Synthesis of cyclic acylsulfoximines

Abstract

Compounds of formula I: [Formula 1] JPEG2026521151000132.jpg3136 (wherein R1, R2, R3, G1, and G2 are as defined herein) The preparation process is provided.

Description

[Technical Field]

[0001] This invention relates to the enantioselective synthesis of cyclic acylsulfoximines, which are intermediates useful in the preparation of pesticides. [Background technology]

[0002] Heterocyclic sulfoximine derivatives that are biocidal in nature have already been described in publications such as International Publication Nos. 2015 / 071180, 2016 / 039441, 2018 / 206348, 2019 / 219689, 102019 / 229089, 2019 / 234158, 2020 / 084075, 2020 / 141136, and 2022253841.

[0003] The synthesis of racemic cyclic benzo-condensed five-membered acylsulfoximines was first reported 50 years ago (Chemische Berichte, vol.108, no.12,1,(1975-12-01), pages 3855-3863; Angew.Chem.Int.Ed.1971,10,76; J.Am.Chem.Soc.1971,93,7333). In the latter two cases, this was achieved by classical acyclic sulfoximine synthesis using hydrazonic acids, followed by cyclization to adjacent acid derivatives (e.g., as shown in Scheme 1). Scheme 1 [ka]

[0004] Starting from enantiomer-enriched sulfoxides, the synthesis of enantiomer-enriched cyclic benzo-condensed acylsulfoximines has also been reported (Chirality 1995, 7, 541; Tetr. Asym. 1996, 7, 361). More recently, cyclic acylsulfoximines have attracted interest from both the agrochemical (International Publication No. 2018211442) and pharmaceutical (International Publication No. 2022094218) industries. In both cases, the target compounds were prepared only in racemic form by the classical cyclization of acyclic sulfoximines on acid derivatives.

[0005] Such cyclic sulfoximines can, in principle, be prepared by either the cyclization of acyclic sulfoximines (pathway A, scheme 2) or intramolecular nitrogen transfer over an adjacent sulfoxide (pathway B, scheme 2), as described below. To date, path A has been the primary method involving oxidative cyclization via path B, and has been reported only for very specific compounds and under conditions unsuitable for the preparation of enantiopurines (Russ. Chem. Bull. Int. Ed. 2004, 53, 916). Scheme 2 [ka]

[0006] Numerous methods have been described for the synthesis of acyclic N-unsubstituted sulfoximines from sulfoxides required in pathway A. Hypervalent iodine is generally used as a reagent either in combination with metal catalysts such as rhodium (Org. Lett., 2004, 6, 1305), copper (Tetrahedron Lett. 1998, 39, 4805), iron (Tetrahedron Lett. 1998, 39, 5015), or silver (Org. Lett., 2005, 7, 4983), or without a catalyst, as described by Bull and Luisi (Angew. Chem. Int. Ed. 2016, 51, 7203). The latter method has been used for the large-scale synthesis of the ATR inhibitor ceraracertib (Org. Process. Res. Dev. 2021, 25, 43). Liang's method using NaN3 and Eaton's reagent (Tetrahedron Lett., 2017, 58, 333-337) avoids hypervalent iodine but is unsuitable for the synthesis of chiral sulfoximines because it leads to racemization of the product when starting from enantiopurine sulfoxide starting materials. The use of azides is also dangerous on a large scale. Other alternative reagents are activated hydroxylamine derivatives such as O-mesityl-hydroxylamine (MSH) (Tetrahedron Lett., 1972, 4137, J. Org. Chem., 1974, 39, 2458), nitrobenzoyl hydroxylamine triflate in combination with an iron catalyst (Angew. Chem. Int. Ed. 2018, 57, 32), or dinitrophenyl hydroxylamine in combination with a rhodium catalyst (Chem. Commun. 2014, 50, 9687). Despite the numerous methods reported, serious drawbacks typically exist, such as the need to use stoichiometric amounts of hypervalent iodine reagents, transition metal catalysts, and the preparation of customized, often unsafe, amination reagents. This is particularly important for large-scale synthesis.

[0007] Considering the shortcomings of the above-mentioned route A, it would be advantageous to develop an alternative method via route B (Scheme 2). This would potentially avoid the handling of hazardous reagents and expensive metal catalysts.

[0008] As shown in Scheme 3, a practical Tiemann rearrangement method for amidine oxime derived from arylnitriles has recently been published (Org. Lett. 2014, 16, 892). Scheme 3 [ka]

[0009] Based on this reactivity, the inventors proposed that an adjacent sulfoxide can block the activated amidine oxime, yielding a cyclic iminosulfoximine, which can then be hydrolyzed to a cyclic acylsulfoximine (Scheme 4). This is most likely to work when the aryl or heteroaryl group in the initial nitrile is electron-deficient and therefore inhibits the rearrangement of the nitro type. Furthermore, the amount of base should be limited to the amount required to activate the amidine oxime. Scheme 4 [ka] [Overview of the Initiative] [Means for solving the problem]

[0010] The present invention provides a process for enantioselectively preparing a cyclic acylsulfoximine of formula (I) in optionally enantioisomerically pure, enantioisomerically concentrated, or racemic form. [ka] During the ceremony, S * However, the (R)- or (S)- is a stereogenic sulfur atom, and the S * However, it is enantiomerically pure, enantiomerically concentrated, or in racemic form. R1 and R3 are independently hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. R2 is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl. G1 and G2 are independently CH or N, provided that at least one of G1 and G2 is N. A) Sulfinyl compound of formula (II) [ka] (In the formula, R1, R2, R3, G1, G2, and S * However, as defined for compounds of formula (I), Sulfonyl chloride of formula (III) [ka] (In the formula, R4 is an alkyl or substituted aryl, preferably R4 is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl, or 2,4-dinitrophenyl.) The compound of formula (IV) is reacted with the presence of a suitable base and in a suitable solvent. [ka] (In the formula, R1, R2, R3, G1, G2 and S * However, this is as defined for the compound of formula (I), and R4 is as defined for the compound of formula (III), B) Compounds of formula (IV) [ka] (In the formula, R1, R2, R3, G1, G2 and S * However, this is as defined for the compound of formula (I), and R4 is as defined for the compound of formula (III). is thermally rearranged in a suitable solvent to give a compound of formula (V)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0011] Optionally, the compound of formula (Va) can be hydrolyzed instead of the compound of formula (V).

[0012] Optionally, the process for the enantioselective preparation of the cyclic acylsulfoximine of formula (I) is as follows: the compound of formula (IV) obtained from step B) [ka] (In the formula, R1, R2, R3, G1, G2 and S * However, by direct rearrangement (as defined for the compound of formula (I), and R4 as defined for the compound of formula (III)), the intermediate compound of formula (IV) is obtained without isolation (i.e., without hydrolysis step C). The compound of formula (I) was prepared by performing a one-pot operation in the presence of water and a suitable co-solvent. [ka] (In the formula, R1, R2, R3, G1, G2 and S * It generates (as defined above).

[0013] Due to the enantioselectivity of the process of the present invention, when starting from enantiomerically pure, enantiomerically concentrated, or racemic compounds of formula (II), the enantiomeric properties of the stereoisomerous sulfur atom S* are completely preserved during the synthesis of the compounds of formula (I). For example, X-ray analysis of the precursor sulfoxide of Example 3 and representative examples of the compounds of formula (I) of Example 44 revealed that sulfur S* * A compound of formula (II) having a (R) stereocenter can be obtained without erosion of enantiomer purity, with sulfur S * It has been shown that this yields a compound of formula (I) having a (R) stereocenter. Similarly, sulfur S * Starting with a sulfoxide concentrated in the (S) enantiomer, we obtain the compound of formula (I) concentrated in the (S) enantiomer. [Modes for carrying out the invention]

[0014] In one embodiment of the present invention, step (A) is: The method comprises reacting a compound of formula (II) with a compound of formula (III) in a suitable solvent (or diluent) in the presence of a suitable base. The ratio of the compound of formula (III) used to the compound of formula (II) is in the range of 3:1 to 1:1, preferably 1.5:1 to 1:1, and more preferably 1.2:1 to 1:1.

[0015] Suitable and preferred bases for step A are trialkylamines such as triethylamine and tributylamine, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydroxides such as potassium hydroxide and sodium hydroxide. Preferably, the base is a trialkylamine, more preferably triethylamine. The ratio of the base used to the sulfonyl chloride of formula (III) is 1.5:1 to 1:1, more preferably 1.2:1 to 1:1.

[0016] Examples of suitable and preferred solvents (or diluents) for step A are esters, nitriles, ethers, and aliphatic, aromatic, or halogenated hydrocarbons.

[0017] Examples include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylene, dioxane, cyclopentyl methyl ether, t-butyl methyl ether, diethyl ether, anisole, and fluorobenzene. Preferably, the solvent is an ether, nitrile, or halogenated hydrocarbon, such as tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, and chlorobenzene.

[0018] Step (B) is, The method comprises thermally rearranging the compound of formula (IV) to the compound of formula (V) in a suitable solvent (or diluent) at a suitable temperature.

[0019] Suitable solvents (or diluents) are polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates and ethers, or mixtures thereof.

[0020] Examples of suitable and preferred solvents include, but are not limited to, acetonitrile, butyronitrile, benzonitrile, ethylene glycol, methanol, ethanol, methyl isobutyl ketone, nitrobenzene, trifluorotoluene, polyethylene glycol, chlorobenzene, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, anisole, N,N-dimethylformamide, N-methylpyrrolidine, sulfolane, 2,5-dimethylisosorbide, dimethylacetamide, silene, or mixtures thereof.

[0021] More preferably, the solvent (or diluent) is N-methylpyrrolidine, sulfolane, acetonitrile, ethylene glycol, ethanol, or a mixture thereof.

[0022] The rearrangement is favorably carried out in the temperature range of 0°C to 150°C. The preferred temperature depends on the electronic properties of the R4 substituent. If R4 is highly electron-withdrawing (e.g., 2,4-dinitrophenyl), the appropriate reaction temperature is in the range of 0°C to 40°C. On the other hand, if R4 is neutral (e.g., methyl) or moderately electron-withdrawing (e.g., tosyl), the preferred temperature is 60°C to 100°C.

[0023] In one embodiment of the process according to the present invention for producing the compound of formula (V), steps (A) and (B) can be advantageously carried out in a one-pot process without isolating the intermediate compound of formula (IV). This is most preferable when R4 in the sulfonyl chloride of formula (III) is highly electron-withdrawing (e.g., 2,4-dinitrophenyl).

[0024] Step (C) is, This method includes hydrolyzing the compound of formula (V) by heating it in an aqueous medium using a suitable co-solvent (or diluent) in the presence of a suitable acid.

[0025] Suitable cosolvents (or diluents) are water-miscible alcohols, ethers, and nitriles.

[0026] Suitable and preferred cosolvents include, but are not limited to, methanol, ethanol, tetrahydrofuran, acetonitrile, and 1,4-dioxane.

[0027] The amount of water used is in the range of stoichiometric amount to 80% of the cosolvent, preferably in the range of 1:3 to 1:1.

[0028] Suitable acids include, but are not limited to, sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, and methanesulfonic acid. Most preferably, the acid is sulfuric acid or hydrochloric acid.

[0029] This hydrolysis is favorably carried out at temperatures of 0°C to 100°C, more preferably 20°C to 60°C.

[0030] In one embodiment of the process according to the present invention for producing the compound of formula (I), steps (B) and (C) can be advantageously carried out in a one-pot manner without isolating the intermediate compound of formula (V). This is achieved by directly heating the compound of formula (IV) in an aqueous medium, optionally in the presence of a suitable acid, using a suitable cosolvent as described above for steps (B) and (C).

[0031] Suitable acids include, but are not limited to, sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, and methanesulfonic acid. Most preferably, the acid is sulfuric acid or hydrochloric acid.

[0032] The compound of formula (II) can be conveniently prepared from the compound of formula (VI), as shown in Scheme 5. In one version (Method A), the compound of formula (VI) will first be oxidized to the compound of formula (VII), optionally in the presence of a chiral catalyst. Then, hydroxylamine will be added to the nitrile group of the compound of formula (VII) to obtain the compound of formula (II). Alternatively (Method B), the order of the steps can be reversed, with hydroxylamine first added to the nitrile portion of the compound of formula (VI) to obtain the compound of formula (VIII), followed by oxidation to obtain the compound of formula (II). When enantiomer-enriched compounds are desired, it is generally advantageous to follow the oxidation route first (Method A). Specific examples of the preparation of the compound of formula (II) by either route are provided in the experimental section. Scheme 5 [ka]

[0033] Compounds of formula (VI) can be prepared by various methods known to those skilled in the art, for example, as described in International Publication Nos. 2016113205, 2014104407 and Tetrahedron 1983, 39, 4153.

[0034] Definition: As used herein, either alone or as part of a chemical group, the term "alkyl" preferably refers to a linear or branched hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, and 2-ethylbutyl. A alkyl group having 1 to 4 carbon atoms is preferred, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, or t-butyl.

[0035] As used herein, the term alkoxy refers to a linear or branched saturated alkyl group having preferably 1 to 6 carbon atoms bonded via an oxygen atom (as described above), namely, for example, one of methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, 1-methylpropoxy, 2-methylpropoxy, or 1,1-dimethylethoxy.

[0036] As used herein, the term cyanoalkyl refers to a linear or branched saturated alkyl group substituted with a cyano group (as described above), such as cyanomethylene, cyanoethylene, 1,1-dimethylcyanomethyl, cyanoisopropyl, cyanomethyl, cyanoethyl, and 1-dimethylcyanomethyl.

[0037] The term cyanoalkoxy refers to a linear or branched saturated alkyloxy group (as described above) that is substituted with a cyano group.

[0038] As used herein, the term "cycloalkyl" refers to 3- to 6-membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopropane, cyclopentane, and cyclohexane.

[0039] As used herein, the term cyanocycloalkyl refers to a 3- to 6-membered cycloalkyl group (as described above) substituted with a cyano group.

[0040] The term "aryl" preferably refers to monocyclic, bicyclic, or polycyclic aromatic systems having 6 to 14, more preferably 6 to 10 ring carbon atoms, such as phenyl, naphthyl, anthryl, phenantrenyl, preferably phenyl. "Aryl" also refers to polycyclic systems, such as tetrahydronaphthyl, indenyl, indanyl, fluorenyl, and biphenyl. Arylalkyls are examples of substituted aryls, which may be further substituted with the same or different substituents on both the aryl and alkyl moieties. Benzyl and 1-phenylethyl are examples of such arylalkyls.

[0041] The terms "halogen" or "halo" refer to fluoro, chloro, bromo, or iodine, especially fluoro, chloro or This represents bromo. A halogen-substituted chemical group, such as a haloalkyl, is substituted with halogens up to one or the maximum number of substituents. When "alkyl" is substituted with a halogen, the halogen atoms can be the same or different and can be bonded to the same carbon atom or different carbon atoms.

[0042] Unless otherwise defined, the term “optionally substituted” means that the group in question may be substituted with zero to a maximum number of substituents independently selected from the following: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclopropyl, cyclohexyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, nitro, cyano, hydroxy, sulfhydryl, acetyl, acetoxy, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, amino, methylamino, dimethylamino, phenyl.

[0043] The term "enantiomerically enriched" means that one of the enantiomers of a compound is, This means that one is present in excess compared to other enantiomers. This excess is referred to below as the enantiomer excess or ee. ee can be determined by chiral GC, HPLC, or SFC analysis. ee is equal to the difference in the amounts of enantiomers divided by the sum of the amounts of enantiomers, and this quotient can be expressed as a percentage by multiplying it by 100. ee can also be called the absolute difference in the mole fraction of each enantiomer in the mixture. For example, if an isomer has an enantiomer excess (ee) of 40%, this means that the mole fraction (or percentage) of such excess isomer is 70%. Thus, in one embodiment, the term “enantiomerically enriched” also refers to an enantiomer excess (ee) of at least 40%, e.g., at least 50%, 60%, 70%, or 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 98%, and most preferably at least 99%.

[0044] A preferred embodiment of the present invention is provided as described below.

[0045] Embodiment 1 optionally provides a process for the enantioselective preparation of a cyclic acylsulfoximine of formula (I) as defined above, in enantioisomerically pure, enantioisomerically concentrated, or racemic form, as described in the detailed description above.

[0046] Embodiment 2 is a process for the enantioselective preparation of the compound of formula (I) according to Embodiment 1, (A) Reacting the compound of formula (II) with the compound of formula (III) in the presence of a suitable base and a suitable solvent (or diluent) to produce the compound of formula (IV), (B) Thermally rearranging the compound of formula (IV) in a suitable solvent (or diluent) at a suitable temperature to produce the compound of formula (V), and optionally adding a suitable base to produce the compound of formula (Va), (C) A process is provided which includes hydrolyzing a compound of formula (V) or a compound of formula (Va) by heating in an aqueous medium using a suitable cosolvent (or diluent) in the presence of a suitable acid to produce a compound of formula (I) as defined above, wherein steps (B) and (C) are optionally carried out in a one-pot manner without isolating the intermediate compound of formula (V) or formula (Va).

[0047] Embodiment 3 provides a process for the enantioselective preparation of the compound of formula (I) according to Embodiments 1-2, wherein preferred alternatives to steps (A)-(C) include the base and solvent (or diluent) used in step (A), the solvent (or diluent), temperature and base in step (B), and the temperature, co-solvent (or diluent) and optionally an acid in step (C), which are used in the processes of Embodiments 1-2 and any combination thereof as described in the detailed description above.

[0048] Execution form 4 provides a process according to execution forms 1 to 3, wherein the compound of formula (V) is prepared when steps (A) and (B) are performed in a one-pot manner without isolating the intermediate compound of formula (IV). This is most preferred when R4 in the sulfonyl chloride of formula (III) is highly electron-withdrawing (e.g., 2,4-dinitrophenyl).

[0049] Regarding embodiments 1 to 4, S * The preferred values ​​for R1, R2, R3, R4, G1, and G2 are any combination of these, as listed below: Preferably, S * is a stereogenic sulfur atom in the (R)- or (S)- configuration, and the S * However, it is enantiomerically pure, enantiomerically concentrated, or in racemic form. S * is a stereogenic sulfur atom in the (R)- or (S)- configuration, and the S * However, a racemic format is also preferable. S * The (R)-stereogenic sulfur atom is the S * It is also preferable that the substance be in a form that is enantiomerically pure or enantiomerically concentrated (as defined above). S * In the (S)-stereogenic sulfur atom, the S * It is even more preferable that the substance is in a form that is enantiomerically pure or enantiomerically concentrated (as defined above).

[0050] Preferably, R1 and R3 are independently hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. More preferably, R1 and R3 are independently hydrogen, halogen, C1-C6-haloalkyl, C1-C6-cyanoalkyl, C1-C6-cyanoalkoxy, C3-C6-cycloalkyl, C3-C6-cyanocycloalkyl, or optionally substituted aryl. Most preferably, R1 and R3 are independently hydrogen, chloro, bromo, trifluoromethyl, cyclopropyl, cyanocyclopropyl, cyanoisopropoxy, cyanoisopropyl, phenyl, or halophenyl.

[0051] Preferably, R2 is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl. More preferably, R2 is a C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-haloalkyl, phenyl, or halophenyl. Most preferably, R2 is ethyl, cyclopropyl, trifluoromethyl, phenyl, or fluorophenyl.

[0052] Preferably, G1 and G2 are independently CH or N, wherein at least one of G1 or G2 is N.

[0053] It is also preferable that G1 is N and G2 is CH, or that G1 is CH and G2 is N, or that both G1 and G2 are N.

[0054] Preferably, R4 is an alkyl or substituted aryl. More preferably, R4 is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl, or 2,4-dinitrophenyl.

[0055] X is a halogen, Preferably, X is chloro. [Examples]

[0056] The following examples serve to illustrate the present invention: Experimental procedure and data Synthesis of amidine oxime of formula (II): The racemic amidine oxime of formula (II) was prepared by one of three general methods (A, B, and C). Amidine oxime enriched with all enantiomers of formula (II) was prepared by method A.

[0057] Method A - Race Seminar: [ka]

[0058] General oxidation procedure (Step 1): To a solution of the starting sulfide in acetic acid, Na2WO4.2H2O (5-10 mol%) was added, followed by the slow addition of 1.1 equivalents of 30% aqueous H2O2. The reaction mixture was stirred at ambient temperature until all the starting materials were consumed. The reaction was quenched by pouring into aqueous NaOH. The resulting mixture was extracted with RINKAN (×2). The combined organic layer was washed with 10% aqueous NaHSO3 and brine and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent under reduced pressure, and this was purified by silica gel chromatography to obtain the desired sulfoxide in pure form.

[0059] Example 1: 3-Ethylsulfinyl-5-(trifluoromethyl)pyridine-2-carbonitrile [ka] It was isolated as a colorless solid in 57% yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.27-1.40(m,3H),2.95-3.09(m,1H),3.21-3.37(m,1H)8.65(d,J=1.45Hz,1H),9.06(d,J=1.09Hz,1H) 19 F NMR(377MHz,CDCl3)δ ppm -62.80(s,3 F)

[0060] General procedure for adding hydroxylamine (Step 2): A 50% NH2OH aqueous solution (1.55 equivalents) was added to a solution of the starting nitrile in ethanol. The reaction mixture was stirred at ambient temperature until all of the starting material was consumed. The reaction mixture was evaporated to dryness to obtain the crude product, which was used in the next step without further purification.

[0061] Example 2: 3-Ethylsulfinyl-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine [ka] It was isolated as a colorless solid with 99% yield. 1 H NMR(400MHz,CDCl3)δ ppm 1.18(t,J=7.45Hz,3H)2.98-3.13(m,1H)3.33-3.49(m,1H)5.68(s,2H)8.50-8.70(m,1H)8.73(d,J=1.8Hz,1H)8.91(d,J=1.1Hz,1H) 19 F NMR(376MHz,CDCl3)δ ppm -62.27(s,3 F)

[0062] Method A - Enantiomeric enrichment: Oxidation with hydrogen peroxide in acetic acid is replaced by iron-catalyzed oxidation with hydrogen peroxide in the presence of a chiral ligand. The second step is similar to a racemic version. In this case, a specific oxidation procedure is provided.

[0063] Example 3: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-bromo-3-ethylsulfanylpyridine-2-carbonitride (2.157 g, 93% purity, 8.25 mmol) in anisole (8.3 ml), (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol) (0.235 g, 97% purity, 0.602 mmol), 4-methoxybenzoic acid (43 mg, 0.28 mmol), and Fe(acac)3 (0.277 g, 0.0784 mmol) were added. The resulting dark red solution was cooled to 10°C, and a 30% H2O2 aqueous solution (1.35 ml, 13.2 mmol) was added. The resulting two-phase mixture was stirred at 10°C for 22 hours. At this stage (complete conversion of the starting materials), the reaction was quenched by adding crushed ice (4 g) and 40% NaHSO3 aqueous solution (2.6 ml). After warming to ambient temperature, the mixture was diluted with toluene (8 ml) and treated with 1 M H2SO4 aqueous solution (0.83 ml). After stirring for 30 minutes, the phases were separated and the organic phase was washed with NaHCO3 aqueous solution (8 ml) and brine (8 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the crude product. Quantitative NMR analysis using 1,3,5-trimethoxybenzene as an internal standard showed a 91% chemical yield for the desired 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitride. The crude product was purified by reverse-phase HPLC (MeCN / water / 0.1% formic acid mobile phase) to obtain 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile (1.63 g, >99% purity, >99.5% ee, >76% isolation yield) as a white powder. 1 H NMR(400MHz,CDCl3)δ 1.32(t,J=7.45Hz,3H),2.99(dq,J=14.0,7.2Hz,1H),3.15-3.36(m,1H),8.50(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,1H) Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:IPA Gradient: 20-60% B in 2 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 240nm Sample concentration: 1 mg / mL in ACN Injection: 2μL result:

[0064] [Table 1]

[0065] For X-ray data analysis, single crystals grown from diisopropyl ether were selected. The mounted crystal specimens had dimensions of 0.4 mm × 0.3 mm × 0.3 mm and were colorless prismatics. Data acquisition was performed at 293 K using a Rigaku Oxford Diffraction Supernova diffractometer. The unit cell was determined to be orthorhombic (space group P212121), and the structure contained one molecule in the crystal asymmetric unit (Figure 1, thin bar representation labeled with chirality). Figure generated with the Flare software package (Cresset). Stereochemistry was clearly determined to be the R isomer using a Flack parameter of 0.02 + / - 0.03. Crystallographic data are summarized in Table 1, and the selected geometric parameters are listed in Table 2. Crystallographic data and structural refinement for 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile.

[0066] [Table 2]

[0067] Computer programs: SuperNova (Oxford Diffraction, 2010), CrysAlis PRO (Agilent, 2011), SIR92 (Altomare et al., 1994), CRYSTALS (Betteridge et al., 2003), CAMERON (Watkin et al., 1996)

[0068] [Table 3]

[0069] Example 4: Preparation of 5-bromo-3-[(R)-ethylsulfinyl'-N'-hydroxypyridine-2-carboxamidine [ka] To a solution of 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile (0.774 g, >99% purity, >99.5% ee, 2.99 mmol) in MeTHF (6.0 ml), 0.37 ml of 50% NH2OH aqueous solution (5.98 mmol) was added in two portions over 10 minutes. After stirring for a further 20 minutes, most of the solvent was evaporated under reduced pressure (approximately 1.2 ml remained). CPME (2.7 ml) was slowly added to induce precipitation. The precipitate was filtered, washed with CPME / MeTHF (7:3, 1.5 ml) in a filter, and dried under vacuum to obtain the title compound (0.713 g, 95% purity, 78% yield) as a white powder. 1 H NMR(400MHz,CDCl3)δ 1.27(t,J=7.45Hz,3H),2.93(dq,J=13.1,7.4Hz,1H),3.32(dq,J=13.1,7.5Hz,1H),5.58(br s,2H),7.55(s,1H),8.59(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H).

[0070] Example 5: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile [ka] A solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitride (241.5 mg, 95% purity, 1.00 mmol), Fe(acac)3 (17.5 mg, 0.0500 mmol), 4-methoxybenzoic acid (3.8 mg, 0.0250 mmol), and 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (48.8 mg, 97% purity, 0.100 mmol) in PhMe (4.0 ml) was to be mixed with 30% H2O2 aqueous solution (0.20 ml, 2.00 mmol) at ambient temperature. After vigorous stirring for 2.5 hours, the reaction mixture was poured into ELISA (23 ml) and quenched by adding 1.0 M Na2S2O3 (2.4 ml). The phases were separated, and the organic phase was washed with 1.0 M HCl (2.3 ml) and NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by reverse-phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to obtain the title compound (234 mg, 97% ee, 95% yield) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 8.77(d,J=2.3Hz,1H),8.18(d,J=2.3Hz,1H),3.26(dq,J=13.6,7.3Hz,1H),3.04(dq,J=13.6,7.3Hz,1H),2.09-1.79(m,4H),1.12(t,J=7.4Hz,3H) Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C Mobile phase: A:CO2 B:IPA Gradient: 20-60% B at 1.8 min ABPR: 1800 psi Flow rate: 2.0ml / min Detection: DAD 210~500nm Sample preparation: Dissolve in MeOH Injection: 2μL result:

[0071] [Table 4]

[0072] Example 6a: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitride (237.0 mg, 97% purity, 1.00 mmol), Fe(acac)3 (3.6 mg, 0.0101 mmol), 4-methoxybenzoic acid (3.8 mg, 0.0251 mmol), and 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dichlorophenol (32.8 mg, 98% purity, 0.110 mmol) in PhOMe (1.0 ml), 0.23 ml of 30% H2O2 aqueous solution (2.11 mmol) was added over 1 hour at 0°C using a syringe pump. The resulting reaction mixture was stirred at the same temperature for a further 20 hours. The reaction mixture was poured into SiO2 (23 ml) and quenched by adding 1.0 M NaHSO3 (2.4 ml). The phases were separated, and the organic phase was washed with 1.0 M HCl (2.3 ml) and aqueous NaHCO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by reverse-phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to obtain the title compound (230 mg, >99.5% ee, 93% yield) as a white powder. Chiral SFC method: Same as in Example 5. result:

[0073] [Table 5]

[0074] Example 6b: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitride (10.61 g, 98% purity, 45.5 mmol), Fe(acac)3 (0.153 g, 0.432 mmol), 4-methoxybenzoic acid (0.234 g, 1.54 mmol), and 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dichlorophenol (1.281 g, 97% purity, 3.30 mmol) in PhOMe (46 ml), 7.8 ml of 30% H2O2 aqueous solution (76.3 mmol) was added over 2 hours at 10°C using a syringe pump. The resulting reaction mixture was then vigorously stirred at the same temperature for a further 22 hours. The reaction was quenched by adding 10.6 ml of 40% NaHSO3 aqueous solution and diluted with PhOMe (53 ml). The phases were separated, and the organic phase was washed with 21 ml of 1 M H2SO4, 21 ml of saturated NaHCO3 aqueous solution, and 21 ml of brine. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (water / MeCN as mobile phase) to obtain the title compound (10.44 g, >99.5% ee, 93% yield) as a white powder. Chiral SFC method: SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C Mobile phase: A:CO2 B:IPA Gradient: 5-20% B at 9.8 min ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 238nm Sample preparation: 1 mg / mL of canACN Injection: 2μL result:

[0075] [Table 6]

[0076] Example 7: Preparation of 5-(1-cyanocyclopropylcan 3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine) [ka] A 100 ml reactor with mechanical stirring was filled with 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitrile (10.60 g, 45.5 mmol, 98% assay), 4-methoxybenzoic acid (0.234 g, 1.54 mmol), Fe(acac)3 (0.153 g, 0.432 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol (1.30 g, 3.33 mmol, 97% assay) and anisole (45.5 ml). The resulting dark red solution was cooled to 10°C, and 30% aqueous H2O2 (7.9 ml, 77.0 mmol) was administered over 1 hour using a syringe pump with vigorous stirring (300 rpm). After administration, the reaction mixture was stirred at the same temperature for a further 14 hours (complete conversion by LC / MS). The reaction was quenched by adding 10.6 ml of 40% NaHSO3 aqueous solution in two parts (exothermic). After 15 minutes, the reaction temperature was raised to 20°C and the mixture was vigorously stirred for 30 minutes (600 rpm) (the reaction color changed to bright yellow). The phase was separated and 10.6 ml of 1 M H2SO4 was added to the organic phase. The resulting mixture was vigorously stirred for 30 minutes. The phase was separated again and the organic phase was washed with brine (3 × 10 ml) until the washing pH was > 6. The organic phase was dried with Na2SO4. After filtering the drying agent, the resulting PhOMe solution was telescoped to the next step. qNMR analysis using 1,3,5-trimethoxybenzene as an internal standard showed a 92% chemical yield of the chiral sulfoxide and approximately 3% of the corresponding sulfone (peroxide). This solution also contains most of the ligands used in oxidation.

[0077] The chiral sulfoxide solution (54.4 g) prepared above was packed into a 100 ml reactor while mechanically stirring. In a separate flask, a 4.7 M NH2OH solution was prepared by treating the NH2OH.HCl solution with a 50% NaOH aqueous solution at 0°C (exothermic reaction). The solution thus prepared (10.0 ml, 47.2 mmol) was added to the sulfoxide solution in PhOMe over 1.5 hours at ambient temperature. After stirring for a further 2 hours (white crystals in an orange liquid), the precipitate was filtered off and washed with PhOMe (23 ml) and water (2 × 23 ml) using a filter. The resulting white powder was resuspended in water (51 ml) and vigorously stirred for 1.5 hours to obtain a stable white suspension. The precipitate was filtered, washed with water (20 ml) in a filter, and dried overnight under high vacuum to obtain the title compound (10.42 g, 97% assay, >99.5% ee, 80% isolation yield in 2 steps) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),8.59(d,J=2.3Hz,1H),8.26(d,J=2.3Hz,1H),6.01(s,2H),3.25(dq,J=13.0,7.4Hz ,1H),2.77(dq,J=13.0,7.4Hz,1H),1.99-1.84(m,2H),1.80-1.65(m,2H),1.16(t,J=7.4Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 149.0,146.1,145.0,140.1,132.9,131.1,121.4,48.8,18.5,18.5,11.7,6.7 Chiral SFC method: SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C Mobile phase: A:CO2 B:MeOH Gradient: 20-60% B at 1.8 min ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 227nm Sample preparation: 1 mg / mL in MeOH Injection: 2μL result:

[0078] [Table 7]

[0079] Example 8: Preparation of 5(1-cyanocyclopropyl)3-[(S)-ethisulfinyl]-N'-hydroxypyridine-2-carboxamidine [ka] A suspension of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile (167.1 mg, 95% purity, 97% ee, 0.648 mmol) in EtOH (1.3 ml) was mixed with 50% NH2OH aqueous solution (0.062 ml, 1.01 mmol). The resulting turbid suspension was stirred for 1 hour. The solvent was evaporated, and the residue was dried under vacuum to obtain the title compound (187.4 mg, 92% purity, 97% ee, 96% yield) as a white powder. Chiral SFC method: Results identical to Example 7:

[0080] [Table 8]

[0081] Example 9: Preparation of 5-(1-cyano-1-methylcanoxy)3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] A solution of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carbonitrile (2.00 g, 82% purity, 6.64 mmol), iron(III) acetylacetone (46.9 mg, 0.133 mmol), 2,4-dichloro-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (0.602 g, 1.99 mmol), and p-anisinic acid (51 mg, 0.332 mmol) in toluene (13 mL) was to be mixed with 30% aqueous hydrogen peroxide (1.36 mL, 50.1 mmol) over 1 hour at ambient temperature. The reaction mixture was stirred for a further 5 hours and then quenched by adding saturated sodium thiosulfate solution at 0°C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (1.55 g, 89% purity, >99.5% ee, 79% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.71(d,J=2.6Hz,1H)8.02(d,J=2.7-Hz,1H)3.28-3.33(m,1H)2.96-3.02(m,1H),1.84(s,6H),1.09(t,J=7.3Hz,3H)

[0082] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IA (4.6mm x 250mm) 5μm Mobile phase: A: TBME B: IPA Uniform concentration: 20% B in 13 minutes Flow rate: 1.0ml / min Detection: 240nm Sample preparation: 1mg / mL in EtOH Injection: 2μL result:

[0083] [Table 9]

[0084] Example 10: Preparation of 5-(1-cyano-1-methylethoxy)-3-[(R'-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine] [ka] To a solution of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfinylpyridine-2-carbonitrile (0.500 g, 97% purity, 1.84 mmol) in ethanol (1.3 mL), 1.00 equivalent, 1.84 mmol of 50% aqueous hydroxylamine was added at 0°C, and the reaction mixture was stirred at ambient temperature for a further 2 hours. An additional portion of 0.20 equivalent, 0.368 mmol of 50% aqueous hydroxylamine was added, and the reaction mixture was stirred for a further 1 hour. Ethyl acetate was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the title compound (0.54 g, 93% purity, 92% yield). 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.53(d,J=2.7Hz,1H),8.13(d,J=2.7Hz,1H),6-02(s,2H) ,3.18-3.29(m,1H),2.85(dd,J=13.1Hz,7.4Hz,1H),1.78(d,J=6.0Hz,6H)1.11(t,J=7.4Hz,3H)

[0085] Example 11: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanylpyridine-2-carbonitrile (6.00 g, 96.5% purity, 25.0 mmol), iron(III) acetylacetone (0.177 g, 0.5 mmol), and 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (1.47 g, 3.75 mmol) in toluene (90 mL), 2.0 equivalents, 50.1 mmol of 30% aqueous hydrogen peroxide was added dropwise at 0°C for 1 hour. The reaction mixture was stirred at 24°C for 2 hours, and then quenched at 0°C by adding saturated Na2S2O3. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude material was purified by column chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (5.48 g, 91% purity, 97% ee, 81% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.10(d,J=2.3Hz,1H),8.35(d,J=2.3Hz,1H),3.28(m,1H),3.04(m,1H),1.82(d,J=1.9Hz,6H),1.12(t,J=7.3Hz,3H)

[0086] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IC (4.6mm x 250mm) 5μm Mobile phase: A: n-hexane B: EtOH Uniform concentration: 30% B in 30 minutes Flow rate: 1.0ml / min Detection: 225nm Sample preparation: 1mg / mL in EtOH Injection: 2μL result:

[0087] [Table 10]

[0088] Example 12: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine [ka] To a solution of 5-(1-cyano-1-methyl-ethyl)3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile (2.00 g, 91% purity, 7.38 mmol) in ethanol (5.0 ml), 0.52 ml of 50% aqueous hydroxylamine (8.49 mmol) was added at room temperature. After stirring at ambient temperature for 1 hour, an additional portion of 50% aqueous hydroxylamine (0.20 ml, 3.4 mmol) was added. Upon complete conversion of the starting materials, the reaction mixture was concentrated under reduced pressure, and the product was collected by filtration. The product was washed with water in a filter and dried under high vacuum to obtain the title compound (1.78 g, 93% purity, 81% yield). 1 H NMR(400MHz,DMSO-d6)δ 10.45(s,1H),8.87(d,J=2.4Hz,1H),8.39(d,J=2.2Hz,1H),6.06(s,2H),3.21-3.31(m,1H),2.78(m,1H),1.79(s,6H),1.15(t,J=7.4Hz,3H)

[0089] Example 13: Preparation of 5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(3-fluorophenyl)-3-methylphenylpyridine-2-carbonitrile (0.800 g, 90% purity, 2.95 mmol), iron(III) acetylacetone (10.4 mg, 0.0295 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (0.213 g, 0.442 mmol), and p-anisinic acid (11.3 mg, 0.0737 mmol) in toluene (6.0 mL), 0.6 mL, 5.9 mmol of 30% H2O2 aqueous solution was added dropwise over 15 minutes. The reaction mixture was stirred for a further 1 hour. The reaction mixture was quenched with saturated sodium thiosulfate, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude material. The title compound (0.73 g, 94% purity, 97% ee, 89% yield) was obtained by purification using silica gel chromatography with cyclohexane and ethyl acetate as eluents. 1 H NMR(400MHz,DMSO-d6)δ 9.29(d,J=2.1Hz,1H),8.64(d,J=2.1Hz,1H),7.89(m,1H),7.80(d,J=7.8Hz,1H),7.64(m,1H),7.41(m,1H),3.04(s,3H)

[0090] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IA (4.6mm x 250mm) 5μm Mobile phase: A: TBME B: IPA Uniform concentration: 30% B in 30 minutes Flow rate: 1.0ml / min Detection: 225nm Sample preparation: 1mg / mL in EtOH Injection: 2μL Results:

[0091] [Table 11]

[0092] Example 14: Preparation of 5-(3-fluorophenyl)N'-hydroxy-3-[(R)-methylsulfinyl]pyridine-2-carboxamidine [ka] To a solution of 5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carbonitrile (0.12 g, 94% purity, 0.434 mmol) in ethanol (0.5 mL), a 50% aqueous solution of hydroxylamine (0.030 mL, 0.434 mmol) was added at room temperature. The reaction mixture was stirred for 2 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (0.11 g, 98% purity, 85% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),9.06(d,J=2.2Hz,1H),8.61(d,J=2.1Hz,1H),7.75(dt,J=10.3,2.2H z,1H),7.67-7.71(m,1H),7.58-7.65(m,1H),7.34(m,1H),6.07(s,2H),2.90(s,3H)

[0093] Example 15: Preparation of 3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carbonitrile [ka] To a solution of 3-ethylsulfanyl-3-(trifluoromethyl)pyridine-2-carbonitrile (0.237 g, 98% purity, 1.00 mmol) in anisole (1.0 ml), (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol) (28.5 mg, 97% purity, 0.073 mmol), 4-methoxybenzoic acid (5.3 mg, 0.034 mmol), and Fe(acac)3 (3.4 mg, 0.010 mmol) were added. The resulting dark red solution was cooled to 10°C, and a 30% H2O2 aqueous solution (0.136 ml, 1.6 mmol) was added. The resulting two-phase mixture was stirred at 10°C for 22 hours. At this stage (complete conversion of the starting materials), the reaction was quenched by adding crushed ice (4 g) and 40% NaHSO3 aqueous solution (0.30 ml). After warming to ambient temperature, the mixture was diluted with HCl (10 ml) and treated with concentrated H2SO4 (50 μl). After stirring for 30 minutes, the phases were separated, and the aqueous layer was extracted again with HCl (15 ml). The combined organic layers were washed with saturated NaHCO3 aqueous solution (8 ml) and brine (8 ml). The organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography (cyclohexane / HCl 100:0~60:40) to obtain the title compound (127 mg, 98% purity, >99% ee, 50% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ 1.27-1.40(m,3H),2.95-3.09(m,1H),3.21-3.37(m,1H)8.65(d,J=1.45Hz,1H),9.06(d,J=1.09Hz,1H) 19 F NMR(377MHz,CDCl3)δ -62.80(s,3 F) Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:MeOH Uniform concentration of 3% B in 2 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 270nm Sample concentration: 1 mg / mL in MeOH Injection: 1μL result:

[0094] [Table 12]

[0095] Example 16: 3-[(R)-ethylsulfinyl]-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine [ka] A solution of 3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carbonitrile (800 mg, 3.16 mmol) in EtOH (25 ml) was mixed with 50% NH2OH aqueous solution (300 μL, 4.9 mmol). The resulting colorless solution was stirred at ambient temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (892 mg, >99% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ 1.18(t,J=7.45Hz,3H)2.98-3.13(m,1H)3.33-3.49(m,1H)5.68(s,2H)8.50-8.70(m,1H)8.73(d,J=1.8Hz,1H)8.91(d,J=1.1Hz,1H) 19 F NMR(376MHz,CDCl3)δ -62.27(s,3 F)

[0096] Method B: [ka]

[0097] According to Method B, the steps are reversed, with hydroxylamine first being added to the functionalized nitrile, followed by the oxidation of the sulfide with hydrogen peroxide to form an amidine oxime.

[0098] General Procedure Step 1: To a solution of the starting nitrile in EtOH (2 ml / mmol), 1.1 equivalents of a 50% NH2OH aqueous solution were added. The reaction mixture was stirred at ambient temperature until the starting material was completely consumed. The reaction mixture was then evaporated to dryness, and the desired product was purified by either trituration with diisopropyl ether or silica gel chromatography. Compounds prepared by this method:

[0099] Example 17: N'-Hydroxy-3-phenylsulfanyl-5-(trifluoromethyl)pyridine-2-carboxamidine [ka] It was isolated as an off-white solid with 99% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.57(s,1H),8.68(d,J=1.1Hz,1H),7.57-7.61(m,2H),7.52-7.56(m,3H),7.15(d,J=1.1Hz,1H),6.01(s,2H); 13 C NMR(101MHz,DMSO-d6)δ 150.0,148.3,140.3,136.7,135.3,131.7,130.6(q,J=4.0Hz),130.5,130.1,124.3(q,J=32.9Hz),123.4(q,J=273.0Hz)

[0100] Example 18: N-hydroxy-3-phenylsulfanylpyrazine-2-carboxamidine [ka] It was isolated as an off-white solid with a yield of 78%. 1H NMR(400MHz,DMSO-d6)δ 10.52(br s,1H),8.33(br s,1H),8.28(br s,1H),7.38-7.51(m,5H),5.96(br s,2H); 13 C NMR(101MHz,DMSO-d6)δ 154.8,149.2,142.6,141.8,138.2,135.4,131.3,129.1,128.8

[0101] Example 19: 5-Chloro-2-ethylsulfanyl-N-hydroxypyridine-3-carboxamidine [ka] It was isolated as an off-white solid with a yield of 76%. 1 H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),8.51(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,1H),5.90(br s,2H),3.03(q,J=7.3Hz,2H),1.22(t,J=7.3Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 156.4,148.4,146.8,135.4,129.3,126.0,24.4,14.1

[0102] Example 20: 5-Chloro-N-hydroxy-2-phenylsulfanylpyridine-3-carboxamidine [ka] It was isolated as an off-white solid with a 91% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.04(s,1H),8.34(d,J=2.2Hz,1H),7.90(d,J=2.2Hz,1H),7.37-7.47(m,5H),6.06(br s,2H); 13¹³C NMR (101 MHz, DMSO-d6) δ 156.0, 148.5, 147.2, 135.7, 134.8, 131.8, 129.1, 128.5, 127.2 (overlap of two signals)

[0103] Example 21: N-hydroxy-2-phenylsulfanyl-5-(trifluoromethyl)pyridine-3-carboxamidine [ka] It was isolated as an off-white solid with a 98% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.64(d,J=2.2Hz,1H),8.09(d,J=2.2Hz,1H),7.47-7.42(m,2H),7.39-7.45(m,3H),6.15(s,2H); 13 C NMR(101MHz,DMSO-d6)δ 162.8,148.5,145.3(q,J=4.0Hz),135.2,132.8(q,J=4.0Hz),131.0,129.2,128.9,127.5,121.2(q,J=32.6Hz),123.4(q,J=272.3Hz)

[0104] General Procedure Step 2: To the solution of amidine oxime prepared in Step 1 in acetic acid (2 ml), Na2WO4.2H2O (5 mol%) and 30% H2O2 aqueous solution (1.1 equivalents) were added. The reaction mixture was then stirred at ambient temperature until all the starting materials were consumed. The reaction mixture was quenched by neutralization with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with RINKAN (3×). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the desired sulfoxide. The crude product was used without further purification or purified by silica gel chromatography.

[0105] Compounds prepared by this method:

[0106] Example 22: 3-(Benzenesulfinyl)-N’-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine

Chem.

[0107] Example 23: 3-(Benzenesulfinyl)-N-hydroxy-pyrazine-2-carboxamidine

Chem.

[0108] Example 24: 5-Chloro-2-ethylsulfinyl-N’-hydroxy-pyridine-3-carboxamidine

Chem.

[0109] Example 25: 2-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-3-carboxamidine [ka] It was isolated as a white solid with an 87% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.38(br s,1H),8.77(d,J=2.5Hz,1H),8.18(d,J=2.5Hz,1H),7.91(dd,J=7.8,1.6Hz,2H),7.43-7.51(m,3H),6.29(s,2H); 13 C NMR(101MHz,DMSO-d6)δ 160.4,149.0,147.1,145.2,136.1,132.2,130.5,130.1,128.7,125.6

[0110] Example 26: 2-(benzenesulfinyl)-N'-hydroxy-5-(trifluoromethyl)pyridine-3-carboxamidine [ka] It was isolated as a white solid with a 94% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.43(s,1H),9.14(d,J=1.5Hz,1H),8.43(d,J=1.5Hz,1H),7.91-8.00(m,2H),7.44-7.51(m,3H),6.38(s,2H);13 C NMR(101MHz,DMSO-d6)δ 166.2,147.2,147.0(q,J=3.3Hz),145.0,134.2(q,J=3.0Hz),130.7,128.9,128.7,125.9,126.1(q,J=33.0Hz),122.9(q,J=273.3Hz)

[0111] Method C: [ka] Method C was used in particular for compounds where G1=N, G2=CH, R1=Cl, R3=H, and R2 is as defined for the compound of formula (I). In this case, the starting amidine oxime is commercially available and can also be prepared as described in International Publication No. CN101029023. In the first step, the corresponding sulfide is produced by nucleophilic aromatic substitution with a thiol in the presence of a base, which is then oxidized using hydrogen peroxide as described for Method B.

[0112] General Procedure Step 1: To a suspension of NaH (1.1-3.1 equivalents) in dried 2-methyltetrahydrofuran (5 ml / mmol), the corresponding thiol (1.1-3.1 equivalents) was added. After stirring at ambient temperature for 10 minutes, heteroarylhydroxylamine was added. The reaction mixture was stirred at 80°C until the starting materials were completely converted. The reaction mixture was then cooled to ambient temperature, and the solvent was evaporated under reduced pressure. The residue was incorporated into ethyl acetate and water. The phases were separated, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The crude product was obtained by evaporation of the solvent under reduced pressure. The crude product was further purified by either trituration with diisopropyl ether or silica gel chromatography.

[0113] Compounds prepared by this method:

[0114] Example 27: 5-Chloro-N'-hydroxy-3-phenylsulfanylpyridine-2-carboxamidine [Chemical formula] It was isolated as an off - white solid in 82% yield. 1 H NMR (400 MHz, DMSO - d6) δ 10.32 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 7.54 - 7.59 (m, 5H), 6.90 (d, J = 2.2 Hz, 1H), 5.88 (s, 2H); 13 C NMR (101 MHz, DMSO - d6) δ 149.9, 143.7, 142.4, 137.2, 135.2, 133.0, 131.9, 130.4, 130.4, 130.0

[0115] Example 28: 5 - chloro - 3 - ethylsulfanyl - N’ - hydroxy - pyridine - 2 - carboxamidine [Chemical formula] It was isolated as an off - white solid in 96% yield. 1 H NMR (400 MHz, DMSO - d6) δ 10.15 (br s, 1H), 8.35 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 5.76 (s, 2H), 2.93 (q, J = 7. 4 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, DMSO - d6) δ 150.0, 144.6, 141.5, 136.5, 132.4, 130.6, 25.7, 12.6

[0116] <00009​​​​​​​​​H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.36(d,J=1.8Hz,1H),7.86(d,J=1.8Hz,1H),5.74(s,2H),3.65(spt,J=6.5Hz,1H),1.25(d,J=6.5Hz,6H); 13 C NMR(101MHz,DMSO-d6)δ 149.9,145.6,141.9,135.6,133.6,130.5,34.5,22.0

[0117] Example 30: 5-Chloro-3-cyclohexylsulfanyl-N-hydroxypyridine-2-carboxamidine [ka] It was isolated as an off-white solid with a 61% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.35(br s,1H),7.86(br s,1H),5.73(br s,2H),3.37-3.52(m,1H),1.92(br d,J=10.9Hz,2H),1.69(br d,J=8.7Hz,2H),1.57-1.63(m,1H),1.37-1.48(m,2H),1.18-1.30(m,3H); 13 C NMR(101MHz,DMSO-d6)δ 149.9,145.7,141.8,135.1,133.4,130.5,42.5,32.0,25.3,25.2

[0118] Example 31: 5-Chloro-N-hydroxy-3-(o-tolylsulfanyl)pyridine-2-carboxamidine [ka] It was isolated as an off-white solid with a 52% yield. 1H NMR(400MHz,DMSO-d6)δ 10.36(s,1H),8.37(d,J=2.2Hz,1H),7.55(d,J=7.6Hz,1H),7.48(d,J=4.0H z,2H),7.33-7.38(m,1H),6.69(d,J=2.2Hz,1H),5.89(s,2H),2.27(s,3H); 13 ¹³C NMR (101 MHz, DMSO-d6) δ 150.0, 143.7, 142.2, 136.6, 136.4, 132.0, 131.4, 130.7, 130.7, 130.4, 127.9, 20.0 (overlap of two signals)

[0119] Example 32: 3-(4-bromophenyl)sulfanyl-5-chloro-N-hydroxypyridine-2-carboxamidine [ka] Isolated as an off-white solid with 80% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.32(s,1H),8.40(d,J=2.2Hz,1H),7.72(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.00(d,J=2.2Hz,1H),5.89(s,2H); 13 C NMR(101MHz,DMSO-d6)δ 149.8,144.0,142.8,136.9,136.3,133.4' 133.3,131.6,130.5,123.5

[0120] Example 33: 5-Chloro-N'-hydroxy-3-(4-methoxyphenyl)sulfanylpyridine-2-carboxamidine [ka] It was isolated as a white solid with a 25% yield. 1H NMR(400MHz,DMSO-d6)δ 10.30(s,1H),8.35(d,J=2.2Hz,1H),7.50(d,J=9.1Hz,2H),7.10(d,J=9.1Hz,2H),6.87(d,J=2.2Hz,1H),5.86(s,2H),3.83(s,3H); 13 C NMR(101MHz,DMSO-d6)δ 160.6,149.9,143.3,142.1,138.3,137.2,132.4,130.4,121.9,116.0,55.4

[0121] Example 34: 5-Chloro-N'-hydroxy-3-[4-(trifluoromethyl)phenyl]sulfanylpyridine-2-carboxamidine [ka] It was isolated as an off-white solid with a 42% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.32(s,1H),8.46(d,J=2.2Hz,1H),7.85(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.16(d,J=2.2Hz,1H),5.91(br s,2H); 13 C NMR(101MHz,DMSO-d6)δ 149.8,144.9,143.5,138.3,135.0,134.7,134.5,130.5,129.4(q,J=31.9Hz),126.9(q,J=3.0Hz),123.9(q,J=272.3Hz)

[0122] General Procedure Step 2: Same as the procedure described for Method B Compounds prepared by this method:

[0123] Example 35: 3-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-2-carboxamidine [ka] Isolated as an off-white solid with 81% yield. 1 1H NMR (400 MHz, CDCl3) δ 10.55 (br s, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 7.71 - 7.79 (m, 2H), 7.30 - 7.38 (m, 3H), 5.45 (br s, 2H); 13 13C NMR (101 MHz, CDCl3) δ 149.2, 148.3, 145.5, 143.8, 142.9, 133.7, 133.1, 130.9, 129.0, 125.9

[0124] Example 36: 5-Chloro-3-ethylsulfinyl-N'-hydroxy-pyridine-2-carboxamidine

Chem.

[0125] Example 37: 5-Chloro-N'-hydroxy-3-isopropylsulfinyl-pyridine-2-carboxamidine

Chem.

[0126] Example 38: 5-Chloro-3-cyclohexylsulfinyl-N'-hydroxy-pyridine-2-carboxamidine

Chem.

[0127] Example 39: 5-Chloro-N'-hydroxy-3-(o-tolylsulfinyl)pyridine-2-carboxamidine

Chem.

[0128] Example 40: 3-(4-bromophenyl)sulfinyl-5-chloro-N'-hydroxypyridine-2-carboxamidine [ka] Isolated as a white solid with 83% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.53(br s,1H),8.76(br s,1H),8.51(br s,1H),7.74(br d,J=8.4Hz,2H),7.63(br d,J=8.4Hz,2H),5.99(br s,2H); 13 C NMR(101MHz,DMSO-d6)δ 148.4,148.1,145.9,144.8,142.5,132.4,132.1,131.8,128.7,124.4

[0129] Example 41: 5-Chloro-N'-hydroxy-3-(4-methoxyphenyl)sulfinylpyridine-2-carboxamidine [ka] It was isolated as a white solid with a 93% yield. 1H NMR(400MHz,CDCl3)δ 9.23(br s,1H),8.65(d,J=2.2Hz,1H),8.51(d,J=2.2Hz,1H),7.68(d,J=9.1Hz,2H),6.79(d,J=9.1Hz,2H),5.41(s,2H),3.73(s,3H); 13 C NMR(101MHz,CDCl3)δ 161.6,149.0,148.1,143.9,142.9,136.1,133.5,132.7,128.0,114.4,55.3

[0130] Example 42: 5-Chloro-N'-hydroxy-3-[4-(trifluoromethyl)phenyl]sulfinylpyridine-2-carboxamidine [ka] It was isolated as a white solid with a 75% yield. 1 H NMR(400MHz,DMSO-d6)δ 10.61(br s,1H),8.79(d,J=2.5Hz,1H),8.53(d,J=2.5Hz,1H),8.03(d,J=8.0Hz,2H),7.79(d,J=8.0Hz,2H),6.02(s,2H); 13 C NMR(101MHz,DMSO-d6)δ 151.2,148.6,148.1,144.9,142.1,132.6,132.2,130.8(q,J=32.6Hz),127.5,125.9(q,J=3.7Hz),123.6(q,J=273.2Hz)

[0131] Preparation of compounds of formulas (IV), (V), and (I):

[0132] Example 43: Preparation of (Z)-[[amino-[5-bromo-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] To a solution of 5-bromo-3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (0.611 g, 95% purity, 1.99 mmol) in THF (4.0 ml), Et3N (0.33 ml, 2.39 mmol), followed by NsCl (0.488 g, 2.20 mmol), was added. The reaction mixture was stirred at ambient temperature for 3 hours. 18 ml of HCl was added, and the resulting mixture was washed with water (3.5 ml), 1 M aqueous HCl (2.5 ml), aqueous NaHCO3 (3.5 ml), and brine (5 ml). Additional HCl (58 ml) was added to prevent precipitation. The combined organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the title compound (1.024 g) in crude form. This material was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ 1.23(t,J=7.4Hz,3H),2.85(dq,J=13.35,7.3Hz,1H),3.27(dq,J=13.26,7.4Hz,1H),5.62(br s,1H),6.61(br s,1H),8.21-8.29(m,2H),8.39-8.48(m,2H),8.62(d,J=2.2Hz,1H),8.69(d,J=2.2Hz,1H).

[0133] Example 44: Preparation of (1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-one [ka] The crude starting material (1.024 g) prepared in Example 43 was dissolved in a mixture of THF (8.0 ml) and water (2.0 ml). The resulting yellow solution was heated in a closed vial at 80°C for 7 hours. The reaction mixture was cooled to ambient temperature and diluted with brine (20 ml). The phases were separated, and the aqueous phase was extracted with SiO2 (2 × 30 mL). The combined organic phases were washed with aqueous NaHCO3 solution, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude residue (approximately 0.49 g) was crystallized from THF (approximately 4.5 ml). The precipitate was filtered, washed with a filter using a minimum amount of cold THF, and dried under vacuum to obtain the title compound (0.329 g, 99% purity, >99.5% ee, 59% yield) as a white crystalline solid. 1 H NMR(400MHz,CDCl3)δ 1.44(t,J=7.3Hz,3H),3.63-3.95(m,2H),8.48(d,J=1.8Hz,1H),9.16(d,J=1.8Hz,1H); 13 C NMR(101MHz,CDCl3)δ 7.64,49.12,124.21,133.71,134.62,152.07,158.54,168.07. Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® AY, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:EtOH Uniform concentration of 30% B achieved in 4.8 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 240nm Sample concentration: 1 mg / mL in ACN Injection: 1μL result:

[0134] [Table 13]

[0135] For X-ray data analysis, single crystals grown from diisopropyl ether / acetonitrile were selected. The mounted crystal sample had dimensions of 0.8 mm × 0.05 mm × 0.05 mm and was a colorless needle. Data acquisition was performed at 293 K using a Rigaku Oxford Diffraction Supernova diffractometer. The unit cell was determined to be orthorhombic (space group P212121), and the structure contained one molecule within the crystallographic asymmetric unit (Figure 2, thin bar representation labeled with chirality). Figure generated with the Flare software package (Cresset). Stereochemistry was clearly determined to be R isomer using a Flack parameter of -0.04+ / -0.04. Crystallographic data are summarized in Table 3, and the selected geometric parameters are listed in Table 4.

[0136] [Table 14]

[0137] Computer programs: SuperNova (Oxford Diffraction, 2010), CrysAlis PRO (Agilent, 2011), SIR92 (Altomare et al., 1994), CRYSTALS (Betteridge et al., 2003), CAMERON (Watkin et al., 1996)

[0138] [Table 15]

[0139] Based on the X-ray data shown above, it can be determined by analogy that the compound of formula (I), derived from a sulfoxide enantiomerically enriched in the R enantiomer, is also enantiomerically enriched in the R isomer, and therefore the entire process proceeds through the preservation of stereochemistry. Subsequently, by starting with a sulfoxide enantiomerically enriched in the S isomer, the compound of formula (I), enantiomerically enriched in the S isomer, can be obtained.

[0140] Example 45: 6-Chloro-1-isopropyl-1-oxo-isothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 5-chloro-N'-hydroxy-3-isopropylsulfinylpyridine-2-carboxamidine (222 mg, 95% purity, 0.806 mmol) in tetrahydrofuran (2.5 ml), Et3N (0.12 ml, 0.886 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.241 g, 0.886 mmol). The reaction mixture was stirred at ambient temperature for 5 hours (complete conversion of the starting materials by LC / MS). Water (0.8 ml) was added, and the resulting mixture was stirred for a further 48 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (195 mg, 72% purity, 71% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ 9.05(d,J=1.8Hz,1H),8.26(d,J=1.8Hz,1H),3.86(spt,J=6.9Hz,1H),1.56(d,J=6.9Hz,3H),1.50(d,J=6.9Hz,3H); 13 C NMR(101MHz,CDCl3)δ 168.5,156.6,152.3,135.8,133.9,131.5,56.8,16.4,15.8

[0141] Example 46: 6-Chloro-1-cyclohexyl-1-oxoisothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 5-chloro-3-cyclohexylsulfinyl-N'-hydroxypyridine-2-carboxamidine (200 mg, 97% purity, 0.643 mmol) in tetrahydrofuran (1.9 ml), Et3N (0.10 ml, 0.707 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.192 g, 0.707 mmol). The reaction mixture was stirred at ambient temperature for 8 hours (complete conversion of the starting materials by LC / MS). Water (0.6 ml) was added, and the resulting mixture was stirred for a further 48 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (180 mg, 77% purity, 76% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.18(br s,1H),9.00-9.12(m,1H),4.14(br t,J=11.4Hz,1H),2.21(br d,J=11.4Hz,1H),1.75-1.91(m,3H),1.58-1.68(m,1H),1.13-1.53(m,5H); 13 C NMR(101MHz,DMSO-d6)δ 168.0,155.9,151.1,134.6,133.7,133.1,61.3,25.0,24.4,24.4,24.2,24.1

[0142] Example 47: [(Z)-[amino[3-(benzenesulfinyl)-5-chloro-2-pyridyl]methylene]amino]4-methylbenzenesulfonate [ka] To a solution of 3-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-2-carboxamidine (1.20 g, 88% purity, 3.57 mmol) in dichloromethane (18 ml), Et3N (0.55 ml, 3.93 mmol) and p-toluenesulfonyl chloride (0.764 g, 3.93 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 hours, and then quenched by adding saturated NaHCO3 aqueous solution. The phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic layers were dried over anhydrous MgSO4. The title compound (1.83 g, 83% purity, 94% yield) was obtained by evaporation of the solvent under reduced pressure. 1 H NMR(400MHz,CDCl3)δ 8.52(d,J=2.2Hz,1H),8.48(d,J=2.2Hz,1H),7.87(d,J=8.4Hz,2H),7.62-7.67( m,2H),7.31-7.40(m,3H),7.25(d,J=8.0Hz,2H),5.40-6.65(m,2H),2.35(s,3H); 13 C NMR(101MHz,CDCl3)δ 153.3,148.6,145.4,145.3,145.0,140.9,135.6,133.4,132.1,130.9,129.5,129.0,128.9,125.6,21.5

[0143] Example 48: [(Z)-[amino[3-(benzenesulfinyl)-5-chloro-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] To a solution of 3-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-2-carboxamidine (300 mg, 92% purity, 0.933 mmol) in dichloromethane (5.0 ml), Et3N (0.14 ml, 1.03 mmol) and 4-nitrobenzenesulfonyl chloride (0.235 g, 1.03 mmol) were added. The reaction mixture was stirred at ambient temperature for 40 minutes, and then quenched by adding saturated NaHCO3 aqueous solution. The phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic layers were dried over anhydrous MgSO4. The title compound (433 mg, 82% purity, 79% yield) was obtained by evaporation of the solvent under reduced pressure. 1 H NMR(400MHz,DMSO-d6)δ 8.82(d,J=2.2Hz,1H),8.35(d,J=9.1Hz,2H),8.30(d,J=2.2Hz,1H),8.18(d,J=8.7Hz,2H),7.32-7.63(m,7H); 13 C NMR(101MHz,DMSO-d6)δ 155.1,150.5,149.8,145.0,144.7,142.7,140.7,134.5,133.0,131.1,130.0,129.2,125.3,124.5

[0144] Example 49: (6-chloro-1-oxo-1-phenyl-isothiazolo[4,5-b]pyridine-3-ylidene)ammonium chloride [ka] To a solution of 3-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-2-carboxamidine (1.12 g, 95% purity, 3.60 mmol) in dichloromethane (11 ml), Et3N (0.53 ml, 3.78 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (1.03 g, 3.78 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The resulting precipitate was filtered, washed with dry dichloromethane in a filter, and dried under high vacuum to obtain the title compound (0.925 g, >99% purity, 82% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 11.77(br s,2H),9.48(d,J=1.1Hz,1H),9.33-9.39(m,1H),8.28(br d,J=8.0Hz,2H),7.99(t,J=8.0Hz,1H),7.82(t,J=8.0Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ 167.0,156.0,147.4,137.2,136.5,135.3,133.7,130.6,130.1,129.3

[0145] Example 50a: 6-Chloro-1-oxo-1-phenyl-isothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 3-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-2-carboxamidine (1.050 g, 95% purity, 3.37 mmol) in tetrahydrofuran (10 ml), Et3N (0.52 ml, 3.71 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (1.01 g, 3.71 mmol). The reaction mixture was stirred first at ambient temperature for 30 minutes, then at 50°C for 2 hours (complete conversion of the starting materials). Water (3.4 ml) and 4% aqueous HCl (0.05 ml) were added, and the resulting mixture was stirred for a further 2 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (1.11 g, 83% purity, 98% yield) as an off-white solid. Further trituration with a small amount of toluene, filtration of the precipitate, and drying under high vacuum yielded a higher purity (97%) material. 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=1.8Hz,1H),7.98-8.11(m,3H),7.82(br t,J=7.4Hz,1H),7.65-7.72(m,2H); 13C NMR(101MHz,CDCl3)δ 168.9,155.9,149.6,138.5,136.0,135.7,132.8,130.5,130.3,129.0

[0146] Example 50b: 6-Chloro-1-oxo-1-phenyl-isothiazolo[4,5-b]pyridine-3-one [ka] A solution of [(Z)-[amino[3-(benzenesulfinyl)-5-chloro-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (1.30 g, 87% purity, 2.51 mmol) in a mixture of THF (25 ml) and water (5 ml) was heated at 80°C for 6 days (complete conversion of the starting materials by LC / MS). The reaction mixture was cooled to ambient temperature and quenched by the addition of saturated NaHCO3 aqueous solution. The resulting mixture was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous MgSO4. By evaporation of the solvent, the title compound (0.679 g, 88% purity, 85% yield) was obtained as an off-white solid.

[0147] Example 50c: 6-Chloro-1-oxo-1-phenyl-isothiazolo[4,5-b]pyridine-3-one [ka] A solution of [(Z)-[amino[3-(benzenesulfinyl)-5-chloro-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate (235 mg, 82% purity, 0.40 mmol) in a mixture of THF (1.2 ml) and water (0.4 ml) was heated at 80°C for 16 hours (approximately 96% conversion). The reaction mixture was cooled to ambient temperature and quenched by adding saturated NaHCO3 aqueous solution. The resulting mixture was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous MgSO4. By evaporation of the solvent, the title compound (160 mg, 66% purity, 95% yield) was obtained as an off-white solid.

[0148] Example 51: 6-Chloro-1-(o-tolyl)-1-oxo-isothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 5-chloro-N'-hydroxy-3-(o-tolylsulfinyl)pyridine-2-carboxamidine (140 mg, 95% purity, 0.429 mmol) in tetrahydrofuran (1.3 ml), Et3N (0.066 ml, 0.47 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.128 g, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 8 hours (complete conversion of the starting materials by LC / MS). Water (0.4 ml) and one drop of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (136 mg, 81% purity, 88% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.20(br s,1H),8.96-9.12(m,1H),8.10(br d,J=7.3Hz,1H),7.78(br s,1H),7.49-7.69(m,2H),2.41(br s,3H); 13 C NMR(101MHz,DMSO-d6)δ 168.4,156.1,149.8,138.9,136.9,136.0,135.2,133.9,132.3,130.6,130.6,127.8,19.7

[0149] Example 52: 1-(4-bromophenyl)-6-chloro-1-oxoisothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 3-(4-bromophenyl)sulfinyl-5-chloro-N'-hydroxypyridine-2-carboxamidine (250 mg, 95% purity, 0.634 mmol) in tetrahydrofuran (1.9 ml), Et3N (0.10 ml, 0.70 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.189 g, 0.70 mmol). The reaction mixture was stirred at ambient temperature for 8 hours (complete conversion of starting materials by LC / MS). Water (0.6 ml) was added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (230 mg, 77% purity, 78% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ 9.00(d,J=1.8Hz,1H),8.07(d,J=1.8Hz,1H),7.87-7.92(m,2H),7.80-7.85(m,2H); 13 C NMR(101MHz,CDCl3)δ 168.6,156.1,149.5,138.1,135.8,133.9,132.2,131.8,130.4,130.3

[0150] Example 53: 6-Chloro-1-(4-methoxyphenyl)-1-oxo-isothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 5-chloro-N'-hydroxy-3-(4-methoxyphenyl)sulfinylpyridine-2-carboxamidine (174 mg, 95% purity, 0.507 mmol) in tetrahydrofuran (1.5 ml), Et3N (0.078 ml, 0.56 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.151 g, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 8 hours (complete conversion of the starting materials by LC / MS). Water (0.5 ml) was added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (142 mg, 82% purity, 74% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.13(d,J=2.2Hz,1H),9.05(d,J=2.2Hz,1H),8.04-8.09(m,2H),7.24-7.29(m,2H),3.89(s,3H); 13 C NMR(101MHz,DMSO-d6)δ 168.7,165.3,155.5,148.9,138.3,134.9,131.7,131.6,122.4,115.8,56.2

[0151] Example 54: 6-Chloro-1-oxo-1-[4-(trifluoromethyl)phenyl]isothiazolo[4,5-b]pyridine-3-one [ka] To a solution of 5-chloro-N'-hydroxy-3-[4-(trifluoromethyl)phenyl]sulfinylpyridine-2-carboxamidine (180 mg, 95% purity, 0.470 mmol) in tetrahydrofuran (1.4 ml), Et3N (0.073 ml, 0.52 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.141 g, 0.52 mmol). The reaction mixture was stirred at ambient temperature for 7 hours (complete conversion of starting materials by LC / MS). Water (0.5 ml) and a few drops of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (172 mg, 84% purity, 89% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.20(d,J=1.5Hz,1H),9.15(d,J=1.5Hz,1H),8.39(d,J=8.4Hz,2H),8.13(d,J=8.4Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ 168.3,156.0,149.7,137.2,136.8,135.0,135.1(q,J=32.6Hz),132.5,130.4,127.4(q,J=4.0Hz),123.1(q,J=273.9Hz)

[0152] Example 55: 1-Oxo-1-phenyl-isothiazolo[4,5-b]pyrazine-3-one [ka] To a solution of 3-(benzenesulfinyl)-N-hydroxypyrazine-2-carboxamidine (250 mg, 95% purity, 0.905 mmol) in tetrahydrofuran (2.7 ml), Et3N (0.14 ml, 1.0 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.271 g, 1.0 mmol). The reaction mixture was stirred at 50°C for 16 hours (complete conversion of the starting materials by LC / MS). Water (0.9 ml) and a few drops of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred at 50°C for a further 7 hours. The reaction was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with SiO(3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase silica gel chromatography to obtain the title compound (167 mg, >99% purity, 75% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.23(d,J=2.2Hz,1H),9.00(d,J=2.2Hz,1H),8.15(d,J=7.4Hz,2H),7.93(t,J=7.4Hz,1H),7.78(t,J=7.4Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ 167.5,155.2,151.0,148.0,145.4,136.4,130.6,130.6,129.6

[0153] Example 56: 1-Oxo-1-phenyl-6-(trifluoromethyl)isothiazolo[4,5-b]pyrazine-3-one [ka] To a solution of 3-(benzenesulfinyl)-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine (515 mg, 99% purity, 1.55 mmol) in tetrahydrofuran (4.6 ml), Et3N (0.24 ml, 1.70 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.463 g, 1.70 mmol). The reaction mixture was stirred at 60°C for 8 hours (complete conversion of the starting materials by LC / MS). Water (1.5 ml) and a few drops of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound (540 mg, 86% purity, 96% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.54(d,J=1.1Hz,1H),9.45(d,J=1.1Hz,1H),8.16-8.23(m,2H),7.88-7.93(m,1H),7.73-7.80(m,2H); 13 C NMR(101MHz,DMSO-d6)δ 168.4,154.3,154.2(q,J=3.3Hz),136.6,136.1,132.3,131.1(q,J=3.5Hz),130.3,129.3,127.6(q,J=33.9Hz),122.8(q,J=273.8Hz)

[0154] Example 57: 5-Chloro-1-ethyl-1-oxo-isothiazolo[5,4-b]pyridine-3-one [ka] To a solution of 5-chloro-2-ethylsulfinyl-N'-hydroxypyridine-3-carboxamidine (400 mg, 95% purity, 1.53 mmol) in tetrahydrofuran (4.6 ml), Et3N (0.24 ml, 1.70 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.412 g, 1.69 mmol). The reaction mixture was stirred at 50°C for 4 hours (complete conversion of the starting materials by LC / MS). Water (1.5 ml) and a few drops of 4% aqueous HCl solution were added (pH < 2), and the resulting mixture was stirred for a further 48 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase HPLC (5-20% MeCN in water) to obtain the title compound (145 mg, >99% purity, 41% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.12(d,J=2.2Hz,1H),8.59(d,J=2.2Hz,1H),3.96-4.12(m,2H),1.33(t,J=7.3Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 166.7,156.8,153.0,137.7,134.0,130.9,46.3,7.0

[0155] Example 58: 5-Chloro-1-oxo-1-phenyl-isothiazolo[5,4-b]pyridine-3-one [ka] To a solution of 2-(benzenesulfinyl)-5-chloro-N'-hydroxypyridine-3-carboxamidine (400 mg, 86% purity, 1.53 mmol) in tetrahydrofuran (3.4 ml), Et3N (0.18 ml, 1.25 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.305 g, 1.25 mmol). The reaction mixture was stirred at 50°C for 6 hours (complete conversion of the starting materials by LC / MS). Water (1.1 ml) and a few drops of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred for a further 16 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase silica gel chromatography (10-100% MeCN in water) to obtain the title compound (151 mg, 90% purity, 43% yield). 1 H NMR(400MHz,CDCl3)δ 8.74(d,J=2.2Hz,1H),8.32(d,J=2.2Hz,1H),8.10(d,J=7.6Hz,2H),7.80(t,J=7.6Hz,1H),7.67(t,J=7.6Hz,2H); 13 C NMR(101MHz,CDCl3)δ 167.8,159.8,153.1,138.2,135.9,133.9,131.5,130.2,129.5,129.2

[0156] Example 59: 1-Oxo-1-phenyl-5-(trifluoromethyl)isothiazolo[5,4-b]pyrazine-3-one [ka] To a solution of 2-(benzenesulfinyl)-N'-hydroxy-5-(trifluoromethyl)pyridine-3-carboxamidine (200 mg, 98% purity, 0.595 mmol) in tetrahydrofuran (1.8 ml), Et3N (0.094 ml, 0.67 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (0.182 g, 0.67 mmol). The reaction mixture was stirred at 50°C for 4 hours (complete conversion of the starting materials by LC / MS). Water (0.6 ml) and a few drops of 4% aqueous HCl solution (pH < 2) were added, and the resulting mixture was stirred for a further 6 hours. The reaction mixture was then quenched by the addition of aqueous NaHCO3 solution, and the resulting mixture was extracted with RINKAN (3×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase silica gel chromatography (10-100% MeCN in water) to obtain the title compound (129 mg, 97% purity, 67% yield). 1 H NMR(400MHz,CDCl3)δ 9.07(d,J=1.1Hz,1H),8.61(d,J=1.1Hz,1H),8.09-8.14(m,2H),7.83(t,J=7.4Hz,1H),7.66-7.72(m,2H); 13 C NMR(101MHz,CDCl3)δ 167.6,165.0,151.3,136.2,132.2(q,J=3.0Hz),130.8,131.4(q,J=33.9Hz),130.3,129.7,127.7,122.2(q,J=274.3Hz)

[0157] Example 60: Preparation of [(Z)-[amino[3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] To a solution of 3-(R)-ethylsulfinyl]-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine (880 mg, 3.13 mmol) in THF (10 ml), Et3N (523 μl, 3.75 mmol), followed by nosyl chloride (763 mg, 3.44 mmol), was added. The reaction mixture was stirred at room temperature for 7 hours, then diluted with water (20 ml) and SiO2 (15 ml). The phases were separated, and the aqueous phase was extracted with SiO2 (2 × 15 mL). The combined organic phases were washed with 1 N aqueous HCl (20 ml) and brine (20 ml). By drying over anhydrous MgSO4 and concentrating under reduced pressure, the title compound (1.32 g, 91% yield) was obtained as a colorless foam. 1 H NMR(400MHz,DMSO-d6)δ 1.05(t,J=7.45Hz,3H)2.64-2.84(m,1H)2.92-3.13(m,1H)7.42-8.07(m,2H)8.27(d,J=8.7Hz,2H)8.42-8.55(m,3H)9.18(d,J=1.1Hz,1H) 19 F NMR(376MHz,DMSO-d6)δ -61.22(s,3 F)

[0158] Example 61: Preparation of (1R)-1-ethyl-1-oxo-6-(trifluoromethyl)isothiazolo[4,5-b]pyridine-3-one [ka] A solution of [(Z)-[amino-[3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate (200 mg, 0.43 mmol) in THF (2.14 ml) and water (0.643 ml) was heated at 65°C for 22 hours. After cooling, the reaction mixture was diluted with SiO (20 ml). The organic layer was washed with 1N aqueous NaOH (10 ml) and brine (15 ml). After drying over anhydrous MgSO4, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (SiO 20-100% in cyclohexane) to obtain the title compound (21 mg, >99% ee, 19% yield) as colorless crystals. 1 H NMR(400MHz,DMSO-d6)δ 1.29(t,J=7.3Hz,4H)4.14(dd,J=7.3,4.00Hz,1H)9.45(d,J=1.45Hz,1H)9.55-9.59(m,1H) 19 F NMR(376MHz,DMSO-d6)δ -60.35(s,3 F) Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:MeOH Gradient: 20-60% B in 2 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 270nm Sample concentration: 1 mg / mL in ACN Injection: 2μL result:

[0159] [Table 16]

[0160] Example 62: [(Z)-[amino-(5-chloro-3-ethylsulfinyl-2-pyridyl)methylene]amino]4-methylbenzenesulfonate [ka] To a solution of 5-chloro-3-ethylsulfinyl-N'-hydroxypyridine-2-carboxamidine (5.00 g, 97% purity, 19.6 mmol) in dichloromethane (130 ml), Et3N (2.9 ml, 20.6 mmol) and p-toluenesulfonyl chloride (4.00 g, 20.6 mmol) were added at 0°C. The reaction mixture was stirred at ambient temperature for 1.5 hours, and then quenched by adding 10% NH4Cl aqueous solution (40 ml). The phases were separated, and the aqueous phase was extracted with dichloromethane (2×). The combined organic layers were washed with brine and dried over anhydrous MgSO4. The title compound (8.01 g, 93% purity, 95% yield) was obtained as a gray powder by evaporation of the solvent under reduced pressure. 1 H NMR(400MHz,DMSO-d6)δ 8.81(d,J=2.2Hz,1H),8.22(d,J=2.2Hz,1H),7.85(d,J=8.4Hz,2H),7.30-7.66( m,4H),2.92-3.02(m,1H),2.64-2.74(m,1H),2.39(s,3H),1.03(t,J=7.4Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 154.2,148.9,145.0,143.3,142.3,133.9,133.5,132.5,129.9,128.1,48.2,21.1,6.0

[0161] Example 63: (6-chloro-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-ylidene)ammonium chloride [ka] To a solution of 5-chloro-3-ethylsulfinyl-N'-hydroxypyridine-2-carboxamidine (1.00 g, 99% purity, 4.00 mmol) in dichloromethane (10 ml), Et3N (0.56 ml, 4.04 mmol) was added, followed by 2,4-dinitrobenzenesulfonyl chloride (1.10 g, 4.04 mmol). The reaction mixture was stirred at ambient temperature for 8 hours. The resulting precipitate was filtered, washed with dry dichloromethane in a filter, and dried under high vacuum to obtain the title compound (1.03 g, >98% purity, 95% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.19(br s,2H),9.55(br s,1H),9.36(br s,1H),4.32-4.63(m,2H),1.42(br s,3H); 13 C NMR(101MHz,DMSO-d6)δ 166.0,156.0,148.4,136.0,134.5,132.8,48.0,6.2

[0162] Example 64: 6-Chloro-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-one [ka] A solution of [(Z)-[amino[5-chloro-3-ethylsulfinyl-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (8.00 g, 96% purity, 19.1 mmol) in a mixture of THF (85 ml) and water (85 ml) was heated at 80°C for 7 days (complete conversion of the starting materials by LC / MS). The reaction mixture was cooled to ambient temperature and quenched by the addition of saturated NaHCO3 aqueous solution. The resulting mixture was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated to obtain a crude residue, which was triturated with diisopropyl ether (15 ml). The precipitate was dried under high vacuum to obtain the title compound (3.24 g, 94% purity, 69% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 9.18(d,J=2.2Hz,1H),9.10(d,J=2.2Hz,1H),4.08(qd,J=7.3,1.3Hz,2H),1.26(t,J=7.3Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 167.9,155.7,151.1,134.5,134.4,132.7,47.4,6.8

[0163] Example 65: Preparation of [(Z)-[amino[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate [ka] To a suspension of 5-(1-cyanocyclopropyl)-3-(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (14.817 g, 94% purity, 49.9 mmol) in MeCN (50 ml), Et3N (13.8 ml, 98.8 mmol) was added. After stirring for 10 minutes, pTsCl (10.13 g, 53.15 mmol) was added in five portions over 20 minutes. After stirring at ambient temperature for 2 hours, the reaction mixture was diluted with ELISA (200 ml). The resulting solution was washed with 1 M HCl (3 × 40 ml), saturated NaHCO3 aqueous solution (40 ml), and brine (40 ml). The organic layer was dried over anhydrous Na2SO4, and the solvent was partially evaporated to approximately 20 ml at 50°C and 150 mbar. The resulting precipitate was filtered, washed with SiO2 (20 ml), and dried under high vacuum to obtain the title compound (14.00 g, 97% purity, 90% yield) as a gray crystalline solid. 1H NMR(400MHz,CDCl3)δ 8.80(d,J=2.2Hz,1H),8.07(d,J=2.2Hz,1H),7.91(d,J=8.4Hz,2H),7.37(d,J=8.0Hz,2H),6.58(s,1H),5.68(s,1H),3.18(qd,J=7.4 ,13.3Hz,1H),2.76(qd,J=7.3,13.3Hz,1H),2.44(s,3H),1.96-1.87(m,2H),1.58(ddd,J=1.6,4.2,5.4Hz,2H),1.15(t,J=7.4Hz,3H); 13 C NMR(101MHz,CDCl3)δ 153.1,147.6,145.4,142.3,141.8,135.6,132.4,129.9,129.7,128.6,120.4,48.2,21.7,19.5,19.5,12.0,6.2

[0164] Example 66: Preparation of [(Z)-[amino[5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] To a suspension of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (2.942 g, 94% purity, 9.92 mmol) in MeTHF (30 ml), Et3N (2.76 ml, 19.8 mmol), followed by 4-nitrobenzenesulfonyl chloride (2.309 g, 10.42 mmol), were added in three portions over 10 minutes. After stirring at ambient temperature for 1.5 hours, the reaction mixture was quenched by adding water (11 ml). The phases were separated, and the organic phase was washed with 1 M HCl (2 × 11 ml) and saturated NaHCO3 (11 ml). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure (30°C, 50 mbar). The foamy residue was redissolved in MeTHF (9 ml) and aged for 1 hour. During this process, a precipitate formed, which was filtered, washed with MTBE in a filter, and dried under high vacuum to obtain the title compound (3.961 g, 93% purity, 85% yield) as an off-white crystalline solid. 1 H NMR(400MHz,CDCl3)δ 1.22(t,J=7.4Hz,3H)1.55-1.62(m,2H)1.90-1.99(m,2H)2.79(dq,J=13.3,7.3Hz,1H)3.18-3.33(m,1H)5.44 -5.84(m,1H)6.49-6.90(m,1H)8.09(d,J=2.5Hz,1H)8.21-8.27(m,2H)8.37-8.44(m,2H)8.83(d,J=2.5Hz,1H)

[0165] Example 67: Preparation of [(Z)-[amino[5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-chlorobenzenesulfonate [ka] To a solution of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (111.5 mg, 97% purity, 0.390 mmol) in MeCN (0.4 ml), Et3N (0.121 ml, 0.872 mmol) and 4-chlorobenzenesulfonyl chloride (103.3 mg, 90% purity, 0.442 mmol) were added. After stirring for 1 hour, the reaction mixture was fractionated between RINKAN (10 ml) and saturated NaHCO3 (10 ml). The phases were separated, the organic phase was dried over anhydrous Na2SO4, and evaporated under reduced pressure to obtain the title compound (202 mg, 87% purity, 99% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 1.18(t,J=7.4Hz,3H)1.56-1.63(m,2H)1.88-1.96(m,2H)2.76(dq,J=13.3,7.4Hz,1H)3.15-3.29(m,1H)5.45-5.96 (m,1H)6.46(s,1H)6.49-6.82(m,1H)7.51-7.58(m,2H)7.93-8.01(m,2H)8.08(d,J=2.2Hz,1H)8.81(d,J=2.5Hz,1H)

[0166] Example 68: Preparation of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitride 4-methylbenzenesulfonate [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (1.99 g, 97% purity, 4.47 mmol) in dried acetonitrile (8.9 ml) was heated in a sealed tube at 80°C for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by reverse-phase silica gel chromatography (0.25-20% MeCN in water). After lyophilization, the title compound (1.15 g, 85% purity, 51% yield) was obtained as a white solid. 1 H NMR(400MHz,CD3CN)δ 10.19(br s,1H),9.45(br s,1H),9.07(d,J=1.8Hz,1H),8.67(d,J =1.8Hz,1H),7.65(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),4.19-3.91(m,2H ),2.34(s,3H),2.05-1.96(m,2H),1.87-1.76(m,2H),1.39(t,J=7.4Hz,3H); 13 C NMR(101MHz,CD3CN)δ 168.2,156.6,149.5,145.8,140.7,140.2,133.2,132.6,129.5,126.8,121.4,49.9,21.4,21.4,13.6,7.2

[0167] Example 69a: Preparation of 1-[(1R)-1-ethyl-1,3-dioxoisothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitride [ka] A solution of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitrilate 4-methylbenzenesulfonate (0.134 g, 85% purity, 0.263 mmol) in a mixture of THF (0.9 ml) and water (0.9 ml) was heated in a sealed vial at 80°C for 20 hours. The organic layer was evaporated under reduced pressure, and the aqueous layer was freeze-dried over 16 hours to obtain the title compound (0.131 g, 52% purity, 99% yield) as a white cottony powder. A portion of the sample was purified by silica gel chromatography (SiO2 / MeOH9:1) for measurement of enantiopurity. 1 H NMR(400MHz,2-DMSO)δ 9.08(d,J=1.8Hz,1H),8.81(d,J=1.8Hz,1H),4.09(dq,J=1.8,7.3Hz,2H),2. 08-1.94(m,2H),1.91-1.86(m,1H),1.85-1.80(m,1H),1.20(t,J=7.3Hz,3H); 13 C NMR(101MHz,2-DMSO)δ 168.5,154.5,151.8,136.3,133.5,130.2,121.0,47.1,19.7,19.2,12.0,6.8 Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® AY, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:EtOH Uniform concentration: 25% B in 4.8 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 230nm Sample concentration: 1 mg / mL in ACN / MeOH Injection: 1μL result:

[0168] [Table 17]

[0169] Example 69b: Preparation of 1-[(1R)-1-ethyl-1,3-dioxoisothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (0.267 g, 97% purity, 0.599 mmol) in a mixture of THF (2.0 ml) and water (2.0 ml) was heated in a sealed tube at 90°C for 20 hours. After cooling to ambient temperature, the THF was evaporated, and the aqueous layer was freeze-dried over 16 hours to obtain the crude title compound (0.258 g, 55% purity, 90% yield) as a white solid. Same chiral SFC method as in Example 69a

[0170] [Table 18]

[0171] Example 70: Preparation of [(Z)-[amino-[5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate [ka] To a solution of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (1.00 g, 83% purity, 2.96 mmol) in 2-methyltetrahydrofuran (10 mL), triethylamine (0.83 mL, 5.92 mmol) and p-toluenesulfonyl chloride (0.624 g, 3.11 mmol) were added at room temperature. The reaction mixture was stirred for 2 hours and quenched by adding water (10 mL). The phases were separated, and the organic phase was washed with 2N HCl and water. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (1.63 g, 71.5% purity, 91% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.91(d,J=2.3Hz,1H),8.36(d,J=2.3Hz,1H),7.86(d,J=8.3Hz,2H),7.44(d,J=8.1Hz,2 H),6.50(s,2H),2.97(m,1H),2.65(m,1H),2.38(s,3H),1.76(s,6H),1.01-1.04(m,3H)

[0172] Example 71: Preparation of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]-2-methyl-propanenitrile [ka] A solution of [(Z)-[amino-[5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (1.00 g, 70% purity, 1.60 mmol) in acetonitrile (10 mL) was stirred at 80°C for 18 hours, then cooled to ambient temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography using tert-butyl methyl ether and methanol as eluates to obtain the title compound (0.25 g, 85% purity, 50% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 9.26(d,J=2.1Hz,1H),8.95(d,J=2.1Hz,1H),3.91-4.15(m,2H),3.13-3.19(s,1H),1.84(s,3H),1.83(s,3H),1.09-1.25(t,J=7.4Hz,3H)

[0173] Example 72: Preparation of 2-[(1R)-1-ethyl-1,3-dioxoisothiazolo[4,5-b]pyridine-6-yl]-2-methylpropanenitrile [ka] A solution of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]-2-methyl-propanenitrile (0.94 g, 85% purity, 3.05 mmol) in a mixture of 1,4-dioxane (9 mL) and water (3 mL) was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using tert-butyl methyl ether and methanol as eluents to obtain the title compound (0.17 g, 92% purity, 94.5% ee, 23% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.33(d,J=2.1Hz,1H),9.05(d,J=2.1Hz,1H),4.13(q,J=7.2Hz,2H),1.86(s,3H),1.84(s,3H),1.23(t,J=7.4Hz,3H).

[0174] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IA (4.6mm x 250mm) 5μm Mobile phase: A: TBME B: EtOH Uniform concentration: 10% B in 22 minutes Flow rate: 1.0ml / min Detection: 230nm Sample preparation: 1mg / mL in EtOH Injection: 1μL result:

[0175] [Table 19]

[0176] Example 73: Preparation of [(Z)-[amino-[5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate [ka] To a solution of 5-(3-fluorophenyl)-N'-hydroxy-3-methylsulfinylpyridine-2-carboxamidine (0.50 g, 89% purity, 1.51 mmol) in 2-methyltetrahydrofuran (3.0 mL), triethylamine (0.42 mL, 3.0 mmol) and p-toluenesulfonyl chloride (0.318 g, 1.58 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 hours and quenched by adding water (10 mL). The phases were separated, and the organic phase was washed with 2N HCl and water. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.685 g, 84% purity, 85% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.10(d,J=2.2Hz,1H),8.56(d,J=2.2Hz,1H),7.89(d,J=8.4Hz,2H),7.76(d,J=9.9Hz ,1H),7.65-7.71(m,1H),7.62(dd,J=8.0,6.0Hz,1H),7.50(d,J=8.0Hz,2H),7.35(br d,J=2.4Hz,1H),2.65(s,3H),2.42(s,3H)

[0177] Example 74: Preparation of (1R)-6-(3-fluorophenyl)-1-methyl-1-oxoisothiazolo[4,5-b]pyridine-3-one [ka] A solution of [5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carboximidoyl]amino]4-methylbenzenesulfonate (0.235 g, 85% purity, 0.447 mmol) in a mixture of 1,4-dioxane (1.3 mL) and water (0.45 mL) was stirred at 80°C for 4 hours. The reaction mixture was then cooled to ambient temperature and quenched by adding saturated sodium bicarbonate aqueous solution. The dioxane was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (0.100 g, 99% purity, >99.5% ee, 80% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.49(d,J=2.0Hz,1H),9.25(d,J=2.0Hz,1H),7.85(m,1H),7.78(d,J=7.7Hz,1H),7.65-7.67(m,1H),7.38-7.43(m,1H),3.91(s,3H).

[0178] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IG (4.6mm x 250mm) 5μm Mobile phase: A: n-hexane B: EtOH / .'' (1:1) Homogeneous concentration: 30% B after 35 minutes Flow rate: 1.0ml / min Detection: 257nm Sample preparation: 1mg / mL in EtOH Injection: 1μL result:

[0179] [Table 20]

[0180] Example 75: Preparation of [(Z)-[amino-[5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] To a solution of 5-(1-cyano-1-methylethoxy)-3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (0.500 g, 95% purity, 1.60 mmol) in 2-methyltetrahydrofuran (5.0 mL), triethylamine (0.45 mL, 3.21 mmol) and 4-nitrobenzenesulfonyl chloride (0.393 g, 1.68 mmol) were added at room temperature. The reaction mixture was stirred for 2 hours and quenched by adding water (5 mL) and 2-methyltetrahydrofuran (5 mL). The phases were separated, and the organic phase was washed with 2N HCl and water. The combined organic phase was further washed with saturated NaHCO3 aqueous solution (10 mL), and the aqueous layer was extracted with ELISA. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to obtain the title compound (0.82 g, 81% purity, 81% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.57(d,J=2.6Hz,1H),8.46-8.50(m,2H),8.24-8.28(m,2H),8.07(d,J=2.6Hz,1H),7.83(br s,2H),2.97-3.02(m,1H),2.63-2.73(m,1H),1.78(s,3H),1.77(s,3H),0.98-1.02(m,3H).

[0181] Example 76: Preparation of (1R)-6-(1-cyano-1-methyl-ethoxy)-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-ylidene]ammonium 4-nitrobenzene sulfonate [ka] A solution of [(Z)-[amino-[5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate (0.500 g, 86.5% purity, 0.900 mmol) in acetonitrile (5 mL) was stirred at 60°C for 2 hours. After completely consuming the starting material, the reaction mixture was evaporated under reduced pressure. The crude material was washed with tert-butyl methyl ether, and the residue was dried under high vacuum to obtain the title compound (0.470 g, 86% purity, 99% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.95(d,J=5.0Hz,2H),9.04-9.05(m,2H),8.18-8.22(m,2H),7.82-7.86(m,2 H),4.46-4.53(m,1H),4.27-4.32(m,1H),1.90(s,6H),1.41(t,J=7.4Hz,3H).

[0182] Example 77: Preparation of 2-[(1R)-1-ethyl-1,3-dioxoisothiazolo[4,5-b]pyridine-6-yl]oxy-2-methyl-propanenitrile [ka] A solution of (1R)-6-(1-cyano-1-methyl-ethoxy)-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-ylidene]ammonium 4-nitrobenzenesulfonate (0.25 g, 86% purity, 0.447 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL) was stirred at 70°C for 2 hours and then concentrated under reduced pressure. A saturated aqueous solution of NaHCO3 (10 mL) was added, and the reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using tert-butyl methyl ether and methanol as eluents to obtain the title compound (0.0670 g, 98% purity, 93% ee, 53% yield) as a colorless semi-solid. 11H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.5 Hz, 1H), 8.78 (d, J = 2.5 Hz, 1H), 4.05 - 4.19 (m, 2H), 1.86 (s, 3H), 1.85 (s, 3H), 1.20 (t, J = 8.0 Hz, 3H).

[0183] Method for chiral analysis: Chiral HPLC: WATERS ACQUITY UPLC Column: Chiral pack-IA (4.6 mm × 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Uniform concentration: 30% B in 30 minutes Flow rate: 1.0 ml / min Detection: 235 nm Sample preparation: 1 mg / mL in EtOH Injection: 1 μL Results:

[0184]

Table 21

Claims

1. Equation (I) 【Chemistry 1】 A process for the enantioselective preparation of cyclic acylsulfoximines, During the ceremony, S * is a stereogenic sulfur atom in the (R)- or (S)- configuration, and the S * However, it is enantiomerically pure, enantiomerically concentrated, or in racemic form. R 1 and R 3 However, independently, these are hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. R 2 However, it is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl, G 1 and G 2 are each independently CH or N, provided that G 1 or G 2 at least one of which is N A) Sulfinyl compounds of formula (II) 【Chemistry 2】 (In the formula, R 1 , R 2 , R 3 G 1 G 2 , and S * However, as defined in formula (I), the sulfonyl chloride of formula (III) 【Transformation 3】 (In the formula, R 4 The compound of formula (IV) is obtained by reacting an alkyl or substituted aryl compound with a suitable base in a suitable solvent. 【Chemistry 4】 (In the formula, R 1 , R 2 , R 3 G 1 G 2 , and S * However, as defined in equation (I), R 4 However, as defined in formula (III), it generates, B) Thermally rearrange the compound of formula (IV) in a suitable solvent to obtain the compound of formula (V) or (Va). 【Transformation 5】 (In the formula, R 1 , R 2 , R 3 G 1 G 2 , and S * However, as defined in formula (I), X is a halogen or SO 2 R 4 And R 4 However, as defined in formula (III), it generates, C) A process comprising hydrolyzing a compound of formula (V) or (Va) with water at a suitable temperature and in the presence of a suitable cosolvent to produce a compound of formula (I).

2. Step B) involves thermally rearranging the compound of formula (IV) in a suitable solvent in the presence of a suitable base to obtain the compound of formula (Va). 【Transformation 6】 (In the formula, R 1 , R 2 , R 3 G 1 G 2 , and S * However, as defined in equation (I), it generates, C) The process according to claim 1, comprising hydrolyzing a compound of formula (Va) with water at a suitable temperature and in the presence of a suitable cosolvent to produce a compound of formula (I).

3. The process according to claim 1, wherein the compound of formula (IV) obtained from step B) is directly rearranged in the presence of water and a suitable cosolvent to produce the compound of formula (I).

4. The process according to claim 1, wherein the base suitable for step A is selected from trialkylamines, alkali metal carbonates, and alkali metal hydroxides.

5. The process according to claim 1, wherein the solvent (or diluent) suitable for step A is selected from esters, nitriles, ethers, and aliphatic, aromatic, and halogenated hydrocarbons.

6. The process according to claim 1 or 2, wherein the solvent (or diluent) suitable for step B is selected from polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates, ethers, and mixtures thereof.

7. The process according to any one of claims 1 to 2 or 6, wherein the rearrangement reaction is carried out at a temperature in the range of 0°C to 150°C.

8. The process according to any one of claims 1 to 3, wherein the hydrolysis of the compound of formula (V) is carried out by heating in an aqueous medium using a suitable cosolvent (or diluent) selected from water-miscible alcohols, ethers, and nitriles, and optionally in the presence of a suitable acid selected from sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, and methanesulfonic acid.

9. The process according to any one of claims 1 to 3 and 8, wherein the hydrolysis is carried out at a temperature in the range of 0°C to 100°C.

10. The process according to any one of claims 1 or 2 and 4 or 5, wherein steps (B) and (C) are carried out in a one-pot manner without isolating the intermediate compound of formula (V) by directly heating the compound of formula (IV) in an aqueous medium and a cosolvent selected from water-miscible alcohols, ethers and nitriles, optionally in the presence of a suitable acid selected from sulfuric acid, hydrochloric acid, trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid and methanesulfonic acid.

11. R 1 and R 3 The process according to any one of claims 1 to 10, wherein the independents are hydrogen, chloro, bromo, trifluoromethyl, cyclopropyl, cyanocyclopropyl, cyanoisopropoxy, cyanoisopropyl, phenyl, or halophenyl.

12. R 2 However, C 1 -C 6 - Alkyl, C 3 -C 6 - Cycloalkyl, C 1 -C 6 - The process according to any one of claims 1 to 11, wherein the process is a haloalkyl, phenyl, or halophenyl.

13. G 1 N is G 2 Is CH or G 1 CH is G 2 Is N, or G 1 and G 2 The process according to any one of claims 1 to 12, wherein both are N.

14. R 4 The process according to any one of claims 1 to 13, wherein is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl, or 2,4-dinitrophenyl.

15. A compound of formula I 【Transformation 7】 During the ceremony, S * However, it is a stereogenic sulfur atom in the (R)- or (S)- configuration, R 1 and R 3 However, independently, these are hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. R 2 However, it is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl, G 1 and G 2 However, independently, it is CH or N, provided that G 1 or G 2 A compound in which at least one of the elements is N.

16. A compound of formula IV, 【Transformation 8】 During the ceremony, S * However, it is a stereogenic sulfur atom in the (R)- or (S)- configuration, R 1 and R 3 However, independently, these are hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. R 2 However, it is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl, G 1 and G 2 However, independently, it is CH or N, provided that G 1 or G 2 At least one of them is N, R 4 A compound that is alkyl or substituted aryl.

17. A compound of formula V or Va, 【Chemistry 9】 During the ceremony, S * However, it is a stereogenic sulfur atom in the (R)- or (S)- configuration, R 1 and R 3 However, independently, these are hydrogen, halogen, haloalkyl, cycloalkyl, cyanocycloalkyl, cyanoalkoxy, cyanoalkyl, or optionally substituted aryl. R 2 However, it is an alkyl, cycloalkyl, haloalkyl, or optionally substituted aryl, G 1 and G 2 However, independently, it is CH or N, provided that G 1 or G 2 At least one of them is N, X is Cl or SO 2 R 4 And, R 4 A compound in which the compound is methyl, p-tosyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl, or 2,4-dinitrophenyl.

18. R 1 and R 3 The compound according to any one of claims 15 to 17, wherein the compound is independently hydrogen, chloro, bromo, trifluoromethyl, cyclopropyl, cyanocyclopropyl, cyanoisopropoxy, cyanoisopropyl, phenyl, or halophenyl.

19. R 2 is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, phenyl or halophenyl, a compound according to any one of claims 15 to 17.

20. G 1 is N, and G 2 is CH, or G 1 is CH, and G 2 is N, or G 1 and G 2 are both N, the compound according to any one of claims 15 to 17.

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