COMPOUND OR SALT, PHARMACEUTICAL COMPOSITION, MEDICINE, METHOD FOR THE PROPHYLAXIS OR TREATMENT OF A DISEASE OR DISORDER ASSOCIATED WITH AN OREXIN TYPE 2 RECEPTOR IN A MAMMAL IN NEED, AND USE OF THE COMPOUND

Abstract

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

Description

COMPOUND OR SALT, PHARMACEUTICAL COMPOSITION, MEDICINE, METHOD FOR THE PROPHYLAXIS OR TREATMENT OF A DISEASE OR DISORDER ASSOCIATED WITH AN OREXIN TYPE 2 RECEPTOR IN A MAMMAL IN NEED, AND USE OF THE COMPOUND Technical Field

[001] The present invention relates to a heterocyclic compound, in particular, a heterocyclic compound with orexin type 2 receptor agonist activity. Fundamentals of the Invention

[002] Orexin is a neuropeptide produced specifically in neurons located sparsely in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of orexin receptors, which are G protein-coupled receptors present mainly in the brain, and two types of subtypes, type 1 and type 2, are known for orexin receptors (unpatented document 1).

[003] Since orexin-producing neurons (orexin neurons) are located in close proximity to the feeding center, and intraventricular administration of the orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide with a behavioral regulation of feeding. Subsequently, however, it was reported that the cause of narcolepsy in dogs is genetic variation of the orexin receptor type 2 (unpatented paper 2), and the role of orexin in the control of sleep and wakefulness was also drawn.

[004] From studies using a transgenic mouse with denatured orexin neurons and a double transgenic mouse obtained by crossing this mouse with a transgenic mouse with orexin overexpression, it was clarified that the symptoms similar to Petition 870250083065, dated 09 / 15 / 2025, page 34 / 258 / 211. Narcolepsy symptoms that appear due to the degeneration of orexin neurons disappear due to sustained orexin expression. Similarly, when orexin peptide was administered intraventricularly to a transgenic mouse with denatured orexin neurons, an improvement in narcolepsy-like symptoms was also observed (non-patent document 3). Studies in orexin receptor type 2 knockout mice suggested that the orexin receptor type 2 is important for maintaining arousal (non-patent document 4, non-patent document 5). This context suggests that orexin receptor type 2 agonists become therapeutic drugs for narcolepsy or therapeutic drugs for other sleep disorders that exhibit excessive sleepiness (non-patent document 6).

[005] Furthermore, it is suggested that a peptide agonist that acts selectively on the orexin type 2 receptor improves obesity due to a high dietary fat load in mice (non-patented document 7).

[006] Furthermore, it is suggested that intraventricular administration of the peptide orexin shortens the systemic anesthetic time in rats (non-patented document 8).

[007] Furthermore, it is suggested that patients with sleep apnea syndrome have low levels of orexin A concentration in plasma (non-patented document 9).

[008] Furthermore, it is suggested that intraventricular administration of orexin peptide improves memory retention in senescence-accelerated mouse model (SAMP8) with cognitive dysfunction (non-patented document 10).

[009] Furthermore, it is suggested that the type 2 Orexin receptor agonist will be a therapeutic drug for heart failure (patent document 1, non-patent document 11).

[0010] In addition, it is suggested that daytime sleepiness in patients Petition 870250083065, dated 09 / 15 / 2025, p. 35 / 258 / 211 with Parkinson's disease is caused by the precipitation of the orexin nerve (unpatented document 12).

[0011] Furthermore, it is suggested that orexin regulates bone formation and bone loss, and the orexin type 2 receptor agonist will be a therapeutic drug for diseases related to bone loss, such as osteoporosis, rheumatoid arthritis and the like (patent document 2).

[0012] Furthermore, it is suggested that the orexin receptor agonist is useful for the prophylaxis or treatment of sepsis, severe sepsis and septic shock, since mortality was significantly improved by the mere continuous administration of orexin from the periphery in a mouse model of septic shock (patent document 3).

[0013] Therefore, a compound with orexin type 2 receptor agonist activity is expected to be useful as a novel therapeutic drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbances of consciousness such as coma and similar conditions, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis and similar conditions, as well as an anesthetic antagonist, a prophylactic or therapeutic drug for side effects and complications due to anesthesia.

[0014] As sulfonamide derivatives, a compound represented by the formula where each symbol is as described in the document Petition 870250083065, dated 09 / 15 / 2025, page 36 / 258 / 211 (Patent Document 4) was reported.

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

[0016] A compound represented by the formula where each symbol is as described in the document (Patent Document 5).

[0017] A compound represented by the formula where each symbol is as described in the document (Patent Document 6).

[0018] A compound represented by the formula R2 where each symbol is as described in the document (Patent Document 7).

[0019] A compound represented by the formula Petition 870250083065, dated 09 / 15 / 2025, page 37 / 258 / 211 where each symbol is as described in the document (Patent Document 8).

[0020] A compound represented by the formula where each symbol is as described in the document (Patent Document 9).

[0021] A compound represented by the formula HN R1 R2(I) where each symbol is as described in the document (Patent Document 10).

[0022] A compound represented by the formula Petition 870250083065, dated 09 / 15 / 2025, page 38 / 258 / 211 where each symbol is as described in the document (Patent Document 11).

[0023] A compound represented by the formula (I) where each symbol is as described in the document (Patent Document 12).

[0024] A compound represented by the formula Θ. R1HN I R2 Lx^-^xYR3 ZX NY (I) Petition 870250083065, dated 09 / 15 / 2025, page 39 / 258 7 / 211 where each symbol is as described in the document (Patent Document 13).

[0025] A compound represented by the formula R3em where each symbol is as described in the document (Patent Document 14).

[0026] A compound represented by the formula where each symbol is as described in the document (Patent Document 15).

[0027] A compound represented by the formula Petition 870250083065, dated 09 / 15 / 2025, page 40 / 258 8 / 211 where each symbol is as described in the document (Patent Document 16).

[0028] A compound represented by the formula where each symbol is as described in the document (Patent Document 17).

[0029] A compound represented by the formula where each symbol is as described in the document (Patent Document 18).

[0030] A compound represented by the formula Petition 870250083065, dated 09 / 15 / 2025, page 41 / 258 / 211 in which each symbol is as described in the document (Patent Document 19).

[0031] A compound represented by the formula where each symbol is as described in the document (Patent Document 20).

[0032] A compound represented by the formula where each symbol is as described in the document (Patent Document 21). Petition 870250083065, dated 09 / 15 / 2025, page 42 / 258 / 211

[0033] A compound represented by the formula in which each symbol is as described in the document (Patent Document 22).

[0034] A compound represented by the formula in which each symbol is as described in the document (Patent Document 23).

[0035] A compound represented by the formula in which each symbol is as described in the document (Patent Document 24). Petition 870250083065, dated 09 / 15 / 2025, page 43 / 258 / 211

[0036] A compound represented by the formula in which each symbol is as described in the document (Patent Document 25).

[0037] The development of a new compound with orexin type 2 receptor agonist activity is desired. [List of Documents] [Patent Documents]

[0038] [Patent Document 1] WO 2015 / 073707 A1

[0039] [Patent Document 2] WO 2015 / 048091 A1

[0040] [Patent Document 3] WO 2015 / 147240 A1

[0041] [Patent Document 4] WO 2012 / 137982 A9

[0042] [Patent Document 5] WO 2017 / 135306 A1

[0043] [Patent Document 6] WO 2018 / 164191 A1

[0044] [Patent Document 7] WO 2018 / 164192 A1

[0045] [Patent Document 8] WO 2019 / 027003 A1

[0046] [Patent Document 9] WO 2019 / 027058 A1

[0047] [Patent Document 10] WO 2020 / 004536 A1

[0048] [Patent Document 11] WO 2020 / 004537 A1

[0049] [Patent Document 12] WO 2020 / 122092 A1

[0050] [Patent Document 13] WO 2020 / 122093 A1

[0051] [Patent Document 14] WO 2020 / 158958 A1 Petition 870250083065, dated 09 / 15 / 2025, page 44 / 258 / 211

[0052] [Patent Document 15] WO 2020 / 167701 A1

[0053] [Patent Document 16] WO 2020 / 167706 A1

[0054] [Patent Document 17] WO 2021 / 106975 A1

[0055] [Patent Document 18] WO 2021 / 108628 A1

[0056] [Patent Document 19] WO 2022 / 140316 A1

[0057] [Patent Document 20] WO 2022 / 232025 A1

[0058] [Patent Document 21] WO 2022 / 251302 A1

[0059] [Patent Document 22] WO 2022 / 251304 A1

[0060] [Patent Document 23] WO 2022 / 051583 A1

[0061] [Patent Document 24] WO 2023 / 167925 A1

[0062] [Patent Document 25] WO 2022 / 109117 A1 [Non-Patent Documents]

[0063] [Non-Patent Document 1] Cell, Vol. 92, 573-585, 1998

[0064] [Non-Patent Document 2] Cell, Vol. 98, 365-376, 1999

[0065] [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004

[0066] [Non-Patent Document 4] Cell, Vol. 98, 437-451, 1999

[0067] [Non-Patent Document 5] Neuron, Vol. 38, 715-730, 2003

[0068] 2013 [Non-Patent Document 6] CNS Drugs, Vol. 27, 83-90,

[0069] 76, 2009 [Non-Patent Document 7] Cell Metabolism, Vol. 9, 64-

[0070] 863, 2003 [Non-Patent Document 8] Neuroscience, Vol. 121, 855-

[0071] 2004 [Non-Patent Document 9] Respiration, Vol. 71, 575-579,

[0072] 2002 [Unpatented Document 10] Peptides, Vol. 23, 1683-1688,

[0073] [Unpatented Document 11] Journal of the American Petition 870250083065, dated 09 / 15 / 2025, page 45 / 258 / 211 College of Cardiology. Vol. 66, 2015, Pages 2522-2533

[0074] [Unpatented Document 12] Brain. Vol. 130, 2007, Pages 1586-1595 Summary of the Invention Problems to be solved by the invention

[0075] The present invention aims to provide a heterocyclic compound with orexin type 2 receptor agonist activity. Ways to solve the problems

[0076] The present inventors have discovered that a compound represented by the following formula (I) or a salt thereof (sometimes referred to as compound (I) in this descriptive report) has an agonist activity at the orexin type 2 receptor. As a result of further studies, they have completed the present invention.

[0077] Consequently, the present invention relates to the following. [1]

[0078] A compound represented by formula (I): in which Ring A is an optionally substituted C6-14 aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, where Y is a ring atom C or N, where the C is bonded to hydrogen or an optional substituent; X is -O-, -S-, -NR1-, -CR2R3-, -O-(CR2R3)-, -(CR2R3)-O-, or Petition 870250083065, dated 09 / 15 / 2025, p. 46 / 258 / 211 an optionally substituted C3-6 cycloalkyl group, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B; R1 is hydrogen, or an optionally substituted C1-6 alkyl group; R2 and R3 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; Ring B is an optionally substituted Co-14 aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group; L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5), -C(R4R5)-C(R7R8)-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R4 and R5 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; R6 is hydrogen or an optionally substituted C1-6 alkyl group; R7 and R8 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; R4 and R6, taken together with the atoms to which they are attached, form a non-aromatic monocyclic heterocyclic ring of 3 to 8 members, optionally substituted; or R4e R5, or R4e R7 taken together with the atom or atoms to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C3-10 cycloalkyl group; Ra is a C1-6 alkyl group, a C3-4 cycloalkyl group, or a mono- or di-C1-6 alkylamino group, wherein each of the C1-6 alkyl, C3-4 cycloalkyl, and mono- or di-C1-6 alkylamino groups is optionally Petition 870250083065, dated 09 / 15 / 2025, p. 47 / 258 / 211 replaced; Rbé is a hydrogen atom or a halogen atom; and Rcé is a hydrogen atom or a halogen atom; or a salt thereof. [2]

[0079] The compound or salt of the above mentioned [1], in which Ring A is where i is the methylene bridge attachment point and ii is the X attachment point; and R11 and R12 are independently hydrogen, halogen, or optionally halogenated C1-6 alkyl groups. [3]

[0080] The compound or salt of the above-mentioned [1] or [2], in which Ring B is selected from: iii Petition 870250083065, dated 09 / 15 / 2025, page 48 / 258 / 211 where iv is the point of attachment of L and iii is the point of attachment to X; R21a, R21b, R21d, R22a, R22b, R22c, R23a, R23b, R23c, and R23d are independently selected from hydrogen, halogen, an optionally halogenated C1-6 alkyl group, a C1-6 alkoxyl group, and a C3-6 cycloalkyl group; and R24 is selected from hydrogen, halogen, an optionally halogenated C1-6 alkyl group and a C3-6 cycloalkyl group. [4]

[0081] The compound or salt of the above-mentioned [1], [2] or [3], in which Ring A is where i is the methylene bridge attachment point and ii is the X attachment point; and R11 and R12 are independently hydrogen, halogen, or C1-6 alkyl groups; X is -O-, -CR2R3-, -O-(CR2R3)-, or -(CR2R3)-O-, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B; Petition 870250083065, dated 09 / 15 / 2025, page 49 / 258 / 211 R2 and R3 are independently hydrogen, halogen, or C1-6 alkyl groups optionally substituted by 1 to 3 substituents selected independently from halogen and C1-6 alkyl groups; Ring B is selected from: σννν' ... where iv is the point of connection of L and iii is the point of connection to X; R21a, R21b, R21d, R22a, R22b, R22c, R23a, R23b, R23c, and R23d are independently selected from hydrogen, halogen, an optionally selected C1-6 alkyl group, a C1-6 alkoxyl group, and a C3-6 cycloalkyl group; R24 is hydrogen or a C1-6 alkyl group; L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5), or -C(R4R5)-C(R7R8)-, wherein the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R4 and R5 are, independently, hydrogen or C1-6 alkyl groups; R6 is hydrogen or an optionally C1-6 alkyl group. Petition 870250083065, dated 09 / 15 / 2025, page 50 / 258 / 211 halogenated; R7 and R8 are independently hydrogen; or when L is -C(R4R5)-NR6- or -NR6-C(R4R5)-, R4 and R6 together with the atoms to which they are attached form a 3- to 8-membered non-aromatic monocyclic heterocyclic ring optionally substituted by 1 to 3 substituents independently selected from halogen and C1-6 alkoxyl group, and R5 is hydrogen; or when L is -C(R4R5)-C(R7R8)-, R4 and R7 together with the carbon atoms to which they are attached form a C3-10 cycloalkyl group, and R5 and R8 are both hydrogen; Rae is a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected independently from halogen atoms and a C1-6 alkoxyl group, a C3-4 cycloalkyl group, or a mono- or di-C1-6 alkylamino group; Rbé is a hydrogen atom or a halogen atom; and Rcé is a hydrogen atom, or a halogen atom. [5]

[0082] The compound or salt of the above-mentioned [1], [2], [3] or [4], wherein Ring A is a phenyl group optionally substituted by 1 to 2 halogen atoms, wherein Y is a ring C atom bonded to hydrogen or halogen; X is -O-, where the left portion of X is bonded to a carbon atom in Ring A that is adjacent to Y, and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted with 1, 2, or 3 substituents selected independently from halogen and C1-6 alkyl groups; L is -CH2-NH-, where the left portion of L is connected to Petition 870250083065, dated 09 / 15 / 2025, p. 51 / 258 / 211 Ring B and the right-hand portion of L is attached to the carbonyl group; Rae is a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C3-4 cycloalkyl group; R is a halogen atom; and Rcé is a halogen atom. [6]

[0083] The compound or salt of the above-mentioned [1] to [5], wherein Ring A is a phenyl group optionally substituted further by 1 to 2 halogen atoms, wherein Y is a ring atom C bonded to halogen; X is -O-, where the left portion of X is bonded to a carbon atom in Ring A that is adjacent to Y, and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted with 1, 2, or 3 C1-6 alkyl groups; L is -CH2-NH-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; Rae is a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; R is a halogen atom; and Rcé is a halogen atom. [7]

[0084] The compound according to the above mentioned [1], wherein the compound is selected from the group consisting of: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene )-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2 Petition 870250083065, dated 09 / 15 / 2025, page 52 / 258 / 211 j][1,8,10]oxadiazacycloheptadecyn-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide; 1-fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8 -(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(a zeno)-14,10-(metheno)pyrrole[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azen o)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; And N-[(15aS,16R)-17,17,20-trifluoro-7 -methyl-1 -oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacicloheptadecin-16-yl]propane-2-sulfonamida; ou um sal dos mesmos. [8]

[0085] A pharmaceutical composition comprising the compound as defined in any of the above-mentioned [1] to [7] or a salt thereof and a pharmacologically acceptable carrier. [9]

[0086] A medicament comprising the compound as defined in any of the above-mentioned [1] to [7] or a salt thereof.

[10] Petition 870250083065, dated 09 / 15 / 2025, page 53 / 258 / 211

[0087] The medicine according to the above mentioned [9], which is an orexin type 2 receptor agonist.

[11]

[0088] The medicine according to the above mentioned [9], which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disturbance of consciousness or side effects and complications due to anesthesia.

[12]

[0089] The medicine according to the above mentioned [9], which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

[13]

[0090] The medicine according to the above mentioned [9], which is an agent for the prophylaxis or treatment of narcolepsy.

[14]

[0091] A method for the prophylaxis or treatment of a disease or disorder associated with a type 2 orexin receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound as defined in any of the above-mentioned [1] to [7] or a salt thereof.

[15]

[0092] The method mentioned above

[14] , in which the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by symptoms similar to narcolepsy, hypersomnia syndrome Petition 870250083065, dated 09 / 15 / 2025, page 54 / 258 / 211 accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications due to anesthesia.

[16]

[0093] The method mentioned above

[14] or

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

[17]

[0094] The method mentioned above

[14] ,

[15] , or

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

[18]

[0095] The compound as defined in any of the above-mentioned [1] to [7] or a salt thereof, for use in therapy.

[19]

[0096] The compound or salt according to the above mentioned

[18] , wherein the therapy comprises treatment of a disease or disorder associated with a type 2 orexin receptor.

[20]

[0097] The compound or salt according to the above mentioned

[19] in which the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disorder of consciousness and side effects and complications due to anesthesia.

[21]

[0098] The compound or salt, according to the above mentioned

[19] Petition 870250083065, dated 09 / 15 / 2025, page 55 / 258 / 211 in which the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

[22]

[0099] The compound or salt according to the above mentioned

[19] , in which the disease or disorder is narcolepsy.

[23]

[00100] Use of the compound as defined in any of the above-mentioned [1] to [7] or a salt thereof in the manufacture of a medicament for the treatment of a disease or disorder associated with an orexin type 2 receptor.

[24]

[00101] Use in accordance with the above-mentioned

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

[25]

[00102] Use in accordance with the above-mentioned

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

[26]

[00103] Use in accordance with the above-mentioned

[23] , where the disease or disorder is narcolepsy. Effect of the Invention

[00104] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for prophylaxis or Petition 870250083065, dated 09 / 15 / 2025, page 56 / 258 / 211 treatment of narcolepsy. (Detailed Description of the Invention)

[00105] The definition of each substituent used in this descriptive report is described in detail below. Unless otherwise specified, each substituent has the following definition.

[00106] In this descriptive report, examples of the “halogen atom” include fluorine, chlorine, bromine, and iodine.

[00107] In this descriptive report, examples of the “C1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

[00108] In this descriptive report, examples of the “optionally halogenated C1-6 alkyl group” include a C1-6 alkyl group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

[00109] In this descriptive report, examples of the “C2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

[00110] In this descriptive report, examples of the “C2-6 alkynyl group” include ethinyl, 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.

[00111] In this descriptive report, examples of the “C3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Petition 870250083065, dated 09 / 15 / 2025, p. 57 / 258 / 211 heptil, ciclo-octil, biciclo[2.2.1]heptil, biciclo[2.2.2]octil, biciclo[3.2.1]octil and adamantil.

[00112] In this descriptive report, examples of the “optionally halogenated C3-10 cycloalkyl group” include a C3-10 cycloalkyl group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[00113] In this descriptive report, examples of the “C3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[00114] In this descriptive report, examples of the “Co-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-antryl, 2-antryl and 9-antryl.

[00115] In this descriptive report, examples of the “C7-16 aralchial group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[00116] In this descriptive report, examples of the “C1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentiloxy, and hexyloxy.

[00117] In this descriptive report, examples of the “optionally halogenated C1-6 alkoxy group” include a C1-6 alkoxy group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

[00118] In this descriptive report, examples of the “C3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[00119] In this descriptive report, examples of the “C1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, Petition 870250083065, dated 09 / 15 / 2025, page 58 / 258 / 211 tert-butylthium, pentylthium and hexylthium.

[00120] In this descriptive report, examples of the “optionally halogenated C1-6 alkylthio group” include a C1-6 alkylthio group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[00121] In this descriptive report, examples of the “C1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl.

[00122] In this descriptive report, examples of the “optionally halogenated C1-6 alkyl-carbonyl group” include a C1-6 alkyl-carbonyl group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

[00123] In this descriptive report, examples of the “C1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[00124] In this descriptive report, examples of the “C6-14 arylcarbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.

[00125] In this descriptive report, examples of the “C7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.

[00126] In this descriptive report, examples of the “5 to 14 membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[00127] In this descriptive report, examples of the “non-aromatic heterocyclylcarbonyl group of 3 to 14 members” include Petition 870250083065, dated 09 / 15 / 2025, page 59 / 258 / 211 morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[00128] In this descriptive report, examples of the “mono- or di-C1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[00129] In this descriptive report, examples of the “mono- or di-C7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

[00130] In this descriptive report, examples of the “C1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[00131] In this descriptive report, examples of the “optionally halogenated C1-6 alkylsulfonyl group” include a C1-6 alkylsulfonyl group optionally with 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[00132] In this descriptive report, examples of the “Cô-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[00133] In this descriptive report, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxyl group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group.

[00134] In this descriptive report, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C1-6 alkyl group, a C2-6 group Petition 870250083065, dated 09 / 15 / 2025, page 60 / 258 / 211 alkenyl, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7-16 aralkyl group.

[00135] In this descriptive report, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally with substituents selected from the following substituent group A. [Replacement group A]

[00136] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6 alkoxy group, (7) a C6-14 aryloxy group (e.g., phenoxy, naphthoxy), (8) a C7-16 aralkyloxy group (e.g., benzyloxy), (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), (11) a C1-6 alkylcarbonyloxy group (e.g., acetoxy, propanoyloxy), (12) a C6-14 arylcarbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) a C1-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a mono- or di-C1-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C6-14 aryl-carbamoyloxy group (e.g., Petition 870250083065, dated 09 / 15 / 2025, page. 61 / 258 / 211 phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) a 5- to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C6-14 arylsulfonyloxy group optionally substituted with a C1-6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6 alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a group non-aromatic heterocyclic group of 3 to 14 members, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C1-6 alkyl-carbonyl group, (26) a C6-14 aryl-carbonyl group, (27) an aromatic heterocyclic carbonyl group of 5 to 14 members,(28) a non-aromatic heterocyclocarbonyl group of 3 to 14 members, (29) a C1-6 alkoxycarbonyl group, (30) a C1-14 aryloxycarbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31) a C7-16 aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or di-C1-6 alkylcarbamoyl group, (35) a C6-14 arylcarbamoyl group (e.g., Petition 870250083065, dated 09 / 15 / 2025, page. 62 / 258 / 211 phenylcarbamoyl), (36) an aromatic heterocyclylcarbamoyl group of 5 to 14 members (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) a non-aromatic heterocyclylcarbamoyl group of 3 to 14 members (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C1-6 alkylsulfonyl group, (39) a C6-14 arylsulfonyl group, (40) an aromatic heterocyclylsulfonyl group of 5 to 14 members (e.g., pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated C1-6 alkylsulfonyl group, (42) a C6-14 arylsulfonyl group (e.g., phenylsulfonyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclosulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,N-ethyl-N-methylamino), (46) a mono- or di-C6-14 arylamino group (e.g., phenylamino), (47) a 5- to 14-membered aromatic heterocyclamino group (e.g., pyridylamino), (48) a C7-16 aralkylamino group (e.g., benzylamino), (49) a formylamino group, (50) a C1-6 alkylcarbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51) a (C1-6 alkyl)(C1-6 alkylcarbonyl)amino group (e.g., Petition 870250083065, dated 09 / 15 / 2025, page. 63 / 258 / 211 example, N-acetyl-N-methylamino), (52) a C1-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53) a C1-6 alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) a C7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55) a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56) a C1-14 arylsulfonylamino group optionally substituted with a C1-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) an optionally halogenated C1-6 alkyl group, (58) a C2-6 alkenyl group, (59) a C2-6 alkynyl group, (60) a C3-10 cycloalkyl group, (61) a C3-10 cycloalkenyl group and (62) a C3-14 aryl group.

[00137] The number of the aforementioned substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

[00138] In this descriptive report, examples of “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridging heterocyclic group, each containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a Petition 870250083065, dated 09 / 15 / 2025, page 64 / 258 / 211 nitrogen atom, a sulfur atom and an oxygen atom.

[00139] In this descriptive report, examples of the “aromatic heterocyclic group” (including “aromatic heterocyclic group of 5 to 14 members”) include an aromatic heterocyclic group of 5 to 14 members (preferably 5 to 10 members) containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[00140] Preferred examples of “aromatic heterocyclic group” include 5- or 6-membered monocyclic aromatic heterocyclic groups, such as tienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;e grupos heterocíclicos aromáticos policíclicos (preferencialmente bi- ou tricíclicos) fundidos de 8 a 14 membros, tais como benzotiofenil, benzofuranil, benzimidazolil, benzoxazolil, benzisoxazolil, benzotiazolil, benzisotiazolil, benzotriazolil, imidazopiridinil, tienopiridinil, furopiridinil, pirrolopiridinil, pirazolopiridinil, oxazolopiridinil, tiazolopiridinil, imidazopirazinil, imidazopirimidinil, tienopirimidinil, furopirimidinil, pirrolopirimidinil, pirazolopirimidinil, oxazolopirimidinil, tiazolopirimidinil, pirazolotriazinil, nafto[2,3-b]tienil, fenoxati-inil, indolil, isoindolil, 1H-indazolil, purinil, isoquinolil, quinolil, ftalazinil, naftiridinil, quinoxalinil, quinazolinil, cinolinil, carbazolil, β-carbolinil, fenantridinil, acridinil, fenazinil, fenotiazinil, fenoxazinil e similares.;

[00141] In this descriptive report, examples of “non-aromatic heterocyclic groups” (including “non-aromatic heterocyclic groups of 3 to 14 members”) include a non-aromatic heterocyclic group of 3 to 14 members (preferably 4 to 10 members) containing, as an atom Petition 870250083065, dated 09 / 15 / 2025, page 65 / 258 / 211 constituent of the ring in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[00142] Preferred examples of “non-aromatic heterocyclic groups” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups, such as aziridinyl, oxiranil, thi-iranil, azetidinil, oxetanil, thietanol, tetrahydrothienyl, tetrahydrofuranil, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinil, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil, azepinil, oxepanil, azocanil, diazocanil and the like; and

[00143] Non-aromatic polycyclic (preferably bi- or tricyclic) fused 9- to 14-membered heterocyclic groups, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinolinyl, tetrahydrocarbazolyl, tetrahydro-βcarbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[00144] In this descriptive report, preferred examples of the “7- to 10-membered bridging heterocyclic group” include quinuclidinil and 7azabicyclo[2.2.1]heptanil.

[00145] In this descriptive report, examples of “nitrogen-containing heterocyclic groups” include a “heterocyclic group” Petition 870250083065, dated 09 / 15 / 2025, page 66 / 258 / 211 containing at least one nitrogen atom as a constituent atom of the ring.

[00146] In this descriptive report, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally with substituents selected from the aforementioned substituent group A.

[00147] The number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

[00148] In this descriptive report, examples of the “acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulphino group, a sulfo group, a sulfamoyl group, and a phosphono group, each optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C1-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group, a 3- to 14-membered non-aromatic heterocyclic group, an amino group, and a mono- or di-C1-6 alkylamino group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a "hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group."

[00149] Examples of the “acyl group” also include a sulfonyl hydrocarbon group, a heterocyclylsulfonyl group, a sulfinyl hydrocarbon group, and a heterocyclylsulfinyl group.

[00150] In this document, the hydrocarbon-sulfonyl group means a sulfonyl group bonded to a hydrocarbon group, the heterocyclic sulfonyl group means a sulfonyl group bonded to a heterocyclic group, the hydrocarbon-sulfinyl group means a sulfinyl group bonded to a group Petition 870250083065, dated 09 / 15 / 2025, page 67 / 258 / 211 hydrocarbon and the heterocyclylsulfinyl group means a sulfinyl group attached to the heterocyclic group.

[00151] Preferred examples of the “acyl group” include a formyl group, a carboxy group, a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkylcarbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclocarbonyl group, a 3- to 14-membered non-aromatic heterocyclocarbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a group C7-16 alkyloxycarbonyl (e.g., benzyloxycarbonyl, phenotiloxycarbonyl), a carbamoyl group, a mono- or di-C1-6 alkylcarbamoyl group, a mono- or di-C2-6 alkenylcarbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10 cycloalkylcarbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclocarbamoyl group (e.g., pyridylcarbamoyl), an N-C1-6 alkyl-N',N'-di-C1-6 alkylhydrazine-carbonyl group, a thiocarbamoyl group, a mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkylthiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16 aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenotylthiocarbamoyl), a 5- to 14-membered aromatic heterocyclohexylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfinyl group, a C1-6 alkylsulfinyl group (e.g., Petition 870250083065, dated 09 / 15 / 2025, p. 68 / 258 / 211 example, methylsulfinyl, ethylsulfinyl), a sulfo group, a C1-6 alkylsulfonyl group, a C1-4 arylsulfonyl group, a phosphone group and a mono- or di-C1-6 alkylphosphone group (for example, dimethylphosphone, diethylphosphone, diisopropylphosphone, dibutylphosphone).

[00152] In this descriptive report, examples of the “optionally substituted amino group” include an amino group optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclocarbonyl group, a 3- to 14-membered non-aromatic heterocyclocarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a C1-4 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent A.

[00153] Preferred examples of the optionally substituted amino group include an amino group, a mono- or di-(C1-6 alkyl optionally halogenated) amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6 alkenylamino group (e.g., diallylamino), a mono- or di-C3-10 cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C6-14 arylamino group (e.g., phenylamino), a mono- or di-C7-16 aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di-(C1-6 alkyl optionally halogenated) carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-C6-14 aryl carbonylamino group (e.g., benzoylamino), a mono- or di-C7-16 aralkylcarbonylamino group (e.g. benzylcarbonylamino), a mono- or di Petition 870250083065, dated 09 / 15 / 2025, page. 69 / 258 / 211 aromatic heterocyclylcarbonylamino group of 5 to 14 members (e.g., nicotinoylamino, isonicotinoylamino), a non-aromatic mono- or diheterocyclylcarbonylamino group of 3 to 14 members (e.g., piperidinylcarbonylamino), a mono- or di-C1-6 alkoxycarbonylamino group (e.g., tert-butoxycarbonylamino), an aromatic heterocyclylamino group of 5 to 14 members (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C1-6 alkylcarbamoyl)amino group (e.g., methylcarbamoylamino), a (mono- or di-C7-16 aralkylcarbamoyl)amino group (e.g., benzylcarbamoylamino), a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C0-14 arylsulfonylamino group (e.g., phenylsulfonylamino), a (C1-6 alkyl)(C1-6 alkyl-carbonyl) amino group (e.g., N-acetyl-Nmethylamino) and a (C1-6 alkyl)(C6-14 aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylamino).

[00154] In this descriptive report, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclocarbonyl group, a 3- to 14-membered non-aromatic heterocyclocarbonyl group, a C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group and a mono- or di-C7-16 group aralkyl-carbamoyl, each of which optionally has 1 to 3 substituents selected from the Substituent A group.

[00155] Preferred examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C1-6 alkylcarbamoyl group, a mono- or di-C2-6 alkenylcarbamoyl group (for example, Petition 870250083065, dated 09 / 15 / 2025, page. 70 / 258 / 211 dialylcarbamoyl), a mono- or di-C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or diC1-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16 arylalkyl-carbamoyl group, a mono- or di-C1-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or diC1-14 aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclocarbamoyl group (e.g., pyridylcarbamoyl).

[00156] In this descriptive report, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 arylcarbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl, each of which optionally has 1 to 3 substituents selected from the Substituent A group.

[00157] Preferred examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16 aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, Petition 870250083065, dated 09 / 15 / 2025, page 71 / 258 / 211 phenethylthiocarbamoyl), a mono- or di-C1-6 alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C6-14 aryl-carbonyl-thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclothiocarbamoyl group (e.g., pyridylthiocarbamoyl).

[00158] In this descriptive report, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally with “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclocarbonyl group, a 3- to 14-membered non-aromatic heterocyclocarbonyl group, a C1-6 alkoxycarbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl, each of which optionally has 1 to 3 substituents selected from the Substituent A group.

[00159] Preferred examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C1-6 alkylsulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C2-6 alkenylsulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C3-10 cycloalkylsulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C6-14 arylsulfamoyl group (e.g., phenylsulfamoyl), a mono- or di-C7-16 aralkylsulfamoyl group (e.g., benzylsulfamoyl, phenotylsulfamoyl), a mono- or di-C1-6 group alkyl-carbonylsulfamoyl (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di-C6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl), and a 5- to 14-membered aromatic heterocyclosulfamoyl group (e.g., pyridylsulfamoyl). Petition 870250083065, dated 09 / 15 / 2025, page 72 / 258 / 211

[00160] In this descriptive report, examples of the “optionally substituted hydroxy group” include a hydroxy group optionally with “a substituent selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclocarbonyl group, a 3- to 14-membered non-aromatic heterocyclocarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a a C1-6 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent A.

[00161] Preferred examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6 alkoxy group, a C2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy), a C6-14 aryloxy group (e.g., phenoxy, naphthyloxy), a C7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C1-6 alkylcarbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14 arylcarbonyloxy group (e.g., benzoyloxy), a C7-16 aralkylcarbonyloxy group (e.g., benzylcarbonyloxy), a 5-chain aromatic heterocyclocarbonyloxy group a 14-membered group (e.g., nicotinoyloxy), a non-aromatic heterocyclylcarbonyloxy group of 3 to 14 members (e.g., piperidinylcarbonyloxy), a C1-6 alkoxycarbonyloxy group (e.g., tert-butoxycarbonyloxy), an aromatic heterocyclyloxy group of 5 to 14 members (e.g., pyridyloxy),a carbamoyloxy group, a C1-6 alkylcarbamoyloxy group (e.g., methylcarbamoyloxy), a C7-16 alkylcarbamoyloxy group (e.g., benzylcarbamoyloxy), a C1-6 alkylsulfonyloxy group (e.g., Petition 870250083065, dated 09 / 15 / 2025, p. 73 / 258 / 211 methylsulfonyloxy, ethylsulfonyloxy) and a Co-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[00162] In this descriptive report, examples of the “optionally substituted sulfanil group” include a sulfanil group optionally with “a substituent selected from a C1-O alkyl group, a C2-O alkenyl group, a C3-O cycloalkyl group, a C1-O aryl group, a C7-O aralkyl group, a C1-O alkyl-carbonyl group, a C1-O aryl-carbonyl group and a 5 to 14 membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent A” and a halogenated sulfanil group.

[00163] Preferred examples of the optionally substituted sulfanyl group include a sulfanyl group (-SH), a C1-6 alkylthio group, a C2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C3-10 cycloalkylthio group (e.g., cyclohexylthio), a C7-16 arylthio group (e.g., phenylthio, naphthylthio), a C7-16 aralkylthio group (e.g., benzylthio, phenethylthio), a C1-6 alkylcarbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C7-14 arylcarbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocycloylthio group (e.g., pyridylthio), and a thio group. halogenated (e.g., pentafluorothio).

[00164] In this descriptive report, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C7-16 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent A”.

[00165] Preferred examples of the optionally substituted silyl group include a tri-C1-6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl). Petition 870250083065, dated 09 / 15 / 2025, p. 74 / 258 / 211

[00166] In this descriptive report, examples of the “hydrocarbon ring” include a C6-14 aromatic hydrocarbon ring, C3-10 cycloalkane and C3-10 cycloalkene.

[00167] In this descriptive report, examples of the “C6-14 aromatic hydrocarbon ring” include benzene and naphthalene.

[00168] In this descriptive report, examples of “C3-10 cycloalkanes” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[00169] In this descriptive report, examples of “C3-10 cycloalkenes” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[00170] In this descriptive report, examples of the “heterocycle” include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a constituent atom of the ring in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[00171] In this descriptive report, examples of the “aromatic heterocycle” include an aromatic heterocycle of 5 to 14 members (preferably 5 to 10 members) containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferred examples of the “aromatic heterocycle” include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, and the like; and

[00172] fused polycyclic aromatic heterocycles of 8 to 14 members (preferably bicyclic or tricyclic), such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, Petition 870250083065, dated 09 / 15 / 2025, p. 75 / 258 / 211 benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathi-ine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and similar.

[00173] In this descriptive report, examples of the “non-aromatic heterocycle” include a non-aromatic heterocycle of 3 to 14 members (preferably 4 to 10 members) containing, as a ring constituent atom in addition to the carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.Preferred examples of "non-aromatic heterocycles" include 3- to 8-membered monocyclic non-aromatic heterocycles, such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and similar substances; and

[00174] Non-aromatic polycyclic heterocycles (preferably bi- or tri-cyclic) fused with 9 to 14 members, such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, Petition 870250083065, dated 09 / 15 / 2025, page 76 / 258 / 211 tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetra- hydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinoline, tetrahydrocarbazole, tetrahydro-e-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octa- hydroisoquinoline and the like.

[00175] In this descriptive report, examples of “nitrogen-containing heterocycles” include a heterocycle containing at least one nitrogen atom as a constituent atom of the ring, within the “heterocycle”.

[00176] In this descriptive report, examples of the “C3-6 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In this descriptive report, examples of the “C3-4 cycloalkyl group” include cyclopropyl and cyclobutyl.

[00177] In this descriptive report, examples of the “mono- or di-C1-6 alkylamino group” include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neo-pentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, 2-ethylbutylamino and the like.

[00178] The definition of each symbol in formula (I) is explained in detail below.

[00179] Ra is a C1-6 alkyl group, a C3-4 cycloalkyl group or a mono- or di-C1-6 alkylamino group, wherein each of the C1-6 alkyl group, C3-4 cycloalkyl group and mono- or di-C1-6 alkylamino group is optionally substituted.

[00180] Examples of the substituent of the above-mentioned “optionally substituted C1-6 alkyl group”, “optionally substituted mono- or di-C1-6 alkylamino group” and “optionally substituted C3-4 cycloalkyl group” include substituents selected from Substituent A. The number of substituents is preferably from 1 to 3. When the number of Petition 870250083065, dated 09 / 15 / 2025, p. 77 / 258 / 211 substitutes is 2 or more, the respective substitutes may be the same or different.

[00181] Rae preferably (1) an optionally substituted C1-6 alkyl group (e.g., methyl, ethyl, isopropyl), (2) an optionally substituted mono- or di-C1-6 alkylamino group (e.g., methylamino, dimethylamino), or (3) an optionally substituted C3-4 cycloalkyl group (e.g., cyclopropyl), Rae preferably (1) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected independently from halogen atoms (e.g., a fluorine atom) and a C1-6 alkoxy group (e.g., methoxy), (2) a C3-4 cycloalkyl group (e.g., cyclopropyl), or (3) a mono- or di-C1-6 alkylamino group (e.g., methylamino, dimethylamino).

[00182] Ra is more preferably (1) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or (2) a C3-4 cycloalkyl group (e.g., cyclopropyl).

[00183] Ra is even more preferably a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

[00184] R is a hydrogen atom or a halogen atom (e.g., a fluorine atom); and Rcé is a hydrogen atom or a halogen atom (for example, a fluorine atom). Petition 870250083065, dated 09 / 15 / 2025, page 78 / 258 / 211

[00185] Preferably, Rb and Rc are both (1) a hydrogen atom, or (2) a halogen atom (e.g., a fluorine atom); or (3) one of Rb and Rc is a hydrogen atom or the other is a halogen atom (e.g., a fluorine atom).

[00186] More preferably, Rbé is a halogen atom (for example, a fluorine atom); and Rcé is a halogen atom (for example, a fluorine atom).

[00187] Ring A is an optionally substituted C6-14 aryl group (e.g., phenyl), or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, where Y is a C or N ring atom, where the C is bonded to hydrogen or an optional substituent.

[00188] Ring A optionally has substituent(s) in addition to the -CH2pyrrolidine ring and X in formula (I). Examples of the substituent include the aforementioned “substituent” selected from the Substituent A group. The number of substituents is preferably from 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[00189] Ring A is preferably a phenyl group optionally further substituted by 1 to 2 substituents selected from (i) a halogen atom (e.g., a fluorine atom), and (ii) a C1-6 alkyl group (e.g., methyl), where Y is a ring atom C bonded to hydrogen or halogen (e.g., a fluorine atom).

[00190] Ring A is more preferably a phenyl group optionally Petition 870250083065, dated 09 / 15 / 2025, page 79 / 258 / 211, still replaced by 1 to 2 halogen atoms (e.g., a fluorine atom), where Y is a ring atom C bonded to hydrogen or halogen (e.g., a fluorine atom).

[00191] Ring A is more preferably a phenyl group optionally further substituted by 1 to 2 halogen atoms (e.g., a fluorine atom), where Y is a ring atom C bonded to a halogen (e.g., a fluorine atom).

[00192] Preferably, Ring A is where i is the methylene bridge attachment point and ii is the X attachment point; and R11 and R12 are independently hydrogen, halogen (e.g., a fluorine atom), or optionally a halogenated C1-6 alkyl group (e.g., methyl).

[00193] Preferably, R11 and R12 are independently hydrogen, halogen (e.g., a fluorine atom) or a C1-6 alkyl group (e.g., methyl).

[00194] More preferably, R11 is hydrogen or halogen (for example, a fluorine atom) and R12 is hydrogen.

[00195] X is -O-, -S-, -NR1-, -CR2R3-, -O-(CR2R3)-, -(CR2R3)-O-, or an optionally substituted C3-6 cycloalkyl group, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B, where: R1 is hydrogen, or an optionally substituted C1-6 alkyl group; and Petition 870250083065, dated 09 / 15 / 2025, page 80 / 258 / 211 R2 and R3 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group.

[00196] Examples of the substituent of the above-mentioned “optionally substituted C1-6 alkyl group” and “optionally substituted C3-6 cycloalkyl group” include substituents selected from Substituent A. The number of substituents is preferably from 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[00197] Preferably, X is -O-, -CR2R3-, -O-(CR2R3)-, or -(CR2R3)O-, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B, where R2 and R3 are independently hydrogen, halogen (e.g., a fluorine atom) or C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 substituents independently selected from halogen and C1-6 alkyl group.

[00198] Preferably, X is -O-, -CR2R3-, -O-(CR2R3)-, or -(CR2R3)O-, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B, where R2 and R3 are independently hydrogen, halogen (e.g., a fluorine atom), or a C1-6 alkyl group (e.g., methyl).

[00199] More preferably, X is -O-, where the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B.

[00200] Ring B is an optionally substituted C6-14 aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group.

[00201] Ring B optionally has substituent(s) in addition to L and X in formula (I). Examples of the substituent include the aforementioned “substituent” selected from the Substituent A group. The number of Petition 870250083065, dated 15 / 09 / 2025, p. 81 / 258 / 211 substituents is preferably from 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[00202] Preferably, Ring B is (1) an optionally substituted C-14 aryl group (e.g., phenyl), or (2) an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle group (e.g., thiazole, pyridine, pyrimidine, pyrazine).

[00203] More preferably, Ring B is (1) a phenyl group optionally substituted with 1 to 3 substituents selected from a halogen atom (e.g., a chlorine atom) and a C1-6 alkyl group (e.g., methyl), (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine) that is optionally substituted with 1 to 3 substituents (specifically 1 to 3 substituents for pyridine, 1 or 2 substituents for thiazole, pyrimidine and pyrazine) selected from (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), (b) an optionally substituted C1-6 alkyl group (e.g., methyl, ethyl, difluoromethyl), (c) a C3-6 cycloalkyl group (e.g., cyclopropyl), and (d) a group C1-6 alkoxy (e.g., methoxy).

[00204] More preferably, Ring B is a pyridine ring optionally substituted with 1, 2 or 3 substituents selected independently from halogen (e.g., a fluorine atom, a chlorine atom) and C1-6 alkyl group (e.g., methyl).

[00205] More preferably, Ring B is Petition 870250083065, dated 15 / 09 / 2025, p. 82 / 258 / 211 a pyridine ring optionally substituted by 1, 2 or 3 C1-6 alkyl groups (e.g., methyl).

[00206] More preferably, Ring B is selected from: σννν' ... where iv is the point of connection of L and iii is the point of connection to X; R21a, R21b, R21d, R22a, R22b, R22c, R23a, R23b, R23c, and R23d are selected independently from hydrogen, halogen (e.g., fluorine atom, chlorine atom, bromine atom), a C1-6 alkyl group (e.g., methyl, ethyl, difluoromethyl), a C1-6 alkoxy group (e.g., methoxy), and a C3-6 cycloalkyl group (e.g., cyclopropyl); R24 is selected from hydrogen, halogen, an optionally halogenated C1-6 alkyl group and a C3-6 cycloalkyl group.

[00207] More preferably, R24 is hydrogen or a C1-6 alkyl group.

[00208] L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5), -C(R4R5)-C(R7R8)-, wherein the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; Petition 870250083065, dated 09 / 15 / 2025, page 83 / 258 / 211 R4 and R5 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; R6 is hydrogen or an optionally substituted C1-6 alkyl group; R7 and R8 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; or R4 and R6, taken together with the atoms to which they are attached, form a non-aromatic monocyclic heterocyclic ring of 3 to 8 members, optionally substituted; or R4e R5, or R4e R7 taken together with the atom or atoms to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C3-10 cycloalkyl group.

[00209] Examples of the substituent of the aforementioned “optionally substituted C1-6 alkyl group”, “optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring” and “optionally substituted C3-10 cycloalkyl group” include substituents selected from substituent group A. The number of substituents is preferably from 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[00210] Preferably, L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5)-, or -C(R4R5)-C(R7R8)-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R4 and R5 are independently hydrogen, or C1-6 alkyl group (e.g., methyl); R6 is hydrogen or an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoromethyl); R7 and R8 are hydrogen; or Petition 870250083065, dated 09 / 15 / 2025, p. 84 / 258 / 211 when L is -C(R4R5)-NR6- or -NR6-C(R4R5)-, R4 and R6 together with the atoms to which they are attached form a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., an azetidine ring, a pyrrolidine ring) optionally substituted by 1 to 3 independently selected halogen substituents (e.g., a fluorine atom) and C1-6 alkoxyl group, and R5 is hydrogen; or when L is -C(R4R5)-C(R7R8)-, R4 and R7 together with the carbon atoms to which they are attached form a C3-10 cycloalkyl group (e.g., cyclopropyl) and R5 and R8 are both hydrogen.

[00211] More preferably, L is -CH2-NH-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group.

[00212] Preferred examples of compound (I) include the following compounds. [Compound A]

[00213] Compound (I) in which Raé (1) an optionally substituted C1-6 alkyl group (for example, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, methoxymethyl), (2) an optionally substituted mono- or di-C1-6 alkylamino group (for example, methylamino, dimethylamino), or (3) an optionally substituted C3-4 cycloalkyl group (for example, cyclopropyl); Rbé (1) a hydrogen atom, or (2) a halogen atom (for example, a fluorine atom); Rcé (1) a hydrogen atom, or (2) a halogen atom (for example, a fluorine atom); Petition 870250083065, dated 09 / 15 / 2025, page 85 / 258 / 211 Ring A is (1) an optionally substituted (e.g., phenyl) C-14 aryl group, or (2) an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, where Y is a C or N ring atom, where the C is bonded to hydrogen or an optional substituent; Ring B is (1) an optionally substituted Co-14 aryl group (e.g., phenyl), or (2) an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle group (e.g., thiazole, pyridine, pyrimidine, pyrazine); X is (1) -o-, (2) -S-, (3) -NR1-, (4) -CR2R3-, (5) -O-(CR2R3)-, (6) -(CR2R3)-O-, or (7) an optionally substituted C3-6 cycloalkyl group, wherein the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B; R1 is hydrogen, or an optionally substituted C1-6 alkyl group. R2 and R3 are independently hydrogen, halogen (e.g., a fluorine atom), or an optionally substituted C1-6 alkyl group (e.g., methyl); L is Petition 870250083065, dated 09 / 15 / 2025, p. 86 / 258 / 211 (1) -C(R4R5)-NR6-, (2) -C(R4R5)-O-, (3) -OC(R4R5)-, (4) -NR6-C(R4R5)-, (5) -C(R4R5)-C(R7R8)-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; and R4 and R5 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group (e.g., methyl); R6 is hydrogen, or an optionally substituted C1-6 alkyl group (e.g., methyl, difluoroethyl); R7 and R8 are independently hydrogen, halogen, or an optionally substituted C1-6 alkyl group; or R4 and R6, taken together with the atoms to which they are attached, form a non-aromatic monocyclic heterocyclic ring of 3 to 8 members optionally substituted (for example, an azetidine ring or a pyrrolidine ring optionally substituted by 1 to 3 substituents selected independently from halogen (for example, a fluorine atom) and C1-6 alkoxy group (for example, methoxy)); or R4e R5, or R4e R7 taken together with the atom or atoms to which they are attached form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C3-10 cycloalkyl group (e.g., cyclopropyl). [Compound B]

[00214] Compound (I) wherein Rae (1) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected independently from halogen atoms (e.g., one atom of Petition 870250083065, dated 09 / 15 / 2025, page 87 / 258 / 211 fluorine) and a C1-6 alkoxy group (e.g., methoxy), (2) a C3-4 cycloalkyl group (e.g., cyclopropyl), or (3) a mono- or di-C1-6 alkylamino group (e.g., methylamino, dimethylamino); Rb is (1) a hydrogen atom, or (2) a halogen atom (e.g., a fluorine atom); Rc is (1) a hydrogen atom, or (2) a halogen atom (e.g., a fluorine atom); Ring A is a phenyl group optionally further substituted by 1 to 2 substituents selected from a halogen atom (e.g., a fluorine atom) and a C1-6 alkyl group (e.g., methyl), where Y is a ring atom C bonded to hydrogen or halogen (e.g., a fluorine atom); Ring B is (1) a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom (e.g., a chlorine atom), (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., thiazole, pyridine, pyrimidine, pyrazine), of which pyridine is optionally substituted by 1 to 3 substituents and of which thiazole, pyrimidine and pyrazine are selected from 1 or 2 substituents, the substituents in all cases being selected from (a) a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom), (b) an optionally substituted C1-6 alkyl group (e.g., methyl, ethyl, difluoromethyl), Petition 870250083065, dated 09 / 15 / 2025, page 88 / 258 / 211 (c) a C3-6 cycloalkyl group (e.g., cyclopropyl), and (d) a C1-6 alkoxy group (e.g., methoxy); X is (1) -o-, (2) -CR2R3-, (3) -O-(CR2R3)-, or (4) -(CR2R3)-O-, where the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B; R2 and R3 are independently (1) hydrogen, (2) halogen (e.g., a fluorine atom), or (3) C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 substituents independently selected from halogen and C1-6 alkyl group; L is (1) -C(R4R5)-NR6-, (2) -C(R4R5)-O-, (3) -OC(R4R5)-, (4) -NR6-C(R4R5)-, (5) -C(R4R5)-C(R7R8)-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; and R4 and R5 are independently (1) hydrogen, or (2) C1-6 alkyl group (e.g., methyl); R6 is (1) hydrogen, or Petition 870250083065, dated 15 / 09 / 2025, p. 89 / 258 / 211 (2) an optionally halogenated C1-6 alkyl group (e.g., methyl, difluoroethyl); R7 and R8 are each hydrogen; or when L is -C(R4R5)-NR6- or -NR6-C(R4R5)-, R4 and R6 together with the atoms to which they are attached form a 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., an azetidine ring, a pyrrolidine ring) optionally substituted by 1 to 3 independently selected halogen substituents (e.g., a fluorine atom) and C1-6 alkoxy group (e.g., methoxy) and R5 is hydrogen; or when L is -C(R4R5)-C(R7R8)-, R4 and R7 together with the atoms to which they are attached form a C3-10 cycloalkyl group (e.g., cyclopropyl) and R5 and R8 are both hydrogen. [Compound C]

[00215] Compound (I) in which Ring A is a phenyl group optionally further substituted by 1 to 2 halogen atoms (e.g., a fluorine atom), wherein Y is a ring atom C bonded to hydrogen or halogen (e.g., a fluorine atom); X is -O-, where the left portion of X is bonded to a carbon atom in Ring A that is adjacent to Y, and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted with 1, 2, or 3 substituents selected independently from halogens (e.g., a fluorine atom, a chlorine atom) and C1-6 alkyl (e.g., methyl); L is -CH2-NH-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; Rae is a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 to 3 halogen atoms (by Petition 870250083065, dated 09 / 15 / 2025, p. 90 / 258 / 211 example, a fluorine atom), or a C3-4 cycloalkyl group (e.g., cyclopropyl); Rb is a halogen atom (for example, a fluorine atom); and Rcé is a halogen atom (for example, a fluorine atom). [Compound D]

[00216] Compound (I) in which Ring A is a phenyl group optionally further substituted by 1 to 2 halogen atoms (e.g., a fluorine atom), where Y is a ring atom C bonded to a halogen (e.g., a fluorine atom); X is -O-, where the left portion of X is bonded to a carbon atom in Ring A that is adjacent to Y, and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted with 1, 2 or 3 C1-6 alkyl groups (e.g., methyl); L is -CH2-NH-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; Rae is a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom); Rbé is a halogen atom (for example, a fluorine atom); and Rcé is a halogen atom (for example, a fluorine atom). [Compound E]

[00217] Compound (I) in which Ring A is Petition 870250083065, dated 09 / 15 / 2025, p. 91 / 258 / 211 a phenyl group optionally further substituted by 1 to 2 halogen atoms (e.g., a fluorine atom), where Y is a ring atom C bonded to a halogen (e.g., a fluorine atom); X is -O-, where the left portion of X is bonded to a carbon atom in Ring A that is adjacent to Y, and the right portion of X is bonded to Ring B; v / VW' ring B is , where R21a, R22a and R23a are independently hydrogen or C1-6 alkyl (e.g., methyl).

[00218] L is -CH2-NH-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; Rae is a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom); Rbé is a halogen atom (for example, a fluorine atom); and Rcé is a halogen atom (for example, a fluorine atom).

[00219] Specific examples of compound (I) include the compounds of Examples 1 to 111 mentioned below.

[00220] Specifically, compound (I) is preferentially N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 2); Petition 870250083065, dated 09 / 15 / 2025, page 92 / 258 / 211 N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 4); N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide or a salt thereof (Example 5); 1-fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 19); N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide ou um sal so mesmo (Example 22); N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide or a salt thereof (Example 36); N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide or a salt thereof (Example 58); or N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide or a salt thereof (Example 97).

[00221] As a salt of a compound represented by formula (I), Petition 870250083065, dated 09 / 15 / 2025, page 93 / 258 / 211 a pharmacologically acceptable salt is preferred and examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid and the like.

[00222] Preferred examples of inorganic-based salts include alkali metal salts, such as sodium salt, potassium salt and the like, alkaline earth metal salts, such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like.

[00223] Preferred examples of organic-based salts include salts containing trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

[00224] Preferred examples of salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[00225] Preferred examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

[00226] Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[00227] The method of producing the compound of the present invention is explained below.

[00228] The raw material compound and the reagent used and the compound obtained at each step in the following production method may each be, Petition 870250083065, dated 09 / 15 / 2025, page 94 / 258 / 211 in the form of a salt, and examples of this salt include those similar to the salts of the compound represented by formula (I) and the like.

[00229] When the compound obtained in each step is a free form, it can be converted into the target salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted into the target free form or into the other salt according to a method known per se.

[00230] The compound obtained in each step can be used directly as the reaction mixture or as a crude product in the subsequent reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation method such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.

[00231] When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly.

[00232] In the reaction at each step, although the reaction time varies depending on the type of reagent and solvent to be used, it is generally 1 min - 48 h, preferably 10 min - 8 h, unless otherwise specified.

[00233] In the reaction at each step, although the reaction temperature varies depending on the type of reagent and solvent to be used, it is generally 78°C - 300°C, preferably -78°C - 150°C, unless otherwise specified.

[00234] In the reaction at each step, although the pressure varies depending on the type of reagent and solvent to be used, it is generally 1 atm - 20 atm, preferably 1 atm - 3 atm, unless otherwise specified.

[00235] The microwave synthesizer, such as the Initiator manufactured by Biotage and similar products, can be used for the reaction at each step. Although Petition 870250083065, dated 09 / 15 / 2025, page 95 / 258 / 211: The reaction temperature varies depending on the type of reagent and solvent to be used, but is generally room temperature - 300°C, preferably 50°C - 250°C, unless otherwise specified. Although the reaction time varies depending on the type of reagent and solvent to be used, it is generally 1 min - 48 h, preferably 1 min - 8 h, unless otherwise specified.

[00236] In the reaction at each step, the reagent is used in an amount of 0.5 equivalent - 20 equivalents, preferably 0.8 equivalent - 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent - 1 equivalent, preferably 0.01 equivalent - 0.2 equivalents, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in an amount of solvent.

[00237] Unless otherwise specified, the reaction at each step is carried out without solvent, or by dissolving or suspending the feedstock compound in a suitable solvent. Examples of solvents include those described in the Examples and the following solvents.

[00238] alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and similar; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2dimethoxyethane and the like; Aromatic hydrocarbons: chlorobenzene, toluene, xylene and similar substances; Saturated hydrocarbons: cyclohexane, hexane and similar substances; amides: N,N-dimethylformamide, N-methylpyrrolidone and the like; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride and similar substances; nitriles: acetonitrile and similar; Petition 870250083065, dated 09 / 15 / 2025, page 96 / 258 / 211 sulfoxides: dimethyl sulfoxide and similar substances; Aromatic organic bases: pyridine and similar; Anhydrides: acetic anhydride and similar anhydrides; Organic acids: formic acid, acetic acid, trifluoroacetic acid and similar acids; Inorganic acids: hydrochloric acid, sulfuric acid and similar acids; Esters: ethyl acetate and similar products; Ketones: acetone, methyl ethyl ketone and similar substances; water.

[00239] The above-mentioned solvent may be used in a mixture of two or more types of the same in an appropriate ratio.

[00240] When a base is used for the reaction at each step, examples of these include those described in the Examples and the following bases.

[00241] Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate and similar; 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 and the like; Metal alkoxides: sodium ethoxide, potassium tert-butoxide and similar substances; Alkali metal hydrides: sodium hydride and similar compounds; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisylazide and similar substances; Organic lithium compounds: n-butyllithium and similar compounds.

[00242] When an acid or an acid catalyst is used for the reaction at each step, examples of these include those described in Petition 870250083065, dated 09 / 15 / 2025, page 97 / 258 / 211 Examples include the following acids and acid catalysts.

[00243] Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and similar acids; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and similar acids; Lewis acid: complex of diethyl ether boron trifluoride, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.

[00244] Unless otherwise specified, the reaction at each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Society of Japan ed.); 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 Volume I-VII Collective (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, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or similar, or the method described in the Examples.

[00245] At each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed.”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter GM Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (PJ Kocienski), or similar methods, or the method described in the Examples. Petition 870250083065, dated 09 / 15 / 2025, page 98 / 258 / 211

[00246] Examples of protecting groups for a hydroxyl group of an alcohol and the like and a phenolic hydroxyl group include ether-type protecting groups, such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranilic ether and the like; carboxylate-type protecting groups, such as acetate ester and the like; sulfonate-type protecting groups, such as methanesulfonate ester and the like; carbonate-type protecting groups, such as tert-butylcarbonate and the like, and the like.

[00247] Examples of protecting groups for a carbonyl group of an aldehyde include acetal-type protecting groups, such as dimethylacetal and the like; cyclic acetal-type protecting groups, such as 1,3-dioxane and the like, and the like.

[00248] Examples of protecting groups for a carbonyl group of a ketone include ketal-type protecting groups, such as dimethyl ketal and the like; cyclic ketal-type protecting groups, such as 1,3-dioxane and the like; oxime-type protecting groups, such as O-methyloxime and the like; hydrazone-type protecting groups, such as N,N-dimethylhydrazone and the like, and the like.

[00249] Examples of protecting groups for a carboxyl group include ester-type protecting groups, such as methyl esters and the like; amide-type protecting groups, such as N,N-dimethylamides and the like, and the like.

[00250] Examples of protecting groups for a thiol include ether-type protecting groups, such as benzyl thioether and the like; ester-type protecting groups, such as thioacetate, thiocarbonate, thiocarbamate and the like, and the like.

[00251] Examples of protecting groups for an amino group and an aromatic heterocycle, such as imidazole, pyrrole, indole and the like, include carbamate-type protecting groups, such as benzyl carbamate and Petition 870250083065, dated 09 / 15 / 2025, page 99 / 258 / 211 similar; amide-type protecting groups, such as acetamide and similar; alkylamine-type protecting groups, such as N-triphenylmethylamine and similar; sulfonamide-type protecting groups, such as methanesulfonamide and similar, and similar.

[00252] Protecting groups can be removed according to a method known per se, for example, employing a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method and the like.

[00253] When the reduction reaction is carried out in each step, examples of reducing agents to be used include metal hydrides, such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes, such as tetrahydrofuran borane complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When the carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar catalyst and the like may be used.

[00254] When the oxidation reaction is carried out at each step, examples of the oxidizing agent to be used include peroxides, such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like; perchlorates, such as tetrabutylammonium perchlorate and the like; chlorates, such as sodium chlorate and the like; chlorites, such as sodium chlorite and the like; periodates, such as sodium periodate and the like; hypervalent iodine reagents, such as iodosylbenzene and the like; manganese-containing reagents, such as manganese dioxide, potassium permanganate and the like; leads, such as Petition 870250083065, dated 09 / 15 / 2025, page 100 / 258 / 211 lead tetraacetate and similar substances; reagents containing chromium, such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and similar substances; halogen compounds, such as N-bromosuccinimide (NBS) and similar substances; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicane-1,4-benzoquinone (DDQ) and similar substances.

[00255] When the radical cyclization reaction is carried out in each step, examples of radical initiators to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4,4'-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of radical reagents to be used include tributylstanane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like.

[00256] When the Wittig reaction is carried out at each step, examples of the Wittig reagent to be used include alkylidene phosphoranes and the like. Alkylidene phosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.

[00257] When the Horner-Emmons reaction is carried out at each step, examples of reagents to be used include phosphonoacetates, such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases, such as alkali metal hydrides, organic lithiums and the like.

[00258] When the Friedel-Crafts reaction is carried out at 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 acid or an inorganic acid may also be used instead of a Lewis acid, and an anhydride, such as anhydride Petition 870250083065, dated 09 / 15 / 2025, page 101 / 258 / 211 acetic and similar substances can also be used instead of an acid chloride.

[00259] When the aromatic nucleophilic substitution reaction is carried out, in each step, a nucleophile (e.g., an amine, imidazole, etc.) and a base (e.g., an organic base, etc.) are used as reagents.

[00260] When the nucleophilic addition reaction by a carbo-anion, the 1,4 nucleophilic addition reaction (Michael addition reaction) by a carbo-anion or nucleophilic substitution reaction by a carbo-anion is carried out in each step, and examples of the base to be used for carbo-anion generation include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.

[00261] When the Grignard reaction is carried out at each step, examples of Grignard reagent to be used include arylmagnesium halides, such as phenylmagnesium bromide and the like; and alkylmagnesium halides, such as methylmagnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metallic magnesium in an ether or tetrahydrofuran as solvent.

[00262] When the Knoevenagel condensation reaction is carried out in each step, a compound with a methylene group activated 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) are used as reagents.

[00263] When the Vilsmeier-Haack reaction is carried out at each step, phosphoryl chloride and an amide derivative (e.g., N,N-dimethylformamide, etc.) are used as reagents.

[00264] When the azidation reaction of an alcohol, an alkyl halide, or a sulfonate is carried out at each step, examples of the aziding agent to be used include diphenylphosphorylazide (DPPA), trimethylsilylazide, Petition 870250083065, dated 09 / 15 / 2025, page 102 / 258 / 211 sodium azide and similar substances. For example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and similar substances are employed.

[00265] When the reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like, and the like.

[00266] When the Mitsunobu reaction is carried out at each step, an azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[00267] When the esterification reaction, amidation reaction, or urea formation reaction is carried out at each step, examples of reagents to be used include acyl halides, such as acid chlorides, acid bromides, and the like; activated carboxylic acids, such as acid anhydrides, activated esters, sulfates, and the like. Examples of carboxylic acid activating agents include carbodiimide condensing agents, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents, such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents, such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); iodide of 2 Petition 870250083065, dated 09 / 15 / 2025, page 103 / 258 / 211 chloro-1-methylpyridinium (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates, such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof and the like. When the condensing agent carbodiimide is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system.

[00268] When the coupling reaction is carried out at each step, examples of the metal catalyst to be used include palladium compounds, such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'bis(diphenylphosphine)ferrocene palladium(II) chloride and the like; nickel compounds, such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds, such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds, such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. Furthermore, a base can be added to the reaction system, and examples of these include inorganic bases and the like.

[00269] When the carbonylation reaction is carried out at each step, examples of the carbonylation agent to be used include 1,1-carbonyldiimidazole (CDI), triphosgene, di(N-succinimidyl) carbonate (DSC), and the like. In addition, a base may be added to the reaction system, and examples of the same include inorganic bases and organic bases and the like.

[00270] When the thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonyl agent. Alternatively, a reagent with a 1,3,2,4 structure Petition 870250083065, dated 09 / 15 / 2025, page 104 / 258 / 211 dithiadiphosphetane-2,4-disulfide (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) etc.) can also be used instead of phosphorus pentasulfide.

[00271] When the sulfonylation reaction is carried out at each step, examples of sulfonylating agents to be used include sulfonyl chloride, sulfamoyl chloride, and the like. In addition, a base may be added to the reaction system, and examples of the same include inorganic bases and organic bases and the like.

[00272] When the Wohl-Ziegler reaction is carried out at each step, examples of halogenating agents to be used include N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, and the like. Furthermore, the reaction can be accelerated by subjecting a radical initiator, such as heat, light, benzoyl peroxide, azobisisobutyronitrile, and the like, to the reaction system.

[00273] When the halogenation reaction of a hydroxyl group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. Furthermore, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like may be employed. Alternatively, a two-step method of producing an alkyl halide comprising converting an alcohol to the corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide may also be employed.

[00274] When the Arbuzov reaction is carried out at each step, examples of reagents to be used include alkyl halides, such as ethyl bromoacetate and the like; and phosphites, such as triethyl phosphite, Petition 870250083065, dated 09 / 15 / 2025, page 105 / 258 / 211 tri(isopropyl) phosphite and similar substances.

[00275] When the sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

[00276] When the hydrolysis reaction is carried out at each step, an acid or a base is used as a reagent. For the acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane and the like can be added to the reducing tert-butyl cation that is by-produced.

[00277] When the dehydration reaction is carried out at each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[00278] Examples of the “protective group” for PG1, PG2, PG3, and PG4 include those exemplified as the “protective group for an amino group and a hydroxy group” mentioned above.

[00279] Examples of the “leaving group” for LG1, LG2, LG3, LG4, and LG5 include halogen atoms, optionally halogenated C1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), optionally substituted C1-6 alkyl-substituted C6-14 arylsulfonyloxy (e.g., benzenesulfonyloxy, toluenesulfonyloxy), and the like. Compound (I) can be produced from compounds (1a)-(4a) and (1b)-(4b) according to the method shown in the following Scheme 1. In the formulas, the symbols are as defined above. Petition 870250083065, dated 09 / 15 / 2025, page 106 / 258 / 211 Carbonylation reaction

[00280] Compound (I) can be produced by subjecting compound (1a) to a carbonylation reaction.

[00281] Compound (I) can be produced by subjecting compound (2a) to an amidation reaction.

[00282] Compound (I) can be produced by subjecting compound (3a) to a nucleophilic substitution reaction.

[00283] Compound (I) can be produced by subjecting compound (4a) to a Mizoroki-Heck reaction followed by reduction. Examples of metal catalysts to be used in the Mizoroki-Heck reaction include palladium compounds, such as palladium(II) acetate and the like. A phosphine ligand can also be added to the reaction system, and examples include triphenylphosphine and the like. In addition, a base can be added to the reaction system, and examples include inorganic bases and organic bases and the like.

[00284] Compound (5) can be produced by subjecting compound (1a) to a carbonylation reaction.

[00285] Compound (5) can be produced by subjecting compound (2a) to an amidation reaction.

[00286] Compound (5) can be produced by subjecting compound (3a) to a nucleophilic substitution reaction.

[00287] Compound (5) can be produced by subjecting compound (4a) to a Mizoroki-Heck reaction followed by reduction. Petition 870250083065, dated 09 / 15 / 2025, pp. 107 / 258 / 211

[00288] Compound (I) can be produced by subjecting compound (5) to deprotection followed by sulfonylation reaction with compound (6). Compound (6) may be commercially readily available or may be produced according to a method known per se.

[00289] Compounds (1a) and (1b) can be produced from compounds (7a) and (7b) according to the method shown in Scheme 2 below, respectively. In the formulas, Rr is cyano or -COORs, Rs is an optionally substituted C1-6 alkyl group, M1 is a metal and the other symbols are as defined above. Scheme 2

[00290] Compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b) to a coupling reaction with compound (8-1), respectively. Compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b) to a coupling reaction with compound (8-2), respectively. Furthermore, compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b) to a coupling reaction with compound (8-3), respectively. Compounds (10a) and (10b) can be produced by subjecting compounds (7a) and (7b) to a nucleophilic substitution reaction with compound (9), respectively.

[00291] When Rr is cyano, compounds (13a) and (13b) can be produced by subjecting compounds (7a) and (7b) to a coupling reaction with compound (11). Examples of compound (11) to be used Petition 870250083065, dated 09 / 15 / 2025, p. 108 / 258 / 211 includes zinc cyanide and similar substances. Examples of the metallic catalyst to be used include tetrakis(triphenylphosphine)palladium(0) and similar substances.

[00292] When Rré -COORs, compounds (13a) and (13b) can also be produced by subjecting compounds (7a) and (7b) to a coupling reaction with carbon monoxide and compound (12). Examples of the metal catalyst to be used include [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloride and the like.

[00293] When Rré is cyan, compounds (10a) and (10b) can be produced by subjecting compounds (13a) and (13b) to reduction followed by protection, respectively.

[00294] Compounds (1a) and (1b) can be produced by subjecting compounds (10a) and (10b) to deprotection, respectively.

[00295] When Rré is cyan, compounds (1a) and (1b) can be produced by subjecting compounds (13a) and (13b) to reduction followed by protection, respectively. When Rré is -COORs, compounds (1a) and (1b) can be produced by subjecting compounds (13a) and (13b) to hydrolysis followed by deprotection, respectively.

[00296] Compounds (2a) and (2b) can be produced from compounds (7a) and (7b) according to the method shown in Scheme 3 below, respectively. In the formulas, Rt is an optionally substituted C1-6 alkyl and the other symbols are as defined above. Petition 870250083065, dated 09 / 15 / 2025, p. 109 / 258 / 211 hydrolysis deprotection Reaction of Mizoroki-Heck reduction

[00297] Compounds (15a) and (15b) can be produced by subjecting compounds (7a) and (7b) to a nucleophilic substitution reaction with compound (14), respectively.

[00298] Compounds (17a) and (17b) can be produced by subjecting compounds (7a) and (7b) to a Mizoroki-Heck reaction with compound (16), respectively.

[00299] Compounds (18a) and (18b) can be produced by subjecting compounds (17a) and (17b) to reduction, respectively.

[00300] Compounds (2a) and (2b) can be produced by subjecting compounds (15a) and (15b) to deprotection followed by hydrolysis, respectively. Compounds (2a) and (2b) can also be produced by subjecting compounds (18a) and (18b) to deprotection followed by hydrolysis, respectively.

[00301] Compounds (3a) and (3b) can be produced from compounds (7a) and (7b) according to the method shown in Scheme 4 below, respectively. Petition 870250083065, dated 09 / 15 / 2025, p. 110 / 258 / 211 Scheme 4 lack of protection Amidation reaction lack of protection

[00302] Compounds (19a) and (19b) can be produced by subjecting compounds (7a) and (7b) to deprotection, respectively.

[00303] Compounds (21a) and (21b) can be produced by subjecting compounds (19a) and (19b) to an amidation reaction with compound (20), respectively.

[00304] Compounds (3a) and (3b) can be produced by subjecting compounds (21a) and (21b) to deprotection, respectively.

[00305] Compounds (4a) and (4b) can be produced from compounds (19a) and (19b) according to the method shown in Scheme 5 below, respectively. Scheme 5 Amidation reaction

[00306] Compounds (4a) and (4b) can be produced by subjecting compounds (19a) and (19b) to an amidation reaction with compound (22), respectively.

[00307] Compounds (7aa), (7ba), (13aa), and (13ba) can be produced from compounds (23a) and (23b) according to the method shown in the following Scheme 6. In the formulas, Xa is -O-, -S-, -NR1-, (CR2R3)-O-, Ru is Rre LG2, and the other symbols are as defined above. Petition 870250083065, dated 09 / 15 / 2025, p. 111 / 258 / 211 Nucleophilic substitution reaction For 7aa and 7ba Sandmeyer reaction

[00308] Compounds (7aa), (7ba), (13aa) and (13ba) can be produced by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (24). When Xa is -O-, compound (7aa), (7ba), (13aa) and (13ba) can also be produced by subjecting compound (23a) and (23b) to a nucleophilic substitution reaction with compound (25).

[00309] Compounds (28a) and (28b) can be produced by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (26). When Xa is -O-, compounds (28a) and (28b) can also be produced by subjecting compounds (23a) and (23b) to a nucleophilic substitution reaction with compound (27).

[00310] Compounds (7aa) and (7ba) can be produced by subjecting compounds (28a) and (28b) to a Sandmeyer reaction. The Sandmeyer reaction is carried out according to a method known per se, for example, the method described in Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin) or similar, or the method described in the Examples. Petition 870250083065, dated 09 / 15 / 2025, p. 112 / 258 / 211

[00311] Compounds (13ab), (13bb), (15ab), and (15bb) can be produced from compounds (29a) and (29b) according to the method shown in the following Scheme 7. In the formulas, Xbé -CR2R3- and optionally substituted C3-4 cycloalkyl group, Rvé Rre -L-COORt, and the other symbols are as defined above. a (32a): R = SÜ2Ra(32b): R = PG1

[00312] Compounds (13ab), (13bb), (15ab) and (15bb) can be produced by subjecting compounds (29a) and (29b) to a coupling reaction with compound (30).

[00313] Compounds (32a) and (32b) can be produced by subjecting compounds (29a) and (29b) to a coupling reaction with carbon monoxide and compound (31).

[00314] Compounds (13ab), (13bb), (15ab) and (15bb) can be produced by subjecting compounds (32a) and (32b) to a fluorination reaction. Examples of fluorination reagent to be used include (diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride and the like.

[00315] Compounds (23aa), (23ba), (23ab) and (23bb) can be produced from compound (33) according to the method shown in Scheme 8 below. In the formulas, Rw is an optionally C1-6 alkyl group Petition 870250083065, dated 09 / 15 / 2025, page 113 / 258 / 211 replaced, M2 is a metal and the other symbols are as defined above. Scheme 8 Sulfonylation reaction for (34a) Protection for (34b) Coupling reaction reduction

[00316] Compound (33) can be produced according to a method known per se, for example, the method described in “WO2020158958”, “WO2019027058”, or the method described in Examples.

[00317] Compound (34a) can be produced by subjecting compound (33) to a sulfonylation reaction with compound (6).

[00318] Compound (34b) can be produced by subjecting compound (33) to protection.

[00319] Compounds (29a) and (29b) can be produced by subjecting compounds (34a) and (34b) to a borylation reaction with compound (35). Examples of the metallic catalyst to be used include [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride and the like. In addition, a base can be added to the reaction system, and examples of this include inorganic bases and organic bases and the like.

[00320] Compounds (23aa) and (23ba) can be produced by subjecting compounds (34a) and (34b) to a substitution reaction with compound (36). Examples of compound (36) to be used include potassium hydroxide and the like. Examples of metallic catalyst to be used include Petition 870250083065, dated 09 / 15 / 2025, p. 114 / 258 / 211 tris(dibenzylideneacetone)dipalladium(0) and similar. Examples of the phosphine ligand to be used include 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl and similar.

[00321] Compounds (23aa) and (23ba) can be produced by subjecting compounds (29a) and (29b) to an oxidation reaction. Examples of the oxidation reagent to be used include sodium peroxoborate tetrahydrate, sodium salt of perboric acid tetrahydrate, and the like.

[00322] Compounds (37a) and (37b) can be produced by subjecting compounds (23aa) and (23ba) to trifluoromethanesulfonylation. Examples of trifluoromethanesulfonylation reagent to be used include trifluoromethanesulfonic anhydride and the like.

[00323] Compounds (39a) and (39b) can be produced by subjecting compounds (37a) and (37b) to a coupling reaction with carbon monoxide and compound (38).

[00324] Compounds (23ab) and (23bb) can be produced by subjecting compounds (39a) and (39b) to reduction.

[00325] In compound (I) thus obtained, an intramolecular functional group can also be converted into an object functional group by a combination of chemical reactions known per se. Examples of chemical reactions include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction and the like.

[00326] In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxyl group, a carbonyl group, or a mercapto group as a substituent, a protecting group commonly used in peptide chemistry can be introduced into these groups, and the target compound can be obtained by removing the protecting group as needed after the reaction. Petition 870250083065, dated 09 / 15 / 2025, page 115 / 258 / 211

[00327] Compound (I) obtained by the above-mentioned production method can be isolated and purified by a known means, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.

[00328] When compound (I) contains an optical isomer, stereoisomer, regio isomer, conformational isomer, and rotamer, these compounds are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from compound (I) is also included in compound (I).

[00329] In this document, an optical isomer can be produced by a method known per se.

[00330] Compound (I) can be a crystal.

[00331] A crystal of compound (I) (hereinafter sometimes abbreviated as the crystal of the present invention) can be produced by crystallizing compound (I) using a crystallization method known per se.

[00332] In this descriptive report, the melting point means a melting point measured, for example, by a micro-melting point apparatus (Yanako, MP-500D or Buchi, B-545), DSC (differential scanning calorimetry analysis) apparatus (METTLER TOLEDO, DSC1) and similar instruments.

[00333] Generally, the melting point sometimes varies depending on the measuring device, measuring conditions, and the like. The crystal in this descriptive report may be a crystal that shows a melting point different from the values ​​described in this descriptive report, provided that the difference is within a general error range.

[00334] The crystal of the present invention is superior in physicochemical properties (e.g., melting point, solubility, stability) and Petition 870250083065, dated 09 / 15 / 2025, p. 116 / 258 / 211 biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion capacity), expression of efficacy) and is extremely useful as a medicine.

[00335] Compound (I) can be used as a prodrug. A prodrug of compound (I) means a compound that is converted into compound (I) of the present invention by a reaction due to an enzyme, gastric acid, etc. under physiological conditions in the living body, i.e., a compound that is converted into compound (I) of the present invention by oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound that is converted into compound (I) of the present invention by hydrolysis, etc. due to gastric acid, etc.

[00336] A prodrug of compound (I) may be a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (for example, a compound obtained by subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxyl group in compound (I) to an acylation, alkylation, phosphorylation or boration (for example, a compound obtained by subjecting a hydroxyl group in compound (I) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in compound (I) to esterification or amidation (for example, a compound obtained by subjecting a carboxyl group in compound (I) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo) esterification) 1,3-dioxolen-4-yl)methyl, cyclohexyloxycarbonylethyl esterification and methylamidation, etc.) and the like. Any of these compounds can be produced from compound (I) by a method known per se.

[00337] A prodrug for compound (I) may also be one that is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

[00338] In this descriptive report, a prodrug may form a salt and, as such, those exemplified as a salt of the compound represented by formula (I) mentioned above may be mentioned.

[00339] Compound (I) can be labeled with an isotope (e.g., 3H, 13C, 14C, 18F, 35S, 125I) and the like.

[00340] Compound (I) labeled with or substituted for an isotope can be used, for example, as a marker used for Positron Emission Tomography (PET) (PET marker) and is useful in the field of medical diagnosis and similar applications.

[00341] Furthermore, compound (I) may be a hydrate or a non-hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

[00342] Compound (I) also encompasses a form of deuterium conversion in which 1H is converted to 2H(D).

[00343] Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. A cocrystal or cocrystal salt means a crystalline substance consisting of two or more special solids at room temperature, each with different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). The cocrystal or cocrystal salt may be produced Petition 870250083065, dated 09 / 15 / 2025, pp. 118 / 258 / 211, by a known cocrystallization method.

[00344] Compound (I) or a prodrug thereof (hereinafter sometimes to be simply abbreviated as the compound of the present invention) can be used as is or in the form of a pharmaceutical composition (also referred to as a medicament) by mixing with a pharmacologically acceptable carrier etc. for mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the prophylaxis or treatment of various diseases mentioned below.

[00345] As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as preparation materials may be used. These are incorporated as excipients, lubricants, binders and disintegrants for solid preparations; or solvents, solubilizing agents, suspending agents, isotonic agents, buffers and quenching agents for liquid preparations; and the like; and preparation additives, such as preservatives, antioxidants, colorants, sweetening agents and the like, may be added as needed.

[00346] Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelled starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and aluminum magnesium metasilicate.

[00347] Preferred examples of lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

[00348] Preferred examples of binders include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, Petition 870250083065, dated 09 / 15 / 2025, page 119 / 258 / 211 hydroxypropylmethylcellulose and polyvinylpyrrolidone.

[00349] Preferred examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose.

[00350] Preferred examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

[00351] Preferred examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[00352] Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbates; and polyoxyethylene hydrogenated castor oil.

[00353] Preferred examples of isotonic agents include sodium chloride, glycerol, D-mannitol, D-sorbitol, and glucose.

[00354] Preferred examples of buffers include phosphate, acetate, carbonate, citrate, etc. buffers.

[00355] Preferred examples of the calming agent include benzyl alcohol.

[00356] Preferred examples of preservatives include oxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Petition 870250083065, dated 09 / 15 / 2025, pages 120 / 258 / 211

[00357] Preferred examples of antioxidants include sulfite salts and ascorbate salts.

[00358] Preferred examples of the dye include aqueous tar food dyes (for example, food dyes such as Food Color Red No. 2 and 3, Food Color Yellow No. 4 and 5, Food Color Blue No. 1 and 2 and similar food dyes), water-insoluble lake dyes (for example, aluminum salt of the aforementioned aqueous tar food dye), natural dyes (for example, β-carotene, chlorophyll, red iron oxide) and the like.

[00359] Preferred examples of sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame and stevia.

[00360] Examples of dosage forms of the above-mentioned pharmaceutical composition include oral preparations 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, granules, syrups, liquids, emulsions, suspensions, aerosols, films (e.g., orally disintegrating films, oral mucosal adhesive films) and the like; and parenteral agents such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (e.g., transdermal absorption preparations, ointments, lotions, adhesive preparations), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops and the like.The compound and the medicament of the present invention can be safely administered, respectively, orally or parenterally (e.g., intrarectal, intravenous, intra-arterial, intramuscular, subcutaneous, intraorganic, intranasal, intradermal, instillation, intracerebral, intravaginal, intraperitoneal, intratumoral administrations). Petition 870250083065, dated 09 / 15 / 2025, pp. 121 / 258 / 211 (proximal areas of the tumor and administration to the lesion).

[00361] These preparations may be a controlled-release preparation (e.g., sustained-release microcapsule), such as an immediate-release preparation, a sustained-release preparation, and the like.

[00362] The pharmaceutical composition may be produced according to a method conventionally used in the field of pharmaceutical formulation, for example, the method described in the Japanese Pharmacopoeia and similar documents.

[00363] Although the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dose of the compound of the present invention and the like, it is, for example, about 0.1 to 100% by weight.

[00364] When an oral preparation is produced, coating may be applied when necessary for purposes of taste masking, enteric solubility or sustainability.

[00365] Examples of coating bases used for coating include sugar coating base, water-soluble film coating base, enteric film coating base, and sustained-release film coating base.

[00366] As a sugar coating base, sucrose is used, and one or more selected types of talc, and precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may additionally be used in combination.

[00367] Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the like; and polysaccharides such as pullulan and Petition 870250083065, dated 09 / 15 / 2025, page 122 / 258 / 211 similar.

[00368] Examples of enteric film coating base include cellulose polymers, such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers, such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] and the like; and naturally occurring substances, such as shellac and the like.

[00369] Examples of sustained-release film coating base materials include cellulose polymers, such as ethylcellulose and the like; and acrylic acid polymers, such as aminoalkylmethacrylate copolymer RS ​​[Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and the like.

[00370] Two or more types of the above-mentioned coating bases may be used in a mixture at an appropriate ratio. In addition, for example, light-protecting agents such as titanium oxide, red ferric oxide and the like may also be used during coating.

[00371] Since the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and fewer side effects, it can be used as a prophylactic or therapeutic agent, or diagnostic agent for various diseases in mammals (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat).

[00372] Furthermore, the compound of the present invention is expected to be superior in central migration.

[00373] The compound of the present invention has excellent activity Petition 870250083065, dated 09 / 15 / 2025, page. 123 / 258 / 211 is an orexin type 2 receptor agonist and can treat, prevent, or improve the risk of various neurological and psychiatric diseases associated with an orexin type 2 receptor. The compound of the present invention is useful as an agent for the prophylaxis or treatment of various diseases, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick type C disease, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, syndrome of GuillainBarré, Rasmussen's encephalitis,Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinic obesity, hyperplasmic obesity, pituitary adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disturbance of consciousness, such as coma and similar conditions, side effects and complications due to anesthesia, sleep disorder, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep disruption, jet lag, jet lag syndrome, alternate worker's sleep disorder, sleep disorder, night terrors, depression, major depression, sleepwalking disorder, enuresis, sleep disorder, Alzheimer's twilight syndrome.Circadian rhythm disorders, fibromyalgia, a condition resulting from declining sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related disease, hypertension, Petition 870250083065, dated 09 / 15 / 2025, page. 124 / 258 / 211 diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeats, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorder, sudden death, polycystic ovarian disease, craniopharyngioma, Froelich syndrome, growth hormone deficiency, mutant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormality, decline in fertility, infertility, decline in male gonadal function, sexual and reproductive dysfunction, such as male and female hirsutism,Fetal defects associated with obesity in pregnant women, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, back pain, gallbladder disease, gout, kidney cancer, risk of secondary outcomes of obesity such as reduced risk of left ventricular hypertrophy, migraine pain, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, diseases of the genital / urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack,Panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders, such as heart bypass surgery and post-transplant brain deficit, stroke, cerebrovascular accident, Petition 870250083065, dated 09 / 15 / 2025, page. 125 / 258 / 211 ischemic stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders associated with muscle spasticity, delirium, amnesic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug dependence, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced parkinsonism syndrome, Jill-do La Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration,Vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury (TBI).

[00374] In particular, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson's disease, Guillain-Barré syndrome and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disturbances of consciousness such as coma and the like, side effects and complications due to anesthesia and the like, or anesthetic antagonist.

[00375] In some respects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome. Petition 870250083065, dated 09 / 15 / 2025, pp. 126 / 258 / 211 accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disordered consciousness, side effects and complications due to anesthesia.

[00376] In some respects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

[00377] In some respects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy.

[00378] Central hypersomnolence disorders (CHD) are characterized by excessive daytime sleepiness in the absence of other sleep disorders, but with the establishment of adequate and regular sleep habits. Central hypersomnolence disorders (CHD) include type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia. Kleine-Levin syndrome, as well as insufficient sleep syndrome and hypersomnia caused by a medical condition, medication or substance, or psychiatric condition are also considered central hypersomnolence disorders. The evaluation of central hypersomnolence disorders (CHD) includes sleep tests in a sleep laboratory (polysomnography, PSG) followed by a multiple sleep latency test (MSLT).

[00379] Symptoms associated with narcolepsy involve abnormal intrusions of REM sleep characteristics into the waking state: for example, sleep-related hallucinations, sleep paralysis or vivid dreams, and confusion between dream and reality. These symptoms can also occur in people without a sleep disorder.

[00380] Some patients with narcolepsy also experience cataplexy (narcolepsy, type 1), which is the loss of muscle tone triggered by emotion, typically laughter or anticipation. Cataplexy can be generalized or partial and is not associated with any loss of Petition 870250083065, dated 09 / 15 / 2025, page 127 / 258 / 211 consciousness. This muscle weakness typically improves within seconds to minutes.

[00381] Patients with idiopathic hypersomnia (IDH) often describe excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours of nighttime sleep), and severe difficulty waking up in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH often describe long, non-restorative daytime naps. Another common symptom of IDH is "brain fog," a feeling of cognitive cloudiness during the day. Klein-Levin syndrome is a rare cyclic hypersomnia disorder.

[00382] One aspect of the disclosure is a method for treating a subject with one or more central hypersomnolence disorders (CHD), the method comprising administering to the subject a compound of the present invention.

[00383] Another aspect of the disclosure is the use of a compound of the present invention for the manufacture of an agent for the treatment of one or more central hypersomnolence disorders (CHD) in a subject.

[00384] Another aspect of the disclosure is a compound of the present invention for use in the treatment of one or more central hypersomnolence disorders (CHD) in a subject.

[00385] Another aspect is a method or use of the previous aspects, in which the subject is narcoleptic. In one aspect, the subject was diagnosed with narcolepsy type 1. In another aspect, the subject was diagnosed with narcolepsy type 2. In yet another aspect, the subject was diagnosed with idiopathic hypersomnia.

[00386] Another aspect is a method or use of the foregoing aspects, wherein administration of the compound of the invention reduces daytime sleepiness, reduces instances of loss of muscle control and / or reduces instances of interrupted sleep in the subject. Petition 870250083065, dated 09 / 15 / 2025, pages 128 / 258 / 211

[00387] Another aspect is a method or use in which a compound of the present invention is administered in an amount effective in reducing excessive daytime sleepiness in adults with narcolepsy.

[00388] Another aspect is a method or use in which a compound of the present invention is administered in an amount effective to increase mean sleep latency.

[00389] Another aspect is a method or use in which a compound of the present invention is administered in an amount effective in reducing cataplexy events.

[00390] Another aspect is a method or use in which a compound of the present invention is administered in an amount effective in reducing disrupted nighttime sleep in the subject.

[00391] Although the dose of the compound of the present invention varies depending on the subject of administration, route of administration, target disease, symptom and the like, for example, when the compound of the present invention is administered orally or parenterally to an adult patient, its dose is, for example, about 0.01 to 100 mg / kg of body weight per dose, preferably 0.1 to 50 mg / kg of body weight per dose and more preferably 0.5 to 20 mg / kg of body weight per dose. This amount is desirably administered in one to three doses per day.

[00392] The compound of the present invention can be used in combination with other drugs (hereinafter referred to as concomitant drug).

[00393] By combining the compound of the present invention and a concomitant drug, a superior effect can be achieved, for example, (1) the dose can be reduced compared with single administration of the compound of the present invention or a concomitant drug, (2) the drug to be combined with the compound of the present invention. Petition 870250083065, dated 09 / 15 / 2025, page 129 / 258 / 211 invention can be selected according to the patients' condition (mild case, severe case and similar), (3) the treatment period can be defined for a longer time by selecting a concomitant drug with action and mechanism different from the compound of the present invention, (4) a sustained treatment effect can be designed by selecting a concomitant drug with action and mechanism different from the compound of the present invention, (5) a synergistic effect can be provided by a combined use of the compound of the present invention and a concomitant drug, and similar, can be achieved.

[00394] In this descriptive report, the compound of the present invention and a concomitant drug used in combination are referred to as the “combining agent of the present invention”.

[00395] When using the combination agent of the present invention, the timing of administration of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof, may be administered to a subject of administration simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the clinically used dose and may be selected appropriately depending on the subject of administration, route of administration, disease, combination, and the like.

[00396] The method of administration of the combination agent of the present invention and the concomitant drug is not particularly limited, and the compound of the present invention and the concomitant drug only need to be combined upon administration. Examples of such a method of administration include the following: Petition 870250083065, dated 09 / 15 / 2025, page 130 / 258 / 211 (1) administration of a single preparation obtained by simultaneous processing of the compound of the present invention and the concomitant drug, (2) simultaneous administration of two types of preparations of the compound of the present invention and the concomitant drug, which were produced separately, by the same route of administration, (3) administration of two types of preparations of the compound of the present invention and the concomitant drug, which were produced separately, by the same route of administration in a staggered manner, (4) simultaneous administration of two types of preparations of the compound of the present invention and the concomitant drug, which were produced separately, by different routes of administration, (5) administration of two types of preparations of the compound of the present invention and the concomitant drug, which were produced separately, by different routes of administration in a staggered manner (for example,administration in the order and composition of the present invention and the concomitant drug, or in the reverse order) and the like.

[00397] The dose of the concomitant drug can be appropriately determined based on the dose used in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the subject of administration, route of administration, target disease, symptom, combination, and the like.

[00398] For example, the content of the compound of the present invention in the combining agent of the present invention differs depending on the form of a preparation, and generally from about 0.01 to about 100% by weight, preferably from about 0.1 to about 50% by weight, more preferably from about 0.5 to about 20% by weight, based on the whole preparation.

[00399] The content of the concomitant drug in the combining agent of the present invention differs depending on the form of a preparation and generally from about 0.01 to about 100% by weight, preferably from Petition 870250083065, dated 09 / 15 / 2025, page 131 / 258 / 211 approximately 0.1 to approximately 50% by weight, additionally preferably approximately 0.5 to approximately 20% by weight, based on the entire preparation.

[00400] The content of additives, such as a carrier and the like, in the combining agent of the present invention differs depending on the form of a preparation and generally from about 1 to about 99.99% by weight, preferably from about 10 to about 90% by weight, based on the preparation.

[00401] Similar levels can be used even when the compound of the present invention and a concomitant drug are formulated separately in preparations.

[00402] Examples of concomitant drugs include the following. A therapeutic drug for narcolepsy (e.g., methylphenidate, amphetamines, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), an anti-obesity drug (amphetamine, benzphetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phentermine, Qnexa (trademark), phenylpropanolamine, pranlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), an acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia agent (e.g., memantine), inhibitor of β amyloid protein production, secretion, accumulation, aggregation and / or deposition, β secretase inhibitor (e.g., 6(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-Diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4Petição 870250083065, de 15 / 09 / 2025, pág. 132 / 258, 100 / 211 yl)methoxytetraline, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2(N,N-dimethylamino)ethyl]tetraline, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2[(N,N-dimethylamino)ethyl]tetraline, an optically active form thereof, a salt thereof and a hydrate thereof, OM99-2 (WO01 / 00663)), γ secretase inhibitor, β amyloid protein aggregation inhibitor (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 vaccine, β amyloid-degrading enzyme and similar, brain function enhancer (e.g., aniracetam, nicergoline), therapeutic drug for Parkinson's disease [(e.g., dopamine receptor agonist (e.g., LDOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitor (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)], therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factor), therapeutic drug for abnormal behavior accompanying the progression of dementia, wandering and the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation regeneration promoter (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-2,3dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5f]isoindole and an optically active form thereof, salt or hydrate. Petition 870250083065, dated 09 / 15 / 2025, pp. 133 / 258 101 / 211 same), non-steroidal anti-inflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drug (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for incontinence, frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitor (e.g., sildenafil (citrate)), dopamine agonist (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivative thereof (e.g., progesterone, estradiol, benzoate of estradiol), therapeutic agent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate),Parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drugs for insomnia (e.g., benzodiazepine medication, non-benzodiazepine medication, melatonin agonist, orexin receptor antagonists), therapeutic drugs for schizophrenia (e.g., typical antipsychotic agents such as haloperidol and similar; atypical antipsychotic agents such as clozapine, olanzapine, risperidone, aripiprazole and similar; medication acting on the metabotropic glutamate receptor or ion channel-conjugated glutamate receptor; phosphodiesterase inhibitor), benzodiazepine medication (e.g., chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, alprazolam, etc.), L-type calcium channel inhibitor (pregabalin, etc.), tricyclic or tetracyclic antidepressant (hydrochloride of imipramine, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.),selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), inhibitor, Petition 870250083065, dated 09 / 15 / 2025, pp. 134 / 258 102 / 211 selective serotonin-norepinephrine reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitor (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1a agonist (buspirone hydrochloride, tandospirone citrate, osemozotane hydrochloride, etc.), 5-HT2a antagonist, 5-HT2a inverse agonist, 5-HT3 antagonist (cyamemazine, etc.), non-selective β-cardiac inhibitor (propranolol hydrochloride, oxprenolol hydrochloride, etc.), antagonist of histamine H1 (hydroxyzine hydrochloride, etc.), CRF antagonist, other anxiolytic drug (meprobamate, etc.), tachykinin antagonist (MK-869, sarreductant, etc.), drug that acts on the metabotropic glutamate receptor, CCK antagonist, and adrenaline antagonist (amibegrone hydrochloride, etc.).), GAT-1 inhibitor (tiagabine hydrochloride, etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine subunit agonist, NMDA antagonist (memantine, etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), CB1 cannabinoid antagonist (rimonabant, etc.), FAAH inhibitor, channel inhibitor sodium, anti-ADHD drug (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.)), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for spasms, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headaches, therapeutic drug to stop smoking, therapeutic drug for myasthenia gravis, therapeutic drug for heart attack. Petition 870250083065, dated 09 / 15 / 2025, pp. 135 / 258 103 / 211 cerebral, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for male and female sexual dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambler, therapeutic drug for restless legs syndrome, therapeutic drug for substance dependence, therapeutic drug for alcohol-related syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for lipid abnormality, such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrate (clofibrate, etc.), squalene synthetase inhibitor), therapeutic drug for abnormal behavior or suppression of dromomania due to dementia (sedatives, anxiolytic drug, etc.).), therapeutic drug for diabetes, therapeutic agent for diabetic complications, therapeutic drug for hypertension, therapeutic drug for hypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, anticancer agent and similar substances.

[00403] Two or more types of the aforementioned concomitant drug may be used in a mixture in an appropriate ratio.

[00404] When the compound of the present invention is applied to each of the aforementioned diseases, it can also be used in combination with biological products (e.g., antibody drug, nucleic acid or nucleic acid derivative, aptamer drug, vaccine preparation), or it can be used in combination with a gene therapy method and the like, or it can also be used in combination with a drug-free treatment in the psychiatric field.

[00405] Examples of antibody drug and vaccine preparation include angiotensin II vaccine preparation, CETP vaccine preparation, CETP antibody, antibody against TNFα and other cytokines, β amyloid vaccine preparation, type 1 diabetes vaccine (by Petition 870250083065, dated 09 / 15 / 2025, pp. 136 / 258 104 / 211 example, DIAPEP-277 from Peptor), anti-HIV antibody and HIV vaccine preparation, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin-type enzymes and products thereof, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in blood coagulation or fibrinolysis system, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance and the like. Furthermore, it can be used in combination with biological products related to growth factors, such as GH, IGF and the like.

[00406] Examples of gene therapy methods include a treatment method using a gene related to a cytokine, renin-angiotensin-like enzyme and its product, G protein, G protein receptor conjugate and phosphorylating enzyme thereof, a treatment method using a DNA decoy, such as NFkB decoy and the like, a treatment method using antisense, a treatment method using a gene related to an enzyme or protein involved in blood lipid metabolism (e.g., a gene related to the metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid), a treatment method using a gene related to an enzyme or protein involved in angiogenesis therapy for peripheral vascular obstruction and the like (e.g., growth factors, such as HGF, VEGF, etc.).), a treatment method using a gene related to a protein involved in glucose metabolism and insulin resistance, antisense against cytokines, such as TNF etc., and similar.

[00407] Examples of drug-free treatment methods in the psychiatric field include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, and psychotherapy, including cognitive therapy. Petition 870250083065, dated 09 / 15 / 2025, pp. 137 / 258 105 / 211 behavioral and similar.

[00408] The compound of the present invention can also be used in combination with various organ regeneration methods, such as cardiac regeneration, renal regeneration, pancreatic regeneration, revascularization and the like, cell transplantation therapy using bone marrow cells (bone marrow-derived mononuclear cells, myelogenous stem cells) or artificial organ using tissue engineering (e.g., artificial blood vessel, cardiomyocyte sheet). Examples

[00409] The present invention is described in more detail in Examples, Test Examples and Formulation Examples below. However, the present invention is not intended to be limited by them, and various alterations or modifications may be made without departing from the scope of the present invention.

[00410] In the examples below, the term “room temperature” generally means approximately 10°C to approximately 35°C. A ratio used for a mixed solvent represents a volume-to-volume ratio unless otherwise specified. Unless otherwise specified, “%” represents % by weight.

[00411] Unless specifically mentioned, elution in column chromatography in the Examples was performed under TLC (thin-layer chromatography) observation. For TLC observation, 60 F254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent for column chromatography was used as a development solvent. A UV detector was used for detection. The term “NH” in silica gel column chromatography indicates that a silica gel functionalized with aminopropylsilane was used. The term “Diol” indicates the use of silica gel functionalized with 3-(2,3-dihydroxypropoxy)propylsilane. The term “C18” used in HPLC (high-performance liquid chromatography) indicates that a silica gel was used. Petition 870250083065, dated 09 / 15 / 2025, pages 138 / 258 106 / 211 functionalized with octadecyl. A ratio used for elution solvents represents a volume-to-volume ratio unless otherwise specified.

[00412] The ACD / SpecManager software (trade name) or similar was used in the 1H NMR analysis. Very broad peaks for protons of hydroxyl groups, amino groups and the like are not always indicated. MS was measured by LC / MS. As an ionization method, the ESI method or APCI method was used. The data indicate experimentally measured (found) values. Generally, a molecular ion peak is observed, and a fragment ion peak is occasionally observed. In the case of a salt, a molecular ion peak or a fragment ion peak of a free form is generally observed.

[00413] The units for sample concentration (c) in optical rotation measurements ([a]n) are in g / 100 mL.

[00414] The elemental analysis values ​​(Anal.) are shown as calculated values ​​(Calc.) and experimentally measured values ​​(Encontrados).

[00415] The X-ray powder diffraction peak in the Examples means the peak measured using Cu Ka rays as the source by the Ultima IV (Rigaku Corporation, Japan) at room temperature. The measurement conditions are as follows.

[00416] Electrical pressure / Electrical current: 40 kV / 50 mA Scan speed: 6 degrees / min. Scan range of 2 Theta: 2-35 degrees.

[00417] The X-ray diffraction crystallinity of powder in Examples was calculated using the Hermans method.

[00418] In the Examples, the following abbreviations are used: mp: melting point MS: mass spectrum Petition 870250083065, dated 09 / 15 / 2025, pp. 139 / 258 107 / 211 M: molar concentration, molarity CDCI3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1H NMR: proton nuclear magnetic resonance LC / MS: liquid chromatography-mass spectrometry ESI: electrospray ionization APCI: chemical ionization at atmospheric pressure Et2O: diethyl ether DIPEA: diisopropylethyl amine IPE: diisopropyl ether CPME: cyclopropyl methyl ether NMP: N-methyl-2-pyrrolidone TFA: trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) TEA: triethylamine MeOH: methanol EtOH: ethanol EtOAc: ethyl acetate CH2Cl2: dichloromethane PE: petroleum ether MsCl: methanesulfonyl chloride CDI: 1,1'-carbonyldiimidazole BOC2O: di-tert-butyl dicarbonate PyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium Petition 870250083065, dated 09 / 15 / 2025, pp. 140 / 258 108 / 211 hexafluorophosphate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5b]pyridinium 3-oxide hexafluorophosphate Pd(Ph3P)4 : tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2: palladium(II) acetate Pd(dppf)Cl2^CH2Cl2: [1,1'bis(diphenylphosphine)ferrocene]palladium(II) dichloride dichloromethane adduct tBuXPhos: 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl XPhos Pd G3: methanesulfonate(2-dicyclohexylphosphino2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) SFC: supercritical fluid chromatography Example 1

[00419] N-[(15aS,16S)-7-Methyl-1-oxo-2,3,15a,16,17,18-hexahydro1H,15H-4,8-(azene)-10,14-(methene)pyrrole [1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide A) tert-Butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00420] To a solution of tert-butyl (2S,3S)-3-amino-2-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate (5.00 g) in CH2Cl2 (50 mL) was added TEA (4.27 g). The mixture was stirred at 20 °C for 30 minutes. Then, MsCl (1.44 g) was added to the mixture slowly at 0 °C. The mixture was stirred at 20 °C under a nitrogen atmosphere for 2 hours. The reaction was stopped with water (50 mL) and stirred for 10 min. Then, it was extracted with CH2Cl2 and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain the titrant compound (5.05 g).

[00421] 1H NMR (400 MHz, DMSO-do) δ 1.05 (9H, s), 1.20-1.35 (2H, m), 1.82-1.92 (1H, m), 2.07-2.15 (1H, m), 2.30-2.40 (1H, m), 2.84-2.91 (2H, Petition 870250083065, dated 09 / 15 / 2025, pp. 141 / 258 109 / 211 m), 2.94 (3H, s), 3.80-3.90 (1H, m), 7.14-7.18 (1H, m), 7.20-7.25 (1H, m), 7.35-7.40 (2H, m), 7.50-7.56 (1H, m).

[00422] B) tert-Butyl (2S,3S)-3-[(methanesulfonyl)amino]-2-{[3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1carboxylate

[00423] To a mixture of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.05 g) and bis(pinacolate)diboron (4.44 g) in toluene (50 mL) were added XPhos Pd G3 (493 mg) and potassium acetate (2.29 g). It was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the title compound (8.75 g).

[00424] MS: [M-Boc+H]+ 381.0

[00425] C) tert-Butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl]-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00426] To a mixture of tert-butyl (2S,3S)-3[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate (5.60 g) in THF (50 mL) and water (50 mL) was added sodium peroxoborate tetrahydrate (4.48 g). It was stirred at 25 °C for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to obtain the title compound (3.50 g).

[00427] MS: [M-Boc+H]+271,1

[00428] D) tert-Butyl (2S,3S)-2-({3-[(6-cyano-3-methylpyridin-2yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00429] To a solution of tert-butyl (2S,3S)-2-[(3-hydroxyphenyl)methyl] Petition 870250083065, dated 15 / 09 / 2025, page 142 / 258 110 / 211 3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (2.00 g) in DMA (15 mL) was added to 6-chloro-5-methylpicolinonitrile (906 mg) and cesium carbonate (2.64 g). The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE) to obtain the title compound (759 mg).

[00430] 1H NMR (400 MHz, DMSO-do) δ 1.08-1.33 (9H, m), 1.801.91 (1H, m), 2.00-2.13 (1H, m), 2.37 (3H, s), 2.87 (3H, s), 3.12-3.30 (4H, m), 3.80-3.92 (1H, m), 4.02-4.11 (1H, m), 6.92-7.21 (3H, m), 7.33 (1H, t, J = 8.0 Hz), 7.41-7.55 (1H, m), 7.68 (1H, d, J = 7.2 Hz), 7.90-7.97 (1H, m).

[00431] E) tert-Butyl (2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00432] To a solution of tert-butyl (2S,3S)-2-({3-[(6-cyano-3methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (759 mg) in MeOH (10 mL) was added nickel(II) chloride hexahydrate (371 mg). Then, sodium borohydride (177 mg) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was slowly stopped by saturated aqueous ammonium chloride solution at 0 °C and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH containing 0.3% ammonium hydroxide) to obtain the title compound (371 mg).

[00433] MS: [M+H]+491.2

[00434] F) N-{(2S,3S)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl]oxy}phenyl)methyl]pyrrolidin-3-yl}methanesulfonamide dihydrochloride

[00435] tert-Butyl (2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (371 Petition 870250083065, dated 09 / 15 / 2025, pp. 143 / 258 111 / 211 mg) in 4 M hydrogen chloride in dioxane (5 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under vacuum to obtain the titrant compound (446 mg).

[00436] MS: [M+H]+391.1

[00437] G) N-[(15aS,16S)-7-Methyl-1-oxo-2,3,15a,16,17,18-hexahydro1H,15H-4,8-(azene)-10,14(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00438] CDI (158 mg) and DIPEA (686 mg) were added to a solution of N-{(2S,3S)-2-[(3-{[6(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]pyrrolidin-3yl}methanesulfonamide dihydrochloride (410 mg) in DMF (410 mL). The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 12 hours for mixture A. Similar to the synthesis of mixture A, mixture B was obtained using N-{(2S,3S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}phenyl)methyl]pyrrolidin-3-yl}methanesulfonamide dihydrochloride (446 mg) in DMF (450 mL) to which CDI (172 mg) and DIPEA (746 mg) were added. Mixtures A and B were combined and concentrated under vacuum. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonium hydroxide / acetonitrile solution) to obtain the titrant compound (230 mg).

[00439] 1H NMR (400 MHz, DMSO-dô) δ 1.71-1.85 (1H, m), 2.022.12 (1H, m), 2.26 (3H, s), 2.76-2.87 (3H, m), 3.01 (3H, s), 3.06-3.15 (1H, m), 3.75-3.86 (2H, m), 4.19-4.27 (1H, m), 4.43-4.53 (1H, m), 6.00 (1H, dd, J = 9.6, 3.6 Hz), 6.86-6.92 (2H, m), 7.10-7.14 (1H, m), 7.17-7.25 (2H,m), 7.55-7.67 (2H, m). Example 2

[00440] N-[(15aS,16R)-17,17-Difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azen o)-10,14-(metheno)pyrrole[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide Petition 870250083065, 15 / 09 / 2025, pág. 144 / 258 112 / 211

[00441] A) tert-Butyl (2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00442] To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (1.00 g) in CH2Cl2 (15 mL) was added TEA (875 mg). The mixture was stirred at 20 °C for 30 minutes. Then, MsCl (400 mg) was added to the mixture at 0 °C slowly. The mixture was stirred at 20 °C under a nitrogen atmosphere for 2 hours. The reaction was quenched with water and stirred for 10 minutes. It was then extracted with CH2Cl2 and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to obtain the title compound (1.07 g).

[00443] 1H NMR (400 MHz, DMSO-d6) δ 1.06 (9H, s), 2.90 (2H, dd, J = 13.6, 4.4 Hz), 2.99 (3H, s), 3.75-3.85 (2H, m), 4.27-4.32 (1H, m), 4.47-4.56 (1H, m), 7.19 (1H, s), 7.20-7.40 (3H, m), 8.17 (1H, d, J = 9.6 Hz).

[00444] B) tert-Butyl (2S,3R)-4,4-difluoro-3[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate

[00445] To a solution of tert-butyl (2S,3R)-2-[(3-chlorophenyl)methyl]4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (970 mg) in toluene (20 mL) was added bis(pinacolate)diboron (869 mg), XPhos Pd G3 (97 mg) and potassium acetate (448 mg). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the titrant compound (1.87 g).

[00446] MS: [M+Na]+539.1

[00447] C) tert-Butyl (2S,3R)-4,4-difluoro-2-[(3-hydroxyphenyl)methyl]-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Petition 870250083065, dated 09 / 15 / 2025, pages 145 / 258 113 / 211

[00448] To a solution of tert-butyl (2S,3R)-4,4-difluoro-3[(methanesulfonyl)amino]-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate (1.87 g) in THF (10 mL) and water (10 mL) was added sodium perborate tethiahydrate (1.39 g) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to yield the titrant compound (774 mg).

[00449] MS: [M+Na]+429.1

[00450] D) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2yl)oxy]phenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1carboxylate

[00451] To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(3hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (770 mg) in DMA (10 mL) was added 6-chloro-5-methylpyridine-2-carbonitrile (318 mg) and cesium carbonate (926 mg). The mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the titrant compound (713 mg).

[00452] 1H NMR (400 MHz, DMSO-do) δ 1.05-1.14 (9H, m), 2.37 (3H, s), 2.56-2.64 (1H, m), 2.70-2.81 (1H, m), 2.87-2.97 (3H, m), 3.70-3.91 (2H, m) 8.05-8.20 (1H, m).

[00453] E) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}phenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1 Petition 870250083065, dated 09 / 15 / 2025, page 146 / 258 114 / 211 carboxylate

[00454] To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]phenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (790 mg) in MeOH (10 mL) was added sodium borohydride (171 mg). Then, nickel(II) chloride hexahydrate (359 mg) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was slowly stopped with aqueous ammonium chloride solution at 0 °C, then extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the titrant compound (676 mg).

[00455] MS: [M+H]+527.3

[00456] F) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl]oxy}phenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride

[00457] A mixture of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (200 mg) and 4 M hydrogen chloride in dioxane (5 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated to obtain the titrant compound (200 mg).

[00458] MS: [M+H]+427.1

[00459] G) N-[(15aS,16R)-17,17-Difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00460] To a solution of N-{(2S,3R)-2-[(3-{[6(aminomethyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-4,4-difluoropyrrolidin-3yl}methanesulfonamide dihydrochloride (200 mg) in DMF (200 mL) was added CDI (71 mg) and DIPEA (310 mg). The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 2 hours. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. A Petition 870250083065, dated 09 / 15 / 2025, pages 147 / 258 The 115 / 211 organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) to obtain the titrant compound (13.8 mg).

[00461] 1H NMR (400 MHz, DMSO-do) δ 2.27 (3H, s), 2.54-2.63 (1H, m), 2.84 (1H, dd, J = 13.6, 4.4 Hz), 3.08 (3H, s), 3.60-3.72 (1H, m), 3.75-3.90 (2H, m), 4.27-4.44 (2H, m), 4.55-4.62 (1H, m), 6.32 (1H, dd, J = 9.2, 2.8 Hz), 6.85-6.92 (2H, m), 7.03 (1H, d, J = 7.2 Hz), 7.18 (1H, s), 7.23 (1H, t, J = 8.0 Hz), 7.56 (1H, d, J = 7.6 Hz), 7.74 (1H, brs). Example 4

[00462] N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl- 1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamida

[00463] A) 3-chloro-2-fluorophenylalanine hydrochloride

[00464] A mixture of 1-(bromomethyl)-3-chloro-2-fluorobenzene (55.0 g), diethyl acetamidomalanate (56.1 g) and EtOH (400 mL) was added to a 20% ethanol solution of sodium ethoxide (88 g) at 0°C. The mixture was refluxed for 2 h 30 min and cooled to room temperature. The impurity was removed by filtration, the filtrate was concentrated under reduced pressure, and a mixture of the residue and 6 M hydrochloric acid (500 mL) was refluxed for 15 h. The reaction solution was concentrated under reduced pressure, and the residue obtained was washed with isopropanol / diisopropyl ether to give the titrant compound (67.1 g).

[00465] MS: [M+H]+ 217.8.

[00466] B) N-(tert-Butoxycarbonyl)-3-chloro-2-fluorophenylalanine

[00467] To a mixture of 3-chloro-2-fluorophenylalanine hydrochloride (67.1 g), 1 M aqueous sodium hydroxide solution (528 mL) and DME (480 mL) was added Boc2O (63.4 g) at room temperature. The mixture was Petition 870250083065, dated 09 / 15 / 2025, pp. 148 / 258 116 / 211 stirred at room temperature for 2 h 30 min and poured into ice water. The mixture was basified with 1 M aqueous sodium hydroxide solution, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solid obtained was washed with diisopropyl ether / hexane to give the titrant compound (63.8 g).

[00468] MS: [MH]-316.0.

[00469] C) tert-Butyl {3-(3-chloro-2-fluorophenyl)-1[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate

[00470] To a mixture of N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine (63.8 g), N-methoxymethanamine hydrochloride (21.5 g), HOBt (29.8 g), TEA (44.7 g) and DMF (425 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (46.2 g) at 0°C. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was added to an aqueous solution of sodium bicarbonate and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained was washed with diisopropyl ether / hexane to give the titrant compound (70.0 g).

[00471] MS, found: 260.9.

[00472] D) tert-Butyl {3-(3-chloro-2-fluorophenyl)-1[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-methoxybenzyl)carbamate

[00473] To a mixture of tert-butyl {3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (70.0 g) and DMF (390 mL) was added 60% sodium hydride (10.1 g) at 0°C. The mixture was stirred at 0°C for 5 min, and then at room temperature for 10 min, and to the reaction mixture were added 1-(chloromethyl)-4-methoxybenzene (60.7 g) and tetrabutylammonium iodide (7.16 g) at 0°C. The mixture was stirred at room temperature. Petition 870250083065, dated 09 / 15 / 2025, pp. 149 / 258 117 / 211 ambient for 2 h 30 min, poured into ice water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (90.7 g).

[00474] MS: [M+H]+ 481.1.

[00475] E) tert-Butyl [1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4methoxyphenyl)methyl]carbamate

[00476] To a mixture of tert-butyl {3-(3-chloro-2-fluorophenyl)-1[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-methoxybenzyl)carbamate (90.7 g) and Et2O (500 mL) was added lithium aluminum hydride (9.30 g) under slow stirring at -78°C. The mixture was stirred at -15°C for 1 h 30 min, and EtOAc and a 10% aqueous solution of potassium hydrogen sulfite were added dropwise sequentially to the reaction mixture at -78°C. The mixture was stirred at room temperature for 15 minutes and water was added to the mixture. The insoluble substance was removed by filtration through Celite, and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (74.7 g).

[00477] MS: [MH]-420.0.

[00478] F) Ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}5-(3-chloro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate

[00479] A mixture of zinc (37.0 g) and THF (500 mL) was added to TMSCl (3.85 g) under an argon atmosphere at room temperature. The mixture was stirred at room temperature for 15 min, and ethyl bromo(difluoro)acetate (71.9 g) was added dropwise to the mixture with vigorous stirring at room temperature, maintaining an internal temperature of approximately 50°C. The mixture was stirred at room temperature for 15 min. Petition 870250083065, dated 09 / 15 / 2025, pp. 150 / 258 118 / 211 min, and a mixture of tert-butyl[1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbamate (74.7 g) and THF (100 mL) was added dropwise to the mixture, maintaining an internal temperature of approximately 40°C. The mixture was stirred at room temperature for 2 hours and added to a 5% aqueous solution of potassium hydrogen sulfite under ice cooling and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (61.6 g).

[00480] MS, found: 490.0.

[00481] G) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1[(4-methoxyphenyl)methyl]pyrrolidin-2-one

[00482] A mixture of ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chloro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate (61.6 g) and EtOH (160 mL) was added to a 4 M hydrogen chloride CPME solution (282 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and the reaction solution was concentrated. EtOH (360 mL) and DIPEA (43.8 g) were added to the residue obtained. The mixture was stirred at 70°C for 1 hour and 30 minutes, and the reaction mixture was poured into ice-cold water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane), and the resulting solid was washed with diisopropyl ether / hexane to give the titrant compound (36.1 g).

[00483] MS: [M+H]+ 399.9.

[00484] H) 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4hydroxypyrrolidin-2-one Petition 870250083065, dated 09 / 15 / 2025, pages 151 / 258 119 / 211

[00485] To a mixture of 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one (36.1 g), CH3CN (315 mL) and water (105 mL) was added ammonium(IV) hexanitrate (99 g) at room temperature. The mixture was stirred at room temperature for 4 hours, poured into ice-cold water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and then by NH silica gel column chromatography (MeOH / EtOAc) to generate the titrant compound (22.7 g).

[00486] MS: [MH]-278.0.

[00487] I) tert-Butyl 2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-carboxylate

[00488] To a mixture of 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2-one (22.7 g) and THF (350 mL) was added dropwise a 1 M borane-THF complex to a THF solution (284 mL) at room temperature. The mixture was slowly heated to 60°C and stirred for 4 h. Water was added dropwise to the mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure. To the residue, 1 M hydrochloric acid (500 mL) was added, and the mixture was vigorously stirred at 60°C for 1 h 30 min. The mixture was slowly added to a 1 M aqueous solution of sodium hydroxide under ice cooling, basified with potassium carbonate, saturated with salt, and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.To a mixture of the residue obtained, sodium bicarbonate (6.83 g) and THF (190 mL) / water (210 mL) was added a solution of Boc2O (19.5 g) in THF (20 mL) at room temperature. The mixture was vigorously stirred at room temperature for 15 h, then poured. Petition 870250083065, dated 09 / 15 / 2025, pages 152 / 258 120 / 211 in water and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (22.2 g).

[00489] MS, found: 265.9.

[00490] J) rac-tert-Butyl (2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate

[00491] To a mixture of tert-butyl 2-[(3-chloro-2-fluorophenyl)methyl]4,4-difluoro-3-hydroxypyrrolidine-1-carboxylate (22.1 g), pyridine (96 g) and EtiO₂ (355 mL) was added dropwise trifluoromethanesulfonic anhydride (51.2 g) under an argon atmosphere at 0°C. The mixture was stirred at room temperature for 2 h 30 min, poured into ice-cold water and extracted with EtO₂Ac / hexane. The organic layer was separated, washed with 10% aqueous citric acid solution, aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtO₂Ac / hexane) to yield the title compound (22.4 g). MS, found: 397.9. K) rac-tert-Butyl (2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4difluoropyrrolidine-1-carboxylate

[00492] To a mixture of rac-tert-butyl (2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate (22.4 g) and CH3CN (265 mL) tetra-n-butylammonium azide (38.3 g) was added at room temperature. The mixture was slowly heated to 80°C, stirred for 1 hour, poured into ice-cold water, and extracted with EtOAc. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Petition 870250083065, dated 09 / 15 / 2025, pages 153 / 258 121 / 211 (EtOAc / hexane) to generate the title compound (16.2 g).

[00493] MS, found: 290.9.

[00494] L) rac-tert-Butyl (2S,3R)-3-amino-2-[(3-chloro-2fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate

[00495] To a mixture of rac-tert-butyl (2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (16.2 g) and THF (200 mL) / water (5 mL) was added PPh3 (13.1 g) under an argon atmosphere at room temperature. The mixture was stirred at 55°C for 18 hours, added to aqueous sodium bicarbonate solution under ice cooling, and extracted with EtOAc / THF. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel NH (EtOAc / hexane) column chromatography to yield the titrant compound and the byproduct, respectively. A mixture of the byproduct obtained and THF (100 mL) / water (10 mL) was added to a 40% aqueous methanamine solution (3.22 g) at room temperature. The mixture was stirred at 70°C for 15 hours, poured into water, and extracted with EtOAc.The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel NH (EtOAc / hexane) column chromatography to generate the titrant compound (14.6 g), which was combined with the titrant compound obtained above.

[00496] MS, found: 308.9.

[00497] M) tert-Butyl (2S,3R)-3-amino-2-[(3-chloro-2fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate

[00498] rac-tert-Butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (14.6 g) was resolved by HPLC (column: CHIRALPAK IA, 50 mmID*500 mmL, 20 μm, mobile phase: hexane / ethanol / diethylamine = 800 / 200 / 1) to give the titrant compound (6.84 g) with a shorter retention time (column: CHIRALPAK IA, 4.6 Petition 870250083065, dated 09 / 15 / 2025, pages 154 / 258 122 / 211 mmID*250 mmL, 5 μO, mobile phase: hexane / ethanol / diethylamine = 800 / 200 / 1).

[00499] MS, found: 309.1.

[00500] N) tert-Butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00501] To a mixture of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (20 g), TEA (22.9 ml) in EtOAc (274 ml) was added MsCl (4.67 ml) at 0 °C. The mixture was stirred at room temperature for 1 hour. Aqueous ammonium chloride solution was added to the mixture. The organic layer was separated, washed with aqueous sodium bicarbonate and brine solution, passed through an NH silica gel pad and concentrated under reduced pressure. The residue was solidified and triturated with Et2O to give the titrant compound (22.5 g).

[00502] MS: [MH]-441.0

[00503] O) tert-Butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00504] To a mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (15 g x 2 batches), Pd2(dba)3 (1.55 g x 2 batches) and tBuXPhos (2.88 g x 2 batches) in DME (135 mL x 2 batches) was added an aqueous solution of 8 M potassium hydroxide (12.7 mL x 2 batches). The mixture was stirred at 120 °C for 2 hours in a medium pressure reactor. The mixture was quenched with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and crystallized with IPE-hexane to yield the titrant compound (17.0 g).

[00505] MS: [MH]-422.9

[00506] P) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1carboxylate Petition 870250083065, dated 09 / 15 / 2025, pages 155 / 258 123 / 211

[00507] A mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.9 g), 6-chloro-5-methylpicolinonitrile (2.33 g), Cs2CO3 (9.06 g) and DMF (60 mL) was stirred at 120 °C for 5 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (5.62 g).

[00508] MS: [MH]-539.0

[00509] Q) tert-Butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3 -methylpyridin-2-yl)oxi]-2-fluorophenyl} methyl)-4,4difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00510] Sodium borohydride (1.967 g) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.62 g) and cobalt(II) chloride (2.70 g) in MeOH (120 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. Then, Boc2O (3.62 mL) was added to the reaction mixture at room temperature and stirred at room temperature for 1 hour. The solvent was removed by concentration and EtOAc, and an aqueous solution of sodium hydrogen carbonate was added to the residue. The insoluble solid was removed by celite and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (4.82 g).

[00511] MS: [M+H]+645.2 R) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2-yl]oxy}-2fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride

[00512] To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert Petition 870250083065, dated 09 / 15 / 2025, pages 156 / 258 124 / 211 butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (4.82 g) in EtOAc (50 mL) was added to 4 M hydrogen chloride in EtOAc (50 mL) at room temperature. The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with EtOAc to yield the title compound (3.85 g).

[00513] MS: [M+H]+ 445.1

[00514] S)N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(a zeno)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00515] To a suspension of di(N-succinimidyl) carbonate (6.67 g) and DIPEA (33.8 g) in dry THF (4200 ml) was added dropwise to a solution of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide dihydrochloride (16.9 g) in dry DMF (200 ml) at 0°C for 60 minutes. The mixture was stirred at room temperature for 16 hours and concentrated to a small volume. EtOAc and water were added to the residue and partitioned. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH3 silica gel column chromatography (EtOAc / hexane). To a solution of the residue thus obtained in EtOAc (600 ml) was added Ecosorb C-941 activated charcoal (1 g) at 55°C, and the mixture was stirred at 55°C for 1 hour. Insoluble materials were filtered and the filtrate was concentrated under reduced pressure.The residue was crystallized from EtOH-heptane to give the title compound (6.16 g).

[00516] 1H NMR (400 MHz, DMSO-d6) δ 2.30 (3H, s), 2.65 (1H, br d,. J = 12.7 Hz), 2.76-2.87 (1H, m), 3.11 (3H, s), 3.60 (1H, br d, J = 14.7 Hz), 3.68-3.88 (2H, m), 4.27-4.48 (2H, m), 4.52-4.62 (1H, m), 6.14 (1H, br d, J = 8.6 Hz), 6.85 (1H, d, J = 7.1 Hz), 6.96-7.03 (1H, m), 7.07 (1H, t, J = 7.7 Hz), Petition 870250083065, dated 09 / 15 / 2025, pp. 157 / 258 125 / 211 7.11-7.18 (1H, m), 7.48-7.61 (1H, m), 8.17 (1H, d, J = 9.5 Hz) Example 5

[00517] N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl- 1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[00518] A) tert-Butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate

[00519] To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (80.0 g x 2 batches) in CH2Cl2 (560 mL x 2 batches) was added TEA (67.0 g x 2 batches) and ethanesulfonyl chloride (42.0 g x 2 batches) at 0 °C. The reaction mixture was stirred at 25 °C under a nitrogen atmosphere for 13 hours. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to obtain the title compound (184 g).

[00520] MS: [M-Boc+H]+ 357.1

[00521] B) tert-Butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate

[00522] A mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (27.0 g x 5 batches), Pd2(dba)3 (16.0 g x 5 batches) and tBuXPhos (8.00 g x 5 batches) in dioxane (243 mL x 5 batches) was added to a 2 M aqueous solution of potassium hydroxide (89.0 mL x 5 batches). The mixture was degassed and purged with nitrogen 3 times. The mixture was stirred under reflux for 2 h under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to Petition 870250083065, dated 09 / 15 / 2025, pages 158 / 258 126 / 211 obtain the titular compound (85.0 g).

[00523] 1H NMR (400 MHz, DMSO-d6) δ 1.01 (9H, s), 1.27 (3H, t, J = 7.2 Hz), 2.93 (1H, d, J = 13.6 Hz), 3.07-3.18 (3H, m), 3.63-3.76 (1H, m), 3.83-3.96 (1H, m), 4.31 (1H, d, J = 8.4 Hz), 4.42-4.57 (1H, m), 6.56-6.63 (1H, m), 6.83 (2H, t, J = 6.8 Hz), 8.18 (1H, d, J = 9.2 Hz), 9.65 (1H, s)

[00524] C) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1carboxylate

[00525] A mixture of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (80.0 g), 6-chloro-5-methylpicolinonitrile (42.0 g), cesium carbonate (119 g) in DMA (560 mL) was stirred at 120 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to obtain the title compound (80.0 g).

[00526] MS: [M+Na]+ 577.1

[00527] D) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine1-carboxylate

[00528] To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (36.1 g x 2 batches) in MeOH (252 mL x 2 batches) was added nickel(II) chloride hexahydrate (16.0 g x 2 batches) and sodium borohydride (7.00 g x 2 batches) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was stopped by aqueous ammonium chloride solution at 0 °C. Then, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and Petition 870250083065, dated 09 / 15 / 2025, pages 159 / 258 127 / 211 concentrated to obtain the titrant compound (70.0 g).

[00529] MS: [M+H]+ 559.3

[00530] E) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide dihydrochloride

[00531] A mixture of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (70.0 g) in 4 M hydrogen chloride in EtOAc (783 mL) was stirred at 25 °C for 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to yield the residue (67.0 g). Then, 52.0 g of the red residue were purified by reversed-phase HPLC (column: Agela C18, mobile phase: 0.4% hydrochloric acid / MeOH) to obtain the titrant compound (26 g).

[00532] MS: [M+H]+459.0

[00533] F)N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(a zeno)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[00534] To a mixture of di(N-succinimidyl)carbonate (2.00 g x 6 batches) and 4-methylmorpholine (4.00 g x 6 batches) in THF (4.11 L x 6 batches) was added a solution of N-{(2S,3R)-2-[(3-{[6(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide dihydrochloride (4.00 g x 6 batches) in DMF (58.0 mL x 6 batches) at 25 °C for 30 minutes. Then, DIPEA (8.00 g x 6 batches) was added in a portion. Finally, the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The crude product was purified by preparative HPLC (column: Phenomenex Titank C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to obtain the titrant compound (4.60 g).

[00535] 1H NMR (400 MHz, DMSO-do) δ 1.29 (3H, t, J = 7.2 Hz), Petition 870250083065, dated 09 / 15 / 2025, pp. 160 / 258 128 / 211 2.30 (3H, s), 2.61-2.69 (1H, m), 2.78-2.89 (1H, m), 3.16-3.21 (2H, m), 3.60 (1H, d, J = 14.4 Hz), 3.70-3.86 (2H, m), 4.24-4.45 (2H, m), 4.52 (1H, t, J = 9.6 Hz), 6.14 (1H, d, J = 8.8 Hz), 6.85 (1H, d, J = 7.2 Hz), 6.96-7.16 (3H, m), 7.55 (1H, d, J = 7.2 Hz), 8.16 (1H, s). Example 7 00536

[00537] A) terc-Butil (2S,3S)-2-{[3-({6-[(3-terc-butoxi-3-oxoprop-1en-1-il]-3-metilpiridin-2-il}oxi)fenil]metil}-3[(metanossulfonil)amino]pirrolidina-1-carboxilato

[00538] To a mixture of tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (495 mg), Pd(OAc)2 (10 mg) and di-tert-butyl-(2-phenylphenyl)phosphane (26 mg) in DMF (5 mL) was added tert-butyl prop-2-enoate (640 mg) and TEA (177 mg) at 25 °C, and the mixture was stirred at 120 °C for 13 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc) to obtain the titrant compound (457 mg).

[00539] MS: [M+H]+ 588.2

[00540] B) tert-Butyl (2S,3S)-2-[(3-{[6-(3-tert-butoxy-3-oxopropyl)-3methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1carboxylate

[00541] To a mixture of tert-butyl (2S,3S)-2-{[3-({6-[3-tert-butoxy-3-oxoprop-1-en-1-yl]-3-methylpyridin-2-yl}oxy)phenyl]methyl}-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (457 mg) in MeOH (5 mL) was added 10% palladium on carbon (moistened with 55% Petition 870250083065, dated 09 / 15 / 2025, pp. 161 / 258 129 / 211 water, 60 mg) at 25 °C, the mixture was stirred at 25 °C for 3 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the titrant compound (411 mg).

[00542] MS: [M+H]+ 590.2

[00543] C) 3-{6-[3-({(2S,3S)-3[(Methanesulfonyl)amino]pyrrolidin-2-yl}methyl)phenoxy]-5-methylpyridin-2yl}propanoic acid

[00544] A mixture of tert-butyl (2S,3S)-2-[(3-{[6-(3-tert-butoxy-3oxopropyl)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (67 mg) in 4 M hydrogen chloride in dioxane (1 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to yield the title compound (48 mg).

[00545] MS: [M+H]+434.2

[00546] D) N-[(1S,19aS)-11-Methyl-5-oxo-2,3,6,7,19,19a-hexahydro1H,5H-8,12-(azene)-14,18-(methene)pyrrolo[2,1-h][1,9]oxazacycloheptadecyn1-yl]methanesulfonamide

[00547] To a solution of 3-{6-[3-({(2S,3S)-3[(methanesulfonyl)amino]pyrrolidin-2-yl}methyl)phenoxy]-5-methylpyridin-2yl}propanoic acid (75 mg) in THF (750 mL) was added PyBOP (125 mg) and TEA (81 mg) at 25 °C, the mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonium hydroxide / acetonitrile solution) followed by lyophilization. The residue thus obtained was subsequently purified by SFC (column: DAICEL CHIRALPAK IG, mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide)) to obtain the titrant compound (14.4 mg).

[00548] 1H NMR (400 MHz, DMSO-d6) δ 1.69-1.83 (1H, m), 2.012.09 (1H, m), 2.20-2.34 (4H, m), 2.66-2.76 (1H, m), 2.81-2.91 (3H, m), 3.01 Petition 870250083065, dated 09 / 15 / 2025, pp. 162 / 258 130 / 211 (3H, s), 3,16-3,29 (2H, m), 3,39-3,45 (1H, m), 3,74-3,86 (1H, m), 4,30-4,39 (1H, m), 6,85-6,96 (3H, m), 7,10-7,16 (1H, m), 7,19-7,28 (1H, m), 7,55 (1H, d, J = 8,0 Hz), 7,71 (1H, d, J = 4,0 Hz). Exemplo 10

[00549] N-[(15aS,16R,17S)-17,20-Difluoro-7-metil-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(meteno)pirrolo[1,2j][1,8,10]oxadiazacicloheptadecin-16-il]metanossulfonamida

[00550] A) Benzil (2S,3R,4S)-4-fluoro-2-{[2-fluoro-3-(4,4,5,5tetrametil-1,3,2-dioxaborolan-2-il)fenil]metil}-3[(metanossulfonil)amino]pirrolidina-1-carboxilato

[00551] To a mixture of benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1 g) in toluene (15 mL) were added bis(pinacolate)diboron (0.830 g), potassium acetate (0.428 g) and XPhos Pd G3 (0.092 g) at room temperature. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to yield the titrant compound (0.961 g).

[00552] MS: [M+H]+ 551.2

[00553] B) Benzyl (2S,3R,4S)-4-fluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00554] To a mixture of benzyl (2S,3R,4S)-4-fluoro-2-{[2-fluoro-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (962.5 mg) in THF (5.0 mL) and water (5.0 mL) sodium peroxoborate tetrahydrate (538 mg) was added at 0 °C. The mixture was stirred at 0 °C to room temperature for 1.5 hours. The mixture was quenched with 1 M hydrochloric acid and extracted with EtOAc. The organic layer was separated, washed with aqueous sodium thiosulfate solution, water and brine, dried over anhydrous sodium sulfate and Petition 870250083065, dated 09 / 15 / 2025, pp. 163 / 258 131 / 211 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was washed with EtOAc-IPE to give the title compound (460 mg).

[00555] MS: [M+H]+ 441.0

[00556] C) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]2-fluorophenyl}methyl)-4-fluoro-3-[(methanesulfonyl)amino]pyrrolidine-1carboxylate

[00557] A mixture of benzyl (2S,3R,4S)-4-fluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (500 mg), 6-chloro-5-methylpicolinonitrile (217 mg), and cesium carbonate (462 mg) in DMA (3 mL) was stirred at 100 °C under a nitrogen atmosphere overnight. The mixture was quenched with aqueous ammonium chloride solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel NH (EtOAc / hexane) column chromatography to give the title compound (431 mg).

[00558] MS: [M+H]+557.1

[00559] D) Benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridin-2-yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamido)pyrrolidine-1-carboxylate

[00560] To a solution of benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4-fluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (430.5 mg) and nickel chloride hexahydrate (184 mg) in MeOH (15 mL) was added sodium borohydride (88 mg) at 0 °C. The mixture was stirred at the same temperature for 30 minutes. After concentration of the resulting mixture, the residue was purified by silica gel NH (MeOH / EtOAc) column chromatography to generate the titrant compound (312 mg).

[00561] MS: [M+H]+561.2 Petition 870250083065, dated 09 / 15 / 2025, pp. 164 / 258 132 / 211

[00562] E) N-{(2S,3R,4S)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}methanesulfonamide dihydrobromide

[00563] To benzyl (2S,3R,4S)-2-(3-((6-(aminomethyl)-3-methylpyridin-2yl)oxy)-2-fluorobenzyl)-4-fluoro-3-(methylsulfonamido)pyrrolidine-1-carboxylate (311.5 mg) was added 30% hydrogen bromide in acetic acid (10 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes and then the solvent was coevaporated twice with toluene. The residue was washed with EtOAc and IPE to give the title compound (378 mg).

[00564] MS: [M+H]+427.1

[00565] F) N-[(15aS,16R,17S)-17,20-Difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(az ene)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00566] To a solution of CDI (99 mg) and DIPEA (0.582 mL) in dry THF (250 mL) was added N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3yl}methanesulfonamide dihydrobromide (327.0 mg) in dry DMF (12.50 mL) dropwise over 30 minutes at room temperature. The reaction mixture was stirred at room temperature under an argon atmosphere for 2 hours. After removal of the THF under reduced pressure, dry THF (250 mL) and dry DMF (12.5 mL) were added to the residue. The mixture was stirred at room temperature overnight. After the removal of THF under reduced pressure, the mixture was tempered with an aqueous solution of sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The crude material was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to generate the titrant compound. Petition 870250083065, dated 09 / 15 / 2025, pp. 165 / 258 133 / 211 (42.0 mg).

[00567] 1H NMR (400 MHz, DMSO-dô) δ 2.26-2.34 (3H, m), 2.68 (1H, br d, J = 12.6 Hz), 2.97 (1H, br t, J = 12.8 Hz), 3.09 (3H, s), 3.49-3.75 (3H, m), 3.86-4.03 (1H, m), 4.35-4.46 (2H, m), 5.28 (1H, dt, J = 56.6, 4.6 Hz), 6.00 (1H, br d, J = 8.8 Hz), 6.83 (1H, d, J = 7.2 Hz), 6.90-7.17 (3H, m), 7.54 (1H, d, J = 7.0 Hz), 7.74 (1H, d, J = 8.4 Hz). Example 19

[00568] 1-Fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8 -(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00569] A) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-[(3chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate

[00570] To a stirred mixture of tert-butyl (2S,3R)-3-amino-2-[(3chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (54.2 g) and sodium bicarbonate (26.2 g) in THF (550 mL) and water (275 mL) was added benzyl chloroformate (23.3 mL) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated and dried over anhydride magnesium sulfate. The organic layer was passed through an NH silica gel pad, eluted with EtOAc, and concentrated under reduced pressure to give the titrant compound (81.5 g). The product was subjected to the next reaction without further purification.

[00571] MS: [MH]-496.9

[00572] B) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate

[00573] To a degassed mixture of tert-butyl (2S,3R)-3{[(benzyloxy)carbonyl]amino}-2-[(3-chloro-2-fluorophenyl)methyl]-4,4difluoropyrrolidine-1-carboxylate (3.76 g), bis(pinacolato)diboron (2.87 g) and Petition 870250083065, dated 09 / 15 / 2025, pp. 166 / 258 134 / 211 potassium acetate (1.48 g) in toluene (37.7 mL) was added XPhos Pd G3 (0.319 g). The mixture was stirred at 100 °C for 5 hours under an argon atmosphere. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.17 g).

[00574] MS: [MH]-589.2

[00575] C) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-4,4difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate

[00576] To a solution of tert-butyl (2S,3R)-3{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (3.17 g) in THF (26.8 mL) and water (26.8 mL) was added sodium salt of perboric acid tetrahydrate (1.65 g) at 0 °C. The mixture was stirred at room temperature for 3 hours. The mixture was acidified (pH = 3~4) with 1 M hydrochloric acid at 0 °C and extracted with EtOAc. The organic layer was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (2.47 g).

[00577] MS: [MH]-479.1

[00578] D) tert-Butyl (2S,3R)-3-amino-4,4-difluoro-2-[(2-fluoro-3hydroxyphenyl)methyl]pyrrolidine-1-carboxylate

[00579] A mixture of tert-butyl (2S,3R)-3{[(benzyloxy)carbonyl]amino}-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (2.47 g) and 10% palladium on carbon (moistened with 55% water, 0.243 g) in EtOH (25.7 mL) was hydrogenated under pressure in a flask at room temperature for 14 hours. The catalyst was removed by filtration and washed with EtOH and THF. The filtrate was concentrated under reduced pressure to give the titrant compound (1.77 g).

[00580] MS: [MH]-345.0 Petition 870250083065, dated 09 / 15 / 2025, pp. 167 / 258 135 / 211

[00581] E) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine1-carboxylate

[00582] A mixture of tert-butyl (2S,3R)-3-amino-4,4-difluoro-2-[(2fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (1.77 g), 6-chloro-5-methylpicolinonitrile (0.819 g), and cesium carbonate (3.33 g) in dry DMF (17.0 mL) was stirred at 120 °C under an argon atmosphere for 1 hour. After cooling to 0 °C, potassium carbonate (0.706 g) and benzyl chloroformate (1.08 mL) were added to the mixture. The reaction mixture was heated to room temperature and stirred for 2 hours. The mixture was diluted with EtOAc and water, and the solution was extracted with EtOAc. The extract was washed with brine. The solution was passed through NH silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the titrant compound (2.88 g).

[00583] MS: [MH]-595.1

[00584] F) tert-Butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]-2fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate

[00585] Sodium borohydride (1.63 g) was slowly added to a solution of tert-butyl (2S,3R)-3-{[(benzyloxy)carbonyl]amino}-2-({3-[(6cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate (5.13 g) and cobalt(II) chloride (2.23 g) in MeOH (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Di-t-butyl dicarbonate (2.99 mL) was added to the reaction mixture at 0 °C and stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction mixture at room temperature and the solid was removed by filtration. The filtrate was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under... Petition 870250083065, dated 09 / 15 / 2025, pp. 168 / 258 136 / 211 reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (3.46 g).

[00586] MS: [MH]-699.1

[00587] G) Benzyl {(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}carbamate

[00588] TFA (9.0 mL) was added to tert-butyl (2S,3R)-3{[(benzyloxy)carbonyl]amino}-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidine-1-carboxylate (4.51 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. It was concentrated under reduced pressure. The residue was purified by silica gel NH (MeOH / EtOAc) column chromatography to give the title compound (3.00 mg).

[00589] MS: [M+H]+501.1

[00590] H) Benzyl [(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]carbamate

[00591] A solution of benzyl {(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3yl}carbamate (2.51 g) in DMF(dry) (81 mL) was added to a solution of di(N-succinimidyl) carbonate (1.41 g) and N-methylmorpholine (1.10 mL) in THF(dry) (2430 mL) at room temperature for 40 minutes. After stirring for 1 hour at room temperature, DIPEA (8.57 mL) was added to the reaction mixture. It was stirred at room temperature for 1.5 hours and then at 70 °C for 2 hours. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with EtOAc. The organic layer was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (2.08 g).

[00592] MS: [M+H]+527.2 Petition 870250083065, dated 09 / 15 / 2025, pp. 169 / 258 137 / 211

[00593] I) (15aS,16R)-16-Amino-17,17,20-trifluoro-7-methyl2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-1-one

[00594] A mixture of benzyl [(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14(metheno)pyrrolo[1,2-j][1,8,10]oxadiazcycloheptadecin-16-yl]carbamate (8.22 g) and 20% palladium hydroxide on activated charcoal (400 mg) in MeOH (80 mL) was hydrogenated under pressure in a balloon at room temperature for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to yield the title compound (5.38 g).

[00595] MS: [M+H]+393.1

[00596] J) 1-Fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8 -(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00597] A solution of fluoromethanesulfonyl chloride (0.790 g) in THF (dry) (10 mL) was added to a solution of (15aS,16R)-16amino-17,17,20-trifluoro-7-methyl-2,3,15a,16,17,18-hexahydro-1H,15H-4,8(azeno)-10,14-(metheno)pyrrolo[1,2-j][1,8,10]oxadiazcycloheptadecin-1-one (2.00 g) in pyridine (10 mL) at 5 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) and silica gel column chromatography (EtOAc / hexane) followed by EtOAc-heptane recrystallization to generate the titrant compound (1.76 g).

[00598] 1H NMR (400 MHz, DMSO-d6) δ 2.30 (3H, s), 2.62-2.69 (1H, m), 2.79-2.88 (1H, m), 3.56-3.64 (1H, m), 3.71-3.88 (2H, m), 4.29-4.46 (2H, m), 4.50-4.58 (1H, m), 5.41-5.66 (2H, m), 6.14-6.19 (1H, m), 6.85 (1H, d, J = 7.2 Hz), 6.97-7.12 (3H, m), 7.53-7.56 (1H, m), 8.79-8.94 (1H, m). Example 22 Petition 870250083065, dated 09 / 15 / 2025, pp. 170 / 258 138 / 211

[00599] N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[00600] A) tert-Butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate

[00601] To a stirred solution of tert-butyl (2S,3R)-3-amino-2-[(3chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (6.2 g) in pyridine (50 mL) cyclopropanesulfonyl chloride (3.64 mL) was added dropwise while cooling in an ice bath. The mixture was stirred at 50 °C for 3 hours. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (7.00 g).

[00602] MS: [MH]-467.9

[00603] B) tert-Butyl (2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate

[00604] A mixture of tert-butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (5000 mg), potassium hydroxide (1795 mg), Pd2dba3 (488 mg), tBuXPhos (906 mg), DME (6 mL) and water (2 mL) was heated to 120 °C for 1 hour under microwave irradiation. The mixture was acidified with aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3600 mg).

[00605] MS: [MH]-449.0

[00606] C) tert-Butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridin-2 Petition 870250083065, dated 09 / 15 / 2025, pp. 171 / 258 139 / 211 yl)oxy]phenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine1-carboxylate

[00607] To a solution of tert-butyl (2S,3R)-3[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (3000 mg) and cesium carbonate (4520 mg) in dry DMF (50 mL) was added 5-chloro-6-fluoropicolinonitrile (1194 mg) at room temperature. The mixture was stirred at 90 °C for 1 hour. The mixture was diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3860 mg).

[00608] MS: [M+CH3CN]+609.0

[00609] D) tert-Butyl (2S,3R)-2-({3-[(6-{[(tertbutoxycarbonyl)amino]methyl}-3-chloropyridin-2-yl)oxy]-2-fluorophenyl} methyl)-3 [(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate

[00610] Sodium borohydride (382 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(3-chloro-6-cyanopyridin-2-yl)oxy]phenyl}methyl)-3[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (2960 mg) and cobalt(II) chloride (1309 mg) in MeOH (60 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. Then, di-t-butyl dicarbonate (1.756 mL) was added to the reaction mixture at room temperature and stirred at room temperature for 1 hour. The solvent was removed by concentration and EtOAc, and an aqueous solution of sodium hydrogen carbonate was added to the residue. The insoluble solid was removed by celite, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (2700 mg). Petition 870250083065, dated 09 / 15 / 2025, pp. 172 / 258 140 / 211

[00611] MS: [M+Na]+713.1

[00612] E) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-chloropyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3yl}cyclopropanesulfonamide dihydrochloride

[00613] To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (2730 mg) in MeOH (30 mL) was added 4 M hydrogen chloride in EtOAc (19.75 mL) at 0 °C. After 30 minutes of stirring at 0 °C, the mixture was allowed to warm to room temperature and stirred overnight. After approximate concentration under reduced pressure, EtOAc was added and the precipitate was collected to yield the titrant compound (2120 mg).

[00614] MS: [M+H]+491.0

[00615] F) N-[(15aS,16R)-7-Chloro-17,17,20-trifluoro-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[00616] To a solution of di(N-succinimidyl) carbonate (963 mg) and DIPEA (3.94 mL) in dry THF (2000 mL) was added N{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloropyridin-2-yl]oxy}-2-fluorophenyl)methyl]4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide dihydrochloride (2120 mg) in dry DMF (30 mL) dropwise over 5 minutes at room temperature. After concentration under reduced pressure, the mixture was quenched with aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was separated, washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) followed by EtOAc-heptane recrystallization to generate the titrant compound (960 mg).

[00617] 1H NMR (300 MHz, DMSO-d6) δ 0.98-1.10 (4H, m), 2.65 Petition 870250083065, dated 09 / 15 / 2025, pp. 173 / 258 141 / 211 2.95 (3H, m), 3.60-3.92 (3H, m), 4.23-4.49 (2H, m), 4.49-4.62 (1H, m), 6.26 (1H, br d, J = 9.0 Hz), 6.99-7.13 (3H, m), 7.15-7.25 (1H, m), 7.90 (1H, d, J = 7.9 Hz), 8.22 (1H, br d, J = 9.0 Hz). Example 33

[00618] N-[(15aS,16S)-7-Metil-1-oxo-1,2,15a,16,17,18-hexahidro15H-4,8-(azeno)-10,14-(meteno)pirrolo[1,2-d][1,12,4]dioxazacicloheptadecin-16-il]metanossulfonamida

[00619] A) terc-Butil (2S,3S)-2-({3-[(6-chloro-3-metüpiridm-2il)oxi]fenil}metil)-3-[(metanossulfonil){[2(trimetilsilil)etoxi]metil}amino]pirrolidina-1-carboxilato

[00620] To a solution of tert-butyl (2S,3S)-2-({3-[(6-chloro-3-methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1.00 g) in THF (10 mL) was added 60% sodium hydride (97 mg) at 0 °C. The mixture was stirred at 0 °C for 0.1 hours, [2-(chloromethoxy)ethyl](trimethyl)silane (403 mg) was added dropwise to the mixture. The mixture was stirred at 20 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the title compound (0.98 g).

[00621] 1H NMR (400 MHz, DMSO-d6) δ -0.02 (9H, s), 0.80-0.88 (2H, m), 1.02-1.15 (9H, m), 1.20-1.25 (2H, m), 2.05-2.34 (5H, m), 2.75-2.94 (1H, m), 3.06 (3H, s), 3.36-3.58 (3H, m), 4.02-4.26 (2H, m), 4.40-4.82 (2H, m), 6.78-7.20 (4H, m), 7.24-7.36 (1H, m), 7.68-7.90 (1H, m).

[00622] B) tert-Butyl (2S,3S)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3methylpyridin-2-yl]oxy}phenyl)methyl]-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate

[00623] A mixture of tert-butyl (2S,3S)-2-({3-[(6-chloro-3 Petition 870250083065, dated 09 / 15 / 2025, pp. 174 / 258 142 / 211 methylpyridin-2-yl)oxy]phenyl}methyl)-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (500 mg), tert-butyl hydroxyacetate (211 mg), 2-(di-t-butylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-propyl-1,1'-biphenyl (19 mg), cesium carbonate (520 mg) and di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane; methanesulfonic acid; palladium; 2-phenylaniline (34 mg) in DME (5 mL) was heated under a nitrogen atmosphere and microwave irradiation at 100 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the title compound (260 mg).

[00624] MS: [M+H]+722.3

[00625] C) N-[(15aS,16S)-7-Methyl-1-oxo-1,2,15a,16,17,18-hexahydro15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2-d][1,12,4]dioxazacycloheptadecin-16-yl]methanesulfonamide

[00626] A solution of the compound tert-butyl (2S,3S)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3-methylpyridin-2-yl]oxy}phenyl)methyl]-3[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (210 mg) in 4 M hydrogen chloride in dioxane (4.20 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. A mixture of the residue thus obtained (130 mg), PyBOP (215 mg), TEA (139 mg) in THF (300 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) followed by SFC purification (column: DAICEL CHIRALPAK AD, mobile phase: C(C EtOH (containing 0.1% ammonium hydroxide)) to generate the titrant compound (3.9 mg).

[00627] 1H NMR (400 MHz, DMSO-d6) δ 1.65-1.81 (1H, m), 1.99Petição 870250083065, on 09 / 15 / 2025, pág. 175 / 258 143 / 211 2.06 (1H, m), 2.19 (3H, s), 2.81-2.87 (1H, m), 3.01 (3H, s), 3.06-3.12 (1H, m), 3.16-3.18 (2H, m), 3.79-3.87 (1H, m), 4.24-4.46 (2H, m), 4.05-4.68 (1H, m), 6.55 (1H, d, J = 8.0 Hz), 6.87 (1H, s), 6.94-6.97 (1H, m), 7.18-7.30 (2H, m), 7.63 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 5.6 Hz). Example 36

[00628] N-[(15aS,16R)-5,17,17,20-Tetrafluoro-7-metil-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-( azeno)-14,10-(meteno)pirrolo[1,2j][1,8,10]oxadiazacicloheptadecin-16-il]metanossulfonamida

[00629] A) terc-Butil (2S,3R)-2-({3-[(6-amino-3-bromo-5fluoropiridin-2-il)oxy]-2-fluorofenil}metil)-4,4-difluoro-3[(metanossulfonil)amino]pirrolidina-1-carboxilato

[00630] Cesium carbonate (1535 mg) was added to a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1000 mg) and 5-bromo-3,6-difluoropyridin-2-amine (739 mg) in MPN (7854 pl) at room temperature. The mixture was stirred at 150 °C for 5.5 hours under microwave irradiation. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (792 mg).

[00631] MS: [M+Na]+635.0

[00632] B) tert-Butyl (2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridin2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00633] To a solution of tert-butyl (2S,3R)-2-({3-[(6-amino-3-bromo-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (791 mg) and trimethylboroxine (0.541 ml) in DME (5 ml) was added carbonate Petition 870250083065, dated 09 / 15 / 2025, pp. 176 / 258 144 / 211 potassium (446 mg) at room temperature. The mixture was stirred at room temperature for 10 minutes. PdCl2(dppf) (94 mg) was added at room temperature. The mixture was heated to 90 °C overnight. The mixture was filtered. The filtrate was diluted with EtOAc and poured into water at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (640 mg).

[00634] MS: [M+H]+ 549.1.

[00635] C) tert-Butyl (2S,3R)-2-({3-[(6-bromo-5-fluoro-3-methylpyridin2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00636] tert-Butylnitrite (196 pl) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-amino-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (639 mg) and copper[I] bromide (234 mg) in acetonitrile (5824 pl) at room temperature. The mixture was stirred at 60 °C for 1.5 hours. EtOAc and water were added to the mixture. The precipitate was removed with celite. The organic layer of the filtrate was separated, washed with aqueous sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (363 mg).

[00637] MS: [MH]-611.0

[00638] D) tert-Butyl (2S,3R)-2-({3-[(6-{[(tertbutoxycarbonyl)amino]methyl}-5-fluoro-3-methylpyridin-2-yl)oxy]-2fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1carboxylate

[00639] A mixture of tert-butyl (2S,3R)-2-({3-[(6-bromo-5-fluoroPetition 870250083065, dated 15 / 09 / 2025, p. 177 / 258 145 / 211 3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (363 mg), potassium [[(tert-Butoxycarbonyl)amino]methyl]trifluoroborate (281 mg), Pd(OAc)2 (13.31 mg), potassium carbonate (164 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (48.7 mg) in toluene (2470 pl) and water (494 pl) was stirred at 85 °C overnight under an argon atmosphere. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (362 mg).

[00640] MS: [M+Na]+685.2

[00641] E) N-[(15aS,16R)-5,17,17,20-Tetrafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-( azene)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00642] TFA (1 ml) was added to tert-butyl (2S,3R)-2-({3-[(6{[(tert-butoxycarbonyl)amino]methyl}-5-fluoro-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (362 mg) at room temperature. The mixture was stirred at room temperature for 30 minutes. After evaporation of the solvent with toluene, the residue was purified by silica gel NH (MeOH / EtOAc) column chromatography. A solution of the residue thus obtained in dry DMF (5 mL) was added dropwise to a mixture of di(N-succinimidyl) carbonate (155 mg) and 4-methylmorpholine (0.363 mL) in dry THF (180 mL) at room temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes. Then, DIPEA (0.961 mL) was added. The mixture was stirred at 60 °C under air for 30 minutes. The mixture was evaporated. The residue was diluted with EtOAc, poured into water at room temperature, and extracted with EtOAc.The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. Petition 870250083065, dated 09 / 15 / 2025, pages 178 / 258 146 / 211 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was solidified with EtOAc-hexane to give the title compound (102 mg).

[00643] 1H NMR (300 MHz, DMSO-d6) δ 2.32 (3H, s), 2.65 (1H, br d, J = 13.2 Hz), 2.73-2.90 (1H, m), 3.11 (3H, s), 3.60-3.95 (3H, m), 4.19-4.47 (2H, m), 4.50-4.62 (1H, m), 6.20 (1H, br d, J = 9.0 Hz), 6.94-7.24 (3H, m), 7.58 (1H, dd, J = 9.4, 0.8 Hz), 8.18 (1H, d, J = 9.4 Hz). Example 40

[00644] N-[(15aS,16S)-2,7-Dimethyl-1-oxo-2,3,15a,16,17,18-hexahydro1H,15H-4,8-(azene)-10,14-(methene)pyrrole [1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00645] A) N-[(4-methoxyphenyl)methyl]-N-[(15aS,16S)-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8- (azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00646] To a solution of N-[(15aS,16S)-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2j][1,8,10]oxadiazcycloheptadecin-16-yl]methanesulfonamide (460 mg) in DMF (5 mL) was added cesium carbonate (360 mg), sodium iodide (17 mg) and 4-methoxybenzyl chloride (208 mg), and was stirred at 80 °C under a nitrogen atmosphere for 15 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to give the title compound (463 mg).

[00647] MS: [M+H]+ 537.5

[00648] B) N-[(15aS,16S)-2,7-Dimethyl-1-oxo-2,3,15a,16,17,18hexahidro-1H,15H-4,8-(azeno)-10,14-(meteno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]-N-[(4methoxyphenyl)methyl]methanesulfonamide Petition 870250083065, 15 / 09 / 2025, pág. 179 / 258 147 / 211

[00649] To a mixture of N-[(4-methoxyphenyl)methyl]-N-[(15aS,16S)-7methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14(metheno)pyrrolo[1,2-j][1,8,10]oxadiazcycloheptadecin-16yl]methanesulfonamide (463 mg) in DMF (5 mL) was added 60% sodium hydride (104 mg) at 0 °C, and the mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes. Then, iodomethane (367 mg) was added to the mixture and it was stirred at 60 °C for 13 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc) to give the title compound (302 mg).

[00650] MS: [M+H]+ 551.1

[00651] C) N-[(15aS,16S)-2,7-Dimethyl-1-oxo-2,3,15a,16,17,18hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide

[00652] To a mixture of N-[(15aS,16S)-2,7-dimethyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2j][1,8,10]oxadiazcycloheptadecin-16-yl]-N-[(4-methoxyphenyl)methyl]methanesulfonamide (272 mg) in CH2Cl2 (3 mL) was added methanesulfonic acid (285 mg) at 25 °C and then stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: 0.05% aqueous ammonium hydroxide solution / acetonitrile), and most of the acetonitrile was removed under reduced pressure and the remaining solvent was removed by lyophilization to generate the titrant compound (136.2 mg).

[00653] 1H NMR (400 MHz, DMSO-d6) δ 1.90-2.01 (1H, m), 2.152.25 (1H, m), 2.78 (3H, s), 2.41 (3H, s), 2.55-2.65 (1H, m), 2.85-2.95 (1H, m), 2.99 (3H, s), 3.05-3.16 (1H, m), 3.35-3.45 (1H, m), 3.70-3.85 (1H, m), Petition 870250083065, dated 09 / 15 / 2025, pp. 180 / 258 148 / 211 3.90–4.00 (1H, m), 4.45–4.55 (1H, m), 4.65–4.75 (1H, m), 6.80–6.90 (2H, m), 6.97 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.24 (1H, t, J = 8.0 Hz), 7.47 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 7.6 Hz). Example 51

[00654] N-[(15aS,16R)-17,17,20-Trifluoro-3,7-dimethyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-( azeno)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazecycloheptadecin-16-yl]methanesulfonamide (optical isomer)

[00655] A)tert-Butyl (2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00656] To a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (328 mg) in THF (4 mL) was added 1 M methylmagnesium bromide in THF (6.07 mL) dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. Then, 1 M methylmagnesium bromide in THF (6.07 mL) was added and the mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0 °C and MeOH (10 mL) was added dropwise. Then, sodium borohydride (68.9 mg) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous ammonium chloride 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 NH (EtOAc / hexane and MeOH / EtOAc) to give the title compound (238 mg).

[00657] MS: [M+H]+ 559.2

[00658] B) N-{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide

[00659] TFA (2 mL) was added to tert-butyl (2S,3R)-2-[(3-{[6-(1 Petition 870250083065, dated 09 / 15 / 2025, pp. 181 / 258 149 / 211 aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (238 mg) in a flask at room temperature. The mixture was stirred at room temperature for 1 hour. After evaporation of the solvent with toluene, the residue was purified by silica gel NH (MeOH / EtOAc) column chromatography to yield the titrant compound (175 mg).

[00660] MS: [M+H]+ 459.2

[00661] C) N-[(15aS,16R)-17,17,20-Trifluoro-3,7-dimethyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide (optical isomer)

[00662] A solution of di(N-succinimidyl) carbonate (100 mg), DIPEA (0.400 mL) and THF (300 mL) was added N{(2S,3R)-2-[(3-{[6-(1-aminoethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide (175 mg) in DMF (10 mL) at room temperature for 30 minutes. The mixture was stirred at room temperature for 1 hour and at 60 °C overnight. The mixture was evaporated. The residue was diluted with EtOAc, poured into water at room temperature, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give two fractions.The less polar fraction was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to generate the titrant compound (14.3 mg) from the less polar fraction. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (3H, br s), 2.29 (3H, s), 2.71-2.93 (2H, m), 3.16 (3H, s), 3.40-3.69 (1H, m), 3.98-4.37 (2H, m), 4.43-4.74 (2H, m),

[00663] 5.57-5.78 (1H, m), 6.88 (1H, d, J = 7.3 Hz), 7.07-7.26 (3H, m), 7.56 (1H, dd, J = 7.4, 0.8 Hz), 8.29 (1H, br d, J = 8.4 Hz). Example 54 Petition 870250083065, dated 09 / 15 / 2025, pp. 182 / 258 150 / 211

[00664] N-[(16aS,17R)-18,18,21-Trifluoro-7-methyl-1-oxo2,3,16a,17,18,19-hexahydro-1H,9H, 16H-4,8-(azene)-11,15(methene)pyrrolo[2,1-h][1,9,11]oxadiazacyclooctadecin-17yl]methanesulfonamide

[00665] A) tert-Butyl (2S,3R)-2-({3-[(6-chloro-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00666] To a mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (444 mg), cesium carbonate (1.1 g) and DMF (8 mL) was added a solution of 6-chloro-2-(chloromethyl)-3-methylpyridine (222 mg) in DMF (1 mL) at room temperature, and the mixture was stirred at 50 °C for 2 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the titrant compound (494 mg).

[00667] MS: [M+H]+ 564.2

[00668] B) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00669] To a mixture of tert-butyl (2S,3R)-2-({3-[(6-chloro-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (184.4 mg), zinc cyanide (122.2 mg) and DMF (3 mL) was added Pd(Ph3P)4 (38 mg) at room temperature, and the mixture was stirred at 120 °C for 2 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (184 mg). Petition 870250083065, dated 09 / 15 / 2025, pp. 183 / 258 151 / 211

[00670] MS: [M+H-(tBu)]+449.1

[00671] C) tert-Butyl (2S,3R)-2-({3-[(6-{[(tertbutoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00672] To a mixture of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (181 mg), cobalt(II) chloride (49.8 mg) and MeOH (3 mL) was added sodium borohydride (42.8 mg) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Boc2O (0.2 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel NH (EtOAc / hexane) column chromatography to yield the title compound (184 mg).

[00673] MS: [M+H]+659.3

[00674] D) N-[(16aS,17R)-18,18,21-Trifluoro-7-methyl-1-oxo2,3,16a,17,18,19-hexahydro-1H,9H, 16H-4,8-(azene)-11,15(methene)pyrrolo[2,1-h][1,9,11]oxadiazacyclooctadecin-17yl]methanesulfonamide

[00675] To a solution of tert-butyl (2S,3R)-2-({3-[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)methoxy]-2-fluorophenyl}methyl)4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (58.5 mg) in MeOH (1 mL) was added 4 M hydrogen chloride in CPME (0.2 mL) at room temperature, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. A solution of the residue in DMF (2 mL) was added to a mixture of di(N-succinimidyl) carbonate (27.9 mg), N-methylmorpholine (80 IU / L) and THF (30 mL) at room temperature, and the mixture was stirred at room temperature for 3 Petition 870250083065, dated 09 / 15 / 2025, pp. 184 / 258 152 / 211 hours. DIPEA (157 l / L) was added and the mixture was stirred at room temperature for 3 hours, then at 60 °C overnight. The mixture was suppressed with aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution). Then, the desired fractions were concentrated, crystallized from hexane-EtOAc, and collected by filtration to provide the titrant compound (6.2 mg).

[00676] 1H NMR (300 MHz, DMSO-d6) δ 2.15-2.46 (6H, m), 2.753.03 (1H, m), 3.09 (3H, s), 3.70-4.64 (5H, m), 5.11-5.75 (2H, m), 6.37-6.85 (3H, m), 6.86-7.13 (1H, m), 7.37-7.58 (1H, m), 8.04-8.38 (1H, m). Example 56

[00677] N-[(15aS,16R,17S)-17,20-Difluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,9H, 15H-8,4-(azene)-10,14(methene)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[00678] A) Benzyl (2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl] methyl}pyrrolidine-1-carboxylate

[00679] XPhos Pd G3 (0.179 g) was added to a mixture of benzyl (2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (2.0 g), bis(pinacolate)diboron (3.22 g), and potassium acetate (0.830 g) in toluene (20 mL) at room temperature under an argon atmosphere. The mixture was stirred at 100 °C under an argon atmosphere for 2 hours. The insoluble material was 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 (2.204 g).

[00680] MS: [M+H]+565.2 Petition 870250083065, dated 09 / 15 / 2025, pages 185 / 258 153 / 211

[00681] B) Benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2yl)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1carboxylate

[00682] Pd(dppf)Cl2OH2Cl2 (141 mg) was added to a mixture of benzyl (2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-{[2-fluoro-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pyrrolidine-1-carboxylate (972 mg), 6-(chloromethyl)-5-methylpicolinonitrile (287 mg) and 2 M aqueous sodium carbonate solution (2.58 mL) in DME (9 mL) and stirred under microwave irradiation at 120 °C for 1 hour. EtOAc and water were added to the reaction mixture at room temperature, then the insoluble material was removed by filtration. The organic layer of the filtrate was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (713 mg).

[00683] MS: [M+H]+ 569.2

[00684] C) Benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1carboxylate

[00685] Sodium borohydride (118 mg) was added to a mixture of benzyl (2S,3R,4S)-2-({3-[(6-cyano-3-methylpyridin-2-yl)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (356 mg) and cobalt(II) chloride (163 mg) in MeOH (3 mL) at 0 °C under an argon atmosphere. The mixture was stirred at 0 °C under an argon atmosphere for 5 hours. EtOAc and water were added to the reaction mixture at room temperature, then the insoluble material was removed by filtration. The organic layer of the filtrate was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, and dried over Petition 870250083065, dated 09 / 15 / 2025, pages 186 / 258 154 / 211 anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / EtOAc) to give the title compound (128 mg).

[00686] MS: [M+H]+ 573.2

[00687] D) N-{(2S,3R,4S)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide

[00688] A mixture of benzyl (2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate (128 mg) and 10% palladium on carbon (moistened with 55% water, 23.79 mg) in MeOH (2 mL) was hydrogenated under pressure in a balloon at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to generate the title compound (90 mg).

[00689] MS: [M+H]+439.1

[00690] E) N-[(15aS,16R,17S)-17,20-Difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,9H,15H-8,4-(azeno)-10,14(metheno)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[00691] A solution of N-{(2S,3R,4S)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3yl}ethanesulfonamide (90 mg) in THF (8 mL) was added to a mixture of di(N-succinimidyl) carbonate (52.6 mg) and 4-methylmorpholine (0.027 mL) in THF (42 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. DIPEA (0.108 mL) was added to the reaction mixture at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc and water were added to the residue at room temperature, and then the organic layer was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by column chromatography. Petition 870250083065, dated 09 / 15 / 2025, pp. 187 / 258 155 / 211 silica gel NH (MeOH / EtOAc). The solid was crystallized from EtOAchexane to give the title compound (3.70 mg).

[00692] 1H NMR (400 MHz, CDCh) δ 1.41-1.52 (3H, m), 2.32-2.43 (3H, m), 2.59-2.79 (1H, m), 3.07-3.25 (2H, m), 3.36-3.77 (2H, m), 3.84-4.25 (4H, m), 4.26-4.71 (3H, m), 4.96 (1H, br d, J = 9.4 Hz), 5.08-5.32 (1H, m), 6.37 (1H, br s), 6.78-6.92 (1H, m), 6.93-7.22 (3H, m), 7.29-7.44 (1H, m). Example 58

[00693] N-[(15aS,16R)-7-Chloro-5,17,17,20-tetrafluoro-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(aze no)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[00694] A) tert-Butyl (2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridin2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4difluoropyrrolidine-1-carboxylate

[00695] Cesium carbonate (17.07 g) was added to a solution of tert-butyl (2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (11.80 g) and 5-chloro-3,6-difluoropyridin-2-amine (7.76 g) in MPN (131 mL) at room temperature. The mixture was stirred at 150 °C for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc, and passed through a celite pad. The celite pad was washed with EtOAc. The filtrate was poured into water and brine. The mixture was filtered through a celite pad. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (12.67 g).

[00696] MS: [M+H]+ 595.1

[00697] B) tert-Butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-Petition 870250083065, dated 09 / 15 / 2025, page 188 / 258 156 / 211 difluoropyrrolidine-1-carboxylate

[00698] tert-Butylnitrite (3.57 mL) was added to a mixture of tert-butyl (2S,3R)-2-({3-[(6-amino-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (12.67 g) and copper[I] bromide (4.28 g) in acetonitrile (130 mL) at room temperature. The mixture was stirred at 60 °C for 1 hour. The mixture was cooled to room temperature. EtOAc and water were added to the mixture. The precipitate was removed using a celite pad. The filtrate was poured into an aqueous solution of EtOAc and sodium thiosulfate at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was suspended in IPE (16 mL) and the mixture was stirred at room temperature overnight.The precipitated solid was collected by filtration, washed with IPE, and dried under reduced pressure to generate the titrant compound (8.07 g).

[00699] MS: [MH]-658.0

[00700] C) tert-Butyl (2S,3R)-2-({3-[(6-{[(tertbutoxycarbonyl)amino]methyl}-3-chloro-5-fluoropyridin-2-yl)oxy]-2fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1carboxylate

[00701] A mixture of tert-butyl (2S,3R)-2-({3-[(6-bromo-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]4,4-difluoropyrrolidine-1-carboxylate (8.07 g), potassium [[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (3.48 g) and potassium carbonate (3.39 g) in toluene (81 mL) and water (16 mL) was degassed with nitrogen for 10 minutes. 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (2.011 g) and Pd(OAc)2 (0.550 g) were added at room temperature. The mixture was stirred at 85 °C under a nitrogen atmosphere for 4.5 hours. Water and Petition 870250083065, dated 09 / 15 / 2025, pp. 189 / 258 157 / 211 EtOAc was added at room temperature and the mixture was filtered with a celite pad. The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (2.92 g).

[00702] MS: [MH]-707.2

[00703] D) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-chloro-5fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3yl}cyclopropanesulfonamide

[00704] TFA (20 mL) was added to tert-butyl (2S,3R)-2-({3-[(6{[(tert-butoxycarbonyl)amino]methyl}-3-chloro-5-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (3.813 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was evaporated. The residue was purified by silica gel NH (EtOAc / hexane) column chromatography to obtain the title compound (2.351 g).

[00705] MS: [M+H]+ 509.0

[00706] E) N-[(15aS,16R)-7-Chloro-5,17,17,20-tetrafluoro-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(aze no)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide

[00707] To a mixture of di(N-succinimidyl) carbonate (0.637 g) and DIPEA (3.16 mL) in dry THF (900 mL) was added a solution of N{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5-fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}cyclopropanesulfonamide (1.15 g) in dry DMF (30 mL) at room temperature for 30 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to give residue A.

[00708] Similar to the synthesis of residue A, residue B was obtained using di(N-succinimidyl) carbonate (0.637 g), DIPEA (3.16 mL), Petition 870250083065, dated 09 / 15 / 2025, pp. 190 / 258 158 / 211 THF (dry) (900 mL), N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-chloro-5fluoropyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3yl}cyclopropanesulfonamide (1.15 g) and DMF (dry) (30 mL).

[00709] Residues A and B were combined and diluted with EtOAc and poured into water at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) followed by EtOAc-hexane recrystallization to generate the titrant compound (1.11 g).

[00710] 1H NMR (400 MHz, CDCl3) δ 1.02-1.38 (4H, m), 2.52-2.63 (1H, m), 2.75-2.86 (1H, m), 2.91-3.02 (1H, m), 3.77-3.98 (2H, m), 3.99-4.24 4.26-4.44 d, J = 7.7 Hz). Example 59

[00711] N-[(16aS,17R,21aS)-18,18,22-Trifluoro-8-methyl-21-oxo2,3,16a,17,18,19,21,21a-octahydro-1H,16H-5,9-(az ene)-11,15(methene)dipyrrolo[1,2-g:1',2'-j][1,5,7,10]oxatriazcycloheptadecyn-17yl]methanesulfonamide

[00712] A) tert-Butyl (2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00713] 2,4-dichloro-5-methylpyrimidine (75 pL) was added to a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (250 mg) and potassium carbonate (200 mg) in dry DMF (3.0 mL) at room temperature. The mixture was stirred at room temperature under an argon atmosphere overnight and then poured into ice water and extracted with EtOAc. The organic layer was separated, washed with brine, and dried over magnesium sulfate. Petition 870250083065, dated 09 / 15 / 2025, pp. 191 / 258 159 / 211 anhydrous and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (246 mg).

[00714] MS: [M+H]+ 551.2

[00715] B) N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride

[00716] 4 M hydrogen chloride in EtOAc (1.0 mL) was added to a solution of tert-butyl (2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (122 mg) in THF (1.0 mL) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours and then concentrated to give the titrant compound (108 mg)

[00717] MS: [M+H]+451.1

[00718] C) tert-Butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carbonyl}pyrrolidine-1-carboxylate

[00719] HATU (110 mg) was added to a solution of N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (108 mg), (tert-butoxycarbonyl)-L-proline (56 mg) and DIPEA (120 pL) in THF(dry) (1.0 mL) and DMF (dry) (1.0 mL) at room temperature. The mixture was stirred at room temperature under an argon atmosphere overnight. HATU (40 mg), DIPEA (60 µL) and (tert-butoxycarbonyl)-L-proline (25 mg) were added and stirring continued for 5 hours. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with aqueous sodium bicarbonate and brine solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc / hexane) to generate the... Petition 870250083065, dated 09 / 15 / 2025, pp. 192 / 258 160 / 211 compound of the title (116 mg).

[00720] MS: [M-Boc+H]+ 548.2

[00721] D) N-[(2S,3R)-2-({3-[(2-Chloro-5-methylpyrimidin-4-yl)oxy]-2fluorophenyl}methyl)-4,4-difluoro-1-L-prolylpyrrolidin-3-yl]methanesulfonamide hydrochloride

[00722] 4 M hydrogen chloride in EtOAc (1.0 mL) was added to a solution of tert-butyl (2S)-2-{(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carbonyl}pyrrolidine-1-carboxylate (115 mg) in THF (1.0 mL) at room temperature. The mixture was stirred at room temperature under an argon atmosphere for 2 hours and then concentrated to give the titrant compound (104 mg).

[00723] MS: [M+H]+548.3

[00724] E) N-[(16aS,17R,21aS)-18,18,22-Trifluoro-8-methyl-21-oxo2,3,16a,17,18,19,21,21a-octahydro-1H,16H-5,9-(a zeno)-11,15(methene)dipyrrolo[1,2-g:1',2'-j][1,5,7,10]oxatriazcycloheptadecin-17yl]methanesulfonamide

[00725] DIPEA (150 pL) was added to a solution of N-[(2S,3R)-2-({3-[(2-chloro-5-methylpyrimidin-4-yl)oxy]-2-fluorophenyl}methyl)4,4-difluoro-1-L-prolylpyrrolidin-3-yl]methanesulfonamide hydrochloride (104 mg) in dry DMF (2 mL) and acetonitrile (30 mL) at room temperature. The mixture was stirred at 80 °C under an argon atmosphere overnight and then concentrated. The residue was purified by preparative HPLC (column: YMCActus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to yield the titrant compound (33.6 mg).

[00726] 1H NMR (400 MHz, DMSO-d6) δ 1.71-1.96 (3H, m), 2.18 (3H, s), 2.24-2.34 (1H, m), 2.73 (1H, br d, J = 11.7 Hz), 2.87-2.99 (1H, m), 3.11 (3H, s), 3.34-3.53 (2H, m), 3.97-4.18 (3H, m), 4.44-4.64 (2H, m), 6,947.06 (2H, m), 7.21 (1H, t, J = 6.1 Hz), 8.15 (1H, s), 8.19-8.34 (1H, m). Petition 870250083065, 15 / 09 / 2025, pág. 193 / 258 161 / 211 Example 62

[00727] N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1 -oxo1,2,15a,16,17,18-hexahidro-15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2d][1,12,4]dioxazacycloheptadecin-16 -yl]methanesulfonamide

[00728] A) tert-Butyl (2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxi]2-fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate

[00729] To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (424 mg) in DMF (3 mL) was added 3-chloro-2,6-difluoropyridine (150 mg) and cesium carbonate (652 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere for 1 hour. The residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (381 mg).

[00730] MS: [MH]-552.0

[00731] B) N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride

[00732] A mixture of tert-butyl (2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (381.4 mg) in 4 M hydrogen chloride in CPME (10 mL) was stirred at room temperature under a dry atmosphere overnight. The mixture was concentrated to obtain the titrant compound (338 mg).

[00733] ​​MS: [MH]-452.9

[00734] C) 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2fluorophenyl}methyl)-4,4-difluoro-3-[(methanesulfonyl)amino]pyrrolidin-1-yl}-2oxoethyl acetate

[00735] A solution of N-[(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoropyrrolidin-3 hydrochloride Petition 870250083065, dated 09 / 15 / 2025, pp. 194 / 258 162 / 211 yl]methanesulfonamide (337.6 mg) in THF (7 mL) were added to TEA (0.288 mL) and acetoxyacetyl chloride (0.081 mL) at 0 °C. The mixture was stirred at 0 °C under a dry atmosphere for 2 hours. The reaction mixture was diluted with EtOAc and then poured into water. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (309 mg).

[00736] MS: [M+H]+ 554.1

[00737] D) N-[(15aS,16R)-7-Chloro-17,17,20-trifluoro-1-oxo1,2,15a,16,17,18-hexahydro-15H-4,8-(azene)-14,10-(methene)pyrrolo[1,2d][1,12,4]dioxazacycloheptadecin-16-yl]methanesulfonamide

[00738] To a solution of 2-{(2S,3R)-2-({3-[(3-chloro-6-fluoropyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3[(methanesulfonyl)amino]pyrrolidin-1-yl}-2-oxoethyl acetate (309 mg) in THF (20 mL) and EtOH (20 mL) was added 1 M aqueous sodium hydroxide solution (4 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and then poured into aqueous ammonium chloride solution. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) and by silica gel NH3 column chromatography (EtOAc / hexane) to obtain the title compound (251 mg).

[00739] 1H NMR (300 MHz, DMSO-d6) δ 2.65-2.99 (2H, m), 3,073.16 (3H, m), 3.57-3.76 (1H, m), 4.09-4.23 (1H, m), 4.26-4.55 (3H, m), 4,564.69 (1H, m), 6.61-6.73 (1H, m), 7.05-7.32 (3H, m), 7.86-8.00 (1H, m), 8.26 (1H, br s). Example 68

[00740] N-[(16aS,17S)-7-Metil-1-oxo-2,3,16a,17,18,19-hexahidroPetição 870250083065, de 15 / 09 / 2025, pág. 195 / 258 163 / 211 1H,10H, 16H-4,8-(azeno)-11,15-(metheno)pyrrole[1,2j][1,8,10]oxadiazacyclooctadecin-17-yl]methanesulfonamide

[00741] A) terc-Butyl (2S,3S)-2-[(3-bromophenyl)methyl]-3[(methanoxysulfonyl){[2-(trimethylsilyl)ethoxi]methyl}amino]pyrrolidine-1carboxylate

[00742] To a solution of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (2000 mg) in dry DMF (15 ml) was added 60% sodium hydride (240 mg) and the reaction mixture was stirred for 5 minutes at room temperature. Then, 2-(chloromethoxy)ethyl](trimethyl)silane (0.980 ml) was added to the mixture and the reaction mixture was stirred for 2 hours at room temperature. The mixture was quenched with aqueous ammonium chloride 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 purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (2470 mg).

[00743] MS: [M+Na]+ 587.0

[00744] B) tert-Butyl (2S,3S)-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino] -2-{[3(methoxycarbonyl)phenyl]methyl}pyrrolidine-1-carboxylate

[00745] To a solution of tert-butyl (2S,3S)-2-[(3-bromophenyl)methyl]3-[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (2470 mg) and TEA (0.916 ml) in DMF (10 ml) and MeOH (3 ml) was added PdCl2(dppf) (321 mg) and the mixture was stirred at 80 °C under a carbon monoxide atmosphere for 6 hours. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (630 mg). Petition 870250083065, dated 09 / 15 / 2025, pp. 196 / 258 164 / 211

[00746] MS: [M+Na]+ 565.2

[00747] C) tert-Butyl (2S,3S)-2-{[3-(hydroxymethyl)phenyl]methyl}-3[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate

[00748] To a solution of tert-butyl (2S,3S)-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]-2-{[3(methoxycarbonyl)phenyl]methyl}pyrrolidine-1-carboxylate (630 mg) in dry THF (5 ml) was added 1 M diisobutylaluminum hydride in hexane (2.90 ml) at 0 °C. The mixture was stirred for 10 minutes at room temperature. Then, sodium sulfate decahydrate was added and the mixture was stirred for 2 hours. After filtration and evaporation under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the titrant compound (508 mg).

[00749] MS: [M+Na]+537.2

[00750] D) tert-Butyl (2S,3S)-2-[(3-{[(6-bromo-3-methylpyridin-2yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate

[00751] To a solution of tert-butyl (2S,3S)-2-{[3(hydroxymethyl)phenyl]methyl}-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (508 mg) in dry DMF (5 ml) was added 60% sodium hydride (47.4 mg) at room temperature. The mixture was stirred at room temperature under an argon atmosphere for 10 minutes. Then, 6-bromo-2-fluoro-3-methylpyridine (281 mg) was added to the solution and the mixture was stirred at room temperature under an argon atmosphere for 30 minutes. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to yield the title compound (437 mg). Petition 870250083065, dated 09 / 15 / 2025, pp. 197 / 258 165 / 211

[00752] MS: [M+Na]+ 706.2

[00753] E) tert-Butyl (2S,3S)-2-[(3-{[(6-{[(tertbutoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl] -3[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1carboxylate

[00754] A mixture of tert-butyl (2S,3S)-2-[(3-{[(6-bromo-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3-[(methanesulfonyl){[2(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (437 mg), potassium [[(tert-Butoxycarbonyl)amino]methyl]trifluoroborate (303 mg), Pd(OAc)2 (14.33 mg), potassium carbonate (176 mg) and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (52.4 mg) in toluene (2659 pl) and water (532 pl) was stirred at 85 °C for 4 hours under an argon atmosphere. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (281 mg).

[00755] MS: [M+H]+736.3

[00756] F) N-[(16aS,17S)-7-Methyl-1-oxo-2,3,16a,17,18,19-hexahydro1H,10H, 16H-4,8-(azene)-11,15-(methene)pyrrolo[1,2j][1,8,10]oxadiazacyclooctadecin-17-yl]methanesulfonamide

[00757] A mixture of tert-butyl (2S,3S)-2-[(3-{[(6-{[(tert-butoxycarbonyl)amino]methyl}-3-methylpyridin-2-yl)oxy]methyl}phenyl)methyl]-3[(methanesulfonyl){[2-(trimethylsilyl)ethoxy]methyl}amino]pyrrolidine-1-carboxylate (281 mg) in TFA (1 mL) was stirred at room temperature for 10 minutes. After evaporation, the residue was purified by silica gel NH4(MeOH / EtOAc) column chromatography. A solution of the residue thus obtained in DMF(dry) (1 mL) was added to a mixture of di(N-succinimidyl) carbonate (32.5 mg), N-methylmorpholine (0.013 mL) and THF(dry) (50 mL) at room temperature, and the mixture was stirred at room temperature. Petition 870250083065, dated 09 / 15 / 2025, pp. 198 / 258 166 / 211 ambient overnight. DIPEA (0.201 ml) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to yield the titrant compound (6.1 mg).

[00758] 1H NMR (300 MHz, CDCb) δ 1.75-1.90 (1H, m), 2.20 (3H, s), 2.26-2.47 (2H, m), 3.06 (3H, s), 3.16-3.32 (2H, m), 3.80-4.08 (3H, m), 4.35 (1H, ddd, J = 10.3, 6.9, 3.2 Hz), 4.51 (1H, dd, J = 16.0, 6.2 Hz), 4.87 (2H, br dd, J = 6.0, 3.0 Hz), 5.26 (1H, d, J = 12.4 Hz), 5.45 (1H, d, J = 12.4 Hz), 6.53 (1H, d, J = 7.5 Hz), 6.91-7.01 (1H, m), 7.09-7.17 (2H, m), 7.21-7.25 (1H, m), 7.48 (1H, s). Example 97

[00759] N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azen o)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide

[00760] A) tert-Butyl (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate

[00761] To a solution of tert-butyl (2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidine-1-carboxylate (4.0 g) in CH2Cl2 (22 mL), in a water bath at room temperature, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.1 mL) was added followed by isopropylsulfonyl chloride (1.9 mL). The mixture was stirred at room temperature for 24 hours. A saturated aqueous solution of ammonium chloride was added to the mixture. The organic layer was separated, washed sequentially with aqueous sodium bicarbonate solution and brine, filtered, and concentrated under reduced pressure. The residue was purified by Petition 870250083065, dated 09 / 15 / 2025, pp. 199 / 258 167 / 211 silica-gel column chromatography (EtOAc / heptane) to generate the title compound (3.1 g).

[00762] MS: [M+2H(-tBu)]+ 415.2

[00763] B) tert-Butyl (2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(propane-2sulfonyl)amino]pyrrolidine-1-carboxylate

[00764] To a mixture of (2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl (987 mg), potassium acetate (411 mg) and bis(pinacolate)diboron (798 mg) in toluene (8.4 mL) was added nitrogen (SP-4-3)[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2yl]phosphine](methanesulfonate)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (180 mg). The mixture was sprayed with nitrogen, then stirred at 80 °C for 16 hours. The mixture was diluted with MeOH, filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / CH2Cl2) to yield the titrant compound (882 mg).

[00765] MS: [M+2H(-tBu)]+507.2.

[00766] C) tert-Butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate

[00767] To a solution of tert-butyl (2S,3R)-4,4-difluoro-2-{[2-fluoro3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (882 mg) in THF-water 1:1 (6.2 mL) sodium perborate tetrahydrate (579 mg) was added at room temperature. The mixture was stirred at room temperature in the open air for 16 hours. The mixture was diluted with water, filtered through fine frit, and the filtrate was extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to yield the title compound (370 Petition 870250083065, dated 09 / 15 / 2025, pp. 200 / 258 168 / 211 mg).

[00768] MS: [M+2H(-tBu)]+397.2.

[00769] D) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]2-fluorophenyl}methyl)-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1carboxylate

[00770] To a mixture of tert-butyl (2S,3R)-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (370 mg) and cesium carbonate (534 mg) in DMA (3 ml) was added 6-chloro-5-methylpicolinonitrile (249 mg). The mixture was stirred at 80°C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / heptane) to yield the title compound (226 mg).

[00771] MS: [M+2H(-tBu)]+513.2.

[00772] E) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate

[00773] Sodium borohydride (45 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)oxy]-2-fluorophenyl}methyl)-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (226 mg) and nickel(II) chloride hexahydrate (94 mg) in MeOH (2.6 mL) at 0 °C. The mixture was stirred at cold temperature for 3 hours and then at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue, containing the titrant compound (230 mg), was transported without purification.

[00774] MS: [M+H]+573.3. Petition 870250083065, dated 09 / 15 / 2025, pages 201 / 258 169 / 211

[00775] F) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}propane-2-sulfonamide dihydrochloride

[00776] A solution of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoro-3-[(propane-2-sulfonyl)amino]pyrrolidine-1-carboxylate (228 mg) in 4 M hydrogen chloride in 1,4-dioxane (4.9 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (5 mL) and then concentrated under reduced pressure to give the titrant compound (225 mg).

[00777] MS: [M+H]+ 473.2.

[00778] G) N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azen o)-14,10-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide

[00779] N,N'-Disuccinimidyl carbonate (76 mg) was added in three portions to a mixture of N-{(2S,3R)-2-[(3-{[6(aminomethyl)-3-methylpyridin-2-yl]oxy}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}propane-2-sulfonamide dihydrochloride (217 mg) and N-methylmorpholine (0.26 mL) in dry THF (380 mL) and dry DMF (15 mL) at room temperature for 5 minutes. The mixture was stirred at room temperature for 4 days and then concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (column: Gemini® NX-C18, mobile phase: 10 mM aqueous ammonium bicarbonate / acetonitrile solution) to yield the titrant compound (83 mg).

[00780] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (6H, app dd, J = 6.8, 4.5 Hz), 2.31 (3H, s), 2.65 (1H, app br d, J = 13.6 Hz), 2.86 (1H, app t, J = 12.6 Hz), 3.26-3.30 (1H, m), 3.60 (1H, br d, J = 14.18 Hz), 3.69-3.91 (2H, m), 4.24-4.46 (2H, m), 4.46-4.55 (1H, m), 6.14 (1H, br d, J = 8.7 Hz), 6.86 (1H, d, J = 7.28 Hz), 6.97-7.04 (1H, m), 7.05-7.13 (2H, m), 7.55 (1H, d, J = Petition 870250083065, 15 / 09 / 2025, pág. 202 / 258 170 / 211 7.3 Hz), 8.11 (1H, d, J = 9.8 Hz). Example 99

[00781] N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(az eno)-14,10-(metheno)pyrrole[1,2j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[00782] A) tert-Butyl N-(6-bromo-5-methylpyridin-2-yl)glycinate

[00783] To a mixture of tert-butyl 2-bromoacetate (12.6 g) and potassium carbonate (16.3 g) in NMP (220 mL) was added 6-bromo-5-methylpyridin-2-amine (11.0 g). The mixture was stirred at 140 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the title compound (8.33 g).

[00784] 1H NMR (400 MHz, CDCh) δ ppm 1.48 (9H, s), 2.22 (3H, s), 3.98 (2H, s), 4.96 (1H, br s), 6.32 (1H, d, J = 8.2 Hz), 7.23 (1H, d, J = 8.07 Hz).

[00785] B) tert-Butyl (2S,3R)-2-{[3-({6-[(2-tert-butoxy-2oxoethyl)amino]-3-methylpyridin-2-yl}oxy)-2-fluorophenyl]methyl}-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate

[00786] A mixture of tert-butyl N-(6-bromo-5-methylpyridin-2-yl)glycinate (206 mg), tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro-3-hydroxyphenyl)methyl]pyrrolidine-1-carboxylate (200 mg), copper iodide (17.4 mg), pyridine-2-carboxylic acid (22.5 mg), and tripotassium phosphate (242 mg) in DMSO (4 mL) was degassed and purged with nitrogen three times and stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and Petition 870250083065, dated 09 / 15 / 2025, pages 203 / 258 171 / 211 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the titrant compound (97.4 mg).

[00787] MS: [M+H]+ 659.2.

[00788] C) N-{6-[3-({(2S,3R)-3-[(Ethanesulfonyl)amino]-4,4difluoropyrrolidin-2-yl}methyl)-2-fluorophenoxy]-5-methylpyridin-2-yl} glycine dihydrochloride

[00789] A solution of (2S,3R)-2-{[3-({6-[(2-tert-butoxy-2-oxoethyl)amino]-3-methylpyridin-2-yl}oxy)-2-fluorophenyl]methyl}-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (150 mg) in 4 M hydrogen chloride in 1,4-dioxane (12 mL) was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (141 mg).

[00790] MS: [M+H]+503.0.

[00791] D) N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(az ene)-14,10-(methene)pyrrolo[1,2j][1,7,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide

[00792] HATU (131 mg) and DIPEA (239 μL) were added to a solution of N-{6-[3-({(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenoxy]-5-methylpyridin-2-yl}glycine dihydrochloride (140 mg) in DMF (140 mL) at room temperature and stirred for 12 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (SiO2, EtOAc / PE) to provide a mixture of the titrant compound and its isomer. The isomeric mixture was purified by preparative SFC (column: DAICEL CHIRALCEL OJ, mobile phase: COb / EtOI I (containing 0.1% ammonium hydroxide)) to generate the titrant compound (15.7 mg, shortest retention time).

[00793] 1H NMR (400 MHz, CDCb) δ ppm 1.42-1.53 ​​(3H, m), 2,182.29 (3H, m), 2.72-3.28 (5H, m), 3.61-3.96 (2H, m), 4.00-4.38 (3H, m), 4,444.64 (1H, m), 4.96-5.22 (1H, m), 6.06-6.29 (1H, m), 6.95-7.18 (3H, m), 7.26 Petition 870250083065, dated 09 / 15 / 2025, pages 204 / 258 172 / 211 (1H, br s). Example 100

[00794] N-[(15aS,16R)-9,9,17,17,20-pentafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,9H, 15H-4,8-(azene)-14,10(methene)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[00795] A) tert-Butyl (2S,3R)-2-{[3-(6-cyano-3-methylpyridine-2carbonyl)-2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4difluoropyrrolidine-1-carboxylate

[00796] A mixture of tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate (1.0 g), 6-bromo-5-methylpyridine-2-carbonitrile (424 mg), Pd(OAc)2 (21 mg), 1,3-bis(2,4,6-trimethylphenyl)imidazol-1-io chloride (63 mg) and cesium carbonate (1.19 g) in 1,4-dioxane (30 mL) was stirred at 80 °C under a carbon monoxide atmosphere (50 psi) for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / PE) to yield the titrant compound (337 mg).

[00797] MS: [M+H]+ 567.1.

[00798] B) tert-Butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)(difluoro)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate

[00799] tert-Butyl (2S,3R)-2-{[3-(6-cyano-3-methylpyridine-2-carbonyl)2-fluorophenyl]methyl}-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (234 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (4.55 g) were combined in a reaction vessel and stirred at 65 °C for 24 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude isolate was purified. Petition 870250083065, dated 09 / 15 / 2025, pages 205 / 258 173 / 211 by preparative HPLC (column: Boston Green ODS, mobile phase: 0.2% aqueous formic acid / acetonitrile solution) to generate the titrant compound (128 mg).

[00800] MS: [M+H]+ 589.0.

[00801] C) tert-Butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2yl](difluoro)methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4difluoropyrrolidine-1-carboxylate

[00802] Sodium borohydride (82.6 mg) was added to a solution of tert-butyl (2S,3R)-2-({3-[(6-cyano-3-methylpyridin-2-yl)(difluoro)methyl]-2-fluorophenyl}methyl)-3-[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (128 mg) and nickel(II) chloride hexahydrate (52.3 mg) in MeOH (5.0 mL) at 0 °C. The reaction mixture was heated to 20 °C and stirred for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the titrant compound (98 mg).

[00803] MS: [M+H]+593.1.

[00804] D) N-{(2S,3R)-2-[(3-{[6-(Aminomethyl)-3-methylpyridin-2yl](difluoro)methyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3yl}ethanesulfonamide trihydrochloride

[00805] A solution of tert-butyl (2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (98 mg) in 4 M hydrogen chloride in 1,4-dioxane (5.4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to yield the title compound (99.5 mg).

[00806] MS: [M+H]+493.0.

[00807] E) N-[(15aS,16R)-9,9,17,17,20-pentafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,9H,15H-4,8-(azene)-14,10Petition 870250083065, from 09 / 15 / 2025, p. 206 / 258 174 / 211 (methene)pyrrolo[1,2-c][1,3]diazacycloheptadecin-16-yl]ethanesulfonamide

[00808] To a suspension of N-{(2S,3R)-2-[(3-{[6-(aminomethyl)-3-methylpyridin-2-yl](difluoro)methyl}-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin3-yl}ethanesulfonamide trichloride (99.5 mg) in THF (15 mL) at 0 °C was added DIPEA (173 μL), followed by 1,1'-carbonyldiimidazole (40.2 mg). The reaction mixture was heated to 45 °C and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure to provide the crude residue which was purified by preparative HPLC (column: Phenomenex C18, mobile phase: 10 mM aqueous ammonium bicarbonate solution (containing 0.05% ammonium hydroxide) / acetonitrile) to generate the titrant compound (26.4 mg).

[00809] 1H NMR (400 MHz, CDCh) δ ppm 1.44 (3H, dt, J = 12.0, 7.3 Hz), 2.64 (3H, br d, J = 11.4 Hz), 2.78-3.01 (1H, m), 3.08-3.28 (2H, m), 3,343.61 (1H, m), 3.69-4.15 (2H, m), 4.18-4.85 (4H, m), 5.13-5.83 (2H, m), 7,107.24 (2H, m), 7.38-7.68 (3H, m). Example 102

[00810] N-[(15aS,16R)-17,17,20-Trifluoro-7-metil- 1-oxo1,2,15a,16,17,18-hexahidro-9H,15H-4,8-(azeno)-10,14-(meteno)pirrolo[1,2d][1,4]oxazacicloheptadecin-16-il]etanossulfonamida

[00811] A) (3-metilpiridin-2-il) acetato de metila

[00812] Acetic anhydride (2.30 mL), pyridine (2.49 mL), and DMAP (199 mg) were added to a solution of (3-methyl-2-pyridyl)methanol (2.0 g) in THF (40 mL). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with water and saturated aqueous sodium bicarbonate solution, then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the titrant compound (2.4 g).

[00813] 1H NMR (400 MHz, CDCh) δ ppm 2.13 (3H, s), 2.36 (3H, s), Petition 870250083065, dated 09 / 15 / 2025, pages 207 / 258 175 / 211 5.23 (2H, s), 7.17 (1H, dd, J = 7.6, 4.8 Hz), 7.49 (1H, d, J = 7.0 Hz), 8.44 (1H, d, J = 4.1 Hz).

[00814] B) (3-Methyl-1-oxide-pyridin-1-io-2-yl)methyl acetate

[00815] To a solution of (3-methylpyridin-2-yl)methyl acetate (2.4 g) in CH2Cl2 (50 mL) was added m-chloroperoxybenzoic acid (4.42 g, 85% purity). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water, tempered with sodium sulfite (5 g), basified with saturated aqueous sodium bicarbonate solution to pH = 8, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the titrant compound (4 g). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.09 (3H, s), 2.50 (3H, s), 5.47 (2H, s), 7.43-7.51 (2H, m), 8.27 (1H, d, J = 6.2 Hz).

[00816] C) (6-chloro-3-methylpyridin-2-yl)methyl acetate

[00817] A mixture of (3-methyl-1-oxy-pyridin-1-io-2yl)methyl acetate (2 g) and phosphoryl chloride (10 mL) was stirred under a nitrogen atmosphere at 90 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, basified with saturated aqueous sodium bicarbonate solution to pH = 8, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to give the title compound (600 mg).

[00818] 1H NMR (400 MHz, CDCh) δ ppm 2.13 (3H, s), 2.34 (3H, s), 5.18 (2H, s), 7.22 (1H, d, J = 8.0 Hz), 7.37-7.48 (1H, m).

[00819] D) tert-Butyl {[6-(hydroxymethyl)-5-methylpyridin-2-yl]oxy}acetate

[00820] To a solution of (6-chloro-3-methylpyridin-2-yl)methyl acetate (400 mg), tert-butyl 2-hydroxyacetate (297 mg), cesium carbonate (1.10 g) and dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (268 mg) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (103 mg) under an atmosphere of Petition 870250083065, dated 09 / 15 / 2025, pages 208 / 258 176 / 211 nitrogen. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE) to yield the titrant compound (140 mg).

[00821] MS: [M+H]+ 254.2.

[00822] E) tert-Butyl {[6-(chloromethyl)-5-methylpyridin-2-yl]oxy}acetate

[00823] To a solution of tert-butyl {[6-(hydroxymethyl)-5-methylpyridin2-yl]oxy}acetate (110 mg) in CH2Cl2 (4 mL) was added thionyl chloride (207 μL). The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the titrant compound (80 mg).

[00824] MS:[M+H]+272,2.

[00825] F) tert-Butyl (2S,3R)-2-[(3-{[6-(2-tert-butoxy-2-oxoethoxy)-3methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4difluoropyrrolidine-1-carboxylate

[00826] To a solution of tert-butyl {[6-(chloromethyl)-5-methylpyridin-2yl]oxy}acetate (80 mg) and tert-butyl (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl}pyrrolidine-1-carboxylate (110 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) was added potassium carbonate (80.7 mg) and Pd(dppf)Cl2.CH2Cl2 (15.9 mg) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography. Petition 870250083065, dated 09 / 15 / 2025, pages 209 / 258 177 / 211 silica gel (EtOAc / PE) to provide the titrant compound (120 mg).

[00827] MS: [M+H]+ 658.3.

[00828] G) [(6-{[3-({(2S,3R)-3[(Ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2-fluorophenyl]methyl}5-methylpyridin-2-yl)oxy]acetic acid dihydrochloridedihydrochloride

[00829] A solution of tert-butyl (2S,3R)-2-[(3-{[6-(2-tert-butoxy-2oxoethoxy)-3-methylpyridin-2-yl]methyl}-2-fluorophenyl)methyl]-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (120 mg) in 4 M hydrogen chloride in 1,4-dioxane (5 mL) was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to yield the title compound (95 mg).

[00830] MS: [M+H]+502.3.

[00831] H) N-[(15aS,16R)-17,17,20-Trifluoro-7-methyl-1-oxo1,2,15a,16,17,18-hexahydro-9H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2d][1,4]oxazacycloheptadecin-16-yl]ethanesulfonamide

[00832] To a solution of [(6-{[3-({(2S,3R)-3[(ethanesulfonyl)amino]-4,4-difluoropyrrolidin-2-yl}methyl)-2fluorophenyl]methyl}-5-methylpyridin-2-yl)oxy]acetic acid dihydrochloride (45 mg) in EtOAc (260 mL) was added dibutyldiphosphonic acid (37.8 mg, 50% purity) and pyridine (130 mL). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched by the addition of water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, mobile phase: 0.1% aqueous TFA / acetonitrile solution) to generate the titrant compound (20.5 mg).

[00833] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (3H, t, J = 7.3 Hz), 2.37 (3H, s), 2.62 (1H, br d, J = 14.2 Hz), 2.94 (1H, br t, J = 12.9 Hz), 3.14-3.23 (2H, m), 3.93 (1H, s), 4.08-4.44 (4H, m), 4.47-4.55 (2H, m), 4.59 Petition 870250083065, of 15 / 09 / 2025, p. 210 / 258 178 / 211 4.67 (1H, m), 6.47-6.56 (1H, m), 6.83-6.91 (1H, m), 6.92-6.99 (1H, m), 7.057.10 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 8.2-3-8.30 (1H, m). Examples 105 and 106

[00834] N-[(9R, 15aS,16R)-17,17,20-Trifluoro-7,9-dimethyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,9H, 15H-4,8-(azeno)-10,1pyrrometheno(4) [1,2-c][1,3]diazacycloheptadecin-16-...

Claims

CLAIMS 1. Compound, characterized in that it is of formula (I) wherein Ring A is an optionally substituted C-14 aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, wherein Y is a ring atom C or N, wherein the C is bonded to hydrogen or to an optional substituent; X is -O-, -S-, -NR1-, -CR2R3-, -O-(CR2R3)-, -(CR2R3)-O-, or an optionally substituted C3-6 cycloalkyl group, wherein the left portion of X is bonded to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is bonded to Ring B; R1 is hydrogen, or an optionally substituted C1-6 alkyl group; R2 and R3 are independently hydrogen, halogen or an optionally substituted C1-6 alkyl group; Ring B is an optionally substituted C6-14 aryl group, or an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group;L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5), -C(R4R5)-C(R7R8)-, where the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R4 and R5 are independently hydrogen, halogen or an optionally substituted C1-6 alkyl group; R6 is hydrogen or an optionally substituted C1-6 alkyl group; R7 and R8 are independently hydrogen, halogen or an optionally substituted C1-6 alkyl group; or R4 and R6, taken together with the atoms to which they are attached, form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring; or R4 and R5, or R4 and R7 taken together with the atom or atoms to which they are attached, form an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic ring, or an optionally substituted C3-10 cycloalkyl group;Ra is a C1-6 alkyl group, a C3-4 cycloalkyl group, or a mono- or di-C1-6 alkylamino group, wherein each of the C1-6 alkyl, C3-6 cycloalkyl, and mono- or di-C1-6 alkylamino groups is optionally substituted; Rb is a hydrogen atom or a halogen atom; and Rc is a hydrogen atom or a halogen atom; or a salt thereof.

2. Compound according to claim 1, characterized in that Ring A is where i is the methylene bridge attachment point and ii is the X attachment point; and Petition 870250083065, dated 09 / 15 / 2025, p. 246 / 258 3 / 10 R11 and R12 are independently hydrogen, halogen or optionally C1-6 halogenated alkyl group; or a salt thereof.

3. Compound according to claim 1, characterized in that ring B is selected from: where iv is the attachment point to L and iii is the attachment point to X; R21a R21b R21d R22a R22b r22c R23a R23b R23c and R23d are independently selected from hydrogen, halogen, an optionally halogenated C1-6 alkyl group, a C1-6 alkoxyl group and a C3-6 cycloalkyl group; and R24 is selected from hydrogen, halogen, an optionally halogenated C1-6 alkyl group and a C3-6 cycloalkyl group; or a salt thereof.

4. Compound according to claim 1, characterized in that Petition 870250083065, dated 09 / 15 / 2025, p. 247 / 258 4 / 10 Ring A is where i is the methylene bridge attachment point and ii is the X attachment point; and R11 and R12 are independently hydrogen, halogen or C1-6 alkyl group; X is -O-, -CR2R3-, -O-(CR2R3)-, or -(CR2R3)-O-, where the left portion of X is attached to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is attached to Ring B; R2 and R3 are independently hydrogen, halogen or C1-6 alkyl group optionally substituted by 1 to 3 substituents selected independently from halogen and C1-6 alkyl group; Ring B is selected from: where iv is the linkage point of L and iii is the linkage point to X;R21a R21b R21d R22a R22b r22c R23a R23b R23c and R23d are independently selected from hydrogen, halogen, an optionally selected C1-6 alkyl group, a C1-6 alkoxyl group and a C3-6 cycloalkyl group; R24 is hydrogen or a C1-6 alkyl group; L is -C(R4R5)-NR6-, -C(R4R5)-O-, -OC(R4R5)-, -NR6-C(R4R5), or -C(R4R5)-C(R7R8)-, wherein the left portion of L is attached to Ring B and the right portion of L is attached to the carbonyl group; R4 and R5 are independently hydrogen or a C1-6 alkyl group; R6 is hydrogen or an optionally halogenated C1-6 alkyl group; R7 and R8 are independently hydrogen; or when L is -C(R4R5)-NR6- or -NR6-C(R4R5)-, R4 and R6 together with the atoms to which they are attached form a 3- to 8-membered non-aromatic monocyclic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C1-6 alkoxyl group, and R5 is hydrogen;or when L is -C(R4R5)-C(R7R8)-, R4 and R7 together with the carbon atoms to which they are attached form a C3-10 cycloalkyl group, and R5 and R8 are both hydrogen; Ra is a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected independently from halogen atoms and a C1-6 alkoxy group, a C3-4 cycloalkyl group or a mono- or di-C1-6 alkylamino group; Rb is a hydrogen atom or a halogen atom; and Rc is a hydrogen atom or a halogen atom; or a salt thereof.

5. Compound according to claim 1, characterized in that Petition 870250083065, dated 09 / 15 / 2025, p. 249 / 258 6 / 10 Ring A is a phenyl group optionally substituted by 1 to 2 halogen atoms, where Y is a ring C atom bonded to hydrogen or halogen; X is -O-, where the left portion of X is bonded to a carbon atom of Ring A that is adjacent to Y and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted by 1, 2 or 3 substituents independently selected from halogen and C1-6 alkyl group; L is -CH2-NH-, where the left portion of L is bonded to Ring B and the right portion of L is bonded to the carbonyl group; Ra is a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C3-4 cycloalkyl group; Rb is a halogen atom; and Rc is a halogen atom; or a salt thereof.

6. Compound according to claim 1, characterized in that Ring A is a phenyl group optionally further substituted by 1 to 2 halogen atoms, where Y is a ring atom C bonded to a halogen; X is -O-, where the left portion of X is bonded to a ring carbon atom in Ring A that is adjacent to Y and the right portion of X is bonded to Ring B; Ring B is a pyridine ring optionally substituted by 1, 2 or 3 C1-6 alkyl groups; L is -CH2-NH-, where the left portion of L is bonded to Ring B and the right portion of L is bonded to the carbonyl group; Ra is a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; Rb is a halogen atom; Rc is a halogen atom; or a salt of halogens.

7. Compound according to claim 1, characterized in that the compound is selected from the group consisting of: N-[(15aS,16R)-17,17-difluoro-7-methyl-1-oxo-2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azeno)-10,14-(metheno)pyrrolo[1,2j][1,8,10]oxadiazcycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1 -oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8-(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]ethanesulfonamide; 1-fluoro-N-[(15aS,16R)-17,17,20-trifluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahydro-1H,15H-4,8 -(azene)-10,14-(methene)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide;N-[(15aS,16R)-7-chloro-17,17,20-trifluoro-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(meteno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; N-[(15aS,16R)-5,17,17,20-tetrafluoro-7-methyl-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(a zeno)-14,10-(metheno)pyrrole[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]methanesulfonamide; N-[(15aS,16R)-7-chloro-5,17,17,20-tetrafluoro-1-oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azen o)-14,10-(metheno)pyrrolo[1,2j][1,8,10]oxadiazacycloheptadecin-16-yl]cyclopropanesulfonamide; and N-[(15aS,16R)-17,17,20-trifluoro-7 -methyl-1 -oxo2,3,15a,16,17,18-hexahidro-1H,15H-4,8-(azeno)-14,10-(metheno)pyrrolo[1,2 Petição 870250083065, de 09 / 15 / 2025, pág. 251 / 258 8 / 10 j][1,8,10]oxadiazacycloheptadecin-16-yl]propane-2-sulfonamide; ou um sal dos mesmos.; 8. Pharmaceutical composition, characterized in that it comprises the compound defined in any one of claims 1 to 7, or a salt thereof, and a pharmacologically acceptable carrier.

9. A medicament, characterized in that it comprises the compound defined in any one of claims 1 to 7 or a salt thereof.

10. A medicament according to claim 9, characterized in that it is an orexin type 2 receptor agonist.

11. A medicament according to claim 9, characterized in that it is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disturbance of consciousness, or side effects and complications due to anesthesia.

12. A medicament according to claim 9, characterized in that it is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

13. A medicament according to claim 9, characterized in that it is an agent for the prophylaxis or treatment of narcolepsy.

14. Method for the prophylaxis or treatment of a disease or disorder associated with a type 2 orexin receptor in a mammal in need, characterized in that it comprises administering to the mammal a therapeutically effective amount of the compound defined in any one of claims 1 to 7 or a salt thereof. Petition 870250083065, dated 09 / 15 / 2025, pp. 252 / 258 9 / 10 15. Method according to claim 14, characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disorder of consciousness, and side effects and complications due to anesthesia.

16. Method according to claim 14, characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

17. Method according to claim 14, characterized in that the disease or disorder is narcolepsy.

18. Compound, agreement defined in any one of claims 1 to 7, or a salt thereof, characterized in that it is for use in therapy.

19. Compound or salt according to claim 18, characterized in that the therapy comprises the treatment of a disease or disorder associated with a type 2 orexin receptor.

20. Compound or salt according to claim 19, characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disturbance of consciousness, and side effects and complications due to anesthesia.

21. Compound or salt according to claim 19, Petition 870250083065, dated 09 / 15 / 2025, pp. 253 / 258 10 / 10 characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

22. Compound or salt according to claim 19, characterized in that the disease or disorder is narcolepsy.

23. Use of the compound, as defined in any one of claims 1 to 7, or a salt thereof, characterized in that it is used in the manufacture of a medicament for the treatment of a disease or disorder associated with a type 2 orexin receptor.

24. Use according to claim 23, characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, disorder of consciousness, and side effects and complications due to anesthesia.

25. Use according to claim 23, characterized in that the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

26. Use according to claim 23, characterized in that the disease or disorder is narcolepsy.