Synthesis of 2-phenyl-2-aminocyclohexane-1-one derivatives

Abstract

The present disclosure relates to a process for making a compound of the formula I and to the enantioselective synthesis to prepare the S or R isomers. It also relates to intermediates in the process.

Description

1 / 121 “SYNTHESIS OF DERIVATIVES OF 2-PHENYL-2-AMINO-CYCLOHEXAN-1-ONE” CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefits of USSN 63 / 435,800, filed December 28, 2022, and USSN 63 / 471,091, filed June 5, 2023, the contents of which are incorporated herein by reference. DESCRIPTION FIELD

[002] The present description refers to new syntheses of 2-aminocyclohexan-1-one derivatives that are useful in the treatment of psychiatric disorders. BASIS OF THE DESCRIPTION

[003] US Patent No. 11,344,510, the contents of which are incorporated herein by reference, describes, in part, compounds useful for the treatment of psychiatric disorders with the following formula: THE ÒKRi ^NR2Rs or pharmaceutically acceptable salts, where Ri is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a portion of the following general formula: wherein, when Ri is phenyl, then R2 and R3 are selected independently from H, CD3, branched or cycloal C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from Petition 870260059814, dated 06 / 18 / 2026, p. 8 / 249 2 / 121 H and C1-C10 alkyl; where D represents a deuterium-enriched H site; provided that one or more of the R2 and R3 sites are different from H; or R2 and R3 are selected independently from C2-C10 alkyl; C2-C10 halo-alkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring; said ring optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; where, when R1 is a portion of the general formula: R2 and R3 are selected independently from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; provided that one or more of R2 and R3 are different from H; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring; said ring optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; and where R6, R7, R8, R9 and R10 are selected independently from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, -C(=O)NR17R18; where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2 Petition 870260059814, dated 06 / 18 / 2026, p. 9 / 249 3 / 121 - C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl; provided that one or more of the R6-R10 are different from H; or provided that when R6 is Cl and R7-R10 are H, or when R7 is Cl and R6, R8-R10 are H, and R2 or R3 is H, then the other of R2 or R3 is C3-C10 alkyl, C2-C10 halo-alkyl, or -R4-O-R5; or provided that when R7 is OH and R6, R8-R10 are H, and R2 or R3 is H, then the other of R2 or R3 is C3-C10 linear or branched alkyl, C2-C10 halo-alkyl, or -R4-OR5; or provided that when R6, R7, or R8 is OMe and the other of R6-R10 is each H, and R2 or R3 is H, then the other of R2 or R3 is C3-C10 alkyl, C2-C10 halo-alkyl, or R4-O-R5; wherein, when R1 is selected from thiazole, thiophene, pyridine, each optionally substituted by one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26; wherein R19, R20, R21, R22, R23, R24, R25 and R26 are each independently selected from H, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl; R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring; the aforementioned ring optionally replaced by one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms.

[004] Also described, in part, are compositions comprising a compound with the general structure (A) useful for the treatment of psychiatric disorders: Petition 870260059814, dated 06 / 18 / 2026, p. 10 / 249 4 / 121 STRUCTURE A wherein Ri is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a general formula moiety (B); where, when Ri is phenyl; then R2 and R3 are selected independently from H, CD3, branched or cyclic C3 alkyl, C4-C10 alkyl, C2-C10 halo-alkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; where D represents a deuterium-enriched H site; and where at least one of R2 and R3 is different from H; or R2 and R3 are selected independently from C2-C10 alkyl; C2-C10 halo-alkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring, said ring optionally substituted by one or more C1-C10 alkyl groups or interrupted by one or more additional nitrogen or oxygen atoms; where, when R1 is a portion of general structure (B): STRUCTURE B Petition 870260059814, dated 06 / 18 / 2026, p. 11 / 249 5 / 121 R2 and R3 are selected independently from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; and where at least one of R2 and R3 is different from H; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring; said ring optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; and R6, R7, R8, R9 and R10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR11, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR12R13, -SR14, -SO2R15, -CO2R16, C(=O)NR17R18; where R11, R12, R13, R14, R15, R16, R17 and R18 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, heteroaryl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl; where at least one of R6-R10 is different from H; and where neither R6 nor R10 is a halogen; provided that when R7 is Cl and R6, R8-R10 are H, and R2 or R3 is H, then the other of R2 or R3 is C3-C10 alkyl, C2-C10 halo-alkyl, or -R4-O-R5; or provided that when R7 is OH and R6, R8-R10 are H, and R2 or R3 is H, then the other of R2 or R3 is C3-C10 alkyl, C2-C10 halo-alkyl, or -R4-O-R5;or provided that when R6, R7, or R8 is OMe and the other of R6 - R10 are each H, and R2 or R3 is H, then the other of R2 or R3 is C3 - C10 alkyl, C2 - C10 halo-alkyl, or -R4-O-R5; wherein, when R1 is selected from thiazole, thiophene, and pyridine, each is optionally replaced by one or more OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -SO2R23, -CO2R24, -C(=O)NR25R26; where R19, R20, R21, R22, R23, R24, R25, and R26 are each independently selected from Petition 870260059814, dated 06 / 18 / 2026, p. 12 / 249 6 / 121 of H, C1 - C10 alkyl, C2 - C10 alkenyl, C2 - C10 alkynyl, aryl, heteroaryl, C(=O)H, C(=O)alkyl, C(=O)aryl, C(=O)heteroaryl; R2 and R3 are selected independently from H, C1-C10 alkyl, C2-C10 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, -R4-O-R5; where R4 is a C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached to form a C3-C9 cycloheteroalkyl ring; said ring optionally substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; or a pharmaceutically acceptable salt or ester of the compound, wherein the composition is enriched in the compound over its opposite enantiomer.

[005] Patent '510 describes methods for preparing compounds described herein. The present description describes different and efficient methods for preparing compounds described herein. The present description provides compounds useful for the treatment of psychiatric disorders, for example, 2-(4-fluorophenyl)-2-(methylamino)cyclohan-1-one hydrochloride and stereoisomers thereof, for example, (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohan-1-one hydrochloride and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohan-1-one hydrochloride. SUMMARY OF DESCRIPTION

[006] The present description refers to a process for preparing the compound of Formula I: THE - CZ8Z8Z3 Ι^Λαγ(Z)χ whose process includes Petition 870260059814, dated 06 / 18 / 2026, p. 13 / 249 7 / 121 (a) react a compound with a ketal protecting group of formula o II η with a sulfinamide of formula H2N Z6 in the presence of Ti(OZ7)a(X1)b to form an imine of Formula V (ÇZ^n (b) react the imine of Formula V with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VII (CZ^n VII (c) react the sulfinamide of Formula VII with acid to form the corresponding amine of Formula VIII (CZiZ2)n Petition 870260059814, dated 06 / 18 / 2026, p. 14 / 249 8 / 121 VIII (d) react the amine of Formula VIII with an acylating agent of Formula Z3COOXo or an acid derivative thereof under amide-forming conditions to form the amide of Formula IX with an acyl group C(=O)Z3 (CZ^n IX (e) reduce the acyl group in Formula IX with an acyl reducing agent under acyl reducing conditions to form the compound of Formula X (ÇZiZ^n Q ò J< <NH-C(Z8)(Z8)(Z3) LJ\r(Z)x(f) deprotect the ketal in the presence of acid to form a compound of Formula I; where each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Z3 is hydrogen, C1-C6 alkyl optionally substituted by one or more halogens, C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy or halogens, or Z3 is D; Each Z independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without hydrogen atoms. Petition 870260059814, dated 06 / 18 / 2026, p. 15 / 249 9 / 121 terminals, for example, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; Each Z8 is independently either H or D; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl or hydrocarbyl aryl or hydrocarbyl ar(C1C3) alkyl, each may be unsubstituted or substituted by one or more halo groups, or C1-C6 alkyl or C1-C6 alkoxy; X1 is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3 or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; provided that, when Ar is thiophene, x is 0, 1, 2, or 3; Air is aril; and

[007] Nu is an aryl nucleophilic agent capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x, provided that when Z3 and each Z8 are D, then the acyl reducing agent is deuterated and the acyl group of formula Z3COOXo or an acid derivative thereof is deuterated.

[008] In another embodiment, Z6 is C1-C6 alkyl or phenyl, which is unsubstituted or substituted by C1-C6 alkyl; Nu is an organometallic compound M, in which the reaction between imine and M is conducted under organometallic reaction conditions to form the sulfonamide of Formula VII; and M is Ar(Z)xMgX or Ar(Z)Li, and Z1, Z2, n, Z3, Z, Z11, Z7, Z8, X1, Xo, a, b, x, and Ar are as defined above. In one embodiment, Z is halo ex is 1 or 2, and in another embodiment, Z is F ex is 1 or 2, for example, x is 1. In yet another embodiment, F is at position 4 (para position) on the phenyl ring. Petition 870260059814, dated 06 / 18 / 2026, p. 16 / 249 10 / 121

[009] In another embodiment, the present description refers to a process for preparing the compound of Formula I herein, comprising (a) reacting a compound with a ketal protecting group of formula II .. 'ZF, with a sulfinamide of formula H2N in the presence of Ti(OZ7)aXw to form an imine of formula VA Z4 Z Z6 VA (b) react the imine of Formula VA with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIA VIIA (c) react the sulfinamide of Formula VIIA with acid to form the corresponding amine of Formula VIIIA Petition 870260059814, dated 06 / 18 / 2026, p. 17 / 249 11 / 121 VIIIA (d) react the amine of Formula VIIIA with an acylating agent of Formula Z3COOXo or an acid derivative thereof to form the amide of Formula IXA with an acyl group (C(=O)Z3 (e) reduce the acyl group in Formula IXA with an acyl-reducing agent to form the compound of Formula XA Petition 870260059814, dated 06 / 18 / 2026, p. 18 / 249 12 / 121 XA (f) deprotecting the ketal to form a compound of Formula I; in which Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogens; each Z is independently selected from halogen (selected from F, Cl, Br, I), OR11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, for example, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, for example, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo or C1-C6 alkyl or C1-C6 alkoxy; Z7 is C1-C4 alkyl; Each Z8 is independently either H or D; X1 is halo; Xo is H or D; Petition 870260059814, dated 06 / 18 / 2026, p. 19 / 249 13 / 121 a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4 x is 0, 1, 2, 3, 4, or 5; and Air is aril; provided that, when Ar is thiophene, x is 0, 1, 2, or 3, and provided that when Z3 and each Z8 are D, then the acyl reducing agent is deuterated and the acyl group of formula Z3COOXo or an acid derivative thereof is deuterated.

[010] In another embodiment, Z6 is C1-C6 alkyl or phenyl, which is unsubstituted or substituted by C1-C6 alkyl; Nu is an organometallic compound M, in which the reaction between imine and M is conducted under organometallic reaction conditions to form the sulfonamide of Formula VII; and M is Ar(Z)xMgX or Ar(Z)Li, and Z4, Z5, n, Z3, Z, Z11, Z7, Ze, X1, Xo, a, b, x, and Ar are as defined above. In one embodiment, Z is halo ex is 1 or 2, and in another embodiment, Z is F ex is 1 or 2, for example, x is 1. In yet another embodiment, F is at position 4 (para position) on the phenyl ring.

[011] Another aspect of the present description is directed to a process for preparing a compound of Formula I, in which Ar is phenyl substituted for fluorine. THE JVNH-C(Z8)(Z8)(Z3) whose process comprises (a) reacting a compound with a ketal protecting group of formula with t-butylsulfinamide in the presence of Ti(OEt)4 to form an imine of Formula V; Petition 870260059814, dated 06 / 18 / 2026, p. 20 / 249 14 / 121 (b) react the imine of Formula V with a Grignard reagent of formula: VI under Grignard reaction conditions to form a sulfinamide product of Formula VII: (CZ,Z2)n VII (c) react the compound of Formula VII with acid to form an amine of Formula VIII: VIII Petition 870260059814, dated 06 / 18 / 2026, p. 21 / 249 15 / 121 (d) react the amine of Formula VIII with an acylating agent of formula Z3COOXo or an acid derivative thereof to form the amide under amide-forming conditions of Formula IX with an acyl group C(=O)Z3 IX (e) reduce the acyl group in Formula IX with an acyl-reducing agent under acyl-reducing conditions to form the compound of Formula X: X; and (f) deprotecting the ketal to form the compound of Formula I; where each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Z3 is hydrogen, C1-C6 alkyl optionally substituted by one or more halogens, C1-C6 alkoxy, C1-C6 alkyl, or aryl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy or halogen or Z3 is D; Petition 870260059814, dated 06 / 18 / 2026, p. 22 / 249 16 / 121 each Z is independently selected from halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, for example, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy or halogen, each Z8 is independently H or D; X is halo; Xo is H or D; eg is 0, 1, 2, 3, or 4; Since when Z3 and each Z8 are D, then the acyl reducing agent is deuterated and the acyl group of formula Z3COOXo or an acid derivative thereof is deuterated. In one embodiment, g is 0 or 1 or 2, and in another embodiment, g is 0 or 1 and in yet another embodiment, g is 0, that is, Zg is H.

[012] In another embodiment, the present description refers to syntheses of corresponding enantiomeric compounds of Formula I, which are the R and S isomers, as described below. In addition, the present description also refers to novel intermediates, both racemic compounds as the R and S stereoisomers, as described below.

[013] In another embodiment, the present description refers to the process of producing pharmaceutically acceptable salts of Formula I and / or its R and S stereoisomers by deprotecting the ketal of formula: (CZ^n 3.NH-C(Zs)((Zs)(Z3) Petition 870260059814, dated 06 / 18 / 2026, p. 23 / 249 17 / 121 X or its stereoisomer R or S, respectively, in the presence of acid or by first deprotecting the ketal group of Formula X or its stereoisomer R or S, respectively, and then treating the deprotected product with acid, wherein Zi, Z2, each Zs, Z3, Z, neg are as defined herein.

[014] In another embodiment, the present description refers to a compound with the following formula: Yc JL^NH'Hci , pharmaceutical compositions comprising the same and methods for the treatment of psychiatric disorders. In another embodiment, the present description refers to the above compound in solid form. In another embodiment, the present descriptive report refers to the R isomer of the hydrochloride salt described above with the formula: R-11 HCl

[015] In another embodiment, the present description refers to the compound R11-HCl in solid form.

[016] In yet another embodiment, the present description refers to a compound with the formula: Petition 870260059814, dated 06 / 18 / 2026, p. 24 / 249 18 / 121 S-11.HC1

[017] In yet another embodiment, the present description refers to a compound with the formula: The CD3 F.

[018] In another embodiment, the present description refers to a compound with the formula: 'la-, while in another embodiment, the present description refers to a compound of formula: S-[D3]-11 HC1 DETAILED DESCRIPTION

[019] The characteristics and other details of the description will now be described more particularly. Before a more detailed description of the present description, certain terms employed in the descriptive report, examples and appended claims are gathered here. These definitions should be read in the light of Petition 870260059814, dated 06 / 18 / 2026, p. 25 / 249 19 / 121 remainder of the description, as understood by one skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art.

[020] The compounds described herein may include at least one asymmetric center. When stereoisomers are specifically designated, these centers are specifically indicated by the symbol R or S, depending on the configuration of the substituents around the chiral atom. However, when stereochemistry is not designated, the structures will be drawn without indicating stereochemistry; these structures are racemic mixtures. Unless otherwise indicated in the structural formula, it should be understood that the present description covers all possible stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof, whenever possible.Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation, such as conversion into a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of specific stereochemistry are commercially available or can be produced and solved by techniques known in the field. Furthermore, the compounds described herein may exist as geometric isomers. The present description covers all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. In addition, the compounds may exist as tautomers; all tautomeric isomers are provided by the present description.Furthermore, the compounds described herein may exist in non-solvated and solvated forms with pharmaceutically acceptable solvents, such as... Petition 870260059814, dated 06 / 18 / 2026, page 26 / 249 20 / 121 water, ethanol, and similar substances; and a mixture of solvents thereof. In general, unless otherwise indicated, solvated forms are considered equivalent to non-solvated forms.

[021] Compounds with general formulas without stereochemical designation will be represented by a Roman numeral, such as I, II, III, IV, V, X, and the like. Compounds with Roman numerals also represent compounds without stereochemical designation having a cyclic ketal as a protecting group. When the protecting group for the carbonyl is a non-cyclic ketal, it is designated with an “A”. For example, an open-chain ketal as the protecting compound for a carbonyl moiety in the molecule will be designated, for example, as VA, XA, and the like. If stereochemistry is designated, the compound will be represented with a letter R or S, depending on whether the compound is an R or S stereoisomer, depending on the configuration around the asymmetric carbon present in it.For example, a compound with formula IR refers to the compound with formula I in the R configuration at the asymmetric carbon atom present in it, and a compound with formula IS refers to the compound with formula I in the S configuration at the asymmetric carbon atom present in it. As another example, the compound designated as compound VAS refers to a compound with formula VA with a non-cyclic ketal in the S configuration.

[022] In some embodiments, a composition prepared herein may be enriched in a specific enantiomer of any compound described herein with respect to the corresponding opposite enantiomer of that compound, so that the mixture is not racemic. In such cases, it is understood that the mixture of isomers in question has enantiomeric excess and optical purity > 0%. The enantiomeric excess or optical purity of the isomeric mixture may be, for example, > 0%, > 5%, > 25%, > 50%, > 75%, > 90%, > 95%, > 97%, > 98% or > 99%. The enantiomeric excess or optical purity of the isomeric mixture can be, for example, 5-100%, 25-100%, 50-100%, 75-100%, 90-100%, 95-100%, 97-100%, 98-100% or 99-100%. Petition 870260059814, dated 06 / 18 / 2026, p. 27 / 249 21 / 121 Thus, for example, a composition including the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer, is contemplated here. Furthermore, if the named compound includes more than one chiral center, the scope of this description also includes compositions containing the various stereoisomers and diastereomers, including mixtures of varying proportions between the various stereoisomers and / or diastereomers or pharmaceutically acceptable salts thereof, as well as compositions including one or more stereoisomers and diastereomers substantially free of one or more of the other stereoisomers and / or diastereomers, respectively. Substantially free means that the composition includes less than, for example, 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2% or 1% of the minor enantiomers or diastereomers.For example, the expression "a compound is enantiomerically pure" refers to the compound being substantially free of other stereoisomers, including any other enantiomers or diastereomers.

[023] For clarity, in the context of the present description, the chemical structures of a compound represented with a specific stereochemical orientation at any particular chiral center, as defined by wedge-and-dash notation, are intended to represent the specified stereoisomer of said compound in substantially pure form, or a mixture enriched in stereoisomers with the specified stereochemical orientation at the defined chiral center over stereoisomers with the opposite orientation at said chiral center.

[024] Pharmaceutically acceptable salts, as used herein, refer to any salt of a compound of Formula I or variations thereof, such as I, IR, or IS, and the like, described above and below herein, including any pharmaceutically acceptable salt wherein the aforementioned compounds are basic in nature and an acidic compound is added to them to form said salt. The phrase pharmaceutically acceptable salts, as used herein, Petition 870260059814, dated 06 / 18 / 2026, page 28 / 249 22 / 121 means those salts of the aforementioned compounds of Formula I or variations thereof, such as IR or IS, and the like, described herein that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of basic groups present in compounds of Formula I or variations thereof, such as IR or IS, and the like, described herein. Pharmaceutically acceptable acidic addition salts include, but are not limited to, hydrochloride, hydrobromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate salts, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).Certain compounds described herein may form pharmaceutically acceptable salts with various amino acids. For a review of pharmaceutically acceptable salts, see BERGE et al., 66 J. PHARM. SCI. 1-19 (1977), and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, edited by P. Heinrich Stahl and Camile G. Wermuth. VHCA, Verlag Helvetica Chimica Acta, Zurich, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002, pp. vix374 (ISBN 3-906390-26-8), the contents of both are incorporated herein by reference.

[025] The present description is also intended to include all isotopes of atoms present in the compounds described herein. Isotopes include those atoms with the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13C and 14C.

[026] It should be noted that any carbon notation in structures throughout this application, when used without additional notation, is intended to represent all carbon isotopes, such as 12C, 13C, or 14C. Furthermore, any compounds Petition 870260059814, dated 06 / 18 / 2026, p. 29 / 249 23 / 121 containing 13C or 14C may specifically have the structure of any of the compounds described herein.

[027] It should be noted that any notation for a hydrogen in structures throughout this application, when used without additional notation, is intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds described herein.

[028] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, using appropriate isotopically labeled reagents in place of the unlabeled reagents employed.

[029] In some embodiments, each D in a chemical structure represents a deuterium-enriched H site, and the level of deuterium-enriched H site of the compost is 20-100%, 50-100%, 70-100%, 90-100%, 95-100%, 97-100% or 99-100%.

[030] It is understood that the substituents and substitution patterns in the compounds used in the method of the present description can be selected by one skilled in the art to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the field from readily available starting materials. If a substituent is substituted by more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, provided that a stable structure results.

[031] When choosing the compounds used in the method of the present description, one skilled in the art will recognize that the various substituents, i.e., Zi, Z2, and the like, must be chosen in accordance with the well-known principles of chemical structure connectivity.

[032] The term about or approximately, as used herein, is defined as being within an acceptable range of error for a given value, Petition 870260059814, dated 06 / 18 / 2026, page 30 / 249 24 / 121 as determined by one skilled in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, approximately may mean within 3 or more standard deviations, as is the practice in the field. Alternatively, approximately may mean a range of up to 20%, a range of up to 10%, a range of up to 5%, and / or a range of up to 1% of a given value. Approximately and about are used interchangeably here.

[033] The term “Nu”, as used herein, refers to a “nucleophile.” As used herein, the term Nu refers to an aryl nucleophile with the Ar(Z)x moiety as the nucleophile, wherein Ar is phenyl, and Zx are as defined herein, which is capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x. Examples include molecules in which the Ar(Z)x moiety is present in an organometallic compound, such as an organomagnesium compound, such as a Grignard reagent, for example, MgBrAr(Z)x, or organolithium compounds, for example, LiAr(Z)x, or organopotassium, sodium, or aluminum compounds, such as organoaluminates, organocopper, zinc, tin, and the like, or is present in a non-metallic compound, such as an organoborate, in which the Ar(Z)x moiety is bonded to a boron atom or arylphosphonium salt, such as a tetraarylphosphonium salt with the moiety [Ar(Z)x]4P+, and the like.When describing a reaction here in which Ar(Z)x is an aryl nucleophile, the term “Nu” will be used to represent the molecule in which Ar(Z)x is present as an aryl nucleophile.

[034] The term “alkyl”, as used herein unless otherwise indicated, refers to a saturated, linear or branched hydrocarbon with the number of carbon atoms specified herein, for example, from 1 to 6 carbon atoms. Exemplary alkyl groups include, but are not limited to, linear or branched hydrocarbons of 1-6, 1-4 or 1-3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2 Petition 870260059814, dated 06 / 18 / 2026, p. 31 / 249 25 / 121 butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[035] The term “alkenyl” as used herein is a branched or unbranched hydrocarbon group with a specified number of carbon atoms and containing at least one double bond as defined below, for example, with 2-6 carbon atoms and 1-3 carbon-carbon double bonds. In some embodiments, alkenyl refers to a branched or unbranched unsaturated hydrocarbon group with three carbon atoms (C3). In some embodiments, alkenyl refers to a branched or unbranched hydrocarbon group with six carbon atoms (Ce). In some embodiments, the term “alkenyl” includes, but is not limited to, vinyl or allyl, 2-methyl-1-pentenyl, 2-propenyl, 1-propenyl, and the like.

[036] The term “alkynyl” as used herein is a branched or unbranched hydrocarbon group with a specified number of carbon atoms and containing at least one triple bond as described below, for example, with 4-6 carbon atoms and 1-3 carbon-carbon triple bonds, and having no terminal hydrogens. In some embodiments, alkynyl refers to a branched or unbranched unsaturated hydrocarbon group with four carbon atoms (C4) without any terminal hydrogen atoms. In some embodiments, alkynyl refers to a branched or unbranched hydrocarbon group with six carbon atoms (Ce) without any terminal hydrogen atoms. Examples include 2-butynyl, 3-pentynyl, 2-penenyl, 2-ethyl-2-butynyl, and the like.

[037] The term “alkyne without terminal hydrogen atoms” or similar term is a term of the field and is understood by one skilled in the art. As understood by one skilled in the art, it refers to an alkyne that does not possess a ---C^CII moiety.

[038] The term “cyano” as used here refers to the radical -CN. Petition 870260059814, dated 06 / 18 / 2026, page 32 / 249 26 / 121

[039] The term “cycloalkyl” or a “carbocyclic group” as used herein, refers to a non-aromatic ring system in which the ring atoms are only carbon atoms containing 3–14 carbon atoms in the ring. These terms include a saturated or partially unsaturated cyclic hydrocarbon group of, for example, 3–6, or 4–6 carbons, referred to herein as C3–C6 cycloalkyl or C4–C6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclopropyl, cyclooctyl, decalinyl, and the like.

[040] The term “halo” or “halogen” or “halide” as used here refers to F, Cl, Br, or I.

[041] The term “acid derivative of ZaCOOXo” refers to an acid halide, ester, or anhydride thereof.

[042] The term “ester” refers to a portion of Formula Z3COOZ12 wherein Z3 is as defined herein, wherein Z12 is C1-C6 alkyl or aryl, wherein alkyl groups and aryl groups are unsubstituted or are substituted by halogen, or C1-C6 alkoxy, or arylC1-C6alkyl, C1-C6 alkyl, aryl, and the like.

[043] The term “anhydride” refers to a compound of formula Z3COOCOZ12, where Z3 and Z12 are as defined herein. In one embodiment, Z12 has the same definition as Z3.

[044] The term aryl, used alone or as part of a larger moiety as in arylalkyl, arylalkoxy, or aryloxyalkyl, refers to monocyclic and bicyclic ring systems with a total of five to fourteen ring atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring atoms. The term aryl may be used interchangeably with the term aryl ring. In certain embodiments of the present description, aryl refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may contain one or more substituents that are not reactive with an Petition 870260059814, dated 06 / 18 / 2026, p. 33 / 249 27 / 121 Grignard reagent. Also included within the scope of the term aryl, as used herein, is a group in which an aromatic ring is linked to one or more non-aromatic rings, such as indanyl, phthalimidinyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, and the like. In addition, aryl refers to thiophene and benzothiophenes.

[045] In the context of the present description, the term “thiophene” should be understood Õ as if referring to a portion with the structure . Furthermore, the term (X? "Benzothiophene" refers to compounds with the formula .

[046] The term “hydrocarbyl aryl” or synonym refers to a monocyclic or bicyclic aromatic ring system with a total of five to 14 carbon atoms in the aromatic ring, wherein at least one ring in the system is aromatic and wherein the ring atoms in the aromatic ring are only carbon atoms. Also included in the scope of hydrocarbyl aryl is a moiety in which an aromatic ring composed only of carbon ring atoms is fused to a cycloalkyl ring, wherein the cycloalkyl ring in the ring system contains only carbon atoms and 5 to 8 carbon atoms. Also included in the term hydrocarbyl aryl groups are C1-C6 alkyl groups substituted on the aryl ring, in which the alkyl groups in them are a bridging group to another moiety. The term “hydrocarbyl aryl” excludes heteroaromatic compounds where at least one of the ring atoms is other than a carbon atom.The hydrocarbyl aryl group can be unsubstituted or substituted with 1, 2, or 3 substituents, which are C1-C6 alkyl, halo, or cycloalkyl. Examples of hydrocarbyl aryl compounds are phenyl, naphthyl, anthracenyl, tolyl, indanyl, xylyl, and the like.

[047] The term hydrocarbyl ar(C1-C3)alkyl refers to an aryl hydrocarbyl group as defined herein, linked to another moiety in the molecule by an alkyl group, as defined herein, containing 1-3 carbon atoms. Examples include benzyl, phenethyl, naphthylmethyl, indanylmethyl, and the like. Petition 870260059814, dated 06 / 18 / 2026, p. 34 / 249 28121

[048] The terms “hydroxy” and “hydroxyl” as used herein refer to the -OH radical.

[049] The term “acyl” as used here refers to the (Z3C=O) group of an organic acid with a COOH group or an organic acid derivative thereof.

[050] The term “ketal” refers to a functional group formed by the substitution of the carbonyl group of a ketone by two alkoxy groups. Ketals are generally formed by the reaction of the carbonyl group of a ketone with two alcohols with 1 to 6 carbon atoms, such as methanol or ethanol, or a diol with 2-6 carbon atoms, such as ethylene glycol or 2,2-dimethylpropane-1,3-diol, and the like under anhydrous conditions, in the presence of an acid.

[051] As defined herein, an “inert solvent” is a solvent that does not react with either the reactants or the products formed in the reaction. Suitable organic solvents for use in the present description include, but are not limited to, alcohols with 1-6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, and the like; ketones with 1-6 carbon atoms, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; ether solvents with 1-6 carbon atoms, such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl t-butyl ether or MTBE, dipropyl ether, diisopropyl ether, and the like, or cyclic ethers with 4-6 carbon atoms, such as THF, dioxane, and the like; Halogenated solvents such as dichloroethane, dichloromethane, chloroform, and the like; esters with 2 to 10 carbon atoms, such as ethyl acetate, isopropyl acetate, n-propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like;Hydrocarbons with 1 to 10 carbon atoms, including aryl groups such as toluene, xylene, cyclohexane, heptane, xylene, and the like; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and the like; and mixtures thereof in various proportions, without limitation. The use of a suitable solvent includes the use of a mixture of solvents of the same. The applicability of a specific solvent to a; Petition 870260059814, dated 06 / 18 / 2026, page 35 / 249 29 / 121 The reaction depends on several factors, such as the type of reaction, the reactants, the products, the reagents used, and the like. One skilled in the art can determine the appropriate solvents for the reactions described herein.

[052] As used herein, the term “protic” refers to a proton or a hydrogen atom or ion. The term “protic solvent,” as used herein, refers to a polar liquid compound that has dissociable hydrogen atoms and is capable of forming a hydrogen bond with oxygen, fluorine, or nitrogen atoms.

[053] The term “polar protic solvent,” as used herein, refers to solvents that have at least one OH or NH bond and are miscible with water. Examples include water, methanol, ethanol, ammonia, and the like.

[054] In the reactions described below, functional groups can be protected by protecting groups. A protecting group, as defined herein, is a molecular structure that is introduced into a specific functional group in a molecule containing two or more functional groups to block the reactivity of the specific functional group under reaction conditions necessary to make modifications in other parts of the molecule. To be useful, a protecting group must meet certain requirements. First, it must react selectively with good yield to protect the desired functional group and be stable under reaction conditions that are used to make modifications in the molecule in other parts. Second, the protecting group needs to be selectively removed with good yield by readily available, preferably non-toxic, reagents under conditions that do not modify other functional groups in the molecule.In one embodiment, the protecting group must form a solid derivative without generating new chiral centers and can be easily separated from the molecule after the desired modification to the molecule has been effected. Furthermore, the protecting group must have a minimum of additional functional groups to avoid new reaction sites during the molecule modification process. Petition 870260059814, dated 06 / 18 / 2026, page 36 / 249 30 / 121

[055] As used herein, the term “Zx” and “Zg” refers to a substituent Z, as defined herein, that is attached to the aryl ring, such as a phenyl group, x or g times, respectively, wherein each substituent Z is the same or different and, where x is 0, 1, 2, 3, 4, or 5 and g is 0, 1, 2, 3, or 4. For example, if x is five, then the aryl ring, for example, phenyl, has five substituents Z, wherein each substituent Z is as defined herein and may be the same or different. If x or g is four, then the aryl ring, for example, phenyl, has four substituents Z, wherein each substituent Z is as defined herein and may be the same or different, and wherein the remaining substituent Z on the aryl ring, for example, phenyl, is hydrogen. If x or g is three, then the aryl ring, for example, phenyl, has three Z substituents, where each Z substituent is as defined here and may be the same or different, and where the remaining Z substituents on the aryl ring, for example, phenyl, are hydrogen.If x or g is two, then there are two Z substituents on the aryl ring, for example, phenyl, which may be the same or different, where each Z substituent on the aryl ring, for example, phenyl, is as defined here, and they may be the same or different, and where the remaining Z substituents on the aryl ring, for example, phenyl, are hydrogen. If x or g is one, then there is only one Z substituent, as defined here, on the aryl ring, for example, phenyl, and the remaining Z substituents on the aryl ring, for example, phenyl, are hydrogen. If x or g is zero, then there are no Z substituents on the ring, and the substituents on aryl, for example, phenyl, are hydrogen.

[056] Some compounds described in this description contain the moiety (CZiZ^n ozO where Zi and Z2 are as defined herein, and en is 2 or 3. This portion represents the ketal protecting group that is formed from HO-(CZ1Z2)n-OH. As used herein, the numbering in the ring is based on the position of the ring atoms, regardless of whether the atom is a carbon or oxygen atom. Thus, a Petition 870260059814, dated 06 / 18 / 2026, page 37 / 249 31 / 121 of the oxygen atoms in the ring are in position 2, with the carbon atom at the bottom apex being in position 1 of the ring. When n is 2, the portion becomes with the numbering of the atoms as shown, where Zi and Z2 are either the same or different and are defined as described herein.

[057] When n is 3, the portion becomes with atom numbering as shown. It is understood that each Z1 in the portions above may be the same or different, and each Z2 in the portions above may be the same or different, and that Zi and Z2 may be the same or different. Thus, for example, when n is 3, one embodiment is where the substituents Zi and Z2 on the carbon atoms labeled 3 and 5 are both hydrogens, while the substituents Zi and Z2 on the carbon atom labeled 4 are both methyl.

[058] As used herein, the term “acyl reducing agent” is a compound that reduces acyl groups, for example, ZaC=O, to a Z3-CH2 or Z3-CD2 group that is known in the field. Examples include sodium borohydride and iodine; lithium aluminum hydride and iodine; Y[N(TMS)2]3; lithium or sodium triethylborohydride in the presence of Petition 870260059814, dated 06 / 18 / 2026, p. 38 / 249 32 / 121 silanes, such as PhSiH3 and alkali metal bases, such as NaOH, or KOH, or NaOMe; (EtO)3SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; Tf2O followed by reduction with sodium borohydride, Et2Zn; Tf2O in the presence of B(C6F5)3 and TMDS, B(C6F5)3 in the presence of TMDS, nickel chloride (dme) in the presence of PhSiH3, and the like.

[059] The term “acylation agent of Formula Z3COOXo”, as used herein, refers to the compound, where Xo is H or D or an acid derivative thereof, such as a halide, ester or anhydride.

[060] The term “deuterated acyl reducing agent” or similar term refers to an acyl reducing agent in which all hydrogen atoms are replaced by deuterium. Examples include NaBD4, LiAlD4, and the like.

[061] The term “acid derivative” refers to an acid halide, or ester, or anhydride of the referenced acid.

[062] In the present description, reference to a particular variable retains the definitions given here. Thus, for example, Z, as mentioned here, refers to the definition of Z given here.

[063] In one embodiment, Zi and Z2 are independently H or C1-C3 alkyl and Z4 and Z5 are independently C1-C3 alkyl, en, Z, Z3, Z6, Z7, Z8, X1, a, b, x and Ar are as defined herein.

[064] In another embodiment, each pair of Z1 and Z2 is the same and each pair of Z5 and Z4 is the same. In other words, a pair of Z1 and Z2 is substituted on the same carbon. A pair of Z4 and Z5 refers to OZ4 and OZ5 being substituted on the same carbon. In each of these embodiments, n, Z, Z3, Z6, Z7, Z8, X1, a, b, x and Ar are as defined herein.

[065] In another embodiment, Z3 is H or C1-C6 unsubstituted alkyl, C1C6 alkyl substituted with halogen or unsubstituted aryl, or aryl substituted with Petition 870260059814, dated 06 / 18 / 2026, p. 39 / 249 33 / 121 halo or C1-C6 alkyl or Z3 is D, en, Z, Zi, Z2, Z4, Z5, Z6, Z7, Zs, Xi, a, b, x and Ar are as defined herein.

[066] In yet another embodiment, Z3 is H or Z3 is D, en, Z, Zi, Z2, Z4, Z5, Z6, Z7, Zs, Xi, a, b, xe Ar are as defined herein. Thus, for example, Z3 is D when each Zs is D en, Z, Zi, Z2, Z4, Z5, Z6, Z7, Xi, a, b, xe Ar are as defined herein.

[067] In one embodiment, Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo or C1-C6 alkyl or C1-C6 alkoxy. In another embodiment, Z6 is C1-C6 alkyl, C3-C6 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo or C1-C6 alkyl. In yet another embodiment, Z6 is C1-C6 alkyl. In still another embodiment, Z6 is C1-C4 alkyl. Examples of Z6 include t-butyl, phenyl, tolyl, and adamantil, and the like. In each of these modalities, n, Z, Zi, Z2, Z3, Z4, Z5, Z7, Zs, Xi, a, b, x and Ar are as defined here.

[068] In one embodiment, Ar is aryl hydrocarbyl or ar(C1-C3)alkyl hydrocarbyl, wherein n, Z, Z1, Z2, Z3, Z4, Z5, Z7, Zs, X1, a, b, x and Z6 are as defined herein. In another embodiment, Ar is phenyl, wherein n, Z, Z1, Z2, Z3, Z4, Z5, Z7, Zs, X1, a, b, x and Z6 are as defined herein.

[069] In yet another embodiment, x is 0, i or 2, where n, Z, Zi, Z2, Z3, Z4, Z5, Z6, Z7, Zs, Xi, a, b, and Ar are as defined herein.

[070] In another embodiment, x is i or 2 and each Z is independently halogen, -OZii, or Ci - Ci0 alkyl, wherein n, Zi, Z2, Z3, Z4, Z5, Z6, Z7, Zs, Xi, a, b, and Ar are as defined herein. [07i] In one embodiment, at least one Z is F en, Zi, Z2, Z3, Z4, Z5, Z6, Z7, Zs, Xi, a, b, xe Ar and any additional Z, if present, are as defined herein. Petition 870260059814, dated 06 / 18 / 2026, p. 40 / 249 34 / 121

[072] In yet another embodiment, Ar is phenyl and at least one Z is F in position 4 of Ar en, Zi, Z2, Z3, Z4, Z5, Z6, Z7, Zs, Xi, a, b, x, and any additional Z, if present, are as defined herein.

[073] Furthermore, in one embodiment, x is 1 and Z is F, en, Zi, Z2, Z3, Z4, Z5, Z6, Z7, Zs, Xi, a, b, and Ar are as defined herein.

[074] In one embodiment, Z6 is alkyl or phenyl that is unsubstituted or substituted by C1-C6 alkyl and each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen en, Z1, Z2, Z3, Z4, Z5, Z7, Zs, X1, a, b, x and Ar are as defined herein.

[075] In another embodiment, Z3 is H, D, or C1-C6 alkyl optionally substituted with one or more fluorine or C1-C3 alkoxy, en, Z, Z1, Z2, Z4, Z5, Z6, Z7, Zs, X1, a, b, x and Ar are as defined herein.

[076] The definitions of the various variables are applicable to the compounds and processes described herein. Furthermore, all the various permutations of the variable definitions, including the subsets of the definitions presented herein, are contemplated by the present description.

[077] In one embodiment, the present description refers to the syntheses of compounds of Formula I as defined herein: THE Anh-cz8z8z3Ι^Λαγ(Z)χ I, where Zs, Z3, Ar, Z ex are as defined here. Petition 870260059814, dated 06 / 18 / 2026, p. 41 / 249 35 / 121

[078] It is prepared by a series of reactions recognized in the art. The starting materials for the reactions described here are commercially available or are prepared using well-known techniques in the field. The starting material undergoes a series of reactions to produce new intermediates, which in turn undergo a series of reactions to produce the compound of Formula I. The synthesis to prepare a compound of Formula I can originate from either of the new intermediates or from the starting material. The synthesis initially described here will be described initially in reverse order, without indicating the stereochemistry. Subsequently, the synthesis will be described in the preparation of the R-isomer and the S-isomer, following the forward direction.

[079] The final step in the synthesis of the compound of Formula I is a deketalization of a compound of Formula X or XA: (CZ1Z2)n °\ / O .NH-C(Z8)(Z8)(Z3) Άγ(Z)χ or where Zi, Z2, Z3, Z4, Z5, Zs, Z, Ar, n, ex are as defined here.

[080] In one embodiment, the compound of Formula X or XA undergoes ketal deprotection under conditions known to one skilled in the art to form a compound of Formula I. Deketalization, in general, is a reaction with which one skilled in the art is quite familiar. In one embodiment, the deprotection is often conducted by reacting the compound of Formula X or XA in acid, for example, protic acids such as HCl, HBr, HI, H2SO4, H3PO4, trifluoroacetic acid (TFA), p-toluenesulfonic acid, and the like, or under aprotic conditions with such Petition 870260059814, dated 06 / 18 / 2026, p. 42 / 249 36 / 121 reagents such as indium(III) trifluoromethanesulfonate in the presence of acetone, sodium tetrakis(3,5-trifluoromethylphenyl)borate, Er(OtF)3, iodine, perchloric acid adsorbed on silica gel, bismuth nitrate, and the like under conditions effective to deprotect the ketal and form the corresponding ketone. The deprotection reaction is conducted in a polar protic solvent, for example, water, alcohol with 1 to 5 carbon atoms, such as methanol, ethanol, isopropanol, propanol, tert-butanol, tamyl alcohol, ethylene glycol, propylene glycol, and the like, or a combination of a polar protic solvent and an aprotic solvent, such as toluene, fluorobenzene, chlorobenzene, dichlorobenzene, and the like. In one embodiment, the deprotection is conducted in water. In another method, the deprotection is carried out in water to which concentrated hydrochloric acid is added, that is, it is performed with concentrated hydrochloric acid in water.The reaction is conducted at effective temperatures, such as from room temperature up to the boiling point of the solvent. In one embodiment, sufficient acid is added to form the acid salt. If the reaction produces the salt instead of the free amino compound, to convert to the free base, such as a compound of Formula I, the acidification step is followed by basification of the reaction mixture from the acidification step described above with a base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and the like, so that the resulting pH is about 8 or higher, for example, from about pH 8 to about pH 14, for example, to a pH of 12-13. The reaction is conducted at effective temperatures, for example, below 40°C, for example, from about 0°C to below 40°C.The basification reaction is carried out in a polar solvent, such as water, and the free base can be extracted into a water-immiscible aprotic solvent, such as ethers, for example, dimethyl ether, diethyl ether, methyl ethyl ether, methyl tert-butyl ether (MTBE), di(propyl) ether, di(isopropyl) ether, or halogenated solvents, for example, dichloromethane (methylene chloride) or chloroform, or hydrocarbon solvents, for example, toluene or benzene, and the like; and solvent mixtures thereof. Petition 870260059814, dated 06 / 18 / 2026, page 43 / 249 37 / 121 Biphasic hydrolysis, such as an aqueous base in ethyl acetate and water or an aqueous acid in toluene and water, can affect the formation of the free base, especially when the product is absorbed by the organic layer and the reactants are in the aqueous layer. This separation facilitates the isolation of the free base from the reactants. The product is the free base of compound I.

[081] The compound with Formulas X and XA is prepared by reducing a compound with Formula IX or Formula IXA, respectively: IX IXA wherein Z1, Z2, n, Z3, Z, x, Z4, Z5, and Ar are as defined herein, with an acyl reducing agent, such as lithium aluminum hydride in the presence of iodine, sodium borohydride in the presence of iodine, sodium borohydride in the presence of AlCl3, CoCl3 / NaBH4, BH3 in DMS, BH3 in THF, N,N-diethylaniline borane complex, Li(iPr)2BH3, BEt3 in the presence of an alkali metal base, such as NaOH, KOH, NaOMe, and the like; Y[N(TMS)2]3 and HBpin; lithium or sodium triethylborohydride in the presence of silanes, such as PhSiH3 and an alkali metal base, such as NaOH, or KOH, or NaOMe; (EtO)3SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; Tf2O followed by reduction with sodium borohydride; Tf2O in the presence of B(C6F5)3 and TMDS, B(C6F5)3 in the presence of TMDS, nickel chloride (dme) in the presence of PhSiH3, and the like.To prepare the compound of Formula X or XA, wherein Z3 is D and both Zs are D, the compound of Formula IX or IXA is reacted with a deuterated acyl reducing agent, such as deuterated lithium aluminum hydride of formula LiAlD4, and in another embodiment, deuterated sodium borohydride of formula NaBD4, both in the... Petition 870260059814, dated 06 / 18 / 2026, p. 44 / 249 38 / 121 presence of iodine. Acyl reduction reactions are conducted in an inert solvent, such as ethers, for example cyclic ethers of 1 to 5 carbon atoms or ethers of formula Z27-O-Z28 at effective temperatures, such as where Z27 and Z28 are independently C1-C6 alkyl groups or Z27 and Z28 taken together with the oxygen atom to which they are attached, form a cyclic ring of 5 or 6 carbon atoms, wherein one or two of the carbon atoms may be replaced by oxygen, provided that neither of the two oxygen atoms is adjacent to each other. Examples of ethers that can be used as an inert solvent include diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, MTBE, tetrahydrofuran or 1,4-dioxane; or it is carried out in other suitable inert solvents, such as chloroform, methylene chloride, and the like; and solvent mixtures thereof.The reaction is conducted at effective temperatures, such as temperatures ranging from about -20°C up to the boiling point of the solvent.

[082] The compound of Formula IX or IXA is prepared by reacting the amine of Formula VIII or VIIIA, (CZ^n / \ or VIII VIIIA respectively, where Z1, Z2, n, Ar, Z, x, Z4, and Z5 are as defined herein, with an acylating agent Z3COOXo, where Z3 is as defined herein and Xo is H or D, or with an acid derivative thereof, such as the corresponding acid halide, such as an acid chloride, corresponding ester, for example, Z3COOZ12, or acid anhydride, such as Z3C(=O)-OC(=O)Zi2, where for example, Z12 Petition 870260059814, dated 06 / 18 / 2026, p. 45 / 249 39 / 121 is C1-C6 alkyl or aryl, wherein alkyl and aryl groups are unsubstituted or are substituted by halogen, or C1-C6 alkoxy, or aryl C1-C6 alkyl, C1-C6 alkyl, and the like, under amide-forming conditions.

[083] For example, amide formation can be carried out by reacting the amine of Formula VIII or VIIIA with Z3C(O)Cl in the presence of an aqueous base, such as NaOH or KOH, under Schotten-Baumann reaction conditions. In addition, other acylating agents or acyl transfer agents known in the art can be used.

[084] When Z3 is D and both Zss are D, then the amine of Formula VIII or VIIIA, respectively, is reacted with DCO2D under amide-forming conditions.

[085] If the amide is formed from a carboxylic acid, then the reaction can be carried out in the presence of coupling agents known in the art, such as carbodiimide, under effective amide-forming methods, with, for example, DCC, DIC, CMC, EDC, and the like, or with other carboxylic acid activators, such as HATU, HBTU, BOP, PyBOP, DEPBT, CDI, TCDI, (2-thiophen-2-ylmethyl)phenyl)boronic acid, 5-methoxy-2-iodophenylboronic acid, ammonia-borane, tetramethyl orthosilicate, triphenylphosphine, XtalFluor-E, N-formylpyrrolidine with trichlorotriazine, DIPEA, DABCO, or any other catalyst and dehydrating agent known in the art, and the like.

[086] The reaction is carried out in the presence of an inert solvent known to one skilled in the art, such as DMF, N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA), DMSO, acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride or chloroform or ethers containing 1-6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene, and the like; and solvent mixtures thereof. The reaction is carried out at temperatures sufficient to form the amide. In one embodiment, the Petition 870260059814, dated 06 / 18 / 2026, p. 46 / 249 40 / 121 reaction is conducted at a temperature ranging from about 0°C at the boiling point of the solvent.

[087] In another embodiment, the acid Z3COOXo is reacted with the compound of Formula VIII or VIIIA in the presence of PPh3 and NBS and Et3N to form a compound of Formula IX or IXA, respectively. In one embodiment, the reaction is carried out in an inert aprotic polar solvent, such as acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride or chloroform or ethers containing 1-6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene, and the like; and solvent mixtures thereof at effective temperatures of the amide of Formula IX or IXA, such as from about 0°C to room temperature.

[088] The compound of Formula VIII or VIIIA is formed by the acid hydrolysis of a sulfinamide of Formula VII or VIIA under amine-forming conditions. (CZ!Z2)n or VIIA where Z1, Z2, n, Ar, Z6, Z, x, Z4, and Z5 are as defined herein.

[089] For example, the amine of Formula VIII or VIIIA is formed by acid hydrolysis of sulfinamide of Formula VII or VIIA, respectively, for example, using a strong protic acid, such as HX1 or nitric acid or sulfuric acid, phosphoric acid Petition 870260059814, dated 06 / 18 / 2026, p. 47 / 249 41 / 121 or trifluoroacetic acid, or para-toluenesulfonic acid, where Xi is a halide. The reaction is carried out in a polar protic solvent, such as the one listed above, at temperatures sufficient to carry out the hydrolysis of sulfinamide to an amine. For example, the reaction can be carried out at temperatures ranging from about 0°C to the boiling point of the solvent.

[090] Sulfinamide of Formula VII or VIIA is formed by reacting an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x, as defined herein, with an imine of Formula V or VA, respectively, under arylation reaction conditions: (CZ^n z4 z A. I °V°NT AS° ÍJ6ÍJz' you VVA where Zi, Z2, n, Z6, Z4, and Z5 ex are as defined herein. Examples include molecules in which the Ar(Z)x moiety is present with an organometallic compound, such as an organomagnesium compound, such as a Grignard reagent MgBrAr(Z)x, or organolithium compounds, for example, LiAr(Z)x, or organopotassium, sodium, or aluminum, such as organoaluminates, or other organometallic compounds, such as organocopper, zinc, tin, and the like, an organoborate, in which the Ar(Z)x moiety is bonded to a boron atom or an arylphosphonium salt, such as a tetraarylphosphonium salt with the [Ar(Z)x]4 P+ moiety, and the like. Examples where the Ar(Z)x moiety is present with an organometallic compound include molecules with the formula Ar(Z)xMgX, Ar(Z)xLi, Ar(Z)xZnX2, InAr(Z)xX, where Ar, Z and X are as defined above and X is a halide, such as Br or Cl. When an organolithium compound is used, the use of additives such as BF3OEt2 and tetramethylethylenediamine (TMEDA) increases the yield.Since aryl nucleophilic agents react with air and water, the reaction is conducted in an inert atmosphere, such as under nitrogen or inert noble gas. The reaction is... Petition 870260059814, dated 06 / 18 / 2026, p. 48 / 249 42 / 121 conducted under conditions that effect the coupling of Ar(Z)x with the six-membered ring. The reaction is generally carried out in an inert solvent, such as ethers, such as dimethyl ether, such as diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, THF, or 1,4-dioxane, or such as hydrocarbon solvents, such as toluene, benzene, hexanes, or n-heptane, and the like, and mixtures of solvents thereof, under conditions effective to form the sulfinamide of Formula VII or VIIA, respectively. The reaction can be carried out at an effective coupling temperature, such as a temperature ranging from about -78°C to about room temperature, when carried out in the aforementioned organic solvents.

[091] Other methods for sulfinamide formation are described in an article by Elzbieta Wojaczynska and Jacek Wojaczynski, entitled “Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds,” Chem. Rev. 2020, 120, 4578-4611, the contents of which are incorporated by reference.

[092] For one skilled in the art, other recognized methods for producing structures such as VIII and VIIIA include the asymmetric addition of alkylmetals to chiral imines, such as one containing an alpha-naphthylethyl group as a chiral auxiliary.

[093] Nucleophilic agents, Nu, are prepared by means of techniques recognized in the field. For example, Grignard reagents are prepared by treating an aryl halide, such as bromide or chloride, with an organometallic metal, such as metallic magnesium, in the presence of an inert solvent, such as THF, in the absence of water and air. Organolithium compounds are also prepared by means of reactions recognized in the art. For example, aryl and lithium compounds are formed by reacting aryl halides with metallic lithium.

[094] The compound with Formula V or VA is prepared by reacting the spiro compound with Formula III or IIIA, respectively: Petition 870260059814, dated 06 / 18 / 2026, page 49 / 249 43 / 121 III or IIIA where Zi, Z2, Z4, Z5, and en are as defined herein with a sulfinilh2n compound, where Z6 is as defined herein in the presence of a titanium compound of formula Ti(OZ?) aX1b, where Z7, a, Xi, and b are as defined herein or another catalyst such as CuSO4. Examples of titanium compounds include Ti(OEt)4, Ti((iOPr)4, TiCl(OiPr)3, TiCl2(OiPr)2, and TiCl3(OiPr). These titanium compounds are commercially available or can be prepared by one skilled in the art. The reaction is carried out in an inert solvent, such as methylene chloride or chloroform or ethers, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ester; or hydrocarbon solvents such as toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, tetrahydrofuran, and the like; and solvent mixtures thereof.

[095] Compounds of Formula III and Formula IIIA are prepared by procedures recognized in the field. Polyhydric alcohols, or polyols, with 1,2 and 1,3 hydroxyl conformations can react with a ketone to form a cyclic ketal. For example, with respect to the preparation of compounds of Formula III, 1,2-cyclohexanedione reacts with a diol of formula HO-(CZ1Z2)n-OH such as ethylene glycol, propylene glycol, 2,2-dimethylpropane-1,3-diol in the presence of an acid, such as HCl, HNO3, H2SO4, phosphoric acid, methanesulfonic acid, ptoluenesulfonic acid, and the like, wherein each Z1 and Z2 are as defined above. The reaction is carried out in an inert solvent, such as methylene chloride or Petition 870260059814, dated 06 / 18 / 2026, page 50 / 249 44 / 121 chloroform or ethers, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ester; or hydrocarbon solvents such as toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, tetrahydrofuran, and the like; and mixtures of solvents thereof. The reaction is conducted at effective temperatures, such as varying from ambient temperature to the boiling point of the solvent. Water may be removed from the mixture during the reaction, either physically with a Dean-Stark trap or similar apparatus, or chemically with a desiccant, such as molecular sieves or drying salts, in order to drive the equilibrium towards the ketal product.

[096] Compounds of Formula IIIA are prepared similarly. Instead of using a diol to react with 1,2-cyclohexanediones, alcohols of Z5OH and Z4OH are used wherein Z5 and Z4 are as defined above. In one embodiment, Z5 and Z4 are the same. The reaction is conducted in the presence of an acid catalyst; most typically, homogeneous catalysis is employed using a protic acid (Brønsted-Lowry acid). For example, sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acids, and mixtures thereof are known to catalyze the formation of ketals. Lewis acids, for example, aprotic acids, have also been used to catalyze the formation of ketals and acetals from alcohols. For example, Clerici et al., Tetrahedron 54, 15679-90 (1998) employ titanium tetrachloride in the presence of ammonia or amine to affect the reaction of methanol with various aldehydes in the presence of ammonia or amine.

[097] The reaction is carried out in an inert solvent, such as cyclohexane, hexane, pentane, petroleum ether, benzene, toluene, ethylbenzene, and the like. The reaction is carried out at effective temperatures ranging from room temperature to the boiling point of the solvent. Water may be removed from the mixture during the reaction, such as with a Dean-Stark trap or similar apparatus, in order to drive the equilibrium towards the ketal product. Petition 870260059814, dated 06 / 18 / 2026, page 51 / 249 45 / 121

[098] Acid addition salts, such as the pharmaceutically acceptable salts of the compounds of Formula I prepared from them with pharmaceutically acceptable acids by standard techniques to form the pharmaceutically acceptable salts thereof. For example, to convert to the halide salt, the compound of Formula I is acidified with HX3, where X3 is Cl or Br, with stirring at a temperature ranging from room temperature to the boiling point of the polar solvent.A reaction can be carried out in a polar protic solvent, such as water, an alcohol with 1-4 carbon atoms, such as methanol, ethanol, propanol, isopropanol or tert-butanol, or a polar solvent, such as an ether, for example, diethyl ether, methyl ethyl ether, methyl tributyl ether, or dipropyl ether or cyclic ether, such as THF or dioxane, a halogenated solvent, such as dichloromethane (methylene chloride) or chloroform, or a hydrocarbon solvent, such as toluene or benzene, and the like, to produce a pharmaceutically acceptable salt of a compound of Formula I.

[099] Thus, summarizing the above starting with 1,2-cyclohexanedione, the compound of Formula I is prepared from the cyclic ketal, as represented in Scheme 1, or from the non-cyclic ketal, as represented in Scheme II: θ (qz,Z2)n THE H++ HO-(CZ1Z2)n-OH — (ÇZ^n (CZ,Z2)n Ti(OZ7)a(X])b V VII Petition 870260059814, dated 06 / 18 / 2026, p. 52 / 249 46 / 121 (ÇZ,Z2)n / \ Z3COOXo acyl reducing agent ^ IX VIII (CZ!Z2)n θ .NH-C(Z8)(Z8)(Z3) Xr(Z)x l.H+ 2.OH- NH CZgZ$Z3Ar(Z)x XI Scheme I VA Z4OH H+ Z5OH-► Petition 870260059814, dated 06 / 18 / 2026, p. 53 / 249 47 / 121 acyl reducing agent ^ THE NH CZ8Z8Z3Ar(Z)x Scheme II

[0100] Using the above procedure, the R and S isomers of Formula I can be prepared, the contents of which are incorporated by reference. For example, using the ............ H2N j ·· , which is the R isomer of sulfinamide used above, the R isomer of Formula I, referred to as IR THE A.NH-C(Z8)(Z8)(Z3) L^J'Ar(Z)x IR is prepared, where Ze, Z3, Z, Ar, Z, Z6 ex are as defined herein. The procedure described above is incorporated by reference.

[0101] The R isomer of sulfinamide, designated as compound with Formula IVR Petition 870260059814, dated 06 / 18 / 2026, p. 54 / 249 48 / 121 h2n j IVR, where Z6 is as defined above, is reacted with compounds of Formula III III or Formula IIIA IIIA where Zi, Z2, n, Z4, and Z5 are as defined above to form compounds of Formula VR and VAR respectively, (ÇZ,Z2)n / \ °vO <-θ [J Z6 Z4 Z5 l 1 vL s^° r < ·> kJ Zó Petition 870260059814, dated 06 / 18 / 2026, p. 55 / 249 49 / 121 VR VAR where Zi, Z2, Z4, Z5, Z6, and n are as defined herein in the presence of a titanium compound of formula Ti(OZ7)aX1b, or CuSO4, where Z7, a, Xi, and b are as defined herein. Examples of titanium compounds include Ti(OEt)4, Ti(iOPr)4, TiCl(OiPr)3, TiCl2(OiPr)2, and TiCl3(OiPr). These titanium compounds are commercially available or can be prepared by those skilled in the art.

[0102] The reaction is carried out in an inert solvent, such as ether solvents, such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl tert-butyl ether (MTBE), dipropyl ether, diisopropyl ether, and the like; halogenated solvents such as dichloroethane, dichloromethane, chloroform, and the like; hydrocarbon solvents such as toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, and the like; and mixtures of solvents thereof. The reaction is carried out at effective temperatures. In one embodiment, the reaction is carried out around room temperature up to the boiling point of the solvent.

[0103] The imines of Formula V and VAR are reacted with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x, as defined herein, under arylation reaction conditions and form compounds of Formula VIIR and VIIAR, respectively: (CZiZ2)n VIIR or where Z1, Z2, n, Z6, Z4, Z5, Ar, Zex are as defined herein. Examples include molecules in which the Ar(Z)x moiety is present in an organometallic compound, such as Petition 870260059814, dated 06 / 18 / 2026, p. 56 / 249 50 / 121 as an organomagnesium compound, such as a Grignard reagent MgBrAr(Z)x, or organolithium compounds, for example, LiAr(Z)x, or organo-potassium, sodium, or aluminum, such as organoaluminates, organocopper, zinc, tin, and the like; or an organoborate, wherein the Ar(Z)x moiety is bonded to a boron atom or arylphosphonium salt such as a tetraarylphosphonium salt with the moiety [Ar(Z)x]4 P+. For example, organometallic examples include molecules of formula Ar(Z)xMgX, Ar(Z)xLi, Ar(Z)xZn(X)2, InAr(Z)xX, where Ar, Z and X are as defined above and X is a halide, such as Br or Cl. When organolithium is used, the use of additives such as BF3OEt2, tetramethylethylenediamine (TMEDA), and the like, increases the yield. Since aryl nucleophilic agents react with air and water, the reaction is conducted in an inert atmosphere, such as under nitrogen or inert noble gas. The reaction is conducted under conditions that effect the coupling of Ar(Z)x with the six-membered ring.The reaction is generally carried out in an inert solvent, such as ethers with 1-6 carbon atoms, such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, THF or 1,4-dioxane; or as hydrocarbon solvents, such as toluene, benzene, hexanes, or n-heptane, and the like; or a mixture of solvents thereof, under effective conditions to form sulfinamide of Formula VII or VIIA, respectively. The reaction can be conducted at an effective coupling temperature, such as a temperature ranging from about 78°C to about room temperature when conducted in the organic solvents mentioned above.

[0104] Nucleophilic agents, Nu, are prepared using recognized techniques in the field. For example, Grignard reagents are prepared by treating an aryl halide, such as aryl bromide or aryl chloride, with an organometal, such as metallic magnesium, in the presence of an inert solvent, such as THF, in the absence of water and air. Organolithium compounds are also prepared Petition 870260059814, dated 06 / 18 / 2026, page 57 / 249 51 / 121 by recognized reactions in the field. For example, aryl lithium compounds are formed by the reaction of aryl halide with metallic lithium.

[0105] Acid hydrolysis of compounds with formula VIIR or VIIAR produces the amine of VIIIR and VIIIAR, respectively, (ZZ,Z2)n / \ VIIIR VIIIAR where Zi, Z2, n, Ar, Z, x, Z4, and Z5 are as defined herein.

[0106] For example, the amine of Formula VIIIR or VIIIAR is formed by acid hydrolysis of sulfinamide of Formula VIIR or VIIAR, respectively, using a strong acid such as HX1 or nitric acid or sulfuric acid, phosphoric acid or trifluoroacetic acid, or para-toluenesulfonic acid, where X1 is a halide. The reaction is carried out in a polar protic solvent, such as those listed above, at temperatures sufficient to carry out the hydrolysis of sulfinamide to an amine. For example, the reaction can be carried out ranging from about 0°C up to the boiling point of the solvent.

[0107] The amines of Formula VIII R and VIIIAR are converted to the corresponding amides of Formula IXR and IXAR, respectively, under amide reaction conditions: Petition 870260059814, dated 06 / 18 / 2026, p. 58 / 249 52 / 121 IXR IXAR where Zi, Z2, n, Z3, Z4, Z5, Ar, Z ex are as defined here.

[0108] The compound of Formula IX or IXA is prepared by reacting the amine of Formula VIII or VIIIA, respectively, wherein Z1, Z2, n, Ar, Z, x, Z4, and Z5 are as defined herein, with an acylating agent, Z3COOXo, wherein Z3 is as defined herein and Xo is H or D, or with an acid derivative thereof, such as the corresponding acid halide, such as acid chloride, corresponding ester, for example, Z3COOZ12, or acid anhydride, such as Z3C(=O)-OC(=O)Zi2, wherein, for example, Z12 is C1-C6 alkyl or aryl, wherein alkyl groups and aryl groups are unsubstituted or halogen-substituted, or C1-C6 alkoxy, or arylC1-C6alkyl, or C1-C6 alkyl under amide-forming conditions. For example, amide formation can be carried out by reacting the amine of Formula VIII or VIIIA with Z3C(O)Cl in the presence of an aqueous base, such as NaOH or KOH, under Schotten-Baumann reaction conditions. Furthermore, other acylating agents or acyl transfer agents known in the art can be used.

[0109] When Z3 is D and both Zs's are both D, then the amine of Formula VIII or VIIIA, respectively, is reacted with DCO2D under amide-forming conditions.

[0110] If the amide is formed from a carboxylic acid, then the reaction is carried out in the presence of coupling agents known in the art, such as Petition 870260059814, dated 06 / 18 / 2026, p. 59 / 249 53 / 121 as carbodiimides under amide-forming conditions, with, for example, DCC, DIC, CMC, EDC, and the like, or with other carboxylic acid activators, such as HATU, HBTU, BOP, PyBOP, DEPBT, CDI, TCDI, (2-thiophen-2-ylmethyl)phenyl)boronic acid, 5-methoxy-2-iodophenylboronic acid, ammonia-borane, tetramethyl orthosilicate, triphenylphosphine, XtalFluor-E, N-formylpyrrolidine with trichlorotriazine, DIPEA, DABCO, or any other catalyst and dehydrating agent known in the art, and the like.

[0111] The reaction is carried out in the presence of an inert solvent known to one skilled in the art, such as DMF, N-methylpyrrolidone (NMP), N,N-dimethylacetamide (DMA), DMSO, acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride or chloroform or ethers containing 1-6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene, and the like; and mixtures of solvents thereof. The reaction is carried out at temperatures sufficient to form the amide. In one embodiment, the reaction is carried out at a temperature ranging from about 0°C to the boiling point of the solvent.

[0112] In another embodiment, the acid Z3COOXo is reacted with the compound of Formula VIIIR or VIIIAR in the presence of PPh3 and NBS and Et3N to form a compound of Formula IXR or IXAR, respectively. In one embodiment, the reaction is carried out in an inert aprotic polar solvent, such as acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride or chloroform or ethers containing 1-6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ester; hydrocarbon solvents such as heptane and toluene, and the like; and solvent mixtures thereof at effective temperatures to form the amide of Formula IXR or IXAR, such as from about 0°C at room temperature.

[0113] The amide of formula IXR and IXAR is reduced by an acyl reducing agent known in the art to produce the compounds XR and XAR: Petition 870260059814, dated 06 / 18 / 2026, p. 60 / 249 54 / 121 (ÇZ]Z2)n NH-C(Z8)(Z8)(Z3) Ar(Z) XR wherein Zi, Z2, n, Ze, Z3, Ar, Z, Z4, Z5, ex are as defined herein. Examples of acyl reducing agents include lithium aluminum hydride in the presence of iodine, sodium borohydride in the presence of iodine, sodium borohydride in the presence of AlCl3, CoCl3 / NaBH4, BH3 in DMS, BH3 in THF, N,N-diethylaniline borane complex, Li(iPr)2BH3, BEt3 in the presence of an alkali metal base such as NaOH, KOH, NaOMe, and the like; Y[N(TMS)2]3 and HBpin; lithium or sodium triethylborohydride in the presence of silanes such as PhSiH3 and alkali metal bases such as NaOH, KOH, or NaOMe; (EtO)3SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; Tf2O followed by reduction with sodium borohydride; Tf2O in the presence of B(C6F5)3 and TMDS; B(C6F5)3 in the presence of TMDS; nickel chloride (dme) in the presence of PhSiH3; and the like.To prepare the compound of Formula X or XA, where Z3 is D and both Z8 are D, the compound of Formula IX or IXA is reacted with a deuterated acyl reducing agent, such as deuterated lithium aluminum hydride of formula LiAlD4, and in another embodiment, deuterated sodium borohydride of formula NaBD4, both in the presence of iodine. The acyl reduction reactions are conducted in an inert solvent, such as ethers, for example cyclic ethers of 1 to 6 carbon atoms and one or two oxygen atoms or ethers of formula Z27-O-Z28 at effective temperatures, wherein Z27 and Z28 are independently C1-C6 alkyl groups or Z27 and Z28 taken together with the oxygen atom to which they are attached form a cyclic ring and, wherein one. Petition 870260059814, dated 06 / 18 / 2026, p. 61 / 249 55 / 121 of the carbon atoms in the ring can be replaced by an oxygen atom, provided that there are no two oxygen atoms adjacent to each other. Examples of ethers that can be used include diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, MTBE, tetrahydrofuran, or 1,4-dioxane, and the like. The reaction can also be carried out in other suitable inert solvents, such as chloroform, methylene chloride, and the like; and solvent mixtures thereof. The reaction is carried out at effective temperatures, such as temperatures ranging from about -20°C up to the boiling point of the solvent.

[0114] The next step in the synthesis of the IR formula compound is a deacetalization of an XR or XAR formula compound.

[0115] In one embodiment, the compound of Formula XR or XAR undergoes ketal deprotection under conditions known to those skilled in the art to form a compound of Formula IR. Someone skilled in the art is quite familiar with deketalization reactions of this type. In one embodiment, the deprotection is often carried out by reacting the compound of Formula XR or XAR in acid, for example, protic acids such as HCl, HBr, HI, H2SO4, H3PO4, trifluoroacetic acid (TFA), p-toluenesulfonic acid, and the like, or under aprotic conditions with reagents such as indium(III) trifluoromethanesulfonate in the presence of acetone, sodium tetrakis(3,5-trifluoromethylphenyl)borate, Er(OtF)3, iodine, perchloric acid adsorbed on silica gel, bismuth nitrate, and the like under conditions effective to deprotect the ketal and form the corresponding ketone.The deprotection reaction is carried out in a polar protic solvent, for example, water, an alcohol with 1 to 5 carbon atoms, such as methanol, ethanol, isopropanol, propanol, tert-butanol, t-amyl alcohol, ethylene glycol, propylene glycol, and the like, or a combination of a polar protic solvent and an aprotic solvent, such as toluene, fluorobenzene, chlorobenzene, dichlorobenzene, and the like. In one embodiment, the deprotection is carried out in water. In another embodiment, it is carried out in water to which acid is added. Petition 870260059814, dated 06 / 18 / 2026, page 62 / 249 56 / 121 concentrated hydrochloric acid is added, i.e., it is carried out in concentrated hydrochloric acid in water. The reaction is carried out at effective temperatures, such as from room temperature up to the boiling point of the solvent. In one embodiment, sufficient acid is added to form the acid salt. If the salt is formed, to convert to the free base, as a compound of Formula I, the acidification step is followed by basification of the reaction mixture from the acidification step described above with a base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and the like, so that the resulting pH is about 8 or higher, for example, from about pH 8 to about pH 14, for example, to a pH of 12-13. It is conducted at effective temperatures, for example, at a temperature below 40°C, for example, from about 0°C to below 40°C.The basification reaction is conducted in a polar solvent, such as water, and the free base can be extracted into a water-immiscible aprotic solvent, such as ethers, for example, dimethyl ether, diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, or MTBE; or as halogenated solvents, such as dichloromethane (methylene chloride) or chloroform, or as hydrocarbon solvents, such as toluene or benzene, and the like. Biphasic hydrolysis, such as an aqueous base in ethyl acetate and water or an aqueous acid in toluene and water, can affect the preparation of the free amine, especially when the product, i.e., the free amine, is absorbed into the organic layer and the reagents are in the aqueous layer. This separation facilitates the isolation of the free base from the reagents. The product is the free base of compound IR.

[0116] Acidic addition salts, such as the pharmaceutically acceptable salts of compounds of Formula IR, are prepared from them with pharmaceutically acceptable acids by standard techniques. For example, to convert the halide salt, the compound of Formula IR is acidified with HX3 where X3 is Cl or Br, with stirring at a temperature ranging from room temperature to the boiling point of the solvent. The reaction can be carried out in a polar protic solvent, such as Petition 870260059814, dated 06 / 18 / 2026, page 63 / 249 57 / 121 as water, an alcohol with 1-4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, or tert-butanol, or a polar solvent, such as ether, for example, diethyl ether, methyl ethyl ether, methyl tributyl ether, or dipropyl ether, a halogenated solvent, such as dichloromethane (methylene chloride) or chloroform, or a hydrocarbon solvent, such as toluene or benzene, and the like, to produce a pharmaceutically acceptable salt of a compound of Formula I.

[0117] Thus, summarizing the above, starting from 1,2-cyclohexanedione, the compound of Formula IR is prepared from the cyclic ketal, as represented in Scheme III, or from the non-cyclic ketal, as represented in Scheme IV: + HO-(CZ1Z2)n-OH H2N Ti(oz7)a(X0b (CZ,Z2)n VIIR (CZ,Z2)n / \ Z3COOXo VIIIR acyl reducing agent ^ IXR Petition 870260059814, dated 06 / 18 / 2026, p. 64 / 249 58 / 121 (ÇZ]Z2)n NH-C(Z8)(Z8)(Z3) Ar(Z). 2.0H- GO NH-C(Z8)(Z8)(Z3) ''Àr(Z)x XR Scheme III ........... + Z4OH + Z5OH Ti(OZ7)a(X,)b?4 Z5 sf;0 VAR Naked VIIar Petition 870260059814, dated 06 / 18 / 2026, p. 65 / 249 59 / 121 acyl reducing agent ^ Scheme IV NH-C(Z8)(Z8)(Z3) ''Ãr(Z)x GO Using the teachings above, and using the S isomer of sulfinamide of formula I, designated as IS, can be prepared, O ,sNH-C(Z8)(Z8)(Z3) Xr(Z)x IS Petition 870260059814, dated 06 / 18 / 2026, p. 66 / 249 60 / 121 where Ze, Z3, Ar, Z, Z6 ex are as defined herein. The procedures and their descriptions above are incorporated by reference, with the understanding that the corresponding S isomer of sulfinamide substitutes for the R isomer of sulfinamide whenever it appears in the description. In this way, the following schemes V (cyclic ketal) and VI (non-cyclic ketal) can be used to prepare the S isomer of Formula IS. O + o IIS-*Z6 (CZ^n H2N^ Ξ / \ Ξ Q o , Ti(OZ7)a(X1)b U ^QZiZ2)r °\ / ° h+ Γ j HO-(CZ1Z2)n-OH — (CZ^nn \ / ° ° °VO *Zz nt <XNH - z6 ^6 Nu [ K ·· __Uw VS VIIS (CZjZ^n °L° Q\r(Z)xZ2XOX» VIIIS (CZ^n °Co J<“,NH-C(Z8)(Z8)(Z3) l.H+ O\r(Z)x2°^ ( A_NII-C(Zs)(Z8)(Z3) ^jAr(Z)x IS Petition 870260059814, dated 06 / 18 / 2026, p. 67 / 249 61 / 121 Z4OH H+ Z5OH—► Ti(OZ7)a(X])b VAS Naked VIIAS VIIIAS acyl reducing agent ^ Petition 870260059814, dated 06 / 18 / 2026, p. 68 / 249 62 / 121 Scheme VI

[0118] Another procedure for preparing the compound of Formula I is a variation of the schemes after the formation of the amine for the compound of Formula VIII. Illustrating with the compound of Formula VIII, in this variation, the amine (CZ^n / \ subjected to reductive amination with Z3C(=O)Zs to form the corresponding amine (CRíRs / n >C.NH-C(R8XR8)(R3) . IL JAr(R)x . . . ~ . of the formula in the presence of reducing amination agents known in the art. Examples include sodium cyanoborohydride (NaBH3CN), sodium borohydride, sodium triacetoxyborohydride (NaBH(OAc)3), and similar reducing amination solvents such as DCE, and the like.

[0119] The corresponding enantiomers can be isolated from the racemic compound by techniques known in the field. Examples include, but are not limited to, the formation of chiral salts and the use of high-performance liquid chromatography (HPLC) or chiral chromatography, and by the formation and crystallization of chiral salts. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, Petition 870260059814, dated 06 / 18 / 2026, page 69 / 249 63 / 121 1981); Wilen, SH, et al., Tetrahedron 33: 2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolution p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0120] Alternatively, chemoselective reductive amination can be carried out from compounds of Formula VIIIR and VIIIAR and VIIIS and VIIIAS with Z3C(=O)Z8 to form a corresponding amine of Formula XR, XAR, XS and XAS using chemoselective reducing amination agents known to those skilled in the art, such as [RuCl2(p-cumene)]2 / Ph2SiH2, dibutyltin chloride in the presence of phenylsilane, and the like. The reactions are conducted in inert solvents such as ethers, cyclic ethers, DCM, and the like.

[0121] In one embodiment, the description describes a method for preparing the compound with the formula: NH-C(Z8)(Z8)(Z3) or pharmaceutically acceptable salts thereof, the method comprising (a) reacting with t-butylsulfinamide in an inert solvent in the presence of Ti(OEt)4 to form an imine of Formula V Petition 870260059814, dated 06 / 18 / 2026, p. 70 / 249 64 / 121 (b) react the imine of Formula V with a Grignard reagent of formula: VI under Grignard conditions to form a sulfinamide product of Formula VII, where X is the halo: (CZ^n VII (c) react the compound of Formula VII with acid to form the corresponding amine of Formula VIII: VIII Petition 870260059814, dated 06 / 18 / 2026, p. 71 / 249 65 / 121 (d) react the amine of Formula VIII with an acylating agent of formula Z3COOXo where Xo is H or acid derivatives thereof or D under amide-forming conditions to form the amide of Formula IX: IX (e) reduce the acyl group (C=O) in formula IX with an acyl reducing agent selected from sodium borohydride or deuterated sodium borohydride, both in the presence of iodine, to form the compound of Formula X: X, (f) deprotect the ketal from step (e) to form the compound of Formula I wherein each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Each Z8 is independently either H or D; Petition 870260059814, dated 06 / 18 / 2026, p. 72 / 249 66 / 121 Z3 is hydrogen, alkyl optionally substituted by one or more halogens or C1-C6 alkoxy or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy or halogen or Z3 is D; each Z is independently a halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, or aryl, e.g., 0, 1, 2, 3, or 4.

[0122] In the reaction scheme above, deuterated compounds are formed when both Z3 and D are deuterated and sodium borohydride in the presence of iodine is used as the acyl reducing agent. Conversely, if a non-deuterated acyl reducing agent is used and a non-deuterated acylation is used, the non-deuterated product of Formula I is produced.

[0123] In one embodiment, Z3 is hydrogen or alkyl with 1-6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; where each Z11 is C1-C10 alkyl, C2-C10 alkynyl, C4-C10 alkynyl without terminal hydrogen atoms, or aryl.

[0124] Compounds of Formula I can be prepared from non-cyclic ketals similarly starting from a compound of formula: The intermediates in the scheme are the corresponding non-cyclic ketals. Petition 870260059814, dated 06 / 18 / 2026, p. 73 / 249 67 / 121

[0125] In another embodiment, the R isomer of the following formula can be prepared using the techniques described above: IR0H N—(C(Z8)(Z8)(Z3)

[0126] The method comprises (a) reacting with (R)-t-butylsulfinamide in an inert solvent in the presence of Ti(OEt)4 to form an imine of formula VR {CZ^n VR (b) react the imine of formula VR with a Grignard reagent of formula: VI under Grignard formation conditions where X is a halo to form a sulfinamide product of Formula VIIR: Petition 870260059814, dated 06 / 18 / 2026, p. 74 / 249 68 / 121 VIIR (c) react the compound of Formula VIIR with acid to form the corresponding amine of Formula VIIIR: (d);(CZ1Z2)n & VIIIR (e) react the amine of formula VIIIR with an acylating agent of formula Z3COOXo where Xo is H or an acid derivative thereof, or Xo is D under amide-forming conditions to form the amide of formula IXR: IXR (f) reduce the acyl group (C=O) in formula IXR with sodium borohydride or deuterated sodium borohydride, both in the presence of iodine, to form the compound of formula XR: Petition 870260059814, dated 06 / 18 / 2026, p. 75 / 249 69 / 121 (ςζ,ζ^η °vÒH NC(Z8)(Z8)(Z3) XR, and (g) deprotecting the ketal to form the compound of Formula IR in which Zi and Z2 are independently H or C1-C6 alkyl; n is 0, 1, 2, or 3; X is halo; Za is hydrogen, alkyl optionally substituted by one or more halogens or C1-C6 alkoxy or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy or halogen or Z3 is D; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, or aryl, e.g. is 0, 1, 2, 3, or 4, and each Z8 is independently H or D.

[0127] In the reaction scheme above, deuterated compounds are formed when both Z3 is D and deuterated sodium borohydride in the presence of iodine is used as the acyl reducing agent. On the other hand, if a non-deuterated acyl reducing agent is used and a non-deuterated acylation agent is used, the non-deuterated product of Formula I is produced.

[0128] In one embodiment, Z3 is hydrogen or alkyl with 1-6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4 Petition 870260059814, dated 06 / 18 / 2026, p. 76 / 249 70 / 121 C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; where each Z11 is C1 - C10 alkyl, C2 - C10 alkynyl, C4 - C10 alkynyl without terminal hydrogen atoms, or aryl.

[0129] Compounds with formula IR can be prepared from non-cyclic ketals similarly starting from a compound with the formula: that the intermediates in the scheme are the corresponding non-cyclic ketals.

[0130] In another example, the S isomer of the following formula is prepared using the methodology described here: IS

[0131] The method comprises (a) reacting with (S)-t-butylsulfinamide in an inert solvent in the presence of Ti(OEt)4 to form an imine of formula VS (CZ^n VS Petition 870260059814, dated 06 / 18 / 2026, p. 77 / 249 71 / 121 (b) react the imine of Formula VS with a Grignard reagent of formula VI: VI under Grignard formation conditions where X is a halo to form a sulfinamide product of Formula VIIS: VIIS (c) react the compound of Formula VIIS with acid to form the corresponding amine of Formula VIIIS: VIIIS (d) react the amine of Formula VIIIS with an acylating agent of formula Z3COOXo where Xo is H or an acid derivative thereof or D under amide-forming conditions to form the amide of Formula IXS: Petition 870260059814, dated 06 / 18 / 2026, p. 78 / 249 72 / 121 IXS (e) reduce the acyl group (C=O) in formula IXS with sodium borohydride or deuterated sodium borohydride, both in the presence of iodine, to form the compound of formula XS: (OZ,ZH^η XS, and (f) deprotecting the ketal in step (e) to form the IS product in which Zi and Z2 are independently H or C1-C6 alkyl; n is 0, 1, 2, or 3; Z3 is hydrogen, alkyl optionally substituted by one or more halogens or C1-C6 alkoxy or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy or halogen or Z3 is D; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; where each Z11 is C1-C10 alkyl, C2-C10 alkynyl, C4-C10 alkynyl without terminal hydrogen atoms, or aryl, e.g. is 0, 1, 2, 3, or 4, and Petition 870260059814, dated 06 / 18 / 2026, p. 79 / 249 73 / 121 each Z8 is independently H or D.

[0132] In the reaction scheme above, deuterated compounds are formed when both Z3 is D and deuterated sodium borohydride in the presence of iodine is used as the acyl reducing agent. On the other hand, if a non-deuterated acyl reducing agent is used and a non-deuterated acylation is used, the non-deuterated product of Formula I is produced.

[0133] In one embodiment, Z3 is hydrogen or alkyl with 1-6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, or aryl.

[0134] The compound of formula IS can be prepared from non-cyclic ketals similarly starting from a compound of formula: The intermediates in the scheme are the corresponding non-cyclic ketals.

[0135] In one embodiment of any formula described herein, Z3 is H, D, or alkyl with 1 or 3 carbon atoms selected from the group consisting of CH3, -CH2-CH3, -CH2-CH2-CH3, -CH-(CH3)2, or D. In another embodiment, Z3 is D or H. In another embodiment, g is 0, 1, or 2. In one embodiment, g is 0. In another embodiment, g is 1, Z is F, and the F is at position 4 of the phenyl ring.

[0136] In one embodiment, n is 2 or 3 and Z1 and Z2 are independently C1C3 alkyl or H. In another embodiment, n is 2 and each Z1 and Z2 is hydrogen. In another embodiment, n is 3 and Z1 and Z2 at position 4 of the ring are both methyl and Z1 and Z2 at positions 3 and 5 of the ring are hydrogen. In another embodiment, n is 3 and the carbon atoms at positions 3 and 5 are unsubstituted. In another embodiment, Z3 is Petition 870260059814, dated 06 / 18 / 2026, p. 80 / 249 74 / 121 hydrogen or alkyl with 1-6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; where each Z11 is C1-C10 alkyl, C2-C10 alkynyl, C4-C10 alkynyl without terminal hydrogen atoms, or aryl.

[0137] Another embodiment refers to a method for forming the compound with the formula: The Me Ã.NH-HC1 θιχ whose method comprises (a) reacting with (R)-t-butylsulfinamide in an inert solvent in the presence of Ti(OEt)4 to form a sulfinamide with the formula (b) react the product of step (a) with a Grignard reagent of formula: Petition 870260059814, dated 06 / 18 / 2026, p. 81 / 249 75 / 121 under Grignard conditions to form a second sulfinamide product with the formula: The F· J (c) react the product of step (b) with acid to form an amine with the formula: F· J (d) react the amine product from step (c) with an acylating agent of The formula HCOOH or an acid derivative thereof under amide-forming conditions will form an amide with the formula: F· · (e) reduce the acyl group (C=O) of the product in step (d) with sodium borohydride in the presence of iodine to form an amine with the formula: Petition 870260059814, dated 06 / 18 / 2026, page 82 / 249 76 / 121 Me Me Me (f) deprotecting the product from step (e) in the presence of an acid selected from concentrated hydrochloric acid, concentrated hydrobromic acid, concentrated nitric acid, or concentrated sulfuric acid, with concentrated HCl, followed by base and reacting the deprotected product with HCl to form OMe Ã.NH-HC1 θιχ compound of formula: * . Petition 870260059814, dated 06 / 18 / 2026, p. 83 / 249 77 / 121

[0138] Another embodiment refers to a method for forming the compound with the formula: whose method involves reacting with (R)-t-butylsulfinamide in an inert solvent in the presence of Ti(0Et)4 to form a sulfinamide with the formula (b) react the product of step (a) with a Grignard reagent of formula: under Grignard conditions to form a second sulfinamide product with the formula: Petition 870260059814, dated 06 / 18 / 2026, p. 84 / 249 78 / 121 (c) react the product of step (b) with an acid to form an amine with the formula: (d) react the amine product from step (c) with an acylating agent of formula DCOOD to form an amine product with the formula: (e) reduce the acyl group (C=O) of the product in step (d) with deuterated sodium borohydride in the presence of iodine to form an amine with the formula: (f) deprotect the product of step (e) in the presence of an acid selected from concentrated hydrochloric acid, concentrated hydrobromic acid, concentrated nitric acid, or concentrated sulfuric acid, react the resulting product with a base, and react the resulting product with HX3, wherein X3 is Br or Cl, to form the compound of formula: Petition 870260059814, dated 06 / 18 / 2026, page 85 / 249 79 / 121

[0139] In the various processes described herein, in one embodiment, Z6 is alkyl or phenyl that is unsubstituted or substituted by C1-C6 alkyl. In another embodiment, in the various processes described herein, each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen.In another embodiment, in the processes described herein, Z6 is alkyl or phenyl that is unsubstituted or substituted by C1-C6 alkyl, and each Z is independently halogen (selected from F, Cl, Br, I), -OZ11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen. In another embodiment, in the various processes described herein, Nu is Ar(Z)xMgX or Ar(Z)xLi, where X is halo, where Z is as defined herein, ex is as defined herein. In one embodiment, in the various processes described herein, Nu is Ar(Z)xMgX, wherein X is halo, Ar is phenyl, and Z and ex are as defined herein.In yet another embodiment, the instantaneous process excludes the specific process for preparing [D3]-11R and [D3]-11R^HCl described in Example 2 starting from 8R to form [D3]-9R, from [D3]-9R to form [D3]-10R, from [D3]-10R to form [D3]-11R^HCl, either directly from it or through [D3]-11R, whether isolated or not.

[0140] In one embodiment, the fluorine atom is a phenyl ring, for example in the para position. In other embodiments, there is no fluorine atom in the ring and the phenyl ring may have up to five substituents, as described in the previous section of the descriptive report. Petition 870260059814, dated 06 / 18 / 2026, p. 86 / 249 80 / 121

[0141] In one embodiment, the present description refers to a formula intermediary: (CZ^n NH-C(Z8)(Z8)(Z3) Ar(Z). (CZ1Z2)n Ar(Z> °\ / bX UxNH-C(Z8)(Z8)(Z3) Petition 870260059814, dated 06 / 18 / 2026, p. 87 / 249 81 / 121 where Ζι, Z2, Z3, Z4, Z5, Ζβ, Z, Ar, x, neg are as defined above.

[0142] In one embodiment, the following intermediate compound may be excluded:

[0143] In another embodiment, the present description refers to a formula intermediary: Petition 870260059814, dated 06 / 18 / 2026, p. 88 / 249 82 / 121 where Ζι, Z2, Z3, Z4, Z5, Z, Ar, x, neg are as defined above. Petition 870260059814, dated 06 / 18 / 2026, p. 89 / 249 83 / 121

[0144] In one embodiment, the following intermediate compound may be

[0145] In another embodiment, the present description refers to an intermediate compound with the formula: Z4 Petition 870260059814, dated 06 / 18 / 2026, p. 90 / 249 84 / 121 where Zi, Z2, Z4, Z5, Z, Ar, x, neg are as defined above.

[0146] In a further embodiment, the present description refers to formula intermediates: (CZ,Z2)n Petition 870260059814, dated 06 / 18 / 2026, p. 91 / 249 85 / 121 (CZ^n where Zi, Z2, Z4, Z5, Z6, Z, Ar, x, neg are as defined above.

[0147] In another version, the following compounds are excluded: In some sports, f is also excluded, but not the corresponding S isomer or racemic mixture. In further embodiments, the Petition 870260059814, dated 06 / 18 / 2026, p. 92 / 249 86 / 121 racemate It is excluded. In another modality, Racemates are additionally excluded. A further aspect of this description refers to intermediates of the following formula: where Zi, Z2, Z4, Z5, Z6, and en are as defined above.

[0148] In one embodiment, the following compounds are excluded: In some sports, (R)i_ t-Bu is excluded, but not the corresponding racemate or the corresponding S enantiomer. Petition 870260059814, dated 06 / 18 / 2026, p. 93 / 249 87 / 121 In additional modalities, the formula racemato is excluded, but not the corresponding S enantiomer. In still other embodiments, both the racemate and the corresponding S enantiomer of formula

[0149] In a further embodiment of the present description, it refers to a formula intermediary: where Zi, Z2, Z4, Z5 and en are as defined above. In one embodiment, the following compounds are excluded:

[0150] In one embodiment of the present description, the present description excludes intermediate compounds described herein, wherein Z1 and Z2 are hydrogen or both are methyl, en is 2 or 3, wherein Z3, Z4, Z5, Z6, Zs, Z, Ar, x, eg are not present. In another embodiment, the present description excludes compounds wherein Z4 and Z5 are either methyl or ethyl or one is methyl and the other is isopropyl, wherein Z1, Z2, Z3, Z5, Zs, Z, Ar, x, neg are not present. In another embodiment, the present description excludes imine intermediate compounds wherein Z6 is t-butyl, Z1 and Z2 are both hydrogen en is 2, and wherein Z1 and Z2 are both methyl en is 3, wherein Z3, Z4, Z5, Z6, Petition 870260059814, dated 06 / 18 / 2026, p. 94 / 249 88 / 121 Zs, Z, Ar, χ, and eg are not present. In another embodiment, the present description excludes compounds in which Ze is t-butyl, Zi and Z2 are both hydrogen, en is 2, Ar is phenyl substituted by Cl in the ortho position when the aryl ring is phenyl, ez or g is 1, and Z3, Z4, Z5, Z, and Zs are not present. In another embodiment, when the intermediate is the R isomer, then Z3 is different from D, F is not in the 4 position of the phenyl ring, n is

[0151] In one embodiment, the present description excludes intermediate compounds identified as 5, 7R, 8R, [Ds]-9R, and [D3]-10R. In another embodiment, the present description excludes 5, 7R, 8R, [Ds]-9R, and [Ds]-10R and enantiomers thereof, including stereoisomers of 7R, such as an enantiomer thereof or a diastereomer thereof. In yet another embodiment, the present description excludes racemic mixtures comprising compounds identified as 5, 7R and 7S, 8R and 8S, [D3]-9R and [D3]-9S, and [D3]-10R and [D3]-11S.

[0152] Another aspect of the present description refers to a compound with the following formula: Petition 870260059814, dated 06 / 18 / 2026, p. 95 / 249 89 / 121 11-HCl and pharmaceutical compositions comprising the same. In another embodiment, the present description refers to the above compound in solid form. In another embodiment, the present descriptive report refers to the R isomer of the hydrochloride salt described above with the formula: R-11 HCl

[0153] In another embodiment, the present description refers to the compound R11-HCl in solid form.

[0154] In another embodiment, the present description refers to the compound with the formula: S-11.HCl .

[0155] In a further embodiment, the present description refers to a compound of the formula: Petition 870260059814, dated 06 / 18 / 2026, p. 96 / 249 90 / 121 O ÇD3 Ί F.

[0156] In another embodiment, the present description refers to a compound with the formula: 'l, while in another embodiment, the present description refers to a compound of formula: CDS Hi;i F S-[D3]-11 HC1

[0157] The compounds described herein that are deuterated will be referred to herein as the deuterated analogues.

[0158] The compounds described herein of Formula I, including IR and IS, the deuterated analogues, or pharmaceutically acceptable salts thereof, are useful for treating psychiatric disorders. The utility is the same as described in U.S. Patent No. 11,344,510, the contents of which are incorporated herein by reference.

[0159] More specifically, in another aspect provided herein is a method of treating depression or anxious depression in an individual in need thereof, the method comprising administering to the individual in need thereof an effective amount of a compound of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof described herein.

[0160] In some embodiments, compounds of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof are orally Petition 870260059814, dated 06 / 18 / 2026, page 97 / 249 91 / 121 administered. For example, compounds of Formula I, IR, IS, or deuterated analogues, or pharmaceutically acceptable salts thereof, are useful in the treatment of psychiatric disorders comprising administering to an individual in need thereof a therapeutically effective amount of a compound or composition described herein. Psychiatric disorders contemplated may include Depressive Disorders, for example, Major Depressive Disorder, Persistent Depressive Disorder, Postpartum Depression, Premenstrual Dysphoric Disorder, Seasonal Affective Disorder, Psychotic Depression, Disruptive Mood Dysregulation Disorder, Substance / Medication-Induced Depressive Disorder, and Depressive Disorder Due to Another Medical Condition.The compounds of Formula I, IR, and IS are useful for treating refractory depression, for example, patients suffering from a depressive disorder that does not respond and / or has not responded to adequate treatment with at least one, or at least two other antidepressant compounds or therapeutics. As used herein, depressive disorder encompasses refractory depression. In some embodiments, the compounds of Formula I, IR, IS, deuterated analogues, and pharmaceutically acceptable salts thereof may be used to treat a psychiatric disorder including Bipolar and Related Disorders, for example, Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, Substance / Medication-Induced Bipolar and Related Disorder, and Bipolar and Related Disorders due to another medical condition.In some embodiments, compounds of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof, may be used to treat a psychiatric disorder, including Substance-Related Disorders, for example, by preventing cravings for substances, decreasing cravings for substances, and / or facilitating cessation or abstinence from substance use. Substance use disorders involve the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, etc. Petition 870260059814, dated 06 / 18 / 2026, page 98 / 249 92 / 121 Stimulants, nicotine, and tobacco. As used herein, substance or substances are psychoactive compounds that can cause dependence, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, methods and compositions may be used to facilitate smoking cessation or opioid cessation.

[0161] In some embodiments, compounds of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof are used to treat a psychiatric disorder including Anxiety Disorders, for example, Separation Anxiety Disorder, Selective Mutism, Specific Phobia, Social Anxiety Disorder (Social Phobia), Panic Disorder, Panic Attack, Agoraphobia, Generalized Anxiety Disorder, Substance / Medication-Induced Anxiety Disorder, and Anxiety Disorder Due to Another Medical Condition.In some embodiments, compounds of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof may be used to treat a psychiatric disorder, including Obsessive-Compulsive and Related Disorders, for example, Obsessive-Compulsive Disorder, Body Dysmorphic Disorder, Hoarding Disorder, Trichotillomania (Hair Pulling Disorder), Excoriation Disorder (Skin Excoriation), Substance / Medication-Induced Obsessive-Compulsive Disorder and Related Disorder, and Obsessive-Compulsive and Related Disorder Due to Another Medical Condition.In some embodiments, compounds of Formula I, IR, IS, deuterated analogs, or pharmaceutically acceptable salts thereof, may be used to treat a psychiatric disorder, including Trauma and Stressor-Related Disorders, for example, Reactive Attachment Disorder, Disinhibited Social Engagement Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, and Adjustment Disorder. In some embodiments, compounds of Formula I, IR, IS, deuterated analogs, or pharmaceutically acceptable salts thereof, may be used to treat a... Petition 870260059814, dated 06 / 18 / 2026, page 99 / 249 93 / 121 psychiatric disorder, including Eating and Feeding Disorders, for example, Anorexia Nervosa, Bulimia Nervosa, Binge Eating Disorder, Pica, Rumination Disorder, and Avoidant / Restrictive Food Intake Disorder.

[0162] In addition, in some embodiments, compounds of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof may be used to treat a psychiatric disorder, including Neurocognitive Disorders, for example, Delirium, Major Neurocognitive Disorder, Mild Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to Alzheimer's Disease, Major or Mild Frontotemporal Neurocognitive Disorder, Major or Mild Neurocognitive Disorder with Lewy Bodies, Major or Mild Vascular Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to Traumatic Brain Injury, Substance / Medication-Induced Major or Mild Neurocognitive Disorder, Major or Mild Neurocognitive Disorder Due to HIV Infection, Major or Mild Neurocognitive Disorder Due to Prion Disease, Major or Mild Neurocognitive Disorder Due to Parkinson's Disease, Disorder Major or Mild Neurocognitive Impairment Due to Huntington's DiseaseMajor or Mild Neurocognitive Disorder Due to Another Medical Condition, and Major or Mild Neurocognitive Disorder Due to Multiple Etiologies. Furthermore, in some embodiments, the compounds of Formula I, IR, IS, deuterated analogs, or pharmaceutically acceptable salts thereof, may be used to treat a psychiatric disorder, including Neurodevelopmental Disorders, for example, Autism Spectrum Disorder, Attention Deficit / Hyperactivity Disorder, Stereotyped Movement Disorder, Tic Disorders, Tourette's Disorder, Persistent (Chronic) Motor or Vocal Tic Disorder, and Provisional Tic Disorder. Additionally, in some embodiments, the compounds of Formula I, IR, IS, deuterated analogs, or pharmaceutically acceptable salts thereof, Petition 870260059814, dated 06 / 18 / 2026, page 100 / 249 94 / 121 can be used to treat a psychiatric disorder, including personality disorders, for example, borderline personality disorder.

[0163] In addition, in some embodiments, the compounds of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof may be used to treat a psychiatric disorder including Sexual Dysfunctions, for example, Delayed Ejaculation, Erectile Disorder, Female Orgasmic Disorder, Female Sexual Interest / Arousal Disorder, Genito-Pelvic Pain / Penetration Disorder, Male Hypoactive Sexual Desire Disorder, Premature Ejaculation (Premature), and Substance / Medication Induced Sexual Dysfunction. In some embodiments, the compounds of Formula I, IR, IS, deuterated analogues, or pharmaceutically acceptable salts thereof may be used to treat a psychiatric disorder, including Gender Dysphoria, for example, Gender Dysphoria.

[0164] The term effective amount or “therapeutically effective amount” refers to an amount of a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof that is effective in achieving a particular physiological and / or pharmacological effect including but not limited to reducing the frequency or severity of sadness or lethargy, depressed mood, feelings of anxiety or sadness, decreased interest in all or almost all activities, significant increase or decrease in appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness, feelings of helplessness, inability to concentrate and recurrent thoughts of death or suicide, or to provide a desired pharmacological and / or physiological effect, for example, by reducing, inhibiting or reversing one or more of the pathophysiological mechanisms underlying neurological dysfunction, modulating dopamine levels or signaling,modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating, Petition 870260059814, dated 06 / 18 / 2026, p. 101 / 249 95 / 121 synaptic connectivity or neurogenesis in certain brain regions, or a combination thereof.

[0165] The term “therapeutic index” used in reference to any compound of Formula I, IR, IS, the deuterated analogues and / or pharmaceutically acceptable salts thereof and associated therapeutic effects and side effects refers to the ratio of the dose of said compound required to induce a particular negative side effect to the dose of said compound required to induce the desired therapeutic effect.

[0166] In some embodiments, methods using the compounds of Formula I, IR, IS, the deuterated analogues, or pharmaceutically acceptable salts thereof include treatment of psychiatric disorder by administering to an individual in need thereof a pharmaceutical composition including from about 0.01 mg to about 400 mg of a compound described herein.In some formulations, doses may be, for example, in the range of approximately 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 300 mg, 20 to 250 mg. mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, with doses of, for example, about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30, mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg being examples.

[0167] In some embodiments, dosages may include amounts of a Formula I, IR, IS compound, the deuterated analogues, or a pharmaceutically acceptable salt thereof in the range of approximately, for example, 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg Petition 870260059814, dated 06 / 18 / 2026, page 102 / 249 96 / 121 to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, and 200 mg being specific examples of doses.

[0168] Typically, dosages of a compound of Formula I, IR, IS, the deuterated analogues described herein, or a pharmaceutically acceptable salt thereof, are administered once, twice, three times, or four times daily, on alternate days, every three days, once a week, or once a month to a patient in need thereof. In some embodiments, the dosage is approximately, for example, 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, for example 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0169] In some embodiments, pharmaceutical compositions for parenteral or inhalation use, for example, a spray or mist of a compound of Formula I, IR, IS, the deuterated analogues or a pharmaceutically acceptable salt thereof, include a concentration of about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the compositions include a compound of Formula I, IR, IS, deuterated analogues or a pharmaceutically acceptable salt thereof in a concentration of, for example, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, or about 0.05 mg / mL to about 1 mg / mL.

[0170] In some embodiments, the composition includes a compound of Formula I, IR, IS, the deuterated analogues or a pharmaceutically acceptable salt thereof. Petition 870260059814, dated 06 / 18 / 2026, p. 103 / 249 97 / 121 at a concentration of, for example, about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to 25 mg / mL, about 5 mg / mL to 50 mg / mL, or about 10 mg / mL to 100 mg / mL. In some embodiments, pharmaceutical compositions are formulated as a total volume of approximately, for example, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0171] Typically, dosages may be administered to an individual once, twice, three, or four times daily, on alternate days, every three days, twice weekly, once weekly, twice monthly, or once monthly. In some embodiments, a compound of Formula I, IR, IS, the deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual once in the morning or once in the evening. In some embodiments, these aforementioned compounds may be administered to an individual once in the morning and once in the evening. In some embodiments, a compound of Formula I, IR, IS, the deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual three times daily (e.g., at breakfast, lunch, and dinner), at a dose, for example, of 50 mg / administration (e.g., 150 mg / day).

[0172] In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 25 mg / day in one or more doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 50 mg / day in one or more doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 75 mg / day in one or more doses. Petition 870260059814, dated 06 / 18 / 2026, p. 104 / 249 98 / 121 doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 100 mg / day in one or more doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 150 mg / day in one or more doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 200 mg / day in one or more doses. In some embodiments, a compound of Formula I, IR, IS, deuterated analogs or pharmaceutically acceptable salts thereof are administered to an individual at a dose of 250 mg / day in one or more doses.

[0173] In some embodiments, the dosage of a Formula I, IR, IS compound, deuterated analogues or pharmaceutically acceptable salts thereof is 0.01-100 mg / kg, 0.5-50 mg / kg, 0.5-10 mg / kg, or 25-50 mg / kg once, twice, three, or four times daily. For example, in some embodiments, the dosage is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg once, twice, three, or four times daily. In some embodiments, an individual is administered a total daily dose of 0.01 mg to 500 mg of a Formula I, IR, IS compound, deuterated analogues or pharmaceutically acceptable salts thereof once, twice, three, or four times daily.In some embodiments, the total amount administered to an individual over a 24-hour period is, for example, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg. In some embodiments, the individual may be started at a low dose and the dosage is increased. In some modalities, the individual may be started with a high dose and the dosage is then decreased. Petition 870260059814, dated 06 / 18 / 2026, page 105 / 249 99 / 121

[0174] In some embodiments, a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a health professional.

[0175] In some embodiments, a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a health professional in a clinic specialized in the administration of psychoactive treatments.

[0176] In some embodiments, a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a health professional at a dose intended to induce a psychedelic experience in the individual.

[0177] In some modalities, administration to a patient under the supervision of a health professional occurs periodically in order to maintain a therapeutic effect on the patient, for example, every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

[0178] In some embodiments, a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof are administered by a patient alone at home or away from the supervision of a health professional.

[0179] In some modalities, self-administration by a patient occurs periodically to maintain a therapeutic effect on the patient, for example, daily, on alternate days, every three days, twice a week, once a week, twice a month, or once a month.

[0180] In some embodiments, a compound of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof may be administered at specific intervals. For example, during treatment a patient Petition 870260059814, dated 06 / 18 / 2026, page 106 / 249 100 / 121 can be administered with a compound of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof every, for example, 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours or 0.25 hours. In some embodiments, a compound of Formula I, IR, IS, or deuterated analogues is in the form of a pharmaceutically acceptable salt.

[0181] In some embodiments, a pharmaceutical composition comprises one or more of the compounds of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof. In some embodiments, a salt of the compound of Formula I, IR, and / or IS, the deuterated analogues, or pharmaceutically acceptable salts thereof are used in any of the methods, uses, or compositions described herein.

[0182] In some embodiments, a pharmaceutically acceptable salt of the compounds of Formula I, IR, and / or IS or the deuterated analogues are used in any of the methods, uses, or compositions described herein.

[0183] The term treatment as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include slowing the progression of the disease, disorder or condition, relieving symptoms and complications, and / or curing or eliminating the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular, a human being.

[0184] The present description also refers to pharmaceutical compositions comprising a compound of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof, in a mixture with pharmaceutically acceptable excipients and, optionally, other therapeutic agents. Petition 870260059814, dated 06 / 18 / 2026, page 107 / 249 101 / 121 auxiliary ingredients must be acceptable in the sense that they are compatible with the other ingredients in the composition and not harmful to the recipients thereof.

[0185] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the field of pharmacy.

[0186] Such methods include the step of combining compounds of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof, or combinations thereof with any auxiliary agent. Auxiliary agents, also including accessory ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and humectants. Such auxiliary agents are appropriately selected in relation to the intended form and route of administration, in accordance with conventional pharmaceutical practices.

[0187] Pharmaceutical compositions suitable for oral administration may be presented in discrete dosage units, such as pills, tablets, coated tablets or capsules, or in powder or granules, or in solution or suspension. The active ingredient composed of the compounds of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof may also be presented in bolus or paste form. The compositions may also be processed into a suppository or enema for rectal administration.

[0188] Tablets may contain the active ingredient compounds comprised of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof and suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Gelatin capsules may contain the active ingredient compounds. Petition 870260059814, dated 06 / 18 / 2026, page 108 / 249 102 / 121 comprising Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents may be used to make pressed tablets. The pressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect them from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. For example, for oral administration in the form of a single-dose tablet or capsule, the active drug component may be combined with a non-toxic, pharmaceutically acceptable, and inert oral carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like.Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

[0189] For oral administration in liquid dosage form, the compounds of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof are combined with any inert, non-toxic and pharmaceutically acceptable oral vehicle, such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms Petition 870260059814, dated 06 / 18 / 2026, page 109 / 249 103 / 121 may contain, for example, solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and suitable melting agents. Liquid dosage forms for oral administration may contain colorants and flavorings to increase patient acceptance.

[0190] For parenteral administration, suitable compositions include sterile aqueous and non-aqueous solutions comprising compounds of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof described herein. In general, water, a suitable oil, saline solution, aqueous dextrose (glucose), related sugar solutions and glycols, such as propylene glycol or polyethylene glycols, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering substances. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its derivatives and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol.The compositions may be presented in single-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a lyophilized (freeze-dried) condition, requiring only the addition of a sterile liquid carrier, for example, water, before use. For transdermal administration, for example, gels, patches or sprays may be considered.

[0191] Compositions or formulations suitable for pulmonary administration, for example by nasal inhalation, include fine powders or mists that can be generated by means of metered-dose pressurized aerosols, nebulizers or insufflators. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or administration system chosen. Petition 870260059814, dated 06 / 18 / 2026, page 110 / 249 104 / 121

[0192] The compounds used in the method of the present description can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds can be administered as components of tissue-targeted emulsions.

[0193] compounds of Formula I, IR, IS, the deuterated analogues or the pharmaceutically acceptable salt thereof, used in the method of the present description, may also be coupled to soluble polymers as targetable drug carriers or as prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of Formula I, IR, IS or pharmaceutically acceptable salts thereof may be coupled to a class of biodegradable polymers useful for obtaining controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates and crosslinked or amphipathic block copolymers of hydrogels.

[0194] The pharmaceutical compositions described herein may be supplied with immediate-release, delayed-release, extended-release, or modified-release profiles. In some varieties, pharmaceutical compositions with different drug release profiles may be combined to create a biphasic or triphasic release profile. For example, pharmaceutical compositions may be supplied with an immediate-release profile and an extended-release profile. Such a composition may be supplied as pulsatile formulations, multilayer tablets, or capsules containing tablets, spheres, granules, etc. Petition 870260059814, dated 06 / 18 / 2026, page 111 / 249 105 / 121

[0195] Pharmaceutical compositions described herein may be endowed with abuse-deterrent characteristics by means of techniques known in the field, for example, by manufacturing a tablet that is difficult to crush or dissolve in water.

[0196] The pharmaceutical composition, as described above, may be combined with packaging material, including instructions for use of the composition for a use as described above.

[0197] The exact dose and administration regimen of the composition comprising compounds of Formula I, IR, IS, the deuterated analogues or pharmaceutically acceptable salts thereof will necessarily depend on the type and magnitude of the therapeutic or nutritional effect to be achieved and may vary depending on factors such as the specific compound, formula, route of administration, or age and condition of the individual to whom the composition will be administered.

[0198] In addition, in some embodiments, the pharmaceutical composition described herein may include a single enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, the deuterated analogs or pharmaceutically acceptable salts thereof. In other embodiments, a pharmaceutical composition described herein may include a mixture of at least one single enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, the deuterated analogs or pharmaceutically acceptable salts thereof together with another enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, the deuterated analogs or pharmaceutically acceptable salt thereof. In other embodiments, said mixture is a racemic mixture. In other embodiments, said mixture is a non-racemic mixture (wherein one enantiomer or diastereomer is enriched in said non-racemic mixture).In some embodiments, the compounds of Formula I, IR, IS, or pharmaceutically acceptable salts thereof are substantially pure, or are enantiomerically pure, or both. Petition 870260059814, dated 06 / 18 / 2026, p. 112 / 249 106 / 121

[0199] Compounds of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof may be administered in various forms, including those detailed herein. Treatment with compound of Formula I, IR, IS, deuterated analogues or pharmaceutically acceptable salts thereof may be a component of combination therapy or adjunctive therapy, i.e., the individual or patient requiring the drug is treated or receives another drug for the disease in conjunction with one or more of the compounds present. This combination therapy may be sequential therapy, in which the patient is treated first with one drug and then with another, or both drugs are administered simultaneously. These may be administered independently by the same route or by two or more different routes of administration, depending on the dosage forms employed.

[0200] The following examples further illustrate the teachings of the present description. The following examples are exemplary of the teachings contained herein. Although this is an exemplification, the teachings for the preparation of the compound described below may be prepared using the teachings contained herein and are not intended to be limited to the following exemplification.

[0201] In the following examples, the following abbreviations are used: p-TSA: Para-toluenesulfonic acid MTBE: Methyl tert-butyl ether EDTE: Ethylenediamine tetraethanol V: Volume Q-NMR: Quantitative NMR THF: Tetrahydrofuran HPLC: High-performance liquid chromatography NLT: Not less than TLC: Thin-layer chromatography DCM: Dichloromethane Petition 870260059814, dated 06 / 18 / 2026, p. 113 / 249 107 / 121 DMSO: Dimethyl sulfoxide ETOAc: Ethyl acetate IPA: Isopropyl alcohol ETOH: Ethanol NaHCO3: Sodium bicarbonate rt: Room temperature (20-25°C) NMP: n-Methyl-2-pyrrolidone

[0202] In the following schemes, compound 5R is a species of the compound with formula VR, compound 7R is a species of the compound with formula VIIR, compound 8R is a species of the compound VIIIR, compound 9R is a species of the compound IXR, compound 10R is a species of XR, and compound 11R is a species of IR. [D3]-11R is a species of the genus IR, corresponding to R-[D3]-11 where Z3 and Zs are both D, [D3]-10R is a species of the genus XR, where Z3 and Zs are both D, and [D]-9R is a species of the genus IXR, where Z3 is D. Similarly, 5S is a species of the genus with formula VS, compound 7S is a species of formula VIIS, compound 8S is a species of VIIIS, compound 9S is a species of IXS, compound 10S is a species of XS, and the compound 11S is a species of IS, [D3]-11S is a species of the genus IS, corresponding to R-[D3]-11, where Z3 and Zs are both D, [D3]-10S is a species of the genus XS, where Z3 and Zs are both D, and [D]-9S is a species of the genus IXS, where Z3 is D. EXAMPLE 1 Petition 870260059814, dated 06 / 18 / 2026, p. 114 / 249 108 / 121 MeOH 3 M HCl 3MMe0H i) NaBH4, l2, THF ii) MeOH iii) aq NaOH 10R Me 11R 5-6 M HCl in I PA n Me 11R'HCI

[0203] General procedure for the syntheses of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-7-one, 3

[0204] A 1000 mL jacketed reactor equipped with a suspended stirrer and a Dean-Stark apparatus was charged with 1,2-cyclohexanedione (50.0 g, 428 mmol), 2,2-dimethylpropane-1,3-diol (54.0 g, 514 mmol), p-TSA (1.66 g, 8.6 mmol), and cyclohexane (200 mL), and the resulting suspension was heated under reflux for 3 h to obtain complete conversion of the starting material. It was then cooled to room temperature and charged with 1N NaOH (aq) followed by MTBE and stirred. The phases were separated, the aqueous phase was further extracted with MTBE, and the combined organic products were washed once with 10% brine and concentrated. The mixture was azeotropated once with toluene to obtain 113 g (Q-NMR assay: 66%, yield 87.6%). The crude product was taken to the Petition 870260059814, dated 06 / 18 / 2026, p. 115 / 249 109 / 121 next step without further purification.1H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 11.1 Hz, 1H), 3.32 (d, J = 11.1 Hz, 1H), 2.38 - 2.35 (m, 2H), 1.8 - 1.79 (m, 2H), 1.67 - 1.63 (m, 4H), 1.06 (s, 3H), 0.55 (s, 3H).

[0205] General procedure for the syntheses of (R, E)-N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-ylidene)-2-methylpropane-2-sulfinamide, 5R

[0206] A round-bottom flask fitted with a suspended stirrer was loaded with compound 3 (33.3 g, 60% by weight, 0.101 mol), t-Bu-Sulfinamide (14.62 g, 0.121 mol), toluene (80 mL), and Ti(OEt4) (25.31 mL, 0.121 mol) at room temperature. The mixture was heated to 80°C for 5–6 h followed by cooling to room temperature to obtain a dark solution. EDTE (47.5 g) was added to this solution, and the mixture was heated to 55°C for 60 minutes followed by cooling to room temperature. 12% NaCl (aq) was added to the above solution, stirred for about 5 minutes, and allowed to stand. The phases were separated, and the aqueous phase was re-extracted twice with toluene. The combined organic products were washed once with water. The organic phase was filtered through an activated carbon and SO2 plug and concentrated to obtain the crude product as a yellow-orange semisolid (18.9 g of liquid product by NMR % by weight, 63%).The product crystallized as a whitish solid after settling, which was filtered and taken to the next step. 1H NMR (400 MHz, CDCla) δ 3.83 (d, J = 11.0 Hz, 1H), 3.72 (d, J = 11.0 Hz, 1H), 3.44 - 3.38 (m, 2H), 3.13 - 3.07 (m, 1H), 2.89-2.83 (m, 1H), 1.98-1.85 (m, 1H), 1.81-1.71 (m, 1H), 1.31 (s, 9H), 1.21 (s, 3H), 0.72 (s, 3H).

[0207] General procedure for syntheses of (R)-N-((R)-7-(4-fluorophenyl)3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-yl)-2-methylpropane-2-sulfinamide, 7R

[0208] To a stirred solution of compound 5R (17.5 g, 58.0 mmol) in THF (70 mL) at -5°C, a 1 M solution of 4-F-phenylmagnesium bromide in THF (116 mL, 116 mmol, 2 equiv.) was added dropwise. The resulting reaction mixture was Petition 870260059814, dated 06 / 18 / 2026, p. 116 / 249 The 110 / 121 mixture was stirred at -5°C for 4 h followed by room temperature for 14 h. TLC (50% EtOAc / hexanes) indicated complete conversion of the starting material. The reaction mixture was then cooled to 0°C and saturated aqueous NH4Cl (70 mL) was added dropwise. After heating to room temperature, the aqueous phase was extracted with MTBE and the combined organic layer was washed with water followed by drying over Na2SO4. Evaporation of the solvent yielded the crude product which was again mixed with heptane followed by filtration to give compound 7R (18.24 g, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.72 - 7.68 (m, 2H), 6.98 - 6.94 (m, 2H), 4.51 (s, 1H), 3.67-3.60 (m, 2H), 3.35 (dd, J = 11.3 Hz and 2.6 Hz, 1H), 3.27 (dd, J = 11.3 Hz and 2.5 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.33 - 2.27 (m, 1H), 2.05-2.01 (m, 1H), 1.98-1.88 (m, 1H), 1.76-1.66 (m, 1H), 1.62-1.45 (m, 2H), 1.17 (s, 9H), 0.84 (s, 3H), 0.69 (s, 3H).

[0209] General procedure for the syntheses of (R)-7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-amine, 8R

[0210] To a suspension of compound 7R (45.0 g, 113 mmol) in methanol (180 mL) at 0°C, a 3 M HCl solution in methanol (113 mL, 339 mmol, 3 equiv.) was added dropwise. The resulting reaction mixture was left at room temperature and stirred for 12–14 h. After the reaction was complete, the mixture was cooled to 0°C and saturated aqueous NaHCO3 (225 mL) was added dropwise. To the resulting suspension, CH2Cl2 (90 mL) was added to dissolve the product and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2 x 90 mL), and the combined organic products were washed with brine and dried (Na2SO4) and concentrated to provide the crude compound 8R (27.1 g, 82% quant) as a white solid, which was carried over to the next step without further purification. 1H NMR (400 MHz, CDC1a) δ 7.62 - 7.52 (m, 2H), 6.99 - 6.90 (m, 2H), 3.57 (dd, J = 23.4, 11.4 Hz, 2H), 3.16 (ddd, J = 11.2, 8.4, 2.7 Hz, 2H), 2.53 - 2.36 (m, 2H), 1.86 - 1.34 (m, 8H), Petition 870260059814, dated 06 / 18 / 2026, p. 117 / 249 111 / 121 0.59 (s, 3H), 0.36 (s, 3H).

[0211] General procedure for syntheses of (R)-N-(7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-yl)formamide, 9R

[0212] A reaction apparatus equipped with a stirrer, thermocouple, and a nitrogen inlet was charged with AC2O (32 mL, 339.56 mmol, 3 equiv.) and HCO2H (12.8 mL, 339.56 mmol, 3 equiv.) at room temperature. The reaction mixture was heated to 60 °C and aged for 3 h, followed by cooling to 0 °C. To the above mixture at 0 °C, a solution of 8R (26.10 g, 88.96 mmol) in CH2Cl2 (125 mL) was added using an addition funnel, and the mixture was stirred at 0 °C for 1.5 to 2 h. HPLC and TLC (30% EtOAc / hexanes) indicated complete conversion of the starting material to the desired product. The reaction was then rapidly cooled by the dropwise addition of a saturated aqueous solution of NaHCOa (520 mL) at 0°C using an addition funnel. The resulting solution was stirred for 30 minutes at 0°C before being transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted with CH2Cl2.The combined organic layer was washed with water and distilled to a low volume. MeOH was then added and distilled to remove any remaining CH2Cl2. The resulting MeOH solution was transferred to a three-necked round-bottom flask, and additional MeOH was added and heated to 55°C for 1 h with stirring. Water (drop by drop) was then added to the stirred solution using an addition funnel over 1 h. The resulting whitish suspension was aged at 50°C for 1 h and allowed to cool to room temperature for 12–14 h.The suspension was then filtered, and the cake was washed with a 1:1 MeOH / water mixture and dried under suction and then in a vacuum oven for 24 hours at 40°C to obtain compound 9R as a white solid (28.16 g, 98%), 1H NMR (400 MHz, CDC1a) δ 8.29 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 12.5 Hz, 1H), 7.49 - 7.37 (m, 2H), 7.03 - 6.89 (m, 2H), 6.43 (d, J = 12.5 Hz, 1H), 6.23 (s, 1H), 3.57 (ddd, J = 24.9, 11.4, 7.2 Hz, 2H), 3.24 - 3.13 (m,. Petition 870260059814, dated 06 / 18 / 2026, p. 118 / 249 112 / 121 2H) 2H), 0.59 (d, 3H), 0.28 (d, J = 23.3 Hz, 3H).

[0213] General procedure for 10R syntheses

[0214] A reactor equipped with a cooler, thermocouple, and suspended stirrer was charged with compound 9R (75 g, 0.23 mol), followed by THF, and stirred for not less than 15 min. NaBH4 (26.5 g, 0.7 mmol) was then charged into this reactor in portions. The resulting suspension was cooled from -10°C to 0°C. An iodine solution (71.1 g, 0.28 mol) in THF was added to the above suspension dropwise using an addition funnel, maintaining the internal temperature between -5°C and 10°C (Caution: rapid gas evolution). After the iodine addition was complete, the mixture was gradually heated to 35-45°C over 30 min and stirred at this temperature for 2-4 h. IPC by HPLC shows a conversion from 9 to 10. The resulting white suspension was cooled from -5°C to 0°C and MeOH was added dropwise for 90 minutes, maintaining the internal temperature below 10°C. After the addition was complete, the mixture was heated to 40-45°C for 30 minutes and aged at that temperature.The complete decomposition of the borane amine intermediate complex was monitored by 19F NMR studies of the reaction mixture.

[0215] In a separate flask, a solution of NaOH (aq) was prepared by dissolving 0.930 g of NaOH in 9 V of water. A portion (20%, 18 V) of this NaOH (aq) solution was initially added dropwise to the reaction mixture above at 40-45°C and aged at that temperature. The formation of a white precipitate was observed immediately after the addition of the NaOH (aq) solution. The remainder of the NaOH (aq) solution was then added slowly over 2.5-3 hours at 40-45°C. After the addition was complete, the internal temperature of the suspension was adjusted to 20-25°C and aged at that temperature. The suspension Petition 870260059814, dated 06 / 18 / 2026, page 119 / 249 The 113 / 121 solution was then filtered, and the cake was washed with a 1:1 MeOH / water mixture and dried under suction. The cake was then reloaded into the reactor followed by water. The resulting suspension was heated to 55-65°C and aged at that temperature. The suspension was then cooled to 20-25°C and aged for 30 min before filtration. The cake was then washed with a 1:1 MeOH / water mixture and dried under suction and then in a vacuum oven at 55-60°C. The product, compound 10R, was obtained as a white solid with a yield of 71% (54.8 g) and a purity of 93.2% by weight by NMR, 3.2% by KF, and 99.4% by HPLC. 1H NMR (400 MHz, CDC1a) δ 7.43 -7.35 (m, 2H), 7.00 - 6.92 (m, 2H), 3.56 (dd, J = 32.3, 11.1 Hz, 2H), 3.10 (ddd, J = 19.8, 11.1, 2.7 Hz, 2H), 2.51 - 2.39 (m, 1H), 2.28 (td, J = 13.3, 3.8 Hz, 1H), 2.04 (s, 3H), 1.87 - 1.58 (m, 4H), 1.55 - 1.31 (m, 2H), 0.55 (s, 3H), 0.27 (s, 3H) ppm.

[0216] Preparation of (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one, 11R

[0217] A 2 L jacketed reactor equipped with a cooler, thermocouple, and suspended stirrer was charged with compound 10R (50 g, 93.4% by weight, 0.152 mol) followed by HPLC water (4 V) at room temperature, and stirring was initiated. The resulting suspension was cooled to an internal temperature of 15°C–25°C. Concentrated HCl (12 N, 4 equiv., 50 mL, 0.76 mol) was added to the above suspension, slowly maintaining the temperature below 35°C. The mixture was heated to an internal temperature of 65–75°C and maintained at this temperature for not less than 12 h. The completion of the reaction was monitored by HPLC. The mixture was then cooled to 20–30°C, and the MTBE was charged and stirred for not less than 10 min. The phases were separated, and the aqueous (lower) phase was reloaded into the reactor.A 3N NaOH (aq) solution was then slowly added using an addition funnel, maintaining the internal temperature below 40°C, to bring the pH of the mixture to 12-13 (measured using pH paper). The resulting white suspension was extracted with MTBE. The combined MTBE layers were washed with water. A. Petition 870260059814, dated 06 / 18 / 2026, pp. 120 / 249 The MTBE layer (114 / 121) was checked by 1H NMR for the removal of the neopentyl glycol side product (not more than 10%; if >10%, repeat the washes with water). The MTBE phase was concentrated to 2 V. Additional MTBE was added and concentrated again, and this process was repeated twice. The resulting MTBE phase was diluted with MTBE, and KF was obtained (KF = not more than 0.2%).

[0218] Formation of HCl salt of 11R

[0219] To the above MTBE solution containing the free base compound 11R at room temperature, a 5-6 N HCl solution in IPA (45.48 mL, 0.228 mol, 1.5 equiv.) was added dropwise while maintaining the internal temperature below 30°C, resulting in the formation of a white precipitate. After the addition was complete, the resulting suspension was aged at 20-30°C for at least 12 h. The suspension was then filtered, the cake was washed with MTBE (3 V x 3, displacement washing, cake washing and fluid paste washing) and dried under suction for not less than 30 min. The cake was then dried in a vacuum oven at 35-45°C for not less than 12 h. The product 11R*HCl was obtained as a white solid with a yield of 91% (34.2 g) and a purity of 99.9% by HPLC, 100.1% by weight by HPLC, and 0.152% by KF.1H NMR (400 MHz, DMSO-de) δ 9.81 (d, J = 302.4 Hz, 2H), 7.47 - 7.28 (m, 4H), 2.44 (p, J = 1.9 Hz, 1H), 2.39 - 2.19 (m, 2H), 2.14 (td, J = 13.5, 3.9 Hz, 1H), 2.06 (s, 3H), 1.96 - 1.85 (m, 1H), 1.85 - 1.72 (m, 1H), 1.66 - 1.38 (m, 2H).

[0220] Using HPLC, this product was determined to be more than 99% pure and anhydrous. EXAMPLE 2 Petition 870260059814, dated 06 / 18 / 2026, pp. 121 / 249 115 / 121 o H2N 'f-Bu 4 Ti(OEt)4, Tol, 100 °C THF MeOH HCla3Mem MeOH NaBD4,l2, THF i) HCl cone. I PA, 70°C ii) 2N NaoH (aq) n CD» [DJ-11R [D3]-11R«HCI

[0221] General procedure for the syntheses of 3

[0222] A jacketed reactor equipped with a stirrer and DeanStark apparatus was charged with 1,2-cyclohexanedione (50.0 g, 428 mmol), 2,2-dimethylpropane-1,3-diol (54.0 g, 514 mmol), p-TSA (1.66 g, 8.6 mmol), and cyclohexane (200 mL, 4 V), and the resulting suspension was heated under reflux for 3 h to obtain complete conversion of the starting material. It was then cooled to 20°C and charged with 1N NaOH (aq) followed by MTBE and stirred. The phases were separated, and the aqueous phase was subsequently extracted with MTBE, and the combined organic products were washed once with 10% brine and concentrated. The mixture was azeotropated once with toluene to obtain 113 g (Q-NMR assay: 66%, yield 87.6%). The crude product was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 11.1 Hz, 1H), 3.32 (d, J = 11.1 Hz, 1H), 2.38 - 2.35 (m, 2H), 1.8-1.79 (m, 2H), 1.67-1.63 (m, 4H), 1.06 (s, 3H), 0.55 (s, 3H). Petition 870260059814, dated 06 / 18 / 2026, pp. 122 / 249 116 / 121

[0223] General procedure for the syntheses of 5

[0224] A 1 L round-bottom flask equipped with a stirrer was loaded with compound 3 (33.3 g, 60% by weight, 0.101 mol), (R)-t-Bu-Sulfinamide (14.62 g, 0.121 mol), toluene (80 mL), and Ti(OEt4) (25.31 mL, 0.121 mol) at room temperature. The mixture was heated to 80°C for 5–6 h followed by cooling to room temperature to obtain a dark solution. EDTE (47.5 g, 2 equiv.) was added to this solution, and the mixture was heated to 55°C for 60 minutes followed by cooling to room temperature. 12% NaCl (aq) was added to the above solution, stirred for about 5 minutes, and allowed to stand. The phases were separated, and the aqueous phase was re-extracted with toluene. The combined organic products were washed with water. The organic phase was filtered through an activated carbon and SO2 plug and concentrated to obtain the crude product as a yellow-orange semisolid (18.9 g of liquid product by NMR, % by weight, 63%).The product crystallized as a whitish solid after settling, which was filtered and taken to the next step. 1H NMR (400 MHz, CDCla) δ 3.83 (d, J = 11.0 Hz, 1H), 3.72 (d, J = 11.0 Hz, 1H), 3.44 - 3.38 (m, 2H), 3.13 - 3.07 (m, 1H), 2.89-2.83 (m, 1H), 1.98-1.85 (m, 1H), 1.81-1.71 (m, 1H), 1.31 (s, 9H), 1.21 (s, 3H), 0.72 (s, 3H).

[0225] General procedure for 7R syntheses

[0226] To a stirred solution of compound 6 (17.5 g, 58.0 mmol) in THF (70 mL) at -5°C, a 1 M solution of 4-F-phenylmagnesium bromide in THF (116 mL, 116 mmol, 2 equiv.) was added dropwise. The resulting reaction mixture was stirred at -5°C for 4 h followed by room temperature for 14 h. TLC (50% EtOAc / hexanes) indicated complete conversion of the starting material. The reaction mixture was then cooled to 0°C and saturated aqueous NH4Cl (70 mL) was added dropwise. After heating to room temperature, the aqueous phase was extracted with MTBE and the combined organic layer was washed with water and then dried over Na2SO4. Evaporation of the solvent yielded the crude product which was Petition 870260059814, dated 06 / 18 / 2026, pp. 123 / 249 117 / 121 again mixed with heptane followed by filtration to give compound 7 (18.24 g, 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.72 - 7.68 (m, 2H), 6.98 - 6.94 (m, 2H), 4.51 (s, 1H), 3.67-3.60 (m, 2H), 3.35 (dd, J = 11.3 Hz and 2.6 Hz, 1H), 3.27 (dd, J = 11.3 Hz and 2.5 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.33 - 2.27 (m, 1H), 2.05-2.01 (m, 1H), 1.98-1.88 (m, 1H), 1.76-1.66 (m, 1H), 1.62-1.45 (m, 2H), 1.17 (s, 9H), 0.84 (s, 3H), 0.69 (s, 3H).

[0227] General procedure for 8R syntheses

[0228] To a suspension of compound 7 (45.0 g, 113 mmol) in methanol (180 mL) at 0°C, a 3 M HCl solution in methanol (113 mL, 339 mmol, 3 equiv.) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12–14 h. After completion of the reaction, the mixture was cooled to 0°C and saturated aqueous NaHCOa (225 mL) was added dropwise. CH2Cl2 was added to the resulting suspension to dissolve the product, and the phases were separated. The aqueous phase was extracted with CH2Cl2, and the combined organic products were washed with brine and dried (Na2SO4) and concentrated to give crude compound 8 (27.1 g, 82% quant) as a white solid, which was carried over in the next step without further purification. 1H NMR (400 MHz, CDCla) δ 7.62 - 7.52 (m, 2H), 6.99 - 6.90 (m, 2H), 3.57 (dd, J = 23.4, 11.4 Hz, 2H), 3.16 (ddd, J = 11.2, 8.4, 2.7 Hz, 2H), 2.53 - 2.36 (m, 2H), 1.86 - 1.34 (m, 8H), 0.59 (s, 3H), 0.36 (s, 3H).

[0229] General procedure for the syntheses of [D]-9R

[0230] A mixture of acetic anhydride (1.9 mL, 13.63 mmol) and d3-formic acid (0.54 mL, 13.63 mmol) was stirred at 60°C for 2 h followed by gradual cooling to 0°C. A solution of compound 8 (1.0 g, 3.41 mmol) in CH2Cl2 (5 mL) was then added to the mixture at 0°C, and the mixture was stirred at 0°C for 2 h. TLC (30% EtOAc / hexanes) indicated complete conversion of the starting material. The mixture was then neutralized by adding Petition 870260059814, dated 06 / 18 / 2026, pp. 124 / 249 118 / 121 slow extraction of an aqueous solution of sodium bicarbonate and extracted with CH2CI2. The combined organic products were washed once with saturated NaHCO3 (aq), water followed by brine, dried (Na2SO4), and concentrated to obtain crude [D]-9 (1.1 g, quantitative) as a whitish solid, which was carried out in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.50 - 7.36 (m, 2H), 7.02 6.88 (m, 2H), 6.56 - 6.11 (m, 1H), 3.66 - 3.49 (m, 2H), 3.26 - 3.11 (m, 2H), 2.98 2.87 (m, 1H), 2.71 - 2.52 (m, 2H), 2.42 - 2.29 (m, 1H), 2.11 - 2.00 (m, 1H), 1.71 1.32 (m, 4H), 0.62 - 0.57 (m, 3H), 0.33 - 0.23 (m, 3H).

[0231] General procedure for the syntheses of [Da]-10R

[0232] To a stirring suspension of [D]-9 (1.1 g, 3.42 mmol) and NaBD4 (572 mg, 13.66 mmol) in THF (4 mL) at 0°C, an iodine solution (1.13 g, 4.44 mmol) in THF (2 mL) was added dropwise. The mixture was then allowed to warm at room temperature for 14 h. The mixture was then cooled to 0°C and rapidly cooled with the slow addition of MeOH (2 mL) followed by heating at 40°C for 1 h. The resulting clear solution was then concentrated and treated with MTBE followed by water and 1 N NaOH (aq) to obtain clear phase separation. The MTBE layer was separated, and the aqueous phase was further extracted with MTBE. The combined organic layers were then washed with water followed by brine, dried (Na2SO4), and concentrated. The crude mixture was purified by chromatography on SiO2 (100% hexane to 30-50% EtOAc / hexanes) to obtain [D3]-10 (710 mg, 67%) as a white solid.1H NMR (400 MHz, CDCla) δ 7.45 - 7.32 (m, 2H), 7.02 - 6.90 (m, 2H), 3.56 (dd, J = 32.3, 11.1 Hz, 2H), 3.16 - 3.03 (m, 2H), 2.51 - 2.41 (m, 1H), 2.27 (td, J = 13.3, 3.8 Hz, 1H), 1.86 - 1.57 (m, 4H), 1.55 - 1.31 (m, 2H), 0.55 (s, 3H), 0.26 (s, 3H);

[0233] General procedure for free base syntheses [D3]-11R

[0234] A solution of [D3]-10 (640 mg, 2.6 mmol) in IPA (4 V) at room temperature was added to a solution of concentrated HCl (4 equiv.) and Petition 870260059814, dated 06 / 18 / 2026, pp. 125 / 249 The 119 / 121 mixture was heated to 70°C for 14 h to obtain complete conversion of the starting material. The mixture was then basified with a 3N NaOH (aq) solution and extracted with MTBE. The combined organic products were washed once with water, dried (Na2SO4), and concentrated to obtain crude [D3]-11 (430 mg, 93%) as a colorless oil, which was carried out in the next step without further purification.

[0235] General procedure for the synthesis of [D3]-11R-HCl salts

[0236] A solution of crude free base [D3]-11 (430 mg) in MTBE (5 mL) was added dropwise to a solution of HCl in IPA (1.5 equiv.) at room temperature. A white suspension was observed forming during the addition of the HCl solution. The resulting white suspension was then stirred at room temperature for 12-14 hours. It was then filtered and washed with MTBE (3 x 3 V) to obtain the [D3]-11-HCl salt (420 mg, 84%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.34 (s, 1H), 7.53 - 7.32 (m, 4H), 3.15 (dt, J = 13.8, 3.0 Hz, 1H), 2.45 - 2.27 (m, 2H), 2.16 - 2.03 (m, 1H), 2.02 - 1.79 (m, 2H), 1.72 -1.48 (m, 2H). EXAMPLE 3 Petition 870260059814, dated 06 / 18 / 2026, pp. 126 / 249 120 / 121 i) NaBH4, l2, THF ii) MeOH iii) aq NaOH

[0237] Using the procedures of Example 1 and replacing (S)-t-Bu sulfinamide with (R)-t-Bu sulfinamide, the compounds identified in the diagram above are prepared. EXAMPLE 4 i) HCl conc. IPA, 70oC ii 2N NaOH (aq) Petition 870260059814, dated 06 / 18 / 2026, pp. 127 / 249 121 / 121

[0238] Using the procedures of Example 2 and replacing (S)-t-Busulfinamide with (R)-t-Bu-sulfinamide, the compounds identified in the diagram above are prepared.

[0239] Although certain features of the invention have been illustrated and described herein, many modifications, substitutions, alterations, and equivalents may occur for those skilled in the art. Therefore, it should be understood that the appended claims are intended to encompass all modifications and alterations that fall within the true spirit of the invention. Petition 870260059814, dated 06 / 18 / 2026, pp. 128 / 249

Claims

1 / 57 1. CLAIMS Compound of formula: (ςζ,ζ^η -C(Z8)(Z8)(Z3) Petition 870250053371, dated 06 / 25 / 2025, p. 129 / 188 2 / 120 Petition 870250053371, dated 06 / 25 / 2025, p. 130 / 188 3 / 57 Petition 870250053371, dated 06 / 25 / 2025, p. 131 / 188 4 / 120 CHARACTERIZED by the fact that each Zi is independently H or C1-C6 alkyl; alkyl optionally substituted by one or more halogens or C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkyl or C1-C6 alkoxy;132 / 188 5 / 57 each Z is independently selected from halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Ar is aryl; each Z8 is independently H or D; ex is 0, 1, 2, 3, 4, or 5; with the condition that when Ar is thiophene, x is 0, 1, 2, or 3, and with the additional conditions that the following compounds are excluded: with claim 1, characterized by.

2. Compound, according to the fact that Z6 is C1-C6 alkyl, aryl hydrocarbyl, or C5-C10 cycloalkyl.

3. Compound according to claim 1 or 2, CHARACTERIZED in that Z6 is t-butyl, phenyl, tolyl, or adamantil. Petition 870250053371, dated 06 / 25 / 2025, p. 133 / 188 6 / 120 4. A compound according to any one of claims 1-3, characterized in that each Z1 and Z2 is independently H or C1-C3 alkyl and Z4 and Z5 are independently C1-C3 alkyl.

5. A compound, according to any one of claims 1-4, CHARACTERIZED in that each pair of Z1 and Z2 is the same and each pair of Z3 and Z4 is the same.

6. Compound, according to any one of claims 1-5, CHARACTERIZED in that Z3 is H, D, or C1-C6 alkyl optionally substituted with one or more fluorine or C1-C3 alkoxy groups.

7. Compound, according to any one of claims 1-6, CHARACTERIZED in that Z3 is H or D.

8. A compound, according to any one of claims 1-7, characterized in that Z3 is D when each Z8 is D.

9. Compound according to any one of claims 1-8, CHARACTERIZED in that Ar is phenyl.

10. A compound, according to any one of claims 1-9, characterized in that x is 0, 1, or 2.

11. Compound, according to any one of claims 1-10, CHARACTERIZED in that x is 1 or 2 and each Z is independently halogen, -OZ11, or C1-C10 alkyl.

12. A compound, according to any one of claims 1-11, CHARACTERIZED in that at least one Z is F.

13. Compound, according to any one of claims 1-12, CHARACTERIZED in that Ar is phenyl and at least one Z is F in position 4 of Ar.

14. Compound, according to any one of claims 1-13, CHARACTERIZED in that x is 1 and Z is F. Petition 870250053371, dated 06 / 25 / 2025, p. 134 / 188 7 / 57 15. Compound, CHARACTERIZED by the fact that it has the following formula: Petition 870250053371, dated 06 / 25 / 2025, page 135 / 188 8 / 120 16. Process for preparing a compound of Formula I NH-CZ8Z8Z3SAr(Z)x CHARACTERIZED in that it comprises (a) reacting a compound with a ketal protecting group of formula II with a sulfinamide of formula H2N Z6 in the presence of Ti(OZ7)a(X1)b to form an imine of Formula V (b) reacting the imine of Formula V with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VII (CZ1Z2)II VII (c) reacting the sulfinamide of Formula VII with acid to form the amine Petition 870250053371, dated 06 / 25 / 2025,p. 136 / 188 9 / 57 corresponding to Formula VIII (CZ^n VIII J (d) react the amine of Formula VIII with an acylating agent of Formula Z3COOH or an acid derivative thereof under amide-forming conditions to form the amide of Formula IX with an acyl group C(=O)Z3 (ÇZ!Z2)n IX (e) reduce the acyl group in Formula IX with an acyl-reducing agent under acyl-reducing conditions to form the compound of Formula X (f) deprotect the ketal of the compound of Formula X to form a compound of Formula I; wherein each Z1 is independently H or C1-C6 alkyl; Petition 870250053371, dated 06 / 25 / 2025, p. 137 / 188 10 / 120 each Z2 is independently H or C1-C6 alkyl; C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen;C3 - C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1 - C10 alkyl, C2 - C10 alkenyl, C3 - C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; Each Z8 is H; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C10 alkoxy, or C1-C6 alkyl; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

17. Process for preparing a compound of Formula I: O nh-cz8z8z3 Ar(Z)x CHARACTERIZED in that it comprises Petition 870250053371, dated 06 / 25 / 2025, p. 138 / 188 11 / 57 (a) reacting a compound with a ketal protecting group of formula O II with a sulfinamide of formula H2N in the presence of Ti(OZ7)a(X1)B to form an imine of Formula VA (b) reacting the imine of Formula VA with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIA (c) reacting the sulfinamide of Formula VIIA with acid to form the corresponding amine of Formula VIIIA Petition 870250053371, dated 06 / 25 / 2025,p. 139 / 188 12 / 120 (d) react the amine of Formula VIIIA with an acylating agent of Formula Z3COOH or an acid derivative thereof to form the amide of Formula IXA with an acyl group C(=O)Z3 (e) reduce the acyl group in Formula IXA with an acyl reducing agent to form the compound of Formula XA Petition 870250053371, dated 06 / 25 / 2025, p. 140 / 188 13 / 57 (f) deprotect the ketal of Formula XA to form a compound of Formula I; where Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; each Z is independently halogen (selected from F, Cl, Br, I), OR11, C1-C10 alkyl, C2-C10 alkynyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms,and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C10 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; Each Z8 is H; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4 x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

18. Procedure for preparing the IR Formula compound Petition 870250053371, dated 06 / 25 / 2025, page. 141 / 188 14 / 120 ><.nh-cz8z8z3 O^'Ar(Z)x IR CHARACTERIZED by the fact that it comprises ^ιΖ2)η Q xo (a) reacting a compound with a ketal protecting group of formula O with nh2—s..„z6 a sulfinamide of formula in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VR (CZ!Z2)n VR (b) reacting the imine of Formula VR with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIR (CZ^n VIIR (c) reacting the sulfinamide of Formula VIIR with acid to form the corresponding amine of Formula VIIIR Petition 870250053371, dated 06 / 25 / 2025, p.142 / 188 15 / 57 (ÇZ^n VIIIR (d) react the amine of Formula VIIIR with an acylation agent of Formula Z3COOH or an acid derivative thereof under amide-forming conditions to form the amide of Formula IXR with an acyl group C(=O)Z3 (ÇZjZAn IXR (e) reduce the acyl group in Formula IXR with an acyl-reducing agent under acyl-reducing conditions to form the compound of Formula XR (CZ,Z2)n NH-C(Z8)(Z8)(Z3) Ar(Z): XR (f) deprotect the ketal of Formula XR to form a compound of Formula IR; 25 / 06 / 2025, p.143 / 188 16 / 120 Z3 is H, C1-C6 alkyl optionally substituted by one or more halogens or C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, or halogens; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; Each Z8 is H; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

19. Process for preparing the compound of formula IR NH-CZ8Z8Z3 Ar(Z)x IR CHARACTERIZED by the fact that it comprises Petition 870250053371, dated 06 / 25 / 2025, page. 144 / 188 17 / 57 (a) react a compound with a ketal protecting group of formula O II nh2—s..„Z(S) with a sulfinamide of formula ·· in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VAR VAR (b) react the imine of Formula VAR with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAR VIIAR (c) react the sulfinamide of Formula VIIAR with acid to form the corresponding amine of Formula VIIIAR Petition 870250053371, dated 06 / 25 / 2025,p. 145 / 188 18 / 120 <NH2 ΓΆγ(Ζ)χ VIIIAR (d) reagir a amina de Fórmula VIIIAR com um agente de acilação de Fórmula Z3COOH ou derivado ácido do mesmo para formar a amida de Fórmula IXAR com um grupo acil C(=O)Z3 IXAR (e) reduzir o grupo acil na Fórmula IXAR com um agente redutor de acil para formar o composto de Fórmula XAR 2.NH-C<Z8)(Z8)(Z3) / 'Ar(Z)x XAR (f) desproteger o cetal de Fórmula XAR para formar um composto de Fórmula IAR; em que Z4 é C1-C6 alquil; Petição 870250053371, de 25 / 06 / 2025, pág. 146 / 188 19 / 57 Z5 é C1-C6 alquil; Z3 é H, C1-C6 alquil opcionalmente substituído por um ou mais halogênio ou C1-C6 alcóxi, ou aril opcionalmente substituído por um ou mais C1-C6 alquil, C1-C6 alcóxi, ou halogênio; cada Zé independentemente halogênio (selecionado a partir de F, Cl, Br, I), OZ11, C1 - C10 alquil, C2 - C10 alquenil, C3 - C10 alquinil sem átomos de hidrogênio terminais, CF3, ou OCF3; em que cada Z11 é independentemente selecionado a partir de C1 - C10 alquil, C2 - C10 alquenil,C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; Each Z8 is H; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

20. Process for preparing the compound of Formula IS O ,.NH-C(Z8)(Z8)(Z3) ^Ar(Z)x IS Petition 870250053371, dated 06 / 25 / 2025, p. 147 / 188 20 / 120 CHARACTERIZED by the fact that it comprises (a) reacting a compound with a ketal protecting group of formula O with wrSz, a sulfinamide of formula · in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VS (b) reacting the imine of Formula VS with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIS (CZ1Z2)n VIIS (c) reacting the sulfinamide of Formula VIIS with acid to form the corresponding amine of Formula VIIIS Petition 870250053371, dated 06 / 25 / 2025, p.148 / 188 21 / 57 (CZ!Z2)n θ Ò χνπ2 ^Ar(Z)X; J VIIIS (d) react the amine of Formula VIIIS with an acylating agent of Formula Z3COOH or an acid derivative thereof under amide-forming conditions to form the amide of Formula IXS with an acyl group C(=O)Z3 IXS (e) reduce the acyl group in Formula IXS with an acyl-reducing agent under acyl-reducing conditions to form the compound of Formula XS (CZ,Z2)n C(Z8)(Z8)(Z3) XS (f) deprotect the ketal of Formula XS to form a compound of Formula IXS; where each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Petition 870250053371, dated 06 / 25 / 2025, p.149 / 188 22 / 120 Z3 is H, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; each Z8 is H; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

21. Process for preparing a compound of formula IS: O ,.NH-C(Z8)(Z8)(Z3) XAr(Z)x IS CHARACTERIZED by the suit of Petition 870250053371, dated 06 / 25 / 2025, p. 150 / 188 23 / 57 (a) react a compound with a ketal protecting group of formula O hkSzj with a sulfinamide of formula · in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VAS VAS (b) react the imine of Formula VAS with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAS VIIAS (c) react the sulfinamide of Formula VIIAS with acid to form the corresponding amine of Formula VIIIAS VIIIAS (d) react the amine of Formula VIIIAS with an acylation agent of Formula Z3COOH or an acid derivative thereof to form the amide of Formula IXAS with a Petition 870250053371, dated 06 / 25 / 2025, page.151 / 188 24 / 120 acyl group C(=O)Z3 IXAS (e) reduce the acyl group in Formula IXAS with an acyl reducing agent to form the compound of Formula XAS θ J) V^NH-C(Z8)(Z8)(Z3) \r(Z)x XAS (f) deprotect the ketal of Formula XAS to form a compound of Formula IS; where Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, C1-C6 alkyl optionally substituted by one or more halogens or C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1-C6 alkoxy, or halogens; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkynyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Petition 870250053371, dated 06 / 25 / 2025, p.152 / 188 25 / 57 Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; Each Z8 is H; X1 is halo; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4 x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

22. Process for preparing the compound of Formula IO nh-cz8z8z3 Ar(Z)x CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of formula reacts with a sulfinamide of formula H2N o π ,.^Z6 in the presence of Ti(OZ7)a(X1)b to form an imine of Formula V Petition 870250053371, dated 06 / 25 / 2025, p. 153 / 188 26 / 120 (b) react the imine of Formula V with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VII (CZ!Z2)n VII (c) react the sulfinamide of Formula VII with an acid to form the corresponding amine of Formula VIII (CZ1Z2)n VIII (d) react the amine of Formula VIII with an acylation agent of Formula Z3COOXo or an acid derivative thereof under amide-forming conditions to form the amide of Formula IX with an acyl group C(=O)Z3 Petition 870250053371, dated 06 / 25 / 2025,pg. 154 / 188 27 / 57 IX (e) reduce the acyl group in Formula IX with a deuterated acyl reducing agent under acyl reduction conditions to form the compound of Formula X (CZ!Z2)n θ Jo X ,NH-C(Z8)(Z8)(Z3) Άγ(Z)χ (f) deprotect the ketal of Formula X to form a compound of Formula I; where each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Z3 is H, D, C1-C6 alkyl optionally substituted by one or more halogens or C1-C6 alkoxy, or aryl optionally substituted by one or more C1-C6 alkyl, C1C6 alkoxy, or halogens; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkynyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy,or halogen; Z7 is C1-C4 alkyl; Each Zs is D; Petition 870250053371, dated 06 / 25 / 2025, p. 155 / 188 28 / 120 Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Xi is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3., 23. Process for preparing the compound of Formula I: I nh-cz8z8z3XAr(Z)x CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of formula II reacts with a sulfinamide of formula H2N Z6 in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VA Petition 870250053371, dated 06 / 25 / 2025, page. 156 / 188 29 / 57 (b) react the imine of Formula VA with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIA VIIA (c) react the sulfinamide of Formula VIIA with acid to form the corresponding amine of Formula VIIIA VIIIA (d) react the amine of Formula VIIIA with an acylation agent of Formula Z3COOXo or an acid derivative thereof to form the amide of Formula IXA with acyl group C(=O)Z3 Petition 870250053371, dated 06 / 25 / 2025, p.157 / 188 30 / 120 (e) reduce the acyl group in Formula IXA with a deuterated acyl reducing agent to form the compound of Formula XA (f) deprotect the ketal of Formula XA to form a compound of Formula I; where Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, D, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1C6 alkoxy, or halogens; Each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without hydrogen atoms. Petition 870250053371, dated 06 / 25 / 2025, page 1.158 / 188 31 / 57 terminals, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; each Z8 is D; X1 is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4 x is 0, 1, 2, 3, 4, or 5; Ar is aryl; and since, when Ar is thiophene, x is 0, 1, 2, or 3.

24. Process for preparing the compound of formula IR IR CHARACTERIZED by the fact that OiZ2)nq ;o (a) reacting a compound with a ketal protecting group of formula Petition 870250053371, dated 06 / 25 / 2025, p. 159 / 188 32 / 120 NH,--S..„Z(S with a sulfinamide of formula · in the presence of Ti(OZ?)a(Xi)b to form an imine of Formula VR VR '6 (b) react the imine of Formula VR with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIR (CZ^n VIIR (c) react the sulfinamide of Formula VIIR with an acylation agent to form the corresponding amine of Formula VIIIR J VIIIR (d) react the amine of Formula VIIIR with an acylation agent of Formula Z3COOXo or an acid derivative thereof under amide-forming conditions to form the amide of Formula IXR with an acyl group C(=O)Z3 Petition 870250053371, of 25 / 06 / 2025page. 160 / 188 33 / 57 IXR (e) reduce the acyl group in Formula IXR with a deuterated acyl reducing agent under acyl reduction conditions to form the compound of Formula XR (CZjZ^n Ar(Z), ok NH-C(Z8)(Z8)(Z3) XR (f) deprotect the ketal of Formula XR to form a compound of Formula IR; wherein each Z1 is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Z3 is H, D, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogens; C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without hydrogen atoms terminals, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkynyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy,or halogen; Petition 870250053371, dated 06 / 25 / 2025, p. 161 / 188 34 / 120 Z7 is C1-C4 alkyl; each Z8 is D; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X1 is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

25. Process for preparing the compound of formula IR: IR nh-cz8z8z3 ''Ar(Z)x CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of formula reacts with a sulfinamide of formula NH2 in the presence of Ti(OZ7)a(X1)b to form an imine of formula VAR Petition 870250053371, dated 06 / 25 / 2025, page. 162 / 188 35 / 57 (b) react the imine of Formula VAR with an aryl nucleophilic agent Nu, capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAR VIIAR (c) react the sulfinamide of Formula VIIAR with acid to form the corresponding amine of Formula VIIIAR VIIIAR (d) react the amine of Formula VIIIAR with an acylation agent of Formula Z3COOXo or an acid derivative thereof to form the amide of Formula IXAR with acyl group C(=O)Z3 IXAR Petition 870250053371, dated 06 / 25 / 2025,pg. 163 / 188 36 / 120 (e) reduce the acyl group in Formula IXAR with a deuterated acyl reducing agent to form the compound of Formula XAR; and XAR (f) deprotect the ketal in Formula XAR to form a compound of Formula IR; where Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, D, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1C6 alkoxy, or halogen; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkynyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl,each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; each Z8 is D; X1 is halo; Petition 870250053371, dated 06 / 25 / 2025, p. 164 / 188 37 / 57 Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4 x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

26. Process for preparing the compound of Formula IS O A_NH-C(Z8)(Z8)(Z3) jAr(Z)x IS CHARACTERIZED by the fact that (a) reacting a compound with a ketal protecting group of formula O with a sulfinamide of formula Sz6 ·· in the presence of Ti(OZ7)a(X1)b to form an imine of Formula VS VS (b) reacting the imine of Formula VS with a Nu aryl nucleophilic agent, capable of Petition 870250053371, dated 06 / 25 / 2025,page. 165 / 188 38 / 120 release an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIS (CZ^n VIIS (c) react the sulfinamide of Formula VIIS with acid to form the corresponding amine of Formula VIIIS (ÇZiZ^n J VIIIS (d) react the amine of Formula VIIIS with an acylation agent of Formula Z3COOXo or an acid derivative thereof under amide-forming conditions to form the amide of Formula IXS with an acyl group C(=O)Z3 IXS (e) reduce the acyl group in Formula IXS with a deuterated acyl reducing agent under acyl-reducing conditions to form the compound of Formula XS Petition 870250053371, dated 06 / 25 / 2025, page (ÇZ^n -C(Z8)(Z8)(Z3) XS (f) deprotect the ketal in Formula XS to form a compound of Formula IS; where each Zi is independently H or C1-C6 alkyl; each Z2 is independently H or C1-C6 alkyl; n is 2 or 3; Z3 is H, D,C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogens; each R independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; each Z8 is D; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X1 is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; Petition 870250053371, dated 06 / 25 / 2025, p. 167 / 188 40 / 120 b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4,or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3.

27. Process for preparing a compound of formula: ,.NH-C(Z8)(Z8)(Z3) ^Ar(Z)x IS CHARACTERIZED by the fact that (a) reacting a compound with a ketal protecting group of formula o Z,0 o H2N-§>»Z6 with a sulfinamide of formula in the presence of Ti(QZ?)a(X1)b to form an imine of Formula VAS VAS (b) reacting the imine of Formula VAS with an aryl nucleophilic agent Nu capable of releasing an aryl nucleophilic moiety of formula Ar(Z)x under arylation reaction conditions to form a sulfinamide of Formula VIIAS Petition 870250053371, dated 06 / 25 / 2025, p. 168 / 188 41 / 57 J VIIAS (c) react the sulfinamide of Formula VIIAS with acid to form the corresponding amine of Formula VIIIAS VIIIAS (d) react the amine of Formula VIIIAS with an acylating agent of Formula Z3COOXo or an acid derivative thereof to form the amide of Formula IXAS with an acyl group C(=O)Z3 IXAS (e) reduce the acyl group in Formula IXAS with a deuterated acyl reducing agent to form the compound of Formula XAS ;NH-C(Z8)(Z8)(Z3) \r(Z)x XAS Petition 870250053371, dated 06 / 25 / 2025, p. 169 / 188 42 / 120 (f) deprotect the ketal in Formula XAS to form a compound of Formula IS; where Z4 is C1-C6 alkyl; Z5 is C1-C6 alkyl; Z3 is H, D, C1-C6 alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1C6 alkoxy, or halogens; each Z is independently halogen (selected from F, Cl, Br, I), OZ11, C1-C10 alkyl, C2-C10 alkynyl, C3-C10 alkynyl without terminal hydrogen atoms, CF3, or OCF3; wherein each Z11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl without terminal hydrogen atoms, and aryl that is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen;Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbyl aryl, or hydrocarbyl ar(C1-C3) alkyl, each of which may be unsubstituted or substituted by one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z7 is C1-C4 alkyl; each Z8 is D; X1 is halo; Xo is H or D; a is 0, 1, 2, 3, or 4; b is 0, 1, 2, 3, or 4; a+b=4; x is 0, 1, 2, 3, 4, or 5; and Ar is aryl; provided that, when Ar is thiophene, x is 0, 1, 2, or 3. Petition 870250053371, dated 25 / 06 / 2025, p. 170 / 188 43 / 57; 28. Process, according to any one of claims 16-27, CHARACTERIZED in that Z6 is C1-C6 alkyl, hydrocarbyl aryl or C5-C10 cycloalkyl.

29. Process, according to any one of claims 16-28, CHARACTERIZED in that Zi and Z2 are independently H or C1-C3 alkyl and Z4 and Z5 are independently C1-C3 alkyl.

30. Process, according to any one of claims 16-29, CHARACTERIZED in that each pair of Z1 and Z2 is the same and each pair of Z4 and Z5 is the same.

31. Process, according to any one of claims 16-30, CHARACTERIZED in that Z3 is H or C1-C6 alkyl optionally substituted by one or more fluorine or C1-C3 alkoxy.

32. Process, according to any one of claims 16-31, CHARACTERIZED in that Ar is phenyl.

33. Process, according to any one of claims 16-32, CHARACTERIZED in that x is 0, 1, or 2.

34. Process, according to any one of claims 16-33, CHARACTERIZED in that x is 1 or 2 and each Z is independently halogen, -OZ11, or C1-C10 alkyl.

35. Process, according to any one of claims 16-34, CHARACTERIZED in that at least one Z is F.

36. Process, according to any one of claims 16-35, CHARACTERIZED in that Ar is phenyl and at least one Z is F in position 4 of Ar.

37. Process, according to any one of claims 16-36, CHARACTERIZED in that x is 1 and Z is F. Petition 870250053371, dated 06 / 25 / 2025, pp. 171 / 188 44 / 120 38. Process, according to any one of claims 16-37, CHARACTERIZED in that Ti(OZ7)a(X1)b is Ti(OEt)4, Ti(OiPr)4, TiCl(OiPr)3, or TiCl2(OiPr)2.

39. Process, according to any one of claims 16-38, CHARACTERIZED in that Nu is Ar(Z)xMgX or Ar(Z)xLi, where X is halo.

40. Process, according to any one of claims 16-39, CHARACTERIZED in that Nu is Ar(Z)xMgX, where X is halo.

41. Process, according to any one of claims 16-40, CHARACTERIZED in that the amine is formed by reacting sulfinamide in a polar protic solvent with nitric acid, sulfuric acid, trifluoroacetic acid, para-toluenesulfonic acid, or HX3, wherein X3 is a halide.

42. Process, according to any one of claims 16-41, CHARACTERIZED in that deketalization occurs in the presence of a protic acid.

43. Process, according to any one of claims 22-42, CHARACTERIZED in that Z3 is H or D.

44. Process according to claim 43, CHARACTERIZED in that Z3 is D.

45. Process according to claim 43, CHARACTERIZED in that Z3 is H.

46. ​​Process, according to any one of claims 16-45, CHARACTERIZED in that O is the protected ketal and is prepared by reacting with HOOH in the presence of acid.

47. Process for forming the compound: Petition 870250053371, dated 06 / 25 / 2025, p. 172 / 188 45 / 57 11-HCl, CHARACTERIZED by the fact that (a) a compound with a ketal protecting group in the OS structure reacts with a sulfinamide of the H2N ^f-Bu structure in the presence of Ti(OEt)4 to form an imine (b) the imine reacts with an organometallic compound of the structure under Grignard coupling conditions to form a sulfinamide Petition 870250053371, dated 06 / 25 / 2025, p. 173 / 188 46 / 120 (c) react sulfinamide 7 with acid to form the corresponding amine (d) react amine 8 with an acylating agent of formula HCOOH or an acid derivative thereof under amide-forming conditions to form the amide (e) reduce the acyl group in 9 with an acyl-reducing agent to form the compound (f) deprotect the ketal of 10 to form compound 11 and then acidify 11 with HCl to form compound 11 - HCl.

48. Process for forming the compound: Petition 870250053371, dated 06 / 25 / 2025, p. 174 / 188 47 / 57 11R-HCI CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of structure reacts with a sulfinamide of structure O(R)II h2n r-Bu in the presence of Ti(OEt)4 to form an imine 5R (b) the imine 5R reacts with an organometallic compound of structure under Grignard coupling conditions to form a sulfinamide 7R (c) the sulfinamide 7R reacts with acid to form the corresponding amine Petition 870250053371, dated 06 / 25 / 2025, p. 175 / 188 48 / 120 8R (d) react the amine 8R with an acylating agent of formula HCOOH or an acid derivative thereof under amide-forming conditions to form amide 9R react the acyl group in 9R with an acyl-reducing agent to form compound 10R (f) deprotect the ketal of 10R to form compound 11R and then acidify 11R with HCl to form compound 11R-HCl 49. Process for forming the compound: Petition 870250053371, dated 06 / 25 / 2025, pp. 176 / 188 49 / 57 CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of structure O(S)II Tis reacts with a sulfinamide of structure in the presence of Ti(OEt)4 to form an imine I <s>a ------ / -Bu 5S (b) react the 5S imine with an organometallic compound of the structure under Grignard coupling conditions to form a 7S sulfinamide (c) react the 7S sulfinamide with acid to form the corresponding amine Petition 870250053371, dated 06 / 25 / 2025, p. 177 / 188 50 / 120 (d) react the 8S amine with an acylating agent of Formula HCOOH or an acid derivative thereof under amide-forming conditions to form the amide (e) react the acyl group in 9S with an acyl-reducing agent under acyl-reducing conditions to form the compound (f) deprotect the ketal of 10S to form the 11S compound and then acidify 11S with HCl to form the 11S-HCl compound.

50. Process for forming the compound: Petition 870250053371, dated 06 / 25 / 2025, p. 178 / 188 51 / 57 CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of structure OS reacts with a sulfinamide of structure H2N ^f-Bu in the presence of Ti(OEt)4 to form an imine (b) imine 5 reacts with an organometallic compound of structure under Grignard coupling conditions to form a sulfinamide (c) sulfinamide 7 reacts with acid to form the corresponding amine Petition 870250053371, dated 06 / 25 / 2025, p. 179 / 188 52 / 120 (d) react amine 8 with a deuterated acylating agent of formula DCOOD or deuterated acid derivative thereof under amide-forming conditions to (e) react the acyl group at [D]-9 with a deuterated acyl-reducing agent under acyl-reducing conditions to form compound (f) deprotect the ketal at [D3]-10 in the presence of acid, then treat the resulting product with base to form compound [D3]-11.

51. Process for forming the compound: [D3]-11R Petition 870250053371, dated 06 / 25 / 2025, p. 180 / 188 53 / 57 CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of structure ORIs reacts with a sulfinamide of structure H2N, / z-Bu in the presence of Ti(OEt)4 to form an imine (b) the imine 5R reacts with an organometallic compound of structure under Grignard coupling conditions to form a sulfinamide 7R (c) the sulfinamide 7R reacts with acid to form the corresponding amine Petition 870250053371, dated 06 / 25 / 2025, p. 181 / 188 54 / 120 8R (d) react the amine 8R with a deuterated acylating agent of formula DCOOD or an acid derivative thereof under amide-forming conditions to form the amide acyl-reducing conditions to form the compound [D3]-10R (f) deprotect the ketal in [D3]-10R in the presence of acid, then treat the resulting product with base to form the compound [D3]-11R.

52. Process for forming the compound: [D3]-11S Petition 870250053371, dated 06 / 25 / 2025, p. 182 / 188 55 / 57 CHARACTERIZED by the fact that (a) a compound with a ketal protecting group of structure reacts with a sulfinamide of structure O H2N >-Bu in the presence of Ti(OEt)4 to form an imine (b) the 5S imine reacts with an organometallic compound of structure under Grignard coupling conditions to form a 7S sulfinamide (c) the 7S sulfinamide reacts with acid to form the corresponding amine Petition 870250053371, dated 06 / 25 / 2025, p. 183 / 188 56 / 120 (d) react the 8S amine with a deuterated acylating agent of formula DCOOD under amide-forming conditions to form the amide [D]-9S (e) reduce the acyl group in [D]-9S with a deuterated acyl-reducing agent under acyl-reducing conditions to form the compound Me. Me [D3]-10S (f) deprotect the ketal in [D3]-10S in the presence of acid, then treat the resulting product with base to form the compound [D3]-11S.

53. Process, according to any one of claims 50-52, CHARACTERIZED in that the deuterated acyl reducing agent is NaBD4 or LiAlD4.

54. Process, according to any one of claims 47-53, CHARACTERIZED in that it is prepared by reacting with HO OH in the presence of acid. Petition 870250053371, dated 06 / 25 / 2025, pp. 184 / 188 57 / 57 55. Process, according to any one of claims 16-54, CHARACTERIZED in that the deprotection step is conducted in concentrated hydrochloric acid in water. Petition 870250053371, dated 06 / 25 / 2025, pp. 185 / 188< / s>