present invention and the accompanying drug are administered simultaneously via different routes of administration. (5) Two formulations of the independently produced compound and concomitant drug of the present invention are administered by different routes of administration in an alternating manner (e.g., in the order of the compound and the concomitant drug of the present invention or in the reverse order).

[0392] The dosage of the concomitant medication can be appropriately determined based on the dosage used in the clinical situation. The mixing ratio of the compound of the present invention with the concomitant medication can be appropriately determined depending on the subject of administration, route of administration, target disease, symptoms, combination, etc.

[0393] For example, the content of the compounds of the present invention in the combination of the present invention varies depending on the formulation, and is generally from about 0.01 wt% to about 100 wt% based on the whole formulation, preferably from about 0.1 wt% to about 50 wt%, and more preferably from about 0.5 wt% to about 20 wt%.

[0394] The content of the accompanying drug in the combination formulation of the present invention varies depending on the formulation form, and is generally from about 0.01 wt% to about 100 wt% based on the whole formulation, preferably from about 0.1 wt% to about 50 wt%, and more preferably from about 0.5 wt% to about 20 wt%.

[0395] The content of additives (such as carriers) in the combination of the present invention varies depending on the formulation, and is typically from about 1 wt% to about 99.99 wt%, preferably from about 10 wt% to about 90 wt%.

[0396] Even when the compounds of the present invention and the accompanying drugs are formulated independently, similar amounts can be used.

[0397] Examples of concomitant medications include the following: therapeutic medications for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium hydroxybutyrate). Oxybate, Modafinil, Caffeine, Weight Loss Drugs (Amphetamine, Benzfetamine, Bromocriptine, Bupropion, Diethylpropion, Exenatide, Liothyronine, Liraglutide, Mazindol, Methamphetamine, Octreotide, Orlistat, Phendimetrazine, Phenmetrazine, Phentermine, Qn) Exa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, topiramate, zimelidine, zonisamide, lorcaserin, metformin, acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galanthamine, 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-Biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dimethylamino)methyltetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyltetrahydronaphthalene, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetrahydronaphthalene Hydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-[4-(1,3-benzodioxane-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, their optically active forms, their salts and hydrates, OM99-2 (WO01 / 00663)), γ-secretase inhibitors, β-amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), β-amyloid vaccines, β-amyloid degrading enzymes, etc., brain function enhancers (e.g., aniracetam, nicergoline), therapeutic drugs for Parkinson's disease [(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline)] Amantadine, monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline, remacemide, riluzole), anti-parasympathetic agents (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone), and therapeutic drugs for amyotrophic lateral sclerosis (ALS)Therapeutic agents such as liluthiazole, neurotrophic factors, and neurodegenerative factors are used to treat abnormal behaviors associated with dementia and wandering (e.g., sedatives, anti-anxiety drugs), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regeneration promoters (e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3- [Dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxacyclopenten[4,5-f]isoindoline and its optically active forms, salts or hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroidal drugs (dexamethasone, hexestrol, cortisone acetate). Disease-modifying antirheumatic drugs (DMARDs), anticytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), treatments for incontinence and urinary frequency (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), and treatments for osteoporosis (e.g., [unclear text - likely related to hormone therapy]).Alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drugs for insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), therapeutic drugs for schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics, etc.).Drugs such as clozapine, olanzapine, risperidone, and aripiprazole; drugs that act on metabolitic glutamate receptors or ion channel-binding glutamate receptors; phosphodiesterase inhibitors; benzodiazepine drugs (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.); L-type calcium channel inhibitors (pregabalin, etc.); tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.). Selective serotonin reuptake inhibitors (SSRIs) include: fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.; serotonin-norepinephrine reuptake inhibitors (Venerafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.); norepinephrine reuptake inhibitors (Reboxetine mesylate, etc.); mirtazapine; trazodone hydrochloride. hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT, 1AAgonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonists, 5-HT 2AReverse agonists, 5-HT3 antagonists (such as cyamemazine), non-selective cardiac beta inhibitors (such as propranolol hydrochloride and oxprenolol hydrochloride), histamine H1 antagonists (such as hydroxyzine hydrochloride), CRF antagonists, other anxiolytics (such as meprobamate), tachykinin antagonists (such as MK-869 and saredutant), drugs acting on metabolized glutamate receptors, CCK antagonists, and β3-adrenergic antagonists (such as amibegron). GAT-1 inhibitors (such as tiagabine hydrochloride), N-type calcium channel inhibitors, carbonic anhydrase II inhibitors, NMDA glycine partial agonists, NMDA antagonists (such as memantine), peripheral benzodiazepine receptor agonists, antidiuretic hormone antagonists, antidiuretic hormone V1b antagonists, antidiuretic hormone V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, niacin receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate) Drugs for treating bipolar disorder include: sulfate, moclobemide, etc.; lithium carbonate, sodium valproate, lamotrigine, lirutizazole, felbamate, etc.; cannabinoid CB1 antagonists (rimonabant, etc.); FAAH inhibitors; sodium channel inhibitors; and anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine).(e.g., hydrochloride), medications for treating alcohol poisoning, autism, chronic fatigue syndrome, spasms, fibromyalgia syndrome, headaches, smoking cessation, myasthenia gravis, cerebral infarction, mania, excessive sleepiness, pain, dysphoric disorder, autonomic ataxia, male and female sexual dysfunction, migraines, pathological gamblers, restless legs syndrome, substance addiction, alcohol-related syndromes, irritable bowel syndrome, and lipid abnormalities (such as cholesterol-lowering drugs (statins, pravastatin sodium)). Sodium), atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthase inhibitors), therapeutic drugs for abnormal behavior caused by dementia or fugue syndrome inhibitors (sedatives, anti-anxiety drugs, etc.), therapeutic drugs for diabetes, treatment agents for diabetic complications, therapeutic drugs for hypertension, therapeutic drugs for hypotension, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0398] Two or more of the above-mentioned concomitant medications may be used in a mixture in appropriate proportions.

[0399] When the compounds of the present invention are used to treat the above-mentioned diseases, the compounds may also be used in combination with biological agents (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), or in combination with gene therapy methods, or in combination with treatments in the field of psychiatry that do not use drugs.

[0400] Examples of antibody drugs and vaccine formulations include vaccines targeting angiotensin II, vaccines targeting CETP, CETP antibodies, antibodies against TNFα and other cytokines, amyloid beta vaccines, type 1 diabetes vaccines (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccines, as well as antibodies or vaccines targeting cytokines, renin-angiotensin-type enzymes and their products, antibodies or vaccines targeting enzymes or proteins involved in lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in coagulation or fibrinolysis systems, antibodies or vaccines targeting proteins involved in glucose metabolism and insulin resistance, and so on. Additionally, it can be used in combination with growth factors, such as GH and IGF.

[0401] Examples of gene therapy include treatments using genes associated with cytokines, renin-angiotensin-type enzymes and their products, G proteins, G protein-binding receptors and their phosphorylases; treatments using DNA decoys (such as NFκB decoys); treatments using antisense genes; treatments using genes associated with enzymes or proteins involved in lipid metabolism (e.g., genes associated with the metabolism, excretion and absorption of cholesterol or triglycerides or HDL-cholesterol or phospholipids); treatments using genes associated with enzymes or proteins involved in angiogenesis therapies such as peripheral vascular occlusion (e.g., growth factors such as HGF, VEGF, etc.); treatments using genes associated with proteins involved in glucose metabolism and insulin resistance; and antisense genes targeting cytokines (such as TNF, etc.).

[0402] Examples of nonpharmacological treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy (including cognitive behavioral therapy).

[0403] The compounds of the present invention can also be used in combination with various organ regeneration methods, such as heart regeneration, kidney regeneration, pancreatic regeneration, vascular reconstruction, cell transplantation therapy using bone marrow cells (monocytes derived from bone marrow, bone marrow-derived stem cells), or using tissue-engineered artificial organs (e.g., artificial blood vessels, cardiomyocyte sheets).

[0404] [Example] The present invention will be explained in detail below through reference to embodiments, experimental embodiments, and formulation embodiments. However, the embodiments do not limit the present invention, and modifications can be made to the embodiments within the scope of the present invention.

[0405] In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Unless otherwise stated, the ratio of mixed solvents is a volume mixing ratio, and unless otherwise stated, % means wt%.

[0406] Unless otherwise stated, elution in the examples was performed by column chromatography under TLC (thin-layer chromatography) observation. For TLC observation, Merck 60 F was used. 254 As a saturated LC plate, the solvent used as the elution solvent in column chromatography is used as the eluent, and detection is performed using a UV detector. In silica gel column chromatography, NH indicates the use of aminopropylsilane-bonded silica gel, and DIOL indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. Preparative HPLC (High Performance Liquid Chromatography) was performed under the following conditions: Columns: Boston Prime C18 (150 mm × 30 mm, 5 μm), Ultimate C18 (100 mm × 30 mm, 3 μm), Gemini NX C18 (150 mm × 30 mm, 5 μm), YMC Triart C18 (250 mm × 50 mm, 7 μm), Exsil plus C18 (150 mm × 50 mm, 5 μm), or Water Xbridge C18 (150 mm × 30 mm, 5 μm); Mobile phase: ammonia / MeCN, water / MeCN (both containing 0.1% TFA), or water / MeCN containing ammonia hydroxide. The C18 designation indicates the use of octadecyl-bonded silica gel. Unless otherwise specified, the elution solvent ratios are volume-mixed ratios.

[0407] for 1 ¹H NMR analysis is performed using software such as ACD / SpecManager (trade name). Sometimes, peaks of hydroxyl, amino, etc., exhibiting extremely flat proton peaks are not described.

[0408] MS is measured by LC / MS. ESI or APCI is used as the ionization method. Data indicate actual measured values ​​(experimental values). Although a molecular ion peak is generally observed, fragment ion peaks are sometimes observed. In the case of salts, either the free molecular ion peak or the fragment ion peak is generally observed.

[0409] In the following embodiments, the following abbreviations are used.

[0410] MS: Mass Spectrometry M: molar concentration N: Equivalent concentration CDCl3: Deuterated chloroform DMSO-d6: Deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid Chromatography-Mass Spectrometry ESI: Electrospray Ionization APCI: Atmospheric Pressure Chemical Ionization Boc: tert-butoxycarbonyl CPME: Cyclopentylmethyl ether DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene Dess Martin periodinane: 3-oxo-1l5-benzo[d][1,2]iodocyclopentene-1,1,1(3H)-trimethyl ester of triacetic acid DMA: N,N-dimethylacetamide DME: 1,2-Dimethoxyethane DMF: N,N-Dimethylformamide EtOAc: Ethyl acetate EtOH: Ethanol IPE: Diisopropyl Ether MeCN: Acetonitrile MeOH: Methanol TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran Pd2(dba)3:tris(diphenylmethyleneacetone)dipalladium(0) Example 1 N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) 4-(2,6-difluorophenyl)-1,2-benzoxazole-3-amine To a mixture of 4-bromo-1,2-benzoxazol-3-amine (7.20 g), pinacol ester (2,6-difluorophenyl)borate (24.3 g), and potassium fluoride (5.94 g) in DMA (60 mL) and water (15 mL), tri-tert-butylphosphonium tetrafluoroborate (0.986 g) and Pd2(dba)3 (1.55 g) were added. The mixture was stirred at 120 °C under an argon atmosphere for 3 hours. After cooling, the mixture was diluted with water and extracted with THF / EtOAc. The extract was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give a crude product. The crude product was wet-milled with cold IPE, and the precipitate was collected by filtration to give the title compound (5.01 g).

[0411] MS: [M+H] + 247.0.

[0412] B) [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M lithium bis(trimethylsilyl)aminoTHF solution (60 mL) was added to a mixture of 6.92 g of 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine in 130 mL of THF at 0 °C. The mixture was stirred at 0 °C for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (6.60 g) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 30 min. An aqueous solution of ammonium chloride and EtOAc were added to the mixture. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (8.34 g).

[0413] MS: [M+H] + 420.9.

[0414] C) (2S,4S)-4-[(ethanesulfonyl)amino]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Ethyl sulfonyl chloride (7.54 mL) was added dropwise to a mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester hydrochloride (15.9 g) and TEA (39.6 mL) in DME (189 mL) at 0 °C. The mixture was stirred overnight at room temperature and then filtered to remove insoluble substances. The filtrate was diluted with EtOAc, washed with 1 M aqueous hydrogen chloride solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (18.4 g).

[0415] MS: [M+H-Boc] + 237.1.

[0416] D) (2S,4S)-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A solution of (2S,4S)-4-[(ethanesulfonyl)amino]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (2.65 g) in THF (30 mL) was added dropwise to a suspension of lithium aluminum hydride (0.36 g) in THF (30 mL) at 0 °C under an argon atmosphere. The mixture was stirred at 0 °C under an argon atmosphere for 2 hours. A saturated aqueous solution of potassium sodium tartrate was added to the mixture at 0 °C. The mixture was diluted with EtOAc and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.18 g).

[0417] MS: [M+H-Boc] + 209.1.

[0418] E) N-[(3S,5S)-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride A solution of 4 M hydrogen chloride in EtOAc (5 mL) was added to a solution of (2S,4S)-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.18 g) in EtOAc (5 mL) at room temperature. The mixture was stirred overnight at room temperature. A white solid formed and was collected by filtration to give the title compound (1.40 g).

[0419] 1 H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 1.58-1.71 (1H,m), 2.23-2.36 (1H, m), 2.88-3.17 (3H, m), 3.29-3.45 (1H, m), 3.51-3.71 (3H,m), 3.91-4.06 (1H, m), 5.39 (1H, br s), 7.56 (1H, d, J = 7.5 Hz), 8.98 (1H,br s), 9.51 (1H, br s).

[0420] F) (2S,4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide A mixture of [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (0.7 g), N-[(3S,5S)-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (0.406 g) and N,N-diisopropylethylamine (0.568 mL) in THF (8.30 mL) was stirred for 44 hours at 70 °C. After cooling, the mixture was purified by silica gel column chromatography (MeOH / EtOAc) to give the title compound (0.39 g).

[0421] MS: [M+H] + 481.1.

[0422] G) N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide Methanesulfonyl chloride (0.084 mL) was added to a mixture of (2S,4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (260 mg), TEA (0.302 mL), and THF (2.0 mL) at 0 °C. The mixture was stirred at room temperature for 30 min. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (2.0 mL). 60% sodium hydride (23.8 mg) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The solid was crystallized from EtOAc-heptane to give the title compound (82 mg).

[0423] 1 H NMR (300 MHz, CDCl3) δ 1.34 (3H, t, J = 7.4 Hz), 1.45-1.53 ​​(1H, m), 2.37-2.52 (1H, m), 2.95-3.13 (3H, m), 3.18-3.28 (1H, m), 3.77-3.94 (2H, m), 4.04-4.23 (3H, m), 6.95-7.08 (2H, m), 7.30-7.44 (2H, m), 7.58-7.70 (2H, m).

[0424] Example 16 N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine A mixture of 4-bromo-1,2-benzoxazol-3-amine (10.0 g), (2,4,6-trifluorophenyl)boronic acid (33.0 g), Pd2(dba)3 (2.15 g), tri-tert-butylphosphonium tetrafluoroborate (1.36 g), and potassium fluoride (8.18 g) in DME (150 mL) and water (30.0 mL) was heated at 80 °C under an argon atmosphere for 16 hours. Solids were removed by filtration, and the filtrate was concentrated to half its original volume under reduced pressure. Water was added to the mixture. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (3.23 g).

[0425] MS: [M+H] + 265.0.

[0426] B) [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution (47.3 mL) of lithium bis(trimethylsilyl)amino in THF was added to a mixture of 5.0 g of 4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine in THF (95 mL) at 0 °C. The mixture was stirred for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (2.79 mL) was added to the mixture. The mixture was stirred for 1 h. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was recrystallized from IPE-hexane to give the title compound (5.72 g).

[0427] MS: [M+H] + 438.9.

[0428] C) 1-(benzooxy)-3,3-difluoropent-4-en-2-ol Add 1 M aqueous hydrogen chloride solution (120 mL) to a solution of ((2,2-diethoxyethoxy)methyl)benzene (31.4 g) in THF (240 mL) and water (120 mL) at room temperature. Stir the mixture at 70 °C for 2 hours. Add EtOAc and water to the mixture at room temperature. Separate the aqueous layer and extract with EtOAc. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the residue. Add indium powder (16.1 g) to a mixture of the residue, 3-bromo-3,3-difluoroprop-1-ene (20.0 g), and DMF (240 mL) at room temperature. Stir the mixture overnight under an argon atmosphere at room temperature. Add EtOAc and water to the mixture at 0 °C. Separate the aqueous layer and extract with EtOAc. Wash the combined organic layers with water and brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (27.2 g).

[0429] 1 H NMR (300 MHz, CDCl3) δ 2.62 (1H, d, J = 4.9 Hz), 3.56-3.75 (2H, m), 3.96-4.10 (1H, m), 4.58 (2H, s), 5.50-5.57 (1H, m), 5.68-5.77 (1H, m), 5.91-6.09 (1H, m), 7.28-7.40 (5H, m).

[0430] D) [1-(benzooxy)-3,3-difluoropent-4-en-2-yl]tert-butyl carbamate Trifluoromethanesulfonic anhydride (28 mL) was added to a mixture of 1-(benzoxy)-3,3-difluoropent-4-en-2-ol (27.1 g) and pyridine (77 mL) in MeCN (400 mL) at 0 °C. The mixture was stirred at 0 °C under an argon atmosphere for 30 min. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with MeCN (400 mL). Tetrabutylammonium azide (66.9 g) was added to the mixture at 0 °C. The mixture was stirred overnight at room temperature under an argon atmosphere. EtOAc-toluene and water were added to the mixture. The aqueous layer was separated, and the organic phase was washed with water and a 1 M aqueous solution of hydrogen chloride, filtered through a silica gel pad, and concentrated under reduced pressure. Water (40 mL) was added to this residue at room temperature. A mixture of triphenylphosphine (34.3 g) and toluene (40 mL) was slowly added to the mixture. The mixture was stirred at 70 °C for 5 hours. After cooling, di-tert-butyl dicarbonate (41.0 mL) and sodium bicarbonate (11.0 g) were added to the mixture at room temperature. The mixture was stirred overnight at room temperature. Water was added to the mixture at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (37.3 g).

[0431] MS: [M+1-Boc] + 228.1.

[0432] E) 1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-2,3-dideoxy-3,3-difluoropentanepentanol Water (40 g) containing 4% osmium oxide (VIII) was added to a mixture of [1-(benzoxy)-3,3-difluoropent-4-en-2-yl]carbamate (37.3 g), 4-methylmorpholine 4-oxide (26.7 g), acetone (360 mL), and water (36 mL) at room temperature. The mixture was stirred overnight under an argon atmosphere. EtOAc and a 10% sodium thiosulfate aqueous solution were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with a 0.1 M aqueous solution of hydrogen chloride and brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure to give the title compound (42.1 g).

[0433] MS: [M+1-Boc] + 262.1.

[0434] F) Racemic-(2R,4S)-2-[(benzoxy)methyl]-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester A solution of toluenesulfonyl chloride (24.4 g) in MeCN (100 mL) was added to a mixture of 1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-2,3-dideoxy-3,3-difluoropentanepentane (42.0 g), 2,8-dimethyl-10H-dibenzo[b,e][1,4]oxaborhexane-10-ol (1.30 g) and N,N-diisopropylethylamine (30 mL) in MeCN (300 mL) at room temperature. The mixture was stirred for 1 hour at room temperature under an argon atmosphere. EtOAc, toluene, and water were added to the mixture at 0 °C. The organic layer was separated, washed with 10% citric acid aqueous solution and brine, and concentrated under reduced pressure. Toluene (300 mL) and TFA (300 mL) were added to this residue at 0 °C. The mixture was stirred for 30 minutes at room temperature. The mixture was concentrated under reduced pressure. The residue was diluted with MeOH (400 mL). Sodium carbonate (49.3 g) was added to the mixture at 0 °C. The mixture was stirred overnight at room temperature. A 10% aqueous acetic acid solution (300 mL) was added to the mixture at 0 °C. The mixture was concentrated under reduced pressure and then diluted with toluene and EtOAc. The organic layer was separated and extracted with a 20% aqueous acetic acid solution. The combined aqueous layers were quenched with potassium carbonate at 0 °C while adjusting the pH to 10. The aqueous layer was extracted with THF-EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Toluene (300 mL), water (300 mL), sodium carbonate (24.6 g), and di-tert-butyl dicarbonate (32.0 mL) were added to the residue at room temperature. The mixture was stirred for 1 hour at room temperature. The aqueous layer was separated and extracted with toluene. The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11.9 g).

[0435] MS: [M+1-Boc] + 244.0.

[0436] G) Racemic-(2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Trifluoromethanesulfonic anhydride (11.7 mL) was added to a mixture of racemic-(2R,4S)-2-[(benzoxy)methyl]-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11.9 g) and pyridine (22.3 mL) in MeCN (120 mL) at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes. EtOAc and water were added to the mixture at 0 °C. The organic layer was separated, washed with 10% citric acid aqueous solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with DMF (120 mL). Tetrabutylammonium azide (21.6 g) was added to the mixture at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes, then stirred overnight at room temperature. EtOAc and water were added to the mixture at 0 °C. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (5.65 g).

[0437] MS: [M+1-Boc] + 269.1.

[0438] H) Racemic-(2R,4R)-4-amino-2-[(benzoxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester A solution of triphenylphosphine (4.83 g) in 10 mL of THF was slowly added to a mixture of racemic (2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (5.65 g) and THF (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the mixture, and the mixture was then heated to 50 °C. The mixture was stirred at 50 °C overnight. EtOAc and brine were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (4.98 g).

[0439] MS: [M+1-Boc] + 243.1.

[0440] I) (2R,4R)-4-amino-2-[(benzooxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester The title compound (7.12 g) with a longer retention time was resolved by SFC (column: DAICEL CHIRALPAK AY, 250 mm × 50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% ammonium hydroxide = 75 / 25 v / v) resolution of racemic-(2R,4R)-4-amino-2-[(benzoxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (16.0 g).

[0441] MS: [M+1] + 343.2.

[0442] J) (2R,4R)-2-[(benzooxy)methyl]-3,3-difluoro-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester Methanesulfonyl chloride (1.86 mL) was added dropwise to a solution of (2R,4R)-4-amino-2-[(benzoxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (5.37 g) and TEA (10.9 mL) in DME (52.3 mL) at 0 °C. The mixture was stirred at 0 °C for 15 minutes, and then stirred overnight at room temperature. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (5.84 g).

[0443] MS: [MH] + 419.0.

[0444] K) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (2R,4R)-2-[(benzoxy)methyl]-3,3-difluoro-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (5.84 g) and 20% palladium hydroxide / carbon (1.18 g) in MeOH (120 mL) was hydrogenated for 15 h at 20 °C under balloon pressure. The catalyst was removed by filtration and the solution was concentrated under reduced pressure to give the title compound (4.45 g).

[0445] MS: [MH] + 329.0.

[0446] L)N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride A 4 M CPME solution (56 mL) of hydrogen chloride was added to a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (4.45 g) and EtOAc (16 mL) at 0 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The volatiles were removed under reduced pressure to give the title compound (3.40 g).

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 3.01 (3H, s), 3.04-3.13 (1H, m), 3.68-3.88(3H, m), 3.96-4.12 (1H, m), 4.49-4.64 (1H, m), 5.44-5.62 (1H, m), 8.07 (1H,d, J = 8.9 Hz), 9.50-10.23 (2H, m).

[0448] M) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide A mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride (2.50 g), [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (5.60 g), TEA (3.93 mL), and THF (75 mL) was stirred for 2 hours at room temperature, and then heated overnight at 60 °C under an argon atmosphere. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.47 g).

[0449] MS: [M+H] + 521.1.

[0450] N) N-{(6R,7aR)-7,7-difluoro-1-hydroxy-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (387 mg), sodium bicarbonate (312 mg), and MeCN (7.5 mL) was stirred for 5 minutes at 0 °C in water. Tetrabutylammonium bromide (47.9 mg), 2,2,6,6-tetramethylpiperidine-1-oxy (23.2 mg), and 1,1-diacetyliodobenzene (263 mg) were added to the mixture at 0 °C. The mixture was vigorously stirred for 5 minutes at 0 °C, then stirred for 15 minutes at room temperature. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (279 mg).

[0451] MS: [M+H] + 519.1.

[0452] O) N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide Trifluoroacetic anhydride (0.152 mL) was added to a solution of N-{(6R,7aR)-7,7-difluoro-1-hydroxy-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (279 mg) in TFA (7.5 mL) at room temperature. The mixture was stirred at 40 °C for 16 h, then stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The solution was extracted with EtOAc / THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from EtOAc, and two batches of pure precipitate were recovered. The residual oil was purified by silica gel column chromatography (EtOAc / hexane). The pure fractions were combined with the obtained precipitate. The substance was recrystallized from EtOH / heptane to give the title compound (165 mg).

[0453] 1H NMR (400 MHz, CDCl3) δ 3.15 (3H, s), 3.22 (1H, dd, J = 11.1, 8.6Hz), 4.13 (1H, dd, J = 11.0, 8.7 Hz), 4.63-4.76 (1H, m), 4.95-5.02 (1H, m), 6.64-6.84 (3H, m), 7.37-7.43 (1H, m), 7.71-7.80 (2H, m).

[0454] Example 24 N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) (2R,4R)-2-[(benzooxy)methyl]-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Ethyl sulfonyl chloride (0.773 mL) was added to a mixture of (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g) and TEA (4.05 mL) in DME (19.5 mL) at 0 °C. The mixture was stirred at 0 °C for 15 minutes, and then stirred overnight at room temperature. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.56 g).

[0455] MS: [M+H-Boc] + 335.1.

[0456] B) N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride A mixture of (2R,4R)-2-[(benzoxy)methyl]-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g) and 20% palladium hydroxide / carbon (663 mg) in MeOH (29.5 mL) was hydrogenated overnight at room temperature under balloon pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue. A 4 M EtOAc solution (20 mL) was added to a mixture of the residue and EtOAc (4 mL) at 0 °C. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure. The residue was wet-milled with EtOAc and the white solid was collected by filtration and washed with EtOAc to give the title compound (1.50 g).

[0457] MS: [M+H] + 245.1.

[0458] C) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (3.34 g) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (1.78 g) and TEA (1.93 g) in THF (50 mL) at 0 °C. The mixture was stirred at 60 °C for 15 h. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.14 g).

[0459] MS: [M+H] + 535.1.

[0460] D) N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide DBU (2.68 g) was added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (3.14 g) and methanesulfonyl chloride (1.35 g) in dichloromethane (30 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. DBU (1.34 g) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the mixture at room temperature. The mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by NH-silica gel column chromatography (EtOAc / hexane). The residue was recrystallized from EtOAc-heptane to give the title compound (1.58 g).

[0461] 1 H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 2.96-3.14 (3H,m), 3.40-3.53 (1H, m), 3.97-4.10 (1H, m), 4.15-4.26 (1H, m), 4.37-4.71 (2H,m), 7.18-7.28 (1H, m), 7.29-7.38 (1H, m), 7.40-7.48 (1H, m), 7.78-7.86 (1H,m), 7.88-7.94 (1H, m), 7.99 (1H, br s).

[0462] Example 33 N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide A 1 M solution of lithium bis(trimethylsilyl)amino in toluene (1.63 mL) and 2,2,2-trichloroethoxycarbonyl chloride (0.120 mL) were added to a mixture of 200 mg of 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine in THF (4 mL) at 0 °C. After stirring for 1 hour, the mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (4 mL). The mixture was then added to the solution at 60 °C. N -[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (228 mg) and DBU (371 mg). After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (252 mg).

[0463] MS: [M+H] + 517.1.

[0464] B) N -{( 6R,7aR )-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide At room temperature to ( 2R, 4R )- N A mixture of -[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide (252 mg) in dichloromethane (2.0 mL) was reacted with DBU (0.22 mL) and methanesulfonyl chloride (0.057 mL). The mixture was stirred for 30 minutes. DBU (0.22 mL) was added to the reaction mixture. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOH / hexane to give the title compound (72.2 mg).

[0465] 1H NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.3 Hz), 3.02-3.15 (3H, m), 3.66-3.79 (1H, m), 4.04-4.21 (2H, m), 4.30-4.42 (2H, m), 4.50 (1H, br d, J =9.3 Hz), 6.95-7.05 (2H, m), 7.30-7.41 (2H, m), 7.61-7.70 (2H, m).

[0466] Example 34 N -{( 6R,7aR )-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide A mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (300 mg), [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (484 mg), DBU (0.504 mL), and THF (10 mL) was heated at 70 °C under microwave irradiation for 2 hours. EtOAc and water were added to the mixture. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (408 mg).

[0467] MS: [M+H] + 503.1.

[0468] B) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide DBU (0.109 mL) was added to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (122 mg) and methanesulfonyl chloride (0.038 mL) in dichloromethane (1.0 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. DBU (54 μL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 30 minutes. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc-hexane to give the title compound (43.6 mg).

[0469] 1 H NMR (400 MHz, CDCl3) δ 3.04-3.11 (4H, m), 3.58 (1H, dd, J = 12.2,8.9 Hz), 4.06-4.24 (2H, m), 4.30-4.48 (2H, m), 4.51-4.60 (1H, m), 6.99 (2H,br d, J = 4.4 Hz), 7.32-7.36 (2H, m), 7.61-7.71 (2H, m).

[0470] Example 47 N-{(6R,7aR)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 2-Bromo-3,6-Difluorobenzaldehyde A 2 M solution of lithium diisopropylaminotrimethylammonium in THF (155 mL) was added dropwise to a mixture of 50.0 g of 1-bromo-2,5-difluorobenzene and 250 mL of THF at -70 °C. After stirring the reaction mixture at the same temperature for 45 min, DMF (38.4 g) was added. The reaction solution was stirred at the same temperature for 2 h. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0 °C. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (46.0 g).

[0471] 1H NMR (400 MHz, CDCl3) δ 7.16-7.20 (1H, m), 7.24-7.40 (1H, m), 10.33(1H, s).

[0472] B) 2-Bromo-3,6-difluorobenzonitrile A mixture of 2-bromo-3,6-difluorobenzaldehyde (46.0 g), diacetic acid iodobenzene (100 g), ammonium acetate (80.2 g), and sodium dodecyl sulfate (12.0 g) in water (200 mL) was stirred for 0.5 h at 70 °C. An aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was stirred at 25 °C for 15 min. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (36.6 g).

[0473] 1 H NMR (400 MHz, CDCl3) δ 7.12-7.26 (1H, m), 7.26-7.45 (1H, m).

[0474] C) 4-Bromo-5-fluorobenzo[d]isoxazole-3-amine Potassium carbonate (34.2 g) was added to a solution of acetylhydroxamic acid (18.6 g) in DMF (300 mL) and water (60 mL). After stirring the mixture at 25 °C for 2 hours, a solution of 2-bromo-3,6-difluorobenzonitrile (18.0 g) in DMF (60 mL) was added, and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was quenched with water at 0 °C, and the precipitate was collected to give the title compound (14.1 g).

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 6.12 (2H, s), 7.45-7.62 (2H, m).

[0476] D) 5-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine To a solution of 12.5 g of 4-bromo-5-fluorobenzo[d]isoxazol-3-amine in DME (200 mL) and water (20 mL), 47.6 g of 2,4,6-trifluorophenylboronic acid, 9.43 g of potassium fluoride, 3.14 g of tri-tert-butylphosphonium tetrafluoroborate, and 4.95 g of Pd₂(dba)₃ were added. The mixture was stirred at 110 °C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (9.1 g).

[0477] MS: [M+H] + 283.0.

[0478] E) [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M lithium bis(trimethylsilyl)aminotriamine solution (22.2 mL) in THF was added dropwise to a solution of 5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (2.85 g) in THF (33.7 mL) at 0 °C. The mixture was stirred for 10 min at the same temperature. 2,2,2-trichloroethoxycarbonyl chloride (1.53 mL) was added dropwise to the mixture while maintaining the temperature below 5 °C. The mixture was stirred for 30 min at 0 °C. The mixture was quenched with saturated ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid was wet-milled with hexane containing 10% EtOAc. The solid was removed by filtration and the filtrate was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.64 g).

[0479] MS: [M+H] + 456.9.

[0480] F) (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide TEA (5.91 mL) was added to a mixture of 2,2,2-trichloroethyl [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (6.50 g), N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (3.79 g) in THF (142 mL). The mixture was stirred overnight at 60 °C under nitrogen atmosphere. The mixture was diluted with EtOAc, insoluble substances were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.78 g).

[0481] MS: [M+H] + 539.1.

[0482] G) N-{(6R,7aR)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide DBU (0.05 mL) and methanesulfonyl chloride (0.013 mL) were added to a solution of (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (60 mg) in dichloromethane (1.0 mL), and the mixture was stirred for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (27.2 mg).

[0483] 1 H NMR (400 MHz, CDCl3) δ 3.07 (3H, s), 3.09-3.14 (1H, m), 3.64 (1H,dd, J = 12.2, 9.0 Hz), 4.10-4.22 (2H, m), 4.34-4.54 (2H, m), 4.61 (1H, br d,J = 9.4 Hz), 6.71-6.84 (2H, m), 7.38-7.49 (1H, m), 7.63 (1H, dd, J = 9.2, 3.7Hz).

[0484] Example 50 N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) 4-Chloro-2-fluoro-6-iodobenzonitrile A mixture of 4-chloro-2-fluorobenzonitrile (10 g), N-iodosuccinimide (15.9 g), 4-methylbenzenesulfonic acid monohydrate (6.11 g), and palladium(II) acetate (1.44 g) in DMF (150 mL) was stirred for 6 hours at 70 °C. After cooling to room temperature, the mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with aqueous sodium thiosulfate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.78 g).

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 7.82-7.88 (1H, m), 8.08 (1H, s).

[0486] B) 6-Chloro-4-iodo-1,2-benzoxazole-3-amine Potassium tert-butoxide (2.98 g) was added to a mixture of 2-propanone oxime (1.94 g) and DMF (58.5 mL) at room temperature. The mixture was stirred for 20 minutes at room temperature under a nitrogen atmosphere. The mixture was then added to a mixture of 4-chloro-2-fluoro-6-iodobenzonitrile (7.13 g) and DMF (19.5 mL) at 0 °C. The mixture was stirred for 5 minutes at 0 °C under a nitrogen atmosphere. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with EtOH (175 mL) and a 6 M aqueous hydrogen chloride solution (60.8 mL). The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. An 8 M aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution were added to the residue at 0 °C. The precipitate was collected by filtration, and the solid was washed with water and IPE to give the title compound (4.70 g).

[0487] MS: [M+H] + 294.9.

[0488] C) 6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazole-3-amine To a mixture of 6-chloro-4-iodo-1,2-benzoxazol-3-amine (5.0 g), pinacol ester (2,6-difluorophenyl)borate (12.2 g), and potassium carbonate (2.96 g) in DMA (34.0 mL) and water (8.50 mL), tri-tert-butylphosphonium tetrafluoroborate (0.493 g) and Pd2(dba)3 (0.777 g) were added. The mixture was stirred at 90 °C under an argon atmosphere for 30 min. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was wet-milled with IPE and the solid was recovered by filtration to give the title compound (1.70 g).

[0489] MS: [M+H] + 281.0.

[0490] D) [6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution of lithium bis(trimethylsilyl)amino in THF (36.2 mL) was added to a solution of 6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine (3.91 g) in THF (69.7 mL). The mixture was stirred at 0 °C under an argon atmosphere for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (3.16 mL) was added to the mixture at 0 °C. The mixture was stirred at 0 °C under an argon atmosphere for 1 h. The mixture was quenched at 0 °C with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.80 g).

[0491] MS: [M+H] + 454.9.

[0492] E) (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide A mixture of [6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (2.66 g), N-[(3S,5S)-5-(hydroxymethyl)pyrrolidine-3-yl]ethanesulfonamide hydrochloride (1.43 g), diisopropylethylamine (2.14 mL), and THF (34.3 mL) was stirred overnight at 70 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.73 g).

[0493] MS: [M+H] + 515.0.

[0494] F) N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide A mixture of (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2.73 g), TEA (2.96 mL), and methanesulfonyl chloride (0.821 mL) in THF (64 mL) was stirred for 30 min at room temperature. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (64 mL). 60% sodium hydride (0.254 g) was added to the mixture at 0 °C. The mixture was heated to room temperature and stirred for 1 h, then quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOH / heptane to give the title compound (0.968 g).

[0495] 1 H NMR (400 MHz, CDCl3) δ 1.33 (3H, t, J = 7.4 Hz), 1.46-1.57 (1H, m), 2.40-2.50 (1H, m), 2.95-3.11 (3H, m), 3.18-3.26 (1H, m), 3.81-3.94 (2H, m),4.04-4.20 (3H, m), 7.02 (2H, q, J = 9.1 Hz), 7.33 (1H, s), 7.35-7.43 (1H, m),7.64 (1H, d, J = 1.6 Hz).

[0496] Example 71 N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide DBU (2.33 mL) was added to a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (2.71 g), methanesulfonyl chloride (0.806 mL), and dichloromethane (30 mL) at 0 °C. The mixture was stirred at room temperature for 30 min. DBU (1.18 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by NH silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOH-heptane to give the title compound (1.21 g).

[0497] 1 H NMR (400 MHz, CDCl3) δ ppm 3.07 (3H, s), 3.13 (1H, dd, J = 12.0,8.3 Hz), 3.64 (1H, dd, J = 11.9, 9.0 Hz), 4.11-4.22 (2H, m), 4.36-4.53 (2H,m), 4.69 (1H, br d, J = 8.9 Hz), 6.72-6.82 (2H, m), 7.31 (1H, d, J = 6.2 Hz), 7.58-7.71 (2H, m).

[0498] Example 72 N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 2,4-Difluoro-6-iodobenzonitrile A mixture of 2,4-difluorobenzonitrile (3 g), N-iodosuccinimide (5.34 g), 4-methylbenzenesulfonic acid hydrate (2.05 g), and palladium(II) acetate (0.242 g) in DMF (45 mL) was heated to 70 °C for 6 hours. After cooling to room temperature, the mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.62 g).

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 7.63-7.80 (1H, m), 7.91-7.98 (1H, m).

[0500] B) 6-Fluoro-4-iodo-1,2-benzoxazole-3-amine A 1 M potassium tert-butoxide solution in THF (2.66 mL) was added to DMF (26 mL) containing 2-acetone oxime (195 mg). The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. This mixture was then added dropwise to a solution of 2,4-difluoro-6-iodobenzonitrile (706 mg) in DMF (8.67 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 5 minutes. The mixture was quenched at 0 °C with saturated ammonium chloride aqueous solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was diluted with EtOH (28.9 mL) and 6 M hydrogen chloride aqueous solution (14.4 mL), and the mixture was stirred at 80 °C under nitrogen atmosphere for 8 hours. The mixture was concentrated under reduced pressure, then neutralized with saturated sodium bicarbonate aqueous solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (286 mg).

[0501] MS: [M+H] + 278.9.

[0502] C) 4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole-3-amine Pd2(dba)3 (47.1 mg) was added to a mixture of 6-fluoro-4-iodo-1,2-benzoxazol-3-amine (286 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (741 mg), potassium fluoride (179 mg), tri-tert-butylphosphonium tetrafluoroborate (29.8 mg) in water (0.560 mL) and DME (2.8 mL) at room temperature. The mixture was stirred under microwave irradiation at 120 °C for 1 hour. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The mixture was then filtered through an NH4Cl filter pad while eluting with EtOAc. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (240 mg).

[0503] MS: [M+H] + 265.0.

[0504] D) [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution of lithium bis(trimethylsilyl)amino in THF (3.47 mL) was added to a solution of 4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-amine (417 mg) in THF (7.89 mL). The mixture was stirred at 0 °C under an argon atmosphere for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (282 µl) was added to the mixture at 0 °C. The mixture was stirred at an argon atmosphere for 1 h. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (460 mg).

[0505] MS: [M+H] + 438.9.

[0506] E) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide DBU (0.084 mL) was added to a solution of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (50.0 mg) and [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (82.0 mg) in THF (1.25 mL). The mixture was stirred under microwave irradiation at 70 °C for 1.5 h. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (73.6 mg).

[0507] MS: [M+H] + 521.1.

[0508] F) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide DBU (0.126 mL) and methanesulfonyl chloride (0.022 mL) were added to a solution of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (73 mg) in dichloromethane (1.3 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (18.7 mg).

[0509] 1 H NMR (400 MHz, CDCl3) δ 2.98-3.14 (4H, m), 3.58 (1H, dd, J = 12.2,9.0 Hz), 4.08-4.49 (4H, m), 4.61 (1H, br d, J = 9.2 Hz), 7.01 (2H, q, J = 8.2Hz), 7.14 (1H, dd, J = 9.4, 1.5 Hz), 7.31-7.44 (2H, m).

[0510] Example 75 N-{(6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 3,6-Difluoro-2-iodobenzamide A mixture of 2,5-difluorobenzonitrile (20 g), N-iodosuccinimide (35.6 g), palladium(II) acetate (1.61 g), and p-toluenesulfonic acid monohydrate (13.7 g) in DMF (500 mL) was stirred for 16 hours at 80 °C. The mixture was quenched with water and extracted with IPE. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (8.76 g).

[0511] MS: [M+H] + 283.9.

[0512] B) 3,6-Difluoro-2-iodobenzonitrile A mixture of 3,6-difluoro-2-iodobenzamide (8.9 g) and trifluoroacetic anhydride (13.3 mL) in pyridine (100 mL) was stirred at 80 °C for 16 h. The mixture was quenched with 1 M aqueous hydrogen chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.83 g).

[0513] 1 H NMR (300 MHz, CDCl3) δ 7.17-7.34 (2H, m).

[0514] C) 2',3,6,6'-Tetrafluoro[1,1'-biphenyl]-2-carboxynitrile A mixture of 3,6-difluoro-2-iodobenzonitrile (500 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (4.53 g), potassium fluoride (329 mg), tri-tert-butylphosphonium tetrafluoroborate (54.7 mg), Pd2(dba)3 (86 mg), and DME (0.5 mL) was stirred for 1 hour at 120 °C under an argon atmosphere in a microwave reactor. The reaction was repeated four times to obtain five batches of crude material, which were then combined. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was washed with hexane to give the title compound (1.98 g).

[0515] 1 H NMR (300 MHz, CDCl3) δ 7.04-7.16 (2H, m), 7.27-7.35 (1H, m), 7.40-7.56 (2H, m).

[0516] D) 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazole-3-amine A mixture of 2',3,6,6'-tetrafluoro[1,1'-biphenyl]-2-carboxynitrile (1.98 g), 2-propanone oxime (1.73 g), and potassium 2-methylprop-2-olate (1.77 g) in DMF (20 mL) was stirred for 1.5 h at room temperature. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product was stirred with a mixture of 6 M aqueous hydrogen chloride solution (2 mL) in EtOH (20 mL) at 80 °C for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.56 g).

[0517] MS: [M+H] + 265.0.

[0518] E) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide A mixture of 300 mg of 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (300 mg) in THF (2 mL) was added to a THF solution of 1 M bis(trimethylsilyl)aminolithium (2.27 mL) and 0.167 mL of 2,2,2-trichloroethoxycarbonyl chloride (0.167 mL). The mixture was stirred for 1 hour. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue (500 mg). A mixture of the residue (250 mg), N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (151 mg), and DBU (0.257 mL) in THF (2 mL) was stirred for 16 hours at 60 °C. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (160 mg).

[0519] MS: [M+H] + 521.1.

[0520] F) N-{(6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (50 mg), sodium bicarbonate (40.4 mg), and Dys-Martin periodide (48.9 mg) in MeCN (1.0 mL) was stirred for 1 hour at room temperature. The mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue, TFA (0.5 mL), and trifluoroacetic anhydride (0.5 mL) were stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (12.9 mg).

[0521] 1H NMR (400 MHz, CDCl3) δ 3.13-3.19 (4H, m), 3.97 (1H, dd, J = 11.3,8.4 Hz), 4.52-4.68 (1H, m), 4.95-5.05 (1H, m), 6.78 (1H, dd, J = 4.8, 1.8Hz), 6.95 (2H, tt, J = 8.5, 1.2 Hz), 7.37-7.46 (1H, m), 7.50-7.55 (1H, m), 7.71 (1H, dd, J = 9.2, 3.5 Hz).

[0522] Example 77 N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide Tetrabutylammonium bromide (0.812 g), 1,1-diacetic iodophenyl (4.46 g), and 2,2,6,6-tetramethylpiperidine-1-oxy (0.394 g) were added to a mixture of (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (6.78 g) and sodium bicarbonate (5.29 g) in MeCN (63 mL) and water (63 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.10 g).

[0523] MS: [M+Na] + 559.1.

[0524] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide Trifluoroacetic anhydride (3.21 mL) was added to a solution of N-(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (6.10 g) in TFA (0.876 mL) at room temperature. The reaction mixture was stirred overnight at 40 °C. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc-heptane to give the title compound (3.36 g).

[0525] 1 H NMR (300 MHz, DMSO-d6) δ 3.04 (3H, s), 3.22-3.29 (1H, m), 4.08-4.19(1H, m), 4.62-4.84 (1H, m), 7.18-7.38 (2H, m), 7.41-7.46 (1H, m), 7.91 (1H,t, J = 9.6 Hz), 8.13-8.20 (1H, m), 8.36 (1H, d, J = 9.4 Hz).

[0526] Example 92 N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide DBU (0.194 mL) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]carbamate 2,2,2-trichloroethyl ester (196 mg) in THF (2 mL) were added to a mixture at room temperature. The mixture was heated at 60 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (111 mg).

[0527] MS: [M+H] + 553.1.

[0528] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide A mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (55.2 mg), Desmartin periodide (50.9 mg), and TFA (0.5 mL) in MeCN (1.0 mL) was stirred for 1 hour at 0 °C. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product, a mixture of TFA (0.5 mL), and trifluoroacetic anhydride (0.5 mL) was stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (20.9 mg).

[0529] 1H NMR (400 MHz, CDCl3) δ 1.46 (3H, t, J = 7.4 Hz), 3.15-3.27 (3H,m), 4.11 (1H, dd, J = 11.1, 8.3 Hz), 4.54-4.71 (1H, m), 4.91 (1H, br d, J =10.0 Hz), 6.62-6.92 (3H, m), 7.53 (1H, t, J = 9.1 Hz), 7.72 (1H, dd, J = 9.2,3.4 Hz).

[0530] Example 102 N-{(6R)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide Add Dysmartin periodine (305 mg) to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (278 mg), sodium bicarbonate (232 mg), and MeCN (3 mL) at room temperature. Stir the mixture for 2 hours. Add EtOAc and water to the mixture at room temperature. Separate the aqueous layer and extract with EtOAc. Combine the organic layers, wash with water and brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (EtOAc / hexane). Add dichloromethane (4 mL) and trifluoroacetic anhydride (2 mL) to the residue at room temperature. Stir the mixture overnight at room temperature. Add EtOAc and a saturated aqueous solution of sodium bicarbonate to the mixture at 0 °C. Separate the aqueous layer and extract with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (77 mg).

[0531] 1H NMR (400 MHz, CDCl3) δ 3.13 (3H, s), 3.17 (1H, dd, J = 11.2, 8.6Hz), 3.97 (1H, dd, J = 11.2, 8.4 Hz), 4.55-4.67 (1H, m), 5.07-5.15(1H, m), 6.76-6.80 (1H, m), 6.89-6.96 (2H, m), 7.32-7.43 (2H, m), 7.68-7.82 (2H, m).

[0532] Example 124 N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) 6-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine A mixture of 6-fluoro-4-iodo-1,2-benzoxazol-3-amine (620 mg), (2,4,6-trifluorophenyl)boronic acid (1.57 g), Pd2(dba)3 (102 mg), tri-tert-butylphosphonium tetrafluoroborate (64.7 mg), and potassium fluoride (389 mg) in DME (4 mL) and water (0.800 mL) was heated for 1 hour at 120 °C in an argon atmosphere in a microwave reactor.

[0533] The crude mixture was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (511 mg).

[0534] MS: [M+H] + 283.0.

[0535] B) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide A 1 M toluene solution (0.886 mL) of lithium bis(trimethylsilyl)aminoamine in THF (2 mL) was added to a mixture of 100 mg of 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine in THF at 0 °C. The mixture was stirred for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (0.052 mL) was added to the mixture. The mixture was stirred for 1 h. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product, N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (99 mg) and DBU (162 mg) in THF (2 mL) was stirred for 16 h at 60 °C. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (85.1 mg).

[0536] MS: [M+H] + 553.1.

[0537] C) N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide DBU (0.049 mL) and methanesulfonyl chloride (0.013 mL) were added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (60 mg) in dichloromethane (2.0 mL). The mixture was stirred for 15 min. DBU (0.049 mL) was added to the mixture. The mixture was stirred for 30 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (16.5 mg).

[0538] 1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.5 Hz), 2.99-3.22 (3H, m), 3.57-3.78 (2H, m), 4.15-4.19 (1H, m), 4.35-4.53 (3H, m), 6.71-6.85 (2H, m), 7.11 (1H, d, J = 9.0 Hz), 7.33 (1H, d, J = 7.8 Hz).

[0539] Example 126 N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 4-Bromo-6-methyl-1,2-benzoxazole-3-amine Potassium tert-butoxide (7.86 g) was added to a solution of ethane-hydroxyxamic acid (5.26 g) in DMF (60 mL). The mixture was stirred at 20 °C for 30 min. A solution of 2-bromo-6-fluoro-4-methylbenzonitrile (5.00 g) in DMF (20 mL) was added to the mixture. The reaction mixture was stirred at 20 °C for 14 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.08 g).

[0540] MS: [M+H] + 227.1.

[0541] B) 4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazole-3-amine A mixture of 4-bromo-6-methyl-1,2-benzoxazol-3-amine (770 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxabortane (1.63 g), Pd2(dba)3 (310 mg), tri-tert-butylphosphonium tetrafluoroborate (197 mg), and potassium fluoride (591 mg) in DME (9 mL) and water (3 mL) was heated for 1 hour at 120 °C under microwave irradiation. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (567 mg).

[0542] MS: [M+H] + 261.0.

[0543] C) [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M THF solution (12.8 mL) of lithium bis(trimethylsilyl)amino was added to a solution of 1.67 g of 4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-amine (39 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min. 0.972 mL of 2,2,2-trichloroethoxycarbonyl chloride was added to the mixture. The mixture was stirred at 0 °C for 30 min. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated and washed with brine. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.86 g).

[0544] MS: [M+H] + 434.9.

[0545] D) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (187 mg) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride (0.162 mL) in THF (2.0 mL). The mixture was stirred at 60 °C for 15 hours, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (190 mg).

[0546] MS: [M+H] + 517.1.

[0547] E) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide 4-Methylbenzenesulfonyl chloride (71.9 mg) was added to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (95 mg) in THF (1.84 mL) and 1 M sodium hydroxide aqueous solution (0.920 mL). The mixture was stirred at -5 °C for 1 hour. The mixture was diluted with EtOAc and washed with brine. The separated aqueous layer was extracted with EtOAc and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (45.0 mg).

[0548] 1 H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.01-3.12 (4H, m), 3.51-3.63(1H, m), 4.02-4.22 (2H, m), 4.24-4.50 (2H, m), 4.54-4.65 (1H, m), 6.92-7.03 (2H m), 7.14-7.18 (1H, m), 7.29-7.40 (1H, m), 7.41-7.44 (1H, m).

[0549] Example 144 N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}-N'-methylthiodiamide A) (2R,4R)-2-[(benzooxy)methyl]-3,3-difluoro-4-[(methylaminosulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester A solution of methylaminosulfonyl chloride (130 mg) in 1 mL of THF was added to a mixture of (2R,4R)-4-amino-2-[(benzoxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (210 mg), TEA (0.255 mL), 4-dimethylaminopyridine (13.1 mg), and THF (2 mL) at 0 °C. The mixture was stirred overnight at room temperature under an argon atmosphere. The mixture was then purified directly by silica gel column chromatography (EtOAc / hexane) to give the title compound (168 mg).

[0550] MS: [M+H-Boc] + 336.1.

[0551] B) [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution of lithium bis(trimethylsilyl)amino in THF (66.7 ml) was added to a mixture of 8.18 g of 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine in THF (120 ml) at -22 °C. After stirring at -22 °C for 10 min, a mixture of 7.37 g of 2,2,2-trichloroethoxycarbonyl chloride and 5.0 ml of THF was added to the mixture at the same temperature. The mixture was stirred at -22 °C under an argon atmosphere for 15 min. An aqueous solution of ammonium chloride and EtOAc were added to the mixture at 0 °C. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.03 g).

[0552] MS: [M+H] + 456.9.

[0553] C) (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylaminosulfonyl)amino]pyrrolidine-1-carboxamide A mixture of (2R,4R)-2-[(benzoxy)methyl]-3,3-difluoro-4-[(methylaminosulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (168 mg) and 20% palladium hydroxide / carbon (27.2 mg) in MeOH (5 mL) was hydrogenated for 2 h at room temperature under balloon pressure. The mixture was diluted with EtOAc and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. EtOAc (5 mL) and a CPME solution of 4 M hydrogen chloride (3.0 mL) were added to the residue at room temperature. The mixture was stirred under a nitrogen atmosphere at room temperature for 3 h. The mixture was concentrated under reduced pressure. THF (3 mL), TEA (0.160 mL), and 2,2,2-trichloroethyl [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (177 mg) were added to the residue at room temperature. The mixture was stirred overnight at 60 °C under an argon atmosphere. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (178 mg).

[0554] MS: [M+H] + 554.1.

[0555] D) N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}-N'-methylthiodiamide 4-Methylbenzenesulfonyl chloride (56.8 mg) was added to a mixture of (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylaminosulfonyl)amino]pyrrolidine-1-carboxamide (80.4 mg), 1 M aqueous sodium hydroxide solution (0.800 mL), and THF (1.6 mL) at -20 °C. The mixture was stirred at the same temperature for 2 hours. EtOAc and saturated aqueous sodium bicarbonate solution were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by NH4 silica gel column chromatography (EtOAc / hexane) to give the title compound (28.5 mg).

[0556] 1 H NMR (300 MHz, CDCl3) δ 2.72 (3H, d, J = 5.3 Hz), 3.17 (1H, dd, J =12.0, 8.0 Hz), 3.62 (1H, dd, J = 12.1, 8.7 Hz), 4.07-4.44 (5H, m), 4.65 (1H,br d, J = 8.0 Hz), 6.69-6.86 (2H, m), 7.11 (1H, dd, J = 9.3, 1.4 Hz), 7.33(1H, dd, J = 7.9, 2.1 Hz).

[0557] Example 149 N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide TEA (7.0 mL) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride (4.20 g), [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (7.03 g), and THF (70 mL) at room temperature. The mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.82 g).

[0558] MS: [M+H] + 539.1.

[0559] B) N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide 4-Methylbenzenesulfonyl chloride (5.76 g) was added to a mixture of (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (7.82 g), 1 M aqueous sodium hydroxide solution (70 mL), and THF (140 mL) at room temperature. The mixture was stirred at room temperature for 30 min. Water and EtOAc were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane), followed by NH-silica gel column chromatography (EtOAc / hexane). The residue was recrystallized (EtOAc / heptane) to give the title compound (4.37 g).

[0560] 1 H NMR (300 MHz, DMSO-d6) δ 2.97 (3H, s), 2.99-3.09 (1H, m), 3.51 (1H,t, J = 10.2 Hz), 3.99-4.10 (1H, m), 4.19 (1H, dd, J = 10.2, 4.1 Hz), 4.37-4.75 (2H, m), 7.20-7.41 (2H, m), 7.44-7.53 (1H, m), 7.88-8.00 (2H, m).

[0561] Example 171 N-{(6R,7aR)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 2-Bromo-3,4,6-trifluorobenzaldehyde A mixture of 2,4,5-trifluorobenzaldehyde (25.0 g), N-bromosuccinimide (33.4 g), palladium(II) acetate (3.51 g), and 4-amino-3-chlorotrifluorotoluene (4.41 mL) in trifluorotoluene (650 mL) and TFA (130 mL) was stirred at 60 °C for 16 hours. The same reaction was repeated twice to obtain two batches of crude product, which were then combined. The mixture was quenched with 1 M sodium hydroxide aqueous solution at 0 °C and extracted with IPE-hexane. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (32.5 g).

[0562] 1 H NMR (400 MHz, CDCl3) δ 7.08 (1H, td, J = 9.7, 6.0 Hz), 10.27 (1H,s).

[0563] B) N-[(E)-(2-bromo-3,4,6-trifluorophenyl)methylene]hydroxylamine A mixture of 32.5 g of 2-bromo-3,4,6-trifluorobenzaldehyde and 18.0 g of 50% aqueous hydroxylamine in 600 mL of EtOH was stirred for 2 hours at 80 °C. The mixture was concentrated under reduced pressure. Hexane was added to the resulting solid and the mixture was stirred for 30 minutes. The solid was collected by filtration to give the title compound (28.8 g).

[0564] MS: [M+H] + 253.9.

[0565] C) 2-Bromo-3,4,6-trifluoro-N'-hydroxybenzene-1-formamidinium N-chlorosuccinimide (15.5 g) was added to a mixture of N-[(E)-(2-bromo-3,4,6-trifluorophenyl)methylene]hydroxylamine (26.8 g) in DMF (400 mL) at 0 °C. The mixture was heated to 60 °C and stirred for 1 hour. The mixture was cooled to 0 °C. The mixture was stirred for 15 minutes. A 27% ammonia solution (1.78 g) was added to the mixture. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (15.9 g).

[0566] MS: [M+H] + 268.9.

[0567] D) 4-Bromo-5,6-difluoro-1,2-benzoxazole-3-amine A mixture of 2-bromo-3,4,6-trifluoro-N'-hydroxybenzene-1-formamidinium (560 mg) and cesium carbonate (678 mg) in 1-methyl-2-pyrrolidone (10 mL) was heated for 15 minutes at 150 °C under an argon atmosphere in a microwave reactor. This process was repeated twice to obtain three batches of crude product, which were then combined. The residues were purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (571 mg).

[0568] MS: [M+H] + 248.9.

[0569] E) 5,6-Difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine A mixture of 4-bromo-5,6-difluoro-1,2-benzoxazol-3-amine (500 mg), (2,4,6-trifluorophenyl)boronic acid (3.53 g), potassium fluoride (350 mg), tri-tert-butylphosphonium tetrafluoroborate (117 mg), and Pd2(dba)3 (184 mg) in DME (10 mL) and water (1.00 mL) was heated to 100 °C. The mixture was stirred at 100 °C for 2 hours. (2,4,6-trifluorophenyl)boronic acid (1.77 g), potassium fluoride (350 mg), tri-tert-butylphosphonium tetrafluoroborate (117 mg), and Pd2(dba)3 (184 mg) were added to the reaction mixture. The mixture was stirred at 100 °C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (379 mg).

[0570] MS: [M+H] + 301.0.

[0571] F) [5,6-Difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution of lithium bis(trimethylsilyl)amino in THF (2.78 mL) was added to a mixture of 5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (379 mg) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. 2,2,2-trichloroethoxycarbonyl chloride (0.191 mL) was added to the reaction mixture. The mixture was stirred for 1 h. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (378 mg).

[0572] MS: [M+H] + 474.9.

[0573] G) (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide A mixture of [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (185 mg), TEA (0.163 mL), and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (104 mg) in THF (3 mL) was stirred for 16 hours at 60 °C. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (186 mg).

[0574] MS: [M+H] + 557.0.

[0575] H) N-{(6R,7aR)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide At 0 °C, a mixture of (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (85.0 mg) and 4-methylbenzenesulfonyl chloride (58.2 mg) in THF (1 mL) was added to a 1 M aqueous sodium hydroxide solution (0.764 mL). The mixture was stirred for 2 hours. The mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and then crystallized from EtOAc-hexane to give the title compound (25.9 mg).

[0576] 1 H NMR (300 MHz, CDCl3) δ 3.07 (3H, s), 3.08-3.14 (1H, m), 3.64 (1H,dd, J = 12.0, 8.7 Hz), 4.11-4.24 (2H, m), 4.34-4.55 (2H, m), 4.59-4.80 (1H,m), 6.80 (2H, d, J = 8.3 Hz), 7.49 (1H, dd, J = 8.5, 5.8 Hz).

[0577] Example 174 N-{(6R)-7,7-difluoro-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide A) 2-Hydroxy-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carboxynitrile A solution of 2,4,6-trifluorobenzaldehyde (20.0 g), ethyl 2-cyanoacetate (14.1 g), acetone (9.18 mL), and ammonium acetate (125 g) in n-butanol (400 mL) was stirred for 3 hours at 130 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (11.1 g).

[0578] MS: [M+H] + 265.1.

[0579] B) 2-Chloro-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carboxynitrile A mixture of 11.1 g of 2-hydroxy-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carboxynitrile was stirred in 60 mL of phosphoryl chloride at 110 °C for 14 h. The reaction mixture was cooled to room temperature and then added dropwise to water with stirring, followed by extraction with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (3.85 g).

[0580] MS: [M+H] + 283.1.

[0581] C) 6-Methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridine-3-amine Potassium tert-butoxide (785 mg) was added to a solution of 2-propanone oxime (597 mg) in THF (20 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. THF (10 mL) containing 2-chloro-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carboxynitrile (2.10 g) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 14 hours. Water was added to the mixture, followed by extraction with EtOAc. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was diluted with EtOH (20 mL) and a 6 M aqueous solution of hydrogen chloride (10 mL). The mixture was stirred at 70 °C under a nitrogen atmosphere for 3 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.20 g).

[0582] MS: [M+H] + 280.1.

[0583] D) [6-Methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]carbamate 2,2,2-trichloroethyl ester A solution of 1 M lithium bis(trimethylsilyl)amino in THF (10.1 mL) was added to a solution of 1.28 g of 6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-amine in THF (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h. 2,2,2-trichloroethoxycarbonyl chloride (1.46 g) was added to the reaction mixture. The mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The mixture was quenched at 0 °C with a saturated aqueous ammonium chloride solution, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.10 g).

[0584] MS: [M+H] + 454.0.

[0585] E) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolidine-1-carboxamide To a solution of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride (440 mg) and N,N-diisopropylethylamine (569 mg) in THF (10 mL), 2,2,2-trichloroethyl 6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]carbamate (500 mg) was added, and the reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (310 mg).

[0586] MS: [M+H] + 536.1.

[0587] F) N-{(6R)-7,7-difluoro-1-hydroxy-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide To a solution of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolidine-1-carboxamide (310 mg) in MeCN (5 mL) and water (5 mL), diiodophenyl diacetate (224 mg), tetrabutylammonium bromide (47 mg), 2,2,6,6-tetramethylpiperidine-1-oxy (23 mg), and sodium bicarbonate (268 mg) were added. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (191 mg).

[0588] MS: [M+H] + 534.1.

[0589] G) N-{(6R)-7,7-difluoro-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide Methyl N-(triethylammonium sulfonyl)carbamate (594 mg) was added to a solution of N-{(6R)-7,7-difluoro-1-hydroxy-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (190 mg) in THF (6 mL), and the mixture was stirred at 50 °C for 1 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water containing ammonium hydroxide / MeCN) to give the title compound (78.5 mg).

[0590] 1H NMR (400 MHz, CDCl3) δ 2.80 (3H, s), 3.12 (3H, s), 3.21-3.31 (1H,m), 4.04-4.14 (1H, m), 4.61-4.78 (1H, m), 5.46 (1H, d, J = 9.6 Hz), 6.67-6.82 (2H, m), 6.84-6.91 (1H, m), 7.29 (1H, s).

[0591] Example 213 N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide A) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester Potassium carbonate (10.5 g) was added to a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g), 1-(chloromethyl)-4-methoxybenzene (5.13 mL), and DMF (101 mL) at room temperature. The mixture was stirred overnight at 60 °C under an argon atmosphere. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.85 g).

[0592] MS: [M+H-Boc] + 351.1.

[0593] B) (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester (2.77 g), N,N-diisopropylethylamine (2.15 mL), and MeCN (12 mL) was added to a mixture at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with EtOAc and water under stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through an NH4 silica gel pad while eluting with EtOAc, and concentrated under reduced pressure to give the title compound (3.11 g).

[0594] MS: [M+Na] + 551.2.

[0595] C) (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester (2.94 g), sodium cyanate (1.78 g), and dimethyl sulfoxide (36 mL) was stirred for 4.5 h at 45–50 °C. The mixture was diluted with aqueous solutions of EtOAc and ammonium chloride while stirring at 0 °C. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.91 g).

[0596] MS: [M+Na] + 482.2.

[0597] D) [(2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolid-2-yl]methyl acetate hydrochloride Trimethylsilane chloride (16.6 mL) was added to a mixture of (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester (1.99 g) and MeOH (60 mL) at room temperature, and the mixture was refluxed for 2.5 h. After adding trimethylsilane chloride (8.30 mL), the mixture was refluxed for 1.5 h. After adding trimethylsilane chloride again (5.54 mL), the mixture was refluxed for 1 h. The mixture was cooled to 0 °C and a white suspension formed. IPE (60 mL) was added, and the mixture was stirred at 0 °C for 10 min. The precipitate was collected, washed with IPE, and dried under reduced pressure to give the title compound (1.75 g).

[0598] MS: [M+H] + 393.1.

[0599] E) (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (1.15 mL) was added to a cooled mixture of [(2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-2-yl]acetate hydrochloride (1.64 g), sodium bicarbonate (0.964 g), THF (30 mL), and water (10 mL) at 0 °C, and the mixture was stirred overnight at room temperature. EtOAc and water were added to the mixture with stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.75 g).

[0600] MS: [M+Na] + 512.2.

[0601] F) (2R,4R)-3,3-difluoro-4-[(methanesulfonyl)amino]-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester To a cooled mixture of (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.71 g), MeCN (36 mL), and pH 6.8 phosphate buffer (24 mL), diammonium cerium(IV) nitrate (6.28 g) was added, and the mixture was stirred at 0 °C for 10 min, followed by stirring at room temperature for 0.5 h. The mixture was diluted with EtOAc, and 10% sodium thiosulfate aqueous solution was added at 0 °C until the yellow color of the reaction disappeared, followed by neutralization with saturated sodium bicarbonate aqueous solution under stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through an NH4 silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.20 g).

[0602] 1 H NMR (300 MHz, CDCl3) δ 1.46 (9H, s), 2.76-3.02 (2H, m), 3.06 (3H,s), 3.15-3.32 (1H, m), 3.72 (3H, s), 4.02-4.56 (3H, m), 5.23 (1H, br d, J =9.6 Hz).

[0603] G) (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester A 4 M lithium borohydride solution in THF (3.89 mL) was added to a mixture of (2R,4R)-3,3-difluoro-4-[(methanesulfonyl)amino]-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.16 g) and THF (20 mL), and the mixture was stirred at 45–50 °C for 4.5 h. Subsequently, the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with aqueous solutions of EtOAc and ammonium chloride while stirring at 0 °C for 20 min, followed by stirring at room temperature for 20 min. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.966 g).

[0604] 1H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 1.65-1.85 (1H, m), 1.94-2.13(1H, m), 3.02-3.21 (4H, m), 3.36-3.87 (3H, m), 4.08-4.46 (3H, m), 4.91-5.24(1H,m).

[0605] H)N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride A mixture of (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (32.7 mg) and a 2 M hydrogen chloride solution in MeOH (2 mL) was refluxed for 0.5 h. After cooling to 0 °C, IPE was added dropwise and the mixture was stirred at 0 °C for 0.5 h. After concentration under reduced pressure, the residue was wet-milled with EtOAc / heptane to form a white solid. The solid was collected, washed with EtOAc, and dried under reduced pressure at 50 °C to give the title compound (23.6 mg).

[0606] 1 H NMR (300 MHz, DMSO-d6) δ 1.85-1.96 (2H, m), 2.99-3.13 (4H, m), 3.51-3.64 (2H, m), 3.68-3.84 (1H, m), 3.99-4.24 (1H, m), 4.52-4.76 (1H, m), 4.83-5.10 (1H, m), 8.12 (1H, d, J = 9.1 Hz), 9.73 (2H, br s).

[0607] I) (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide TEA (0.252 mL) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidine-3-yl]methanesulfonamide hydrochloride (170 mg), [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (280 mg), and THF (3.0 mL) at room temperature. The mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (318 mg).

[0608] MS: [M+H] + 535.2.

[0609] J) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide At room temperature, methanesulfonic anhydride (187 mg) was added to a mixture of (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (318 mg), triethylamine (0.412 mL), and MeCN (3.0 mL). The mixture was stirred for 10 minutes at room temperature under a nitrogen atmosphere, then diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The solid was crystallized from EtOAc-heptane to give the title compound (198 mg).

[0610] 1 H NMR (400 MHz, CDCl3) δ 1.92-2.14 (1H, m), 2.15-2.30 (1H, m), 2.54-2.79 (1H, m), 3.10 (3H, s), 3.35-4.15 (4H, m), 4.17-4.45 (1H, m), 4.56-4.83 (1H, m), 6.60-6.88 (2H, m), 7.27-7.31 (1H, m), 7.60-7.68 (2H, m).

[0611] Example 242 N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}cyclopropanesulfonamide A) (2R,4R)-4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (2R,4R)-4-amino-2-[(benzoxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (10.2 g) and 10% palladium hydroxide / carbon (500 mg) in EtOH (200 mL) was hydrogenated for 16 h at room temperature under balloon pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (7.49 g).

[0612] MS: [M+H-Boc] + 153.1.

[0613] B) (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (2R,4R)-4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (7.52 g), 1H-imidazolium (6.08 g), and tert-butyldimethylsilane chloride (4.94 g) in DMF (50 mL) was stirred for 40 min at room temperature under an argon atmosphere. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11.4 g).

[0614] MS: [M+H-Boc] + 267.2.

[0615] C) (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Cyclopropanesulfonyl chloride (7.86 g) and 4-dimethylaminopyridine (1.37 g) were added to a solution of (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (4.10 g) and TEA (9.34 mL) in anhydrous THF (50 mL), and the mixture was stirred at 70 °C under a nitrogen atmosphere for 14 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.15 g).

[0616] 1 H NMR (400 MHz, CDCl3) δ 0.09-0.20 (6H, m), 0.92 (9H, s), 0.95-1.21(4H, m), 1.47 (9H, s), 2.35-2.48 (1H, m), 3.36-3.54 (1H, m), 3.77-4.05 (3H, m), 4.09-4.27 (2H, m), 6.31-6.70 (1H, m).

[0617] D) (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Potassium carbonate (6.09 g) was added to a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (4.15 g) and 4-methoxybenzyl chloride (3.45 g) in anhydrous DMF (60 mL) at 20 °C, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 7 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.80 g).

[0618] MS: [M+H-Boc] + 491.2.

[0619] E) (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A solution of 1 M tetrabutylammonium fluoride in THF (12.2 mL) was added to a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (4.80 g) in anhydrous THF (50 mL), and the mixture was stirred at 20 °C under a nitrogen atmosphere for 1 hour. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4.10 g).

[0620] MS: [M+Na] + 499.3.

[0621] F) (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester Methanesulfonic anhydride (2.83 g) was added to a mixture of (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.10 g) and TEA (4.52 mL) in dichloromethane (40 mL) at 20 °C, and the mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with EtOAc and water under stirring. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.18 g).

[0622] MS: [M+Na] + 577.1.

[0623] G) (2R,4R)-2-(cyanomethyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Sodium cyanide (1.58 g) was added to a mixture of (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester (4.18 g) and dimethyl sulfoxide (50 mL), and the mixture was stirred at 50 °C under a nitrogen atmosphere for 4 hours. The mixture was diluted with EtOAc and water while stirring. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (2.75 g).

[0624] MS: [M+H-Boc] + 386.2.

[0625] H)[(2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidone-2-yl]methyl acetate hydrochloride Trimethylsilane chloride (9.23 g) was added to a mixture of (2R,4R)-2-(cyanomethyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.75 g) and MeOH (40 mL) at 25 °C, and the mixture was stirred at 65 °C under a nitrogen atmosphere for 14 hours. Trimethylsilane chloride (4.62 g) was added, and the mixture was stirred at 65 °C under a nitrogen atmosphere for 1 hour. Trimethylsilane chloride (4.62 g) was added, and the mixture was stirred at 65 °C under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure to give the title compound (2.70 g).

[0626] MS: [M+H] + 419.0.

[0627] I) (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (2.47 g) and sodium bicarbonate (2.38 g) were added to a mixture of [(2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidone-2-yl]acetate hydrochloride (2.70 g), THF (30 mL), and water (15 mL) at 25 °C, and the mixture was stirred at 25 °C under a nitrogen atmosphere for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (2.65 g).

[0628] MS: [M+Na] + 541.1.

[0629] J) (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester At 0 °C, 8.40 g of diammonium cerium(IV) nitrate was added to a mixture of (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.65 g), MeCN (50 mL), and pH 6.8 phosphate buffer (30 mL), and the mixture was stirred at 20 °C under a nitrogen atmosphere for 2 hours. The mixture was diluted with EtOAc and 10% sodium thiosulfate aqueous solution was added until the yellow color of the reaction disappeared, and saturated sodium bicarbonate aqueous solution was added with stirring for neutralization. The mixture was filtered and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.75 g).

[0630] MS: [M+H-Boc] + 298.9.

[0631] K) (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A 2 M lithium borohydride solution in THF was added dropwise (13.2 mL) to a mixture of (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.75 g) and THF (20 mL) at 20 °C. The mixture was stirred at 60 °C for 2 h. The mixture was slowly quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.60 g).

[0632] MS: [M+H-Boc] + 270.9.

[0633] L)N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]cyclopropanesulfonamide hydrochloride A solution of (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g) in 25 mL of 4 M hydrogen chloride EtOAc solution was stirred for 1 hour at 20 °C. The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound (1.15 g).

[0634] 1H NMR (400 MHz, DMSO-d6) δ 0.89-1.06 (4H, m), 1.83-2.22 (2H, m), 2.53-2.65 (1H, m), 3.09-3.23 (1H, m), 3.50-3.73 (3H, m), 4.06-4.20 (1H, m), 4.50-4.70 (1H, m), 8.08-8.20 (1H, m), 10.28 (2H, m).

[0635] M) (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (107 mg) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]cyclopropanesulfonamide hydrochloride (50.0 mg) and TEA (91.0 μL) in THF (4 mL). The mixture was stirred at 60 °C under a nitrogen atmosphere for 14 hours. The reaction mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, EtOAc / petroleum ether) to give the title compound (45 mg).

[0636] MS: [M+H] + 561.0.

[0637] N) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}cyclopropanesulfonamide TEA (65.0 mg) and methanesulfonic anhydride (42.0 mg) were added to a mixture of (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (45.0 mg) and MeCN (2 mL) at 0 °C. The mixture was stirred at 25 °C for 10 h. The reaction mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonium hydroxide) and then lyophilized to give the title compound (7.2 mg).

[0638] 1 ¹H NMR (400 MHz, CDCl₃) δ 1.02–1.13 (2H, m), 1.14–1.32 (2H, m), 1.97–2.29 (2H, m), 2.46–2.57 (1H, m), 2.58–2.80 (1H, m), 3.40–4.42 (5H, m), 4.46–4.64 (1H, m), 6.61–6.92 (2H, m), 7.27–7.31 (1H, m, overlapping with CDCl₃ signal), 7.60–7.67 (2H, m).

[0639] Example 243 N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide A) (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide TEA (0.059 mL) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]methanesulfonamide hydrochloride (39.5 mg), [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (67.0 mg), and THF (1.0 mL) at room temperature. The mixture was stirred overnight at 60 °C under nitrogen. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (66 mg).

[0640] MS: [M+H] + 571.2.

[0641] B) N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide Methanesulfonic anhydride (36.3 mg) was added to a mixture of (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (66.0 mg), TEA (0.080 mL), and MeCN (1.0 mL) at room temperature. The mixture was stirred under nitrogen at room temperature for 10 min, then diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The solid was crystallized from EtOAc-heptane to give the title compound (53.0 mg).

[0642] 1 H NMR (400 MHz, CDCl3) δ 1.92-2.10 (1H, m), 2.16-2.28 (1H, m), 2.49-2.81 (1H, m), 3.10 (3H, s), 3.18-4.18 (4H, m), 4.22-4.43 (1H, m), 4.50-4.67 (1H, m), 6.66-6.93 (2H, m), 7.43-7.55 (1H, m).

[0643] Example 260 N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide A) (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Ethylenesulfonyl chloride (4.68 g) was added to a solution of (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (8.90 g) and TEA (7.37 g) in dichloromethane (100 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 1 hour. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (10.7 g).

[0644] 1 H NMR (400 MHz, CDCl3) δ 0.08-0.21 (6H, m), 0.90-0.96 (9H, m), 1.37(3H, t, J = 7.6 Hz), 1.47 (9H, s), 2.92-3.16 (2H, m), 3.36-3.55 (1H, m),3.74-4.12 (4H, m), 4.14-4.30 (1H, m), 6.30-6.69 (1H, m).

[0645] B) (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Potassium carbonate (16.1 g) was added to a mixture of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate tert-butyl ester (10.7 g) and 1-(chloromethyl)-4-methoxybenzene (9.11 g) in DMF (150 mL). The mixture was stirred at 60 °C for 7 h. The reaction mixture was quenched with water at 0 °C and then extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (10.8 g).

[0646] 1H NMR (400 MHz, CDCl3) δ 0.01-0.07 (6H, m), 0.87 (9H, s), 1.36 (3H,t, J = 7.2 Hz), 1.43 (9H, s), 2.82-3.37 (3H, m), 3.74-4.03 (7H, m), 4.38-4.87(3H,m), 6.79-6.91(2H,m), 7.22-7.26(2H,m).

[0647] C) (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A solution of 1 M tetrabutylammonium fluoride in THF (28.0 mL) was added to a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (10.8 g) in THF (200 mL), and the mixture was stirred at 20 °C under a nitrogen atmosphere for 16 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (8.05 g).

[0648] 1 H NMR (400 MHz, CDCl3) δ 1.33 (3H, t, J = 7.2 Hz), 1.43 (9H, s), 2.75-3.08 (2H, m), 3.22-3.41 (1H, m), 3.60-3.74 (1H, m), 3.76-3.85 (4H, m),3.94-4.08 (2H, m), 4.34-4.54 (2H, m), 4.60-4.77 (2H, m), 6.84-6.92 (2H, m),7.27-7.36 (2H, m).

[0649] D) (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester Methanesulfonic anhydride (300 mg) was added to a mixture of (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg) and TEA (349 mg) in dichloromethane (10 mL) at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The mixture was diluted with EtOAc and water while stirring. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (480 mg).

[0650] MS: [M+Na] + 565.2.

[0651] E) (2R,4R)-2-(cyanomethyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Sodium cyanide (3.19 g) was added to a mixture of (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester (8.42 g) and dimethyl sulfoxide (120 mL), and the mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The mixture was diluted with EtOAc and water while stirring. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (5.18 g).

[0652] MS: [M+Na] + 496.2.

[0653] F) [(2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidone-2-yl]methyl acetate hydrochloride Trimethylsilane chloride (17.8 g) was added to a mixture of (2R,4R)-2-(cyanomethyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (5.18 g) and MeOH (100 mL) at 25 °C, and the mixture was stirred at 65 °C under a nitrogen atmosphere for 14 hours. The mixture was concentrated under reduced pressure to give the title compound (4.84 g).

[0654] MS: [M+H] + 407.1.

[0655] G) (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (4.77 g) and sodium bicarbonate (4.59 g) were added to a mixture of [(2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidone-2-yl]acetate hydrochloride (4.84 g), THF (80 mL), and water (40 mL) at 20 °C, and the mixture was stirred at 20 °C under a nitrogen atmosphere for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.53 g).

[0656] 1 H NMR (400 MHz, CDCl3) δ 1.35 (3H, t, J = 7.2 Hz), 1.41 (9H, s), 2.63-3.10 (4H, m), 3.12-3.43 (1H, m), 3.67-3.84 (7H, m), 4.34-4.52 (2H, m), 4.60-4.83 (2H, m), 6.87 (2H, d, J = 8.4 Hz), 7.26-7.37 (2H, m).

[0657] H) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester At 0 °C, 545 mg of diammonium cerium(IV) nitrate was added to a mixture of (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg), MeCN (8 mL), and pH 6.8 phosphate buffer (4 mL), and the mixture was stirred at 25 °C under a nitrogen atmosphere for 1 hour. The mixture was diluted with EtOAc and 10% sodium thiosulfate aqueous solution was added until the yellow color of the reaction disappeared, and saturated sodium bicarbonate aqueous solution was added with stirring for neutralization. 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 (EtOAc / petroleum ether) to give the title compound (110 mg).

[0658] MS: [M+H-Boc] + 286.9.

[0659] I) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester A 4 M lithium borohydride solution in THF was added dropwise (0.53 mL) to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (162 mg) and THF (5 mL) at 25 °C. The mixture was stirred at 60 °C for 2 hours. The mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (146 mg).

[0660] MS: [M+H-Boc] + 258.9.

[0661] J) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride A 4 M dioxane solution (2 mL) of hydrogen chloride was added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (146 mg) and EtOAc (2 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure and co-evaporated with EtOAc to give the title compound (120 mg).

[0662] 1 ¹H NMR (400 MHz, DMSO-d6) δ 1.22 (3H, t, J = 7.2 Hz), 1.84–1.97 (2H, m), 2.99–3.17 (3H, m), 3.51–3.58 (2H, m, overlapping with dioxane signal), 3.63–3.77 (1H, m), 4.06–4.16 (1H, m), 4.49–4.69 (1H, m), 6.53 (1H, brs), 8.15 (1H, d, J = 8.8 Hz), 10.11 (2H, brs).

[0663] K) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester (45 mg) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (20 mg) and TEA (28 mg) in THF (2 mL) at 0 °C. The mixture was stirred at 60 °C under a nitrogen atmosphere for 14 hours. The reaction mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (22 mg).

[0664] MS: [M+H] + 549.1.

[0665] L) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide TEA (16 mg) and methanesulfonic anhydride (21 mg) were added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (22 mg) and MeCN (2 mL) at 0 °C. The mixture was stirred at 25 °C for 14 h. The reaction mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonium hydroxide) and then lyophilized to give the title compound (6.2 mg).

[0666] 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, t, J = 7.2 Hz), 1.99-2.30 (2H, m), 2.47-2.90 (1H, m), 3.17 (2H, q, J = 7.6 Hz), 3.38-4.45 (5H, m), 4.48-4.84(1H,m), 6.60-6.97(2H,m), 7.27-7.36(1H,m), 7.61-7.70(2H,m).

[0667] Example 265 N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide A) [4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]carbamate 2,2,2-trichloroethyl ester A 1 M solution (37.9 mL) of lithium bis(trimethylsilyl)amino in hexane was added dropwise to a solution of 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (4.00 g) in THF (40 mL) at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h. 2,2,2-trichloroethoxycarbonyl chloride (4.81 g) was added. The mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.5 g).

[0668] 1 H NMR (400 MHz, CDCl3) δ 4.40-4.57 (2H, m), 6.85 (1H, brs), 7.04-7.12(2H, m), 7.42-7.53 (2H, m), 7.61-7.68 (1H, m).

[0669] B) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide TEA (288 mg) was added to a solution of 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]carbamate (500 mg) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidone-3-yl]ethanesulfonamide hydrochloride (335 mg) in THF (8 mL), and the mixture was stirred at 60 °C under nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (551 mg).

[0670] MS: [M+H] + 534.9.

[0671] C) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide TEA (121 mg) and methanesulfonyl methanesulfonate (71 mg) were added to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (80 mg) and MeCN (3 mL) at 0 °C. The mixture was stirred at 28 °C for 2 hours. The reaction mixture was decanted into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonium hydroxide) and then lyophilized to give the title compound (48 mg).

[0672] 1 H NMR (400 MHz, CDCl3) δ 1.94-2.25 (2H, m), 2.29-3.05 (1H, m), 3.08(3H, s), 3.13-4.40 (5H, m), 4.71-4.98 (1H, m), 6.86-7.18 (2H, m), 7.37-7.52 (2H, m), 7.57-7.65 (1H, m).

[0673] Example 282 N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide A) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide TEA (112 mg) was added to a solution of 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate (195 mg) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidine-3-yl]ethanesulfonamide hydrochloride (137 mg) in THF (7 mL), and the mixture was stirred at 60 °C for 14 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (234 mg).

[0674] MS: [M+H] + 535.0.

[0675] B) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide A mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide (234 mg) and sodium bicarbonate (184 mg) in MeCN (4 mL) and water (2 mL) was stirred at 0 °C. Then, diiodobenzene diacetate (170 mg), tetrabutylammonium bromide (28 mg), and 2,2,6,6-tetramethylpiperidine-1-oxy (14 mg) were added to the mixture at 0 °C. The mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (197 mg).

[0676] MS: [M+H] + 533.0.

[0677] C) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide Methyl N-(triethylammonium sulfonyl)carbamate (542 mg) was added to a solution of N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide (242 mg) and THF (8 mL). The mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: water containing ammonium hydroxide / MeCN) and then lyophilized to give the title compound (132 mg).

[0678] 1 H NMR (400 MHz, CDCl3) δ 1.44 (3H, t, J = 7.2 Hz), 3.03-3.22 (3H, m), 3.88-4.05 (1H, m), 4.41-4.65 (1H, m), 5.38-5.59 (1H, m), 6.72-6.78 (1H, m), 6.88-6.96 (2H, m), 7.16-7.23 (1H, m), 7.32-7.45 (2H, m).

[0679] The compounds of the examples are shown in the table below. MS in the table refers to actual measured values. The compounds of Examples 2-15, 17-23, 25-32, 35-46, 48, 49, 51-70, 73, 74, 76, 78-91, 93-101, 103-123, 125, 127-143, 145-148, 150-170, 172, 173, 175-212, 214-241, 244-259, 261-264, 266-281 and 283-340 in the table below were produced according to the methods described in the above examples or similar methods.

[0680] Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Experimental Example 1: Obtaining Cells Stably Expressing Human Orexin Type 2 Receptor (hOX2R) To obtain cellular clones stably expressing the human orexin type 2 receptor, human orexin type 2 (residues 1-444, NCBI reference sequence: AK314279) was constructed in the pcDNA3.1 (+) vector (Invitrogen) for expression in mammalian cells. This plasmid DNA was transfected into CHO-K1 cells via electroporation, and stable clones were obtained through limiting dilution using G418 resistance as a selection marker.

[0681] Experimental Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells forcibly expressing the human OX2 receptor were seeded at 10,000 cells / well in 384-well black clear plates (BD falcon) and incubated at room temperature for 30 minutes, followed by incubation at 37°C and 5% CO2 for 1 day. After removing the culture medium from the cell plate, assay buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4 AM (Dojin Kagaku), 0.08% Pluronic F127 (Dojin Kagaku), and 1.25 mM probenecid (Dojin Kagaku)) was added to 30 μL / well. The cells were incubated at 37°C in a 5% CO2 incubator for 30 minutes, followed by incubation at room temperature for another 30 minutes. The test compound diluted with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at 10 μL / well, and fluorescence values ​​were measured every 1 second for 1 minute using an FDSS μCELL (Hamamatsu Photonics), followed by measurements every 2 seconds for 1 minute. The measurement duration was 1 minute and 40 seconds. The amount of fluorescence value when DMSO was added to replace the test compound was defined as 0%, and the amount of fluorescence value when 10 nM of orexin A (human) (Peptide Institute) was added was defined as 100%. The activity (%) of the test compound was calculated. Table 2 shows the activity of each compound at a concentration of 3 μM. These results clearly demonstrate that the compounds of the present invention possess orexin type 2 receptor activating activity.

[0682] Table 2-1 Test compounds OX2R agonist activity (3uM, %) 1 104 2 108 4 105 5 106 6 96 7 105 9 92 12 105 16 107 17 104 20 97 21 81 24 104 25 96 26 97 28 106 29 101 30 94 32 94 33 108 34 106 37 101 38 111 39 106 40 103 41 100 43 100 46 102 47 91 49 94 50 103 Table 2-2 Test compounds OX2R agonist activity (3uM, %) 55 108 56 99 57 88 58 88 63 107 65 99 66 97 67 97 68 109 69 96 70 105 71 97 72 98 73 105 74 104 75 99 76 105 77 100 78 104 79 99 83 84 84 92 85 95 86 103 87 91 88 79 89 95 90 107 91 103 92 98 93 99 Table 2-3 Test compounds OX2R agonist activity (3uM, %) 94 106 95 104 102 100 103 106 105 96 106 103 107 101 108 109 109 103 111 90 112 99 113 102 116 93 117 97 118 91 119 105 121 93 124 101 125 103 126 97 127 102 128 98 129 103 130 99 131 96 132 94 135 100 136 99 139 101 140 100 141 94 Table 2-4 Test compounds OX2R agonist activity (3uM, %) 142 99 144 102 145 105 149 95 152 92 153 96 154 98 155 96 156 102 157 96 158 103 160 99 162 102 163 103 164 108 165 97 166 92 167 97 168 102 169 103 170 94 171 100 172 98 174 95 175 98 176 89 179 109 180 100 181 105 182 84 183 101 Table 2-5 Test compounds OX2R agonist activity (3uM, %) 184 101 185 104 186 101 189 103 190 96 191 98 193 103 194 92 Table 2-6 Test compounds OX2R agonist activity (3uM, %) 195 106 196 106 197 115 198 112 199 105 200 122 201 114 202 99 203 114 204 109 205 107 206 110 207 113 208 102 209 96 210 94 211 108 212 100 213 104 214 106 215 99 216 101 217 104 218 108 219 103 220 112 221 104 222 107 223 104 Table 2-7 Test compounds OX2R agonist activity (3uM, %) 224 109 225 106 226 93 227 98 228 102 229 113 230 111 231 103 232 107 233 109 234 111 235 113 236 108 237 110 238 106 239 95 240 106 241 100 242 105 243 109 244 89 245 108 246 107 247 101 248 107 249 102 250 99 251 109 252 96 Table 2-8 Test compounds OX2R agonist activity (3uM, %) 253 101 254 95 255 107 256 103 257 110 258 100 259 96 260 108 261 105 262 114 263 114 264 107 265 107 266 103 267 101 268 104 269 104 270 109 271 107 272 109 273 103 274 102 275 103 276 100 277 106 278 109 279 104 280 101 281 107 Table 2-9 Test compounds OX2R agonist activity (3uM, %) 282 105 283 107 284 109 285 105 286 105 287 101 288 101 289 97 290 106 291 106 292 106 293 113 294 104 295 113 296 102 297 107 298 105 299 104 300 105 301 98 302 103 303 103 304 117 305 113 306 101 307 101 308 100 309 107 310 100 Table 2-10 Test compounds OX2R agonist activity (3uM, %) 311 99 312 100 313 99 314 113 315 105 316 105 317 110 318 105 319 107 320 104 321 108 322 99 323 97 324 97 325 101 326 99 327 118 328 103 329 101 330 109 331 45 332 106 333 68 334 111 335 101 336 98 337 79 338 100 339 96 340 92 Experimental Example 3: Evaluation of the arousal-inducing effect on cynomolgus monkeys The arousal effect was assessed by measuring electroencephalography (EEG), electromyogra...

Claims

1. A compound represented by formula (I): (I) in X 1 It is NR 8 or CR 9 ; X 2 It is O, NR 10 Or S; X 3 and X 4 Both are C or X 3 and X 4 One of them is N and the other is C; X 5 It is CR 11 Or N; X 6 It is CR 12 ; X 7 It is CR 13 Or N; X 8 It is CR 14 Or N; X 9 It is CR 2 Or N; X 10 It is CR 15 Or N; R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino; R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 alkyl, or When r is 0, then R 2 and R 3 They can come together to form bonds, or When X 10 It is CR 15 When, then R 3 Able to work with R 15 They come together to form bonds; R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 5 It is a 4-, 5-, or 6-membered monocyclic group that can be optionally substituted; R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl; m is 0 or 1; q is 1 or 2; r is 0 or 1; R 9 R 11 R 12 and R 13 Each is an independent hydrogen atom, with optional substitutions of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 8 and R 10 Each of them does not exist independently, or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 Alkyl; and R 14 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 alkyl; R 15 It is a hydrogen atom, a halogen atom, or an optionally substituted C atom. 1-6 alkyl, or R 15 Able to work with R 3 They come together to form bonds; Or its salt.

2. The compound according to claim 1, wherein the compound is represented by formula (Ib): (One) in R 1 C is arbitrarily replaced 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted single or two C 1-6 Alkylamino; R 2 and R 3 Each is independently a hydrogen atom or an optionally substituted C atom 1-6 alkyl, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom, with optional substitution of C atoms. 1-6 Alkyl, optionally substituted C 1-6 alkoxy or hydroxyl groups; R 5 It is a 5- or 6-membered monocyclic group that can be optionally substituted; R 6 and R 7 Each carbon atom is independently a hydrogen atom, a halogen atom, or optionally substituted. 1-6 alkyl; m is 0 or 1; q is 1 or 2; X 1 It is NR 8 or CR 9 ; X 2 It is O, NR 10 Or S; X 3 and X 4 Both are C or X 3 and X 4 One of them is N and the other is C; X 5 It is CR 11 Or N; X 6 It is CR 12 ; X 7 It is CR 13 Or N; R 9 R 11 R 12 and R 13 Each is an independent hydrogen atom, with optional substitutions of C atoms. 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 alkoxy or hydroxyl; and R 8 and R 10 Each of them does not exist independently, or is selected from hydrogen atoms and optionally substituted C atoms. 1-6 alkyl; Or its salt.

3. The compound according to claim 2, wherein... R 1 yes (1) C10 cells optionally substituted with 1 to 3 independently selected substituents from the following 1-6 alkyl: (i) Halogen atoms, (ii) C 1-6 alkoxy groups, and (iii) C 3-6 cycloalkyl, (2) C 3-10 cycloalkyl, or (3) Single or double C 1-6 Alkylamino; R 2 and R 3 Each is an independent hydrogen atom or a carbon atom. 1-6 Alkyl, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom, C 1-6 Alkyl, C 1-6 alkoxy or hydroxyl groups; R 5 It is phenyl, pyrazolyl, furanyl, thiophenyl, or thiazolyl, any of which may optionally be selected independently by one or more C14 groups. 1-6 Alkyl group, halogen atom, halogen group (C 1-6 )alkyl and C 1-6 Substitution of alkoxy groups; m is 0 or 1; q is 1 or 2; R 6 and R 7 Each is independently a hydrogen atom, a halogen atom, or a carbon atom. 1-6 alkyl; X 1 X 2 X 3 X 4 X 5 X 6 and X 7 The ring system is selected to form a ring system, which is one of the following: (i) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (ii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (iii) X 1 It is NR 8 And R 8 Does not exist, X 2 It is O, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is N; (iv) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is N, X 6 It is CR 12 And X 7 It is CR 13 ; (v) X 1 It is NR 8 And R 8 Does not exist, X 2 It is S, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vi) X 1 It is NR 8 And X 2 It is NR 10 And R 8 and R 10 One of them does not exist and R 8 and R 10 The other one is C 1-6 Alkyl, X 3 and X 4 Both are C and X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ; (vii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is N, X 4 It is C, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;as well as (viii) X 1 It is CR 9 X 2 It is NR 10 And R 10 Does not exist, X 3 It is C, X 4 It is N, X 5 It is CR 11 X 6 It is CR 12 And X 7 It is CR 13 ;and R 9 R 11 R 12 and R 13 Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl group, halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl (C 1-6 )alkoxy, halogen (C 1-6 )alkyl, halogen (C 1-6 )alkoxy, C 1-6 Alkoxy (C 1-6 )alkyl, azahexacyclic butyl, C 1-6 Alkoxy, hydroxyl and hydroxyl (C 1-6 )alkyl; Or its salt.

4. The compound according to claim 1, wherein the compound is represented by formula (Ic): (Ic) in R 1 It is C 1-6 Alkyl or mono-C 1-6 Alkylamino; R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that is optionally substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is an independent hydrogen atom or a halogen atom; X 5 It is CH or N; and R 12 and R 13 Each is an independent hydrogen atom, C 1-6 Alkyl or halogen atom; Or its salt.

5. The compound according to claim 4, wherein... R 1 It is C 1-6 alkyl; R 2 and R 3 Each is a hydrogen atom, or R 2 and R 3 They come together to form bonds; R 4 It is a hydrogen atom; R 5 It is a phenyl group that has been substituted with 1 to 3 halogen atoms; R 6 and R 7 Each is a halogen atom; X 5 It is CH; and R 12 and R 13 Each is an independent hydrogen atom or a halogen atom; Or its salt.

6. The compound according to claim 1, wherein the compound is selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl} ethanesulfonamide; Or its salt.

7. A method for preventing or treating diseases or conditions associated with orexin type 2 receptors in mammals in need, the method comprising administering to the mammal a therapeutically effective amount of a compound or a salt thereof as defined in any one of claims 1 to 6.

8. The method of claim 7, wherein the disease or condition is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications caused by anesthesia.

9. The method of claim 7, wherein the disease or condition is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

10. The method of claim 7, wherein the disease or condition is narcolepsy.

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