Heterocyclic compound and its use

Description

"HETEROCYCLIC COMPOUND AND ITS USE" Technical Field

[001] The present invention relates to a specific heterocyclic compound and its use. Background of the Technique

[002] 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin2-one (“brexpiprazole” below) or a salt thereof has partial agonist action on dopamine D2 receptors, antagonist action on serotonin 5-HT2A receptors, and antagonist action on α1-adrenergic receptors. In addition to these actions, brexpiprazole or a salt thereof also has inhibitory action on serotonin uptake (or inhibitory action on serotonin reuptake), and is known to have a broad therapeutic spectrum for diseases of the central nervous system (particularly schizophrenia) (Patent Literature (PTL) 1 and 2).

[003] One of the drug design methods in the pharmaceutical field is the development of a drug that aims to improve the properties of a known drug molecule (for example, to increase its efficacy or slow its metabolism in vivo) by chemical conversion or modification of some functional groups of the drug molecule.

[004] It is eagerly anticipated that the development of such a drug using brexpiprazole will lead to a compound with improved properties and offer new therapeutic options for diseases of the central nervous system. List of References Patent Literature PTL 1: JP2006-316052A PTL 2: WO2013 / 035892A Summary of the Invention Technical Problem Petition 870260084657, dated 08 / 20 / 2026, p. 6 / 800 2 / 375

[005] One of the objectives to be achieved by the present invention is the presentation of a new therapeutic agent for diseases of the central nervous system. Solution to the Problem

[006] Extensive research was carried out and a new heterocyclic compound represented by the following formula (I) and a salt thereof were successfully developed: and it was found that this compound may be a new therapeutic agent for diseases of the central nervous system. The present invention includes, for example, the material described in the following items. Item 1. A compound represented by formula (I) or a salt thereof: in what R1 and R2 each independently represent -O; -OR4, or Kip4Nap4Nb R3 represents hydrogen or alkyl, R4, R4Na and R4Nb each independently represent hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl, each optionally having 1 to 3 substituents, wherein alkyl represented by R4, R4Na, or R4Nb may have a structure in which one or more methylene groups (-CH2-) are substituted by -O-, -S-, -CO-, -NH-, -SiRsiaRsib-, or Petition 870260084657, dated 20 / 08 / 2026, p. 7 / 800 3 / 375 (CO)O-, if R1 and R2 both represent -OR4, R1 and R2 may be identical or different, and if R1 and R2 both represent -NR4NaR4Nb, R1 and R2 may be identical or different. Item 2. The compound or salt thereof according to item 1, where R1 represents -O; R2 represents -OR4 or -NR4NaR4Nb, and R4, R4Na, and R4Nb are as defined above. Item 3. A compound represented by formula (I) or a salt thereof: in what R1 represents -O; R2 represents -OR4or -NR4NaR4Nb, R3 represents hydrogen or C1-6 alkyl. R4 represents hydrogen or any of the following items (OI) to (5), -NR4NaR4Nb represents the following items (i) or (ii): (0-1): C1-18 alkenyl optionally having 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxy, (0-2): C1-18 alkadienyl optionally having 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxy, (0-3): C1-18 alkynyl optionally having 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, and C1-6 alkoxy, (1-1): R4a1, wherein R4a1 represents Petition 870260084657, dated 08 / 20 / 2026, page 8 / 800 4 / 375 - CnH2n+1, - CnH2n-1, - CnH2n-3, CnH2n-OH - CnH2n-2-OH, OR - CnH2n-4-OH, where n represents 1 to 24, with the condition that in -CnH2n-1, n is 2 or more; in -CnH2n-3, n is 2 or more; in -CnH2n-2-, n is 2 or more; and in -CnH2n-4-, n is 2 or more, (1-2): R4a2, where R4a2 represents - CHX1X2, - Cn-1H2n-2-CHX1X2, -Cn-1H2n-4-CHX1X2, or -Cn-1H2n-6-CHX1X2, where n represents 2 to 24, with the condition that in -Cn-1H2n-4-, n represents 3 or more; in -Cn-1H2n-5-, n represents 3 or more, X1 and X2 are identical or different and represent hydrogen or halogen (F, Cl, Br, or I), with the condition that X1 or X2, or both, represent halogen, (1-3): R4a3, where R4a3 represents -CnH2n-R4-1, -Cn-1H2n-2-CHR4-1aR4-1b, -CnH2n-2-R4-1, or - CnH2n-4-R4-1, where n represents 1 to 24, with the condition that in -CnH2n-2-, n represents 2 or more; in -CnH2n-4-, n represents 2 or more, Petition 870260084657, dated 08 / 20 / 2026, p. 9 / 800 5 / 375 R4-1 represents C1-6 alkoxy, -O-phenyl, or a heterocyclic group optionally substituted with C1-6 alkyl or halogen. R4-1ae R4-1b are identical or different and represent -C1-3 alkyleneC1-3 alkoxy, or identical or different and represent -CO-O-C1-3 alkyl or -CH2-CO-O-C1-3 alkyl, (2): R4b, where R4b represents - (CpH2p-O)q-CrH2r-R4-2, - (CpH2p-O)q-CrH2r-2-R4-2, - (CpH2p-2-O)q-CrH2r-R4-2, or - (CpH2p-2-O)q-CrH2r-2-R4-2, where p represents 1 to 4, q represents 1 to 4, r represents 1 to 4, with the condition that in CpH2p-2, p represents 2 or more, in CrH2r-2, r represents 2 or more, when q is 2 to 4, 2 to 4 repetitive structures, whose number of repetitions is represented by q, may be identical or different, R4-2 represents hydrogen, hydroxy, or cycloalkyl, phenyl, benzyl, or a heterocyclic group, each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (3): -CaH2a-CO-O-RCOO or -CaH2a-CO-O-CH2-RCOO wherein α represents 1 to 10, wherein -RCOO represents hydrogen, C1-6 alkyl or C1-6 alkoxy, each optionally substituted with 1 to 3 C1-6 alkoxy groups, or cycloalkyl, phenyl, benzyl, or a heterocyclic group, each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (4): -CpH2p-O-CO-ROCOwhere β represents 1 to 10, where -ROCOrepresents R4a1, R4b, or -CaH2a-CO-O-RCOO, or -CaH2a-CO-NH-RCOO, -CaH2a-NH-CO-RCOO, or -CaH2a-NH-CO-O-RCOO Petition 870260084657, dated 08 / 20 / 2026, p. 10 / 800 6 / 375 wherein -RC00 is as defined above, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from C1-6 alkyl, C16 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (5): -CyH2y-0-C0-0-R0C00 wherein γ represents 1 to 10, wherein -R0C00 represents hydrogen, R4a1, R4b, or -CaH2a-CO-O-RC00 wherein -RC00 is as defined above, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from C1-6 alkyl, C16 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (i) R4Nae R4Nb are identical or different and represent C1-6 alkyl optionally substituted with 1 to 3 C1-6 alkoxy groups, (ii) R4Na represents hydrogen, and R4Nb represents C1-6 alkyl optionally substituted with 1 to 3 C1-6 alkoxy groups, or represents CaH2a-CO-O-RC00 or -CaH2a-CO-NH-RC00 where -RC00 is as defined above. Item 4. The compound or salt thereof according to any one of items 1 to 3, wherein the heterocyclic group has a structure in which a hydrogen atom bonded to a constituent atom of a heterocycle is removed from the heterocycle, the heterocycle being selected from the group consisting of furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline. Item 5. compound or salt thereof according to any of items 1 to 4, wherein -0R4 represents any of the groups listed in Table 1 below, when an asterisk “*” represents the side opposite R4 with respect to the oxygen atom (*-0R4): Petition 870260084657, dated 08 / 20 / 2026, page 11 / 800 7 / 375 Table 1 *-OH s' 0 *·^ .^X 0 x J^O_ * '^0^ o ^77 * o · * 'Ο·'''·''ί:ί^^ x\^0h o - HO OH * 7θΛ··-'·''' Oh J *'Ό''~^-^'ΟΗ J 0 *-'0-^íí^'OH ο—X ^OH / \ # 0 v OH K ,-OH 0 OH O + ,. ,-Χ Λ 0 ΌΗ| ^O'^^'Oh Petition 870260084657, dated 08 / 20 / 2026, p. 12 / 800 8 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 13 / 800 9 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 14 / 800 10 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 15 / 800 11 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 16 / 800 12 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 17 / 800 13 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 18 / 800 14 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 19 / 800 15 / 375 e -NR4NaR4Nb represents any of the groups listed in Table 2 below, where the asterisk represents the opposite side to R4NaR4Nb. Petition 870260084657, dated 08 / 20 / 2026, page 20 / 800 16 / 375 relative to the nitrogen atom (*-NR4NaR4Nb): Table 2 Item 6. A pharmaceutical composition comprising the compound or a salt thereof of any of items 1 to 5 and a pharmaceutically acceptable carrier. Item 7. The pharmaceutical composition according to item 6, comprising the Petition 870260084657, dated 08 / 20 / 2026, page 21 / 800 17 / 375 compound or salt thereof of any of items 1 to 5, a suspending agent, and a dispersing medium, wherein the pharmaceutical composition is in the form of a suspension. Item 8. The pharmaceutical composition, according to item 7, where the average particle diameter of the particles in the suspension varies from 0.5 to 30 μm. Item 9. The pharmaceutical composition according to item 7, in which the average particle diameter of the particles in the suspension varies from 50 to 500 nm. Item 10. The pharmaceutical composition according to any one of items 7 to 9, wherein the suspending agent is carboxymethyl cellulose or a salt thereof, and the dispersing medium is a liquid containing water for injection. Item 11. A pharmaceutical composition comprising a viscous mixture of a) the compound or salt thereof from any of items 1 to 5, b) two or more liquid crystal-forming lipids or gel-forming lipids, and c) a biocompatible organic solvent, wherein the pharmaceutical composition is a precursor preparation used to form a liquid crystalline phase or lipogel structure by placing the pharmaceutical composition in contact with an aqueous fluid in vivo. Item 12. The pharmaceutical composition according to item 11, where b) the Petition 870260084657, dated 08 / 20 / 2026, page 22 / 800 18 / 375 two or more liquid crystal forming lipids or gel forming lipids contain b-1) at least one diacylglycerol, and b-2) at least one phosphatidylcholine. Item 13. A pharmaceutical composition comprising a viscous mixture of a) the compound or salt thereof of any of items 1 to 5, b-1) at least one diacylglycerol, b-2) at least one phosphatidylcholine, and c) a biocompatible organic solvent. Item 14. A microsphere comprising the compound or salt thereof of any of items 1 to 5 as an active ingredient. Item 15. The microsphere according to item 14, comprising the compound of any of items 1 to 5 and a biodegradable polymer. Item 16. The microsphere according to item 15, wherein the biodegradable polymer is at least one member selected from the group consisting of polylactic acid and a lactic acid-glycol copolymer. Item 17. The microsphere conforms to any of items 14 to 16, having an average particle diameter of 5 to 150 μm (preferably 30 to 100 μm). Item 18. A pharmaceutical composition comprising microspheres of any of items 14 to 17 in the form of a suspension. Item 19. A pharmaceutical composition comprising microspheres of Petition 870260084657, dated 08 / 20 / 2026, page 23 / 800 19 / 375 any of items 14 to 17 in the form of an oil suspension. Item 20. The pharmaceutical composition according to item 19, where the oil is a triglyceride of medium-chain fatty acids. Item 21. The pharmaceutical composition according to any of items 6 to 13 and 18 to 20, which is for use in intramuscular administration or subcutaneous administration. Item 22. The pharmaceutical composition according to any one of items 6 to 13 and 18 to 21, which is for use in the prevention and / or treatment of a disease of the central nervous system. Item 23. The pharmaceutical composition according to item 22, where the central nervous system disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant schizophrenia,refractory or chronic, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism spectrum disorder, Tourette syndrome, tic disorder, disorder, Petition 870260084657, dated 08 / 20 / 2026, page 24 / 800 20 / 375 of attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Item 24. The pharmaceutical composition according to any of items 6 to 13 and 18 to 23, which is administered at intervals of 1 day or 2 to 3 days. Item 25. The pharmaceutical composition according to any of items 6 to 13 and 18 to 23, which is administered at intervals of 2 weeks or more. Item 26. The pharmaceutical composition according to any of items 6 to 13 and 18 to 23, which is administered at intervals of 4 weeks or more. Item 27. An agent for the prevention and / or treatment of a disease of the central nervous system, comprising the compound or salt thereof of any of items 1 to 5 as an active ingredient. Item 28. The agent according to item 27, where the central nervous system disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizo Petition 870260084657, dated 08 / 20 / 2026, page 25 / 800 21 / 375 phrenia, cognitive impairment caused by treatment-resistant, refractory, or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism spectrum disorder, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Item 29. Use of the compound or salt thereof from any of items 1 to 5 as a medicine. Item 30. A method for the prevention and / or treatment of a disease of the central nervous system, comprising administering the compound or salt thereof from any of items 1 to 5 to a human being or animal. Item 31. The method according to item 30, in which the central nervous system disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical dependency disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by schizophrenia resistance. Petition 870260084657, dated 08 / 20 / 2026, page 26 / 800 22 / 375 attempts treatment, refractory or chronic, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism spectrum disorder, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Item A-1. A compound represented by formula (I) or a salt thereof: (I) in which R1 and R2 each independently represent -O' or -OR4, R3 represents hydrogen or alkyl. R4 represents hydrogen or alkyl, optionally having 1 to 3 substituents, wherein alkyl represented by R4 may have some carbon atoms substituted by -O- and / or -(CO)O-, and if R1 and R2 both represent -OR4, R4 may be identical or different. Item A-2. The compound or salt thereof according to item A-1, wherein the alkyl represented by R4 has the carbon atom of a terminal methyl group substituted by -O- or -(CO)O-, the -O- or -(CO)O- has the RC1 substituent attached to one of its ends, and RC1 represents hydrogen, lower alkyl, optionally substituted cycloalkyl, or an optionally substituted heterocyclic group. Item A-3. Petition 870260084657, dated 08 / 20 / 2026, p. 27 / 800 23 / 375 The compound or salt thereof according to item A-1 or A-2, wherein the alkyl substituent optionally having 1 to 3 substituents is (i) a substituent attached to a carbon atom of the alkyl, or (ii) a substituent (RC1) attached to an end of the -O- or (CO)O-, wherein the substituent in (i) is halogen, hydroxy, lower alkyl, lower alkoxy, cycloalkyl, carboxy, lower alkyl amino carbonyl, or an optionally substituted heterocyclic group, and the substituent (RC1) in (ii) is hydrogen, lower alkyl, optionally substituted cycloalkyl, or an optionally substituted heterocyclic group. Item A-4. The compound or salt thereof according to any of items A1 to A-3, where the compound represented by formula (I) is a compound represented by formula (II): where R3 and R4 are as defined above. Item A-5. The compound or salt thereof according to any of items A1 to A-4, wherein R3 represents hydrogen or C1-6 alkyl. R4 represents hydrogen or C1-18 alkyl optionally having 1 to 3 substituents, wherein the alkyl represented by R4 may have 1 to 5 carbon atoms substituted by -O- and / or -(CO)O-, and if R1 and R2 both represent -OR4, R4 may be identical or Petition 870260084657, dated 08 / 20 / 2026, page 28 / 800 24 / 375 different. Item A-6. The compound or salt thereof according to any of items A-1 to A-5, wherein R4 represents hydrogen or C1-18 alkyl optionally having 1 to 3 substituents, the substituents each independently representing hydrogen, halogen, hydroxyl, lower alkoxy, -O-(CH2)n-OR5, -O(CO)(CH2)n-OR5a, -(CO)OR6, -(CO)NR7R8, -O(CO)R9, -O(CO)OR10, O(CO)(CR11R12)n(CO)OR13, C3-7 cycloalkyl, or an optionally substituted heterocyclic group. R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, or C3-7 cycloalkyl. R7 and R8 independently represent hydrogen or lower alkyl groups optionally having 1 or 2 carbon atoms substituted by an oxygen atom or a nitrogen atom. R7 and R8 can be linked to form a ring. R11 and R12 independently represent hydrogen or C1-16 alkyl, wherein if two or more R11s are present, the two or more R11s independently represent hydrogen or C1-16 alkyl, and if two or more R12s are present, the two or more R12s independently represent hydrogen or C1-16 alkyl, n represents an integer from 1 to 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and if R1 and R2 both represent -OR4, R4 may be identical or different. Item A-7. The compound or salt thereof according to any of items A1 to A-6, Petition 870260084657, dated 08 / 20 / 2026, page 29 / 800 25 / 375 in which R4 represents hydrogen or -(AY)m-R14, A represents C1-18 alkylene, Y represents a bond, -O-, -(CO)O-, -O(CO)O-, or -(CO)NH-, R14 represents hydrogen, C1-18 alkyl, hydroxyl, cycloalkyl, or a heterocyclic group, where represents an integer from 0 to 5 (0, 1, 2, 3, 4, or 5). Item A-8. The compound or salt thereof according to any of items A4 to A-6, wherein R4 represents hydrogen or C1-8 alkyl optionally having a substituent, the substituent independently representing hydroxy, lower alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, -O(CO)R9, O(CO)OR10, -O(CO)-A-(CO)OR13, or morpholinyl optionally having two C1-6 alkyl groups, n represents an integer from 1 to 10, R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, an optionally substituted heterocyclic group, or C3-7 cycloalkyl, and A represents C1-6 alkylene. Item A-9. The compound or salt thereof according to any of items A4 to A-6, wherein R4 represents hydrogen or C1-8 alkyl optionally having a substituent, the substituent independently representing Petition 870260084657, dated 08 / 20 / 2026, page 30 / 800 26 / 375 hydroxy, C1-6 alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, -O(CO)R9, -O(CO)-A-(CO)OR13, or a heterocyclic group optionally having two C1-6 alkyl groups, n represents an integer from 1 to 10, R5 represents C1-6 alkyl, R5a represents C1-6 alkyl, R6 represents C1-6 alkyl, R9 represents C1-16 alkyl, R13 represents C1-6 alkyl or pyridyl optionally having C1-6 alkyl, and A represents C1-6 alkylene. Item A-10. The compound or salt thereof according to any one of items A4 to A-9, wherein the heterocyclic group has a structure in which a hydrogen atom bonded to a constituent atom of a heterocycle is removed from the heterocycle, the heterocycle being selected from the group consisting of furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline. Item A-11. A pharmaceutical composition comprising the compound or a salt thereof of any of items A-1 to A-10 and a pharmaceutically acceptable carrier. Item A-12. The pharmaceutical composition according to item A-11, comprising the compound or salt thereof of any of items A-1 to A-10, a suspending agent, and a dispersing medium, wherein the pharmaceutical composition is in the form of a suspension. Petition 870260084657, dated 08 / 20 / 2026, page 31 / 800 27 / 375 Item A-13. The pharmaceutical composition is in accordance with item A-12, where the average particle diameter of the particles in the suspension ranges from 0.5 to 30 μm. Item A-14. The pharmaceutical composition according to item A-12, where the average particle diameter of the particles in the suspension ranges from 50 to 500 nm. Item A-15. The pharmaceutical composition according to any one of items A-12 to A-14, wherein the suspending agent is carboxymethyl cellulose or a salt thereof, and the dispersing medium is a liquid containing water for injection. Item A-16. A pharmaceutical composition comprising a viscous mixture of a) the compound or salt thereof from any of items A-1 to A-10, b) two or more liquid crystal-forming lipids or gel-forming lipids, and c) a biocompatible organic solvent, wherein the pharmaceutical composition is a precursor preparation used to form a liquid crystalline phase or lipogel structure by placing the pharmaceutical composition in contact with an aqueous fluid in vivo. Item A-17. The pharmaceutical composition according to item A-16, wherein b) the two or more liquid crystal-forming lipids or gel-forming lipids contain b-1) at least one diacylglycerol, and Petition 870260084657, dated 08 / 20 / 2026, page 32 / 800 28 / 375 b-2) at least one phosphatidylcholine. Item A-18. A pharmaceutical composition comprising a viscous mixture of a) the compound or salt thereof of any of items A-1 to A-10, b-1) at least one diacylglycerol, b-2) at least one phosphatidylcholine, and c) a biocompatible organic solvent. Item A-19. A microsphere comprising the compound or salt thereof of any of items A-1 to A-10 as an active ingredient. Item A-20. A microsphere according to item A-19, comprising the compound of any of items A-1 to A-10 and a biodegradable polymer. Item A-21. A microsphere according to item A-20, wherein the biodegradable polymer is at least one member selected from the group consisting of polylactic acid and a lactic acid-glycol copolymer. Item A-22. The microsphere conforms to any of items A-19 to A-21, having an average particle diameter of 5 to 150 μm (preferably 30 to 100 μm). Item A-23. A pharmaceutical composition comprising microspheres of any of items A-19 to A-22 in the form of a suspension. Item A-24. A pharmaceutical composition comprising microspheres of any of items A-19 to A-22 in the form of an oil suspension. Petition 870260084657, dated 08 / 20 / 2026, page 33 / 800 29 / 375 Item A-25. The pharmaceutical composition according to item A-24, where the oil is a triglyceride of medium-chain fatty acids. Item A-26. The pharmaceutical composition according to any of items A-11 to A-18 and A-23 to A-25, which is for use in intramuscular administration or subcutaneous administration. Item A-27. The pharmaceutical composition according to any of items A-11 to A-18 and A-23 to A-26, which is for use in the prevention and / or treatment of a disease of the central nervous system. Item A-28. An agent for the prevention and / or treatment of a disease of the central nervous system, comprising the compound or salt thereof of any of items A-1 to A-10 as an active ingredient. Item A-29. The agent according to item A-28, wherein the central nervous system disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by schizophrenia resistance Petition 870260084657, dated 08 / 20 / 2026, page 34 / 800 30 / 375 attempts treatment, refractory or chronic, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism spectrum disorder, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. Item A-30. Use of the compound or salt thereof of any of items A-1 to A10 as a medicine. Item A-31. A method for the prevention and / or treatment of a disease of the central nervous system, comprising administering the compound or salt thereof from any of items A-1 to A-10 to a human being or animal. Item A-32. The method according to item A-31, where the central nervous system disease is selected from the group consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia, cognitive impairment caused by treatment-resistant, refractory or chronic schizophrenia, vomiting,motion sickness Petition 870260084657, dated 08 / 20 / 2026, page 35 / 800 31 / 375 obesity, migraine, pain, mental retardation, autism spectrum disorder, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. In the above items, the “heterocycle” for the optionally substituted heterocyclic group is, for example, a monocyclic or polycyclic heterocycle, saturated or unsaturated, containing as ring constituent atoms 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, and includes, for example, a monocyclic, bicyclic or tricyclic heterocycle, saturated or unsaturated, of 3 to 15 members, preferably 5 to 10 members.

[007] Specifically, examples of heterocycles include furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline. A heterocyclic group has a structure in which a hydrogen atom bonded to a constituent atom of a heterocycle is removed from the heterocycle.

[008] In the above items, the optionally substituted heterocyclic group substituent includes halogen, hydroxy, C1-6 alkyl optionally substituted with halogen, hydroxy, oxo, or C1-6 alkoxy, and C1-6 alkoxy optionally substituted with halogen, hydroxy, or oxo.

[009] The number of substituents is, for example, 1, 2, or 3. Advantageous Effects of the Invention

[0010] The compound represented by formula (I) has a structure in which a specific nitrogen atom of brexpiprazole is chemically modified. After the compound represented by formula (I) is administered in vivo, the compound is converted to brexpiprazole under physiological conditions. Petition 870260084657, dated 08 / 20 / 2026, page 36 / 800 32 / 375

[0011] The compound represented by formula (I) includes (1) compounds having relatively low cytotoxicity. The compound represented by formula (I) includes (2) compounds that are highly stable and easy to handle. The compound represented by formula (I) includes (3) compounds that are absorbed relatively rapidly subcutaneously. The compound represented by formula (I) includes (4) compounds that are rapidly converted to brexpiprazole in vivo. The compound represented by formula (I) includes (5) compounds that are suitable for injection, in particular, subcutaneous injection. The compound represented by formula (I) includes (6) compounds that are suitable for long-acting injection that maintains the concentration of brexpiprazole in the blood for one to four weeks or more, in particular, long-acting subcutaneous injection. Brief Description of the Drawings

[0012] Fig. 1 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example A to rats (dose: 1.25 mg / kg) (N=3, mean ± standard deviation).

[0013] Fig. 2 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example D (aqueous suspension of the compound of Example 1) to rats (dose: 31.3 mg / kg) (N=3, mean ± standard deviation).

[0014] Fig. 3 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example E (aqueous suspension of the zinc salt of the compound from Example 1) to rats (dose: 33.2 mg / kg) (N=3, mean ± standard deviation).

[0015] Fig. 4 is a graph showing the changes in plasma drug concentration after subcutaneous administration of Petition 870260084657, dated 08 / 20 / 2026, p. 37 / 800 33 / 375 pharmaceutical composition of Example F (liquid crystal / lipid gel formulation of the compound from Example 1) to rats (dose: 31.3 mg / kg) (N=3, mean ± standard deviation).

[0016] Fig. 5 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example G (liquid crystal / lipid gel formulation of the zinc salt of the compound of Example 1) to rats (dose: 33.2 mg / kg) (N=3, mean ± standard deviation).

[0017] Fig. 6 shows the results of polarized light microscopy observation of the microspheres from Production Example I.

[0018] Fig. 7 shows the results of polarized light microscopy observation of the microspheres from Production Example J.

[0019] Fig. 8 shows the results of polarized light microscopy observation of the microspheres from Production Example K.

[0020] Fig. 9 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example H to rats (dose: 31.3 mg / kg) (microsphere formulation of the compound of Example 1 (RG 505, 1.5 times relative to the API)) (N=5 until day 14, N=3 after day 21, mean ± standard deviation).

[0021] Fig. 10 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example J to rats (dose: 31.3 mg / kg) (microsphere formulation of the compound of Example 1 (RG 504, 2 times relative to the API)) (N=5 until day 14, N=3 after day 21, mean ± standard deviation).

[0022] Fig. 11 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example K to rats (dose: 31.3 mg / kg) (microsphere formulation of the compound of Example 1 (RG 503, 1.5 Petition 870260084657, dated 08 / 20 / 2026, page 38 / 800 34 / 375 times in relation to the IFA)) (N=5 until day 14, N=3 after day 21, mean ± standard deviation).

[0023] Fig. 12 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example L to rats (dose: 31.3 mg / kg) (microsphere formulation of the compound of Example 1 (RG 503, 2 times relative to the API)) (N=3, mean ± standard deviation).

[0024] Fig. 13 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example P (aqueous suspension of the compound of Example 3) to rats (dose: 29.8 mg / kg) (N=5, mean ± standard deviation).

[0025] Fig. 14 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example Q (aqueous suspension of the compound of Example 10) to rats (dose: 35.5 mg / kg) (N=3, mean ± standard deviation).

[0026] Fig. 15 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example R (aqueous suspension of the compound of Example 12) to rats (dose: 34.7 mg / kg) (N=3, mean ± standard deviation).

[0027] Fig. 16 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example S (aqueous suspension of the compound of Example 13) to rats (dose: 36.3 mg / kg) (N=3, mean ± standard deviation).

[0028] Fig. 17 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example T (aqueous suspension of the com Petition 870260084657, dated 08 / 20 / 2026, page 39 / 800 35 / 375 position of Example 44) to rats (dose: 37.1 mg / kg) (N=3, mean ± standard deviation).

[0029] Fig. 18 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example U (aqueous suspension of the compound of Example 92) to rats (dose: 36.3 mg / kg) (N=3, mean ± standard deviation).

[0030] Fig. 19 is a graph showing the changes in plasma drug concentration after subcutaneous administration of the pharmaceutical composition of Example V (aqueous suspension of the compound of Example 121) to rats (dose: 37.1 mg / kg) (N=3, mean ± standard deviation). Description of Modalities

[0031] The following items describe in more detail embodiments that fall within the scope of the present invention. Although the present invention includes a specific novel heterocyclic compound and a salt thereof (in particular, a pharmaceutically acceptable salt), a pharmaceutical composition containing the compound and / or salt thereof as an active ingredient, and the use thereof, the present invention is not limited to the same. The present invention encompasses all the subject matter disclosed in this descriptive report and which can be identified by a person skilled in the art.

[0032] The specific new heterocyclic compound that falls within the scope of the present invention is a heterocyclic compound represented by formula (I): in what R1 and R2 each independently represent -O; -OR4, or Petition 870260084657, dated 08 / 20 / 2026, page 40 / 800 36 / 375 -NR4NaR4Nb R3 represents hydrogen or alkyl. R4, R4Na, and R4Nb each independently represent hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl, each optionally having 1 to 3 substituents, wherein alkyl represented by R4, R4Na, or R4Nb may have a structure in which one or more methylene groups (-CH2-) are substituted by -O-, -S-, -CO-, -NH-, -SiRsiaRsib-, or (CO)O-. If R1 and R2 both represent -OR4, then R1 and R2 may be identical or different, and if R1 and R2 both represent -NR4NaR4Nb, then R1 and R2 may be identical or different. Rsiae Rsibsão identical or different and represent hydrogen or C1-6 alkyl.

[0033] In this descriptive report, the compound represented by formula (I) is also referred to as “compound (I)”.

[0034] In the present descriptive report, alkenyl is, for example, linear or branched alkenyl having 1 to 18 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms (C1-18 alkenyl), more preferably C1-12 alkenyl, and even more preferably C1-8 alkenyl or C1-6 alkenyl. Alkenyl also includes both cis and trans forms, among the stereoisomers due to a carbon-carbon double bond. In this descriptive report, alkadienyl is, for example, linear or branched alkadienyl having 1 to 18 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms (C1-18 alkadienyl), more preferably C1-12 alkadienyl, and even more preferably C1-8 alkadienyl or C1-6 alkadienyl. Alkadienyl also includes both cis and trans forms, between the es Petition 870260084657, dated 08 / 20 / 2026, p. 41 / 800 37 / 375 tereoisineris due to a carbon-carbon double bond.

[0035] Specifically, alkadienyl includes those with any (cis, cis), (cis, trans), (trans, cis), or (trans, trans) structure, which are in order based on the carbon-carbon double bond present closest to the alkadienyl end.

[0036] In the present descriptive report, alkynyl is, for example, linear or branched alkynyl having 1 to 18 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms (C1-18 alkynyl), more preferably C1-12 alkynyl, and even more preferably C1-8 alkynyl or C1-6 alkynyl.

[0037] If R4, R4Na, or R4Nb represents alkenyl, alkadienyl, or alkynyl, the alkenyl may have one or multiple (e.g., 1 to 3, preferably 1) substituents (substituent groups), the alkadienyl may have one or multiple (e.g., 1 to 3, preferably 1) substituents (substituent groups), and the alkynyl may have one or multiple (e.g., 1 to 3, preferably 1) substituents (substituent groups). Examples of such substituents include halogen, hydroxyl, lower alkyl, and lower alkoxy.

[0038] In the present descriptive report, alkyl is, for example, linear or branched alkyl having 1 to 24 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) carbon atoms (C1-24 alkyl), more preferably C1-18 alkyl, and even more preferably C1-16 alkyl, C1-12 alkyl, C1-8 alkyl, or C1-6 alkyl.

[0039] More specifically, alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, heptyl, octyl, nonyl, decyl, tetradecyl, or similar.

[0040] In this descriptive report, alkyl represented by R4, R4Na, or R4Nb includes alkyl groups with a structure in which one or more methylene groups (-CH2-) are replaced by -O-, -S-, -CO-, -NH-, Petition 870260084657, dated 08 / 20 / 2026, p. 42 / 800 38 / 375 -SiRsiaRsib-, or -(CO)O-. Rsia and Rsib are identical or different and represent hydrogen or C1-6 alkyl.

[0041] More specifically, in this descriptive report, alkyl represented by R4, R4Na, or R4Nb includes alkyl with the substitution structure described above and alkyl without such a substitution structure. Alkyl groups other than alkyl represented by R4, R4Na, or R4Nb are alkyl without such a substitution structure, unless otherwise indicated.

[0042] In the alkyl with the substitution structure, the number of substituted methylene groups depends on the number of carbons in the alkyl before the substitution, but is preferably 1 to 8 (1, 2, 3, 4, 5, 6, 7, or 8), more preferably 1 to 6, and even more preferably 1 to 5 or 1 to 4.

[0043] It is preferable that R1 and R2 are both -OR4, or that R1 is -O-, and R2be -OR4or NR4NaR4Nb.

[0044] If R3 is alkyl, lower alkyl is particularly preferred, more specifically, C1-4 alkyl is preferred, and methyl or ethyl is more preferred.

[0045] In this descriptive report, “lower” as used for substituents with a carbon chain indicates the number of carbon atoms from one to six (1, 2, 3, 4, 5, or 6).

[0046] If R4, R4Na, or R4Nb is alkyl, specifically C1-24 alkyl is preferred, and C1-18 alkyl is more preferred. The alkyl, as described above, may have the substitution structure (a structure in which one or more methylene groups (-CH2-) are substituted by -O-, -S-, -CO-, NH-, -SiRsiaRsib-, or -(CO)O-). As described above, the number of substituted methylene groups depends on the number of carbons in the alkyl before substitution, but is preferably 1 to 8 (1, 2, 3, 4, 5, 6, 7, or 8), more preferably 1 to 6, and even more preferably 1 to 5 or 1 to 4. In -OR4 or -NR4NaR4Nb independently represented Petition 870260084657, dated 08 / 20 / 2026, p. 43 / 800 39 / 375 by R1e R2, if the asterisk “*” is on the side of the oxygen atom (i.e., on the side where -OR4 or -NR4NaR4N is bonded to a phosphorus atom), -(CO)O- can be *(CO)O- or *-O(CO)-. If multiple methylene groups are substituted, the structures after the substitution (i.e., -O-, -S-, -CO-, -NH-, -SiRsiaRsib-, or -(CO)O-) can be identical or different.

[0047] For example, -(CH2)2-O-(CH2)2-O-CH3 is an example of the substitution of two methylene groups by -O- in -(CH2)6-CH3. As another example, -CH2-(CO)O-CH2-CH3 is an example of the substitution of one methylene group by *-(CO)O- in -(CH2)3-CH3. As yet another example, -(CH2)3-O(CO)-CH3 is an example of the substitution of one methylene group by *-O(CO)- in -(CH2)4-CH3.

[0048] If R4, R4Na, or R4Nb represents alkyl, the alkyl may have one or multiple (e.g., 1 to 3) substituents (substituent groups).

[0049] The substituent is present by attaching to a carbon atom of the alkyl or to the nitrogen atom of the -NH- that replaces a methylene group; or if the methylene group in a methyl group at the end of the alkyl (the underlined part of -CH2-H) is substituted, the substituent is present by attaching to an end of the substitution structure and not to the hydrogen (that is, if the substituent is specifically expressed as “RC1,” the substituent is present in the form of -O-RC1, -S-RC1, -CO-RC1, -NH-RC1, -SiRsiaRsib-RC1, or -(CO)O-RC1, or -O(CO)-RC1).

[0050] Examples of substituents attached to a carbon atom of the alkyl include halogen, hydroxy, alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), cycloalkyl, carboxy, alkyl amino carbonyl (preferably lower alkyl amino carbonyl), optionally substituted phenyl or benzyl, and optionally substituted heterocyclic groups (a group with a structure in which Petition 870260084657, dated 08 / 20 / 2026, page 44 / 800 40 / 375 a hydrogen atom bonded to a constituent atom of an optionally substituted heterocyclic group is removed from the heterocycle).

[0051] In this descriptive report, examples of halogens include fluorine, chlorine, bromine, and iodine (F, Cl, Br, and I), with fluorine, chlorine, or bromine being preferred.

[0052] In this descriptive report, alkylene is, for example, a linear or branched alkylene group having 1 to 20 carbon atoms.

[0053] More specific examples include methylene, ethylene, trimethylene, tetramethylene, hexamethylene, heptamethylene, octamethylene, decamethylene, undecamethylene, dodecamethylene, 1-methylethylene, 2-ethyltrimethylene, 1-methyl-heptamethylene, 2-methyl-heptamethylene, 1-butylhexamethylene, 2-methyl-5-ethyl-heptamethylene, 2,3,6-trimethyl-heptamethylene, and 6-ethyldecamethylene.

[0054] In this descriptive report, alkoxy is, for example, a linear or branched alkoxy having 1 to 6 carbon atoms (C1-6 alkoxy); specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and 3-methylpentyloxy.

[0055] In this descriptive report, cycloalkyl is, for example, cyclic alkyl having 3 to 7 (3, 4, 5, 6, or 7) carbon atoms (C3-7 cycloalkyl); specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0056] A cycloalkyl group has a structure in which a hydrogen atom bonded to a carbon atom between the constituent carbon atoms of the cycloalkyl group is removed.

[0057] In this descriptive report, a “heterocycle” is, for example, a monocyclic or polycyclic heterocycle, saturated or unsaturated, containing as ring constituent atoms 1 to 5 heteroatoms independently selected from the nitrogen-containing group, Petition 870260084657, dated 08 / 20 / 2026, page 45 / 800 41 / 375 oxygen and sulfur, and includes, for example, a monocyclic, bicyclic or tricyclic heterocycle, saturated or unsaturated, of 3 to 15 members, preferably 5 to 10 members.

[0058] Specifically, examples of heterocycles include furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline. A heterocyclic group has a structure in which a hydrogen atom bonded to a constituent atom of a heterocycle is removed from the heterocycle.

[0059] In this descriptive report, examples of lower alkyl aminocarbonyl groups include a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, and an isopropylaminocarbonyl group.

[0060] Optionally substituted phenyl or benzyl substituents or optionally substituted heterocyclic groups may be, for example, the same substituents for alkyl represented by R4.

[0061] The substituent also includes halogen, hydroxy, C1-6 alkyl optionally substituted with halogen, hydroxy, oxo, or C1-6 alkoxy, and C1-6 alkoxy optionally substituted with halogen, hydroxy, or oxo.

[0062] The number of optionally substituted phenyl or benzyl substituents or of an optionally substituted heterocyclic group is, for example, 1, 2, or 3.

[0063] Among those that fall within the scope of compound (I), a compound in which R1 represents -O-, R2 represents -OR4 or -NR4NaR4Nb, and R3 represents hydrogen or methyl is preferred.

[0064] In this case, R4ou -NR4NaR4Nbé more preferably, for example, the following group. (R4: Example 1 Preferable) Petition 870260084657, dated 08 / 20 / 2026, p. 46 / 800 42 / 375 R4 represents R4a1, R4a2, or R4a3. R4a1 represents - CnH2n+1, - CnH2n-1, - CnH2n-3, CnH2n-OH -CnH2n-2-OH (preferably having a single carbon-carbon double bond in -CnH2n-2-), or -CnH2n-4-OH (more preferably having two carbon-carbon double bonds or a single carbon-carbon triple bond in -CnH2n-4 (In the formulas above, n represents 1 to 24. n can represent, but without limitation, for example, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, n represents 2 or more in -CnH2n-1, n represents 2 or more in -CnH2n3, n represents 2 or more in -CnH2n-2-, and n represents 2 or more in CnH2n-4-). R4a2 represents - CHX1X2, Cn-1H2n-2-CHX1X2, - Cn-1H2n-4-CHX1X2 (more preferably having a single carbon-carbon double bond in -Cn-1H2n-4-), or - Cn-1H2n-6-CHX1X2 (more preferably having two carbon-carbon double bonds or a single carbon-carbon triple bond in -Cn1H2n-6-)

[0065] (In the formulas above, n represents 2 to 24. n can represent, however without limitation, for example, 2 to 18, 2 to 12, 2 to 10, or 2 to 6. However, n represents 3 or more in -Cn-1H2n-6-.) X1 and X2 can be identical or different and represent hydrogen or halogen (F, Cl, Br, or I). However, at least one of them is preferably a halogen. R4a3 represents Petition 870260084657, dated 08 / 20 / 2026, page 47 / 800 43 / 375 -CnH2n-R4-1, -Cn-iH2n-2-CHR4'1aR4'1b, -CnH2n-2-R4-1, OU -CnH2n-4-R4-1 (where n represents 1 to 24. n may represent, but is not limited to, for example, 1 to 18, 1 to 12, 1 to 10, or 1 to 6. However, n represents 2 or more in -CnH2n-2-, en represents 2 or more in -CnH2n-4-. R4'1 represents C1-6 alkoxy, -O-phenyl, or a heterocyclic group optionally substituted with C1-6 alkyl or halogen. The same also applies to the following.

[0066] If R4'1 is the heterocyclic group described above, preferred examples of R41 include, but without particular limitation, the following groups. (R4: Example 2 Preferable) R4 represents R4b, and R4b represents -(CPH2p-O)q-CrH2r-R4-2, -(CpH2p-O)q-CrH2r-2-R4-2, -(CPH2p-2-O)q-CrH2r-R4-2, or -(CpH2p-2-O)q-CrH2r-2-R4-2

[0067] (In the formulas above, p represents 1 to 4, q represents 1 to 4, er represents 1 to 4. However, p represents 2 or more in CPH2p.2, er represents 2 or more in CrH2r-2. When q is 2 to 4, 2 to 4 structures Petition 870260084657, dated 08 / 20 / 2026, p. 48 / 800 44 / 375 repeating groups, whose number of repetitions is represented by q, may be identical or different. R4-2 represents hydrogen, hydroxyl, or “cycloalkyl, phenyl, benzyl, or a heterocyclic group, each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-3 alkylene-C1-3 alkoxy, and nitro”). The same applies to the following. (R4: Example 3 Preferable) R4 represents -CaH2a-CO-O-RCO° or -CaH2a-CO-O-CH2-RCO° (α represents 1 to 10). -RCOO represents hydrogen, C1-6 alkyl or C1-6 alkoxy each optionally substituted with 1 to 3 C1-6 alkoxy groups, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro. The same applies to the following. R4 preferably represents -Ca^a-CO-O-RCOO. - RCOO preferably represents hydrogen or C1-6 alkyl optionally substituted with 1 to 3 C1-6 alkoxy groups. (R4: Example 4 Preferable) R4 represents -CpH2p-O-CO-ROCO (β represents 1 to 10). - ROCO represents R4a1, R4b, or -CαH2α-CO-O-RCOO; or -CoHarCO-NHRCOO, - CaH2a-NH-CO-RCOO, or -CaH2a-NH-CO-O-RCOO; or cycloalkyl, phenyl, benzyl, or a heterocyclic group, each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro.

[0068] The same applies to the following. (R4: Example 5 Preferable) R4represents -CγH2γ-O-CO-O-ROCOO(γ represents 1 to 10). -ROCOO represents hydrogen, R4a1, R4b, or -CαH2α-CO-O-RCOO; or cycloalkyl, phenyl, benzyl, or a heterocyclic group, each optional. Petition 870260084657, dated 08 / 20 / 2026, p. 49 / 800 45 / 375 finally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-3 alkylene-C1-3 alkoxy, and nitro. The same applies to the following. (NR4NaR4Nb: Example i Preferred) R4Nae and R4Nbsão are identical or different and represent C1-6 alkyl optionally substituted with 1a 3 C1-6 alkoxy groups. (NR4NaR4Nb: Example ii Preferable) R4Na represents hydrogen, R4N represents C1-6 alkyl optionally substituted with C1-6 alkoxy; or -CaH2a-CO-O-RCOO or -CaH2a-CO-NH-RCOO

[0069] The alphabetic symbols used in the preferred examples may be identical or different. For example, -RCOO is explained in Preferred Example 3, and also in Preferred Examples 4 and 5. RCOO in Preferred Examples 3 to 5 may be identical or different within the scope described above.

[0070] Additionally, the following tables present preferred examples of R2 in relation to R1 and R2 when R1 is -O-, and R2 is -OR4 or NR4NaR4Nb. In Table 3, the asterisk “*” indicates the side on which R2 is bonded to the phosphorus atom. All optical isomers of the structural formulas shown in Table 3 are also covered by the present invention. Table 3 Petition 870260084657, dated 08 / 20 / 2026, p. 50 / 800 46 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 51 / 800 47 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 52 / 800 48 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 53 / 800 49 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 54 / 800 50 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 55 / 800 51 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 56 / 800 52 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 57 / 800 53 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 58 / 800 54 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 59 / 800 55 / 375

[0071] In a more preferred embodiment, compound (I) is a compound represented by the following formula (II): (where R3 and R4 are as defined above). In this descriptive report, among the compounds that fall within the scope of compound (I), the compound represented by formula (II) is also specifically referred to as “compound (II).” Compound (II) has a structure in which R1 is -O; and R2 is -OR4 in formula (I).

[0072] A Preferred Example of compound (II) is further described below. However, the above description also includes the description of compound (II), and compound (II) is not limited by the following explanation.

[0073] R4 can be, specifically, hydrogen or C1-18 alkyl Petition 870260084657, dated 08 / 20 / 2026, p. 60 / 800 56 / 375 optionally having 1 to 3 substitutes.

[0074] The substituents independently represent halogen, hydroxyl, lower alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, (CO)OR6, -(CO)NR7R8, -O(CO)R9, -O(CO)OR10, -O(CO)-(CR11R12)n(CO)OR13, C3-7 cycloalkyl, or an optionally substituted heterocyclic group. R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, an optionally substituted heterocyclic group, or C3-7 cycloalkyl. R7 and R8 independently represent hydrogen or lower alkyl optionally having 1 or 2 carbon atoms substituted with an oxygen atom or with a nitrogen atom. R7 and R8 may be linked to form a ring.R11 and R12 independently represent hydrogen, C1-16 alkyl, or C3-7 cycloalkyl, wherein if two or more R11s are present, the two or more R11s independently represent hydrogen, C1-16 alkyl, or C3-7 cycloalkyl, and if two or more R12s are present, the two or more R12s independently represent hydrogen, C1-16 alkyl, or C3-7 cycloalkyl. n represents an integer from 1 to 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0075] For alkyl, “optionally having 1 or 2 carbon atoms substituted by an oxygen atom or by a nitrogen atom” is synonymous with “one or more methylene groups (-CH2-) may be substituted by -O- or -NH”.

[0076] Although not particularly limited, examples of the optionally substituted heterocyclic group include the groups listed above as R4-1 representing a heterocyclic group optionally substituted with C1-6 alkyl or halogen. Without any particular limitation, if R7 and R8 are linked to form a ring, examples of NR7R8 include groups with a structure in which a hydrogen atom bonded to a nitrogen atom is removed, among the groups listed as R4-1 representing an optionally substituted heterocyclic group. Petition 870260084657, dated 08 / 20 / 2026, page 61 / 800 57 / 375 te replaced with C1-6 alkyl or halogen.

[0077] R4 is more preferably hydrogen or C1-8 alkyl optionally having a substituent.

[0078] The substituent independently represents hydroxy, lower alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, -O(CO)R9, -O(CO)OR10, -O(CO)-A-(CO)OR13, or morpholinyl optionally having two C1-6 alkyl groups. R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, an optionally substituted heterocyclic group, or C3-7 cycloalkyl. A represents C1-6 alkylene. n is as defined above.

[0079] R4 is more preferably hydrogen or C1-8 alkyl optionally having a substituent. The substituent independently represents hydroxy, C1-6 alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, (CO)OR6, -O(CO)R9, -O(CO)-A-(CO)OR13, or a heterocyclic group optionally having two C1-6 alkyl groups. R5 represents C1-6 alkyl. R5a represents C1-6 alkyl. R6 represents C1-6 alkyl. R9 represents C1-16 alkyl. R13 represents C1-6 alkyl or pyridyl optionally having C1-6 alkyl. A represents C1-6 alkylene. n is as defined above.

[0080] R4 also represents hydrogen or -(AY)m-R14 where A represents C1-18 alkylene, Y represents a bond, -O-, -(CO)O-, or -(CO)NH-, R14 represents hydrogen, halogen, C1-18 alkyl, hydroxy, cycloalkyl, or a heterocyclic group, and represents an integer from 0 to 5 (0, 1, 2, 3, 4, or 5).

[0081] In -OR4 independently represented by R1 and R2, if the asterisk “*” is on the side of the oxygen atom (that is, on the side of the phosphorus atom to which -OR4 is bonded), -(CO)O- can be *-(CO)O or *-O(CO)-, and -(CO)NH- can be *-(CO)NH- or *-NH(CO)-.

[0082] Table 4 below presents more preferable examples of the specific compound (I). Petition 870260084657, dated 08 / 20 / 2026, p. 62 / 800 58 / 375 Table 4 Petition 870260084657, dated 08 / 20 / 2026, p. 63 / 800 59 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 64 / 800 60 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 65 / 800 61 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 66 / 800 62 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 67 / 800 63 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 68 / 800 64 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 69 / 800 65 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 70 / 800 66 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 71 / 800 67 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 72 / 800 68 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 73 / 800 69 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 74 / 800 70 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 75 / 800 71 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 76 / 800 72 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 77 / 800 73 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 78 / 800 74 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 79 / 800 75 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 80 / 800 76 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 81 / 800 77 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 82 / 800 78 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 83 / 800 79 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 84 / 800 80 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 85 / 800 81 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 86 / 800 82 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 87 / 800 83 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 88 / 800 84 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 89 / 800 85 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 90 / 800 86 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 91 / 800 87 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 92 / 800 88 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 93 / 800 89 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 94 / 800 90 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 95 / 800 91 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 96 / 800 92 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 97 / 800 93 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 98 / 800 94 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 99 / 800 95 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 100 / 800 96 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 101 / 800 97 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 102 / 800 98 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 103 / 800 99 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 104 / 800 100 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 105 / 800 101 / 375

[0083] In one embodiment, examples of diseases that can be prevented and / or treated with compound (I) or a salt thereof include the following central nervous system diseases: schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia,Cognitive impairment caused by treatment-resistant, refractory, or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, mental retardation, special needs disorder, Petition 870260084657, dated 08 / 20 / 2026, page 106 / 800 102 / 375 autistic tro, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder. General Production Method

[0084] Compound (I) can be produced, for example, according to the following general production methods. However, the method is not limited to these methods.

[0085] The starting materials for use may be commercial products, or they may be synthesized according to a known method or by a method equivalent to a known method.

[0086] The solvents, acids, bases, protecting groups, and displaceable groups used in the production of compound (I) may be any of those commonly used in the field of synthetic organic chemistry.

[0087] In the production of compound (I), the product in the form of a reaction solution or crude product may be used in the subsequent reaction, or the product may be isolated from the reaction mixture according to a common method and easily purified by common separation techniques. Examples of common separation techniques include filtration, extraction, condensation, evaporation, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution.

[0088] In the production of compound (I), reactions such as alkylation, hydrolysis, amination, esterification, amidation, etherification, oxidation, and reduction can be carried out according to known methods.

[0089] These various commonly used reagents and methods are described, for example, in Organic Functional Group Preparations (2nd ed., Academic Press, Inc., 1989); Comprehensive Organic Transformations (VCH Publishers, Inc., 1989, PGM Wuts); and Greene's Petition 870260084657, dated 08 / 20 / 2026, p. 107 / 800 103 / 375 Protective Groups in Organic Synthesis (4th ed., 2006, TW Greene, John Wiley & Sons, New York, 1991).

[0090] In the general method for producing compound (I), the starting materials, the intermediate compounds, and compound (I) may be in their salt form; the target compound obtained in each reaction may also be in the form of a salt.

[0091] If these compounds are free compounds, they can be converted to their desired salt form according to a known method. If the compounds are in the form of a salt, they can be converted to their free form or another desired salt form according to a known method.

[0092] The following describes, in particular, a method for producing compound (II). The following method for producing compound (II) is a specific example of the method for producing compound (I). A person skilled in the art will understand that compound (I) can be produced by the same operations according to the specific example. A person skilled in the art will also understand that compound (I) can be produced according to the production methods described in the Examples, methods known in the prior art, or methods easily conceivable from known methods.

[0093] Compound (II) can be produced, for example, according to the production method described below. The production method described below is an example and is not intended to limit the production method of compound (II). In the following reaction formulas, each starting material can form a salt if it does not inhibit the reactions. The salt for use can be those listed as examples of salts of compound (II).

[0094] For starting materials whose specific production method is not described, commercial products may be used, or the starting materials may be produced according to a method. Petition 870260084657, dated 08 / 20 / 2026, page 108 / 800 104 / 375 known or a method equivalent to a known method. The solvents, acids, bases, protecting groups, and displaceable groups in the production of compound (II) may be any of those commonly used in the field of synthetic organic chemistry.

[0095] In the production of compound (II), the product in the form of a reaction solution or crude product may be used in the subsequent reaction, or the product may be isolated from the reaction mixture according to a known method and easily purified by common separation techniques. Examples of common separation techniques include filtration, extraction, condensation, evaporation, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution.

[0096] More specifically, compound (II) can be synthesized, for example, according to a method classified in step A and step B below. Step A: Phosphoric acid coupling reaction

[0097] In the formula above, LG represents a displaceable group, and R15 represents alkyl optionally having 1 to 3 substituents where alkyl may have some carbon atoms substituted by -O- and / or (CO)O-. Other alphabetical symbols are as defined above. For alkyl represented by R15, the explanation for R4 applies directly. R4 and R15 may be identical or different, and are preferably Petition 870260084657, dated 08 / 20 / 2026, p. 109 / 800 105 / 375 different. R15 is more preferably linear or optionally substituted branched alkyl.

[0098] Compound (II-1) can be obtained by reacting compound (1) with compound (2) in an inert solvent, in the presence or absence of a base depending on the reaction conditions (Step A-1). Compound (1) is brexpiprazole.

[0099] Compound (1) can be produced according to the method described in PTL document 1 (JP2006-316052A), and can be used in free form or in the form of a salt. Examples of compound (1) in the form of a salt include salts of inorganic acids, such as hydrochloride, sulfate, phosphate, hydrobromide, iodide, and nitrate; salts of organic acids, such as formate, propionate, oxalate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, malonate, succinate, maleate, fumarate, malate, and lactate; and salts of amino acids, such as aspartate and glutamate.

[00100] Examples of displaceable groups include halogen atoms (e.g., chlorine, bromine, and iodine), alkylsulfonyloxy groups (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), and arylsulfonyloxy groups (e.g., benzenesulfonyloxy, ptoluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy).

[00101] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; Petition 870260084657, dated 08 / 20 / 2026, page 110 / 800 106 / 375 other organic solvents; and mixed solvents thereof, with halogenated hydrocarbon type solvents (e.g., DCM) or polar aprotic solvents (e.g., MeCN) being preferred.

[00102] The base for use may be selected, for example, from a wide range of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkyl amines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquid, they can also be used as a solvent.These bases can be used alone or in a combination of two or more. The amount of base to be used typically ranges from 0.1 to 10 moles, and preferably from 0.1 to 5 moles, per mole of compound (1).

[00103] The reaction conditions are not particularly limited, and the reaction can normally occur under refrigeration, at room temperature, or under heating conditions. Preferably, the reaction is carried out at a temperature ranging from room temperature to 100°C for 30 minutes to 350 hours, more preferably 1 hour to 200 hours, and particularly preferably 1 hour to 48 hours. Compound (II) can be obtained by reacting compound (II-1) in an inert solvent, under acidic or basic conditions or with an alkali metal halide, although the conditions of Petition 870260084657, dated 08 / 20 / 2026, p. 111 / 800 107 / 375 reaction are not limited (Step A-2).

[00104] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixed solvents of these, with halogenated hydrocarbon type solvents (e.g., DCM), polar aprotic solvents (e.g., MeCN), or ketone type solvents (e.g., acetone) being preferred.

[00105] The base for use may be selected, for example, from within a wide range of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkyl amines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquid, they can also be used as a solvent.These bases can be used alone or in a combination of two or more. The amount of base for... Petition 870260084657, dated 08 / 20 / 2026, p. 112 / 800 108 / 375 usage typically varies from 0.1 to 10 mol, and preferably 0.1 to 5 mol, per mol of compound (11-1).

[00106] Examples of acids include inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids, such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. These acids may be used in a combination of two or more in appropriate proportions. The amount of acid for use typically ranges from 1 molar equivalent to an excess amount relative to compound (II1). Examples of alkali metal halides include Lil, Nal, and Kl. The amount of alkali metal halide for use typically ranges from 1 molar equivalent to an excess amount relative to compound (II-1).

[00107] The reaction conditions are not limited, and the reaction normally occurs under refrigeration, at room temperature, or under heating conditions. Preferably, the reaction is carried out at a temperature ranging from room temperature up to 100°C for 0.5 to 350 hours. Stage B: Protection-Unprotection Step B-1 phosphoric acid coupling reaction protection Stage A: Lack of protection

[00108] (In the formula above, PG represents a protecting group for a hydroxyl group, -OR16 represents an alkoxy group or -O; and others Petition 870260084657, dated 08 / 20 / 2026, page 113 / 800 109 / 375 symbols are as defined above.)

[00109] Compound (1) can be protected with an appropriate protecting group to form compound (3) (Step B-1), and subjected to the coupling reaction with phosphoric acid (Step A), followed by release of the protecting group (Step B-2), thus synthesizing compound (II), which is a final product (Step B). When performing step A, the operation can be completed after step A-1 (i.e., reaction of compound (3) with compound (2) to obtain a compound corresponding to compound (II-1) (i.e., compound (4) in which -OR16 is an alkoxy group)), or subsequently step A-2 can be performed to obtain a compound corresponding to compound (II) (i.e., compound (4) in which -OR16 is -O-). Step B-1: Protection Reaction

[00110] The protecting group (-OPG) for a hydroxyl group can be any of those used in the field of synthetic organic chemistry.Examples include ethers (e.g., methyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, tetrahydropyranoyl, phenacyl, cyclopropylmethyl, allyl, prenyl, propargyl, t-butyl, benzyl, 4-(dimethylamino)carbonylbenzyl, 4-methylsulfinylbenzyl, 9-antrylmethyl, and 4-picolyl); silyl ethers (e.g., trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tri-isopropylsilyl); esters (e.g., formate, acetate, levulinate, pivaloate, benzoate, and 9-fluorenecarboxylate); Carbonates (e.g., methyl, t-butyl, isopropyl, allyl, 4-methylsulfinylbenzyl, 2,2,2-trichloroethyl, vinyl, and benzyl); aryl carbamates (e.g., phenylcarbamate); phosphinates (e.g., dimethylphosphinyl and dimethylphosphinothioyl); and sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, and benzylsulfonate). An example of a preferred protecting group is an ether.

[00111] For example, the protection reaction can be carried out with compound (1) in an inert solvent in the presence of a base for Petition 870260084657, dated 08 / 20 / 2026, page 114 / 800 110 / 375 obtain compound (3).

[00112] The base for use may be, for example, a known inorganic base. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), alkali metal hydrides (e.g., NaH and KH), and silver carbonate. The amount of base for use typically ranges from 1 molar equivalent to an amount in excess relative to compound (1).

[00113] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixed solvents thereof. These inert solvents can be used in a combination of two or more in appropriate proportions. Preferably, the inert solvent is an ether-type solvent, such as cyclopentyl methyl ether.

[00114] The reaction temperature typically ranges from -80 to 150°C.

[00115] Reaction time typically ranges from 0.1 to 200 hours. Step B-2: Deprotection Reaction

[00116] The deprotection reaction of compound (4) can be a Petition 870260084657, dated 08 / 20 / 2026, page 115 / 800 111 / 375 known reaction according to the type of protecting group. For example, the deprotection reaction can be carried out by deprotecting compound (4) in an inert solvent or without a solvent in the presence or absence of an acid to obtain compound (II).

[00117] Examples of acids include inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids, such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. These acids may be used in a combination of two or more in appropriate proportions. The amount of acid for use typically ranges from 1 molar equivalent to an amount in excess of the intermediate (4).

[00118] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixed solvents thereof. These inert solvents can be used in a combination of two or more in appropriate proportions.

[00119] The reaction temperature typically ranges from -80 to 150°C.

[00120] Reaction time typically ranges from 0.1 to 200 hours.

[00121] In addition, several compounds (II) can also be synthesized by means of a substitution reaction or a reaction of Petition 870260084657, dated 08 / 20 / 2026, page 116 / 800 112 / 375 condensation using a compound in which R4 is a hydrogen atom in compound (II) (represented as compound (5) in the formula below). An example is described below. Step C-1: Substitution Reaction Hey, Stage C-1

[00122] In the formula above, LG represents a displaceable group, and R4 is as defined above (excluding, however, a hydrogen atom).

[00123] Compound (5) can be reacted with R4-LG in an inert solvent or without a solvent in the presence or absence of a base according to reaction conditions to obtain compound (II) (Step C-1: substitution reaction).

[00124] Examples of displaceable groups include halogen atoms (e.g., chlorine, bromine, and iodine), alkylsulfonyloxy groups (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), arylsulfonyloxy groups (e.g., benzenesulfonyloxy, ptoluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy).

[00125] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, EI2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; Petition 870260084657, dated 08 / 20 / 2026, page 117 / 800 113 / 375 other organic solvents; and mixed solvents of these, with polar aprotic solvents (e.g., MeCN), ketone-type solvents (e.g., acetone), or mixed solvents of any of these with water being preferred.

[00126] The base for use can be selected, for example, from a wide range of known inorganic and organic bases.

[00127] Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkyl amines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquid, they can also be used as a solvent. These bases can be used alone or in a combination of two or more.

[00128] The amount of base to be used typically ranges from 1 molar equivalent up to an excess amount per mole of compound (5) to be reacted.

[00129] The reaction conditions are not particularly limited. The reaction temperature typically ranges from -80°C to 150°C. The reaction time typically ranges from 0.1 hours to 200 hours. Step C-2, C-2': Condensation Reaction Petition 870260084657, dated 08 / 20 / 2026, page 118 / 800 114 / 375 Stage C-2

[00130] In the formula above, R4 is as defined above (excluding, however, one hydrogen atom).

[00131] For example, compound (5) can be reacted with an alcohol (R4OH) in an inert solvent or without a solvent in the presence or absence of a base according to reaction conditions, in the presence of a condensing agent, to obtain compound (II) (Step C-2: condensation reaction).

[00132] The use of an amine (HNR4NaR4Nb) in place of the alcohol also produces compound (II') in which R1 is -O; and R2 is NR4NaR4Nb (Step C-2': condensation reaction).

[00133] Examples of inert solvents include water; alcoholic solvents, such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, EI2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixed solvents of these, with halogenated hydrocarbon type solvents (e.g., DCM), polar aprotic solvents (e.g., MeCN and DMF), ketone type solvents (e.g., acetone), or mixed solvents of any of these, water being preferred. Petition 870260084657, dated 08 / 20 / 2026, p. 119 / 800 115 / 375

[00134] The base for use may be selected, for example, from within a wide range of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkyl amines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquid, they can also be used as a solvent.These bases can be used individually or in a combination of two or more.

[00135] The amount of base to be used typically ranges from 1 molar equivalent to an excess amount per mole of compound (5) to be reacted.

[00136] The condensing agent for use may be selected, for example, from a wide range of known condensing agents. Examples include 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide (WSC) or an HCl salt thereof; 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium; N-cyclohexyl-N'-morpholinoethyl carbodiimide hexafluorophosphate; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethyl carbodiimide; N,N'-diisopropyl carbodiimide; N,N'-carbonylbis(2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1 Petition 870260084657, dated 08 / 20 / 2026, page 120 / 800 116 / 375 chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; alkyl haloformates, such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salts; internal salts of 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and Vilsmeier reagents prepared by reacting DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.

[00137] The reaction conditions are not particularly limited. The reaction temperature typically ranges from -80°C to 150°C. The reaction time typically ranges from 0.1 hours to 200 hours.

[00138] In addition, several compounds (II) can also be synthesized by carrying out an acylation reaction using compound (5). The acylation reaction is a C-1 modality (substitution reaction). An example is described below. Step C-3: Acylation Reaction acylation reaction

[00139] In the formula above, R17 and R18 are preferably, for example, alkyl groups optionally having 1 to 3 substituents (e.g., C1-18 alkyl groups). R17 and R18 may be identical or different.

[00140] For example, compound (5) can be reacted with an acylating agent such as carboxylic anhydride in an inert solvent or without a solvent in the presence of a base according to reaction conditions to obtain compound (II) (Step C-3: acylation reaction).

[00141] Examples of inert solvents include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethylene Petition 870260084657, dated 08 / 20 / 2026, page 121 / 800 117 / 375 nol, and ethylene glycol; ketone-type solvents, such as acetone and methyl ethyl ketone; ether-type solvents, such as THF, dioxane, Et2O, diisopropyl ether, cyclopentyl methyl ether, and diglyne; ester-type solvents, such as AcOMe and AcOEt; polar aprotic solvents, such as MeCN, DMF, and DMSO; hydrocarbon-type solvents, such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon-type solvents, such as chloroform, DCE, and DCM; other organic solvents; and mixed solvents thereof, with halogenated hydrocarbon type solvents (e.g., DCM), polar aprotic solvents (e.g., MeCN and DMF), or ketone type solvents (e.g., acetone) being preferred.

[00142] The base for use may be selected, for example, from a wide range of known inorganic and organic bases. Examples of inorganic bases include alkali metals (e.g., sodium and potassium), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate), alkali metal hydroxides (e.g., LiOH, NaOH, and KOH), alkali metal carbonates (e.g., Li2CO3, Na2CO3, K2CO3, and Cs2CO3), lower alkoxides of alkali metals (e.g., sodium methoxide and sodium ethoxide), and alkali metal hydrides (e.g., NaH and KH). Examples of organic bases include trialkyl amines (e.g., trimethylamine, TEA, and DIPEA), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. If these bases are liquid, they can also be used as a solvent.These bases can be used individually or in a combination of two or more.

[00143] The amount of base to be used typically ranges from 1 molar equivalent up to an excess amount per mole of compound (5) to be reacted. Petition 870260084657, dated 08 / 20 / 2026, page 122 / 800 118 / 375

[00144] The reaction conditions are not particularly limited. The reaction temperature typically ranges from -80°C to 150°C. The reaction time typically ranges from 0.1 hours to 200 hours.

[00145] In this descriptive report, compound (I), the starting materials, and the intermediate compounds can be used in the form of a chemically acceptable geometric isomer, stereoisomer, optical isomer, or tautomer. These isomers can be isolated according to a common optical resolution method or can be produced from corresponding optically active starting materials.

[00146] In this descriptive report, compound (I), the starting materials, and the intermediate compounds may be in the form of a salt. The target compound obtained in each reaction may also be in the form of a salt. If the compound obtained in each reaction is a free compound, the free compound may be converted into a target salt according to a known method. If the compound is a salt, the compound may be converted into its free form or into another target salt according to a known method. Examples of such a salt are described below.

[00147] The salt is preferably a pharmaceutically acceptable salt; for example, metallic salts (e.g., alkali metal salts, alkaline earth metal salts, and zinc salts) are preferred. Acid addition salts and base addition salts are also preferred. Examples of acids for acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; organic acids such as formic acid, propionic acid, oxalic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, acetic acid, citric acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, Petition 870260084657, dated 08 / 20 / 2026, page 123 / 800 119 / 375 and lactic acid; and amino acids, such as aspartic acid and glutamic acid. Examples of bases for base addition salts include metals, such as alkali metals (e.g., sodium and potassium), and alkaline earth metals (e.g., calcium and magnesium); inorganic bases, such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, calcium hydroxide, and cesium hydroxide);Organic bases, such as methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, picoline, choline, N-methylmorpholine, DBN, DBU, and DABCO; amino acids, such as lysine and arginine; and ammonia.

[00148] Compound (I) or a salt thereof may also be used in the form of various solvates (in particular, hydrate). Compound (I) or a salt thereof may also be used in a polymorphic crystalline form. Compound (I) or a salt thereof may also be used in the form of a pharmaceutically acceptable cocrystal or cocrystal salt. A cocrystal or cocrystal salt means a crystalline substance composed of two or more odd substances that are solid at room temperature, each with different physical properties (e.g., structure, melting point, and heat of fusion). Cocrystals and cocrystal salts may be produced according to a known cocrystallization method.

[00149] Compound (I) includes compounds in which one or more atoms of formula (I) are replaced by one or more atoms of Petition 870260084657, dated 08 / 20 / 2026, p. 124 / 800 120 / 375 isotope. Examples of isotope atoms include deuterium (2H), tritium (3H), 13C, 15N, and 18O. Compound (I) also includes compounds labeled with various radioactive or non-radioactive isotopes.

[00150] Compound (I) can be used in combination with various therapeutic or prophylactic agents for diseases that can be treated by compound (I). Compound (I) and a combined therapeutic or prophylactic agent can be administered simultaneously, or they can be administered consecutively or at desired time intervals. The simultaneous administration of compound (I) and a therapeutic or prophylactic agent can be a combined drug or a combination of separately formulated preparations.

[00151] The following is a description of a pharmaceutical formulation containing compound (I) as an active ingredient (“pharmaceutical composition” below).

[00152] A pharmaceutical formulation is a formulation of compound (I) in a common pharmaceutical formulation form and is prepared using compound (I) or a salt thereof and a pharmaceutically acceptable carrier. Such carriers include fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants, suspending agents, dissolving aids, isotonic agents, diluents such as solvents, and commonly used excipients.

[00153] Such a pharmaceutical formulation may be in a form selected from a variety of forms depending on the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections, nasal sprays, and inhalants, with injections being particularly preferred. Injections include an injection for intramuscular administration and an injection for subcutaneous administration, with an injection for subcutaneous administration being particularly preferred. Petition 870260084657, dated 08 / 20 / 2026, p. 125 / 800 121 / 375

[00154] Carriers for use in tablet formation may be selected from a wide range of known carriers. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, dextrose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dehydrated starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption enhancers, such as quaternary ammonium bases and sodium lauryl sulfate;Humectants, such as glycerin and starch; adsorbents, such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants, such as purified talc, stearates, boric acid powder, and polyethylene glycol.

[00155] In addition, the tablets may optionally be made as tablets with a common coating, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or bilayer or multilayer tablets.

[00156] Carriers for use in pill making can be selected from a wide range of known carriers. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminarin and agar.

[00157] Carriers for use in the formation of suppositories may Petition 870260084657, dated 08 / 20 / 2026, page 126 / 800 122 / 375 can be selected from a wide range of known carriers. Examples include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[00158] If the pharmaceutical formulation is prepared in the form of an injection, the liquid, emulsion, or suspension is sterile and preferably isotonic to blood.

[00159] Diluents for use in the formation of these liquids, emulsions, or suspensions may be selected from widely used known diluents, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.

[00160] In this case, the pharmaceutical formulation may contain a salt, glucose, amino acids, or glycerin in a quantity sufficient to prepare an isotonic solution, as well as a commonly used dissolving aid, buffering agent, analgesic, etc., and may also contain, if necessary, a preservative, a stabilizer, an antioxidant, a solubilizer, a pH regulator, and other drugs.

[00161] Brexpiprazole is known to be useful in relieving symptoms accompanied by severe agitation, destruction, and violent behavior in dementia associated with Alzheimer's disease. As immediate-release injections of antipsychotic agents are known to be useful as a therapeutic agent for the relief of symptoms in acute-phase patients with severe agitation, destruction, and violent behavior in schizophrenia, etc., it is expected that injections that immediately release brexpiprazole into the bloodstream will be useful as a therapeutic agent for the relief of symptoms in acute-phase patients with agitation in schizophrenia and dementia associated with Alzheimer's disease. Pharmaceutical compositions comprising compound (1) and designed to be in a Petition 870260084657, dated 08 / 20 / 2026, page 127 / 800 123 / 375 preferred injectable form according to medical needs obtain immediate efficacy by subcutaneous or intramuscular administration and by the immediate release of brexpiprazole in a therapeutically effective amount into the patient's bloodstream over a short period of time (e.g., a few hours) for use in the acute phase of agitation etc. Examples of a preferred injectable form of such injections for use in the acute phase include an injection obtained by dissolving compound (1) in water for injection, a biocompatible organic solvent, or a mixture of water for injection and a biocompatible organic solvent to which an appropriate isotonic agent, buffering agent, pH regulator, solubilizer, among others, are added as needed.

[00162] Examples of solubilizers include polysorbate 80, polysorbate 60, polyoxyethylene-hardened castor oil 60, poloxamer, β-cyclodextrin, and sulfobutyl ether-cyclodextrin.

[00163] Examples of isotonic agents include alkali metal chlorides, such as sodium chloride and potassium chloride; sugar alcohols, such as mannitol, sorbitol, xylitol, and maltitol; sugars, such as glucose, trehalose, and maltose; and glycerin. The composition may not comprise an isotonic agent. If an isotonic agent is present, the concentration of the isotonic agent in the composition is preferably such that the osmotic pressure of a solution of the composition is isotonic. The concentration depends on the type of isotonic agent. For example, in the case of alkali metal chlorides, the concentration preferably ranges from 0.5 to 20 mg / mL, and more preferably from 2 to 10 mg / mL; in the case of sugar alcohols, the concentration preferably ranges from 10 mg / mL to 200 mg / mL, and more preferably from 20 to 100 mg / mL.

[00164] Examples of buffering agents include phosphates, such as sodium phosphate, sodium dihydrogen phosphate, hydrogen phosphate Petition 870260084657, dated 08 / 20 / 2026, page 128 / 800 124 / 375 monosodium, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and potassium dihydrogen phosphate; borates, such as sodium borate and potassium borate; citrates, such as sodium citrate and disodium citrate; acetates, such as sodium acetate and potassium acetate; carbonates, such as sodium carbonate and sodium bicarbonate, and trishydroxymethylaminomethane (Tris). The concentration of buffering agent in the composition varies, for example, from 0.01 to 5.0 mg / mL, and preferably from 0.1 to 2 mg / mL.

[00165] pH regulators can be either acidic or basic. Examples of acidic pH regulators include hydrochloric acid, phosphoric acid, acetic acid, and citric acid. Examples of basic pH regulators include sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide. The pH regulator is usually added in an appropriate amount depending on the desired pH of the composition.

[00166] Examples of biocompatible organic solvents include those that are miscible in water. Examples of such solvents include alcohols, such as ethanol, propanol, isopropanol, propylene glycol, and glycerin, and dimethyl sulfoxide, N-methyl-2-pyrrolidone, polyethylene glycol 300, and polyethylene glycol 400.

[00167] Agitation associated with schizophrenia, depression, and Alzheimer's disease is often treated with once-daily tablets. However, in cases involving medication refusal or agitation, taking tablets can be difficult. In such cases, long-acting injections (preferably long-acting subcutaneous injections) administered daily at intervals of several days are considered useful formulations since drug administration is reliably conducted and they are convenient to use. The composition is expected to... Petition 870260084657, dated 08 / 20 / 2026, page 129 / 800 125 / 375 pharmaceutical containing compound (1) and designed to be a preferred injectable form according to medical needs achieve efficacy for one day or up to several days by subcutaneous or intramuscular administration and by the continuous distribution of brexpiprazole in a therapeutically effective amount in the patient's bloodstream for a relatively short period of time (one day up to several days) even in patients who have difficulty taking tablets.

[00168] In the treatment of schizophrenia, long-acting injections are a useful dosage form to improve treatment and preventive effects in patients with poor drug tolerance. In general, for drugs to exert therapeutic effects, it is desirable that the drug concentration in the blood immediately reaches the therapeutic range and then maintains a certain level. Although formulations of aripiprazole and paliperidone palmitate (trade names: ABILIFY aqueous prolonged-release suspension for IM injection and XEPLION aqueous suspension for IM injection) are clinically used as typical long-acting injections for schizophrenia as indicated, these drugs are poorly soluble and exhibit slow dissolution after administration; thus, the combined use of oral agents or reduction of injection intervals is necessary to compensate for drug concentration in the blood at the start of treatment.The pharmaceutical composition containing compound (1) and designed to be in a preferred injectable form according to medical needs is expected to improve treatment and preventive effects in patients with poor tolerance to medication by subcutaneous or intramuscular administration and by the continuous delivery of brexpiprazole in a therapeutically effective amount into the patient's bloodstream immediately and for a relatively short period of time (one to four weeks or more). Petition 870260084657, dated 08 / 20 / 2026, p. 130 / 800 126 / 375 more), even in patients in whom treatment or preventive effects are not expected to be sufficient due to poor medication tolerance.

[00169] Examples of a preferred injectable form of a long-acting injection that delivers brexpiprazole continuously for one to several days or for one to several weeks or more include a pharmaceutical composition in the form of a suspension containing compound (1), a suspending agent, and a dispersing medium.

[00170] The concentration of compound (1) in the composition is not particularly limited as long as it is an effective concentration according to the use of the composition described above. The concentration of compound (1) in the composition is, for example, 50 mg / mL or more, preferably 100 mg / mL or more, more preferably 150 mg / mL or more, and even more preferably 200 mg / mL or 250 mg / mL or more, based on brexpiprazole. The upper limit is not particularly limited, and is, for example, 1000 mg / mL or less, 750 mg / mL or less, or 500 mg / mL or less. For example, the concentration for use may vary in the range of 50 to 1000 mg / mL.

[00171] The suspending agent contained in the composition is not particularly limited as long as it is pharmaceutically acceptable and can achieve a predetermined viscosity. Examples of suspending agents include carboxymethyl cellulose and its salts; polyoxyethylene-polyoxypropylene block copolymers, such as Poloxamer; and polyethylene glycol (which is also known as “Macrogol”).

[00172] Examples of carboxymethyl cellulose salts include metallic salts, such as alkali metal salts, and ammonium salts. Specific examples include sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, lithium carboxymethyl cellulose, ammonium carboxymethyl cellulose, and mixtures thereof. In one embodiment, the suspending agent preferably contains carboxymethyl cellulose and / or a salt thereof, and in particular preferably contains carboxymethyl cellulose. Petition 870260084657, dated 08 / 20 / 2026, page 131 / 800 127 / 375 if sodium. The suspending agent may be used alone or in a combination of two or more. The concentration of the suspending agent in the composition is, for example, 0.1 mg / mL or more, preferably 0.2 mg / mL or more, and more preferably 0.5 mg / mL or more. The concentration of the suspending agent in the composition is, for example, 100 mg / mL or less, preferably 50 mg / mL or less, and more preferably 25 mg / mL or less. The concentration of the suspending agent in the composition varies, for example, from 0.1 to 50 mg / mL.

[00173] The dispersing medium contained in the composition is not particularly limited as long as it is pharmaceutically acceptable and capable of dispersing the active ingredient. The dispersing medium may be used alone or in a combination of two or more different types. The dispersing medium preferably contains at least water.Examples of dispersion media include water, physiological saline solution, and a solvent containing water and the biocompatible organic solvent mentioned above. In a preferred embodiment, the dispersion medium is water, and it is particularly preferable to use purified water, sterile purified water, water for injection, or similar.

[00174] The composition may also include any additives. Additives may be any pharmaceutically acceptable additives, and may be, for example, the isotonic agents, buffering agents, and pH regulators mentioned above. Additives may be used alone or in a combination of two or more.

[00175] The average particle diameter of the suspended compound (1) is, for example, 0.1 to 30 μm, and preferably 0.5 to 20 μm. These ranges are preferable for maintaining the action for a prolonged period. On the other hand, to obtain a high concentration of the drug in the blood immediately after administration, the average particle diameter of the suspended compound (1) is preferably, for example, Petition 870260084657, dated 08 / 20 / 2026, page 132 / 800 128 / 375 500 nm or less, and more preferably 50 to 500 nm. The average particle diameter is measured by a laser diffraction scattering method. To measure the average particle diameter by a laser diffraction scattering method, for example, SALD-3100 or SALD-2300 (manufacturer: Shimadzu Corporation) can be used.

[00176] For the method of preparing the composition, a wet grinding method is preferably used. The wet grinding method is preferably wet ball milling, high-pressure homogenization, high-shear homogenization, bead milling (e.g., Dyno Mill), or similar. In addition to these grinding methods, other methods, such as low-energy grinding and high-energy grinding (e.g., roller milling) may also be used. Examples of other preparation methods include controlled crystallization.

[00177] In one embodiment, the composition can be produced, for example, by a method comprising step 1 of mixing the compound (1), a suspending agent, and a dispersion medium, step 2 of subjecting the suspension obtained by mixing to grinding in a bead mill, and step 3 of removing the beads from the suspension obtained by grinding in a bead mill. In step 1, the mixing order of each component is not particularly limited. In one embodiment, step 1 includes the step of mixing different components of the active ingredient to obtain a carrier solution, and the step of mixing the carrier solution with the active ingredient. In step 2, the grinding method in a bead mill is not particularly limited. In one embodiment, step 2 is the step of adding beads to the suspension, followed by stirring. Examples of bead material include zirconia, alumina, and glass. The diameter of the beads varies, for example, from 0.1 to 5 mm, and preferably 0.2 to 3 mm.The average particle diameter. Petition 870260084657, dated 08 / 20 / 2026, page 133 / 800 129 / 375 of the particles of compound (1) obtained by grinding in a bead mill can be appropriately adjusted by adjusting, for example, the bead size, the rotation speed (peripheral speed) during grinding, the grinding time. In step 3, the method of removing the beads is not particularly limited. In one embodiment, step 3 is the step of collecting the composition using a syringe needle (e.g., 22G or less), a pipette, or a mesh filter (e.g., an 80 μm mesh filter) with a pore size smaller than that of the beads.

[00178] Examples of another preferable injectable form for long-acting injection that continuously delivers brexpiprazole for one day or several days or for one to four weeks or more include a pharmaceutical composition that is a low-viscosity precursor preparation containing a mixture of compound (1), two or more liquid crystal-forming lipids or gel-forming lipids, and at least one biocompatible organic solvent, and that forms or is capable of forming at least one liquid crystal or lipid gel phase structure when placed in contact with an aqueous fluid in vivo.

[00179] The precursor preparation generally does not contain a significant amount of water before administration and is a low-viscosity liquid or suspension in which two or more liquid crystal-forming lipids or gel-forming lipids are dissolved in a biocompatible organic solvent. The liquid crystal-forming lipids or gel-forming lipids are amphiphilic components of specific types, and a combined use of at least one diacylglycerol and at least one phosphatidylcholine is preferred. By dissolving the liquid crystal-forming lipids or gel-forming lipids in at least one biocompatible organic solvent, a low-viscosity solution can be prepared, and by dissolving or suspending the Petition 870260084657, dated 08 / 20 / 2026, page 134 / 800 130 / 375 compound (1) in these solutions, a precursor preparation such as a preferably low viscosity liquid or suspension may be prepared. Such a precursor preparation forms a liquid crystal phase structure or a high viscosity lipid gel upon contact with an aqueous fluid in vivo after administration. Typically, the aqueous fluid is a body fluid, in particular, extravascular fluid, extracellular / interstitial fluid, or plasma, and the precursor preparation forms a liquid crystal phase structure or a high viscosity lipid gel upon contact with such fluid (e.g., in vivo fluid).

[00180] The precursor preparation, which is a low viscosity liquid or suspension, represents a liquid or suspension that can be easily administered to an individual, and particularly represents a mixture that is easily administered with a device consisting of a traditional syringe or needle. In a particularly preferred embodiment, the precursor preparation, in which compound (1) is dissolved, or the medium before compound (1) is suspended, may be a mixture that can pass through a traditional sterile filter membrane, such as a 0.22 μm syringe filter. A typical suitable viscosity range at 20°C varies, for example, from 0.1 to 5,000 mPa^s, preferably 1 to 1,000 mPa^s, and more preferably 1 to 500 mPa^s.

[00181] The viscosity above is measured with a rotary rheometer under conditions of a temperature of 20°C and a shear rate in the range of 9000 to 10000 (l / s). Examples of rotary rheometers include Discovery Hybrid Rheometer 2 (DHR-2) and Discovery Hybrid Rheometer 3 (DHR-3) (manufacturer: TA Instruments).

[00182] The precursor preparation can form a liquid crystal structure called a lyotropic liquid crystal when amphiphilic compounds (two or more liquid crystal-forming lipids or lipids) Petition 870260084657, dated 08 / 20 / 2026, page 135 / 800 131 / 375 gel formers) are exposed to aqueous fluid after being administered in vivo. Known examples of such liquid crystal structures include a hexagonal structure in which cylindrical aggregates form a hexagonal crystalline system, a layered lamellar structure, an inverse hexagonal structure in which water is placed in the cylinder and the hydrophobic part is directed outwards, a structure in which spherical micelles form a cubic system in an aqueous (or oily) phase, a bicontinuous cubic structure in which lipid bilayers are arranged three-dimensionally forming a curved surface. The present inventors have discovered that after administration of the precursor preparation in vivo, the liquid crystal or liquid gel is formed, and thus the release of compound (1) after administration is controlled, and the released compound (1) is converted into brexpiprazole in vivo, enabling the continuous distribution of brexpiprazole.

[00183] Gel or liquid crystal formation can be confirmed by injecting the precursor preparation into water and confirming the formation of clumps. Gel or liquid crystal formation can be confirmed by analyzing the clumps obtained by a small-angle X-ray scattering (SAXS) method. In some cases, the liquid crystal may form in the gel state (liquid crystal gel).

[00184] Diacylglycerol has two nonpolar “tail” groups. These two nonpolar groups may be the same or different, may have the same number of carbon atoms or a different number of carbon atoms, and each of them may be independently saturated or unsaturated. Both 1,3-diacylglycerol and 1,2-diacylglycerol can be used. Examples of nonpolar groups include C6-C32 alkyl groups and C6-C32 alkenyl groups, which are typically present as long-chain carboxylic acid esters. Descriptions of these are often made by means of the number of carbon atoms and the degree of unsaturation in the chain. Petition 870260084657, dated 08 / 20 / 2026, page 136 / 800 132 / 375 carbons. Therefore, CX:Z represents a hydrocarbon chain where X represents the number of carbon atoms, and Z represents the degree of unsaturation. Examples include, in particular, a caproyl group (C6:0), a capryloyl group (C8:0), a capryl group (C10:0), a lauroyl group (C12:0), a myristoyl group (C14:0), a palmitoyl group (C16:0), a phytanoyl group (C16:0), a palmitoleoyl group (C16:1), a stearoyl group (C18:0), an oleoyl group (C18:1), an elaidoyl group (C18:1), a linoleoyl group (C18:2), a linolenoyl group (C18:3), an arachidonoyl group (C20:4), a beenoyl group (C22:0), and a lignoceroyl group (C24:9).

[00185] Therefore, typical nonpolar chains include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmilic acid, phytanic acid, palmitolic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, and lignoceric acid, and those based on fatty acids of natural lipid esters containing alcohols corresponding to these fatty acids. Preferred nonpolar chains include palmilic acid, stearic acid, oleic acid, and linoleic acid, and particularly preferred is oleic acid.

[00186] Diacylglycerol is not particularly limited and is preferably, for example, a diacylglycerol with the same nonpolar chains mentioned above or with different chains. Among these, glycerol dioleate (GDO) is particularly preferred.

[00187] Diacylglycerols can be used alone or in a combination of two or more.

[00188] Phosphatidylcholine (PC) is a generic term for phospholipids having a structure in which choline is linked to the phosphate ester as the hydrophilic part of the glycerophospholipid, while two fatty acids are linked to the glycerol ester structure as the hydrophobic part. Several phospholipids belong to the phosphatidylcholine group due to... Petition 870260084657, dated 08 / 20 / 2026, p. 137 / 800 133 / 375 large number of fatty acid combinations. Examples of preferable sources of phospholipids include eggs, heart (e.g., beef heart), brain and liver (e.g., beef liver), and plant sources including soy. A single PC or a mixture of multiple PCs derived from such sources may be used. Soy PC (SPC) or egg-derived PC, or a mixture thereof, are preferred, and most preferred is essentially pure SPC (high-purity SPC).

[00189] Liquid crystal-forming lipids or gel-forming lipids for use are preferably a combination of at least one diacylglycerol and at least one phosphatidylcholine. In particular, a combined use of one or more diacylglycerols specifically mentioned above and one or more phosphatidylcholines specifically mentioned above is preferred. A particularly preferred combination of liquid crystal-forming lipids or gel-forming lipids is the combination of GDO and PC, in particular, the combination of GDO and PC from soy and / or PC from egg.

[00190] The biocompatible organic solvent is preferably, for example, one that is miscible in water, and typical solvents include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides, and sulfoxides. Alcohols are particularly suitable, forming groups of suitable solvents. Examples of suitable alcohols include ethanol, isopropanol, propylene glycol, glycerin, and glycerol formal, with ethanol being more preferred. Examples of ketones include acetone, n-methylpyrrolidone (NMP), 2-pyrrolidone, and propylene carbonate. Examples of suitable ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethyl isobarbide, and polyethylene glycol. Examples of suitable esters include ethyl acetate and isopropyl acetate. Dimethyl sulfide is a suitable sulfide-type solvent. Examples of suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethyl sulfoxide. Petition 870260084657, dated 08 / 20 / 2026, page 138 / 800 134 / 375 (DMSO), respectively. Biocompatible organic solvents may be used alone or in a combination of two or more.

[00191] In the low viscosity precursor preparation containing a mixture of two or more liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent, a combination of SPC, GDO, and ethanol is preferred, and a combination of SPC, GDO, ethanol, and DMSO is also suitable. A preferred low viscosity precursor preparation is prepared by dissolving or suspending compound (1) in a solution containing two or more of the liquid crystal-forming lipids or gel-forming lipids and at least one biocompatible organic solvent.

[00192] Yet another example of a preferred injectable form of a long-acting injection that continuously delivers brexpiprazole for one to several days or for one to four weeks or more includes microspheres comprising compound (1) as an active ingredient. Microspheres herein generally refers to a spherical formulation with a particle diameter ranging from about a few micrometers to several tens of micrometers, and may have an irregular surface. The microsphere of the present invention usually comprises a carrier, such as a base polymer (e.g., a biodegradable polymer).

[00193] The microspheres of the present invention have an average particle diameter of preferably 5 to 150 μm, more preferably 10 to 120 μm, even more preferably 20 to 100 μm, and even more preferably 30 to 85 μm to obtain the desired controlled release properties of compound (I). To obtain the desired controlled release properties, the average particle diameter can be reduced if the absorption rate needs to be faster, and the average particle diameter can be increased if the absorption rate needs to be faster. Petition 870260084657, dated 08 / 20 / 2026, page 139 / 800 135 / 375 absorption needs to be slower.

[00194] To obtain the desired controlled-release properties of compound (I) and desired variations in blood drug concentration of brexpiprazole, the percentage of inclusion of compound (1) in the microsphere of the present invention is preferably 80% or more. The amount of the parent drug added to a batch formulation may be increased to improve the percentage of inclusion.

[00195] In the microsphere of the present invention, the content of compound (I) preferably varies from 10 to 50% by weight, more preferably 20 to 45% by weight, and even more preferably 30 to 40% by weight, with a view to obtaining the desired controlled-release properties of compound (I) and desired variations in the blood concentration of brexpiprazole drug.

[00196] The microsphere of the present invention preferably comprises a biodegradable polymer as a base polymer. The biodegradable polymer for use in the present invention may be those that are gradually degraded in vivo to achieve the desired systemic release performance.Examples include homopolymers and copolymers thereof, such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer (poly(lactic-co-glycolic acid): PLGA), polycitric acid, polymalic acid, lactic acid-aspartic acid copolymer, lactic acid-hydroxycaproic acid copolymer, glycolic acid-hydroxycaproic acid copolymers, polypropiolactone, polybutyrolactone, polyvalerolactone, polycaprolactone, polytrimethylene carbonate, poly-p-dioxanone, poly-α-cyanoacrylate, poly β-hydroxybutyrate, polytrimethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene, poly-Y-benzyl-L-glutamic acid, poly-L-alanine carbonate, polyalginic acid, polycarbonate, polyesteramide, polyamino acid, polyalkylene alkylate, polyethylene glycol, e. Petition 870260084657, dated 08 / 20 / 2026, pp. 140 / 800 136 / 375 polyurethane. Among these, polylactic acids and lactic acid-glycolic acid copolymers are preferred. These biodegradable polymers can be used alone or in a combination of two or more.

[00197] The molecular weight of a polylactic acid or lactic acid-glycolic acid copolymer, when used, can be appropriately selected from a wide range, and usually varies from about 2000 to 200000, preferably from about 4000 to 100000, and more preferably from about 10000 to 70000.

[00198] The molecular weight above refers to the number-average molecular weight in terms of the weight of polystyrene, as measured by gel permeation chromatography (GPC) using polystyrene as a reference material.

[00199] The lactic acid:glycolic acid (lactide:glycolide) ratio in a lactic acid-glycolic acid copolymer is not particularly limited and can be suitably selected from a wide range; it typically ranges from about 99:1 to 1:99 based on molecular number, and preferably from about 85:15 to 50:50 based on molecular number.

[00200] Polylactic acid may be poly-D-lactic acid, poly-L-lactic acid, or poly-DL-lactic acid, and preferably poly-DL-lactic acid. The lactic acid-glycolic acid copolymer may be a D-lactic acid-glycolic acid copolymer, an L-lactic acid-glycolic acid copolymer, or a DL-lactic acid-glycolic acid copolymer, and is preferably a DL-lactic acid-glycolic acid copolymer.

[00201] Polylactic acid or lactic acid-glycolic acid copolymer for use can be produced according to known methods or can be commercial products (e.g., Resomer and Lactel (produced by Evonik)).

[00202] The microsphere of the present invention may comprise a Petition 870260084657, dated 08 / 20 / 2026, page 141 / 800 137 / 375 non-degradable biocompatible polymer, in addition to the biodegradable polymer. The microsphere of the present invention may also comprise any additives such as emulsifiers.

[00203] The microsphere of the present invention can be produced according to methods known in the field of pharmaceutical preparations using the components listed above. From the point of view of obtaining microspheres with excellent systemic release performance, excellent flowability at the time of filling, and excellent syringe penetration at the time of administration, the microsphere of the present invention is preferably produced by a method comprising the steps of dissolving or suspending compound (I) or a salt thereof and the biodegradable polymer in an organic solvent, emulsifying the solution or suspension in the presence or absence of an emulsifier, and then removing the organic solvent. This method may also further comprise steps known in the field of pharmaceutical preparations (e.g., filtration step and granulation step).

[00204] Below, the production method for the microsphere of the present invention is described in more detail.

[00205] The method for producing the microsphere of the present invention comprises the steps of: obtaining a solution or suspension containing compound (I) and the biodegradable polymer in an organic solvent; mixing the solution or suspension obtained with water and emulsifying the mixture in the presence or absence of an emulsifier to obtain an emulsion; and removing the organic solvent from the emulsion obtained.

[00206] First, compound (I) and the biodegradable polymer are dissolved or suspended in an organic solvent to obtain a homogeneous solution or suspension. Compound (I) may be dissolved or suspended in the organic solvent. The biodegradable polymer is preferably dissolved in the organic solvent. Petition 870260084657, dated 08 / 20 / 2026, page 142 / 800 138 / 375

[00207] The organic solvent for use in the production of the microsphere of the present invention may be any organic solvent capable of dissolving the biodegradable polymer. Examples include halogenated hydrocarbons such as chloroform, dichloroethane, trichloroethane, dichloromethane, and carbon tetrachloride; ethers such as ethyl ether and isopropyl ether; fatty acid esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as ethanol, methanol, isopropanol, and benzyl alcohol; nitriles such as acetonitrile; amides such as dimethylformamide; acetone; and other water-miscible or water-immiscible organic solvents. These organic solvents may be used alone or in a combination of two or more. Among these, water-immiscible organic solvents are preferred, and dichloromethane is particularly preferred.

[00208] Acids or bases may be added to these organic solvents. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, and oleic acid, with acetic acid being particularly preferred.

[00209] The proportions of compound (I) or a salt thereof and the organic solvent are normally such that the amount of compound (I) or a salt thereof varies from about 0.01 to 30 parts by weight, preferably about 0.1 to 20 parts by weight, and more preferably about 1 to 10 parts by weight, per 100 parts by weight of the organic solvent.

[00210] The proportions of the biodegradable polymer and the organic solvent are normally such that the amount of biodegradable polymer varies from about 0.01 to 30 parts by weight, preferably from about 0.1 to 20 parts by weight, and more preferably from about 1 to 10 parts by weight, per 100 parts by weight of the organic solvent. Petition 870260084657, dated 08 / 20 / 2026, page 143 / 800 139 / 375

[00211] Next, the organic solvent solution or suspension obtained (containing compound (I), the biodegradable polymer, and the organic solvent) is emulsified. That is, the organic solvent solution obtained is mixed with water (i.e., external phase) to obtain an O / W emulsion in which the organic solvent solution is uniformly dispersed in water, or the organic solvent suspension obtained is mixed with water (i.e., external phase) to obtain an S (solid) / O / W emulsion in which the suspension is uniformly dispersed in water.

[00212] The water for use is not particularly limited and is preferably that which is accepted in the area of ​​pharmaceutical preparations such as purified water and water for injection.

[00213] The proportions of the organic solvent solution or suspension and water are not particularly limited, provided that an O / W or S / O / W emulsion having the desired particle size is obtained. The proportions are normally such that the amount of solution or suspension is about 0.001 to 0.2 parts by volume, preferably about 0.005 to 0.1 parts by volume, and more preferably about 0.01 to 0.05 parts by volume, per part by volume of water.

[00214] In the present invention, an emulsifier can be used with the use of a water-miscible or water-immiscible organic solvent. If a water-miscible organic solvent is used, an emulsifier is preferably used. The emulsifier for use in the present invention can be any emulsifier capable of forming an O / W or S / O / W emulsion, and preferably a stable O / W or S / O / W emulsion. Examples include anionic surfactants such as sodium oleate, sodium stearate, and sodium lauryl sulfate; nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives; and polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, and Petition 870260084657, dated 08 / 20 / 2026, page 144 / 800 140 / 375 hyaluronic acid. These emulsifiers can be used alone or in a combination of two or more.

[00215] The emulsifier can be added to the aqueous phase before emulsification.

[00216] The amount of emulsifier for use is not particularly limited and can be selected from a wide range. The concentration of the emulsifier in the aqueous solution varies, for example, from about 0.0001 to 20% by weight, preferably from about 0.001 to 10% by weight, and more preferably from about 0.001 to 5% by weight.

[00217] The method of preparing the O / W or S / O / W emulsion is not particularly limited. The emulsion can be prepared by a method that causes the solution or suspension of organic solvent (containing compound (I) or a salt thereof, the biodegradable polymer, and the organic solvent) to be dispersed in water as droplets or micelles of suitable size. Examples of the preparation method include a method in which a mixture of the solution or suspension and water is stirred at an appropriate rotational speed in a homogenizer or similar to refine the solution or suspension in water and thus obtain an O / W or S / O / W emulsion; a method in which a mixture of the solution or suspension and water is passed through a fine-pore filter, such as a ceramic filter, at a constant speed to refine the solution or suspension, followed by mixing with water.

[00218] Emulsion formation can be carried out in multiple stages as needed.

[00219] The desired particle diameter can be obtained by adjusting the stirring force during emulsion formation. That is, the particle diameter can be reduced by increasing the stirring force during emulsion formation. Petition 870260084657, dated 08 / 20 / 2026, page 145 / 800 141 / 375

[00220] Removing the organic solvent from the O / W or S / O / W emulsion results in an aqueous suspension of microspheres.

[00221] The organic solvent can be removed according to commonly used methods. For example, removal can be effected by heating during agitation with a propeller stirrer or a magnetic stirrer, gradually reducing the pressure, or adjusting the vacuum level with a rotary evaporator, etc. for desorption.

[00222] The microsphere suspension thus obtained is washed by adding a suitable solution or solvent, if necessary, to remove free compound (I) adhering to the surfaces of the microspheres. Examples of cleaning solutions and solvents include ethanol and alkaline solutions, such as 1 N sodium hydroxide solution. The microspheres separated by centrifugation or filtration are washed repeatedly with distilled water, and, if necessary, with a suitable solution or solvent, to remove free compound (I), emulsifier, etc. adhering to the surfaces of the microspheres. Examples of cleaning solutions and solvents include ethanol and alkaline solutions, such as 1 N sodium hydroxide solution. After separation, the microspheres are heated, as necessary, to more completely dissolve the water from the microspheres at reduced pressure and desorb the solvent from the microspheres.The washed microspheres can be resuspended in water in the presence or absence of sugar, sugar alcohols, or other additives, and then freeze-dried to obtain a microsphere powder. The freeze-drying conditions are not particularly limited as long as the microspheres can be dried.

[00223] Furthermore, the dry microspheres can be sieved through a sieve, as needed, to obtain microspheres with the desired average particle diameter.

[00224] The microsphere of the present invention, particularly the mi Petition 870260084657, dated 08 / 20 / 2026, page 146 / 800 142 / 375 microsphere obtained by the production method described above exhibits excellent systemic release performance. The microsphere of the present invention can release compound (I) or a salt thereof in a therapeutic amount for at least one week, preferably two, three or four weeks, and more preferably six weeks or more. The microsphere of the present invention can exhibit the above effects, in particular, when suspended in water for injection to obtain an aqueous suspension injection.

[00225] The microsphere of the present invention obtained by the production method typically has a spherical shape. Due to its spherical shape, the microsphere of the present invention achieves excellent flowability during filling in production and excellent syringe penetration (needle penetration) during administration, and causes less irritation at the injection site when administered as an intramuscular or subcutaneous injection.

[00226] The microsphere of the present invention can be administered to patients, for example, as an injection of an aqueous suspension containing the microsphere containing compound (I), a vehicle for the same, and water for injection. Alternatively, in another embodiment, the microsphere of the present invention can be administered to patients, for example, as an injection of an oily suspension containing the microsphere containing compound (I), a vehicle for the same, and an oil. For example, a triglyceride (in particular, a medium-chain fatty acid triglyceride) is suitable as the oil used herein.

[00227] The microsphere content in the injection suspension of the present invention is not particularly limited as long as the microspheres are dispersed in the injection, and typically ranges from about 5 to 50% by weight, preferably from about 10 to 40% by weight, and more preferably from about 10 to 30% by weight. Petition 870260084657, dated 08 / 20 / 2026, page 147 / 800 143 / 375

[00228] Examples of the vehicle used in the present invention include the suspending agents, isotonic agents, buffering agents, and pH regulators mentioned above.

[00229] In this descriptive report, the term “therapeutically effective amount” refers to an amount that is effective in providing therapeutic utility, such as symptom relief, when administered to humans and non-human animals. The specific dose of the substance administered to obtain therapeutic utility will, of course, be determined, for example, based on specific settings, such as the specific substance to be administered, the route of administration, the pathological condition to be treated, and the individual to be treated. For example, the pharmaceutical formulation may comprise compound (I) or a salt thereof in an amount of 1 to 70% by weight, based on the amount of compound (I).

[00230] For example, for subcutaneous or intramuscular administration, a daily dose that may produce satisfactory results may vary in the order of about 0.001 to 1.5 mg / kg. The recommended daily dose for subcutaneous or intramuscular administration may vary from about 0.1 mg to 500 mg, and preferably 0.1 mg to 100 mg, which may be adequately administered once daily or in two to four divided doses per day. Therefore, the unit dosage form for subcutaneous or intramuscular administration may contain compound (I) or a salt thereof in an amount of, for example, about 0.1 mg to 500 mg based on the amount of compound (I), along with a pharmaceutically acceptable diluent or carrier. The upper or lower limit of this range (0.1 mg to 500 mg) may vary, for example, from 0.2, 0.5, 1.2, 3, 5, 10, 20, 50, 100, 200, 300, or 400 mg. For example, the range preferably varies from 0.2 to 100 mg or 0.5 to 50 mg, and more preferably from 0.5 to 10 mg.

[00231] In this descriptive report, the term “pharmaceuticalmen Petition 870260084657, dated 08 / 20 / 2026, page 148 / 800 "144 / 375 acceptable" means that a compound, a composition comprising the compound, or its dosage form is within a range that has an appropriate risk / benefit ratio for application to humans or animals without causing excessive toxicity, irritation, allergic reaction, or other adverse effects.

[00232] Although not particularly limited, the pharmaceutical formulation comprising compound (I) or a salt thereof is preferably, for example, an injection. The injection includes an injection for intramuscular administration or an injection for subcutaneous administration, with an injection for subcutaneous administration being particularly preferred.

[00233] In this descriptive report, the terms “comprising” and “containing” also include “essentially consisting of” and “consisting of”; furthermore, the present invention encompasses any combination of the constituent elements described in this descriptive report.

[00234] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present invention described above can be combined in any way specifying the materials encompassed by the present invention. In other words, the present invention encompasses all materials comprising all combinations of the combinable characteristics described in this descriptive report. Examples

[00235] The embodiments of the present invention are described in more detail in relation to the Examples below. However, the embodiments of the present invention are not limited to the following Examples.

[00236] The following abbreviations may be used in this descriptive report. Petition 870260084657, dated 08 / 20 / 2026, page 149 / 800 145 / 375 REX: Example of a numerical reference Example: Numerical example STR: Structural formula Data: Data on physical properties (1-NMR: δ (ppm) in 1H-NMR in dimethyl sulfoxide-d6; 2-NMR: δ (ppm) in 1H-NMR in CDCh; 3-NMR: δ (ppm) in 1H-NMR in CD3OD; 4-NMR: δ (ppm) in 1H-NMR in CD3CO2D, or MS: mass spectrum)

[00238] In addition, the following abbreviations may be used for compound names and reagent names. Table 5 Abbreviation Reagent Name AcOEt Ethyl acetate AcOH Acetic acid AcOMe Methyl acetate AcONa Sodium acetate CDI 1,1'-Carbonyldiimidazole Cs2CO3 Cesium carbonate DABCO 1,4-Diazabicyclo[2.2.2]octane DBN 1,5-Diazabicyclo[4.3.0]-5-nonene DBU 1,8-Diazabicyclo[5.4.0]-7-undecene DCE 1,2-Dichloroethane DCM Dichloromethane DHP 3,4-Dihydro-2H-pyran DIPEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Et2O Diethyl ether EtOH Ethanol Petition 870260084657, dated 08 / 20 / 2026, pages 150 / 800 146 / 375 HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl Hydrochloric acid HOBt 1-Hydroxytriazole K2CO3 Potassium carbonate KOH Potassium hydroxide LI2CO3 Lithium carbonate LiI Lithium iodide LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MgSO4 Magnesium sulfate Na2CO3 Sodium carbonate NaH Sodium hydride NaHCO3 Sodium bicarbonate NaI Sodium iodide NaOH Sodium hydroxide Na2SO4 Sodium sulfate NMP N-Methylpyrrolidone Pd / C Palladium on carbon PPTS Pyridinium p-toluenesulfonate TEA Triethylamine TFA Trifluoroacetic acid Tf2O Trifluoromethanesulfonic anhydride THF Tetrahydrofuran WSC 3-Ethyl-1-(3-dimethylaminopropyl) carbodiimide WSC^HCl 3-Ethyl-1-(3-dimethylaminopropyl) carbodiimide hydrochloride Petition 870260084657, dated 08 / 20 / 2026, page 151 / 800 147 / 375

[00239] In the following examples, “ambient temperature” generally ranges from about 10 to 35°C. Mixed solvent ratios are volume ratios unless otherwise noted. The unit “%” indicates weight percentage unless otherwise noted.

[00240] The 1H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR (Bruker Avance III 400 (400 MHz), Bruker Avance Neo 400 (400 MHz), or Bruker Avance III HD (500 MHz)). Example 1 (EX 1)

[00241] NaI (2.074 g), K2CO3 (1.913 g), and di-tert-butyl(chloromethyl)phosphate (3.58 g) were added to a mixture of 7-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one (3.0 g), MeCN (30 mL) and DCM (90 mL) were added, and the resulting mixture was stirred at room temperature. Three days later, di-tert-butyl(chloromethyl)phosphate (1.790 g) and NaI (1.037 g) were added, and the resulting mixture was stirred. After another 4 days, water was added to the reaction mixture, and the resulting mixture was stirred. The organic layer was extracted and concentrated under reduced pressure. The resulting product was dissolved in DCM (90 mL), TFA (5.33 mL) was added, and the mixture was stirred at room temperature for 3 hours. A 1 N aqueous solution of NaOH (138 mL) was added to the reaction mixture, and the mixture was stirred for 20 minutes. The aqueous layer was separated from the reaction mixture and washed with DCM and Et2O. AcOH (3.96 mL) was added to the aqueous layer and stirred at room temperature for 1 hour. The precipitated solid was removed by filtration to obtain a crude product.The crude product was purified by reversed-phase silica gel column chromatography (0.1% AcOH MeCN / 0.1% AcOH H2O) and concentrated under reduced pressure to give (4-(benzo[b]thiophen-4-yl)-1-((4-((2-oxo-1,2-dihydroquinolin-7-hydrogen phosphate) Petition 870260084657, dated 20 / 08 / 2026, p. 152 / 800. 148 / 375 yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (1.71 g). RMN1; 1.77-1.89 (2H, m), 1.89-2.01 (2H, m), 3.37-3.86 (11H, m), 4.10 (2H, t, J = 6.3 Hz), 5.11 (2H, d, J = 9.0 Hz), 6.29 (1H, d, J = 9.4 Hz), 6.80 (1H, dd, J = 2.4, 8.7 Hz), 6.95-7.05 (2H, m), 7.31 (1H, dd, J = 7.9, 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.54 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.5 Hz), 7.79 (1H, d, J = 9.5 Hz), 11.93 (1H, br). Example 2 (EX 2)

[00242] In a nitrogen atmosphere, a mixture of tert-butyl phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-(((2-(tert-butoxy)quinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (15.7 g), AcOH (42.3 mL), and TFA (14.1 mL) was stirred at 40°C for 1.5 hours. The reaction mixture was cooled to 10°C or less, a solution of AcONa (19.6 g) in water (170 mL) / MeCN (70.7 mL) was added to it, and the remaining liquid was washed with water (30 mL) and combined. The resulting mixture was stirred at room temperature for 1 hour, water (71 mL) was further added to it, and the mixture was stirred at 0°C for 1 hour. Precipitates were subjected to separation. solid-liquid, and the resulting product was washed with water (71 mL) and MeCN / water (1:4, 71 mL), and air-dried at 40°C for 12 hours to give (4-(benzo[b]thiophen-4-yl)-1-((4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (13.81 g). NMR1; 1.75-1.90 (2H, m), 1.90-2.00 (2H, m), 3.40-3.85 (11H, m), 4.09 (2H, t, J = 6.4 Hz), 5.11 (2H, d, J = 9.2 Hz), 6.29 (1H, d, J = 9.6 Hz), (1H, dd, J = 2.4 Hz, 8.8 Hz), 6.95-7.05 (2H, m), 7.31 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.51 (1H, d, J = 5.6 Hz), J = 8.0 Hz), 7.76 (1H, d, J = 5.6 Hz), 7.79 (1H, d, J = 9.6 Hz), 11.93 (1H, br). Example 3 (EX 3)

[00243] Di-ter-butyl (chloromethyl) phosphate (1.82 g) was dissolved Petition 870260084657, of 20 / 08 / 2026, p. 153 / 800 149 / 375 in MeCN / DCM (1 / 1) (60 mL), and 7-((4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (2.2 g) was added to it. After purging with nitrogen, the mixture was stirred at 40°C overnight, protected from light with aluminum foil. The reaction mixture was concentrated under reduced pressure to remove a large part of the DCM, and then extracted with the addition of AcOEt / MeOH (9 / 1) and a 10% aqueous solution of Na2S2O3. The organic layer was separated and concentrated under reduced pressure. AcOH (30 mL) was added to the residue, and the mixture was stirred at 40°C for 2 hours. silica-gel column (DCM / MeOH) to give iodide of 4-(benzo[b]thiophen-4-yl)-1-(((diethoxyphosphoryl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazine-1-ium (3.1 g).Acetone (120 mL) and NaI (2.55 g) were added to the mixture, and it was stirred at 60°C overnight. The mixture was cooled to room temperature, the liquid was removed, and water (50 mL) and AcOH (2.5 mL) were added to the residue under ice cooling. Water (80 mL) was added to the mixture, and it was stirred at room temperature for 8 hours. The precipitate was removed by filtration and washed with water. After drying under reduced pressure, silica gel column chromatography (DCM / MeOH) was performed for purification. After the addition of MeCN / water for crystallization, the product was removed by filtration and washed with water. The resulting solid was dried under reduced pressure to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl ethyl phosphate (1.1 g). RMN1; 1,13 (3H, t, J = 7,1 Hz), 1,78-1,89 (2H, m), 1,89-2,01 (2H, m), 3,38-3,49 (4H, m), 3,53-3,66 (4H, m), 3,70-3,82 (4H, m), 4,10 (2H, t, J = 6,1 Hz), 5,09 (2H, d, J = 9,1 Hz), 6,30 (1H, d, J = 9,4 Hz), 6,82 (1H, Petição 870260084657, de 20 / 08 / 2026, pág. 154 / 800 150 / 375 dd, J = 2,4 Hz, 8,7 Hz), 6,89 (1H, d, J = 2,3 Hz), 7,01 (1H, d, J = 7,4 Hz), 7,32 (1H, t, J = 7,8 Hz), 7,51 (1H, d, J = 5,5 Hz), 7,56 (1H, d, J = 8,7 Hz), 7,71 (1H, d, J = 8,0 Hz), 7,77 (1H, d, J = 5,6 Hz), 7,80 (1H, d, J = 9,1 Hz), 11,69 (1H, s). Exemplo 4 (EX 4)

[00244] MeCN (44 mL) and water (44 mL) were added to tert-butyl phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-(tert-butoxy)quinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (11.1 g), and the mixture was stirred at 45°C, followed by the addition of water (22 mL). After confirming the disappearance of the starting material, NaHCO3 (1.1 g) was added, and the mixture was concentrated under reduced pressure and extracted with 10% MeOH / DCM (100 mL). The resulting organic layer was concentrated, and the crude product was purified by silica-gel column chromatography (DCM / MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl tert-butyl phosphate (8.7 g). 3-NMR; 1.47 (9H, s), 1.95-2.04 (2H, m), 2.05-2.15 (2H, m), 3.40-3.60 (4H, m), 3.65-3.70 (2H, m), 3.70-3.80 (2H, m), 3.85-3.95 (2H, m), 4.20 (2H, t, J = 6.0 Hz), 5.16 (2H, d, J = 8.0 Hz), 6.44 (1H, d, J = 9.6 Hz), 6.88-6.92 (2H, m), 7.03 (1H, dd, J = 0.4, 7.6 Hz), 7.29 (1H, t, J = 8.0 Hz), 7.49 (1H, dd, J = 0.8, 5.6 Hz), 7.55-7.58 (2H, m), 7.64 (1H, d, J = 8.0 Hz), 7.87 (1H, d, J = 7.6 Hz). Example 5 (EX 5)

[00245] Isopropyl alcohol (10 mL), water (2 mL), and WSC^HCl (317 mg) were added at room temperature to (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (300 mg), and the mixture was stirred at 70°C for 10 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with DCM / MeOH (9 / 1). The organic layer was concentrated, and the residue was purified by chroma Petition 870260084657, dated 08 / 20 / 2026, p. 155 / 800 Column tography on silica-gel (DCM / MeOH) 151 / 375 to give phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-propyl)(imethyl isom4-1-1). RMN1; 1.14 (6H, d, J = 6.2 Hz), 1.78–1.89 (2H, m), 1.89–2.01 (2H, m), 3.41–3.49 (4H, m), 3.53–3.66 (4H, m), 3.66.1, J = 42 (2H Hz), 4.25–4.34 (1H, m), 5.08 (2H, d, J = 7.2 Hz), 6.30 (1H, dd, J = 2.0 Hz, 9.4 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.7 d J = 6), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, 7 J = 8.0), Hz), 7.80 (1H, d, J = 9.1 Hz), 11.69 (1H, s). Example 6 (EX 6)

[00246] 1,3-Propanediol (10 mL), water (2 mL), and WSC^HCl (212 mg) were added at room temperature to (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (300 mg), and the mixture was stirred at 40°C. After 30 minutes, the mixture was heated to 50°C. After another 30 minutes, the mixture was again heated to 60°C. After another 2 hours, the mixture was cooled to room temperature and azeotropated with AcOEt, and the residue was purified by silica gel column chromatography (DCM / MeOH). The resulting product was dispersed and washed with AcOEt, and the insoluble solid was removed by filtration, followed by drying under reduced pressure to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(3-hydroxypropyl) phosphate (200 mg). RMN1; 1,57-1,68 (2H, m), 1,78-1,89 (2H, m), 1,89-2,01 (2H, m), 3,403,52 (6H, m), 3,53-3,66 (4H, m), 3,70-3,82 (4H, m), 4,10 (2H, t, J = 6,1 Hz), 4,70 (1H, t, J = 5,6 Hz), 5,10 (2H, d, J = 9,0 Hz), 6,30 (1H, d, J = 9,4 Hz), 6,82 (1H, dd, J = 2,4 Hz, 8,7 Hz), 6,89 (1H, d, J = 2,3 Hz), 7,01 (1H, d, J = 7,4 Hz), 7,32 (1H, t, J = 7,8 Hz), 7,51 (1H, d, J = 5,5 Hz), 7,56 (1H, d, J = 8,7 Hz), 7,71 (1H, d, J = 8,0 Hz), 7,77 (1H, d, J = 5,6 Petição 870260084657, de 20 / 08 / 2026, pág. 156 / 800 152 / 375 Hz), 7,81 (1H, d, J = 9,4 Hz), 11,67 (1H, s). Exemplo 7 (EX 7)

[00247] Diethylene glycol monomethyl ether (10.00 mL), water (2 mL), and WSC^HCl (353 mg) were added at room temperature to (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (500 mg), and the mixture was stirred at 40°C. After 3 hours, WSC^HCl (176 mg) was added. The mixture was stirred at 40°C for 3 hours. Water was added to the reaction mixture and extracted with DCM / MeOH (9 / 1). The organic layer was concentrated, and the residue was purified by silica-gel column chromatography (DCM / MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(2-(2-methoxyethoxy)ethyl) phosphate (188 mg). RMN1; 1,78-1,89 (2H, m), 1,89-2,01 (2H, m), 3,21 (3H, s), 3,40-3,48 (6H, m), 3,42-3,49 (4H, m), 3,53-3,68 (4H, m), 3,70-3,85 (4H, m), 4,10 (2H, t, J = 5,2 Hz), 5,09 (2H, d, J = 9,0 Hz), 6,30 (1H, d, J = 9,4 Hz), 6,82 (1H, dd, J = 2,4 Hz, 8,7 Hz), 6,89 (1H, d, J = 2,3 Hz), 7,01 (1H, d, J = 7,3 Hz), 7,32 (1H, t, J = 7,8 Hz), 7,51 (1H, d, J = 5,5 Hz), 7,56 (1H, d, J = 8,7 Hz), 7,71 (1H, d, J = 8,0 Hz), 7,77 (1H, d, J = 5,6 Hz), 7,80 (1H, d, J = 9,1 Hz), 11,67 (1H, s). Exemplo 8 (EX 8)

[00248] Acetone / water (9 / 1) (10 mL), ethyl glycolate (3 mL), and WSC^HCl (529 mg) were added at room temperature to (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (500 mg), and the mixture was stirred at 40°C for 5 hours, followed by overnight stirring at room temperature. DCM / MeOH (9 / 1) and water were added to the reaction mixture, and the precipitate was removed by filtration. The organic layer of the filtrate was concentrated and purified along with the filtered precipitate obtained above by silica gel column chromatography. Petition 870260084657, dated 08 / 20 / 2026, page 157 / 800 153 / 375 (DCM / MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (2-ethoxy-2oxoethyl) phosphate (16 mg). RMN1; 1,18 (3H, t, J = 7,1 Hz), 1,78-1,89 (2H, m), 1,89-2,01 (2H, m), 3,42-3,49 (4H, m), 3,51-3,68 (4H, m), 3,70-3,82 (2H, m), 4,10 (2H, J = 9,6 Hz), 4,06-4,15 (2H, m), 4,35 (2H, d, J = 9,6 Hz), 5,12 (2H, d, J = 8,8 Hz), 6,30 (1H, dd, J = 1,8 Hz, 9,4 Hz), 6,83 (1H, dd, J = 2,4 Hz, 8,7 Hz), 6,87 (1H, d, J = 2,3 Hz), 7,01 (1H, d, J = 7,5 Hz), 7,33 (1H, t, J = 7,8 Hz), 7,52 (1H, d, J = 5,5 Hz), 7,57 (1H, d, J = 9,0 Hz), 7,72 (1H, d, J = 8,0 Hz), 7,77 (1H, d, J = 5,6 Hz), 7,81 (1H, d, J = 9,1 Hz), 11,65 (1H, s). Exemplo 9 (EX 9)

[00249] (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) was suspended in a mixture of ethylene glycol (10 mL) and water (1 mL), WSC^HCl (1.06 g) was added to the same, and the mixture was stirred at 45°C for 5 hours. Acetone and AcOEt were added to the reaction mixture, the mixture was concentrated at reduced pressure three times, and water was removed azeotropically. The concentrated residue was purified directly by medium pressure liquid chromatography (DCM / MeOH).

[00250] Water and a mixed solvent of DCM-MeOH = 4:1 were added to the resulting product, and the mixture was stirred and extracted. The organic layer was concentrated under reduced pressure, acetone was added to the resulting oil, and the mixture was stirred at room temperature overnight.The precipitated solid was removed by filtration and air dried to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl (2-hydroxymethylgyl) phosphate (71). NMR1; 1.78-1.88 (2H, m), 1.90-1.99 (2H, m), 3.42-3.48 (2H, m), 3.493.55 (2H, m), 3.56-3.68 (4H, m), 3.72-3.80 (4H, m), 4.1-J (2H, m Petition 870260084657, of 20 / 08 / 2026, p. 158 / 800 154 / 375 Hz), 5.11 (2H, d, J= 9.5 Hz), 6.30 (1H, dd, J = 9.5 Hz, 1.8 Hz), 6.83 (1H, dd, J = 8.6 Hz, 2.4 Hz), 6.88 (1H, d, J = 2.4 Hz), J Hz), 7.32 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.8 Hz), 9.4 Hz), 11.7 (1H, s). Example 10 (EX 10)

[00251] (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) was suspended in a mixture of 1,4-butanediol (20 mL) and water (4 mL), WSC^HCl (1.06 g) was added to the same, and the mixture was stirred at 60°C for 5 hours. Acetone and AcOEt were added to the reaction mixture, the mixture was concentrated under reduced pressure three times, and water was removed azeotropically. The concentrated residue was purified directly twice by medium-pressure liquid chromatography (1st: silica gel, 2nd: amino silica gel, eluent: DCM / MeOH). The resulting amorphous product was suspended in water (5 mL), and acetone was added for dissolution. After standing at room temperature overnight, the precipitated crystals were removed by filtration and air-dried at 25°C overnight to give (4(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(4-hydroxybutyl) phosphate (438 mg). RMN1; 1.39-1.49 (2H, m), 1.50-1.58 (2H, m), 1.78-1.88 (2H, m), 1.891.99 (2H, m), 3.37-3.42 (2H, m), 3.42-3.48 (2H, m), 3.53-3.67 (4H, m), 3.68-3.80 (4H, m), 4.10 (2H, t, J = 6.1 Hz), 4.43 (1H, t, J = 5.2 Hz), 5.09 (2H, d, J = 9.1 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H, dd, J = 8.6 Hz, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.6 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J= 9.5 Hz), 11.7 (1H, s). Example 11 (EX 11) Petition 870260084657, dated 08 / 20 / 2026, p. 159 / 800 155 / 375

[00252] (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) and 1,8-octanediol (3 g) were suspended in a mixed solvent of acetone (8 mL) and water (2 mL). WSC^HCl (0.71 g) was added to the mixture, and it was stirred at 50°C for 3 hours. Acetone and AcOEt were added to the reaction mixture, which was concentrated under reduced pressure, and water was azeotropically removed three times. The concentrated residue was directly purified twice by medium-pressure liquid chromatography (1st: silica gel, 2nd: amino silica gel, eluent: DCM / MeOH). The resulting amorphous product was suspended in water (5 mL), and acetone was added for dissolution.After resting at room temperature overnight, the precipitated crystals were removed by filtration and air-dried at 25°C overnight to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(8-hydroxyoctyl) phosphate (176 mg). RMN1; 1.18-1.29 (8H, m), 1.33-1.42 (2H, m), 1.45-1.52 (2H, m), 1.781.87 (2H, m), 1.88-1.98 (2H, m), 3.42-3.50 (4H, m), 3.53-3.80 (8H, m), 4.10 (2H, t, J = 6.1 Hz), 4.34 (1H, t, J = 5.2 Hz), 5.00 (2H, d, J = 9.0 Hz), 6.30 (1H, dd, J = 9.4 Hz, 1.4 Hz), 6.81 (1H, dd, J = 8.6 Hz, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.01 (1H,d,J=7.4Hz), 7.32 (1H,t,J=7.8Hz), 7.51 (1H,dd,J=5.6Hz, 0.4Hz), 7.56 (1H,d,J=8.7Hz), 7.71 (1H,d,J=8.1Hz), 7.76 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.7 (1H, s). Example 12 (EX 12)

[00253] (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) was suspended in a mixture of 2-methoxyethanol (20 mL) and water (2 mL). WSC^HCl (1.06 g) was added to the mixture, and it was stirred at 60°C for 3 hours. Acetone and AcOEt were added to the reaction mixture, the mixture was concentrated under reduced pressure, and water was removed. Petition 870260084657, dated 08 / 20 / 2026, pp. 160 / 800 156 / 375 azeotropically three times. The concentrated residue was purified directly twice by medium-pressure liquid chromatography (1st: silica gel, 2nd: amino silica gel, eluent: DCM / MeOH).

[00254] The resulting amorphous product was suspended in water (5 mL), and acetone was added for dissolution. After standing at room temperature overnight, the precipitated crystals were removed by filtration and air-dried at 25°C overnight to give (2-methoxyethyl)(4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl phosphate (320 mg). RMN1; 1.79-1.88 (2H, m), 1.89-1.98 (2H, m), 3.24 (3H, s), 3.40-3.48 (4H, m), 3.55-3.67 (4H, m), 4.10 (2H, t, J = 6.1 Hz), 5.09 (2H, d, J = 9.0 Hz), 6.30 (1H, d, J = 9.5 Hz), 6.82 (1H, dd, J = 8.7 Hz, 2.4 Hz), 6.89 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.7 (1H, s). Example 13 (EX 13)

[00255] (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) was suspended in a mixed solution of ethylene glycol monoisopropyl ether (20 mL) and water (2 mL). WSC^HCl (0.71 g) was added to the same, and the mixture was stirred at 50°C for 7 hours. Acetone and AcOEt were added to the reaction mixture, the mixture was concentrated under reduced pressure, and water was azeotropically removed three times. The concentrated residue was purified directly twice by medium-pressure liquid chromatography (1st: silica gel, 2nd: amino silica gel, eluent: DCM / MeOH).

[00256] The resulting amorphous product was suspended in water (5 mL), and acetone (15 mL) was added for dissolution. After standing at room temperature for 5 days, the precipitated crystals were removed by filtration and air-dried at 25°C overnight to give Petition 870260084657, dated 08 / 20 / 2026, page 161 / 800 157 / 375 phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-isopropoxyethyl) (290 mg). RMN1; 1.06 (6H, d, J = 6.1 Hz), 1.78-1.88 (2H, m), 1.89-2.00 (2H, m), 3.42-3.48 (4H, m), 3.49-3.68 (4H, m), 3.72.0-3, J = 4 (4 Hz), 5.10 (2H, d, J = 9.1 Hz), 6.30 (1H, dd, J = 9.4 Hz, 1.4 Hz), 6.82 (1H, dd, J = 8.6 Hz, 2.4 Hz), 6.89 (1H, d, J = 2.7), H = 2.4 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H7, d, J = 7.9 Hz), 9.5 Hz), 11.7 (1H, s). Example 14 (EX 14)

[00257] Morpholine (1.2 mL) was added at room temperature to a solution of (2-bromoethyl)phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (300 mg) in THF (12 mL), and the mixture was stirred at 40°C for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH). After the resulting product was dissolved in MeCN / H2O (1 / 1), MeCN was added. The precipitate was removed by filtration and washed with MeCN. The resulting product was dried at room temperature to give (2-morpholinoethyl) (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl phosphate (164 mg). RMN1; 1.78-1.89 (2H, m), 1.89-2.01 (2H, m), 2.34-2.41 (4H, m), 2.46 (2H, t, J = 6.1 Hz), 3.42-3.49 (4H, m), 3.50-3.68 (8H, m), 3.71-3.85 (4H, m), 4.10 (2H, t, J = 6.1 Hz), 5.10 (2H, d, J = 9.1 Hz), 6.30 (1H, d, J = 9.4 Hz), 6.82 (1H, dd, J = 2.4, 8.7 Hz), 6.89 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.6 Hz), 7.80 (1H, d, J = 9.1 Hz), 11.68 (1H, s). Example 15 (EX 15)

[00258] Pyridine (4 mL) and acetic anhydride (2 mL) were added Petition 870260084657, dated 08 / 20 / 2026, p. 162 / 800 158 / 375 at room temperature to (3-hydroxypropyl) phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (200 mg), and the mixture was stirred overnight. The reaction mixture was concentrated and azeotropated with toluene. The residue was purified by silica gel column chromatography (DCM / MeOH). EtOH / H2O (1 / 1) was added, the mixture was dispersed and washed at 40°C, and the insoluble solid was removed by filtration. The resulting product was washed with water and dried at room temperature to give 3-acetoxypropyl phosphate of ((4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl) (126 mg). RMN3; 1,92-2,05 (7H, m), 2,04-2,16 (2H, m), 3,45-3,56 (4H, m), 3,643,73 (2H, m), 3,74-3,83 (2H, m), 3,86-3,93 (2H, m), 4,01 (2H, q, J = 6,2 Hz), 4,15-4,25 (4H, m), 4,52-4,65 (4H, m), 5,20( 2H, d, J = 8,1 Hz), 6,44 (1H, d, J = 9,4 Hz), 6,89 (1H, d, J = 2,4 Hz), 6,92 (1H, dd, J = 2,4, 8,7 Hz), 7,05 (1H, d, J = 7,7 Hz), 7,30 (1H, t, J = 7,9 Hz), 7,49 (1H, dd, J = 0,8, 5,6 Hz), 7,57 (1H, d, J = 5,2 Hz), 7,59 (1H, d, J = 2,0 Hz), 7,65 (1H, d, J = 8,1 Hz), 7,88 (1H, d, J = 9,4 Hz). Exemplo 16 (EX 16)

[00259] Chloromethyl hexanoate (494 mg) was added with stirring to a mixture of (4-(benzo[b]thiophen-4-yl)-1(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL), and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and acetone (2 mL) was then added, followed by stirring. The precipitated solid was removed by filtration. The resulting product was washed with acetone / water (3:1) and then washed with acetone to obtain a crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added, and the precipitated solid was... Petition 870260084657, dated 08 / 20 / 2026, page 163 / 800 159 / 375 removed by filtration. The resulting product was washed with acetone and dried to give phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (()methyl)mg RMN1; 0.79 (3H, t, J = 6.9 Hz), 1.12–1.27 (4H, m), 1.42–1.53 (2H, m), 1.78–1.89 (2H, m), 1.89–2.01 (2H, m), 2.30 (2.5, 2.5, t, J = m), 3.52–3.70 (4H, m), 3.70–3.82 (2H, m), 4.09 (2H, t, J = 6.0 Hz), 5.09 (2H, d, J = 8.9 Hz), 5.42 (2H, d, J = 12.1, d J = 1 = 6 9.4 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.9 d Hz, ( 7.9 d Hz, 0.6 Hz, 5.5 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.81 (1H, d, J = 9.6 s 4). ( 11 Example 17 (EX 17)

[00260] Chloromethyl decanoate (220 mg) was added with stirring to a mixture of (4-(benzo[b]thiophen-4-yl)-1(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (630 mg), acetone (6 mL), water (3 mL), and DIPEA (0.522 mL), and the mixture was stirred under reflux. After 1 hour, chloromethyl decanoate (220 mg) was added. After another 1 hour, chloromethyl decanoate (220 mg) was added. After stirring for another 2 hours, acetone (3 mL) was added. After another 3 hours, DIPEA (0.348 mL) and chloromethyl decanoate (220 mg) were added. After another hour, chloromethyl decanoate (220 mg) was added. After another 1.5 hours, heating was stopped, and the mixture was cooled to room temperature and stirred for eight nights. After stirring at reflux for 2 hours, the mixture was cooled to room temperature and stirred for another hour.After acetone (3 mL) was added, the solid precipitate was removed by filtration. The resulting product was washed with acetone / water (3:1) and then washed with acetone to obtain a crude product. Acetone (5 mL) and water (1 mL). Petition 870260084657, dated 08 / 20 / 2026, page 164 / 800 160 / 375 were added to the same, and the mixture was stirred under reflux for 30 minutes. After cooling to room temperature, the precipitated solid was removed by filtration, washed with acetone / water (3:1) and then with acetone, and dried to give (4-(benzo[b]thiophen4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1yl)methyl((decanoyloxy)methyl) phosphate (370 mg). RMN1; 0,82 (3H, t, J = 6,9 Hz), 1,11-1,26 (12H, m), 1,41-1,51 (2H, m), 1,78-1,89 (2H, m), 1,89-2,01 (2H, m), 2,30 (2H, t, J = 7,5 Hz), 3,423,50 (4H, m), 3,53-3,69 (4H, m), 3,71-3,82 (2H, m), 4,09 (2H, t, J = 6,0 Hz), 5,09 (2H, d, J = 8,9 Hz), 5,42 (2H, d, J = 12,8 Hz), 6,30 (1H, dd, J = 1,8 Hz, 9,5 Hz), 6,82 (1H, dd, J = 2,4 Hz, 8,6 Hz), 6,85 (1H, d, J = 2,3 Hz), 7,01 (1H, d, J = 7,4 Hz), 7,32 (1H, dd, J = 7,9 Hz, 7,9 Hz), 7,52 (1H, dd, J = 0,42 Hz, 5,5 Hz), 7,56 (1H, d, J = 8,6 Hz), 7,71 (1H, d, J = 8,1 Hz), 7,77 (1H, d, J = 5,5 Hz), 7,80 (1H, d, J = 9,5 Hz), 11,63 (1H, s). Exemplo 18 (EX 18)

[00261] Chloromethylcyclohexane carboxylate (530 mg) was added with stirring to a mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL), and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and acetone (2 mL) was then added, followed by stirring. The precipitated solid was removed by filtration, and the resulting product was washed with acetone / water (3:1) and then washed with acetone to obtain a crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added to it, and the precipitated solid was removed by filtration.The resulting product was washed with acetone and dried to give (((cyclo-hexanocarbonyl)oxy)methyl)phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-di-hydroquinoline-7-mg)oxyumyl-1-92)butyl). Petition 870260084657, dated 20 / 08 / 2026, p. 165 / 800 161 / 375 RMN1; 1.05–1.39 (5H, m), 1.46–1.55 (1H, m), 1.56–1.66 (2H, m), 1,751.89 (4H, m), 1.89–2.00 (2H, m), 2.23–2.34 (1H, 3), 1H, 3, m 3.52–3.70 (4H, m), 3.70–3.82 (2H, m), 4.09 (2H, t, J = 6.0 Hz), 5.10 (2H, d, J = 9.1 Hz), 5.42 (2H, d, J = 12.5, J = 1 Hz), d = H6,30 Hz), 6.82 (1H, dd, J = 2.4 Hz, 8.6 Hz), 6.86 (1H, d, J = 2.4 Hz), 7.01 (1H, d, J = 7.4 Hz), 7.32 (1H, dd, J = 7.9 Hz, J = 2), H = 7.9 Hz, 5.6 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 1H, s65 (1H, s65).

[0146] Example 19 (EX 19)

[00262] Cyclohexyl chloromethyl carbonate (578 mg) was added with stirring to a mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (632 mg), acetone (6 mL), water (2 mL), and DIPEA (0.524 mL), and the mixture was stirred under reflux. After 8 hours, the mixture was cooled to room temperature, and acetone (2 mL) was then added, followed by stirring. The precipitated solid was removed by filtration and washed with acetone / water (3:1) and then with acetone to obtain a crude product. Purification was performed by silica gel column chromatography (DCM / MeOH). Acetone (3 mL) and water (1 mL) were added to the same, and the precipitated solid was removed by filtration. The resulting product was washed with acetone and dried to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl ((((cyclohexyloxy)carbonyl)oxy)methyl) phosphate (296 mg). RMN1; 1,04-1,17 (1H, m), 1,18-1,37 (4H, m), 1,37-1,47 (1H, m), 1,521,63 (2H, m), 1,75-1,89 (4H, m), 1,89-2,00 (2H, m), 3,42-3,50 (4H, m), 3,53-3,70 (4H, m), 3,70-3,81 (2H, m), 4,09 (2H, t, J = 6,0 Hz), 4,474,55 (1H, m), 5,09 (2H, d, J = 8,5 Hz), 5,43 (2H, d, J = 13,3 Hz), 6,30 (1H, dd, J = 1,9 Hz, 9,5 Hz), 6,83 (1H, dd, J = 2,4 Hz, 8,6 Hz), 6,85 (1H, Petição 870260084657, de 20 / 08 / 2026, pág. 166 / 800 162 / 375 d, J = 2,3 Hz), 7,00 (1H, d, J = 7,4 Hz), 7,32 (1H, dd, J = 7,8 Hz, 7,8 Hz), 7,52 (1H, dd, J = 0,4 Hz, 5,6 Hz), 7,56 (1H, d, J = 8,6 Hz), 7,72 (1H, d, J = 8,0 Hz), 7,77 (1H, d, J = 5,5 Hz), 7,81 (1H, d, J = 9,5 Hz), 11,63 (1H, s). Exemplo 20 (EX 20)

[00263] NaI (306 mg), K2CO3 (282 mg), and dibutyl (chloromethyl)phosphate (528 mg) were added to a solution of 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (500 mg) in MeCN / DCM (30 mL) (2 / 1). After purging with nitrogen, the mixture was stirred at 40°C overnight protected from light with aluminum foil. Dibutyl (chloromethyl)phosphate (132 mg) and NaI (77 mg) were added to the same, and the mixture was stirred at 40°C for 8 hours. Saturated aqueous DCM and NaHCO3 were added, and extracted with DCM. The organic layer was concentrated, and MeCN (10 mL), water (5 mL), and AcOH (0.5 mL) were added to the residue. The mixture was stirred at room temperature overnight. AcOEt / MeOH=9 / 1 and water were added to the reaction mixture and extracted.The organic layer was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH) to give 4-(benzo[b]thiophen-4-yl)-1-(((dibutoxyphosphoryl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium iodide (545 mg). 2-MRN; 0.92 (6H, t, J = 7.4 Hz), 1.33-1.46 (4H, m), 1.64-1.75 (4H, m), 1.94-2.04 (2H, m), 2.13-2.25 (2H m), 3.41-3.60 (4H, m), 3.85-4.18 (8H, m), 4.20 (4H, q, J = 6.6 Hz, 14.0 Hz), 5.75 (2H, d, J = 8.7 Hz), 6.42 (1H, d, J = 9.4 Hz), 6.71 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.92 (1H, d, J = 7.4 Hz), 7.12 (1H, d, J = 2.2 Hz), 7.19 (1H, t, J = 7.9 Hz), 7.30 (1H, d, J = 8.7 Hz), 7.35-7.42 (2H, m), 7.56 (1H, s), 7.58 (1H, d, J = 2.2 Hz), 11.04 (1H, s). Example of Reference 1 (REX 1)

[00264] In a nitrogen atmosphere, 7-(4-(benzo[b]thiophen-4-yl Petition 870260084657, dated 08 / 20 / 2026, p. 167 / 800 163 / 375 piperazin-1-yl)butoxy)-1H-quinolin-2-one (15.0 g) and silver carbonate (20.0 g) were suspended in CPME (300 mL) in a 500 mL round-bottom flask. Then, 2-bromo-2-methylpropane (7.84 mL) was added, and the mixture was stirred at 90°C for 9 hours under light protection conditions. The insoluble matter was filtered through Celite and washed with AcOEt (150 mL). The solvent was evaporated under reduced pressure, MeCN (180 mL) was added to the residue, and the mixture was stirred. The precipitated crystals were subjected to solid-liquid separation, and the resulting product was washed with MeCN (60 mL) and air-dried at 40°C to give 7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-(tert-butoxy)quinoline (16.0 g). NMR2; 1.69 (9H, s), 1.75–1.83 (2H, m), 1.89–1.96 (2H, m), 2.55 (2H, t, J = 7.6 Hz), 2.73 (4H, m), 3.2 (4H, m), 4.15 (2H 6, d, d, J = 7.6 Hz), 6.89 (1H, d, J = 7.6 Hz), 6.99 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.15 (1H, d, J = 2.4 Hz), 7.27 (1H, t, J = 7.3 m = 7.3 m 8), 7.53–7.56 (2H, m), 7.82 (1H, d, J = 8.4 Hz). Reference Example 2 (REX 2)

[00265] Under a nitrogen atmosphere, 7-(4-(4-(benzo[b]thiophen-4yl)piperazine-1-yl)butoxy)-2-(ter -buthoxy)quinoline (16 g), NaI (9.8 g), and K2CO3 (9.0 g) were suspended in MeCN (240 mL) in a 1000 mL round-bottom flask. Di-tert-butyl(chloromethyl)phosphate (16.9 g) was added, and the mixture was stirred at 25–40°C for 2 days. Water (240 mL) was then added and stirred at 45°C for 1 hour. Subsequently, a large portion of the MeCN was removed by distillation under reduced pressure. The resulting crystals were cooled to 0°C, subjected to solid-liquid separation, washed with MeCN / water (1:4, 80 mL), and dried under vacuum at 40°C for 16 hours. The resulting crystals (19 g) were placed in a 1 L flask, and AcOEt (300 mL) and TEA (1 mL) were added, followed by stirring for 30 minutes. After solid-liquid separation, the resulting product was... Petition 870260084657, dated 08 / 20 / 2026, page 168 / 800 164 / 375 was washed with AcOEt (150 mL) and vacuum dried at 30 °C for 5 h to afford ter-butyl phosphate of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-(terbutoxy)quinolin-7-yl)yl)pyoxyethyl) (15.73 g). NMR3; 1.47 (9H, s), 1.66 (9H, s), 1.95–2.05 (2H, m), 2.10–2.20 (2H, m), 3.40–3.60 (4H, m), 3.65–3.70 (2H, m), 3.70–3.85 (H m), 4.24 (2H, t, J = 5.6 Hz), 5.15 (2H, d, J = 8.0 Hz), 6.65 (2H, d, J = 8.8 Hz), 7.00 (1H, dd, J = 8.8 Hz, J = 0.8 Hz), J = 7.8d 2.4 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.49 (1H, dd, J = 5.6 Hz, J = 0.8 Hz), 7.57–7.85 (3H, J (1 = H8.9). Reference Example 3 (REX 3)

[00266] NaH (55% oil) (151 mg) was suspended in THF (10 mL), 7-(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one (500 mg) was added to it, chloromethyl hexanoate (570 mg) was added dropwise, and the mixture was stirred at 50°C for 2 hours. After cooling to 0°C, the resulting product was rapidly cooled with an aqueous solution of ammonium chloride. Extraction was carried out with AcOEt, followed by drying over Na2SO4. The resulting product was purified by medium-pressure silica gel column chromatography to give (7-(4-(4(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl hexanoate (217 mg). NMR2; 0.85 (3H, t, J = 6.8 Hz), 1.25–1.33 (4H, m), 1.58–1.69 (2H, m), 1.70–1.85 (2H, m), 1.85–1.95 (m, 2H), 2.5, J 4 (2H = 2, t, t, = 7.4 Hz), 2.67–2.78 (4H, m), 3.15–3.25 (4H, m), 4.08 (2H, t, J = 6.2 Hz), 6.34 (2H, brs), 6.52 (1H, d, J = 9.5 Hz), J =H6.84 Hz), 6.84–6.92 (2H, m), 7.27 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.37–7.43 (2H, m), 7.45 (1H, d, J = 8.6 Hz), 7.55 (1H7, d, J = Hz), 7.6 (1H7, d, J = Hz 9.5 Hz). Reference Example 4 (REX 4)

[00267] 7-(4-(4-(Benzo[b]thiophen-4-yl)piperazine-1-yl)butoxy)quinolinePetition 870260084657, dated 20 / 08 / 2026, p. 169 / 800 165 / 375 2(1H)-one (4.0 g) was dissolved in DCM (120 mL). Then, a solution of iodomethyl piperidine-1-carboxylate (2.98 g) in DCM (10 mL) was added at room temperature with stirring, and the mixture was stirred at room temperature for 2 hours. After standing overnight, the resulting product was filtered, washed with DCM, and dried to obtain a crude product. The crude product was recrystallized in DCM / DMF (3 / 2) (140 mL) to give 4-(benzo[b]thiophen-4-yl)1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)-1-(((piperidine-1-carbonyl)oxy)methyl)piperazin-1-ium iodide (4.06 g). RMN1; 1.32-1.63 (6H, m), 1.80-2.04 (4H, m), 3.25-3.40 (2H, m), 3.403.58 (6H, m), 3.58-3.88 (6H, m), 4.10 (2H, t, J = 5.6 Hz), 5.55 (2H, s), 6.32 (1H, dd, J = 1.4 Hz, 9.5 Hz), 6.74-6.95 (2H, m), 7.04 (1H, d, J = 7.6 Hz), 7.34 (1H, dd, J = 7.8 Hz, 7.8 Hz), 7.54 (1H, d, J = 5.5 Hz), 7.59 (1H, d, J = 9.4 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.82 (1H, d, J = 9.5 Hz), 11.64 (1H, s). Example of Reference 5 (REX 5)

[00268] 4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)-1-((propionyloxy)methyl)piperazine-1-ium iodide was obtained in the same manner as in Reference Example 4. RMN1; 1.07 (3H, t, J = 7.4 Hz), 1.71-2.00 (4H, m), 2.56 (2H, q, J = 7.4 Hz), 3.47-3.52 (4H, m), 3.63-3.71 (2H, m), 3.71-3.86 (4H, m), 4.10 (2H, t, J = 5.6 Hz), 5.55 (2H, s), 6.32 (1H, dd, J = 1.5 Hz, 9.4 Hz), 6.77-6.87 (2H, m), 7.03 (1H, d, J = 7.6 Hz), 7.34 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.53 (1H, d, J = 5.6 Hz), 7.59 (1H, d, J = 8.5 Hz), 7.73 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 5.5 Hz), 7.82 (1H, d, J = 9.5 Hz), 11.65 (1H, s). Example of Reference 6 (REX 6)

[00269] 4-(benzo[b]thiophen-4-yl)-1-((hexanoyloxy)methyl)-1-(4((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium iodide was obtained in the same manner as in Reference Example 4. NMR1; 0.83 (3H, t, J = 6.9 Hz), 1.13-1.31 (4H, m), 1.46-1.58 (2H, m), Petition 870260084657, dated 08 / 20 / 2026, pp. 170 / 800 166 / 375 1.80-2.02 (4H, m), 2.44-2.55 (2H, m), 3.48-3.54 (4H, m), 3.64-3.88 (6H, m), 4.10 (2H, t, J = 5.5 Hz), 5.57 (2H, s), 6.29-6.37 (1H, m), 6.80-6.88 (2H, m), 7.05 (1H, d, J = 7.5 Hz), 7.35 (1H, dd, J = 7.9 Hz, 7.9 Hz), 7.54 (1H, d, J = 5.5 Hz), 7.60 (1H, d, J = 9.4 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.84 (1H, d, J = 9.5 Hz), 11.65 (1H, s). Reference Example 7 (REX 7)

[00270] 4-(Benzo[b]thiophen-4-yl)-1-((((hexyloxy)carbonyl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazine-1-ium iodide was obtained in the same manner as in Reference Example 4. RMN1; 0.85 (3H, t, J = 6.9 Hz), 1.17-1.37 (6H, m), 1.50-1.67 (2H, m), 1.77-2.03 (4H, m), 3.40-3.56 (4H, m), 3.63-3.90 (6H, m), 4.09 (2H, t, J = 5.7 Hz) Hz, 7.9 Hz), 7.54 (1H, dd, J = 0.4 Hz, 5.5 Hz), 7.58 (1H, d, J = 8.8 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 5.5 Hz), 7.82 (1H, d, J = 9.5 Hz), 11.63 (1H, s).

[00271] The following tables show, respectively, the structural formulas of the compounds in the Reference Examples (Reference Examples 1 to 7) and the compounds in the Examples (Examples 1 to 20) obtained by methods in accordance with those described above. Table 6 Petition 870260084657, dated 08 / 20 / 2026, p. 171 / 800 167 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 172 / 800 168 / 375 Table 7 Petition 870260084657, dated 08 / 20 / 2026, p. 173 / 800 169 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 174 / 800 170 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 175 / 800 171 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 176 / 800 172 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 177 / 800 173 / 375

[00272] Compounds from the Examples other than those listed above were also synthesized and examined; the Example numbers, structural formulas, production methods, and NMR analysis data thereof are listed in the tables below. Each Example number has been denoted as ΈΧ N” (where n is an integer from 1 to 161), for convenience. ΈΧ N” may also be shown as “Example N” and similar. Petition 870260084657, dated 08 / 20 / 2026, p. 178 / 800 174 / 375

[00273] In addition, the compounds used in the synthesis of each Example are also listed in the tables below with their numbers, structural formulas, production methods, and NMR analysis data, as Reference Examples 8 to 67. The number of each Reference Example has been indicated as “REX M” (where M is an integer from 8 to 67), for convenience. “REX M” may also be shown as “Reference Example M” and similar. Petition 870260084657, dated 08 / 20 / 2026, page 179 / 800 Table 8 EX21 A mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (15 g) and water (450 mL) was heated to 50 °C. 1N NaOH (23.73 mL) was added, followed by cooling to room temperature. DCM (300 mL) and MeOH (30 mL) were added for liquid separation. It was separated into three phases: an organic phase, an aqueous phase, and an emulsion phase. Water (300 mL), DCM (100 mL), and MeOH (10 mL) were added to the emulsion phase for extraction. This operation was performed three times. All aqueous phases were combined and washed with Et2O (300 mL). On the other hand, zinc chloride (1.520 g) was mixed with water (150 mL) and filtered. The filtrate was slowly added dropwise to the aqueous phase obtained previously. The mixture was stirred at room temperature for 2 hours. The solid was removed by filtration and washed with water and then with a mixed solvent of acetone / water (5:1).The moist crystals were dispersed in water (100 mL) and acetone (500 mL), and stirred at room temperature overnight. The solid was removed by filtration, washed with acetone / water (5:1), and then washed with acetone to obtain a white solid. The solid was air-dried at room temperature until a constant weight was achieved. Then, the solid was dried under reduced pressure at 40°C to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl zinc(II) phosphate (11.8 g). NMR4; 1.92-2.03(2H, m), 2.04-2.20(2H, m), 3.41-3.68(4H, m), 3.68-3.89(4H, m), 3.89-4.05(2H, m), 4.10-4.31(2H, m), 5.44(2H, d, J=6.6Hz), 6.71(1H, d, J=9.4Hz), 6.89(1H, s), 6.937.07(2H, m), 7.29(1H, dd, J=7.8Hz, 7.8Hz), 7.48(1H, d, J=5.4Hz), 7.55(1H, d, J=5.5Hz), 7.61(1H, d, J=8.8Hz), 7.66(1H, d, J=8.0Hz), 7.97(1H, d, J=9.3Hz). 175 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 180 / 800 EX22 EX23 1N NaOH (3.32 mL) was added to a mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (2.0 g) and water (4 mL), followed by stirring at room temperature. Acetone (36 mL) was added in appropriate portions and stirred for about 2 hours. The solid was removed by filtration, washed with water / acetone (1:5), and then washed with acetone. The solid was air-dried at room temperature to give (4-(benzo[b]thiophen-4yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl sodium phosphate (1.98 g). Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (632 mg) e clorometil isobutirato (450 mg), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxy)butil)piperazin-1 -ium-1 -il)metil ((isobutiriloxi)metil) fosfato (477 mg) for the first time or at least a few seconds 16. RMN3; 1.90-2.01(2H, m), 2.03-2.14(2H, m), 3.39-3.50(2H, m), 3.50-3.59(2H, m), 3.59-3.73(4H, m), 3.85-3.95(2H, m), 4.20(2H, t, J=6.0Hz), 5.08(2H, d, J=7.2Hz), 6.43(1H, d, J=9.4Hz), 6.87-6.95(2H, m), 7.04(1H, dd, J=0.5Hz, 7.6Hz), 7.28(1H, dd, J=7.9Hz, 7.9Hz), 7.50(1H, dd, J=0.7Hz, 5.6Hz), 7.55(1H, d, J=1.8Hz), 7.58(1H, d, J=2.1Hz), 7.63(1H, d, J=8.1Hz), 7.87(1H, d, J=9.4Hz). RMN1; 1.08(6H, d, J=7.0Hz), 1.781.89(2H, m), 1.892.00(2H, m), 2.512.59(1H, m), 3.413.50(4H, m), 3.533.69(4H, m), 3.713.81(2H, m), 4.09(2H, t, J=6.0Hz), 5.10(2H, d, J=9.1Hz), 5.43(2H, d, J=12.5Hz), 6.30(1H, dd, J=1.9Hz, 9.5Hz), 6.82(1H, dd, 176 / 375 Petition: 870260084657, on August 20, 2026, page. 181 / 800 J = 2.4Hz, 8.6Hz), 6.85(1H, d, J=2.3Hz), 7.01(1H, J=7.3Hz), 7.33(1H, dd, J=7.9Hz, 7.9Hz), 7.50-7.59(1H, m), 7.5,1(H), 7.5,1=H.8, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.5Hz), 11.64(1H, s). EX24 Η sçvO^ ΐχτ Yj 5 0 Ο^χθΑ / Using (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazinomethyl-hydro)hyperazine-1 -1 (632 mg) and chloromethyl pivalate (519 mg), (4-(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)obmethyl fo (umymethyl7) phostylophate method ((methylpivaloxy) mg similar to the method of synthesis of EX 16. NMR1; 1.14(9H, s), 1.78-1.88(2H, m), 1.88-2.00(2H, m), 3.41-3.50(4H, m), 3.53-3.69(4H, m), 3.71-3.81(2H, m), = H0, t-Hz), 5.11(2H, d, J=9.4Hz), 5.43(2H, d, J=12.1Hz), 6.30(1H, dd, J=1.9Hz, 9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.61Hz), 6.85(=1H.4, d J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.5Hz, 5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d,. 177 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 182 / 800 J = 5.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 11.64 (1H, s). EX25 Η ΟζΟί XXX Yj °>C° 1 8 Using (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -genomethyl)mgmethyl -yl (63)mg 1-chloroethyl octanoate (0.62 g), (4-(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (1-emyl297) phosphosphate mg method similar to the method of synthesis of EX 16. NMR1; 0.79(3H, t, J=6.9Hz), 1.071.25(8H, m), 1.35(3H, d, J=5.2Hz), 1.401.52(2H, m), 1.781.89(2H, m), 1.892.00(2.2, m), 2.892.00(2.2, m), 3.403.50(4H, m), 3.523.70(4H, m), 3.703.82(2H, m), 4.09(2H, t, J=6.0Hz), 5.015.14(2H, m), 6.256.34(J.6, m(1=H2,82), 6.86(1H, d, J=2.2Hz), 7.00(1H, d, J=7.6Hz), 7.32(1H, dd, J=7.8Hz, 7.8Hz), 7.52(1H, d, J=5.4Hz), 7.56(1H,1,=1H(1.7d=8.7Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.5Hz), 11.64(1H, s). 178 / 375 Petition: 870260084657, on August 20, 2026, page. 183 / 800 E clorometil octanoato (578 mg), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil ((octanoiloxi)metil) sulfate (321 mg) for the first time and the same time. método de sintese do EX 16. RMN1; 0.80(3H, t, J=6.9Hz), 1.101.25(8H, m), 1.411.52(2H, m), 1.781.89(2H, m), 1.892.00(2H, m), 2.30(2H, t, J=7.5Hz), 3.423.50(4H, m), 3.533.69(4H, m), 3.713.81(2H, m), 4.09(2H, t, J=6.0Hz), 5.09(2H, d, J=8.9Hz), 5.42(2H, d, J=12.7Hz), 6.30(1H, dd, J=1.9Hz, 9.5Hz), 6.82(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.4Hz, 5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.63(1H, s). 179 / 375 Petition: 870260084657, on August 20, 2026, page. 184 / 800 EX27 Η sÇ\^nO'si Yj °>*° 5 Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (2.53 g) e clorometil 3-metoxipropanoato (2.03 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((3metoxipropanoil)oxi)metil) fosfato (947 mg) for the first time. It's better to do this síntese do EX 16. RMN1; 1.78-1.89(2H, m), 1.89-2.00(2H, m), 2.58(2H, t, J=6.1Hz), 3.19(3H, s), 3.413.50(4H, m), 3.503.69(6H, m), 3.703.80(2H, m), 4.09(2H, t, J=6.0Hz), 5.09(2H, d, J=8.9Hz), 5.44(2H, d, J=12.9Hz), 6.30(1H, dd, J=1.9Hz, 9.4Hz), 6.83(1H, dd, J=2.4Hz, 8.6Hz), 6.85(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.33(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, d, J=5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 180 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 185 / 800 EX28 Η Yj Vo 5 o' Xo-\0>*^X0X\ Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 hydro -chloromethyl)methyl 3-ethoxypropanoate (2.00 g) synthesized in REX 8, (4-(benzo[b]thiophene-4-yl)-1(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methylpropato)(panothyl.2-ethoxy) was obtained by a method similar to the synthesis method of EX 16. NMR1; 1.04(3H, t, J=7.0Hz), 1.781.89(2H, m), 1.892.00(2H, m), 2.57(2H, t, J=6.2Hz), 3.37(2H, q, J=7.0Hz), 3.413.50), 3.5(4H), m 3.703.80(2H, m), 4.09(2H, t, J=6.1Hz), 5.09(2H, d, J=9.0Hz), 5.44(2H, d, J=12.9Hz), 6.30(1H, dd, J=1.9Hz, 9.8.3Hz(1.8,6Hz), 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.49-7.54(1H, m), 7.56(H,7.2 d, J=8 J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.64(1H, s). 181 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 186 / 800 EX29 Η Ύ] 'Μ0 S ο' Χο—\0Χ / °χ Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihidroquinolin-7-yl)oxi)butyl)piperazin-1 -ium-1 -yl)methyl hydrogen phosphate (1.90 g) and chloromethyl 2-methoxyacetate (1.37 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihidroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl ((2methoxyacetoxi)methyl) phosphate (82 mg) obtained in the same way method of synthesis do EX 16. RMN1; 1.79-1.89(2H, m), 1.89-2.00(2H, m), 3.30(3H, s), 3.413.49(4H, m), 3.543.69(4H, m), 3.703.80(2H, m), 4.054.13(4H, m), 5.09(2H, d, J=9.0Hz), 5.49(2H, d, J=13.3Hz), 6.30(1H, dd, J=2.0Hz, 9.5Hz), 6.83(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.6Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.51(1H, d, J=5.2Hz), 7.56(1H, d, J=8.6Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.83(1H, d, J=9.5Hz), 11.62(1H, s). 182 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 187 / 800 EX30 Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (3.67 g) e clorometil 2-etoxiacetato (2.66 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxy)butil)piperazin-1 -ium-1 -il)metil ((2etoxiacetoxi)metil)fosfato (304 mg) for the first time and the first half 16. RMN1; 1.08(3H, t, J=7.0Hz), 1.791.89(2H, m), 1.892.00(2H, m), 3.423.51(6H, m), 3.543.69(4H, m), 3.703.80(2H, m), 4.064.13(4H, m), 5.09(2H, d, J=9.0Hz), 5.49(2H, d, J=13.2Hz), 6.30(1H, dd, J=2.0Hz, 9.5Hz), 6.83(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.7Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.51(1H, d, J=5.2Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.5Hz), 11.63(1H, Sl________________ 183 / 375 Petition: 870260084657, on August 20, 2026, page. 188 / 800 EX31 Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (632 mg) e 1-(chlorometil) 5-etil 3,3dimetilpentanedioato (710 mg) Sintetizado no REX 9, (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7il)oxi)butil)piperazin-1 -ium-1 -il)metil (((5-etoxi-3,3-dimetil5-oxopentanoil)oxi)metil) fosfato (539 mg) foi obtido I am very happy and then the text of EX 16. RMN1; 1.02(6H, s), 1.13(3H, t, J=7.1Hz), 1.79-1.89(2H, m), 1.89-2.00(2H, m), 2.34(2H, s), 2.40(2H, s), 3.42-3.50(4H, m), 3.53-3.70(4H, m), 3.71-3.81(2H, m), 4.00(2H, q, J=7.1Hz), 4.09(2H, t, J=6.0Hz), 5.10(2H, d, J=9.0Hz), 5.42(2H, d, J=12.5Hz), 6.30(1H, dd, J=1.8Hz, 9.4Hz), 6.82(1H, dd, J=2.4Hz, 8.6Hz), 6.86(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.6Hz, 5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.64(1H, Sl________________ 184 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 189 / 800 EX32 Η 3Ο^νΟί Yj °-x° to 0- ο^οΑ,οχ-χ / οχ Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoperalin-7-yl)yl) -yl)methyl hydrogenophosphate (632 mg) and chloromethyl (2-methoxyethyl) carbonate (532 mg), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2di-hydroquinolin-7-yl)oxy)butyl)-piperazine-1 ((((2-methoxyethoxy)carbonyl)oxy)methyl) phosphate (282 mg) was obtained in a method similar to the synthesis method of EX 19. NMR1; 1.78-1.89(2H, m), 1.89-2.00(2H, m),3.20(3H, s), 3.413.52(6H, m), 3.533.69(4H, m), 3.703.80(2H, m), 4.09(2H, t), J 4.184.23(2H, m), 5.08(2H, d, J=8.6Hz), 5.45(2H, d, J=13.5Hz), 6.30(1H, dd, J=1.9Hz, 9.4Hz), 6.80-6.87(2H, m(7), 7.04. 7.33(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, dd, J=0.4Hz, 5.5Hz), 7.56(1H, d, J=8.5Hz), 7.72(1H, d, J=8.1Hz), 7.77(H=7.5 d, d, d J = 9.5 Hz), 11.63 (1H, s). 185 / 375 Petition: 870260084657, on August 20, 2026, page. 190 / 800 EX33 o. ο ) \ %z° \ / ^° Sfa o Ο= / 'tn Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (632 mg) e clorometil (2-(2metoxietoxi)etil) carbonato (701 mg), (4-(benzo[b]tiofen4-il)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7il)oxi)butil)piperazin-1 -ium-1 -il)metil (3-oxo-2,4,7,10tetraoxaundecil) fosfato (312 mg) This is what I do first ao método de texto do EX 19. RMN1; 1.79-1.89(2H, m), 1.89-2.00(2H, m), 3.01(3H, s), 3.363.40(2H, m), 3.423.51(6H, m), 3.533.69(6H, m), 3.703.81(2H, m), 4.10(2H, t, J=5.9Hz), 4.164.23(2H, m), 5.09(2H, d, J=8.5Hz), 5.45(2H, d, J=13.5Hz), 6.30(1H, dd, J=1.7Hz, 9.5Hz), 6.80-6.87(2H, m), 7.01(1H, d, J=7.6Hz), 7.33(1H, dd, J=7.8Hz, 7.8Hz), 7.52(1H, d, J=5.6Hz), 7.56(1H, d, J=8.5Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 186 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 191 / 800 EX34 Η Yj °χ° fi θ' ^Ο'^θΑ.θ^χ / θχ^θ / Χ / θχ Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihidroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl hydrogen phosphate (632 mg) and chloromethyl (2-(2-(2methoxiethoxi)ethoxi)ethyl) carbonate (802 mg), (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl (3-oxo-2,4,7,10,13pentaoxatetradecyl) phosphate (378 mg) was obtained using a method similar to the synthesis method of EX 19. RMN1; 1.79-1.89(2H, m), 1.89-2.00(2H, m), 3.20(3H, s), 3.363.41(2H, m), 3.423.50(10H, m), 3.533.69(6H, m), 3.703.80(2H, m), 4.10(2H, t, J=6.0Hz), 4.174.23(2H, m), 5.09(2H, d, J=8.5Hz), 5.45(2H, d, J=13.5Hz), 6.30(1H, dd, J=1.8Hz, 9.4Hz), 6.80-6.87(2H, m), 7.01(1H, d, J=7.6Hz), 7.33(1H, dd, J=7.9Hz, 7.9Hz), 7.52(1H, d, J=5.6Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 187 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 192 / 800 EX35 Η / Χ·0ί o XXJ U Xw-x Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -clorogenomethyl)hydrogenyl hydrogen (4-methoxybutyl) carbonate (2.36 g) synthesized in REX 10, (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1 -ium-bonyl-1()oxy(4)carbonate ()toxy(4)methyl phosphate (1.38 g) was obtained by a similar method to the synthesis method of EX 19. NMR1; 1.42-1.52(2H, m), 1.52-1.63(2H, m), 1.78-1.89(2H, m), 1.89-2.00(2H, m),3.16(3H, s), 3.23(2H, t, J=6.2Hz), m3.5.4. 3.53-3.70(4H, m), 3.71-3.81(2H, m), 4.04-4.13(4H, m), 5.09(2H, d, J=8.6Hz), 5.44(2H, d, J=13.4Hz), 6.30, J=1.9, dd, 6.82(1H, dd, J=2.4Hz, 8.5Hz), 6.85(1H, d, J=2.3Hz), 7.01(1H, d, J=7.4Hz), 7.32(1H, dd, J=7.9Hz, 7.9Hz), 7.52, J(=1H.4.dd 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 188 / 375 Petition 870260084657, dated 08 / 20 / 2026, page 193 / 800 EX36 1-Octanol (5 mL) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (0.5 g) were mixed, and water (0.5 mL) was added and stirred. Then, WSC-HCl (0.53 g) and acetone (2 mL) were added, and the mixture was heated and stirred for 6 hours. Water and ethyl acetate were added to the reaction mixture, followed by stirring, and the precipitated solid was removed by filtration and purified by column chromatography on silica gel (eluent: DCM-MeOH). The resulting product was dissolved in water, and acetone was added for crystallization. The resulting crystals were air-dried at 25°C to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl octyl phosphate (81 mg). RMN1; 0.82 (3H, t, J = 6.7Hz), 1.14–1.29 (10H, m), 1.44–1.53 (2H, m) 1.78–1.88 (2H, m), 1.89–1.99 (2H, m), 3.40–3.50 (2H, m), 3.40–3.50 (4.7). 4.10 (2H, t, J = 6.1Hz), 5.10 (2H, d, J = 9.0Hz), 6.30 (1H, dd, J = 9.5Hz, 1.8Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), H 7.1, dd = 8.1Hz (J = 2.4Hz). d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 J = 1H.8, d 9.5Hz), 11.7 (1H, s) 189 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 194 / 800 EX37 Using nerol (5 mL) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 yl)methyl hydrogenophosphate (0.5 g), (Z)-(4-(benzo[b]thiophene-4yl)-1-(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine1-ium-1-yl)methyl (3,7-dimethyloctate-2,6-diene-1-yl-yl-hane mgte) emphate phosphate method (82 AND 45. RMN1; 1.53 (3H, s) , 1.61 (3H, s), 1.67 (3H, s), 1.60-1.79 (2H, m), 1.80-2.02 (6H, m), 3.40-3.49 (4H, m), 3.53-3.68 (4H, m), 3.72-3.80 (2H, m), 4.10 (2H, t, J = 6.0Hz), 4.24 (2H, t, J = 7.0Hz), 5.04 (1H, brs), 5.08 (2H, d, J = 9.0Hz), 5.31 (2H, t, J = 6.8Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, Sl____________ 190 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 195 / 800 EX38 Η ζ\ / \ / ο\ / Χ / Ν\ / ζο OvQ 0 W ΤΎ °>*° Using geraniol (5 mL) and (4-(benzo[b]thiophene-4-yl)-1-(4-((2oxo-1,2-di-butyl-1-hydroxy)pyoperalin-7 -ium-1 il)methyl hydrogenophosphate (1.0 g), (E)-(4-(benzo[b]thiophene-4yl)-1-(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine1-ium-1-yl)methyl,methyl,6-diphthaene-phosphate (82 mg) was obtained in a method similar to the synthesis of EX 45. NMR1; 1.54 (3H, s), 1.60 (3H, s), 1.61 (3H, s), 1.80–1.88 (2H, m), 1.89–1.98 (4H, m), 1.99–2.07 (2H, m), 3.40–3.50, 3.5 m (4H, m), 3.72–3.80 (2H, m), 4.10 (2H, t, J = 6.2Hz), 4.26 (2H, t, J = 6.9Hz), 5.04 (1H, t, J = 6.8Hz), 5.09 (2H, d, J = 9.0Hz), H 6.3, t 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.5 d, 7.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s) . 191 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 196 / 800 EX39 Η here. pJ TY °χ° 1 Using 1,3-butanediol (5 mL) and (4-(benzo[b]thiophen-4-yl)-1(4-((2-oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogen (0.5 (4-(benzo[b]thiophen4-yl)-1 -(4-(((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (3-hydroxybutyl) phosphate (110 mg) was obtained by EX 1 4 ; a method similar to RM 1.05 (2.5H, d, J = 6.2Hz), 1.17 (0.5H, d, J = 6.2Hz), 1.42-1.50 (1H, m), 1.52-1.63 (1H, m), 1.78-1.89 (2H, m, m), 1.03-20-2). (4H, m), 3.52–3.69 (4H, m), 3.70–3.79 (2H, m), 3.80–3.88 (1H, m), 4.10 (2H, t, J = 6.1Hz), 4.80 (1H, d, J = 4.6Hz), d 5.09 (1H, dd, J = 9.5Hz, 1.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, d, t, J 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 192 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 197 / 800 EX40 Η çcOi 0 CCJ TJV 0' ΌΗ Using 3-methylbutane-1,3-diol (5 mL) and (4(benzo[b]thiophene-4-yl)-1 -(4-(((2)oxo-1,2-di-hydroquinoylene-1butylyl-7yl)oxy hydrogenophosphate (0.5 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (3hydroxy-3-methyl method àmilbutyl 20) mg phosphate synthesis of EX 45. NMR1; 1.09 (6H, s), 1.66 (2H, t, J = 7.4Hz), 1.78-1.89 (2H, m), 1.90-1.99 (2H, m), 3.41-3.48 (4H, m), 3.55 m, 3.68 (4H, 8-H), 3.3. (2H, q, J = 7.4Hz), 4.10 (2H, t, J = 5.9Hz), 4.34(1H, s), 5.10 (2H, d, J = 9.1Hz), 6.30 (1H, d, J = 9.5Hz), 6.83 (1H, 8.86Hz, J = d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 J = 1H. 8, d 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s) . 193 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 198 / 800 EX41 Using trans -2-butene-1,4-diol (2.5 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogenophosphate (0.5 g), (4(b) (E)-(4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (4hydroxybut-2-en-1-yl) phosphate e synthet à ummi domi doobhando (200 mg) method 45. RMN1; 1.79–1.88 (2H, m), 1.89–1.98 (2H, m), 3.40–3.50 (4H, m), 3.53–3.68 (4H, m), 3.70–3.80 (2H, m), 3.92 (2H, t, J ( H2 = 5.3), 3.3. 6.1Hz), 4.20-4.26 (2H, m), 4.72 (1H, d, J = 5.5Hz), 5.09 (2H, d, J = 8.9Hz), 6.30 (1H, dd, J = 9.5Hz, 1.6Hz), 6.82, J = 9.5Hz, 1.6Hz), 6.82, J = 2.8Hz (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), H7.7, d, J = 8.7Hz d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 194 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 199 / 800 EX42 Η ΤΎ / =\ 0' Ό—' '—OH Using cis-2-butene-1,4-diol (10 mL) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-yl)oxo-1,2-di-hydroquinoline-1-butyl-1yl)pyoxyperan) hydrogenophosphate (2.0 g), (Z)-(4-(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (4hydroxybut1 umtyl-90mg-2-enpha-en method similar to synthesis of the EX 45. NMR1; 1.80–1.88 (2H, m), 1.89–2.00 (2H, m), 3.40–3.50 (4H, m), 3.52–3.69 (4H, m), 3.71–3.80 (2H, m), 3.96–4.01 (2H 4. 8, t, m), 2.96–4.01 (2H 4. 3, t, m). 4.33 (2H, dd, J = 8.7Hz, 5.4Hz), 4.88 (1H, t, J = 5.5Hz), 5.09 (2H, d, J = 8.9Hz), 6.30 (1H, dd, J = 9.5Hz, 1.6Hz), J 2.8, dd,1 (1 6.88 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7 d, 7Hz (7.7Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 195 / 375 Petition 870260084657, dated 08 / 20 / 2026, pages 200 / 800 EX43 1,6-hexanediol (30 g) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (5 g) were mixed, and acetone (40 mL) and water (10 mL) were added and stirred. Then, WSC-HCl (3.53 g) was added, and the mixture was heated and stirred at 50°C for 8 hours. Ethyl acetate was added to the reaction mixture and concentrated under reduced pressure repeatedly to azetropically remove water. The solution was purified by column chromatography on silica gel (eluent: DCM-MeOH). The resulting product was recrystallized in acetone-water to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(6-hydroxyhexyl) phosphate (1.27 g). RMN1; 1.21-1.32 (4H, m), 1.33-1.43 (2H, m), 1.44-1.52 (2H, m), 1.79-1.87 (2H, m), 1.90-2.00 (2H, m), 3.40-3.51 (4H, m), 3.53-3.80 (8H, m), 4.09 (2H, t, J = 6.1Hz), 4.38 (2H, t, J = 5.2Hz), 5.09 (2H, d, J = 9.1Hz), 6.30 (1H, dd, J = 9.5Hz, 1.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.90 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 196 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 201 / 800 EX44 1,7-heptanediol (35 g) was heated and stirred to a specified temperature of 65°C, and water (4 mL) and WSCHCl (5.29 g) were added, followed by heating and stirring. Once in solution, (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (5 g) was added in 0.5 g portions at 5-10 minute intervals, and after the addition, the mixture was further heated and stirred for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added and concentrated under reduced pressure to azeotropically remove water. The reaction mixture was directly purified by column chromatography on silica gel (eluent: DCM-MeOH). The resulting product was dissolved in methanol (6.6 mL), and while stirring, saturated ethyl acetate-water was gradually added.The precipitated crystals are removed by filtering and dried to give (4(benzo[b]thiofen-4-yl)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7yl)oxi)butyl)piperazin-1-ium-1-yl)methyl (7-hidroxi-heptyl) phosphate (3.0 g). RMN1; 1.20-1.32 (6H, m), 1.32-1.41 (2H, m), 1.42-1.52 (2H, m), 1.78-1.88 (2H, m), 1.89-2.01 (2H, m), 3.40-3.51 (4H, m), 3.52-3.80 (8H, m), 4.10 (2H, t, J = 5.9Hz), 4.34 (2H, t, J = 5.2Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, d, J = 8.6Hz), 6.90 (1H, br-s), 7.01 (1H, d, J = 7.7Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 197 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 202 / 800 EX45 Η çoO^io XXX Using 1,9-nonanodiol (10.5 mL) and (4-(benzo[b]thiophen-4yl)-1-(4-((2-oxo-1,2-di-hidroquinolin-7-yl)oxy)butyl)piperazin1-ium-1-yl)methyl hydrogen phosphate (1.0 g), (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7yl)oxi)butyl)piperazin-1-ium-1-yl)methyl (9-hidroxinonyl) phosphate (513 mg) was obtained using a similar method summarized in EX 45. RMN1; 1.18-1.30 (10H, m), 1.32-1.43 (2H, m), 1.44-1.51 (2H, m), 1.80-1.89 (2H, m), 1.90-2.01 (2H, m), 3.40-3.50 (4H, m), 3.51-3.80 (8H, m), 4.10 (2H, t, J = 6.1Hz), 4.36 (2H, t, J = 5.0Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 198 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 203 / 800 EX46 Usando ciclopropano-1,1-diildimetanol (3.76 g) e (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1.0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil ((1(hidroximetil)ciclopropil)metil) fosfato (380 mg) immediately and immediately after síntese do EX 44. RMN1; 0.35 (4H, s), 1.78-1.89 (2H, m), 1.90-2.00 (2H, m), 3.40-3.50 (4H, m), 3.55-3.62 (4H, m), 3.65 (2H, d, J = 8.1Hz), 3.70-3.80 (2H, m), 4.10 (2H, t, J = 6.1Hz), 5.04 (1H, t, J = 6.2Hz), 5.09 (2H, d, J = 8.9Hz), 6.30 (1H, d, J = 9.5Hz), 6.81 (1H, dd, J = 8.6Hz, 2.4Hz), 6.87 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.5Hz), 7.32 (1H, d, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 199 / 375 Petition: 870260084657, on August 20, 2026, page. 204 / 800 EX47 Usando 2,2-dimetil-1,3-propanodiol (3.83 g) e (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1.0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxy)butil)piperazin-1 -ium-1 -il)metil (3hidroxi-2,2-dimetilpropil) fosfato (230 mg) for the first time and then do it EX 44. RMN1; 0.76 (6H, s), 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 3.13 (2H, d, J = 6.6Hz), 3.40-3.50 (6H, m), 3.55-3.68 (2H, m), 3.70-3.80 (2H, m), 4.06-4.15 (3H, m), 5.10 (2H, d, J = 8.8Hz), 5.18 (1H, t, J = 6.5Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, Sl________________ 200 / 375 Petition: 870260084657, on August 20, 2026, page. 205 / 800 EX48 Using (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl hydrogenophosphate (1.0 g) and 3-methoxy-10 mLpropanol, (4(benzo[b]thiophen-4-yl)-1 -(4-(((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (3-methoxypropyl) phosphate (160 mg) was obtained by the same method 44 . RMN1; 1.74 (2H, q, J = 6.5Hz), 1.78-1.88 (2H, m), 1.89-1.99 (2H, m), 3.25 (3H, s), 3.36 (2H, t, J = 6.5Hz), 3.42-3.48, m (3.5 (4), m 3.72–3.79 (4H, m), 4.10 (2H, t, J = 6.1Hz), 5.09 (2H, d, J = 9.2Hz), 6.30 (1H, dd, J = 9.4Hz, 1.8Hz), 6.89 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.7 d, J = 7.7Hz), 1 7.80 (1H, d, J = 9.4Hz), 11.7 (1H, s) . 201 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 206 / 800 EX49 \ z° \ / ^° 'bo Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxi)butyl)piperazin-1 -ium-1 -yl)methyl hydrogen phosphate (1.0 g) and 1.4 mL of methyl ether (1.4 mL), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl (4methoxybutyl) phosphate (106 mg) was obtained in the same manner as in NMR 14. EXN; 1.48-1.57 (4H, m), 1.78-1.88 (2H, m), 1.89-1.98 (2H, m), 3.19 (3H, s), 3.26-3.32 (2H, t, m), 3.42-3.50 (4H, m), 3.55-1.88 (4, 6H), m 3.68-3.79 (4H, m), 4.09 (2H, t, J = 6.7Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.4Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4H, d, J = 6.8Hz), J 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.9Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.7Hz), J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 202 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 207 / 800 EX50 Η here I 7 \p / / ° / U xJ / p\ x\ J 0' 0 —\ Using ethylene glycol monoisobutyl ether (10 mL) and (4-(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoxynbutyl)1-yl)pyro -yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2isobutophate phosphate umethyl2) method to synthesis of the EX 44. NMR1; 0.81 (6H, d, J = 6.7Hz), 1.75 (1H, sept, J = 6.7Hz), 1.801.89 (2H, m), 1.902.00 (2H, m), 3.13 (2H, d, J = 6.7Hz), 3-0 (60.8-3), 3.40.8-3. (4H, m), 3.71-3.82 (4H, m), 4.10 (2H, t, J = 6.1Hz), 5.09 (2H, d, J = 9.2Hz), 6.30 (1H, dd, J = 9.5Hz, 1.6Hz), 6.88, J = 9.5Hz, 1.6Hz), 6.88, J = 2.8Hz (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.2Hz), 7.32 (1H, t, J = 7.8Hz), 7.50 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), H7.7, d = 1 = 7.71 (H d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 203 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 208 / 800 EX51 Η çcOi 0 OJ Τ η Λ 11 Λ ζρ\ / X / \ Ο· ο — —1 2-(cyclopropylmethoxy)ethan-1-ol (1.28 g) and ethyldiisopropylamine (3.21 mL) were dissolved in DCM (40 mL), and Tf2O (2.18 mL) was slowly added dropwise with stirring over ice. After 1 hour, water was added to the reaction mixture and stirred, and the organic layer was separated and concentrated under reduced pressure to give 2-(cyclopropylmethoxy)ethan-1-ol triflate. This was dissolved in acetonitrile (5 mL). (4-(benzo[b]thiophen-4-yl)-1-(4((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (2.0 g) was then suspended in a mixed solvent of acetonitrile (20 mL) and water (4 mL), and DIPEA (3.21 mL) was added and stirred to put it into solution. This solution was heated and stirred to 65 °C, and the acetonitrile solution of the triflate was added, followed by heating and stirring for 1 hour.After cooling the reaction mixture to room temperature, ethyl acetate was added and concentrated under reduced pressure to azeotropically remove water. The reaction mixture was purified by silica gel column chromatography (eluent: DCMMeOH). The resulting ethyl acetate-methanol product recrystallized to give (4-(benzo[b]thiophen-4-yl)1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(2-(cyclopropylmethoxy)ethyl)phosphate (995 mg). 1NMR; 0.08-0.15 (4H, m), 0.38-0.47 (2H, m), 0.90-1.00 (1H, m), 1.79-1.89 (2H, m), 1.90-2.00 (2H, m), 3.20 (2H, d, J = 6.8Hz), 3.40-3.51 (6H, m), 3.51-3.70 (4H, m), 3.71-3.85 (4H, m), 4.10 (2H, t, J = 6.1Hz), 5.10 (2H, d, J = 8.9Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.33 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.57 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 204 / 375 Petition: 870260084657, on August 20, 2026, page. 209 / 800 EX 52 Η 0- 0 0 fosfato (81 mg) fosfato (81 mg) foi obtido em I'm so happy à síntese do EX 44. RMN1; 1.51-1.57 (4H, m), 1.78-1.89 (2H, m), 1.90-2.00 (2H, m), 3.23 (3H, s), 3.40-3.50 (6H, m), 3.51-3.68 (6H, m), 3.69-3.80 (4H, m), 4.10 (2H, t, J = 6.1Hz), 4.58 (2H, s), 5.09 (2H, d, J = 9.1Hz), 6.30 (1H, d, J = 9.4Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 205 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 210 / 800 EX53 / =(jo / \ '° / ° o Using (4-(methoxymethyl)cyclo-hexyl)methanol (0.87 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-ylyl)piomethyl-1)butyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl ((4(methoxymethyl method)fomimethobyl81-mgphosphal) similar to synthesis of the EX 52. RMN1 0.80–0.92 (4H, m), 1.37–1.79 (4H, m), 1.80–1.89 (2H, m), 1.90–1.3 (2H, m), 1.90–2.00 (2H, m), 1.90–2.00; 3.40–3.58 (4H, m), 3.51 (2H, t, J = 6.4Hz), 3.52–3.68 (4H, m), 3.70–3.82 (2H, m), 4.10 (2H, d, J = 6.1Hz), 5.08 J = 6.3, d 9.5Hz), 6.82 (1H, dd, J = 8.7Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), H 7.5, dd, J = 1 d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 206 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 211 / 800 EX54 Η çuQ „ Ou u Using (2,2-dimethyl-1,3-dioxane-5-yl)methanol (0.81 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-1-yl)yl)ioperazine-butyl) hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl ((202dimethyl-1,3-phatho)methyl-dioxane obtained by a similar method to the synthesis of EX 52. NMR1; 3.70–3.80 (4H, m), 3.85 (2H, dd, J = 11.8Hz, 4.2Hz), 4.10 (2H, t, J = 6.1Hz), 5.10 (2H, d, J = 9.0Hz), 6.30 (1H, 1.85Hz, J = 1 dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.71 J (1 = H8,7). (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s) . 207 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 212 / 800 Pyridine (0.98 mL) was dissolved in DCM (30 mL), and Tf2O (2.05 mL) was added dropwise with stirring under ice-cooling conditions. After 10 minutes, the solution in DCM (5 mL) of 1,3-dimethoxypropan-2-ol (1.33 mL) was added dropwise and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and Et2O was added to the residue. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a triflate as a brown oil. (4-(Benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (2.0 g) was then suspended in a mixed solvent of MeCN (20 mL) and water (4 mL), and DIPEA (2.57 mL) was added and stirred to put it into solution. The solution was heated and stirred at 50 °C, and a solution in acetonitrile (5 mL) of the triflate was added and further stirred for 1 hour.Heating was stopped, and the reaction mixture was cooled to room temperature and concentrated at reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: DCM-MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(1,3-dimethoxypropan-2-yl)phosphate (470 mg). 1NMR; 1.80-1.89 (2H, m), 1.90-2.00 (2H, m), 3.26 (6H, s), 3.40-3.50 (8H, m), 3.55-3.68 (4H, m), 3.73-3.81 (2H, m), 4.10 (2H, t, J = 6.1Hz), 4.22 (1H, sept, J = 5.2Hz), 5.08 (2H, d, J = 8.8Hz), 6.31 (1H, dd, J = 9.5Hz, 1.3Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.33 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 208 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 213 / 800 EX6 Usando 6-hydroxy-hexil benzoato (1.02 g) sintetizado no REX 13 e (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (1.0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2oxo-1,2-di-hydroquinolin-7-il)oxi)butil)piperazin-1-ium-1il)metil (6-(benzoiloxi)hexil) sulfate (6i0 mg) until it starts to work 56. RMN1; 1.30-1.40 (4H, m), 1.45-1.57 (2H, m), 1.62-1.71 (2H, m), 1.78-1.88 (2H, m), 1.89-2.00 (2H, m), 3.40-3.50 (4H, m), 3.53-3.67 (4H, m), 3.68-3.70 (4H, m), 4.09 (2H, t, J = 6.1Hz), 4.24 (2H, t, J = 6.6Hz), 5.09 (2H, d, J = 9.1Hz), 6.29 (1H, d, J = 9.5Hz), 6.81 (1H, dd, J = 8.7Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.487.57 (4H, m), 7.64 (1H, t, J = 6.2Hz), 7.71 (1H, d, J = 8.1Hz), 7.74-7.81 (2H, m), 7.95 (2H, d, J = 6.2Hz), 11.7 (1H, s). 209 / 375 Petition: 870260084657, on August 20, 2026, page. 214 / 800 EX57 Η Z\ -0 svVU i LXJ Υί v° ΓΤ U Λ / \ / s. _z\ q / o- o — >< 0 Using 6-hydroxy-hexyl 4-methoxybenzoate (1.16 g) synthesized in REX 14 and (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo1-di-hydroquinoperalin-7-butyl-1) -yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 yl)methyl (6-(foxyl9)methoxyphosphate)methoxyben obtained by a similar method to synthesis of EX 56. NMR1; 1.30–1.41 (4H, m), 1.48–1.57 (2H, m), 1.61–1.72 (2H, m), 1.80–1.89 (2H, m), 1.90–2.00 (2H, m), 3.40–3.50, m (3.5 (4H, m), 3.70-3.80 (4H, m), 3.82 (3H, s), 4.10 (2H, t, J = 6.0Hz), 4.20 (2H, t, J = 6.6Hz), 5.09 (2H, d, J = 9.1Hz), 6.30 (H 6, d5, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 6.98-7.06 (3H, m), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.55 (1H, d, J = 5.5Hz), 7.55 (7 H. 8, d, J = 2.4Hz). 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 7.89 (2H, d, J = 6.9Hz), 11.7 (1H, s) . 210 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 215 / 800 EX58 Η γχΧΧ OCX Yj XX 0 Using either 6-hydroxy-hexyl 6-methylpicolinate (2.0 g) synthesized in REX 16 e (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 yl)methyl (6-((6-methylpicolinoyl)oxy)hexyl) phosphate to synthet EX umte semethy semi (35 mg) emi 56. NMR1; 1.30–1.41 (4H, m), 1.47–1.56 (2H, m), 1.65–1.72 (2H, m), 1.78–1.87 (2H, m), 1.90–2.00 (2H, m), 2.52 (3H, s, 3.3–m), 3.3–40. (4H, m), 3.66–3.80 (4H, m), 4.09 (2H, t, J = 6.2Hz), 4.26 (2H, t, J = 6.7Hz), 5.09 (2H, d, J = 9.0Hz), 6.29 (1H, dd, J, J = 9.4Hz). = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.9Hz), 7.47 (1H, dd, J = 6.4Hz, H 72.51Hz), 7.55 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.76 (1H, d, J = 5.5Hz), 7.79 (1H, d, J = 9.5Hz), 7.82-7.88 (2H, m), 11.7 (1H, s). 211 / 375 Petition: 870260084657, on August 20, 2026, page. 216 / 800 EX 59 fosfato (150 mg) fosfato (150 mg) foi It's possible for me to feel better síntese do EX 45. RMN1; 0.84 (9H, s), 1.41-1.58 (4H, m), 1.78-1.88 (2H, m), 1.89-2.00 (2H, m), 3.40-3.50 (4H, m), 3.52-3.67 (6H, m), 3.68-3.80 (4H, m), 4.10 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 9.1Hz), 6.31 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.7Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.3Hz), 7.32 (1H,t, J = 7.9Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.76 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 212 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 217 / 800 EX60 Η aOíTW ​​0 0 x< X^ 0 Using ethyl 6-hydroxyhexanoate (0.99 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxymethyl)1-butyl)pi hydrogenophosphate (0.5 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6ethoxy-6-oxo-emhatho-umhexyl (obtyl1) phospha method synthesis of EX 52. NMR1; 1.15 (3H, t, J = 7.1Hz), 1.22–1.33 (2H, m), 1.45–1.56 (4H, m), 1.78–1.89 (2H, m), 1.90–2.00 (2H, m), 3.40–3.50–H3.8 (4.H), 4.01 (2H, q, J = 7.1Hz), 4.09 (2H, t, J = 6.5Hz), 5.09 (2H, d, J = 9.1Hz), 6.30 (1H, dd, J = 9.5Hz, 1.8Hz), 6.82 (1H 2. 8.4.4Hz, J = d, J = 2.4Hz), 7.01 (1H, d, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 J = 7.1H, d, d 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 213 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 218 / 800 EX61 Η CUT) 0 OQ II 1 Q zP\ ^Br o- 0 Using 4-bromobutan-1-ol (1.06 g) and (4-(benzo[b]thiophen4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7- yl)oxy-opperazine-1-imetyl) hydrogen phosphate (1.0 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (4bromobutyl) phosphate (440 mg) was obtained from a solution of EX 52. NMR1; 1.57-1.66 (2H, m), 1.79-1.89 (4H, m), 1.90-2.00 (2H, m), 3.40-3.50 (4H, m), 3.51-3.68 (6H, m), 3.70-3.80 (4H, m), 4.10 J, t 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.3Hz), t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 5.5Hz), (1H, s). 214 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 219 / 800 EX62 \ %z° YX° O tZ Using 4-chlorobut-2-in-1-ol (0.24 g) and (4-(benzo[b]thiophene4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7- il)oxy)genolyl-hydroyl-1)piperazine-piperazine (0.5 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -EX)methyl (4chlorobut-2-in-1-yl) phosphate emptyo method fo umi obsendi 230 mg 56. NMR1; 1.78–1.88 (2H, m), 1.89–2.00 (2H, m), 3.17 (2H, d, J = 5.2Hz), 3.40–3.50 (4H, m), 3.55–3.70 (4H, m), 4.08–4.13 (2.5), m 5.09 (2H, d, J = 8.9Hz), 6.30 (1H, dd, J = 9.5Hz, 1.8Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), H 7.3, d = 2.4Hz (H t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 J (1H, d, d). 215 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 220 / 800 EX63 / =O oc / \ \ '° / / ™ o Using 7-bromo-heptane-1-ol (1.08 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)iperamethyl-1-butyl) hydrogenophosphate (1.0 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (7bromo-heptyl) phosphate emtho via umi6melseobhando method (7bromo-heptyl) 52. NMR1; 1.30-1.50 (6H, m), 1.44-1.52 (2H, m), 1.74 (2H, sext, J = 7.2Hz), 1.80-1.89 (2H, m), 1.90-2.00 (2.H, m), 3.40-H8, m3 (2.6), 3.40-H8, m 4.10 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (H7.2, d1 = J = 7.4Hz), 7.33 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (H7, d, J = 5), 9.5Hz), 11.7 (1H, s). 216 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 221 / 800 EX64 Η ovOi or (XJ 0- ,ζ-^γ γ Using ter-butyl (4-hydroxybutyl)carbamate (1.74 g) and (4(benzo[b]thiophene-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-yl-1)quinoxyperalin-dibutyl -ium-1 -yl)methyl (4((ter-butotoxiccarbonyl)amino)butyl) phosphate (35 mg) was obtained by a similar method to the synthesis of EX 45. RMN1 1.35 (9H, s), 1.37-1.52 (4H, 1.1), 1.37-1.52; 1.90–2.00 (2H, m), 2.91 (2H, sext, J = 6.5Hz), 3.40–3.50 (4H, m), 3.51–3.80 (8H, m), 4.10 (2H, t, J = 6.0Hz), 5.9, dJ (H =6) dd, J = 9.5Hz, 1.3Hz), 6.80 (1H, br-t, J = 6.0Hz), 6.83 (1H, dd, J = 8.7Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.01 (H7, 3. d, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.57 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.76 (1H, d, J = 5.5Hz), 7.81 (H 1, 1. d, J = 1). 217 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 222 / 800 EX65 Using 3-(methylthio)propan-1-ol (5 mL) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (0.5 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl (3(methylthio)propyl) phosphate (180 mg) was obtained in a method similar to the synthesis of EX 45 . NMR1; 1.77 (2H, sext, J = 7.4Hz), 1.82-1.88 (2H, m), 1.90-2.00 (2H, m), 2.02 (3H, s), 3.40-3.50 (4H, m), 3.50-3.67 (4H, m), 3.50-3.67 (4H, m), 2-3.2 (4.1 m), 4.1 m. (2H, t, J = 6.1Hz), 5.10 (2H, d, J = 8.9Hz), 6.31 (1H, d, J = 9.5Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.57 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.76 (1H, d, J = 8.1Hz), J = 9.5Hz), 11.7 (1H, Sl________________ 218 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 223 / 800 EX66 Η OJA iXj U ' / vJA Using chloromethyl 2,2-dimethyl-1,3-dioxane-5-carboxylate (1.15 g) synthesized in REX 20 and (4-(benzo[b]thiophene-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophen4-yl)-1 -(4-(2-oxo-ylhydro-1)quinoxyperalin-di-but -ium-1 -yl)methyl (((2,2-dimethyl-1,3dioxane-5-carbonyl)oxy)methyl) phosphate (220 mg) was obtained in a method similar to the synthesis method of EX 68. NMR1; 1.28 (6H, s), 1.79–1.89 (2H, m), 1.90–2.00 (2H, m), 2.75 (1H, sept, J = 6.5Hz), 3.40–3.50 (4H, m), 3.52–3.68 (4H, m–3), 3.92–4.01 (4H, m), 4.09 (2H, t, J = 6.0Hz), 5.10 (2H, d, J = 9.0Hz), 5.47 (2H, d, J = 13.0Hz), 6.30 (1H, d, J = 9.6, J = 1 = H6.8.8). 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (J,7.7.6 (J = 8), 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s). 219 / 375 Petition 870260084657, dated 08 / 20 / 2026, page 224 / 800 EX67 (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (0.5 g) and DIPEA (0.96 mL) were dissolved in a mixed solvent of acetone (10 mL) and water (4 mL), chloromethyl ethyl glutarate (REX 17, 1.15 g) was added, and the mixture was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were removed by filtration. The crude crystals were purified by column chromatography on silica gel (eluent: DCM-MeOH). The resulting solid was recrystallized in acetone-water to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butylpiperazin-1-ium-1-yl)methyl(((5-ethoxy-5oxopentanoyl)oxy)methyl) phosphate (880 mg). RMN1; 1.13 (3H, t, J = 7.1Hz), 1.17 (2H, sext, J = 7.3Hz), 1.80-1.89 (2H, m), 1.90-2.00 (2H, m), 2.30 (2H, t, J = 7.4Hz), 2.38 (2H, t, J = 7.4Hz), 3.40-3.50 (4H, m), 3.53-3.69 (4H, m), 3.70-3.80 (2H, m), 4.01 (2H, q, J = 7.1Hz), 4.09 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 9.0Hz), 5.43 (2H, d, J = 12.8Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, Sl________________ 220 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 225 / 800 EX68 Η αΟι 0 W where T °x ·< „ ü JX / ? Ή; Using 5-(ter-butoxy)-5-oxopentanoic acid (5 g), chloromethyl ester was synthesized in the same manner as in REX 17 and reacted with (4-(benzo[b]thiophene-4-yl)-1-(4-((2oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 yl)methyl hydrogenophosphate (0.5 g) in the same manner as non-EX 68 to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (((5-(ter-butoxy)-5-oxopentanoyl)oxy (H3.3)methyl phospha). s), 1.71 (2H, sext, J = 7.5Hz), 1.79–1.88 (2H, m), 1.89–2.00 (2H, m), 2.20 (2H, t, J = 7.5Hz), 2.36 (2H, t, J = 7.5Hz (H, 3.5Hz), 3.4. 3.55–3.70 (4H, m), 3.72–3.80 (2H, m), 4.09 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 9.0Hz), 5.43 (2H, d, J = 12.8Hz), H 6.8, d = 1 = 1 dd, J = 8.6Hz, 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.71 J (1 = H8.5). (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s). 221 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 226 / 800 EX69 4-(Benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((5-(tert-butoxy)-5oxopentanoyl)oxy)methyl) phosphate (2.5 g) synthesized in EX 69 was placed in a flask and TFA (5 mL) was added at room temperature and stirred for 1 hour. After the reaction was complete, DCM was added to the reaction mixture and concentrated at reduced pressure twice to remove excess TFA. The residue was purified by medium pressure liquid chromatography (eluent: DCMMeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((4-carboxybutanoyl)oxy)methyl) phosphate (1.83 g). RMN1; 1.76 (2H, sext, J = 7.4Hz), 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 2.25 (2H, t, J = 7.4Hz), 2.37 (2H, t, J = 7.4Hz), 3.40-3.50 (4H, m), 3.54-3.70 (4H, m), 3.72-3.80 (2H, m), 4.09 (2H, t, J = 6.0Hz), 5.10 (2H, d, J = 9.0Hz), 5.44 (2H, d, J = 12.8Hz), 6.30 (1H, d, J = 9.5Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s), 12.2 (1H, br-s). 222 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 227 / 800 EX70 Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((5((4-metoxibenzil)oxi)-3,3-dimetil-5-oxopentanoil)oxi)metil) fosfato (0.2 g) sintetizado no EX 72, (4-(benzo[b]tiofen-4il)-1-(4-((2-oxo-1,2-di-hydroquinolin-7-il)oxi)butil)piperazin1 -ium-1 -il)metil (((4-carboxi-3,3-dimetil-5oxopentanoil)oxi)metil) fosfato (120 mg) foi Obtido em um metodo This will also work at the same time as EX 70. RMN1; 1.04 (6H, s), 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 2.30 (2H, s), 2.41 (2H, s), 3.40-3.50 (4H, m), 3.53-3.70 (4H, m), 3.71-3.80 (2H, m), 4.09 (2H, t, J = 6.0Hz), 5.11 (2H, d, J = 9.0Hz), 5.43 (2H, d, J = 12.8Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s), 12.2 (1H, brSl________________ 223 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 228 / 800 EX 71 (4-(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (1.0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((5((4-metoxibenzil)oxi)-3,3-dimetil-5-oxopentanoil)oxi)metil) phosphorus (740 mg) foi obtido em um método semelhante ao método de sintese do EX 68. RMN1; 1.00 (6H, s), 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 2.38 (2H, s), 2.39 (2H, s), 3.40-3.50 (4H, m), 3.54-3.67 (4H, m), 3.73 (3H, s), 3.73-3.81 (2H, m), 4.08 (2H, t, J = 6.0Hz), 4.97 (2H, s), 5.09 (2H, d, J = 9.0Hz), 5.41 (2H, d, J = 12.5Hz), 6.30 (1H, dd, J = 9.5Hz, 1.6Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 6.90 (2H, d, J = 8.7Hz), 7.00 (1H, d, J = 7.6Hz), 7.26 (2H, d, J = 8.7Hz), 7.31 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.55 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.75 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.6 (1H, s). 224 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 229 / 800 EX72 ο ' { 'X ZX / A xz y \ OZ \ \ z° \ / ^° 'b QJ^AO= / ω Using (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo)1,2-dihydroquinolin-7-methyl-1)yl)pioxybutyl (((4carboxybutanoyl)oxy)methyl) phosphate (300 mg) synthesized in EX 70 and isopropylamine (39 mg), (4-(benzo[b]thiophene-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)ioperamethyl1-1)butyl (((5-(isopropylamine)-5oxopentanoyl)oxy)methyl) phosphate (295 mg) was obtained in the same way as in EX 74. NMR1; 1.00 (6H, d, J = 6.6Hz), 1.75 (2H, sext, J = 7.3Hz), 1.791.88 (2H, m), 1.892.00 (2H, m), 2.07 (2H, t, J = 7.4Hz), 2.2, H = 2 (2 3.40–3.50 (4H, m), 3.54–3.70 (4H, m), 3.72–3.81 (3H, m), 4.03–4.12 (2H, m), 5.11 (2H, d, J = 9.0Hz), 5.44 (1H, d.3, J = Hz), 5.44 (2H, d.3, J = 9.5Hz, 1.6Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = H 7.5 d, 7.2Hz (1 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 7.84 (1H, brs), 11.6 (1H, s). 225 / 375 Petition 870260084657, dated 08 / 20 / 2026, pages 230 / 800 EX73 4-(Benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((4-carboxybutanoyl)oxy)methyl) phosphate (300 mg) synthesized in EX 70 was dissolved in a mixed solvent of DCM (5 mL) and MeOH (2 mL), and 2,2-dimethyl-1,3-dioxan-5-amine (86 mg) and DMT-MM (81 mg) were added and stirred at room temperature overnight. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM-MeOH). The resulting product was crystallized from acetone-water to give (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((5-((2,2-dimethyl-1,3dioxan-5-yl)amino)-5-oxopentanoyl)oxy)methyl) phosphate (332 mg). RMN1; 1.28 (3H, s), 1.34 (3H, s), 1.75 (2H, sext, J = 7.4Hz), 1.801.88 (2H, m), 1.892.00 (2H, m), 2.15 (2H, t, J = 7.4Hz), 2.33 (2H, t, J = 7.4Hz), 3.40-3.50 (4H, m), 3.54-3.80 (11H, m), 4.06-4.18 (3H, m), 5.11 (2H, d, J = 8.9Hz), 5.44 (2H, d, J = 13.5Hz), 6.30 (1H, dd, J = 9.5Hz, 1.6Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s). 226 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 231 / 800 EX74 Η 0 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1.5 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((6((2,2-dimethyl-1,3-dioxan-5-il)metoxi)-6oxohexanoil)oxi)methyl) phosphate (138 mg) was obtained using a method similar to that used in EX 68. RMN1; 1.28 (3H, s), 1.31 (3H, s), 1.46-1.53 ​​(4H, m), 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 2.28 (2H, t, J = 6.8Hz), 2.34 (2H, t, J = 6.8Hz), 3.40-3.50 (4H, m), 3.55-3.68 (6H, m), 3.70-3.81 (2H, m), 3.86 (2H, dd, J = 11.9Hz, 4.0Hz), 4.03 (2H, d, J = 7.1Hz), 4.09 (2H, d, J = 6.1Hz), 5.09 (2H, d, J = 8.9Hz), 5.43 (2H, d, J = 12.7Hz), 6.30 (1H, dd, J = 9.5Hz, 1.7Hz), 6.85 (1H, dd, J = 8.6Hz, 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s). 227 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 232 / 800 EX75 Η çuX / W ΤΎ °χ o °-- '''Χ-'-Χ HV^-N ο I Using chloromethyl 10-(isopropylamine)-10-oxodecanoate (1.07 g) synthesized in REX 26 and (4]-thio-1-phenzo[b -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophen4-yl)-1 -(4-(2-oxo-ylhydro-1)quinoxyperalin-di-but -ium-1 -yl)methyl (((10(isopropylamine)-10-oxodecanoyl)oxy)methyl) phosphate (880 mg) was obtained by a method similar to the synthesis method of EX 68. NMR1; 1.00 (6H, d, J = 6.6Hz), 1.10–1.22 (8H, m), 1.38–1.52 (4H, m), 1.79–1.89 (2H, m), 1.90–2.00 (2H, m), 1.97 (2H, 2.3, t0 = J = 7.4Hz), 3.40–3.50 (4H, m), 3.53–3.69 (4H, m), 3.71–3.82 (3H, m), 4.09 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 8.3 Hz (6.2 Hz), d 5.4 (1H, dd, J = 9.5Hz, 1.4Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, d, t, J = 7.5Hz). 5.5Hz), 7.56 (1H, d, J = 8.6Hz), 7.61 (1H, br-d, J = 7.5Hz), 7.72 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.6 (1H, s). 228 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 233 / 800 EX76 çuxroy it yd cr o— 0 °XV^S'O^' Using l -(chloromethyl) 12-(2-methoxyethyl) dodecanedioate (1.86 g) synthesized in REX 28 and (4-(benzo[b]thiophene-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophen4-yl)-1 -(4-(2-oxo-ylhydro-1)quinoxyperalin-di-but -ium-1 -yl)methyl (((12-(2-methoxyethoxy)12-oxododecanoyl)oxy)methyl) phosphate (740 mg) was obtained in a method similar to the synthesis method of EX 68. NMR1; 1.13–1.30 (12H, m), 1.42–1.51 (4H, m), 1.78–1.88 (2H, m), 1.89–2.00 (2H, m), 2.28 (4H, sext, J = 7.4Hz), 3.24,5.5 (3.4 (6), s 3.53–3.71 (4H, m), 3.73–3.82 (2H, m), 4.05–4.15 (4H, m), 5.10 (2H, d, J = 8.8Hz), 5.43 (2H, d, J = 12.8Hz), 6.82, J (1 = 1H, d (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 7.6 d,66), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 229 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 234 / 800 EX77 Using chloromethyl ((benzyloxy)carbonyl)glycinate (1.42 g) synthesized in REX 29 and (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)hydrazine-hydrogen-1 il. gmethyl)oxy) (4-(benzo[b]thiophene-4-yl)-1(4-(((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1 -yl)methyl (((((benzyloxy)semelyl carbonyl)glycyl)oxy)methylcyte aphoseo method fose umi mgto (72 of EX 68. RMN1; 1.79-1.88 (2H, m), 1.89-2.00 (2H, m), 3.40-3.50 (4H, m), 3.52-3.69 (4H, m), 3.70-3.80 (2H, m), 3.84 (2H, d, J = 6.2Hz), 4.09 (2H, d, J = 6.0Hz), 5.02 (2H, s), 5.03-5.15 (2H, m), 5.48 (2H, d, J = 13.6Hz), 6.30 (1H, dd, J = 9.5Hz, 1.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.6Hz), 7.24-7.40 (6H, m), 7.51 (1H, d, J = 5.5Hz), 7.55 (1H, d, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.73-7.82 (3H,m), 11.6 (1H, s). 230 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 235 / 800 EX78 Η çuXW [I \ o Xí^ 0- o-^\ Jl °^\ H Using chloromethyl 4-(ter-butoxycarbonyl)amino)butanoate synthesized in REX 30 (3.06 g) and (4-(benzo[b]thiophene-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogenophosphate (2.2 g), (4-(benzo[b]thiophene4-yl)-1 -(4-(2-oxo-hydro-hydro-1,2)quinoxyperalin-di-but -ium-1 -yl)methyl (((4-(terbutotoxiccarbonyl)amino)butanyl)oxy)methyl) phosphate (2.12 g) was obtained in a method similar to the synthesis method of EX 68). RMN1; 1.34 (9H, s), 1.62 (2H, sext, J = 7.3Hz), 1.80–1.89 (2H, m), 1.90–2.00 (2H, m), 2.33 (2H, t, J = 7.4Hz), 2.88–2.43), m3.3, m 3.52–3.69 (4H, m), 3.70–3.80 (2H, m), 4.10 (2H, t, J = 6.0Hz), 5.09 (2H, d, J = 9.0Hz), 5.43 (2H, d, J = 19.6Hz), J 1.5 = d 1,1 (1 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.85 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.6Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (H 7. 5. d5, J = 8.6Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.6 (1H, s). 231 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 236 / 800 EX79 Η çjO^ or QJ HJ ^R< o °· *^0 Using chloromethyl 2-acetoxybenzoate synthesized in REX 31 (2.52 g) and (4-(benzo[b]thiophen-4-yl)-1-(4-(4-(2-oxo)1)quinoxylene-dibutyl-hydroxy -ium-1 -yl)methyl hydrogenophosphate (2.0 g), (2-acetoxybenzoyl)oxy)methyl ((4(benzo[b]thiophene-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)mg)oxy)to6-1)piperazine-piperazine was obtained by a method similar to the synthesis method of EX 68. NMR1; 1.71–1.81 (2H, m), 1.82–1.96 (2H, m), 2.31 (3H, s), 3.35–3.45 (4H, m), 3.48–3.66 (4H, m), 3.67–3.76 (2H, m), H 6.0, t 4.03 (2H, m). (2H, d, J = 9.0Hz), 5.65 (2H, d, J = 13.6Hz), 6.30 (1H, dd, J = 9.5Hz, 1.2Hz), 6.81 (1H, dd, J = 8.6Hz, 2.4Hz), 6.13 J = 1H, 9. d, d 7.6Hz), 7.23 (1H, dd, J = 8.1Hz, 0.9Hz), 7.31 (1H, t, J = 7.8Hz), 7.38 (1H, td, J = 7.7Hz, 1.0Hz), 7.46 (1H, d, J = 7.6 d = 75.5Hz), 7.65 (1H, td, J = 8.0Hz, 1.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 8.00 (1H, dd, J = 7.8Hz, 1.7Hz), 11.6 (1H, s). 232 / 375 Petition 870260084657, dated 08 / 20 / 2026, page 237 / 800 EX80 Using chloromethyl 2-methylnicotinate synthesized in REX 32 (1.02 g) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g), (4-(benzo[b]thiophen-4-yl)-1-(4-(2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1yl)methyl (((2-methylnicotinoyl)oxy)methyl) phosphate (510 mg) was obtained in a method similar to the EX 68 synthesis method. RMN1; 1.72-1.81 (2H, m), 1.83-1.96 (2H, m), 2.72 (3H, s), 3.38-3.48 (4H, m), 3.39-3.66 (4H, m), 3.68-3.78 (2H, m), 4.04 (2H, t, J = 6.1Hz), 5.12 (2H, d, J = 9.1Hz), 5.71 (2H, d, J = 13.4Hz), 6.30 (1H, d, J = 9.5Hz), 6.81 (1H, dd, J = 8.6Hz, 2.4Hz), 6.84 (1H, d, J = 2.4Hz), 6.96 (1H, d, J = 7.5Hz), 7.28-7.37 (2H, m), 7.49 (1H, d, J = 5.5Hz), 7.55 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 8.23 (1H, dd, J = 7.9Hz, 1.8Hz), 8.60 (1H, dd, J = 4.8Hz, 1.8Hz), 11.6 (1H, s). 233 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 238 / 800 EX81 / xorrw lí T °χ ά „ HJ XT ,9 xe^ G \ \ II / = o^\ / \ ΓΜ N Using chloromethyl 1-(2-methoxyethyl)-1H-indazole-3carboxylate synthesized in REX 66[-ylthio](b enzo-4 g) e -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-yl-1)quinoxyperalin-dibutyl -ium-1 -yl)methyl (((1 (2-methoxyethyl)-1H-indazole-3-carbonyl)oxy)methyl) phosphate (300 mg) was obtained in a similar method to the synthesis method of EX 68. NMR1;H 1,62.7,-78; 3.12 (3H, s), 3.35-3.45 (4H, m), 3.47-3.66 (4H, m), 3.68-3.78 (4H, m), 3.99 (2H, t, J = 6.1Hz), 4.66 (2H, t, J = 5.8 d,2Hz), 5.89 (2H, d, J = 13.6Hz), 6.30 (1H, d, J = 9.5Hz), 6.78 (1H, dd, J = 8.6Hz, 2.4Hz), 6.82 (1H, d, J = 2.4Hz), 6.89 (H7.2, d, J = 7.9Hz), 7.33 (1H, t, J = 7.9Hz), 7.427.49 (2H, m), 7.54 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J7 = 7.78-Hz),82 (2H, m), 8.14 (1H, d, J = 8.2Hz) 11.6 (1H, s). 234 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 239 / 800 EX82 Using methyl (ter-butoxycarbonyl)-L-serinate (3 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogenophospha (0.5 g (S)-(4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2(ter-butoxycarbonyl)amino)-3-methoxy method (emthoxyl-umirop35) do phospha-3-mg similar to EX 45 synthesis. RMN1; 1.35 (9H, s), 1.80-1.89 (2H, m), 1.90-2.00 (2H, m), 3.40-3.50 (4H, m), 3.57-3.70 (7H, m), 3.70-3.80 (2H, m), 3.92-4.08 (1H, m), 4.10 (2H, t, J = 6.1Hz), 4.15-4.22 (1H, m), 5.09 (2H, d, J = 8.7Hz), 6.31 (1H, dd, J = 9.5Hz, 1.5Hz), 6.83 (1H, dd, J = 8.6Hz, 2.4Hz), 6.86 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), 7.33 (1H, t, J = 7.8Hz), 7.52 (1H, d, J = 5.5Hz), 7.57 (1H, d, J = 8.6Hz), 7.72 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 9.5Hz), 11.7 (1H, s). 235 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 240 / 800 EX83 çÇOÇTXâ °· Using 3-phenoxypropane-1-ol (5 mL) and (4(benzo[b]thiophene-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-0.geno.1yl-hymethol-1), 4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (3phenoxypropyl) phosphate (160 mg) was obtained from RM1 by a similar method. 1.71–1.82 (2H, m), 1.85–2.01 (4H, m), 3.40–3.50 (4H, m), 3.50–3.61 (4H, m), 3.89 (2H, sext, J = 6.4Hz), 4.02 (2H = 4. 3, t, J). 6.1Hz), 5.08 (2H, d, J = 9.1Hz), 6.30 (1H, d, J = 9.5Hz), 6.81 (1H, dd, J = 8.6Hz, 2.4Hz), 6.856.94 (4H, m), 6.92-H = 1.7.2.4, d m), 7.32 (1H, t, J = 7.8Hz), 7.50 (1H, d, J = 5.5Hz), 7.55 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 7.5 d,5Hz), 11.7 (1H, s) . 236 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 241 / 800 EX84 Usando 6-hydroxy-hexil 4-nitrobenzoato sintetizado no REX 15 (1.2 g) e (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2di-hidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (1.0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2oxo-1,2-di-hydroquinolin-7-il)oxi)butil)piperazin-1-ium-1il)metil (6-((4-nitrobenzoil)oxi)hexil) fosfato (140 mg) for the whole month. síntese do EX 56. RMN1; 1.30-1.45 (4H, m), 1.46-1.57 (2H, m), 1.66-1.75 (2H, m), 1.77-1.87 (2H, m), 1.90-2.00 (2H, m), 3.40-3.50 (4H, m), 3.55-3.68 (4H, m), 3.69-3.80 (4H, m), 4.09 (2H, t, J = 6.1Hz), 4.29 (2H, t, J = 6.6Hz), 5.09 (2H, d, J = 9.0Hz), 6.28 (1H, d, J = 9.5Hz), 6.80 (1H, dd, J = 8.6Hz, 2.4Hz), 6.88 (1H, d, J = 2.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.31 (1H, t, J = 7.8Hz), 7.50 (1H, d, J = 5.5Hz), 7.54 (1H, d, J = 8.7Hz), 7.70 (1H, d, J = 8.0Hz), 7.76 (1H, d, J = 5.5Hz), 7.78 (1H, d, J = 9.5Hz), 8.17 (2H, d, J = 9.0Hz), 8.33 (2H, d, J = 9.0Hz), 11.7 (1H, s). 237 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 242 / 800 EX85 Η / X / X / X / X .N. çlOVTW TJ σ °\.....ΛΆ- '---' OH Using trans-1,4-cyclohexanodimethanol (3.83 g) and (4(benzo[b]thiophene-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogenophosphate (1.0 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-yl-1)quinoxyperalin-dibutyl -ium-1 -yl)methyl (((1r,4r)-4-(hydroxymethyl)cyclo-hexyl)methyl) phosphate (160 mg) was obtained by a method similar to the synthesis of EX 44. NMR1; 0.75–0.95 (4H, m), 1.20–1.30 (1H, m), 1.35–1.45 (1H, m), 1.71 (4H, d, J = 8.6Hz),1.79–1.88 (2H, m), 1.89–2.00 (H 5,4 t), 1.89–2.00 (H 5,2, m). 3.40–3.49 (4H, m), 3.51 (2H, t, J = 6.4Hz), 3.55–3.67 (4H, m), 3.70–3.80 (2H, m), 4.10 (2H, d, J = 6.1Hz), 4.35 J = 1H.5, t 9.0Hz), 6.30 (1H, d, J = 9.5Hz), 6.82 (1H, dd, J = 8.6Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.01 (1H, d, J = 7.5Hz), H 7.5, t, J = 1 d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 7.77 (1H, d, J = 5.5Hz), 7.80 (1H, d, J = 9.5Hz), 11.7 (1H, s). 238 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 243 / 800 EX86 A solution of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1.0 g) in a mixed solvent of MeOH (30 mL) and water (3 mL) was suspended. WSC^HCl (1.06 g) was added, and the resulting mixture was stirred at 40°C for 5 hours. Acetone and AcOEt were added to the reaction mixture, and the resulting mixture was concentrated three times under reduced pressure to azeotropically remove water. The concentrate was purified directly by column chromatography on silica gel (eluent: DCM-MeOH). The resulting product was suspended in water (4.5 mL). Acetone (9 mL) was added to dissolve the suspension. The resulting solution was left to stand at room temperature overnight, resulting in the precipitation of crystals. The precipitated crystals were collected by filtration.After drying in air at 25°C, (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl methyl phosphate (723 mg) was obtained. NMR1; 1.82-1.98 (4H, m), 3.39-3.49 (7H, m), 3.53-3.67 (4H, m), 3.72-3.79 (2H, m), 3.55-3.68 (4H, m), 3.68-3.79 (4H, m), 4.10 J, t (2.1H), t = 6.1. 5.10 (2H, d, J = 8.9Hz), 6.30 (1H, dd, J = 9.4Hz, 1.7Hz), 6.82 (1H, dd, J = 8.7Hz, 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.00 (1H, J = 7.4Hz), 7.32 (1H, t, J = 7.8Hz), 7.51 (1H, d, J = 5.5Hz), 7.56 (1H, d, J = 8.7Hz), 7.71 (1H, d, J = 8.1Hz), 9.4Hz), 11.7 (1H, s). 239 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 244 / 800 EX87 Η çcOi 0 ΧΧΤ ϊ J °>'° / ο- CT— Using 1-propyl alcohol (20 mL) e (4-(benzo[b]thiophen-4yl)-1-(4-((2-oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine1-ium-1-yl)methyl hydrogenphosphate (0.5 g), (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl propyl phosphate (326 mg) was obtained by a method similar to the synthesis of EX 45. NMR1; 0.85 (3H, t, J=7.4Hz), 1.52 (2H, h, J=7.1Hz), 1.80-1.88 (2H, m), 1.92-1.97 (2H, m), 3.37-3.53 (6H, m), 3.54-3.71 (4H, 2H, 2-8), m), 4.11 (2H, t, J=6.1Hz), 5.09 (2H, d, J=9.1Hz), 6.30 (1H, d, J=9.3Hz), 6.83 (1H, dd, J=8.7Hz, 2.4Hz), J=7.3Hz), 7.33 (1H, t, J=7.8Hz), 7.52 (1H, dd, J=5.5Hz, 0.9Hz), 7.57 (1H, d, J=8.7Hz), 7.72 (1H, d, J=8.1Hz), 7.77 (1H, d, 7.8Hz), 7.61Hz. (1H, d, J=9.4Hz), 11.69 (1H, s). 240 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 245 / 800 EX88 NaI (208 mg) was added to a solution of 4-(benzo[b]thiophen-4-yl)-1-(((dibutoxyphosphoryl)oxy)methyl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium iodide) (545 mg) in acetone (12 mL) at room temperature, and the reaction mixture was stirred at 60°C in a nitrogen atmosphere. After 3 hours, NaI (104 mg) and acetone (6 mL) were added, and the resulting mixture was stirred for 3 hours at 60°C and stirred at room temperature overnight. 50 mL of DCM / MeOH = 9 / 1 was added. AcOH (0.398 mL) was dissolved in H2O (30 mL) and the resulting solution was added dropwise. The insoluble matter was removed by filtration and washed vigorously with H2O. The residue was purified by silica gel chromatography (DCM / MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methylbutyl phosphate (242 mg). RMN1; 0.86(3H, t, J=7.4Hz), 1.231.37(2H, m), 1.421.54(2H, m), 1.791.87(2H, m), 1.892.00(2H, m), 3.433.47(4H, m), 3.533.66(4H, m), 3.70(2H, q, J=6.7Hz), 3.733.80(2H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.30(1H, dd, J=9.5Hz, 2.0Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, d, J=7.2Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.69(1H, s). 241 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 246 / 800 EX89 Η çcOi . Π JU (4(benzo[b]tiofen-4-il)-1 -(4-(2-oxo-1,2-di-hydroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil isobutil phosphate (125 mg) for the first time and then enters the EX 45. RMN1; 0.84(6H, d, J=6.7Hz), 1.681.80(1H, m), 1.811.87(2H, m), 1.902.00(2H, m), 3.433.52(4H, m), 3.533.66(6H, m), 3.723.80(2H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.2Hz), 6.30(1H, dd, J=9.5Hz, 1.6Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.33(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.6Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.4Hz), 11.68(1H, s). 242 / 375 Petition: 870260084657, on August 20, 2026, page. 247 / 800 EX90 DIPEA (0.482 mL), 1-(chloro-1-pyrrolidininimethylene)pyrrolidinium hexafluorophosphate (918 mg), and cyclopropyl methanol (0.373 mL) were added to a solution of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (500 mg) in DMF (5 mL) at room temperature, and stirred at 80°C for 8 hours. The reaction system was returned to room temperature. H2O was added, and the resulting mixture was stirred overnight. The precipitate was removed by filtration and washed vigorously with H2O. The residue was purified by silica gel column chromatography (DCM / MeOH). Acetone / H2O = 1 / 1 was added, and the precipitate was removed by filtration and left to stand at room temperature overnight to give (4-(benzo[b]thiophen-4-yl)1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(cyclopropylmethyl)phosphate (84 mg). RMN1; 0.14-0.22(2H, m), 0.39-0.48(2H, m), 1.80-1.87(2H, m), 1.89-2.00(2H, m), 3.30-3.41(2H, m), 3.43-3.47(4H, m), 3.55(2H, t, J=7.2Hz), 3.54-3.66(2H, m), 3.72-3.80(2H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.2Hz), 6.30(1H, d, J=9.4Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.6Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.68(1H, s). 243 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 248 / 800 EX91 (4-(Benzo[b]thiophen-4-yl)-1-(4-(2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (3 g) was suspended in 1,5-pentanediol (80 mL). WSQHCl (2.1 g) was added, and the resulting mixture was stirred at 60°C for 1 hour. Water was added to the reaction mixture, and the resulting mixture was concentrated. The concentrate was directly purified twice by medium-pressure liquid chromatography (silica gel, eluents: cOEt / DCM / MeOH). The resulting amorphous product was dissolved in a mixed solvent of acetone (8 mL) and water (8 mL). Water (4 mL) was added to the solution with stirring. The precipitated crystals were collected by filtration and air-dried at 25°C overnight to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(4-hydroxypentyl) phosphate (2.2 g). RMN1; 1.24-1.36(2H, m), 1.36-1.45(2H, m), 1.45-1.56(2H, m), 1.79-1.87(2H, m), 1.89-2.00(2H, m), 3.32-3.40(2H, m), 3.44(4H, d, J=5.9Hz), 3.53-3.66(4H, m), 3.70(2H, q, J=6.8Hz), 3.73-3.79(2H, m), 4.10(2H, t, J=6.1Hz), 4.39(1H, t, J=5.2Hz), 5.09(2H, d, J=9.1Hz), 6.30(1H, d, J=9.0Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.90(1H, d, J=2.4Hz), 7.00(1H, dd, J=7.8Hz, 0.8Hz), 7.32(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.5Hz), 11.70(1H, Sl________________ 244 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 249 / 800 Using diethylene glycol (20 mL) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (2-(2-hydroxyethoxy)ethyl) phosphate (654 mg) was obtained by a method similar to the synthesis of EX 45. MRN1; 1.80—1.88(2H, m), 1.89—2.01(2H, m), 3.36-3.55(10H, m), 3.55-3.67(4H, m), 3.72-3.79(2H, m), 3.79-3.87(2H, m), 4.10(2H, t, J=6.1Hz), 4.72(1H, t, J=5.5Hz), 5.10(2H, d, J=8.9Hz), 6.30(1H, dd, J=9.4Hz, 1.3Hz), 6.83(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.5Hz), 7.01(1H, dd, J=7.8Hz, 0.9Hz), 7.32(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.68(1H, s). 245 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 250 / 800 EX93 Using 2-ethoxyethanol (3.7 mL) and (4-(benzo[b]thiophen-4-yl)1 -(4-(2-oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogen phosphate (5 g), (4-(b]thiophen-4-yl) -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-ethoxyethyl) phosphate (3.6 g) was obtained in a method similar to the synthesis of EX 56 . NMR1; 1.08(3H, t, J=7.0Hz), 1.801.87(2H, m), 1.892.00(2H, m), 3.41(2H, q, J=7.0Hz), 3.433.50(6H, m), 3.533.67(4H, m, 3.69), 3.49, m. 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.266.33(1H, m), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.0Hz, dd(1Hz). J=7.6Hz, 0.8Hz), 7.33(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.5Hz, 7.5Hz, J=7.5Hz. 7.80(1H, d, J=9.5Hz), 11.68(1H, s). 246 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 251 / 800 EX94 Η z\ Z\ / \ z°\ z^, zN\zO çcOj QJ Ϊ η ν° U z\ zX ^0. XX 0' o — — X Using ethylene glycol monoproyl ether (2 mL) and (4(benzo[b]thiophen-4-yl)-1 -(4-(2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-hydrogeno-1 gphosphamethyl (4-(benzo[b]thiophen-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2propoxyethyl) phosphate (397 mg) was obtained from RM 15 by a similar method. 0.83(3H, t, J=7.4Hz), 1.48(2H, h, J=7.2Hz), 1.791.88(2H, m), 1.892.00(2H, m), 3.243.40(4H, m), 3.413.51 (9.5.H3), 6(4H, H3), 3.723.85(4H, m), 4.11(2H, t, J=6.1Hz), 5.10(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.5Hz, 2.0Hz), 6.83(H, dd, J=8.8.6Hz(1Hz), 2 J = 2.4Hz), 7.01(1H, d, J=7.5Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, d, J=5.3Hz), 7.57(1H, d, J=8.6Hz), 7.72(J,5,=1.H=8.7Hz), 7.81(1H, d, J=9.5Hz), 11.68(1H, s). 247 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 252 / 800 EX95 Η çuOi. UJ I 1 V 1! Z / \ / 0' 0 Use monobutyl glycol (20 mL) and (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1 g), RMN3 0.86(3H, t, J=7.4Hz), 1.251.38(2H, m), 1.451.57(2H, m), 1.942.04(2H, m), 2.062.16(2H, m), 3.45(2H, t, J=6.7Hz), 3.503.54(4H, m), 3.573.64(2H, m), 3.653.73(2H, m), 3.743.81(2H, m), 3.823.92(2H, m), 4.004.08(2H, m), 4.20(2H, t, J=5.9Hz), 5.20(2H, d, J=7.8Hz), 6.44(1H, d, J=9.4Hz) 6.89(1H, d, J=2.4Hz), 6.92(1H, dd, J=8.7Hz, 2.4Hz), 7.05(1H, dd, J=7.7Hz, 0.8Hz), 7.30(1H, t, J=7.9Hz), 7.49(1H, dd, J=5.5Hz, 0.9Hz), 7.57(1H, d, J=5.1Hz), 7.59(1H, d, J=2.0Hz), 7.65(1H, d, J=8.1Hz), 7.88(1H, d, J=9.4Hz). 248 / 375 Petition: 870260084657, on August 20, 2026, page. 253 / 800 EX96 Η χΟι . WU >0χ / χ / x X^ o- ovox Using 3-(benzo[b]thiophen-4yl)-1-(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)hydrogen0-genol-5-zymethol-1), (4(benzo[b]thiophene-4-yl)-1 -(4-(((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (3-ethoxypropyl) phosphate (308 mg) was obtained by EX 1 5 ; a method similar to RM 1.07(3H, t, J=7.0Hz), 1.73(2H, p, J=6.4Hz), 1.791.87(2H, m), 1.921.97(2H, m), 3.363.42(4H, m), 3.423.47 (7.5.H3), 6.5H, m 3.713.80(4H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.5Hz, 2.0Hz), 6.82(1H, dd, J=8.8.7Hz(H6), 2 J=2.4Hz), 7.01(1H, d, J=7.5Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.6Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(H=7.7, d, d J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.68 (1H, s). 249 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 254 / 800 EX97 Η çcOi 0 XXX 0- 0 0 Using diethylene glycol monoethyl ether (5 mL) and (4(benzo[b]thiophen-4-yl)-1 -(4-(2-oxo-1,2-di-hydroquinoline-7yl)piomethyl-1)butyl hydrogenophosphate (0.5 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2-(2hemethoxyethoxy à humelyte fomi (5ethyl se3and) mg) phosphate synthesis of EX 45. NMR1; 1.06(3H, t, J=7.0Hz), 1.801.88(2H, m), 1.892.01(2H, m), 3.39(3H, q, J=7.0Hz), 3.423.48(7H, m), 3.483.54 m(3.24, m), 6(4H, m3), 3.713.85(4H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.5Hz, 1.7Hz), 6.82(1H, dd, J=8.8.8Hz(H6, 2 J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.71(H=7.7, d, d J = 5.6 Hz), 7.81 (1H, d, J = 9.5 Hz), 11.67 (1H, s). 250 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 255 / 800 EX98 (4-(Benzo[b]thiophen-4-yl)-1-(4-(2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (0.5 g) was suspended in diethylene glycol monobutyl ether (20 mL) and water (1 mL). WSC^HCl (0.53 g) was added to the suspension, and the resulting mixture was stirred at 60°C for 5 hours. AcOEt was added to the reaction mixture, and the resulting mixture was allowed to stand. The AcOEt layer was removed by decantation, and the residue was purified twice by column chromatography on silica gel (1st purification: silica gel, 2nd purification: amino silica gel, eluent: DCM / MeOH). The amorphous product obtained was suspended in water, and acetone was added to dissolve the suspension.After stirring at room temperature overnight, the precipitated crystals were collected by filtration and air-dried at 25°C overnight to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(2-(2-butoxyethoxy)ethyl) phosphate (177 mg). NMR1; 0.82(3H, t, J=7.3Hz), 1,181.32(2H, m), 1,361.48(2H, m), 1,801.88(2H, m), 1,892.02(2H, m), 3,233.37(2H, m), 3,403.48(6H, m), 3,483.54(4H, m), 3,543.69(4H, m), 3,713.85(4H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.30(1H, dd, J=9.4Hz, 2.0Hz), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.4Hz), 11.67(1H, Sl________________ 251 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 256 / 800 EX99 (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (1 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo1,2-di-hydroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetrametiltetra-hydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]piran-5-il)metil)fosfato (863 mg) when it comes to the same time 56.RMN1; 1.25(3H, s), 1.26(3H, s), 1.31(3H, s), 1.43(3H, s), 1.801.87(2H, m), 1.892.00(2H, m), 3.403.49(5H, m), 3.523.68(4H, m), 3.703.86(3H, m), 3.863.94(1H, m), 4.10(2H, t, J=6.1Hz), 4.23(1H, dd, J=8.0Hz, 1.9Hz), 4.32(1H, dd, J=5.0Hz, 2.4Hz), 4.57(1H, dd, J=8.0Hz, 2.3Hz), 5.04 - 5.17(2H, m), 5.44(1H, d, J=5.0Hz), 6.30(1H, dd, J=9.5Hz, 1.9Hz), 6.83(1H, dd, J=8.6Hz, 2.4Hz), 6.88(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.8Hz), 7.32(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.67(1H, s). 252 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 257 / 800 EX100 Η ✓N. Λ onc^CU YJ z< 0' O-- r Using (4-(benzo[b]thiophene-4-yl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6hydroxy-hexyl) (6hydroxy-hexyl) 6-acetoxy-hexyl ((4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl) phosphate (375 mg) was obtained from the same EX 15 1.24-1.32(4H, m), 1.43-1.57(4H, m), 1.79-1.87(2H, m), 1.92-1.96(2H, m), 1.98(3H, s), 3.433.49(4H, m), 3.433.6. J=6.7Hz), 3.723.79(2H, m), 3.95(2H, t, J=6.7Hz), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.30(1H, d, J=9.82,dHz(= J8,6). 2.4Hz), 6.90(1H, d, J=2.4Hz), 7.00(1H, d, J=7.6Hz), 7.32(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.6Hz, 0.8Hz), 7.16(H=1.7 d, d, d J = 8.0Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.70(1H, s). 253 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 258 / 800 EX101 Η çcOi 0 OC / T Ύ °x° 0 Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2)oxo-1,2-di-hydroquinoylene-1butylyl-7yl)oxy hydrogenophosphate (0.8 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6(pivaloloxy) àihexyl obhando) mg synthesis in EX 56. NMR1; 1.11(9H, s), 1.25-1.33(4H, m), 1.45-1.57(4H, m), 1.79-1.87(2H, m), 1.92-1.97(2H, m), 3.43-3.47(4H, m), 3.6-3(4H, 3.6-). q, J=6.7Hz), 3.72-3.79(2H, m), 3.96(2H, t, J=6.5Hz), 4.06-4.15(2H, m), 5.09(2H, d, J=9.1Hz), 6.30(1H, dd, J=1.8.5Hz(1 J=8.7Hz, 2.4Hz), 6.90(1H, d, J=2.4Hz), 7.00(1H, dd, J=7.7Hz, 0.8Hz), 7.32(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.7Hz(J.1Hz), H 0.8). 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.70(1H, s). 254 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 259 / 800 EX102 Η here 0 XJJ there η three / / ? __ [1 A zp\ .* [Abs] 00 0 Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxymethyl)1-butyl)pivalate hydrogenophosphate (0.8 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6(pivaloloxy) àihexyl obhando) mg synthesis in EX 56. NMR1; 1.17(3H, t, J=7.1Hz), 1.32(3H, d, J=6.9Hz), 1.811.87(2H, m), 1.881.99(2H, m), 3.423.47(4H, m), 3.513.68(3.2H, m), 8.2H, m3 4.024.14(4H, m), 4.554.66(1H, m), 5.08(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.5Hz, 1.7Hz), 6.83(1H, dd, J=8.7Hz),= H6, 2.8Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H,5,=1H(1.7.7Hz), 7.81(1H, d, J=9.5Hz), 11.65(1H, s). 255 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 260 / 800 EX103 Η ι UJXJ ® 0- o\ 0 Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-1yl-7yl)pymethyl-butyl) hydrogenophosphate (0.8 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6(pivaloloxy) àihexyl obhando) mg synthesis in EX 56. NMR1; 1.17(3H, t, J=7.1Hz), 1.33(3H, d, J=6.8Hz), 1.791.87(2H, m), 1.881.99(2H, m), 3.413.69(4H, m), 3.533.69(3.2.0), 8(H, m3), 4.024.15(4H, m), 4.554.66(1H, m), 5.09(2H, d, J=9.0Hz), 6.30(1H, d, J=9.5Hz), 6.83(1H, dd, J=8.6Hz), 2.2, H=1.7, 6.87( d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.57(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.5, J=H5.5. J = 9.5 Hz), 11.65 (1H, s). 256 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 261 / 800 EX104 Η W®. 0- head. 0 ° Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl phosphate hydrogen0. (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6(pivaloyloxy)hexyl) phosphate (397 mg) was obtained from semeltido. RMN1; 1.17(6H, dd, J=6.2Hz, 1.3Hz), 1.31(3H, d, J=6.8Hz), 1.78–1.87(2H, m), 1.89–2.00(2H, m), 3.43–3.51(2H, m), 3.53), 1.31. 3.70-3.82(2H, m), 4.09(2H, t, J=6.0Hz), 4.51-4.63(1H, m), 4.80-4.95(1H, m), 5.09(2H, d, J=9.1Hz), 6.30(H=6.8, d, J(H J=8.6Hz, 2.4Hz), 6.87(1H, d, J=2.3Hz), 7.01(1H, d, J=7.7Hz), 7.33(1H, t, J=7.8Hz), 7.52(1H, d, J=5.5Hz), 7.56(H=1.8H,2, d J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.65(1H, s). 257 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 262 / 800 EX105 Η çlO) o TJJ [1 J >< ? ® °' °Ίγ° 0 Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrophotol (0.8), g. (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl (6(pivaloyloxy)hexyl) phosphate (397 mg) was obtained in a similar manner to EXRM note 15; 1.29(3H, d, J=6.9Hz), 1.39(9H, s), 1.79-1.87(2H, m), 1.88-1.98(2H, m), 3.43-3.47(4H, m), 3.53-3.68(4H, m), 3.53-3.68(4H, m), 3.7-3.8,(2H, m), 4.09(2H, t, J=6.0Hz), 4.43-4.55(1H, m), 5.09(2H, d, J=9.1Hz), 6.30(1H, dd, J=9.4Hz, 2.0Hz), 6.82(1H, dd, J=8.7Hz, 2.6.8Hz), 2.8Hz. d, J=2.5Hz), 7.00(1H, dd, J=7.8Hz, 0.9Hz), 7.32(1H, t, J=7.8Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz, 7.1Hz), d(1Hz). J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.4Hz), 11.65(1H, s). 258 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 263 / 800 EX106 H / xx\ x~x xthx X <Sx ^Nx x^O α,Ο / Τ W [i T ox / / s __ ü A zp\ ? (Absl °' °Ύ° 1 0 ' Usando 6-hidroxi-hexil pivalato (1.34 g) e (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hidrogenofosfato (0.8 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (6(pivaloiloxi)hexil) fosfato (397 mg) foi obtido de maneira semelhante à síntese no EX 56. RMN1; 0.85(6H, dd, J=6.8Hz, 1.7Hz), 1.34(3H, d, J=6.9Hz), 1.79-1.89(2H, m), 1.89-1.99(2H, m), 3.42-3.47(4H, m), 3.53-3.68(4H, m), 3.76(2H, s), 3.79(1H, dd, J=10.5Hz, 6.5Hz), 3.86(1H, dd, J=10.5Hz, 6.8Hz), 4.09(2H, t, J=6.0Hz), 4.58-4.70(1H, m), 5.09(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.5Hz, 1.9Hz), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.87(2H, d, J=2.4Hz), 7.00(1H, d, J=7.6Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.64(1H, s). 259 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 264 / 800 EX107 Η ✓s. ✓N. ^,0 aATW ]| T ox zP ? ,__, ü J zp\ (Ãbs) °' °X° Γ 0 Using 6-hydroxy-hexyl pivalate (1.34 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2)oxo-1,2-di-hydroquinoyl-1-butyl-yl-7yl)oxy hydrogenophosphate (0.8 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (6(pivaloloxy) àihexyl obhando) mg synthesis in EX 56. NMR1; 0.81(6H, d, J=7.4Hz), 1.181.30(4H, m), 1.33(3H, d, J=6.9Hz), 1.421.55(1H, m), 1.791.87(2H, m), 1.881.99(7.4, m), 4(2H, m3), 3.533.68(4H, m), 3.733.81(2H, m), 3.91(1H, dd, J=10.9Hz, 5.8Hz), 4.00(1H, dd, J=10.9Hz, 5.9Hz), 4.09(2H,17(t-H), J=4.6). 5.09(2H, d, J=8.9Hz), 6.30(1H, dd, J=9.5Hz, 2.0Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.87(1H, d, J=2.4Hz), 7.10(7.3,2, d J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 1.52(1H.5). 260 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 265 / 800 EX108 Η οΑ ο AJ li T / / ~ ϋ À ζρ\ f lAbs) 0- __ 0 °^\ Using 2-ethoxyethyl (S)-2-hydroxypropanoate synthesized in REX 36 (0.8 g) and (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl hydrogenophosphate (0.5 g), (R)-(4-(benzo[b]thiophene-4-yl)-1-(4((2-oxo-1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium1-yl)methyl (1-(2-ethoxyethoxy)-1-oxopropane-2 method fo umi 5-yl7 mghandol synthesis of EX 56. NMR1; 1.07(3H, t, J=7.0Hz), 1.33(3H, d, J=6.9Hz), 1.811.87(2H, m), 1.911.96(2H, m), 3.373.47(6H, m), 3.53(2H, t, J=7.0Hz), m(31.8.8). 3.723.81(2H, m), 4.064.24(4H, m), 4.584.70(1H, m), 5.08(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.4Hz, 1.8Hz), 6.43, J=2, Hz). 6.87(1H, d, J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.32(1H, t, J=7.8Hz), 7.52(1H, d, J=5.7Hz), 7.56(1H, d, J=8.7Hz), J.7, d71( d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.64(1H, s). 261 / 375 Petition: 870260084657, on August 20, 2026, page. 266 / 800 EX 109 fosfato (457 mg) fosfato (457 mg) foi obtido em I feel like I'm talking to you do EX 56.RMN1; 0.87(3H, t, J=7.4Hz), 1.17(3H, t, J=7.1Hz), 1.581.78(2H, m), 1.801.87(2H, m), 1.882.00(2H, m), 3.423.50(4H, m), 3.543.68(4H, m), 3.733.81(2H, m), 4.014.18(4H, m), 4.444.53(1H, m), 5.09(2H, d, J=9.1Hz), 6.31(1H, dd, J=9.5Hz, 1.7Hz), 6.83(1H, dd, J=8.7Hz, 2.4Hz), 6.87(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.8Hz, 0.9Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.9Hz), 7.57(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.5Hz), 11.65(1H, s). 262 / 375 Petition: 870260084657, on August 20, 2026, page. 267 / 800 EX110 Usando L-(-)-dietil malato (0.92 mL) e (4-(benzo[b]tiofen4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1 g), (R)-(4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxy)butil)piperazin-1 -ium-1 -il)metil (1,4dietoxi-1,4-dioxobutan-2-il) sulfate (283 mg) for the whole month à síntese do EX 56. RMN1; 1.16(6H, dt, J=8.6Hz, 7.1Hz), 1.79-1.88(2H, m), 1.89-2.00(2H, m), 2.62-2.86(2H, m), 3.43-3.47(4H, m), 3.52-3.69(4H, m), 3.73-3.80(2H, m), 3.98-4.16(6H, m), 4.82(1H, dt, J=9.6Hz, 6.0Hz), 5.09(2H, d, J=9.0Hz), 6.30(1H, dd, J=9.4Hz, 1.8Hz), 6.83(1H, dd, J=8.6Hz, 2.4Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 263 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 268 / 800 EX111 Η γγ γ s\ A > 1 Yk A Η ΊΓ °-χ '° η [I \ j?' ο °· '°—\__ιι OH TFA (0.1 mL) was added to a suspension of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(3-(tert-butoxy)-3-oxopropyl)phosphate (90 mg) in DCM (4 mL) under ice-cooling conditions and the resulting mixture was stirred at room temperature for 2 hours. TFA (0.8 mL) was added and stirred for 2 hours. The reaction system was concentrated, and the residue was azeotropated with dCm and purified by silica gel column chromatography (DCM / MeOH) to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(2-carboxyethyl)phosphate (45 mg). 1NMR; 1.79-1.87(2H, m), 1.89-2.01(2H, m), 2.28(2H, t, J=6.8Hz), 3.42-3.47(4H, m), 3.53-3.68(4H, m), 3.77(2H, d, J=11.5Hz), 3.93(2H, q, J=6.9Hz), 4.10(2H, t, J=6.5Hz), 5.12(2H, d, J=8.4Hz), 6.28(1H, d, J=9.5Hz), 6.78(1H, dd, J=8.6Hz, 2.4Hz), 7.01(1H, d, J=7.7Hz), 7.12(1H, s), 7.31(1H, t, J=7.9Hz), 7.497.56(2H, m), 7.70(1H, d, J=8.1Hz), 7.75(1H, d, J=5.5Hz), 7.78(1H, d, J=9.5Hz), 12.41(1H, s). EX112 Η çcOi 0 VJ IJ >\Υ Usando 6-chlorohexanol (2 mL) e (4-(benzo[b]tiofen-4-il)1 -(4-((2-oxo-1,2-di-hidroquinolin-7-il)oxi)butil)piperazin-1 ium-1-il)metil hydrogenofosfato (1 g), (4-(benzo[b]tiofen-4il)-1-(4-((2-oxo-1,2-di-hydroquinolin-7-il)oxy)butil)piperazin1-ium-1-il)metil (5-chloropentil) fosfato (625 mg) for the first time and the same amount of EX 56. RMN1; 1.24-1.41(4H, m), 1.42-1.55(2H, m), 1.60-1.72(2H, m), 1.79-1.87(2H, m), 1.89-2.01(2H, m), 3.43-3.47(4H, m), 3.52-3.65(6H, m), 3.69(2H, q, J=6.7Hz), 3.75(2H, t, J=6.9Hz), 4.06-4.15(2H, m), 5.09(2H, d, J=9.1Hz), 6.30(1H, dd, J=9.4Hz,. 264 / 375 Petition: 870260084657, on August 20, 2026, page. 269 / 800 1.9Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.8Hz), 7.32(1H, t, J=7.9Hz,=1.5d), d.5.51 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.4Hz), 11.69(1H, s). EX113 Η cvOt . Cjj TJ \Z 0' O'XXzXX^XBr Using 6-bromohexanol (1 mL) and (4-(benzo[b]thiophen-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperathogen-1ymethylhydrogen-1 g), (4-(benzo[b]thiophen4-yl)-1 -(4-(2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (5-bromopentyl) phosphate (738 mg) was obtained in EX 15 by a method similar to RM 1.23—1.42(4H, m), 1.42-1.55(2H, m), 1.60-1.72(2H, m), 1.80-1.87(2H, m), 1.88—2.00(2H, m), 3.43-3.47(2.4H, m), 3.43-3.47(2.4H, m), 3.53-3.66(4H, m), 3.69(2H, q, J=6.7Hz), 3.72-3.79(2H, m), 4.10(2H, t, J=6.1Hz), 5.09(2H, d, J=9.1Hz), 6.30, J(=1H, dd 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.90(1H, d, J=2.4Hz), 7.00(1H, dd, J=7.7Hz, 0.9Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.6Hz, 0.8Hz),. 265 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 270 / 800 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.70(1H, s). EX114 H CuCX o XXX ΥΎ °χ° F ο- (τηΖ' F DIPEA (0.482 mL) was added to a suspension of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1-ium-1-yl)methyl hydrogen phosphate (300 mg) in MeCN / H2O (10 mL) (3 / 1) at room temperature, and the resulting mixture was heated to 80°C and 2,2-difluoroethyl trifluoromethanesulfonate (0.219 mL) was added. The resulting mixture was stirred for 30 minutes and then returned to room temperature. purified by silica gel column chromatography (DCM / MeOH).The product obtained was recrystallized in acetone / H2O, and the crystals were collected by filtration and dried at room temperature to give (4(benzo[b]thiophen-4-yl)-1-(4-(2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl(2,2-difluoroethyl)phosphate (217 mg). 1NMR; 1.80-1.87 (2H, m), 1.92-1.97 (2H, m), 3.40-3.48 (4H, m), 3.53-3.68 (4H, m), 3.71-3.79 (2H, m), 3.86-4.01 (2H, m), 4.10 (2H, t, J=6.1Hz), 5.11 (2H, d, J=8.9Hz), 6.15 (1H, t, J=3.8Hz), 6.30 (1H, dd, J=9.6Hz, 1.9Hz), 6.82 (1H, dd, J.=8.6Hz, 2.4Hz), 6.86 (1H, d, J=2.4Hz), 7.01 (1H, d, J=7.1Hz), 7.33 (1H, t, J=7.9Hz), 7.51 (1H, dd, J=5.6Hz, 0.8Hz), 7.56 (1H, d, J=8.6Hz), 7.71 (1H, d, J=8.1Hz), 7.77 (1H, d,. 266 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 271 / 800 J=5.5Hz), 7.80 (1H, d, J=9.4Hz), 11.64 (1H, s) EX115 Η ÇXO) or OCX ux '—N\__ Using cis-2,6-dimethylmorpholine (15 mL) and (4(benzo-b]thiophene- -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-bromoethyl) phosphate (3 g), (4-(benzo[b]thiophen-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2((2S,6R)-2,6-dimethylmorpholino da fo)methyl queti g) phosphate Example 14. NMR1; 0.98(3H, s), 1.00(3H, s), 1.61(2H, t, J=10.7Hz), 1.811.86(2H, m), 1.892.00(2H, m), 2.44(2H, t, J=6.2Hz), 2.0,J=1Hz(2H). 3.403.54(6H, m), 3.543.69(4H, m), 3.723.85(4H, m), 4.10(2H, t, J=6.1Hz), 5.10(2H, d, J=9.3Hz), 6.30(1H, dd, J=1.9Hz), J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.5Hz), 7.01(1H, d, J=7.5Hz), 7.33(1H, t, J=7.8Hz), 7.51(1H, d, J=5.5Hz), 7.56(H=1.7 d,2, d J = 8.0Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.4Hz), 11.68(1H, s). 267 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 272 / 800 EX116 Η A .N. Using 1-methylpiperazine (0.25 mL), NaI (138 mg), and (4(benzo[b]thiophene-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinolin-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-bromoethyl) phosphate (0.3 g), (4-(benzo[b]thiophene-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl (2-(4methylpiperazine-1-yl)ethyl) phosphate1 was obtained from mesima fo.4 mg RMN1; 1.80-1.88(2H, m), 1.92-1.97(2H, m), 2.09(3H, s), 2.232.27(4H, m), 2.352.40(4H, m), 2.45(2H, t, J=6.2H, m), 3.433, 3.433 3.533.67(4H, m), 3.723.84(4H, m), 4.10(2H, t, J=6.1Hz), 5.10(2H, d, J=9.1Hz), 6.30(1H, d, J=9.4Hz), 6.82(H=1H=1H.8, 7Hz, dd d, J=2.4Hz), 7.01(1H, d, J=7.7Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.71, J=1.7(1H J = 5.5 Hz), 7.80 (1H, d, J = 9.5 Hz), 11.68 (1H, s). 268 / 375 Petition 870260084657, of 20 / 08 / 2026, p. 273 / 800 EX117 Η / O çcOTTW Ϊ Y °>' <\ 0- cr-\J ) Using piperidine (1 mL), DIPEA (0.12 mL), and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1-ium-1-yl)methyl (2-bromoethyl) phosphate (0.22 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1 -yl)methyl (2(piperidin-1-yl)ethyl) phosphate (101 mg) was obtained from the same method as Example 14; 1.30-1.36(2H, m), 1.39-1.48(4H, m), 1.81-1.87(2H, m), 1.92-1.97(2H, m), 2.30-2.34(4H, m), 2.41(2H, t, J=6.3Hz), 3.40(4H, m), 3.40, m). 3.53-3.67(4H, m), 3.69-3.82(4H, m), 4.10(2H, t, J=6.1Hz), 5.10(2H, d, J=9.1Hz), 6.30(1H, dd, J=9.5Hz, 1.9Hz), 6.8H, dd, J=9.5Hz, 1.9Hz), 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=7.6Hz), 7.56(1H, d, J=7.6Hz). 7.71(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.4Hz), 11.68(1H, s). 269 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 274 / 800 EX118 K2CO3 (63.7 mg) was added to a suspension of 4,4-difluoropiperidine hydrochloride (48.4 mg) in MeCN (4 mL) at room temperature, and the resulting mixture was stirred for 15 minutes. (4-(Benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1yl)methyl(2-bromoethyl) phosphate (100 mg) was added, and the resulting mixture was stirred at 50°C. DMF (1 mL) was added, and the resulting mixture was heated to 50°C. 4,4-difluoropiperidine ester hydrochloride (48.4 mg) and K2CO3 (105 mg) were added, and the resulting mixture was heated to 60°C. NaI (46.1 mg) was added and the resulting mixture was stirred at 70°C overnight. H2O was added to the reaction system, and the resulting mixture was extracted with DCM / MeOH = 9 / 1. The organic layer was collected and concentrated.The residue was purified by chromatography in a silica gel (DCM / MeOH) column to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-di-hidroquinolin-7-yl)oxy)butyl)piperazin-1 -ium-1yl)methyl (2-(4,4-difluoropiperidin-1-yl)ethyl) phosphate (36 mg). RMN1; 1.81-2.01(8H, m), 2.55(2H, t, J=6.1Hz), 3.293.39(4H, m), 3.443.48(4H, m), 3.533.68(4H, m), 3.703.85(4H, m), 4.10(2H, t, J=6.1Hz), 5.10(2H, d, J=9.1Hz), 6.30(1H, d, J=9.5Hz), 6.82(1H, dd, J=8.7Hz, 2.4Hz), 6.89(1H, d, J=2.4Hz), 7.01(1H, d, J=7.6Hz), 7.33(1H, t, J=7.9Hz), 7.51(1H, dd, J=5.5Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.71(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.68(1H, Sl________________ 270 / 375 Petition 870260084657, 08 / 20 / 2026, pág. 275 / 800 EX119 Η / XZ\ ----. / X / 0 γγ YS\X Λ J | IL li ίΓ '° 0' o—\ 11 Using chloromethylpropanoate (3.2 g) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)butyl)piperazine-1gnylphosmethyl-1 (4-(benzo[b]thiophen-4-yl)-1-(4-(((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -yl)methyl ((propionyloxy)methyl) phosphate (747 mg) was synthesized as RM121; 1.00(3H, t, J=7.5Hz), 1.801.88(2H, m), 1.921.96(2H, m), 2.35(2H, q, J=7.5Hz), 3.423.49(4H, m), 3.543.68 (3.2, m3), 80(H2, m3), 4.10(2H, t, J=6.0Hz), 5.09(2H, d, J=8.9Hz), 5.43(2H, d, J=12.8Hz), 6.30(1H, d, J=9.4Hz), 6.83(1H, dd, J=8.6Hz(J=1, 2.8Hz), 6.8Hz 7.01(1H, dd, J=7.7Hz, 0.8Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.57(1H, d, J=8.6Hz), 7.72(H=7.7 d, d J = 5.5 Hz), 7.81 (1H, d, J = 9.5 Hz), 11.64 (1H, s). 271 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 276 / 800 EX120 H X / O çcorrw [1 \ o 0' o—\ 11 Chloromethylbutyrate (6 mL) was added to a mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-di--7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (8 g), acetone (120 mL), water (40 mL), and DIPEA (7 mL) with stirring, and then the resulting mixture was stirred under reflux. After 18 hours, the mixture was cooled to room temperature. Water (100 mL) was then added and the resulting mixture was stirred. The precipitated solid was collected by filtration and washed with water to obtain a crude product. The crude product was purified by column chromatography on silica gel (DCM / MeOH). Acetone (800 mL) and water (240 mL) were added, and the resulting mixture was heated to 60°C to dissolve the crude product. The temperature was then reduced to 0°C with stirring.The precipitated solid was removed by filtration, washed with water, and dried to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl((butyloxy)methyl) phosphate (5.8 g). 1NMR; 0.85(3H, t, J=7.4Hz), 1.52(2H, h, J=7.4Hz), 1,801.88(2H, m), 1,921.97(2H, m), 2.30(2H, t, J=7.3Hz), 3,443.48(4H, m), 3,543.68(4H, m), 3.723.80(2H, m), 4.10(2H, t, J=6.0Hz), 5.09(2H, d, J=9.0Hz), 5.43(2H, d, J=12.7Hz), 6.30(1H, d, J=9.3Hz), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.8Hz, 0.9Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 272 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 277 / 800 EX121 Using iodomethyl 2,2-dimethylbutanoate synthesized in REX 38 (1.48 g) and (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo1,2-di-hydroquinolin-7-yl)oxy)butyl)piperazinemethyl-1 dro1 -ium) (4-(benzo[b]thiophene-4-yl)-1-(4-(((2oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 yl)methyl (((2,2-dimethylbutanoyl)oxy)methyl) phosphate to synthet EX umte semethyl method (731 mg) emi 121. RMN1; 0.78 (3H, t, J=7.5Hz), 1.09 (6H, s), 1.50 (2H, q, J=7.5Hz), 1.81–1.87 (2H, m), 1.92–1.96 (2H, m), 3.43–3.48 (4H, m–3), 3.72–3.80 (2H, m), 4.09 (2H, t, J=6.1Hz), 5.10 (2H, d, J=9.4Hz), 5.43 (2H, d, J=11.9Hz), 6.30 (1H, d, J=9.5Hz), 6.5, dH=1= 6.85 (1H, d, J=2.4Hz), 7.01 (1H, d, J=7.5Hz), 7.33 (1H, t, J=7.9Hz), 7.52 (1H, dd, J=5.5Hz, 0.8Hz), 7.56 (1H, d, J=1.7.7Hz), 7.77 (1H, d, J=5.5Hz), 7.81 (1H, d, J=9.5Hz), 11.64 (1H, Sl________________ 273 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 278 / 800 EX122 Η ÇC01 0 W Ϊ JV ,0 \Z 0' 0-^\ Jj Usando o clorometil 2,2-dimetilpentanoato sintetizado no REX 39 (4.6 g) e (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2di-hidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil hydrogenofosfato (3.5 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2oxo-1,2-di-hidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 il)metil (((2,2-dimetilpentanoil)oxi)metil) fosfato (2.62 g) You can use it at the same time as EX 121. RMN1; 0.82(3H, t, J=7.3Hz), 1.10(6H, s), 1.12-1.25(2H, m), 1.39-1.48(2H, m), 1.80-1.88(2H, m), 1.92-1.97(2H, m), 3.43-3.49(4H, m), 3.53-3.69(4H, m), 3.72-3.80(2H, m), 4.09(2H, t, J=6.1Hz), 5.11(2H, d, J=9.3Hz), 5.42(2H, d, J=11.7Hz), 6.30(1H, dd, J=9.5Hz, 1.8Hz), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.8Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.5Hz), 11.64(1H, s). 274 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 279 / 800 EX123 Η ç / Οί . Q. J Ίι Τ °χ ν ζ> (1 \ ο ο- ο—\ 11 (Abs] (X Λ Using chloromethyl(3r,5r,7r)-adamanthane-1-carboxylate synthesized in REX 40 (1.4 g) and (4-(benzo[b]thiophene-4-yl)-1(4-(((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl hydrogenophosphate (1 g), (((1s,3s)adamantan-1 o xy -methyl) ((4-(benzo[b]thiophen-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl) phosphate (760 mg) was obtained in a method similar to RM 8121; EX 6 (6H, m), 1.77–1.88 (7H, m), 1.88–2.02 (6H, m), 3.41–3.49 (4H, m), 3.52–3.70 (4H, m), 3.73–3.81 (2H, m), 4.10 (5.H.1, t J = 9.2 Hz), 5.42 (2H, d, J = 12.1 Hz), 6.30 (1H, dd, J = 9.4 Hz, 1.7 Hz), 6.83 (1 H, dd, J = 8.6 Hz, 2.4 Hz), 6.86 (1H, d, J = 7.81 Hz (= 1 H 7). 0.9Hz), 7.33 (1H, t, J=7.9Hz), 7.52 (1H, dd, J=5.5Hz, 0.9Hz), 7.57 (1H, d, J=8.6Hz), 7.72 (1H, d, J=8.1Hz), 7.17 (H=7.5 d,5, d J = 9.5 Hz), 11.65 (1H, s). 275 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 280 / 800 EX124 Η / X 'Χ^ζ\ / ο\ΖΧ / Ν\ζ>ο αΟί. QJ TJ °>f 0 xí^ o- oX JI OH PPTS (163 mg) was added to a solution of (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-dihydroquinolin-7yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((3-(tetrahydro-2Hpyran-2-yl)oxy)propanoyl)oxy)methyl)phosphate (790 mg) was synthesized in a method similar to the synthesis of EX 16 (Example 16) in EtOH (10 mL) at room temperature, and the resulting mixture was stirred at 50 ° C for 5 hours. The reaction system was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH). After H2O (5 mL) and acetone (5 mL) were added, H2O (5 mL) was added and the resulting mixture was heated to 40°C. The precipitate was removed by filtration and dried at room temperature to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((3hydroxypropanoyl)oxy)methyl) phosphate (448 mg). 1NMR; 1.80-1.88(2H, m), 1.92-1.96(2H, m), 2.47(2H, d, J=6.0Hz), 3.38-3.50(4H, m), 3.53-3.62(2H, m), 3.62-3.70(4H, m), 3.71-3.79(2H, m), 4.10(2H, t, J=6.1Hz), 4.96(1H, t, J=5.4Hz), 5.10(2H, d, J=8.9Hz), 5.45(2H, d, J=13.5Hz), 6.30(1H, dd, J=9.5Hz, 1.2Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.32(1H, t, J=7.8Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.57(1H, d, J=8.6Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 276 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 281 / 800 EX125 Η çcOi 0 W 11 T 0X' / r. I! A λ / 9 0- O'-Λ Ά ' V-OH Usando (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((6(tetra-hydro-2H-piran-2-il)oxi)hexanoil)oxi)metil) fosfato (1.1 g) sinthesized and made to fit EX 16 (Exemplo 16) (1.1 g), (4-(benzo[b]tiofen-4-il)-1(4-((2-oxo-1,2-di-hydroquinolin-7-il)oxi)butil)piperazin-1 ium-1-il)metil (6-hydrroxihexanoil)oxy)metil) fosfato (620 mg) for the month and the same amount of money EX 125. RMN1; 1.19-1.31(2H, m), 1.31-1.42(2H, m), 1.41-1.56(2H, m), 1.80-1.88(2H, m), 1.92-1.97(2H, m), 2.31(2H, t, J=7.4Hz), 3.30-3.37(2H, m), 3.43-3.48(4H, m), 3.49-3.68(4H, m), 3.72-3.80(2H, m), 4.10(2H, t, J=6.0Hz), 4.40(1H, t, J=5.2Hz), 5.09(2H, d, J=8.9Hz), 5.43(2H, d, J=12.7Hz), 6.30(1H, d, J=9.5Hz), 6.83(1H, dd, J=8.6Hz, 2.4Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.8Hz, 0.8Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.2Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.64(1H, s). 277 / 375 Petition 870260084657, dated 08 / 20 / 2026, p. 282 / 800 EX126 Η A 0 WU (4-(benzo[b]tiofen-4-il)-1(4-((2-oxo-1,2-di-hidroquinolin-7-il)oxi)butil)piperazin-1 ium-1-il)metil hydrogenofosfato (0.5 g), (4-(benzo[b]tiofen4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1 -ium-1 -il)metil (((tetra-hydro-2Hpiran-4-carbonil)oxi)metil) fosfato (448 mg) foi obtido em um It will start at $121.RMN1; 1.48-1.62(2H, m), 1.69-1.77(2H, m), 1.79-1.87(2H, m), 1.92-1.96(2H, m), 2.58(1H, tt, J=11.1Hz, 4.1Hz), 3.18-3.33(2H, m), 3.43-3.48(4H, m), 3.54-3.68(4H, m), 3.72-3.82(4H, m), 4.09(2H, t, J=6.0Hz), 5.10(2H, d, J=9.1Hz), 5.45(2H, d, J=12.6Hz), 6.30(1H, dd, J=9.4Hz, 1.9Hz), 6.83(1H, dd, J=8.6Hz, 2.4Hz), 6.86(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.8Hz), 7.33(1H, t, J=7.8Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.7Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.64(1H, s). 278 / 375 Petition 870260084657, dated 08 / 20 / 2026, page 283 / 800 EX127 Using chloromethyl 2-(ter-butoxycarbonyl)amino)-2-methylpropanoate synthesized in REX 47 (1.6 g) and (4-(benzo[b]thiophen-4-yl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (1 g), (4-(benzo[b]thiophen-4-yl)-1-(4-((2-oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl (((2(ter-butoxycarbonyl)amino)-2-methylpropanoyl)oxy)methyl) phosphate (280 mg) was obtained in a method similar to the synthesis of EX 121. RMN1; 1.33(6H, s), 1.34(9H, s), 1.811.86(2H, m), 1.881.97(2H, m), 3.433.48(4H, m), 3.543.69(4H, m), 3.713.76(2H, m), 4.09(2H, t, J=6.2Hz), 5.10(2H, d, J=9.2Hz), 5.42(2H, d, J=12.3Hz), 6.30(1H, dd, J=9.4Hz, 1.8Hz), 6.82(1H, dd, J=8.6Hz, 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.00(1H, d, J=7.6Hz), 7.27(1H, s), 7.32(1H, t, J=7.9Hz), 7.51(1H, d, J=5.5Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.63(1H, s). 279 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 284 / 800 EX128 (4-(benzo[b]tiofen-4-il)-1-(4-(((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (((etoxicarbonil)oxi)metil)fosfato (1.9 g) for the first time until the end 121.RMN1; 1.18(3H, t, J=7.1Hz), 1.811.88(2H, m), 1.921.96(2H, m), 3.423.47(4H, m), 3.533.68(4H, m), 3.723.80(2H, m), 4.044.17(2H, m), 4.12(2H, q, J=7.1Hz), 5.09(2H, d, J=8.6Hz), 5.44(2H, d, J=13.3Hz), 6.30(1H, d, J=9.4Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.01(1H, d, J=7.5Hz), 7.33(1H, t, J=7.8Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.81(1H, d, J=9.5Hz), 11.62(1H, s). 280 / 375 Petition: 870260084657, on August 20, 2026, page. 285 / 800 EX129 Η αθι. W here T °\ά „ |i JX ,? Ο σ Using chloromethyl isopropyl carbonate (1 mL) and (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-hydroquinoline-7yl)oxy)hydroylphotyl-1)piperazine (0.7 g), (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoline-7-yl)oxy)butyl)piperazine-1 -ium-1 -EX)methyl (isopropoxycarbonyl)oxy)methyl)phosphate fomintel method (isopropoxycarbonyl)oxy)methyl) phosphate emeto (symlte semel40 mg method) 121. RMN1; 4.09(2H, t, J=6.0Hz), 4.704.83(1H, m), 5.09(2H, d, J=8.6Hz), 5.42(2H, d, J=13.2Hz), 6.30(1H, dd, J=9.5Hz, 1.5,d=18Hz(1.83Hz), 2.4Hz), 6.85(1H, d, J=2.0Hz), 7.01(1H, d, J=7.8Hz), 7.32(1H, t, J=7.8Hz), 7.51(1H, dd, J=5.6Hz, 0.7Hz), 7.16(H=1.7 d, d, d J = 8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 281 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 286 / 800 EX130 Η Χχ XX Λ Q^J}XXXJ lí T °XV r\ w °· θ-χΑθ Using or (4-(benzo[b]thiophene-4-yl)-1-(4-((2-oxo-1,2-dihydroquinoperalin-7but-1)yl)pio -yl)methyl ((((3((3((tetra-hydro-2H-pyran-2yl)oxy)propoxy)carbonyl)oxy)methyl)phosphate (747 mg),) (4(benzo[b]thiophen-4-yl)-1 -(4-((2-oxo-1,2-di-yl-1)hydroquinozyne)butyl -yl)methyl ((((3hydroxypropoxy)carbonyl)oxy)methyl) phosphate (516 mg) was obtained in a method similar to the synthesis of EX 125. NMR1; 1.63–1.78(2H, m), 1.80–1.89(2H, m), 1.92—1.96(2H, m), 3.37–3.49(6H, m), 3.53–3.69(4H, m), 3.72–3.80(2.2H, m), 3.72–3.80(2.2H, m), 4.16(2H, t, J=6.5Hz), 4.60(1H, t, J=5.2Hz), 5.09(2H, d, J=8.6Hz), 5.44(2H, d, J=13.4Hz), 6.30(1H, dd, J=9.5Hz(J,1=1.8dHz), 6.8d 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz), 0.8Hz(1H=1 H 7.56), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 282 / 375 Petition: 870260084657, on August 20, 2026, page. 287 / 800 EX131 Η ΌφΟί . 0 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2oxo-1,2-di-hydroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 il)metil ((((2-etoxietoxi)carbonil)oxi)metil) fosfato (613 mg) for the first time and then eat it. síntese do EX 121. RMN1; 1.04(3H, t, J=7.0Hz), 1.85(2H, d, J=6.9Hz), 1.921.96(2H, m), 3.363.41(4H, m), 3.44(4H, d, J=6.9Hz), 3.493.54(2H, m), 3.543.60(2H, m), 3.603.68(2H, m), 3.723.79(2H, m), 4.09(2H, t, J=6.1Hz), 4.164.22(2H, m), 5.09(2H, d, J=8.6Hz), 5.45(2H, d, J=13.5Hz), 6.30(1H, dd, J=9.4Hz, 2.0Hz), 6.79-6.87(2H, m), 7.01(1H, d, J=7.5Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.5Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 283 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 288 / 800 EX132 Iodomethyl (2-isopropoxyethyl) carbonate (9.3 g) was added to a mixture of (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1-yl)methyl hydrogen phosphate (3 g), acetone (45 mL), water (15 mL), and DIPEA (6 mL) with stirring, and then stirred under reflux. After 1 hour, the reaction system was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH). Acetone (5 mL) and water (5 mL) were added, and the resulting mixture was heated to 50°C to dissolve the purified residue. Water (10 mL) was further added and the resulting mixture was cooled over ice. The precipitated solid was removed by filtration, washed with water, and air-dried at room temperature to give (4-(benzo[b]thiophen-4-yl)-1-(4-((2oxo-1,2-dihydroquinolin-7-yl)oxy)butyl)piperazin-1-ium-1yl)methyl ((((2-isopropoxyethyloxy)carbonyl)oxy)methyl) phosphate (2.9 g). RMN1; 1.02(6H, d, J=6.1Hz), 1.801.88(2H, m), 1.921.96(2H, m), 3.423.54(7H, m), 3.543.69(4H, m), 3.723.80(2H, m), 4.10(2H, t, J=6.1Hz), 4.134.19(2H, m), 5.09(2H, d, J=8.5Hz), 5.45(2H, d, J=13.4Hz), 6.30(1H, d, J=9.1Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.8Hz, 0.9Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.9Hz), 7.57(1H, d, J=8.5Hz), 7.72(1H, d, J=8.0Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, Sl________________ 284 / 375 Petição 870260084657, de 20 / 08 / 2026, pág. 289 / 800 EX133 Η çuXi . Ou lí T °x Z „ U AU Using chloromethyl (2-(2-ethoxyethoxy)ethyl) carbonate synthesized in REX 52 (2.5 g) and (4-(benzo[b]thiophen-4-yl)-1-(4(2-oxo-1,2-di-hydroquinoperazine-1butyl-1-yl)pioxy hydrogenophosphate (1 g), (4-(benzo[b]thiophen-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl (3-oxo-2,4,7,1 focyl7-umy30 phosphadote mg method similar to synthesis of the EX 121. RMN1 1.05(3H, t, J=7.0Hz), 1,821.86(2H, m), 3,203.41(6H, m), 3,203.41(6H, m), 3.423,H3.50(6H, m); 3.723.76(2H, m), 4.09(2H, t, J=6.1Hz), 4.164.23(2H, m), 5.09(2H, d, J=8.6Hz), 5.45(2H, d, J=13.4-Hz), 6.30(J=6.7(1Hz, d, m), 7.01(1H, d, J=7.5Hz), 7.33(1H, t, J=7.8Hz), 7.52(1H, d, J=5.8Hz), 7.56(1H, d, J=8.5Hz), 7.72(1H, d, J=8.1Hz(1= H. 7.77). 7.81(1H, d, J=9.5Hz), 11.62(1H, s). 285 / 375 Petition 870260084657, dated 20 / 08 / 2026, p. 290 / 800 EX134 Η Ο^Οί o W τι ητ ox / / 11J X / ? °· °^Λ Using 2-(2-butoxyethoxy)ethyl (iodomethyl) carbonate (10 g) synthesized in REX 54 and (4-(benzo[b]thiophen-4-yl)-1-(4((2-oxo-1,2-di-hydroquinoline-7-yl)pyperamethyl)butyl hydrogenophosphate (3 g), (4-(benzo[b]thiophen-4-yl)1 -(4-((2-oxo-1,2-di-hydroquinoline-7-yl)oxy)butyl)piperazine-1 ium-1-yl)methyl (3-oxo-2,4,7,10 emyl obtrade umyl.tetraox) gttraox method similar to synthesis of the EX 121. NMR1; 0.83(3H, t, J=7.3Hz), 1.181.32(2H, m), 1.351.47(2H, m), 1.801.88(2H, m), 1.921.96(2H, m), 3.30(2H, t, J=4.34H3), 3.443.50(4H, m), 3.533.68(6H, m), 3.723.79(2H, m), 4.09(2H, t, J=6.0Hz), 4.164.23(2H, m), 5.09(2H, d, J=5.5 d=8.6Hz), 6.30(1H, d, J=9.5Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.85(1H, d, J=2.4Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.32(7.d.9, t J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.80(1H, d, J=9.5Hz), 11.63(1H, s). 286 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 291 / 800 EX135 Use or clorometil (2-(2-(2-etoxietoxi)etoxi)etil) carbonate (2.5 g) with no REX 55 e (4-(benzo[b]tiofen4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (3oxo-2,4,7,10,13-pentaoxapentadecil) fosfato (415 mg) foi obtido em And then it starts with EX 121. RMN1; 1.06(3H, t, J=7.0Hz), 1.811.88(2H, m), 1.921.96(2H, m), 3.38(2H, q, J=7.0Hz), 3.423.51(12H, m), 3.533.68(6H, m), 3.723.79(2H, m), 4.09(2H, t, J=6.1Hz), 4.174.23(2H, m), 5.09(2H, d, J=8.6Hz), 5.45(2H, d, J=13.4Hz), 6.30(1H, dd, J=9.5Hz, 1.8Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.85(1H, d, J=2.3Hz), 7.01(1H, d, J=7.6Hz), 7.32(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.5Hz, 0.9Hz), 7.56(1H, d, J=8.6Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.6Hz), 7.80(1H, d, J=9.5Hz), 11.62(1H, s). 287 / 375 Petition: 870260084657, on August 20, 2026, page. 292 / 800 EX136 Η ÇUOi 0 XXJ ΎΎ / / ? °· °^° Usando o clorometil (2-(2-(2-isopropoxietoxi)etoxi)etil) carbonato (1.6 g) sintetizado no REX 56 e (4(benzo[b]tiofen-4-il)-1 -(4-((2-oxo-1,2-di-hidroquinolin-7il)oxi)butil)piperazin-1-ium-1-il)metil hydrogenofosfato (1 g), (4-(benzo[b]tiofen-4-il)-1-(4-((2-oxo-1,2-dihidroquinolin-7-il)oxi)butil)piperazin-1 -ium-1 -il)metil (14metil-3-oxo-2,4,7,10,13-pentaoxapentadecil) fosfato (604 mg) foi obtido I am set to return to EX 121. RMN1; 1.04(6H, d, J=6.1Hz), 1.801.88(2H, m), 1.921.96(2H, m), 3.383.52(14H, m), 3.553.68(6H, m), 3.723.79(2H, m), 4.10(2H, t, J=6.0Hz), 4.174.23(2H, m), 5.09(2H, d, J=8.6Hz), 5.45(2H, d, J=13.5Hz), 6.83(1H, dd, J=8.5Hz, 2.4Hz), 6.85(1H, d, J=2.5Hz), 7.01(1H, dd, J=7.7Hz, 0.9Hz), 7.33(1H, t, J=7.9Hz), 7.52(1H, dd, J=5.6Hz, 0.8Hz), 7.56(1H, d, J=8.5Hz), 7.72(1H, d, J=8.1Hz), 7.77(1H, d, J=5.5Hz), 7.81(1H, d, J=9.5Hz), 11.63(1H, s). 288 / 375 Petition 870260084657, dated 08 / 20 / 2026, pp. 293 / 800 EX137 Η ΑΧ ✓θ'ν ✓S...

Claims

1. Compound, characterized in that it is represented by formula (I) or a salt thereof: (I) wherein R1 and R2 each independently represent -O', OR4, or -NR4NaR4Nb, R3 represents hydrogen or alkyl, R4, R4Na, and R4Nb each independently represent hydrogen, or alkyl, alkenyl, alkadienyl, or alkynyl, each optionally having 1 to 3 substituents, wherein alkyl represented by R4, R4Na, or R4Nb may have a structure in which one or more methylene groups (-CH2-) are substituted by -O-, -S-, -CO-, -NH-, -SiRsiaRsib-, or -(CO)O-, Rsia and Rsib may be identical or different and represent hydrogen or C1-6 alkyl, if R1 and R2 both represent -OR4, R1 and R2 may be identical or different, and if R1 R1 and R2 both represent -NR4NaR4Nb, R1 and R2 can be identical or different.

2. Compound or salt thereof, according to claim 1, characterized in that R1 represents -O', R2 represents -OR4 or -NR4NaR4Nb wherein R4, R4Na, and R4Nb are as defined above.

3. Compound, characterized by the fact that it is represented by formula (I) or a salt thereof: Petition 870260084657, dated 20 / 08 / 2026, page 381 / 800 2 / 20 where R1 represents -O; R2 represents -OR4 or -NR4NaR4Nb, R3 represents hydrogen or C1-6 alkyl, R4 represents hydrogen or any of the following items (0-1) to (5), -NR4NaR4Nb represents the following items (i) or (ii): (0-1): C1-18 alkenyl optionally having 1 to 3 substituents selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, (0-2): C1-18 alkadienyl optionally having 1 to 3 substituents selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, (0-3): C1-18 alkynyl optionally having 1 to 3 substituents selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, (1-1): R4a1, wherein R4a1 represents -CnH2n+1, -CnH2n-1, -CnH2n-3, -CnH2n-2OH, OR -CnH2n-4-OH, where n represents 1 to 24, with the condition that in -CnH2n-1, n is 2 or more; in -CnH2n-3, n is 2 or more; in -CnH2n-2-,n is 2 or more; and in -CnH2n-4-, n is 2 or more, (1-2): R4a2, where R4a2 represents Petition 870260084657, of 20 / 08 / 2026, p. 382 / 800 3 / 20 - CHX1X2, - Cn-lH2n-2-CHX1X2, - Cn-lH2n-4-CHX1X2, OR - Cn-lH2n-6-CHX1X2, where n represents 2 to 24, with the condition that in -Cn-iH2n-4-, n represents 3 or more; in -Cn-1H2n-6-, n represents 3 or more, X1 and X2 are identical or different and represent hydrogen or halogen (F, Cl, Br, or I), with the condition that X1 or X2, or both, represent halogen, (1-3): R4a3, where R4a3 represents -CnH2n-R4-1, - Cn-1H2n-2-CHR4-1aR4-1b, - CnH2n-2-R4-1, or - CnH2n-4-R4-1, where n represents 1 to 24, with the condition that in -CnH2n-2-, n represents 2 or more; In -CnH2n-4-, n represents 2 or more, R4-1 represents C1-6 alkoxy, -O-phenyl, or a heterocyclic group optionally substituted with C1-6 alkyl or halogen, R4-1a and R4-1b are identical or different and represent -C1-3 alkylene C1-3 alkoxy,or identical or different and represent -CO-O-C1-3 alkyl or -CH2-CO-O-C1-3 alkyl, (2): R4b, where R4b represents -(CpH2p-O)q-CrH2r-R4-2, -(CpH2p-O)q-CrH2r-2-R4-2, -(CpH2p-2-O)q-CrH2r-R4-2, or -(CpH2p-2-O)q-CrH2r-2-R4-2, Petition 870260084657, dated 20 / 08 / 2026, p. 383 / 800 4 / 20 where p represents 1 to 4, q represents 1 to 4, r represents 1 to 4, with the condition that in CpH2p-2, p represents 2 or more, in CrH2r-2, r represents 2 or more, when q is 2 to 4, 2 to 4 repeating structures, whose number of repetitions is represented by q, may be identical or different, R4-2 represents hydrogen, hydroxy, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (3): -CaH2a-CO-O-RCOO or -CaH2a-CO-O-CH2-RC°° where α represents 1 to 10, where -RCO° represents hydrogen,C1-6 alkyl or C1-6 alkoxy each optionally substituted with 1 to 3 C1-6 alkoxy groups, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from C1-6 alkyl, C1-6 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (4): -CpH2p-O-CO-ROCO where β represents 1 to 10, where -ROCO represents R4a1, R4b, or -CaH2a-CO-O-RCOO, or -CaH2a-CO-NH-RCOO, -CaH2a-NH-CO-RCOO, or -CaH2a-NH-CO-O-RCOO where -RCOO is as defined above, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from among C1-6 alkyl, C16 alkoxy, -C1-3 alkylene-C1-3 alkoxy, and nitro, (5): -CY^YO-CO-O-ROCOO wherein γ represents 1 to 10, wherein -ROCOO represents hydrogen, R4a1, R4b, or -CaH2a-CO-O-RCOO wherein -RCOO is as defined above, or cycloalkyl, phenyl, benzyl, or a heterocyclic group each optionally having 1 to 3 substituents selected from among C1-6 alkyl, C16 alkoxy,-C1-3 alkylene-C1-3 alkoxy, and nitro, (i) R4Na and R4Nb are identical or different and represent C1-6 alkyl Petition 870260084657, 20 / 08 / 2026, p. 384 / 800 5 / 20 optionally substituted with 1 to 3 C1-6 alkoxy groups, (ii) R4Na represents hydrogen, and R4Nb represents C1-6 alkyl optionally substituted with 1 to 3 C1-6 alkoxy groups, or represents CaH2a-CO-O-RCOO or -CaH2a-CO-NH-RCOO where -RCOO is as defined above., 4. A compound or salt thereof, according to any one of claims 1 to 3, characterized in that the heterocyclic group has a structure in which a hydrogen atom bonded to a constituent atom of a heterocycle is removed from the heterocycle, the heterocycle being selected from the group consisting of furan, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrolidine, imidazolidine, thiophene, piperidine, piperazine, oxazole, isoxazole, oxadiazole, morpholine, indole, indazole, benzimidazole, and quinoline.

5. Compound or salt thereof, according to claim 1 or 2, characterized in that -OR4 represents any of the following groups where the asterisk “*” represents the side opposite R4 with respect to the oxygen atom (*-OR4): Petition 870260084657, dated 20 / 08 / 2026, p. 385 / 800 6 / 20 Petition 870260084657, dated 20 / 08 / 2026, p. 386 / 800 7 / 20 Petition 870260084657, dated 20 / 08 / 2026, p. 387 / 800 8 / 20 Petition 870260084657, dated 20 / 08 / 2026, p. 388 / 800 9 / 20 Petition 870260084657, dated 08 / 20 / 2026, p. 389 / 800 10 / 20 Petition 870260084657, dated 08 / 20 / 2026, p. 390 / 800 11 / 20 Petition 870260084657, dated 08 / 20 / 2026, p. 391 / 800 12 / 20 Petition 870260084657, dated 08 / 20 / 2026, p. 392 / 800 13 / 20 Petition 870260084657, dated 08 / 20 / 2026, p. 393 / 800 14 / 20 and -NR4NaR4Nb represents any of the groups listed below where the asterisk represents the opposite side to R4NaR4Nb in relation to Petition 870260084657, dated 08 / 20 / 2026, page 394 / 800 15 / 20 6. Compound, characterized in that it is represented by formula (II) or a salt thereof: (II) wherein, R3 represents hydrogen or C1-6 alkyl, R4 represents hydrogen or optionally C1-18 alkyl Petition 870260084657, dated 20 / 08 / 2026, page.395 / 800 16 / 20 having 1 to 3 substituents, the substituent independently represents halogen, hydroxyl, C1-6 alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, (CO)NR7R8, -O(CO)R9, -O(CO)OR10, -O(CO)(CR11R12)n(CO)OR13, C3-7 cycloalkyl, or an optionally substituted heterocyclic group, R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, or C3-7 cycloalkyl, R7 and R8 independently represent hydrogen or C1-6 alkyl optionally having one or two methylene groups substituted with an oxygen atom or with a nitrogen atom, R7 and R8 may be linked to form a ring, R11 and R12 independently represent hydrogen or C116 alkyl, wherein if two or more R11s are present, the two or more R11s independently represent hydrogen or C1-16 alkyl, and if two or more R12s are present, the two or more R12s independently represent hydrogen or C1-16 alkyl, wherein represents an integer from 1 to 10.

7. Compound or salt thereof, according to claim 6, characterized in that R4 represents hydrogen or -(AY)m-R14, A represents C1-18 alkylene, Y represents -O-, -(CO)O-, -O(CO)O-, or -(CO)NH-, R14 represents hydrogen, C1-18 alkyl, hydroxy, cycloalkyl, or a heterocyclic group, and in represents an integer from 0 to 5.

8. Compound or salt thereof, according to claim 6, characterized in that R4 represents hydrogen or C1-8 alkyl optionally having a substituent, the substituent independently representing hydroxyl, C1-6. Petition 870260084657, dated 20 / 08 / 2026, p. 396 / 800 17 / 20 alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, -O(CO)R9, O(CO)OR10, -O(CO)-A-(CO)OR13, or morpholinyl optionally having two C1-6 alkyl groups, n represents an integer from 1 to 10, R5, R5a, R6, R9, R10, and R13 independently represent hydrogen, C1-16 alkyl, an optionally substituted heterocyclic group, or C3-7 cycloalkyl, and A represents C1-6 alkylene.

9. Compound or salt thereof, according to claim 6, characterized in that R4 represents hydrogen or C1-8 alkyl optionally having a substituent, the substituent independently representing hydroxy, C1-6 alkoxy, -O-(CH2)n-OR5, -O(CO)-(CH2)n-OR5a, -(CO)OR6, -O(CO)R9, O(CO)-A-(CO)OR13, or a heterocyclic group optionally having one or two C1-6 alkyl groups, n represents an integer from 1 to 10, R5 represents C1-6 alkyl, R5a represents C1-6 alkyl, R6 represents C1-6 alkyl, R9 represents C1-16 alkyl, R13 represents C1-6 alkyl or pyridyl optionally having C1-6 alkyl, and A represents C1-6 alkylene.

10. Pharmaceutical composition, characterized in that it comprises the compound or a salt thereof as defined in any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. Pharmaceutical composition, according to claim 10, characterized in that it comprises the compound or salt of the same as defined in any one of claims 1 to 9, a suspending agent, and a dispersing medium, wherein the pharmaceutical composition is in the form of a suspension.

12. Pharmaceutical composition, according to claim 11, characterized in that the average particle diameter of the particles in the suspension is 0.5 to 30 μm.

13. Pharmaceutical composition, according to claim 11, characterized in that the average particle diameter of the particles in the suspension varies from 50 to 500 nm.

14. Pharmaceutical composition, according to any one of claims 11 to 13, characterized in that the suspending agent is carboxymethyl cellulose or a salt thereof, and the dispersing medium is a liquid containing water for injection.

15. Pharmaceutical composition, characterized in that it comprises a viscous mixture of a) the compound or a salt thereof as defined in any one of claims 1 to 9, b) two or more liquid crystal-forming lipids or gel-forming lipids, and c) a biocompatible organic solvent, wherein the pharmaceutical composition is a precursor preparation used to form a liquid crystalline phase structure or lipogel by placing the pharmaceutical composition in contact with an aqueous fluid in vivo.

16. Pharmaceutical composition, according to claim 15, characterized in that b) the two or more liquid crystal forming lipids or gel forming lipids contain b-1) at least one diacylglycerol, and b-2) at least one phosphatidylcholine.

17. Pharmaceutical composition, characterized by the fact that Petition 870260084657, dated 08 / 20 / 2026, page 398 / 800 19 / 20, comprises a viscous mixture of a) the compound or salt thereof as defined in any of claims 1 to 9, b-1) at least one diacylglycerol, b-2) at least one phosphatidylcholine, and c) a biocompatible organic solvent.

18. Microsphere, characterized in that it comprises the compound or salt thereof as defined in any of claims 1 to 9 as an active ingredient.

19. Microsphere, according to claim 18, characterized in that it comprises the compound as defined in any one of claims 1 to 9 and a biodegradable polymer.

20. Microsphere, according to claim 19, characterized in that the biodegradable polymer is at least one member selected from the group consisting of polylactic acid and a lactic acid-glycol copolymer.

21. Microsphere, according to any one of claims 18 to 20, characterized in that it has an average particle diameter of 5 to 150 μm.

22. Pharmaceutical composition, characterized in that it comprises the microsphere as defined in any one of claims 18 to 21 in the form of a suspension.

23. Pharmaceutical composition, characterized in that it comprises the microsphere as defined in any one of claims 18 to 21 in the form of a suspension in oil.

24. Pharmaceutical composition, according to claim 23, characterized in that the oil is a triglyceride of medium-chain fatty acids.

25. Pharmaceutical composition, according to any one of claims 10 to 17 and 22 to 24, characterized by the fact that it is for use in intramuscular or subcutaneous administration.

26. Pharmaceutical composition, according to any one of claims 10 to 17 and 22 to 25, characterized in that it is for use in the prevention and / or treatment of a disease of the central nervous system.

27. Pharmaceutical composition, according to claim 26, characterized in that the central nervous system disease is selected from the groups consisting of schizophrenia, treatment-resistant, refractory or chronic schizophrenia, schizoaffective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, chemical disorder, anhedonia, delirium, Alzheimer's disease, Parkinson's disease, cognitive impairment, cognitive impairment associated with neurodegenerative diseases, cognitive impairment due to neurodegenerative diseases, cognitive impairment in schizophrenia,Cognitive impairment caused by treatment-resistant, refractory, or chronic schizophrenia, vomiting, motion sickness, obesity, migraine, pain, intellectual disability, autism spectrum disorder, Tourette syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, impulsive symptoms associated with dementia, and borderline personality disorder.

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