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

Abstract

The present disclosure provides a compound of formula I The present disclosure relates to a method for making the compound of formula JPEG2026501636000311.jpg21170 and an enantioselective synthesis for preparing its S or R isomer. The present disclosure also relates to intermediates in the method.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 435,800, filed December 28, 2022, and U.S. Patent Application No. 63 / 471,091, filed June 5, 2023, the contents of both of which are incorporated by reference.

[0002] The present disclosure relates to a novel synthesis of 2-aminocyclohexan-1-one derivatives useful in the treatment of psychiatric disorders. [Background technology]

[0003] U.S. Pat. No. 11,344,510, the contents of which are incorporated by reference, describes, in part, compounds of the following formula: [ka] A compound having or a pharmaceutically acceptable salt thereof (wherein R1 is phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, or a group represented by the following general formula: [ka] and wherein when R1 is phenyl, R2 and R3 are independently selected from H, C D3, branched or cyclo C3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; wherein R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; wherein D represents a deuterium-enriched H moiety; with the proviso that one or more of R2 and R3 are different from H; or R2 and R3 are independently selected from C2-C10 alkyl; C2-C10 haloalkyl, -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 form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyl or interrupted by one or more additional nitrogen or oxygen atoms; where R1 is the general formula [ka] When it is a part of R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; with the proviso that one or more of R2 and R3 is different from H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyls and may be interrupted by one or more additional nitrogen or oxygen atoms; wherein R6, R7, R8, R9, and R 10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), -OR, C-C alkyl, C-C alkenyl, C-C alkynyl, CN, CF, OCF, NO, -NR, -SR, -SO, -CO, -C(=O)NR; wherein 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, and -C(=O)heteroaryl; However, R6~R 10 one or more of R6 is different from H; or with the proviso that R7 to R10 is H, or R7 is Cl, and R6, R8 to R 10 is H, and when R2 or R3 is H, the other R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; or However, R7 is OH, and R6, R8 to R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is a straight chain or branched C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; or provided that R6, R7, or R8 is OMe, and R6 to R 10 and the other is each H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; wherein R1 is each one or more of OH, halogen (selected from F, Cl, Br, and I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -S02R23, -C02R24, and -C(=O)NR25R26, wherein R19, R20, R21, R22, R23, R24, R25, and R26 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, and C(=O)heteroaryl; wherein 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 form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyls and interrupted by one or more additional nitrogen or oxygen atoms.

[0004] U.S. Pat. No. 11,344,510 describes, in part, compounds having the general structure (A) useful for treating psychiatric disorders: [ka] wherein R1 is selected from the group consisting of phenyl, optionally substituted thiazole, optionally substituted thiophene, optionally substituted pyridine, a moiety of general formula (B); Wherein, when R1 is phenyl; R2 and R3 are independently selected from H, CD3, branched or cycloC3 alkyl, C4-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; where D represents a deuterium-enriched H moiety; where at least one of R2 and R3 is other than H; or R2 and R3 are independently selected from C2-C10 alkyl; C2-C10 haloalkyl, -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 form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyls and may be interrupted by one or more additional nitrogen or oxygen atoms; where R1 is a group having the general structure (B): [ka] When it is a part of R2 and R3 are independently selected from H, C1-C10 alkyl, C2-C10 haloalkyl, -R4-O-R5; where R4 is C2-C10 alkylene and R5 is selected from H and C1-C10 alkyl; where at least one of R2 and R3 is other than H; or R2 and R3 together with the nitrogen atom to which they are attached form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyls and may be interrupted by one or more additional nitrogen or oxygen atoms; R6, R7, R8, R9 and R 10 are independently selected from H, OH, halogen (selected from F, Cl, Br, I), —OR, C-C alkyl, C-C alkenyl, C-C alkynyl, CN, CF, OCF, NO, —NR, R, R, R, R, R, R, R, R, and R are each independently selected from H, C-C alkyl, C-C alkenyl, C-C alkynyl, aryl, heteroaryl, —C(═O)H, —C(═O) alkyl, —C(═O) aryl, and —C(═O) heteroaryl; 10 is other than H; where R and R 10 is not a halogen; provided that R7 is Cl and R6, R8 to R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; or However, R7 is OH, and R6, R8 to R 10 is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; or provided that R6, R7, or R8 is OMe, and R6 to R 10 and the other is H, and when R2 or R3 is H, the other of R2 or R3 is C3-C10 alkyl, C2-C10 haloalkyl, or -R4-O-R5; wherein R1 is selected from thiazole, thiophene, and pyridine, each of which may be substituted with one or more of OH, halogen (selected from F, Cl, Br, I), -OR19, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, CN, CF3, OCF3, NO2, -NR20R21, -SR22, -S2R23, -C02R24, -C(=O)NR25R26 (wherein R19, R20, R21, R22, R23, R24, R25, and R26 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, and 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 form a C3-C9 cycloheteroalkyl ring; said ring may be substituted by one or more C1-C10 alkyls and may be interrupted by one or more additional nitrogen or oxygen atoms. or a pharmaceutically acceptable salt or ester of said compound, wherein said compound is enriched in said compound relative to its opposite enantiomer.

[0005] U.S. Patent No. 11,344,510 discloses a method for preparing the compounds disclosed therein. The present disclosure discloses a different and efficient method for preparing the compounds disclosed therein. The present disclosure provides compounds useful for treating psychiatric disorders, such as 2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride and its stereoisomers, such as (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride and (S)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one hydrochloride. [Primary Technology Documents] [Chartered documents]

[0006]

Patent Document 1

Non-licensed literature

[0007]

Non-licensed literature 1

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0008] The present disclosure provides compounds of formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula (a) [ka] The compound having the ketal protecting group of Ti(OZ7)a(X1) b In the presence of Eq. [ka] by reacting with a sulfinamide of formula V [ka] forming an imine of (b) converting the imine of formula V above into a compound of formula Ar(Z) x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VII [ka] forming a sulfinamide of (c) reacting the sulfinamide of formula VII with an acid to give the corresponding sulfinamide of formula VIII [ka] forming an amine of (d) reacting an amine of formula VIII above with an amine of formula ZCOOX under amide-forming conditions o or its acid derivative to give a compound of formula IX having an acyl group C(=O)Z3 [ka] forming an amide of (e) reducing the acyl group in formula IX with an acyl reducing agent under acyl reducing conditions to form a compound of formula X [ka] forming a compound of (f) deprotecting the ketal in the presence of an acid to form a compound of formula I; A method including (In the formula, 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 with one or more halogens, C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyls, C1-C6 alkoxy, or halogens, or Z3 is D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, for example, C4-C10 alkynyl having no terminal hydrogen atoms, CF3, or OCF3; 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atom, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z7 is C1-C4 alkyl; each Z8 is independently H or D; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, or hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which is optionally unsubstituted or substituted with one or more halo, or C1-C6 alkyl, or C1-C6 alkoxy; X1 is a halo; X o 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; Ar is aryl; Nu is an aryl nucleophile capable of delivering an aryl nucleophilic moiety of formula Ar(Z)x, provided that when Z3 and each Z8 is D, the acyl reducing agent is deuterated and has the formula Z3COOX o The acyl group of or its acid derivative is deuterated.

[0009] In another embodiment, Z6 is C1-C6 alkyl or phenyl unsubstituted or substituted with C1-C6 alkyl; Nu is an organometallic compound M, wherein the reaction of M with an imine is carried out under organometallic reaction conditions to form a sulfonamide of formula VII; M is Ar(Z)xMgX or Ar(Z)Li, and Z1, Z2, n, Z3, Z, Z 11 , Z7, Z8, X1, X o , a, b, x, and Ar are as defined hereinabove. In an embodiment, Z is halo and x is 1 or 2, and in another embodiment, Z is F and x is 1 or 2, e.g., x is 1. In a further embodiment, F is in the 4-position (para position of the phenyl ring).

[0010] In another embodiment, the present disclosure provides a method for preparing a compound of formula I herein, comprising: Formula (a) [ka] The compound having the ketal protecting group was reacted with Ti(OZ7) a X 1b In the presence of Eq. [ka] by reacting with a sulfinamide of formula VA [ka] forming an imine of (b) converting the imine of formula VA to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIA [ka] forming a sulfinamide of (c) reacting the sulfinamide of formula VIIA above with an acid to give the corresponding sulfinamide of formula VIIIA [ka] forming an amine of (d) converting an amine of formula VIIIA above into an amine of formula ZCOOX o or its acid derivative to give a compound of formula IXA having an acyl group (C(=O)Z3 [ka] forming an amide of (e) reducing the acyl group in formula IXA with an acyl reducing agent to form formula XA [ka] forming a compound of (f) deprotecting the ketal to form a compound of formula I; A method including (In the formula, 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 alkyls, C1-C6 alkoxys, or halogens; Each Z is independently a halogen (selected from F, Cl, Br, I), -OR 11 , C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, for example, C4-C10 alkynyl having no terminal hydrogen atoms, CF3, or OCF3; 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, for example, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, or C1-C6 alkyl, or C1-C6 alkoxy; Z7 is C1-C4 alkyl; each Z8 is independently H or D; X1 is a halo; X o 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; with the proviso that when Ar is thiophene, x is 0, 1, 2, or 3, and with the proviso that when Z3 and each Z8 is D, the acyl reducing agent is deuterated and has the formula Z3COOX o The acyl group of or its acid derivative is deuterated. Regarding.

[0011] In another embodiment, Z6 is C1-C6 alkyl or phenyl unsubstituted or substituted with C1-C6 alkyl; Nu is an organometallic compound M, wherein the reaction of M with an imine is carried out under organometallic reaction conditions to form a sulfonamide of formula VII; M is Ar(Z)xMgX or Ar(Z)Li, and Z4, Z5, n, Z3, Z, Z 11 , Z7, Z8, X1, X o , a, b, x, and Ar are as defined hereinabove. In an embodiment, Z is halo and x is 1 or 2, and in another embodiment, Z is F and x is 1 or 2, e.g., x is 1. In a further embodiment, F is in the 4-position (para position of the phenyl ring).

[0012] Another aspect of the present disclosure is a compound of formula I, wherein Ar is phenyl substituted with fluoro. [ka] 1. A method for preparing a compound of formula (I), comprising: Formula (a) [ka] is reacted with t-butylsulfinamide in the presence of Ti(OEt) to form a compound of formula V [ka] forming an imine of (b) reacting an imine of formula V above with an imine of formula: [ka] by reacting with a Grignard reagent of formula VII: [ka] forming a sulfinamide product of (c) reacting a compound of formula VII with an acid to form a compound of formula VIII: [ka] and forming an amine of (d) reacting an amine of formula VIII above with an amine of formula ZCOOX under amide-forming conditions o or its acid derivative to give a compound of formula IX having an acyl group C(=O)Z3 [ka] forming an amide of (e) reducing the acyl group in formula IX with an acyl reducing agent under acyl reducing conditions to form a compound of formula X [ka] forming a compound of (f) deprotecting the ketal to form a compound of formula I; A method including (In the formula, 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 with one or more halogens, C1-C6 alkoxy, C1-C6 alkyl, or aryl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen, or Z3 is D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11, C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, for example, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; each Z8 is independently H or D; X is halo; X o is H or D; g is 0, 1, 2, 3, or 4; provided that when Z3 and each Z8 is D, the acyl reducing agent is deuterated and has the formula Z3COOX o The acyl group of or its acid derivative is deuterated. In an embodiment, g is 0 or 1 or 2, in another embodiment, g is 0 or 1, and in a further embodiment, g is 0, i.e., Z g is H.

[0013] In another embodiment, the present disclosure relates to the synthesis of the corresponding enantiomeric compounds of formula I, i.e., the R and S isomers, as described herein below. Additionally, the present disclosure also relates to novel intermediates, racemates, and both the R and S stereoisomers, as described herein below.

[0014] In another embodiment, the present disclosure provides a compound of the formula: [ka] or the ketal of its R or S stereoisomer, respectively, in the presence of an acid, or by first deprotecting the ketal group of formula X or its R or S stereoisomer, respectively, and then treating the deprotected product with an acid, wherein Z1, Z2, each Z8, Z3, Z, n, and g are as defined herein.

[0015] In another embodiment, the present disclosure provides a compound of the formula: [ka] In another embodiment, the present disclosure relates to a compound having the formula: [ka] The present invention relates to the R isomer of the hydrochloride salt described herein above having the formula:

[0016] In another embodiment, the present disclosure relates to the compound R-11-HCl in solid form.

[0017] In still further embodiments, the present disclosure provides a compound of the formula: [ka] The present invention relates to a compound having the formula:

[0018] In still further embodiments, the present disclosure provides a compound of the formula: [ka] The present invention relates to the compound

[0019] In another embodiment, the present disclosure provides a compound of the formula: [ka] However, in another embodiment, the present disclosure relates to compounds of the formula: [ka] The present invention relates to the compound DETAILED DESCRIPTION OF THE INVENTION

[0020] The features and other details of the present disclosure will be more specifically described. Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims will be summarized here. These definitions should be read in light of the remainder of the disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0021] The compounds disclosed herein may contain at least one asymmetric center. When stereoisomers are specifically designated, these centers are specifically designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral atom. However, when stereochemistry is not specified, structures are drawn without indicating stereochemistry, and these structures are racemic mixtures. Unless otherwise indicated in the structural formula, it should be understood that the present disclosure encompasses all possible stereochemically isomeric forms to the extent possible, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparation of a mixture of enantiomeric products followed by separation, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatography column, or any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Furthermore, the compounds disclosed herein may exist as geometric isomers. The present disclosure contemplates all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as appropriate mixtures thereof. Furthermore, the compounds may exist as tautomers, with all tautomeric isomers being provided by the present disclosure. Furthermore, the compounds disclosed herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and mixtures of such solvents. In general, unless otherwise specified, solvated forms are considered equivalent to unsolvated forms.

[0022] Compounds of a general formula without a stereochemistry designation are designated by Roman numerals, e.g., I, II, III, IV, V, X, etc. Compounds designated by Roman numerals also represent compounds without a stereochemistry designation that have a cyclic ketal as a protecting group. When the carbonyl protecting group is an acyclic ketal, it is designated with "A." For example, open-chain ketals as protecting compounds for carbonyl moieties in molecules are designated, e.g., VA, XA, etc. When a stereochemistry is designated, the compound is designated with the letter R or S depending on the configuration around the asymmetric carbon present therein, depending on whether the compound is an R or S stereoisomer. For example, a compound of formula IR refers to a compound of formula I in which the asymmetric carbon atom present therein is in the R configuration, and a compound of formula IS refers to a compound of formula I in which the asymmetric carbon atom present therein is in the S configuration. As another example, a compound designated as compound VAS refers to a compound of formula VA having an acyclic ketal in the S configuration.

[0023] In some embodiments, the compositions prepared herein may be enriched in a particular enantiomer of any compound disclosed herein relative to the corresponding opposite enantiomer of that compound, such that the mixture is not racemic. In such cases, the target mixture of isomers has an enantiomeric excess, which is understood to have an optical purity of >0%. The enantiomeric excess or optical purity of an isomeric mixture may be, for example, >0%, >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%. The enantiomeric excess or optical purity of an isomeric mixture may be, for example, 5-100%, 25-100%, 50-100%, 75-100%, 90-100%, 95-100%, 97-100%, 98-100%, or 99-100%. Thus, for example, contemplated herein are compositions comprising the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer. Furthermore, where a named compound contains one or more chiral centers, the scope of the present disclosure also includes compositions comprising various stereoisomers and diastereomers, including mixtures of various stereoisomers and / or diastereomers or pharmaceutically acceptable salts thereof, in various ratios, as well as compositions comprising one or more stereoisomers and diastereomers, each substantially free of one or more of the other stereoisomers and / or diastereomers. By "substantially free," it is meant that the composition contains, for example, less than 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of a minor enantiomer or diastereomer. For example, the statement that a compound is enantiomerically pure means that the compound is substantially free of other stereoisomers, including any other enantiomers or diastereomers.

[0024] For clarity, in the context of this disclosure, a chemical structure of a compound represented with a particular stereochemical orientation at any particular chiral center, as defined by the wedge and dash notation, is intended to represent the designated stereoisomer of said compound in substantially pure form, or a mixture enriched in the stereoisomer having the designated stereochemical orientation at the defined chiral center over the stereoisomer having the opposite orientation at said chiral center.

[0025] "Pharmaceutically acceptable salts," as used herein, refer to any salt of a compound of formula I or a variant thereof, such as I, IR, or IS, including any pharmaceutically acceptable salts disclosed herein above and below, where the compound is essentially basic and an acidic compound is added thereto to form the salt. The phrase "pharmaceutically acceptable salts," as used herein, refers to a salt of a compound of formula I or a variant thereof, such as IR or IS, as disclosed herein, that is safe and effective for pharmaceutical use in mammals and possesses the desired biological activity. Pharmaceutically acceptable salts include salts of basic groups present in compounds of formula I or a variant thereof, such as IR or IS, as disclosed herein. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salt. Certain compounds disclosed herein can 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 Camille G. Wermuth, VHCA, Verlag Helvetica Chimica Acta, Zurich, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002, pp. vix-374 (ISBN 3-906390-26-8), the contents of both of which are incorporated herein by reference.

[0026] The present disclosure is also intended to include all isotopes of atoms occurring in the compounds disclosed herein. Isotopes include atoms having 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 13 C and 14 Contains C.

[0027] Throughout this application, any designation of a carbon in a structure, when used without further designation, is 12 C. 13 C, or 14 It will be noted that all isotopes of carbon, such as C, are intended to represent. 13 C or 14 Any compound containing C can specifically have the structure of any of the compounds disclosed herein.

[0028] Throughout this application, any designation of hydrogen in a structure, when used without further designation, is 1 H, 2 H, or 3 It will also be noted that all isotopes of hydrogen, such as H, are intended to represent. 2 H or 3 Any compound containing H can specifically have the structure of any of the compounds disclosed herein.

[0029] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, substituting an appropriate isotopically labeled reagent for the non-labeled reagent employed.

[0030] In some embodiments, each D in the chemical structure represents a deuterium-enriched H site, and the level of deuterium-enriched H sites in the compound is between 20-100%, 50-100%, 70-100%, 90-100%, 95-100%, 97-100%, or 99-100%.

[0031] It is understood that the substituents and substitution patterns of the compounds used in the methods of the present disclosure can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by techniques known in the art. When a substituent is itself substituted with two or more groups, it is understood that these multiple groups can be present on the same carbon or on different carbons, so long as a stable structure is obtained.

[0032] In selecting compounds for use in the methods of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e., Z1, Z2, etc., are selected according to well-known principles of linkage of chemical structures.

[0033] The term "about" or "approximately," as used herein, is defined as being within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, in accordance with practice in the art. Alternatively, "about" can mean within 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. "About" and "approximately" are used interchangeably herein.

[0034] The term "Nu" as used herein refers to a "nucleophile." As used herein, the term Nu refers to Ar(Z) as a nucleophile. x

[0023] The term "aryl nucleophile" refers to an aryl nucleophile having a moiety, where Ar is phenyl, and Z and x are as defined herein, of the formula Ar(Z) x It is possible to deliver aryl nucleophilic moieties such as Ar(Z) x The moiety is present in an organometallic molecule, such as an organomagnesium compound, e.g., a Grignard reagent, e.g., MgBrAr(Z) x , or organolithium compounds, such as LiAr(Z) x, or organopotassium, organosodium, or organoaluminum, such as organoaluminates, organocuprates, zinc, tin, etc., or molecules present in nonmetallic compounds, such as Ar(Z) x Organoborates in which the moiety is bonded to the boron atom, or [Ar(Z) x ]4P + Arylphosphonium salts such as tetraarylphosphonium salts having an Ar(Z) moiety are also included. x When describing reactions herein in which Ar(Z) is an aryl nucleophile, the term "Nu" refers to Ar(Z) x is used to represent molecules that exist as aryl nucleophiles.

[0035] The term "alkyl," as used herein, unless otherwise indicated, refers to a saturated, straight-chain or branched hydrocarbon having the number of carbon atoms specified herein, e.g., 1 to 6 carbon atoms. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons of 1 to 6, 1 to 4, or 1 to 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-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.

[0036] The term "alkenyl," as used herein, refers to a branched or unbranched hydrocarbon group having the specified number of carbon atoms and containing at least one double bond, e.g., 2 to 6 carbon atoms and 1 to 3 carbon-carbon double bonds, as defined herein below. In some embodiments, alkenyl refers to a branched or unbranched unsaturated hydrocarbon group having three carbon atoms (C3). In some embodiments, alkenyl refers to a branched or unbranched hydrocarbon group having six carbon atoms (C6). In some embodiments, the term "alkenyl" includes, but is not limited to, vinyl or allyl, 2-methyl-1-pentenyl, 2-propenyl, 1-propenyl, etc.

[0037] The term "alkynyl," as used herein, refers to a branched or unbranched hydrocarbon group having the specified number of carbon atoms and containing at least one triple bond, e.g., 4 to 6 carbon atoms and 1 to 3 carbon-carbon triple bonds, and no terminal hydrogen, as described herein below. In some embodiments, alkynyl refers to a branched or unbranched unsaturated hydrocarbon group having four carbon atoms (C4) without a terminal hydrogen atom. In some embodiments, alkynyl refers to a branched or unbranched hydrocarbon group having six carbon atoms (C6) without a terminal hydrogen atom. Examples include 2-butynyl, 3-pentynyl, 2-penenyyl, 2-ethyl-2-butynyl, and the like.

[0038] The term "alkyne without a terminal hydrogen atom" or similar terms is a term of the art and is understood by those of ordinary skill in the art. As understood by those of ordinary skill in the art, it means: [ka] refers to an alkyne that does not have a moiety.

[0039] The term "cyano," as used herein, refers to a --CN group.

[0040] The term "cycloalkyl" or "carbocyclic group," as used herein, refers to a non-aromatic ring system in which the ring atoms are solely carbon atoms, containing 3 to 14 ring carbon atoms. These terms include, for example, saturated or partially unsaturated cyclic hydrocarbon groups of 3 to 6 or 4 to 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.

[0041] The terms "halo" or "halogen" or "halide" as used herein refer to F, Cl, Br, or I.

[0042] "Z3COOX o The term "acid derivative of" refers to the acid halide, ester, or anhydride thereof.

[0043] The term "ester" refers to an ester of the formula ZCOOZ 12 where Z is as defined herein and Z 12 is C1-C6 alkyl or aryl, and the alkyl and aryl groups are unsubstituted or substituted with halogen, or C1-C6 alkoxy, or arylC1-C6 alkyl, C1-C6 alkyl, aryl, etc.

[0044] The term "anhydrate" refers to a compound of the formula ZCOOCOZ 12 where Z3 and Z 12 is as defined herein. In embodiments, Z 12 has the same definition as Z3.

[0045] 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 having a total of 5 to 14 ring atoms, wherein at least one ring in the system is aromatic, and wherein each ring in the system has 3 to 7 ring atoms. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents that are not reactive with Grignard reagents. Further included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. Additionally, aryl refers to thiophene and benzothiophene.

[0046] In the context of the present disclosure, the term "thiophene" refers to the structure [ka] It should be understood that the term "benzothiophene" refers to a moiety having the formula [ka] This refers to the compound.

[0047] "Hydrocarbylaryl" or its synonyms refers to an aromatic monocyclic or bicyclic ring system having a total of 5 to 14 carbon ring atoms in the aromatic ring, where at least one ring in the system is aromatic and where the ring atoms in the aromatic ring are exclusively carbon atoms. Also included within the scope of hydrocarbylaryl are moieties in which an aromatic ring composed exclusively of carbon ring atoms is fused to a cycloalkyl ring, where the cycloalkyl ring of the ring system contains exclusively carbon atoms and contains 5 to 8 carbon atoms. Also included within the term hydrocarbylaryl group are C1-C6 alkyl groups substituted on the aryl ring, where the alkyl group is a bridging group to another moiety. The term "hydrocarbylaryl" excludes heteroaromatic compounds in which at least one of the ring atoms is other than a carbon atom. Hydrocarbylaryl groups may be unsubstituted or substituted with one, two, or three substituents that are C1-C6 alkyl, halo, or cycloalkyl. Examples of hydrocarbyl aryl compounds are phenyl, naphthyl, anthracenyl, tolyl, indanyl, xylyl, and the like.

[0048] The term hydrocarbyl ar(C1-C3) alkyl refers to a hydrocarbyl aryl group, as defined herein, that is attached to another moiety in the molecule by an alkyl group, as defined herein, containing from 1 to 3 carbon atoms. Examples include benzyl, phenethyl, naphthylmethyl, indanylmethyl, and the like.

[0049] The terms "hydroxy" and "hydroxyl," as used herein, refer to an --OH group.

[0050] The term "acyl," as used herein, refers to the (Z3C=O) group of an organic acid or organic acid derivative thereof having a COOH group.

[0051] The term "ketal" refers to a functional group formed by the substitution of two alkoxy groups at the carbonyl group of a ketone. Ketals are generally formed by the reaction of the carbonyl group of a ketone with two alcohols having 1 to 6 carbon atoms, such as methanol or ethanol, or diols having 2 to 6 carbon atoms, such as ethylene glycol or 2,2-dimethylpropane-1,3-diol, in the presence of an acid under anhydrous conditions.

[0052] As defined herein, an "inert solvent" is a solvent that does not react with either the reactants or the products formed during the reaction. Organic solvents suitable for use in the present disclosure include, but are not limited to, alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, etc.; ketones having 1 to 6 carbon atoms, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; ether solvents having 1 to 6 carbon atoms, such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl t-butyl ether (MTBE), dipropyl ether, diisopropyl ether, etc., or cyclic ethers having 4 to 6 carbon atoms, such as THF, dioxane, etc.; halogenated solvents, such as dichloroethane, dichloromethane, chloroform, etc.; esters having 2 to 10 carbon atoms, such as ethyl acetate, isopropyl acetate, n-propyl acetate, etc.; nitriles, such as acetonitrile, propionitrile, etc.; hydrocarbons having 1 to 10 carbon atoms containing an aryl group, such as toluene, xylene, cyclohexane, heptane, xylene, etc.; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), etc.; and mixtures thereof in various proportions without limitation. The use of suitable solvents includes the use of mixtures of such solvents. The suitability of a particular solvent for a reaction depends on several factors, such as the type of reaction, reactants, products, and reagents used. One of ordinary skill in the art can determine suitable solvents for the reactions described herein.

[0053] As used herein, the term "protic" refers to a proton or hydrogen atom or ion. The term "protic solvent" as used herein refers to a polar liquid compound that has dissociable hydrogen atoms and can form hydrogen bonds with oxygen, fluorine, or nitrogen atoms.

[0054] The term "protic polar solvent," as used herein, refers to a solvent that has at least one OH or NH bond and is miscible with water. Examples include water, methanol, ethanol, ammonia, etc.

[0055] In the reactions described herein below, functional groups can be protected by protecting groups. A protecting group, as defined herein, is a molecular framework introduced at a specific functional group in a molecule containing two or more functional groups to inhibit the reactivity of that specific functional group under the reaction conditions required to modify elsewhere in the molecule. To be useful, a protecting group must meet certain requirements. First, the protecting group must react selectively in good yield to protect the desired functional group and be stable under the reaction conditions used to modify elsewhere in the molecule. Second, the protecting group must be selectively removed in good yield with readily available, preferably non-toxic, reagents under conditions that do not modify other functional groups on the molecule. In embodiments, the protecting group should form a solid derivative without creating new chiral centers and be easily separated from the molecule after the desired modifications have been made to the molecule. Furthermore, the protecting group should have a minimum of additional functional groups to avoid further reactive sites during the process of modifying the molecule.

[0056] As used herein, "Z x " and "Z gThe term "" refers to Z substituents, as defined herein, attached x or g times, respectively, to an aryl ring, such as a phenyl group, where each Z substituent is the same or different, where x is 0, 1, 2, 3, 4, or 5, and g is 0, 1, 2, 3, or 4. For example, when x is 5, the aryl, e.g., phenyl, ring has five Z substituents, where each Z substituent is as defined herein and may be the same or different. When x or g is 4, the aryl, e.g., phenyl, ring has four Z substituents, where each Z substituent is as defined herein and may be the same or different, where the remaining Z substituents on the aryl, e.g., phenyl, ring are hydrogen. When x or g is 3, the aryl, e.g., phenyl, ring has three Z substituents, where each Z substituent is as defined herein and may be the same or different, where the remaining Z substituents on the aryl, e.g., phenyl, ring are hydrogen. When x or g is 2, there are two Z substituents, which may be the same or different, on the aryl, e.g., phenyl, ring, where each Z substituent on the aryl, e.g., phenyl, ring is as defined herein and may be the same or different, and where the remaining Z substituents on the aryl, e.g., phenyl, ring are hydrogen. When x or g is 1, there is only one Z substituent, as defined herein, on the aryl, e.g., phenyl, ring, and the remaining Z substituents on the aryl, e.g., phenyl, ring are hydrogen. When x or g is 0, there are no Z substituents on the ring, and the substituents on the aryl, e.g., phenyl, ring are hydrogen.

[0057] Some compounds described in this disclosure may comprise a moiety [ka] Including, where Z1 and Z2 are as defined herein, and n is 2 or 3. This moiety represents a ketal protecting group formed from HO-(CZ1Z2)n-OH. As used herein, the numbering within the ring is based on the position of the atoms within the ring, regardless of whether the atom is a carbon atom or an oxygen atom. Thus, one of the oxygen atoms within the ring is at the 2-position of the ring, and the carbon atom at the bottom apex is at the 1-position. When n is 2, this moiety represents a ketal protecting group formed from HO-(CZ1Z2)n-OH. As used herein, the numbering within the ring is based on the position of the atoms within the ring, regardless of whether the atoms are carbon atoms or oxygen atoms. Thus, one of the oxygen atoms within the ring is at the 2-position of the ring, and the carbon atom at the bottom apex is at the 1-position. When n is 2, this moiety represents a ketal protecting group formed from HO-(CZ1Z2)n-OH. [ka] where atom numbering is as indicated, and where Z1 and Z2 are the same or different and are defined as described herein.

[0058] When n is 3, this part [ka] where atom numbering is as indicated. It is understood that each Z1 in the above moiety can be the same or different, each Z2 in the above moiety can be the same or different, and Z1 and Z2 can be the same or different. Thus, for example, when n is 3, an embodiment would be: [ka] and where the Z1 and Z2 substituents on the carbon atoms labeled 3 and 5 are both hydrogen, while the Z1 and Z2 substituents on the carbon atom labeled 4 are both methyl.

[0059] As used herein, the term "acyl reducing agent" refers to a compound known in the art that reduces an acyl group, such as ZC=O, to a Z-CH or Z-CD group. Examples include sodium borohydride and iodine; lithium aluminum hydride and iodine; Y[N(TMS)]; lithium triethylborohydride or sodium triethylborohydride in the presence of a silane, such as PhSiH, and an alkali metal base, such as NaOH, KOH, or NaOMe; (EtO)SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; TfO followed by reduction with sodium borohydride and EtZn; TfO in the presence of B(CF) and TMDS; B(CF) in the presence of TMDS; nickel chloride (dme) in the presence of PhSiH; and the like.

[0060] “Formula Z3COOX o As used herein, the term "acylating agent of X" refers to o is H or D, or an acid derivative thereof, such as a halide, ester, or anhydride.

[0061] The term "deuterated acyl reducing agent" or similar terms refers to an acyl reducing agent in which all hydrogen atoms have been replaced by deuterium. Examples include NaBD4, LiAlD4, etc.

[0062] The term "acid derivative" refers to an acid halide, or ester, or anhydride of the referenced acid.

[0063] In this disclosure, references to particular variables maintain the definitions given herein. Thus, for example, Z, when recited herein, refers to the definition of Z given herein.

[0064] In an embodiment, Z1 and Z2 are independently H or C1-C3 alkyl, Z4 and Z5 are independently C1-C3 alkyl, and n, Z, Z3, Z6, Z7, Z8, X1, a, b, x, and Ar are as defined herein.

[0065] In another embodiment, each pair of Z1 and Z2 are the same, and each pair of Z5 and Z4 are the same. In other words, each pair of Z1 and Z2 are substituted on the same carbon. A pair of Z4 and Z5 refers to OZ4 and OZ5 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.

[0066] In further embodiments, Z3 is H, or unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with halogen, or unsubstituted aryl, or aryl substituted with halo or C1-C6 alkyl, or Z3 is D, and n, Z, Z1, Z2, Z4, Z5, Z6, Z7, Z8, X1, a, b, x, and Ar are as defined herein.

[0067] In yet another embodiment, Z3 is H, or Z3 is D and n, Z, Z1, Z2, Z4, Z5, Z6, Z7, Z8, X1, a, b, x, and Ar are as defined herein. Thus, for example, when each Z8 is D, Z3 is D and n, Z, Z1, Z2, Z4, Z5, Z6, Z7, X1, a, b, x, and Ar are as defined herein.

[0068] In an embodiment, Z6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkyl, or C1-C6 alkoxy. In another embodiment, Z6 is C1-C6 alkyl, C3-C6 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo or C1-C6 alkyl. In another embodiment, Z6 is C1-C6 alkyl. In yet another embodiment, Z6 is C1-C4 alkyl. Examples of Z6 include t-butyl, phenyl, tolyl, adamantyl, and the like. In each of these embodiments, n, Z, Z1, Z2, Z3, Z4, Z5, Z7, Z8, X1, a, b, x, and Ar are as defined herein.

[0069] In an embodiment, Ar is hydrocarbylaryl or hydrocarbylar(C1-C3)alkyl, where n, Z, Z1, Z2, Z3, Z4, Z5, Z7, Z8, X1, a, b, x, and Z6 are as defined herein. In another embodiment, Ar is phenyl, where n, Z, Z1, Z2, Z3, Z4, Z5, Z7, Z8, X1, a, b, x, and Z6 are as defined herein.

[0070] In still further embodiments, x is 0, 1, or 2, where n, Z, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, X1, a, b, and Ar are as defined herein.

[0071] In another embodiment, x is 1 or 2 and each Z is independently halogen, -OZ 11 , or C1-C10 alkyl, where n, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, X1, a, b, and Ar are as defined herein.

[0072] In an embodiment, at least one Z is F, and n, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, X1, a, b, x, and Ar, and any additional Z, if present, are as defined herein.

[0073] In still further embodiments, Ar is phenyl, at least one Z is F at the 4-position of Ar, and n, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, X1, a, b, x, and, if present, any additional Z, are as defined herein.

[0074] Further, in embodiments, x is 1, Z is F, and n, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, X1, a, b, and Ar are as defined herein.

[0075] In embodiments, Z6 is alkyl or phenyl unsubstituted or substituted with C1-C6 alkyl, and each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl that is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen, and n, Z1, Z2, Z3, Z4, Z5, Z7, Z8, X1, a, b, x, and Ar are as defined herein.

[0076] In a further embodiment, Z3 is H, D, or C1-C6 alkyl optionally substituted with one or more fluoro or C1-C3 alkoxy, and n, Z, Z1, Z2, Z4, Z5, Z6, Z7, Z8, X1, a, b, x, and Ar are as defined herein.

[0077] The various definitions of variables are applicable to the compounds and methods described herein. Additionally, all of the various permutations of the definitions of variables, including any subset of the definitions provided herein, are contemplated by the present disclosure.

[0078] In embodiments, the present disclosure provides compounds of formula I: [ka] wherein Z, Z, Ar, Z, and x are as defined herein.

[0079] It is prepared by a series of reactions recognized in the art. The starting materials for the reactions described herein are either commercially available or prepared using techniques well known in the art. The starting materials undergo a series of reactions to produce novel intermediates, which in turn undergo a series of reactions to produce compounds of Formula I. The synthesis to prepare compounds of Formula I can occur from any one of the novel intermediates or from the starting materials. The synthesis described first herein is described in reverse without indicating stereochemistry. The synthesis is then described in a forward direction with the preparation of the R and S isomers.

[0080] The final step in the synthesis of compounds of formula I is to prepare a compound of formula X or XA: [ka] Deketalization of the compound wherein Z1, Z2, Z3, Z4, Z5, Z8, Z, Ar, n, and x are as defined herein.

[0081] In embodiments, a compound of formula X or XA undergoes ketal deprotection under conditions known to those of skill in the art to form a compound of formula I. In general, deketalization is a reaction familiar to those of skill in the art. In embodiments, deprotection is often carried out by reacting a compound of formula X or XA under conditions effective to deprotect the ketal and form the corresponding ketone, such as in a protic acid, e.g., HCl, HBr, HI, HSO, HPO, trifluoroacetic acid (TFA), p-toluenesulfonic acid, or under aprotic conditions with a reagent such as indium(III) trifluoromethanesulfonate, sodium tetrakis(3,5-trifluoromethylphenyl)borate, Er(OtF), iodine, perchloric acid adsorbed on silica gel, bismuth nitrate, or the like, in the presence of acetone. The deprotection reaction is carried out in a polar protic solvent, such as water, an alcohol having 1 to 5 carbon atoms, such as methanol, ethanol, isopropanol, propanol, tert-butanol, t-amyl alcohol, ethylene glycol, propylene glycol, or the like, or a combination of a polar protic solvent and an aprotic solvent, such as toluene, fluorobenzene, chlorobenzene, or dichlorobenzene. In an embodiment, the deprotection is carried out in water. In another embodiment, the deprotection is carried out in water to which concentrated hydrochloric acid has been added, i.e., the deprotection is carried out using concentrated hydrochloric acid in water. The reaction is carried out at an effective temperature, such as from about room temperature to the boiling point of the solvent. In an embodiment, sufficient acid is added to form an acid salt. If the reaction produces a salt instead of a free amino compound, then the acid step is followed by basification of the reaction mixture from the acidification step described herein above with a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., so that the resulting pH is about 8 or higher, e.g., about pH 8 to about pH 14, e.g., pH 12 to 13, in order to convert to the free base, e.g., compound of formula I. This is carried out at an effective temperature, e.g., below 40°C, e.g., 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, e.g., dimethyl ether, diethyl ether, methyl ethyl ether, methyl t-butyl ether (MTBE), di(propyl)ether, di(isopropyl)ether, or halogenated solvents, e.g., dichloromethane (methylene chloride) or chloroform, or hydrocarbon solvents, e.g., toluene or benzene, and mixtures thereof. Biphasic hydrolysis, e.g., aqueous base in ethyl acetate and water, or aqueous acid in toluene and water, can affect the formation of the free base, especially when the product is in the organic layer and the reagent is in the aqueous layer. This separation facilitates the isolation of the free base from the reagent. The product is the free base of Compound I.

[0082] Compounds of formula X and XA may be represented by formula IX or formula IXA, respectively. [ka] (wherein Z1, Z2, n, Z3, Z, x, Z4, Z5, and Ar are as defined herein) can be reacted 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, borane N,N-dimethylaniline complex, Li(iPr)2BH3, BEt3;Y[N(TMS)2]3, and HBpin in the presence of an alkali metal base such as NaOH, KOH, NaOMe, etc. lithium triethylborohydride or sodium triethylborohydride in the presence of a silane, such as PhSiH3, and an alkali metal base, such as NaOH, KOH, or NaOMe; (EtO)3SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; reduction with Tf2O followed by sodium borohydride; reduction with Tf2O in the presence of B(CF5)3 and TMDS, B(CF5)3 in the presence of TMDS, nickel chloride (dme) in the presence of PhSiH3, etc. To prepare compounds of formula X or XA where Z3 is D and both Z8' are D, compounds of formula IX or IXA are 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 reaction is carried out in an inert solvent, such as an ether, for example a cyclic ether of 1 to 5 carbon atoms or a carboxylic acid ester of formula Z 27 -OZ 28 in ether at an effective temperature, e.g., where Z 27 and Z 28 are independently a C1 to C6 alkyl group, or Z 27and Z8, together with the oxygen atom to which they are attached, form a cyclic ring of 5 to 6 carbon atoms, wherein one or two of the carbon atoms may be replaced with oxygen, as long as the two oxygen atoms are not adjacent to each other. Examples of ethers that can be used as inert solvents include diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, MTBE, tetrahydrofuran, or 1,4-dioxane; or it can be carried out in other suitable inert solvents, such as chloroform, methylene chloride, etc., and mixtures of these solvents. The reaction is carried out at an effective temperature, such as a temperature ranging from about -20°C to the boiling point of the solvent.

[0083] Compounds of formula IX or IXA may be compounds of formula VIII or VIIIA, respectively: [ka] wherein Z1, Z2, n, Ar, Z, x, Z4, and Z5 are as defined herein, under amide forming conditions with an acylating agent Z3COOX o wherein Z3 is as defined herein and X o is H or D) or its acid derivatives, such as the corresponding acid halides, for example the acid chlorides, the corresponding esters, for example Z3COOZ 12 or acid anhydrides, such as ZC(=O)-OC(=O)Z 12 (wherein, for example, Z 12 is C1-C6 alkyl or aryl, and the alkyl and aryl groups are unsubstituted or substituted with halogen, or C1-C6 alkoxy, or aryl C1-C6 alkyl, C1-C6 alkyl, etc. It is prepared by reacting with

[0084] For example, amide formation can be achieved by reacting an amine of formula VIII or VIIIA with ZC(O)Cl in the presence of an aqueous base such as NaOH or KOH under Schotten-Baumann reaction conditions. Additionally, other acylating or acyl transfer agents known in the art can be used.

[0085] When Z3 is D and both Z8' are D, an amine of formula VIII or VIIIA, respectively, is reacted with DCO2D under amide forming conditions.

[0086] When the amide is formed from a carboxylic acid, the reaction can be carried out in the presence of a coupling agent known in the art, such as a carbodiimide, using, for example, DCC, DIC, CMC, EDC, or other carboxylic acid activating agents, 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 and trichlorotriazine, DIPEA, DABCO, or any other catalyst and dehydrating agent known in the art, under methods effective for amide formation.

[0087] The reaction is carried out in the presence of an inert solvent known to those 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 an ether containing 1 to 6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, or t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene; and mixtures of these solvents. The reaction is carried out at a temperature sufficient to form the amide. In embodiments, the reaction is carried out at a temperature ranging from about 0° C. to the boiling point of the solvent.

[0088] In another embodiment, the acid ZCOOX ois reacted with a compound of Formula VIII or VIIIA in the presence of PPh and NBS and EtN to form a compound of Formula IX or IXA, respectively. In embodiments, the reaction is carried out in an inert aprotic polar solvent such as acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride, or chloroform, or an ether containing 1 to 6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene; and mixtures of such solvents, at a temperature effective to form the amide of Formula IX or IXA, for example, from about 0° C. to room temperature.

[0089] Compounds of formula VIII or VIIIA are formed from the acid hydrolysis of sulfinamides of formula VII or VIIA under amine-forming conditions. [ka] (wherein Z1, Z2, n, Ar, Z6, Z, x, Z4, and Z5 are as defined herein).

[0090] For example, amines of formula VIII or VIIIA can be formed by acid hydrolysis of sulfinamides of formula VII or VIIA, respectively, using, for example, a strong protic acid such as HX1 or nitric acid or sulfuric acid, phosphoric acid or trifluoroacetic acid, or paratoluenesulfonic acid, where X1 is a halide. The reaction is carried out in a polar protic solvent, such as those listed hereinabove, at a temperature sufficient to effect hydrolysis of the sulfinamide to the amine. For example, the reaction can be carried out at a temperature ranging from about 0° C. to the boiling point of the solvent.

[0091] The sulfinamide of formula VII or VIIA has the formula Ar(Z) as defined herein. x are formed by reacting an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula V or VA, respectively, under arylation reaction conditions: [ka] (wherein Z1, Z2, n, Z6, Z4, and Z5, and x are as defined herein). For example, Ar(Z) x Molecules in which the moiety is an organometallic, e.g., organomagnesium compounds, e.g., the Grignard reagent MgBrAr(Z) x , or organolithium compounds such as LiAr(Z) x or organopotassium, organosodium, or organoaluminum, such as organoaluminates, or molecules present with other organometallics, such as organocuppers, zinc, tin, etc., Ar(Z) x Organoborates in which the moiety is bonded to the boron atom, or [Ar(Z) x ]4P + Arylphosphonium salts such as tetraarylphosphonium salts having an Ar(Z) moiety are also included. x An example of a moiety present in an organometallic compound is the compound of the formula Ar(Z). x MgX, Ar(Z) x Li, Ar(Z)xZnX2, InAr(Z)xX molecules are included, where Ar, Z, and x are as defined hereinabove, and X is a halide such as Br or Cl. When organolithium is utilized, the use of additives such as BF3·OEt2, tetramethylethylenediamine (TMEDA), etc., increases the yield. Because aryl nucleophiles react with air and water, the reaction is carried out in an inert atmosphere, such as under nitrogen or an inert noble gas. The reaction can be carried out by condensing Ar(Z) x and the six-membered ring. The reaction is generally carried out in an inert solvent, such as an ether, e.g., dimethyl ether, diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, THF, or 1,4-dioxane, or a hydrocarbon solvent, e.g., toluene, benzene, hexane, or n-heptane, and mixtures thereof, under conditions effective to form the sulfinamide of Formula VII or VIIA, respectively. The reaction can be carried out at an effective temperature for the coupling, e.g., a temperature ranging from about −78° C. to about room temperature when carried out in the organic solvents listed hereinabove.

[0092] Another method for forming sulfinamides is described in the article by Elzbieta Wojaczynska and Jacek Wojaczynski entitled "Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds," Chem. Rev. 2020, 120, pp. 4578-4611, the contents of which are incorporated by reference.

[0093] Other recognized methods for preparing structures such as VIII and VIIIA include the asymmetric addition of alkylmetals to chiral imines such as those containing an alpha-naphthylethyl group as the chiral auxiliary.

[0094] Nucleophiles, Nu, are prepared by art-recognized techniques. For example, Grignard reagents are prepared by treating an aryl halide, such as an aryl bromide or aryl chloride, with an organometallic metal, such as magnesium metal, in the presence of an inert solvent, such as THF, in the absence of water and air. Organolithium compounds are also prepared by art-recognized reactions. For example, aryllithium compounds are formed by reacting an aryl halide with lithium metal.

[0095] Compounds of formula V or VA may be represented by formula III or IIIA, respectively: [ka] wherein Z1, Z2, Z4, Z5, and n are as defined herein, are reacted with a sulfinyl compound [ka] wherein Z6 is as defined herein, and a compound of formula Ti(OZ7) a X 1bwherein Z, a, X, and b are as defined herein, are prepared by reacting a titanium compound of the formula (I) in the presence of a catalyst such as CuSO. Examples of titanium compounds include Ti(OEt), Ti((iOPr), TiCl(OiPr), TiCl(OiPr), and TiCl(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 an ether such as THF or dioxane, diethyl ether, dimethyl ether, t-butyl methyl ester; or a hydrocarbon solvent such as toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, tetrahydrofuran, and the like; and mixtures of these solvents. The reaction is carried out at an effective temperature. In embodiments, the reaction is carried out at from about room temperature to the boiling point of the solvent.

[0096] The compounds of Formula III and Formula IIIA are prepared by art-recognized procedures. Polyhydric alcohols, i.e., polyols, having 1,2 and 1,3 hydroxy conformations can be reacted with ketones to form cyclic ketals. For example, for the preparation of compounds of Formula III, 1,2-cyclohexanedione is reacted with a diol of the formula HO-(CZ1Z2)n-OH, such as ethylene glycol, propylene glycol, or 2,2-dimethylpropane-1,3-diol, in the presence of an acid, such as HCl, HNO3, H2SO4, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, or the like, where n and each of Z1 and Z2 are as defined hereinabove. The reaction is carried out in an inert solvent, such as methylene chloride or chloroform, or an ether, such as THF or dioxane, diethyl ether, dimethyl ether, or t-butyl methyl ester; or a hydrocarbon solvent, such as toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, tetrahydrofuran, or the like; and mixtures of these solvents. The reaction is carried out at an effective temperature, such as from about room temperature to the boiling point of the solvent. During the reaction, water may be removed from the mixture either physically, using a Dean-Stark trap or similar device, or chemically, using a drying agent, such as molecular sieves or a desiccant salt, to drive the equilibrium toward the ketal product.

[0097] Compounds of Formula IIIA are prepared similarly. Instead of using a diol to react with 1,2-cyclohexanedione, alcohols Z5OH and Z4OH are utilized, where Z5 and Z4 are as defined hereinabove. In embodiments, Z5 and Z4 are identical. The reaction is carried out in the presence of an acid catalyst, most typically homogeneous catalysis using a protic acid (Bronsted-Lowry acid). For example, sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, and mixtures thereof are known to catalyze ketal formation. Lewis acids, e.g., aprotic acids, have also been used to catalyze the formation of ketals and acetals from alcohols. For example, Clerici et al., Tetrahedron 54, pp. 15679-90 (1998), used titanium tetrachloride in the presence of ammonia or an amine to affect the reaction of various aldehydes with methanol in the presence of ammonia or an amine.

[0098] The reaction is carried out in an inert solvent, such as cyclohexane, hexane, pentane, petroleum ether, benzene, toluene, ethylbenzene, etc. The reaction is carried out at an effective temperature, such as from about room temperature to the boiling point of the solvent. During the reaction, water may be removed from the mixture using, for example, a Dean-Stark trap or similar device, to drive the equilibrium toward the ketal product.

[0099] Acid addition salts, e.g., pharmaceutically acceptable salts of compounds of Formula I, can be prepared therefrom by standard techniques using a pharmaceutically acceptable acid to form the pharmaceutically acceptable salt. For example, to convert to a halide salt, a compound of Formula I can be 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. The reaction can be carried out in a polar protic solvent, such as water, an alcohol having 1 to 4 carbon atoms, e.g., methanol, ethanol, propanol, isopropanol, or tert-butanol, or a polar solvent, e.g., an ether, e.g., diethyl ether, methyl ethyl ether, methyl tributyl ether, or dipropyl ether, or a cyclic ether, e.g., THF or dioxane, a halogenated solvent, e.g., dichloromethane (methylene chloride) or chloroform, or a hydrocarbon solvent, e.g., toluene or benzene, to produce a pharmaceutically acceptable salt of a compound of Formula I.

[0100] Thus, to summarize the above, starting from 1,2-cyclohexanedione, compounds of formula I are prepared from the cyclic ketal as shown in Scheme 1, or from the acyclic ketal as shown in Scheme II: [ka] [ka] The above procedures can be used to prepare the R and S isomers of formula I, the contents of which are incorporated by reference. For example, the R isomer of the sulfinamide used herein above is [ka] Utilizing IR [ka] The R isomer of formula I is prepared by the procedure designated: where Z, Z, Z, Ar, Z, Z, and x are as defined herein. The procedures described herein above are incorporated by reference.

[0101] formulaIVR [ka] wherein Z6 is as defined hereinabove, is reacted with the R isomer of the sulfinamide designated as a compound of formula Ti(OZ7) a X 1b wherein Z7, a, X1, and b are as defined herein, or CuSO4, in the presence of a titanium compound of formula III [ka] or Formula IIIA [ka] wherein Z1, Z2, n, Z4, and Z5 are as defined hereinabove, to give compounds of the formulae VR and VAR, respectively. [ka] where Z1, Z2, Z4, Z5, Z6, and n 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 one skilled in the art.

[0102] The reaction is carried out in an inert solvent, such as an ether solvent, for example, dimethyl ether, diethyl ether, methyl ethyl ether, methyl t-butyl ether (MTBE), dipropyl ether, diisopropyl ether, etc.; a halogenated solvent, for example, dichloroethane, dichloromethane, chloroform, etc.; a hydrocarbon solvent, for example, toluene, benzene, ethylbenzene, pentane, hexane, cyclohexane, petroleum ether, etc.; and a mixture of these solvents. The reaction is carried out at an effective temperature. In an embodiment, the reaction is carried out at about room temperature to the boiling point of the solvent.

[0103] The imines of formula V and VAR can be reacted with imines of formula Ar(Z) as defined herein under arylation reaction conditions. x to form compounds of formula VIIR and VIIAR, respectively; [ka] where Z, Z, n, Z, Z, Z, and Z, and x are as defined herein. For example, Ar(Z) x Molecules in which the moiety is present in organometallics, such as organomagnesium compounds, e.g., the Grignard reagent MgBrAr(Z) x , or organolithium compounds, such as LiAr(Z) x or organopotassium, organosodium, or organoaluminum, such as organoaluminates, organocuppers, zinc, tin, etc.; or Ar(Z) x Organoborates in which the moiety is bonded to the boron atom, or [Ar(Z) x ]4P + Examples of organometallic compounds include arylphosphonium salts such as tetraarylphosphonium salts having a moiety of the formula Ar(Z) x MgX, Ar(Z) xExamples of suitable nucleophiles include Li, Ar(Z)xZn(X)2, and InAr(Z)xX molecules, where Ar, Z, and x are as defined hereinabove, and X is a halide such as Br or Cl. When organolithium is utilized, the use of additives such as BF3·OEt2, tetramethylethylenediamine (TMEDA), etc., increases the yield. Because aryl nucleophiles react with air and water, the reaction is carried out in an inert atmosphere, such as under nitrogen or an inert noble gas. The reaction proceeds in the presence of Ar(Z) x and a six-membered ring. The reaction is generally carried out in an inert solvent, such as an ether having 1 to 6 carbon atoms, e.g., dimethyl ether, diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, THF, or 1,4-dioxane; or a hydrocarbon solvent, e.g., toluene, benzene, hexane, or n-heptane; or a mixture of such solvents, under conditions effective to form the sulfinamide of Formula VII or VIIA, respectively. The reaction can be carried out at an effective temperature for the coupling, e.g., a temperature ranging from about −78° C. to about room temperature when carried out in the organic solvents listed hereinabove.

[0104] Nucleophiles, Nu, are prepared by art-recognized techniques. For example, Grignard reagents are prepared by treating an aryl halide, such as an aryl bromide or aryl chloride, with an organometallic, such as magnesium metal, in the presence of an inert solvent, such as THF, in the absence of water and air. Organolithium compounds are also prepared by art-recognized reactions. For example, aryllithium compounds are formed by reacting an aryl halide with lithium metal.

[0105] Acid hydrolysis of compounds of formula VIIR or VIIAR produces amines of formula VIIIR and VIIIAR, respectively; [ka] wherein Z1, Z2, n, Ar, Z, x, Z4, and Z5 are as defined herein.

[0106] For example, amines of formula VIIIR or VIIIAR can be formed by acid hydrolysis of sulfinamides 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 paratoluenesulfonic acid, where X1 is a halide. The reaction is carried out in a polar protic solvent, such as those listed herein above, at a temperature sufficient to effect hydrolysis of the sulfinamide to the amine. For example, the reaction can be carried out at a temperature ranging from about 0° C. to the boiling point of the solvent.

[0107] Amines of formula VIIIR and VIIIAR are converted to the corresponding amides of formula IXR and IXAR, respectively, under amide reaction conditions: [ka] wherein Z1, Z2, n, Z3, Z4, Z5, Ar, Z, and x are as defined herein.

[0108] Compounds of formula IX or IXA can be prepared by reacting an 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, Z3COOX, under amide forming conditions. o wherein Z3 is as defined herein and X o is H or D) or its acid derivatives, such as the corresponding acid halides, for example the acid chlorides, the corresponding esters, for example Z3COOZ 12 or acid anhydrides, such as ZC(=O)-OC(=O)Z 12 (wherein, for example, Z 12is prepared by reacting an amine of formula VIII or VIIIA with a C1-C6 alkyl or aryl, where the alkyl and aryl groups are unsubstituted or substituted with halogen, C1-C6 alkoxy, aryl C1-C6 alkyl, or C1-C6 alkyl. For example, amide formation can be achieved by reacting an amine of formula VIII or VIIIA with ZC(O)Cl in the presence of an aqueous base such as NaOH or KOH under Schotten-Baumann reaction conditions. Additionally, other acylating or acyl transfer agents known in the art can be used.

[0109] When Z3 is D and both Z8' are D, an amine of formula VIII or VIIIA, respectively, is reacted with DCO2D under amide forming conditions.

[0110] When the amide is formed from a carboxylic acid, the reaction is carried out under amide forming conditions in the presence of coupling agents known in the art, such as carbodiimides, for example, using DCC, DIC, CMC, EDC, or other carboxylic acid activating agents, 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 and trichlorotriazine, DIPEA, DABCO, or any other catalyst and dehydrating agent known in the art.

[0111] The reaction is carried out in the presence of an inert solvent known to those 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 an ether containing 1 to 6 carbon atoms, such as THF or dioxane, diethyl ether, dimethyl ether, or t-butyl methyl ether; hydrocarbon solvents such as heptane and toluene; and mixtures of these solvents. The reaction is carried out at a temperature sufficient to form the amide. In embodiments, 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 ZCOOX o is reacted with a 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 embodiments, the reaction is carried out in an inert aprotic polar solvent such as acetonitrile, ethyl acetate, isopropyl acetate, methylene chloride, or chloroform, or an ether containing 1 to 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 mixtures of such solvents, at a temperature effective to form the amide of Formula IXR or IXAR, for example, from about 0° C. to room temperature.

[0113] Amides of formula IXR and IXAR are reduced with art-known acyl reducing agents to give compounds of formula XR and XAR: [ka] wherein Z1, Z2, n, Z8, Z3, Ar, Z, Z4, Z5, and x 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, borane N,N-dimethylaniline complex, Li(iPr)2BH3, BEt3 in the presence of an alkali metal base such as NaOH, KOH, NaOMe, etc.; Y[N(TMS)2]3 and HBpin; silanes such as PhSiH3 and alkali Examples of reducing agents include lithium or sodium triethylborohydride in the presence of a metal base such as NaOH, KOH, or NaOMe; (EtO)SiH; 1,1,3,3-tetramethyldisiloxane; 1,2-bis(dimethylsilyl)benzene; TfO followed by reduction with sodium borohydride; TfO in the presence of B(CF) and TMDS; B(CF) in the presence of TMDS; nickel chloride (dme) in the presence of PhSiH. To prepare compounds of formula X or XA where Z is D and both Z' are D, compounds of formula IX or IXA are reacted with a deuterated acyl reducing agent, such as deuterated lithium aluminum hydride of formula LiAlD, and in another embodiment, deuterated sodium borohydride of formula NaBD, both in the presence of iodine. The acyl reduction reaction is carried out in an inert solvent, such as an ether, for example a cyclic ether of 1 to 6 carbon atoms and 1 or 2 oxygen atoms, or a cyclic ether of formula Z 27 -OZ 28 in ether at an effective temperature, where Z 27 and Z 28 are independently a C1 to C6 alkyl group, or Z 27 and Z 28are taken together with the oxygen atom to which they are attached to form a cyclic ring, in which one of the carbon atoms in the ring may be replaced with an oxygen atom, as long as the two oxygen atoms are not 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. The reaction can also be carried out in other suitable inert solvents, such as chloroform, methylene chloride, and mixtures of these solvents. The reaction is carried out at an effective temperature, such as a temperature ranging from about -20°C to the boiling point of the solvent.

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

[0115] In embodiments, a compound of formula XR or XAR undergoes ketal deprotection to form a compound of formula IR under conditions known to those of skill in the art. Those of skill in the art are familiar with this type of deketalization reaction. In embodiments, deprotection is often carried out by reacting a compound of formula XR or XAR under conditions effective to deprotect the ketal and form the corresponding ketone, such as in a protic acid, e.g., HCl, HBr, HI, HSO, HPO, trifluoroacetic acid (TFA), p-toluenesulfonic acid, or under aprotic conditions with a reagent such as indium(III) trifluoromethanesulfonate, sodium tetrakis(3,5-trifluoromethylphenyl)borate, Er(OtF), iodine, perchloric acid adsorbed on silica gel, bismuth nitrate, or the like, in the presence of acetone. The deprotection reaction is carried out in a polar protic solvent, such as water, an alcohol having 1 to 5 carbon atoms, such as methanol, ethanol, isopropanol, propanol, tert-butanol, t-amyl alcohol, ethylene glycol, propylene glycol, or the like, or a combination of a polar protic solvent and an aprotic solvent, such as toluene, fluorobenzene, chlorobenzene, or dichlorobenzene. In an embodiment, the deprotection is carried out in water. In another embodiment, the deprotection is carried out in water to which concentrated hydrochloric acid has been added, i.e., the deprotection is carried out in concentrated hydrochloric acid in water. The reaction is carried out at an effective temperature, such as from about room temperature to the boiling point of the solvent. In an embodiment, sufficient acid is added to form an acid salt. If a salt is formed, the acid step is followed by basification of the reaction mixture from the acidification step described hereinabove with a base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, to a resulting pH of about 8 or higher, e.g., about pH 8 to about pH 14, e.g., pH 12 to 13, to convert the salt to a free base, such as a compound of Formula I. This is carried out at an effective temperature, 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 an ether, e.g., dimethyl ether, diethyl ether, methyl ethyl ether, methyl tributyl ether, dipropyl ether, diisopropyl ether, or MTBE; or a halogenated solvent, e.g., dichloromethane (methylene chloride) or chloroform; or a hydrocarbon solvent, e.g., toluene or benzene. Biphasic hydrolysis, e.g., aqueous base in ethyl acetate and water, or aqueous acid in toluene and water, can affect the preparation of the free amine, especially when the product, i.e., the free amine, is incorporated into the organic layer and the reagent is in the aqueous layer. This separation facilitates the isolation of the free base from the reagent. The product is the free base of compound IR.

[0116] Acid addition salts, e.g., pharmaceutically acceptable salts of a compound of formula IR, are prepared therefrom using a pharmaceutically acceptable acid by standard techniques. For example, to convert to a halide salt, a 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 may be carried out in a polar protic solvent, such as water, an alcohol having 1 to 4 carbon atoms, e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, or tert-butanol, or a polar solvent, e.g., an ether, e.g., diethyl ether, methyl ethyl ether, methyl tributyl ether, or dipropyl ether, a halogenated solvent, e.g., dichloromethane (methylene chloride) or chloroform, or a hydrocarbon solvent, e.g., toluene or benzene, to produce a pharmaceutically acceptable salt of a compound of formula I.

[0117] Thus, to summarize the above, starting from 1,2-cyclohexanedione, compounds of formula IR are prepared from the cyclic ketal as shown in Scheme III, or from the acyclic ketal as shown in Scheme IV: [ka] [ka] [ka] Using the teachings hereinabove, the formula [ka] Using the S-isomer of sulfinamide, The S isomer of formula I, designated IS, can be prepared: [ka] wherein Z, Z, Ar, Z, Z, and x are as defined herein. The procedures and descriptions thereof set forth herein above are incorporated by reference, with the understanding that whenever the R isomer of a sulfinamide appears in the description, the corresponding S isomer of the sulfinamide is substituted for the R isomer of the sulfinamide. Thus, the S isomer of formula IS can be prepared using the following Schemes V (cyclic ketals) and VI (acyclic ketals). [ka] [ka] [ka]

[0118] Another procedure for preparing compounds of formula I is a variation of the scheme after the amine for compounds of formula VIII has been formed. In this variation, the amine, as shown for compounds of formula VIII, is [ka] is subjected to reductive amination with Z3C(=O)Z8 in the presence of a reductive aminating agent known in the art to give the corresponding [ka] Examples include sodium cyanoborohydride (NaBHCN), sodium borohydride, sodium triacetoxyborohydride (NaBH(OAc)), and the like in a reductive amination solvent such as DCE.

[0119] The corresponding enantiomers are isolated from the racemate by techniques known in the art. Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography (HPLC), as well as the formation and crystallization of chiral salts. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 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 Resolutions, p. 268 (EL Eliel, ed., University of Notre Dame Press, Notre Dame, Ind., 1972).

[0120] Alternatively, chemoselective reductive amination can be carried out from compounds of formulas VIIIR and VIIIAR, and VIIIS and VIIIAS with ZC(=O)Z to form the corresponding amines of formulas XR, XAR, XS, and XAS using chemoselective reductive amination agents known to those skilled in the art, such as [RuCl(p-cymene)] / PhSiH, dibutyltin chloride in the presence of phenylsilane, etc. The reaction is carried out in an inert solvent, such as an ether, a cyclic ether, DCM, etc.

[0121] In embodiments, the present disclosure provides a compound of the formula: [ka] Compounds of or a pharmaceutically acceptable salt thereof, comprising the steps of: (a) [ka] is reacted with t-butylsulfinamide in the presence of Ti(OEt) in an inert solvent to give a compound of formula V [ka] and forming an imine of (b) reacting an imine of formula V above with an imine of formula: [ka] with a Grignard reagent of formula VII, wherein X is halo, to form a sulfinamide product of formula VII: [ka] (c) reacting the compound of formula VII with an acid to form the corresponding compound of formula VIII: [ka] and forming an amine of (d) reacting an amine of formula VIII above with an amine of formula ZCOOX under amide-forming conditions o (In the formula, X o is H) or its acid derivative or D to give a compound of formula IX: [ka] and forming an amide of (e) reducing 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 provide a compound of formula X: [ka] forming a compound of (f) deprotecting the ketal of step (e) to form a compound of formula I; a method comprising: 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 H or D; Z3 is hydrogen, alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyls, C1-C6 alkoxys, or halogens, or Z3 is D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is a C1-C10 alkyl, a C2-C10 alkenyl, a C3-C10 alkynyl having no terminal hydrogen atom, or an aryl, and g is 0, 1, 2, 3, or 4.

[0122] In the above reaction scheme, when both Z3 are D and deuterated sodium borohydride in the presence of iodine is used as the acyl reducing agent, a deuterated compound is formed. On the other hand, when a non-deuterated acyl reducing agent is used and non-deuterated acylation is utilized, the non-deuterated product of formula I is produced.

[0123] In an embodiment, Z3 is hydrogen or alkyl having 1 to 6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11is C1 to C10 alkyl, C2 to C10 alkenyl, C4 to C10 alkynyl having no terminal hydrogen atom, or aryl.

[0124] Compounds of formula I have the formula: [ka] can be prepared from the acyclic ketal starting similarly from the compound of formula (I), where the intermediate in the scheme is the corresponding acyclic ketal.

[0125] In another embodiment, the R isomer of the following formula can be prepared using the techniques described hereinabove: [ka] .

[0126] The method is: (a) [ka] with (R)-t-butylsulfinamide in the presence of Ti(OEt) in an inert solvent to give a compound of formula VR [ka] and forming an imine of (b) reacting an imine of formula VR with an imine of formula: [ka] wherein X is halo, to give a Grignard reagent of formula VIIR: [ka] forming a sulfinamide product of (c) reacting a compound of formula VIIR with an acid to form the corresponding compound of formula VIIIR: (d) [ka] and forming an amine of (e) reacting an amine of formula VIIIR above with an amine of formula ZCOOX under amide forming conditions o (In the formula, X o is H or its acid derivative, or X o is reacted with an acylating agent of formula IXR: [ka] and forming an amide of (f) reducing the acyl group (C═O) in formula IXR with sodium borohydride or deuterated sodium borohydride, both in the presence of iodine, to give formula XR: [ka] forming a compound of (g) deprotecting the ketal to form a compound of formula IR; where: Z1 and Z2 are independently H or C1-C6 alkyl; n is 0, 1, 2 or 3; X is halo; Z3 is hydrogen, alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyls, C1-C6 alkoxys, or halogens, or Z3 is D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is a C1-C10 alkyl, a C2-C10 alkenyl, a C3-C10 alkynyl having no terminal hydrogen atom, or an aryl, g is 0, 1, 2, 3, or 4; Each Z8 is independently H or D.

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

[0128] In an embodiment, Z3 is hydrogen or alkyl having 1 to 6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is C1 to C10 alkyl, C2 to C10 alkenyl, C4 to C10 alkynyl having no terminal hydrogen atom, or aryl.

[0129] The compound of formula IR has the formula: [ka] can be prepared from the acyclic ketal starting similarly from the compound of formula (I), where the intermediate in the scheme is the corresponding acyclic ketal.

[0130] In another embodiment, the S isomer of the following formula is prepared using the methodology described herein: [ka] .

[0131] The method is: (a) [ka] is reacted with (S)-t-butylsulfinamide in the presence of Ti(OEt) in an inert solvent to give a compound of formula VS [ka] forming an imine of (b) converting an imine of formula VS above into an imine of formula VI: [ka] wherein X is halo, to give a Grignard reagent of formula VIIS: [ka] forming a sulfinamide product of (c) reacting the compound of formula VIIS with an acid to form the corresponding compound of formula VIIIS: [ka] and forming an amine of (d) reacting an amine of formula VIIIS above with an amine of formula ZCOOX under amide forming conditions o wherein Xo is H or an acid derivative thereof or D, to give an acylating agent of formula IXS: [ka] and forming an amide of (e) reducing the acyl group (C=O) in formula IXS with sodium borohydride or deuterated sodium borohydride, both in the presence of iodine, to give formula XS: [ka] forming a compound of (f) deprotecting the ketal of step (e) to form the IS product; where Z1 and Z2 are independently H or C1-C6 alkyl; n is 0, 1, 2 or 3; Z3 is hydrogen, alkyl optionally substituted with one or more halogens or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyls, C1-C6 alkoxys, or halogens, or Z3 is D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is a C1-C10 alkyl, a C2-C10 alkenyl, a C4-C10 alkynyl having no terminal hydrogen atom, or an aryl, g is 0, 1, 2, 3, or 4; Each Z8 is independently H or D.

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

[0133] In an embodiment, Z3 is hydrogen or alkyl having 1 to 6 carbon atoms or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is C1 to C10 alkyl, C2 to C10 alkenyl, C4 to C10 alkynyl having no terminal hydrogen atom, or aryl.

[0134] The compound of formula IS has the formula: [ka] can be prepared from the acyclic ketal starting similarly from the compound of formula (I), where the intermediate in the scheme is the corresponding acyclic ketal.

[0135] In any of the embodiments of the formulae disclosed herein, Z3 is H, D, or alkyl having 1 to 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 an embodiment, g is 0. In a further embodiment, g is 1 and Z is F, wherein F is at the 4-position of the phenyl ring.

[0136] In an embodiment, n is 2 or 3, and Z1 and Z2 are independently C1-C3 alkyl or H. In a further embodiment, n is 2, and each Z1 and Z2 is hydrogen. In a further embodiment, n is 3, and Z1 and Z2 at the 4-position of the ring are both methyl, and Z1 and Z2 at the 3- and 5-positions of the ring are hydrogen. In another embodiment, n is 3, and the carbon atoms at the 3- and 5-positions are unsubstituted. In another embodiment, Z3 is hydrogen, an alkyl having 1 to 6 carbon atoms, or D. In another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is C1 to C10 alkyl, C2 to C10 alkenyl, C4 to C10 alkynyl having no terminal hydrogen atom, or aryl.

[0137] A further embodiment is a compound of the formula: [ka] 1. A method for forming a compound having the formula: (a) [ka] is reacted with (R)-t-butylsulfinamide in the presence of Ti(OEt) in an inert solvent to give a compound of formula [ka] forming a sulfinamide having the formula: (b) treating the product of step (a) under Grignard forming conditions with a compound of the formula: [ka] by reacting with a Grignard reagent of the formula: [ka] and forming a second sulfinamide product having: (c) reacting the product of step (b) with an acid to form a compound of the formula: [ka] forming an amine having (d) reacting the amine product from step (c) with an acylating agent of formula HCOOH or an acid derivative thereof under amide forming conditions to produce a compound of formula: [ka] forming an amide having (e) reducing the acyl group (C=O) of the product of step (d) with sodium borohydride in the presence of iodine to give a compound of the formula: [ka] forming an amine having (f) deprotecting the product of step (e) in the presence of concentrated HCl and an acid selected from concentrated hydrochloric acid, concentrated hydrobromic acid, concentrated nitric acid, or concentrated sulfuric acid, followed by adding a base and reacting the deprotected product with HCl to form a compound of the formula: [ka] forming a compound of The present invention relates to a method comprising:

[0138] Another embodiment is a compound of the formula: [ka] 1. A method for forming a compound having the formula: (a) [ka] is reacted with (R)-t-butylsulfinamide in the presence of Ti(OEt) in an inert solvent to give a compound of formula [ka] forming a sulfinamide having the formula: (b) treating the product of step (a) under Grignard forming conditions with a compound of the formula: [ka] by reacting with a Grignard reagent of the formula: [ka] and forming a second sulfinamide product having: (c) reacting the product of step (b) with an acid to form a compound of the formula: [ka] forming an amine having (d) reacting the amine product from step (c) with an acylating agent of formula DCOOD to form a compound of formula: [ka] forming an amide product having the formula: (e) reducing the acyl group (C=O) of the product of step (d) with deuterated sodium borohydride in the presence of iodine to give a compound of the formula: [ka] forming an amine having (f) deprotecting 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, reacting the resulting product with a base, and then reacting the resulting product with HX3 (wherein X3 is Br or Cl) to form a compound of the formula: [ka] forming a compound of The present invention relates to a method comprising:

[0139] In various methods described herein, in embodiments, Z6 is alkyl or phenyl unsubstituted or substituted with C1-C6 alkyl. In various methods described herein, in another embodiment, each Z is independently halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen. In the methods described herein, in further embodiments herein, Z6 is alkyl or phenyl unsubstituted or substituted with C1-C6 alkyl, and each Z is independently selected from halogen (selected from F, Cl, Br, I), -OZ 11 , C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atom, CF3, or OCF3; 11 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen. In various methods described herein, in another embodiment, Nu is selected from Ar(Z) x MgX or Ar(Z) xLi, where X is halo, where Z is as defined herein, and x is as defined herein. In various methods described herein, in embodiments, Nu is Ar(Z)MgX, where X is halo, Ar is phenyl, and Z and x are as defined herein. In yet another embodiment, the methods of the present invention exclude the specific methods for preparing [D3]-11R and [D3]-11R·HCl, described in Example 2, starting from 8R to form [D3]-9R, starting from [D3]-9R to form [D3]-10R, and starting from [D3]-10R to form [D3]-11R·HCl either directly therefrom or via [D3]-11R, whether isolated or not.

[0140] In embodiments, the fluorine atom is in the para position on the phenyl ring, for example. In other embodiments, there are no fluorine atoms on the ring, and the phenyl ring can have up to five substituents, as described in the previous section of this specification.

[0141] In embodiments, the present disclosure provides a compound of the formula: [ka] [ka] wherein Z1, Z2, Z3, Z4, Z5, Z8, Z, Ar, x, n, and g are as defined hereinabove.

[0142] In embodiments, the following intermediate compounds may be excluded: [ka] .

[0143] In a further embodiment, the present disclosure provides a compound of the formula: [ka] wherein Z1, Z2, Z3, Z4, Z5, Z, Ar, x, n, and g are as defined hereinabove.

[0144] In embodiments, the following intermediate compounds may be excluded: [ka] .

[0145] In still further embodiments, the present disclosure provides a compound of the formula: [ka] wherein Z1, Z2, Z4, Z5, Z, Ar, x, n, and g are as defined hereinabove.

[0146] In still further embodiments, the present disclosure provides a compound of the formula: [ka] wherein Z1, Z2, Z4, Z5, Z6, Z, Ar, x, n, and g are as defined hereinabove.

[0147] In a further embodiment, the following compounds are excluded: [ka] . In some embodiments, [ka] is also excluded, but not the corresponding S isomer or racemic mixture. In additional embodiments, the racemate [ka] In another embodiment, [ka] and the racemate thereof are further excluded. A further aspect of the present disclosure is a compound of the formula: [ka] wherein Z1, Z2, Z4, Z5, Z6, and n are as defined hereinabove.

[0148] In embodiments, the following compounds are excluded: [ka] In some embodiments, [ka] is excluded, but not the corresponding racemate or the corresponding S enantiomer. [ka] In yet a further embodiment, the racemate and the corresponding S enantiomer of formula [ka] and the corresponding S enantiomers of

[0149] Yet further embodiments of the present disclosure include compounds of the formula: [ka] wherein Z1, Z2, Z4, Z5, and n are as defined hereinabove. In embodiments, the following compounds are excluded: [ka] .

[0150] In an embodiment of the disclosure, the disclosure excludes intermediate compounds disclosed herein in which Z1 and Z2 are hydrogen or both are methyl, n is 2 or 3, and Z3, Z4, Z5, Z6, Z8, Z, Ar, x, and g are absent. In another embodiment, the disclosure excludes compounds in which, when Z1, Z2, Z3, Z5, Z8, Z, Ar, x, n, and g are absent, Z4 and Z5 are both methyl or ethyl, or one is methyl and the other is isopropyl. In another embodiment, the disclosure excludes imine intermediate compounds in which Z6 is t-butyl, Z1 and Z2 are both hydrogen, and n is 2, and imine intermediate compounds in which, when Z3, Z4, Z5, Z6, Z8, Z, Ar, x, and g are absent, Z1 and Z2 are both methyl and n is 3. In another embodiment, the present disclosure excludes compounds where the aryl ring is phenyl, z or g is 1, when Z3, Z4, Z5, Z, and Z8 are absent, Z6 is t-butyl, Z1 and Z2 are both hydrogen, n is 2, and Ar is phenyl substituted with Cl in the ortho position. When the intermediate is an R isomer, Z3 is other than D, F is not at the 4-position of the phenyl ring, and n is other than 3; [ka] teeth, [ka] In an embodiment, the present disclosure provides [ka] Exclude.

[0151] In embodiments, the disclosure excludes the intermediate compounds identified as 5, 7R, 8R, [D3]-9R, and [D3]-10R. In another embodiment, the disclosure excludes 5, 7R, 8R, [D3]-9R, and [D3]-10R, and their enantiomers, including stereoisomers of 7R, such as enantiomers or diastereomers thereof. In further embodiments, the disclosure excludes racemic mixtures containing 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 disclosure is a compound of the formula: [ka] In another embodiment, the present disclosure relates to a compound having the formula: [ka] The present invention relates to the R isomer of the hydrochloride salt described herein above having the formula:

[0153] In another embodiment, the present disclosure relates to the compound R-11-HCl in solid form.

[0154] In still further embodiments, the present disclosure provides a compound of the formula: [ka] The present invention relates to a compound having the formula:

[0155] In still further embodiments, the present disclosure provides a compound of the formula: [ka] The present invention relates to the compound

[0156] In another embodiment, the present disclosure provides a compound of the formula: [ka] However, in another embodiment, the present disclosure relates to compounds of the formula: [ka] The present invention relates to the compound

[0157] Compounds described herein that are deuterated are referred to herein as deuterated analogs.

[0158] The compounds disclosed herein of Formula I, including IR and IS, their deuterated analogs, or pharmaceutically acceptable salts thereof, are useful for treating psychiatric disorders, the utility of which is similar to that described in U.S. Pat. No. 11,344,510, the contents of which are incorporated by reference.

[0159] More specifically, in another aspect, there is provided a method of treating depression or anxiety depression in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof disclosed herein.

[0160] In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is orally administered. For example, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is useful in treating a psychiatric disorder, comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a subject in need thereof. Contemplated psychiatric disorders may include depressive disorders, such as 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 disorders due to another medical condition. The compound of Formula I, IR, IS is useful for treating patients suffering from treatment-refractory depression, e.g., depressive disorders that are unresponsive and / or have not responded to an adequate course of at least one or at least two other antidepressant compounds or therapeutic agents. As used herein, "depressive disorder" includes treatment-refractory depression. In some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, and pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including bipolar disorder and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition. In some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including substance-related disorders, for example, to prevent substance use craving, reduce substance use craving, and / or promote substance use cessation or abstinence. Substance use disorders include abuse of psychoactive compounds, such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, a "substance" or "substances" is a psychoactive compound that can be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco.For example, the methods and compositions can be used to promote smoking cessation or cessation of opioid use.

[0161] In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat psychiatric disorders including anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorders due to another medical condition. In embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat psychiatric disorders including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair pulling disorder), excoriation (skin picking disorder), substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to another medical condition. In some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including trauma and stressor-related disorders, such as reactive attachment disorder, disinhibited interpersonal interaction disorder, post-traumatic stress disorder, acute and stress disorders, and adjustment disorders. In some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including eating behavior disorders and eating disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder.

[0162] Further, in some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof can be used to treat a psychiatric disorder including a neurocognitive disorder, e.g., delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder due to Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder due to traumatic brain injury, substance / medication induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder due to HIV infection, severe or mild neurocognitive disorder due to prion disease, severe or mild neurocognitive disorder due to Parkinson's disease, severe or mild neurocognitive disorder due to Huntington's disease, severe or mild neurocognitive disorder due to another medical condition, and severe or mild neurocognitive disorder due to multiple causes. Further, in some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including neurodevelopmental disorders, e.g., autism spectrum disorders, attention-deficit / hyperactivity disorder, stereotypic movement disorders, tic disorders, Tourette's syndrome, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder. Further, in some embodiments, compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders, including personality disorders, e.g., borderline personality disorder.

[0163] Additionally, in some embodiments, compounds of Formula I, IR, IS, deuterated analogs thereof, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders including sexual dysfunction, e.g., delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genito-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature (early) ejaculation, and substance / medication-induced sexual dysfunction. In some embodiments, compounds of Formula I, IR, IS, deuterated analogs thereof, or pharmaceutically acceptable salts thereof can be used to treat psychiatric disorders including gender dysphoria, e.g., gender dysphoria.

[0164] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof effective to achieve a particular pharmacological and / or physiological effect, or effective to provide a desired pharmacological and / or physiological effect, such as 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 synaptic connectivity or neurogenesis in a particular brain region, or a combination thereof, including, but not limited to, reducing the frequency or severity of sadness or lethargy, depressed mood, anxious or sad feelings, decreased interest in all or almost all activities, significantly increased or decreased appetite causing weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, lack of concentration, and recurring thoughts of death or suicide.

[0165] The term "therapeutic index" as used with respect to any compound of Formula I, IR, IS, its deuterated analogs, and / or pharmaceutically acceptable salts thereof, and associated therapeutic effects and side effects, refers to the ratio of the dose of the compound required to elicit a particular negative side effect to the dose of the compound required to elicit the desired therapeutic effect.

[0166] In some embodiments, the method of using a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof includes treating a psychiatric disorder by administering to a subject in need thereof a pharmaceutical composition comprising about 0.01 mg to about 400 mg of a compound disclosed herein. In some embodiments, the dose may be, for example, about 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, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 25 The dose may be in the range of 0 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, or 100 to 200 mg, and examples thereof include doses of 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.

[0167] In some embodiments, a dosage can include an amount of a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof in the range of, for example, about 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 to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2 mg to 10 mg, including 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 10 mg, 15 ... Illustrative dosages include 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.

[0168] Typically, a dosage of a compound of Formula I, IR, IS, a deuterated analog disclosed herein, or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof once, twice, three times, or four times daily, every other day, every third day, weekly, or monthly. In some embodiments, the dosage is, for example, about 1-400 mg / day, or 1-300 mg / day, or 1-250 mg / day, or 1-200 mg / day, e.g., 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 inhaled administration, such as sprays or mists, of a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, contain a concentration of about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition contains a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, for example, at a concentration of 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 comprises a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, e.g., at a concentration of 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, the pharmaceutical composition is formulated to a total volume of, e.g., about 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0171] Typically, dosages may be administered to a subject once, twice, three times, or four times a day, every other day, every three days, twice a week, once a week, twice a month, or once a month. In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a subject once in the morning or once in the evening. In some embodiments, these above-mentioned compounds may be administered to a subject once in the morning and once in the evening. In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, for example, 50 mg / administration (e.g., 150 mg / day).

[0172] In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or pharmaceutically acceptable salt thereof is administered to a subject at a dose of 25 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is administered to a subject at a dose of 50 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is administered to a subject at a dose of 75 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is administered to a subject at a dose of 100 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is administered to a subject at a dose of 150 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 200 mg / day in one or more doses. In some embodiments, the compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 250 mg / day in one or more doses.

[0173] In some embodiments, the dosage of the compound of Formula I, IR, IS, its deuterated analog, or pharmaceutically acceptable salt 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 times, 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 times, or four times daily. In some embodiments, a subject is administered a total daily dose of 0.01 mg-500 mg of the compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof, once, twice, three times, or four times daily. In some embodiments, the total amount administered to a subject within 24 hours 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, or 600 mg. In some embodiments, a subject can start at a low dose, and the dosage is gradually increased. In some embodiments, a subject can start at a high dose, and the dosage is gradually reduced.

[0174] In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a patient under the supervision of a healthcare provider.

[0175] In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a patient under the supervision of a healthcare provider in a clinic that specializes in the delivery of psychoactive treatments.

[0176] In some embodiments, a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered to a patient under the supervision of a healthcare provider at a dose intended to induce a hallucinatory experience in the subject.

[0177] In some embodiments, administration to a patient under the supervision of a healthcare provider occurs periodically, 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, to maintain therapeutic effect in the patient.

[0178] In some embodiments, the compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof is administered by the patient themselves at home or otherwise away from the supervision of a healthcare provider.

[0179] In some embodiments, self-administration is performed periodically, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month, to maintain therapeutic effect in the patient.

[0180] In some embodiments, the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt may be administered at regular intervals. For example, during treatment, the patient may receive the compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt at intervals of, 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, the compound of Formula I, IR, IS, or its deuterated analog is in the form of a pharmaceutically acceptable salt.

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

[0182] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula I, IR, and / or IS, or a deuterated analog thereof, is 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 delaying the progression of the disease, disorder, or condition, alleviating or reducing symptoms and complications, and / or curing or eliminating the disease, disorder, or condition. The patient being treated is preferably a mammal, in particular a human.

[0184] Accordingly, the present disclosure also relates to pharmaceutical compositions comprising a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant and optionally other therapeutic agents. The adjuvant must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient 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 via an implant. The compositions may be prepared by any method well known in the art of pharmacy.

[0186] Such methods include the step of bringing into association a compound of Formula I, IR, IS, a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, or a combination thereof, with any adjuvants. Adjuvants also include accessory ingredients and include carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, wetting agents, and the like, conventional in the art. Such adjuvants will be appropriately selected in accordance with conventional pharmaceutical practice for the intended form and route of administration.

[0187] Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage units, such as pills, tablets, dragees or capsules, or powders or granules, or as solutions or suspensions. The active ingredient, consisting of a compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt, can also be presented as a bolus or paste. The composition can also be processed into a suppository or enema for rectal administration.

[0188] Tablets may contain an active ingredient compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof, as well as suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow-inducing agents, and melting agents. Gelatin capsules may contain an active ingredient compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof, as well as powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. For oral administration, for example, in tablet or capsule dosage unit form, the active drug ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert 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, glucose or beta-lactose, natural sugars such as 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 compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt is combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats or 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 may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

[0190] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions composed of a compound of Formula I, IR, or IS disclosed herein, its deuterated analog, or a pharmaceutically acceptable salt thereof. Generally, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers, and, if necessary, buffers. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizers. Citric acid and its salts and sodium EDTA may also be used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol. Compositions can be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, prior to use. For transdermal administration, for example, gels, patches, or sprays can be envisioned.

[0191] Compositions or formulations suitable for pulmonary administration, e.g., by nasal inhalation, include fine dusts or mists that may be generated by metered-dose pressurized aerosols, nebulizers, or inhalers. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0192] The compounds used in the methods of the present disclosure 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 a component of a tissue-targeted emulsion.

[0193] The compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts used in the methods of the present disclosure can also be conjugated to soluble polymers as targetable drug carriers or prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or palmitoyl-substituted polyethyleneoxide-polylysine. Furthermore, the compounds of Formula I, IR, IS, or pharmaceutically acceptable salts thereof can be conjugated to biodegradable polymer classes useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0194] The pharmaceutical compositions herein may be provided with immediate-release, delayed-release, sustained-release, or modified-release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles may be combined to create a biphasic or triphasic release profile. For example, pharmaceutical compositions may be provided with immediate-release and sustained-release profiles. Such compositions may be provided as pulsatile formulations, multi-layer tablets, or capsules containing tablets, beads, granules, etc.

[0195] The pharmaceutical compositions herein may be provided with abuse-deterrent features by techniques known in the art, for example, by making tablets that are difficult to crush or difficult to dissolve in water.

[0196] The pharmaceutical compositions described herein may be combined with packaging material containing instructions for use of the composition for the uses described herein.

[0197] The precise dosage and administration regimen of compositions comprising a compound of Formula I, IR, IS, its deuterated analog, or its pharmaceutically acceptable salt 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 particular compound, formulation, route of administration, or the age and condition of the individual subject to which the composition is administered.

[0198] Furthermore, in some embodiments, the pharmaceutical compositions disclosed herein may comprise a single enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutical compositions disclosed herein may comprise a mixture of at least one single enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof with another enantiomer, diastereomer, or structural isomer of a compound of Formula I, IR, IS, its deuterated analog, or a pharmaceutically acceptable salt thereof. In further embodiments, the mixture is a racemic mixture. In other embodiments, the mixture is a non-racemic mixture (wherein one enantiomer or diastereomer is enriched in the non-racemic mixture). In some embodiments, the compound of Formula I, IR, IS, or a pharmaceutically acceptable salt thereof is substantially pure, enantiomerically pure, or both.

[0199] The compounds of Formula I, IR, IS, their deuterated analogs, or pharmaceutically acceptable salts thereof can be administered in various forms, including those detailed herein. Treatment with the compounds of Formula I, IR, IS, their deuterated analogs, or their pharmaceutically acceptable salts can be a component of combination therapy or adjunctive therapy, i.e., a subject or patient in need of a drug is treated for a disease or given another drug in conjunction with one or more of the compounds. This combination therapy can be sequential therapy, in which the patient is first treated with one drug and then the other or two drugs are given simultaneously. They can be administered independently by the same route or by two or more different routes of administration, depending on the dosage form used.

[0200] The following examples further illustrate the teachings of the present disclosure.The following examples are illustrative of the teachings herein.This is illustrative, but the teachings for preparing the compounds described below in this specification can be prepared using the teachings herein, and are not intended to be limited to the following examples.

[0201] In the examples below, the following abbreviations are used: p-TSA: paratoluenesulfonic acid MTBE: Methyl tert-butyl ether EDTE: Ethylenediaminetetraethanol V: Volume Q-NMR: Quantitative NMR THF: tetrahydrofuran HPLC: High-performance liquid chromatography NLT: That's all TLC: thin layer chromatography DCM: dichloromethane DMSO: dimethyl sulfoxide ETOAc: Ethyl acetate IPA: Isopropyl alcohol ETOH: Ethanol NaHCO3: Sodium bicarbonate rt: Room temperature (20~25℃) NMP: n-methyl-2-pyrrolidone

[0202] In the following scheme, compound 5R is a species of the genus of compounds of formula VR, compound 7R is a species of compounds of formula VIIR, compound 8R is a species of compounds of formula VIIIR, compound 9R is a species of compounds of formula IXR, compound 10R is a species of XR, compound 11R is a species of IR, [D3]-11R is a species of the genus IR where Z3 and Z8 are both D, corresponding to R-[D3]-11, [D3]-10R is a species of the genus XR where Z3 and Z8 are both D, and [D]-9R is a species of the genus IXR where Z3 is D. Similarly, compound 5S is a species of the genus VS, compound 7S is a species of the formula VIIS, compound 8S is a species of the formula VIIIS, compound 9S is a species of the formula IXS, compound 10S is a species of the formula XS, compound 11S is a species of the formula IS, [D3]-11S is a species of the genus IS where Z3 and Z8 are both D, corresponding to R-[D3]-11, [D3]-10S is a species of the genus XS where Z3 and Z8 are both D, and [D]-9S is a species of the genus IXS where Z3 is D. [Example]

[0203] [ka]

[0204] General procedure for the synthesis of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-one, 3 A 1000 mL jacketed reactor equipped with an overhead stirrer and 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). The resulting suspension was heated at reflux for 3 h to obtain complete conversion of the starting material. It was then cooled to room temperature and stirred with 1 N NaOH (aq) followed by MTBE. The phases were separated, and the aqueous layer was further extracted with MTBE. The combined organics were washed once with 10% brine and concentrated. The mixture was azeotroped once with toluene to give 113 g (Q-NMR assay: 66%, 87.6% yield). The crude product was carried on to the next step without further purification. 1 H 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 synthesis of (R,E)-N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-ylidene)-2-methylpropane-2-sulfinamide, 5R A round-bottom flask equipped with an overhead stirrer was charged with compound 3 (33.3 g, 60% wt.%, 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 at 80 °C for 5-6 h and then cooled to room temperature to give a dark solution. EDTE (47.5 g) was added to the solution, and the mixture was heated at 55 °C for 60 min and then cooled to room temperature. 12% NaCl (aq) was added to the above solution, stirred for approximately 5 min, and allowed to settle. The phases were separated, and the aqueous phase was re-extracted twice with toluene. The combined organics were washed once with water. The organic phase was filtered through a plug of activated carbon and SiO2 and concentrated to give the crude product as a yellow-orange semisolid (18.9 g, 63% pure product by NMR). The product crystallized on standing as an off-white solid which was filtered and carried on to the next step. 1 H NMR (400 MHz, CDCl3) 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).

[0206] General procedure for the synthesis of (R)-N-((R)-7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-yl)-2-methylpropane-2-sulfinamide, 7R To a stirred solution of compound 5R (17.5 g, 58.0 mmol) in THF (70 mL) at −5 °C was added dropwise a 1 M solution of 4-F-phenylmagnesium bromide in THF (116 mL, 116 mmol, 2 equiv.). The resulting reaction mixture was stirred at −5 °C for 4 h, followed by stirring at 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 warming to room temperature, the aqueous phase was extracted with MTBE, and the combined organic layers were washed with water and then dried over Na2SO4. Evaporation of the solvent gave the crude product, which was reslurried in heptane followed by filtration to give compound 7R (18.24 g, 79%) as a white solid. 1 H 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 and 2.5 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.33 - 2.27 (m, 1H), 2.05-2.01 (m, 1 H), 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).

[0207] General procedure for the synthesis of (R)-7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecane-7-amine, 8R To a suspension of compound 7R (45.0 g, 113 mmol) in methanol (180 mL) at 0 °C, a solution of 3 M HCl 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 NaHCO3 (225 mL) was added dropwise. To the resulting suspension, CHCl2 (90 mL) was added to dissolve the product, and the phases were separated. The aqueous phase was extracted with CHCl2 (2 × 90 mL), and the combined organics were washed with brine, dried (NaSO4), and concentrated to give crude compound 8R (27.1 g, 82% quantitative) as a white solid, which was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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).

[0208] General procedure for the synthesis of (R)-N-(7-(4-fluorophenyl)-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-7-yl)formamide, 9R A reactor equipped with a stirrer, thermocouple, and nitrogen inlet was charged with AcO (32 mL, 339.56 mmol, 3 equiv.) and HCOH (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. Using an addition funnel, a solution of 8R (26.10 g, 88.96 mmol) in CHCl (125 mL) was added to the above mixture at 0 °C, and the mixture was stirred at 0 °C for 1.5–2 h. HPLC and TLC (30% EtOAc / hexane) showed complete conversion of the starting material to the desired product. The reaction was then quenched at 0 °C by the dropwise addition of saturated aqueous NaHCO (520 mL) using an addition funnel. The resulting solution was stirred at 0 °C for 30 min and then transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted with CHCl. The combined organic layers were washed with water and distilled to a small volume, then MeOH was added and distilled to remove residual CHCl. ​​The resulting MeOH solution was transferred to a three-neck round-bottom flask, additional MeOH was added, and the mixture was heated to 55°C with stirring for 1 hour. Using an addition funnel, water was then added dropwise to the stirred solution over 1 hour. The resulting off-white suspension was aged at 50°C for 1 hour and allowed to cool to room temperature for 12-14 hours. The suspension was then filtered, and the cake was washed with a 1:1 MeOH / water mixture, dried under suction, and then dried in a vacuum oven at 40°C for 24 hours to give compound 9R as a white solid (28.16 g, 98%). 1H NMR (400 MHz, CDCl3) 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, 2H), 2.91 (dq, J = 13.6, 3.0 Hz, 1H), 2.72 - 2.51 (m, 2H), 2.42 - 2.27 (m, 1H), 2.10 - 1.97 (m, 1H), 1.71 - 1.59 (m, 3H), 1.58 - 1.33 (m, 2H), 0.59 (d, 3H), 0.28 (d, J = 23.3 Hz, 3H).

[0209] General procedure for the synthesis of 10R A reactor equipped with a refrigerator, thermocouple, and overhead stirrer was charged with compound 9R (75 g, 0.23 mol) followed by THF and stirred for 15 min or more. Then, NaBH4 (26.5 g, 0.7 mmol) was added portionwise to the reactor. The resulting suspension was cooled to -10°C to 0°C. A solution of iodine (71.1 g, 0.28 mol) in THF was added dropwise to the above suspension using a dropping funnel, while maintaining the internal temperature between -5°C and 10°C (Caution: rapid gas evolution). Upon completion of the iodine addition, the mixture was gradually warmed to 35°C to 45°C over 30 min and stirred at that temperature for 2 to 4 h. IPC by HPLC indicated the conversion of 9 to 10. The resulting white suspension was cooled to -5°C to 0°C, and MeOH was added dropwise over 90 min, maintaining the internal temperature below 10°C. Upon completion of the addition, the mixture was heated to 40-45°C over 30 minutes and aged at that temperature. Complete decomposition of the intermediate amine borane complex was observed by precipitation of the reaction mixture. 19 It was monitored by F NMR studies.

[0210] In a separate flask, an aqueous solution of NaOH was prepared by dissolving 0.930 g of NaOH in 9 V of water. A portion of this aqueous NaOH solution (20%, 18 V) was first added dropwise to the reaction mixture at 40–45°C and aged at this temperature. Immediately after the addition of the aqueous NaOH solution, the formation of a white precipitate was observed. The remaining aqueous NaOH solution was then added slowly over 2.5–3 h at 40–45°C. At the end of the addition, the internal temperature of the suspension was set to 20–25°C and aged at this temperature. The suspension was then filtered, and the cake was washed with a 1:1 MeOH / water mixture and dried under vacuum. The cake was then recharged into the reactor, followed by water. The resulting suspension was heated to 55–65°C and aged at this temperature. The suspension was then cooled to 20–25°C, aged for 30 min, and filtered. The cake was then washed with a 1:1 mixture of MeOH / water, dried under suction, and then dried in a vacuum oven at 55-60° C. The product, compound 10R, was obtained as a white solid in 71% (54.8 g) yield with 93.2 wt % purity by NMR, 3.2% KF and 99.4 A% purity by HPLC. 1 H NMR (400 MHz, CDCl3) 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.

[0211] Preparation of (R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-one, 11R A 2 L jacketed reactor equipped with a chiller, thermocouple, and overhead stirrer was charged with compound 10R (50 g, 93.4 wt%, 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 15-25 °C. Concentrated HCl (12 N, 4 equiv., 50 mL, 0.76 mol) was slowly added to the above suspension while maintaining the temperature below 35 °C. The mixture was heated to an internal temperature of 65-75 °C and aged at this temperature for ≥12 h. The completion of the reaction was monitored by HPLC. The mixture was then cooled to 20-30 °C, charged with MTBE, and stirred for ≥10 min. The phases were separated, and the aqueous phase (bottom) was recharged to the reactor. Then, using an addition funnel, 3 N aqueous NaOH was slowly added while maintaining the internal temperature below 40 °C, until the pH of the mixture reached 12-13 (measured using pH paper). The resulting white suspension was extracted with MTBE. The combined MTBE layers were washed with water. For removal of neopentyl glycol by-product, the MTBE layers were 1 The residue was confirmed by H NMR (<10%, if >10%, repeat water wash). The MTBE phase was concentrated to 2V. Additional MTBE was added and concentrated again, and this process was repeated twice. The resulting MTBE phase was diluted with MTBE to obtain a KF (<0.2%).

[0212] HCl salt formation of 11R To the above MTBE solution containing the free base compound 11R, a 5-6 N HCl solution in IPA (45.48 mL, 0.228 mol, 1.5 equiv.) was added dropwise at room temperature, maintaining the internal temperature below 30 °C, and the formation of a white precipitate was observed. At the end of the addition, the resulting suspension was aged at 20-30 °C for >12 h. The suspension was then filtered, and the cake was washed with MTBE (3V × 3, displacement wash, cake wash, and slurry wash) and dried under vacuum for >30 min. The cake was then dried in a vacuum oven at 35-45 °C for >12 h. The product, 11R·HCl, was obtained as a white solid in 91% yield (34.2 g) with 99.9% HPLC purity, 100.1 wt % by HPLC, and 0.152% KF. 1H NMR (400 MHz, DMSO-d6) 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).

[0213] Using HPLC, the product was determined to be greater than 99% pure and anhydrous. [Example]

[0214] [ka]

[0215] General procedure for the synthesis of 3 A jacketed reactor equipped with a mechanical stirrer and 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, 4V). The resulting suspension was heated at reflux for 3 h to obtain complete conversion of the starting material. It was then cooled to 20 °C and stirred with 1 N NaOH (aq) followed by MTBE. The phases were separated, and the aqueous layer was further extracted with MTBE. The combined organics were washed once with 10% brine and concentrated. The mixture was azeotroped once with toluene to give 113 g (Q-NMR assay: 66%, 87.6% yield). The crude product was carried on 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).

[0216] General procedure for the synthesis of 5 A 1 L round-bottom flask equipped with a mechanical stirrer was charged with compound 3 (33.3 g, 60% wt.%, 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 at 80 °C for 5-6 h and then cooled to room temperature to give a dark solution. EDTE (47.5 g, 2 equiv.) was added to this solution, and the mixture was heated at 55 °C for 60 min and then cooled to room temperature. 12% NaCl (aq.) was added to the above solution, stirred for approximately 5 min, and allowed to settle. The phases were separated, and the aqueous phase was re-extracted with toluene. The combined organics were washed with water. The organic phase was filtered through a plug of activated carbon and Si02 and concentrated to give the crude product as a yellow-orange semi-solid (18.9 g, 63% pure product wt. by NMR). The product crystallized on standing as an off-white solid, which was filtered and carried on to the next step. 1 H NMR (400 MHz, CDCl3) 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).

[0217] General procedure for the synthesis of 7R 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 stirring at room temperature for 14 h. TLC (50% EtOAc / hexane) showed 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 warming to room temperature, the aqueous phase was extracted with MTBE, and the combined organic layers were washed with water and then dried over Na2SO4. Evaporation of the solvent gave the crude product, which was reslurried in heptane, followed by filtration to give compound 7 (18.24 g, 79%) as a white solid. 1 H 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 and 2.5 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.33 - 2.27 (m, 1H), 2.05-2.01 (m, 1 H), 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).

[0218] General procedure for the synthesis of 8R To a suspension of compound 7 (45.0 g, 113 mmol) in methanol (180 mL) at 0 °C, a solution of 3 M HCl 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 NaHCO (225 mL) was added dropwise. To the resulting suspension, CHCl was added to dissolve the product, and the phases were separated. The aqueous phase was extracted with CHCl, and the combined organics were washed with brine, dried (NaSO), and concentrated to give crude compound 8 (27.1 g, 82% quantitative) as a white solid, which was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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).

[0219] General procedure for the synthesis of [D]-9R A mixture of acetic anhydride (1.9 mL, 13.63 mmol) and formic acid-d3 (0.54 mL, 13.63 mmol) was stirred at 60 °C for 2 h and then gradually cooled to 0 °C. Then, a solution of compound 8 (1.0 g, 3.41 mmol) in CHCl2 (5 mL) was added to the above mixture at 0 °C, and the mixture was allowed to stir at 0 °C for 2 h. TLC (30% EtOAc / hexane) showed complete conversion of the starting material. The mixture was then neutralized by slow addition of an aqueous solution of sodium bicarbonate and extracted with CHCl2. The combined organics were washed once with saturated NaHCO3 (aq), water, and brine, dried (NaSO4), and concentrated to give crude [D]-9 (1.1 g, quantitative) as an off-white solid, which was carried on to 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).

[0220] General procedure for the synthesis of [D3]-10R To a stirred suspension of [D]-9 (1.1 g, 3.42 mmol) and NaBD4 (572 mg, 13.66 mmol) in THF (4 mL) at 0 °C, a solution of iodine (1.13 g, 4.44 mmol) in THF (2 mL) was added dropwise. The mixture was then allowed to warm to room temperature for 14 h. The mixture was then cooled to 0 °C and quenched by 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 a clear phase separation. The MTBE layer was separated, and the aqueous phase was further extracted with MTBE. The combined organics were then washed with water, followed by brine, dried (Na2SO4), and concentrated. The crude mixture was purified by chromatography on SiO 2 (100% hexanes to 30-50% EtOAc / hexanes) to afford [D3]-10 (710 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) 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); 19 F NMR (376 MHz, CDCl3) δ -118.7.

[0221] General procedure for the synthesis of [D3]-11R free base To a solution of [D3]-10 (640 mg, 2.6 mmol) in IPA (4 V) at room temperature, a solution of concentrated HCl (4 equiv.) was added, and the mixture was heated at 70 °C for 14 h to obtain complete conversion of the starting material. The mixture was then basified with 3 N aqueous NaOH and extracted with MTBE. The combined organics were washed once with water, dried (Na2SO4), and concentrated to give crude [D3]-11 (430 mg, 93%) as a colorless oil, which was carried on to the next step without further purification.

[0222] General procedure for the synthesis of [D3]-11R-HCl salts To a solution of crude [D3]-11 free base (430 mg) in MTBE (5 mL) was added dropwise HCl solution (1.5 equiv.) in IPA at room temperature. During the addition of the HCl solution, the formation of a white suspension was observed. The resulting white suspension was then stirred at room temperature for 12–14 min. It was then filtered and washed with MTBE (3 × 3 mL) to give [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]

[0223] [ka]

[0224] Using the procedure of Example 1, substituting (S)-t-Bu-sulfinamide for (R)-t-Bu-sulfinamide, prepare the compound identified in the scheme herein above. [Example]

[0225] [ka]

[0226] Using the procedure of Example 2, substituting (S)-t-Bu-sulfinamide for (R)-t-Bu-sulfinamide, prepare the compound identified in the scheme herein above.

[0227] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. formula 【Chemistry 1A】 【Chemistry 1B】 【Chemical 1C】 Compounds of (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkyl, or C1-C6 alkoxy; each Z 8 are independently H or D; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Ar is aryl; each Z 8 are independently H or D; x is 0, 1, 2, 3, 4, or 5; provided that when Ar is thiophene, x is 0, 1, 2, or 3. In addition, the following compounds are excluded: 【Chemistry 2】 。

2. Z 6 is a C1-C6 alkyl, hydrocarbyl aryl, or C5-C10 cycloalkyl.

3. Z 6 3. The compound of claim 1 or 2, wherein is t-butyl, phenyl, tolyl, or adamantyl.

4. each Z 1 and Z 2 are independently H or C1-C3 alkyl, and Z 4 and Z 5 is independently C1-C3 alkyl.

5. Z 1 and Z 2 Each pair of Z 3 and Z 4 5. The compound of claim 1, wherein each pair of:

6. Z 3 is H, D, or C1-C6 alkyl optionally substituted with one or more fluoro or C1-C3 alkoxy.

7. Z 3 is H or D.

8. each Z 8 When is D, Z 3 The compound of any one of claims 1 to 7, wherein is D.

9. 9. The compound of claim 1, wherein Ar is phenyl.

10. 10. The compound of claim 1, wherein x is 0, 1, or 2.

11. x is 1 or 2, and each Z is independently a halogen, -OZ 11 or C1-C10 alkyl.

12. 12. The compound of claim 1, wherein at least one Z is F.

13. 13. The compound of any one of claims 1 to 12, wherein Ar is phenyl and at least one Z is F at the 4-position of Ar.

14. 14. The compound of any one of claims 1 to 13, wherein x is 1 and Z is F.

15. formula: 【Transformation 3】 Compound.

16. Formula I: 【Chemistry 4】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Transformation 5】 The compound having the ketal protecting group of 7 )a(X 1 ) b In the presence of Eq. 【Transformation 6】 by reacting with a sulfinamide of formula V 【Transformation 7】 forming an imine of (b) converting the imine of formula V to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VII 【Transformation 8】 forming a sulfinamide of (c) reacting the sulfinamide of formula VII with an acid to form the corresponding sulfinamide of formula VIII 【Chemistry 9】 forming an amine of (d) converting said amine of formula VIII into an amine of formula Z under amide-forming conditions 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 Formula IX having 【Chemistry 10】 forming an amide of (e) reducing the acyl group in formula IX with an acyl reducing agent under acyl reducing conditions to form a compound of formula X 【Chemistry 11】 forming a compound of (f) deprotecting the ketal of the compound of formula X to form a compound of formula I; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is H; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C10 alkoxy, or C1-C6 alkyl; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

17. Formula I: 【Chemistry 12】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 13】 The compound having the ketal protecting group of 7 )a(X 1 ) b In the presence of Eq. 【Chemistry 14】 by reacting with a sulfinamide of formula VA 【Chemistry 15】 forming an imine of (b) converting the imine of formula VA to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIA 【Chemistry 16】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIA with an acid to form the corresponding sulfinamide of formula VIIIA 【Chemistry 17】 forming an amine of (d) converting said amine of formula VIIIA into an amine of formula Z 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 Formula IXA having [Chemistry 18] forming an amide of (e) reducing the acyl group in formula IXA with an acyl reducing agent to form formula XA 【Chemistry 19】 forming a compound of (f) deprotecting the ketal of formula XA to form a compound of formula I; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OR 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C10 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is H; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

18. Formula IR 【Chemistry 20】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 21】 The compound having the ketal protecting group of 7 )a(X 1 ) b In the presence of Eq. 【Chemistry 22】 by reacting with a sulfinamide of formula VR 【Chemistry 23】 forming an imine of (b) converting the imine of formula VR into an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIR 【Chemistry 24】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIR with an acid to form the corresponding sulfinamide of formula VIIIR 【Chemistry 25】 forming an amine of (d) converting said amine of formula VIIIR into an amine of formula Z under amide forming conditions 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 having the formula IXR 【Chemistry 26】 forming an amide of (e) reducing the acyl group in formula IXR with an acyl reducing agent under acyl reducing conditions to give a compound of formula XR 【Chemistry 27】 forming a compound of (f) deprotecting the ketal of formula XR to form a compound of formula IR; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is H; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

19. Formula IR 【Chemistry 28】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 29】 The compound having the ketal protecting group of 7 )a(X 1 ) b In the presence of Eq. 【Transformation 30】 by reacting with a sulfinamide of formula VAR 【Chemistry 31】 forming an imine of (a) converting the imine of formula VAR to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIAR 【Chemistry 32】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIAR with an acid to form the corresponding sulfinamide of formula VIIIAR 【Transformation 33】 forming an amine of (d) converting said amine of formula VIIIAR into an amine of formula Z 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 having the formula IXAR 【Transformation 34】 forming an amide of ( e) reducing the acyl group in formula IXAR with an acyl reducing agent to form a compound of formula XAR 【Chemistry 35】 forming a compound of (f) deprotecting the ketal of formula XAR to form a compound of formula IAR; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is H; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

20. formula IS 【Transformation 36】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 37】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Transformation 38】 by reacting with a sulfinamide of formula VS 【Chemistry 39】 forming an imine of (b) converting the imine of formula VS to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIS 【Chemistry 40】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIS with an acid to form the corresponding sulfinamide of formula VIIIS 【Chemistry 41】 forming an amine of (d) converting said amine of formula VIIIS to an amine of formula Z under amide forming conditions 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 Formula IXS with 【Chemistry 42】 forming an amide of (e) reducing the acyl group in formula IXS with an acyl reducing agent under acyl reducing conditions to give formula XS 【Chemistry 43】 forming a compound of (f) deprotecting the ketal of formula XS to form a compound of formula IS; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is H; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

21. Formula IS: 【Chemistry 44】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 45】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Chemistry 46】 by reacting with a sulfinamide of formula VAS 【Chemistry 47】 forming an imine of (b) converting the imine of formula VAS to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIAS 【Chemistry 48】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIAS with an acid to give the corresponding sulfinamide of formula VIIIAS 【Chemistry 49】 forming an amine of (d) converting said amine of formula VIIIAS into an amine of formula Z 3 The acyl group C(=O)Z is formed by reacting COOH with an acylating agent or its acid derivative. 3 Formula IXAS having [Transformation 50] forming an amide of (e) Reducing the acyl group in formula IXAS with an acyl reducing agent to give formula XAS 【Chemistry 51】 forming a compound of (f) deprotecting the ketal of formula XAS to form a compound of formula IS; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is H; X 1 is a 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; Ar is aryl; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

22. Formula I 【Chemistry 52】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 53】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Chemistry 54】 by reacting with a sulfinamide of formula V 【Transformation 55】 forming an imine of (b) converting the imine of formula V to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VII 【Transformation 56】 forming a sulfinamide of (c) reacting the sulfinamide of formula VII with an acid to form the corresponding sulfinamide of formula VIII 【Chemistry 57】 forming an amine of (d) converting said amine of formula VIII into an amine of formula Z under amide-forming conditions 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 Formula IX having 【Chemistry 58】 forming an amide of (e) reducing the acyl group in formula IX with a deuterated acyl reducing agent under acyl reducing conditions to give a compound of formula X 【Chemistry 59】 forming a compound of (f) deprotecting the ketal of formula X to form a compound of formula I; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is D; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

23. Formula I: 【Transformation 60】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 61】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Transformation 62】 by reacting with a sulfinamide of formula VA 【Transformation 63】 forming an imine of (b) converting the imine of formula VA to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIA 【Chemistry 64】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIA with an acid to form the corresponding sulfinamide of formula VIIIA 【Transformation 65】 forming an amine of (d) converting said amine of formula VIIIA into an amine of formula Z 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 Formula IXA having 【Chemical Formula 66】 forming an amide of (e) reducing the acyl group in formula IXA with a deuterated acyl reducing agent to form formula XA 【Transformation 67】 forming a compound of (f) deprotecting the ketal of formula XA to form a compound of formula I; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is D; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

24. Formula IR 【Transformation 68】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Transformation 69】 The compound having the ketal protecting group of 7 )a(X 1 ) b In the presence of Eq. 【Transformation 70】 by reacting with a sulfinamide of formula VR 【Chemistry 71】 forming an imine of (b) converting the imine of formula VR into an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIR 【Chemistry 72】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIR with an acylating agent to form the corresponding sulfinamide of formula VIIIR 【Transformation 73】 forming an amine of (d) converting said amine of formula VIIIR into an amine of formula Z under amide forming conditions 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 having the formula IXR 【Chemistry 74】 forming an amide of (e) reducing the acyl group in formula IXR with a deuterated acyl reducing agent under acyl reducing conditions to give a compound of formula XR 【Chemistry 75】 forming a compound of (f) deprotecting the ketal of formula XR to form a compound of formula IR; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is D; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

25. Formula IR: 【Transformation 76】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemical 77】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Transformation 78】 by reacting with a sulfinamide of formula VAR 【Chemistry 79】 forming an imine of (b) converting the imine of formula VAR to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIAR 【Chemistry 80】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIAR with an acid to form the corresponding sulfinamide of formula VIIIAR 【Chemistry 81】 forming an amine of (d) converting said amine of formula VIIIAR into an amine of formula Z 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 having the formula IXAR 【Chemistry 82】 forming an amide of (e) reducing the acyl group in formula IXAR with a deuterated acyl reducing agent to form a compound of formula XAR 【Chemistry 83】 forming a compound of (f) deprotecting the ketal in formula XAR to form a compound of formula IR; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is D; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

26. formula IS 【Chemical 84】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemical 85】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Chemical 86】 by reacting with a sulfinamide of formula VS 【Transformation 87】 forming an imine of (b) converting the imine of formula VS to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIS 【Chemical 88】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIS with an acid to form the corresponding sulfinamide of formula VIIIS 【Chemistry 89】 forming an amine of (d) converting said amine of formula VIIIS to an amine of formula Z under amide forming conditions 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 Formula IXS with 【Chemistry 90】 forming an amide of (e) reducing the acyl group in formula IXS with a deuterated acyl reducing agent under acyl reducing conditions to give a compound of formula XS 【Chemistry 91】 forming a compound of (f) deprotecting the ketal in formula XS to form a compound of formula IS; A method including (In the formula, each Z 1 are independently H or C1-C6 alkyl; each Z 2 are independently H or C1-C6 alkyl; n is 2 or 3; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each R is independently a halogen (selected from F, Cl, Br, and I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 7 is C1-C4 alkyl; each Z 8 is D; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

27. formula 【Chemistry 92】 1. A method for preparing a compound of formula (I), comprising: Formula (a) 【Chemistry 93】 The compound having the ketal protecting group of 7 ) a (X 1 ) b In the presence of Eq. 【Chemical 94】 by reacting with a sulfinamide of formula VAS 【Chemical 95】 forming an imine of (b) converting the imine of formula VAS to an imine of formula Ar(Z) under arylation reaction conditions x with an aryl nucleophile Nu capable of delivering an aryl nucleophilic moiety of formula VIIAS 【Chemistry 96】 forming a sulfinamide of (c) reacting the sulfinamide of formula VIIAS with an acid to give the corresponding sulfinamide of formula VIIIAS 【Chemistry 97】 forming an amine of (d) converting said amine of formula VIIIAS into an amine of formula Z 3 COOX o or its acid derivative to form the acyl group C(=O)Z 3 Formula IXAS having 【Chem.98】 forming an amide of (e) Reducing the acyl group in formula IXAS with a deuterated acyl reducing agent to give formula XAS 【Chem.99】 forming a compound of (f) deprotecting the ketal in formula XAS to form a compound of formula IS; A method including (In the formula, Z 4 is C1-C6 alkyl; Z 5 is C1-C6 alkyl; Z 3 is H, D, C1-C6 alkyl optionally substituted with one or more halogen or C1-C6 alkoxy, or aryl optionally substituted with one or more C1-C6 alkyl, C1-C6 alkoxy, or halogen; Each Z is independently a halogen (selected from F, Cl, Br, I), -OZ 11 , C1 to C10 alkyl, C2 to C10 alkenyl, C3 to C10 alkynyl having no terminal hydrogen atom, CF 3 , or OCF 3 where each Z 11 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C4-C10 alkynyl having no terminal hydrogen atoms, and aryl unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, or halogen; Z 6 is C1-C6 alkyl, C3-C10 cycloalkyl, hydrocarbylaryl, or hydrocarbylar(C1-C3)alkyl, each of which may be unsubstituted or substituted with one or more halo, C1-C6 alkoxy, or C1-C6 alkyl; Z 7 is C1-C4 alkyl; each Z 8 is D; X 1 is a halo; X o 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; provided that when Ar is thiophene, x is 0, 1, 2, or 3).

28. Z 6 is C1-C6 alkyl, hydrocarbyl aryl, or C5-C10 cycloalkyl.

29. Z 1 and Z 2 are independently H or C1-C3 alkyl, and Z 4 and Z 5 is independently a C1-C3 alkyl.

30. Z 1 and Z 2 Each pair of Z 4 and Z 5 30. The method of any one of claims 16 to 29, wherein each pair of are identical.

31. Z 3 31. The method of any one of claims 16 to 30, wherein is H or C1-C6 alkyl optionally substituted with one or more fluoro or C1-C3 alkoxy.

32. 32. The method of any one of claims 16 to 31, wherein Ar is phenyl.

33. 33. The method of any one of claims 16 to 32, wherein x is 0, 1, or 2.

34. x is 1 or 2, and each Z is independently a halogen, -OZ 11 or C1-C10 alkyl.

35. 35. The method of any one of claims 16 to 34, wherein at least one Z is F.

36. 36. The method of any one of claims 16 to 35, wherein Ar is phenyl and at least one Z is F at the 4-position of Ar.

37. 37. The method of any one of claims 16 to 36, wherein x is 1 and Z is F.

38. Ti(OZ 7 ) a (X 1 ) b But Ti(OEt) 4 , Ti(OiPr) 4 , TiCl(OiPr) 3 , or TiCl 2 (OiPr) 2 38. The method of any one of claims 16 to 37, wherein

39. Nu is Ar(Z) x MgX or Ar(Z) x 39. The method of any one of claims 16 to 38, wherein X is Li, where X is halo.

40. Nu is Ar(Z) x 40. The method of any one of claims 16 to 39, wherein the compound is MgX, where X is halo.

41. The amine is reacted with the sulfinamide in a polar protic solvent with nitric acid, sulfuric acid, trifluoroacetic acid, para-toluenesulfonic acid, or HX 3 (In the formula, X 3 41. The method of any one of claims 16 to 40, wherein the compound is formed by reacting with a compound having a structure in which

42. 42. The method of any one of claims 16 to 41, wherein the deketalization occurs in the presence of a protic acid.

43. Z 3 is H or D.

44. Z 3 The method of claim 43, wherein is D.

45. Z 3 44. The method of claim 43, wherein is H. 【Request Item 46】 【Convert 100】 is a protected ketal, 【Chemistry 101】 in the presence of an acid 【Chemical Engineering 102】 46. ​​The method of any one of claims 16 to 45, wherein the compound is prepared by reacting

47. compound 【Chemistry 103】 1. A method for forming a compound comprising: (a) Structure 【Chemical 104】 The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of 【Chemistry 105】 by reacting with sulfinamide to give imine 【Chemistry 106】 forming a (b) The imine 5 is reacted with the structure 【Chemistry 107】 by reacting with an organometallic compound of 【Chemistry 108】 forming a (c) reacting the sulfinamide 7 with an acid to form the corresponding amine 【Chemistry 109】 forming a (d) reacting the amine 8 with an acylating agent of formula HCOOH or its acid derivative under amide forming conditions to give an amide 【Chemical 110】 forming a (e) The acyl group in 9 is reduced with an acyl reducing agent to give the compound 【Chemistry 111】 forming a (f) deprotecting the ketal of 10 to form compound 11, and then acidifying 11 with HCl to form compound 11·HCl; A method comprising:

48. compound 【Chemistry 112】 1. A method for forming a compound comprising: (a) Structure 【Chemistry 113】 The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of 【Chemical 114】 by reacting with sulfinamide to give imine 【Chemical 115】 forming a (b) The imine 5R is reacted with the structure 【Chemistry 116】 by reacting with an organometallic compound of 【Chemistry 117】 forming a (c) reacting the sulfinamide 7R with an acid to form the corresponding amine 【Chemistry 118】 forming a (d) reacting the amine 8R with an acylating agent of formula HCOOH or its acid derivative under amide forming conditions to form an amide 【Chemical 119】 and forming (e) The acyl group in 9R is reduced with an acyl reducing agent to give the compound 【Chemical 120】 forming a (f) deprotecting the ketal of 10R to form compound 11R, and then acidifying 11R with HCl to form compound 11R·HCl; A method comprising:

49. Compound: 【Chemistry 121】 1. A method for forming a compound comprising: (a) Structure 【Chemistry 122】 The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of 【Chemical 123】 by reacting with sulfinamide to give imine 【Chemistry 124】 forming a (b) The imine 5S is subjected to Grignard coupling conditions to give the structure 【Chemistry 125】 by reacting with an organometallic compound of 【Chemistry 126】 forming a (c) reacting the sulfinamide 7S with an acid to form the corresponding amine 【Chemistry 127】 forming a (d) reacting the amine 8S with an acylating agent of formula HCOOH or its acid derivative under amide forming conditions to form an amide 【Chemistry 128】 and forming (e) The acyl group in 9S is reduced with an acyl reducing agent under acyl reducing conditions to give the compound 【Chemistry 129】 forming a (f) deprotecting the ketal of 10S to form compound 11S, and then acidifying 11S with HCl to form compound 11S.HCl; A method comprising:

50. compound 【Chemistry 130】 1. A method for forming a compound comprising: (a) Structure 【Chemistry 131】 The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of 【Chemistry 132】 by reacting with sulfinamide to give imine 【Chemistry 133】 and forming (b) The imine 5 is reacted with the structure 【Chemistry 134】 by reacting with an organometallic compound of 【Chemistry 135】 forming a (c) reacting the sulfinamide 7 with an acid to form the corresponding amine 【Transformation 136】 forming a (d) reacting the amine 8 with a deuterated acylating agent of formula DCOOD or a deuterated acid derivative thereof under amide forming conditions to give the amide 【Chemistry 137】 forming a (e) The acyl group in [D]-9 is reduced with a deuterated acyl reducing agent under acyl reducing conditions to give compound [D]-9. 【Chemistry 138】 forming a (f) [D 3 The ketal in ]-10 is deprotected in the presence of acid, and the resulting product is then treated with base to give compound [D 3 forming ]-11; A method comprising:

51. compound 【Chemistry 139】 1. A method for forming a compound comprising: (a) Structure [Chemical 140] The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of 【Chemistry 141】 by reacting with sulfinamide to give imine 【Chemistry 142】 forming a (b) The imine 5R is reacted with the structure 【Chemistry 143】 by reacting with an organometallic compound of 【Chemistry 144】 forming a (c) reacting the sulfinamide 7R with an acid to form the corresponding amine 【Chemistry 145】 forming a (d) reacting the amine 8R with a deuterated acylating agent of formula DCOOD or its acid derivative under amide forming conditions to form an amide 【Chemistry 146】 forming a (e) The acyl group in [D]-9R is reduced with a deuterated acyl reducing agent under acyl reducing conditions to give the compound 【Chemistry 147】 forming a (f) [D 3 The ketal in ]-10R is deprotected in the presence of acid, and the resulting product is then treated with base to give compound [D 3 forming ]-11R; A method comprising:

52. compound 【Chemistry 148】 1. A method for forming a compound comprising: (a) Structure 【Chemistry 149】 The compound having the ketal protecting group is reacted with Ti(OEt) 4 In the presence of [Chemical 150] by reacting with sulfinamide to give imine 【Chemistry 151】 forming a (b) The imine 5S is subjected to Grignard coupling conditions to give the structure 【Chemistry 152】 by reacting with an organometallic compound of 【Chemistry 153】 forming a (c) reacting the sulfinamide 7S with an acid to form the corresponding amine 【Chemistry 154】 forming a (d) reacting the amine 8S with a deuterated acylating agent of formula DCOOD under amide forming conditions to form the amide 【Chemistry 155】 forming a (e) The acyl group in [D]-9S is reduced with a deuterated acyl reducing agent under acyl reducing conditions to give the compound 【Chemistry 156】 forming a (f) [D 3 The ketal in ]-10S is deprotected in the presence of acid, and the resulting product is then treated with base to give compound [D 3 forming ]-11S; A method comprising:

53. The deuterated acyl reducing agent is NaBD 4 or LiAlD 4 53. The method of any one of claims 50 to 52, wherein 【Request Item 54】 【Chemistry 157】 but, 【Chemistry 158】 in the presence of an acid 【Chemistry 159】 54. The method of any one of claims 47 to 53, wherein the compound is prepared by reacting

55. 55. The method of any one of claims 16 to 54, wherein the deprotecting step is carried out in concentrated hydrochloric acid in water.

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