Synthesis of sulfoximines containing the benzimidazole moiety

Abstract

Formula (I) (wherein R 1 , R 2 , S * , R 3 , R 4 , X 1 , and X 2 are as defined herein) is provided a method for preparing an enantiomerically enriched sulfoximine. 【Chemical Formula 1】 JPEG2026531124000151.jpg42161

Description

[Technical Field]

[0001] The present invention relates to the enantioselective synthesis of sulfoximines containing a benzimidazole moiety. Such compounds have pesticidal activity, particularly insecticidal activity, and are useful as active ingredients for controlling animal pests, including arthropods, especially insects. [Background technology]

[0002] Biologically active heterocyclic sulfoximine derivatives are described in publications such as International Publication Nos. 2015 / 071180, 2016 / 039441, 2018 / 206348, 2019 / 219689, 2019 / 229089, 2019 / 234158, 2020 / 084075, and 2020 / 141136.

[0003] International Publication No. 2022 / 253841 discloses the stereoselective synthesis of sulfoximines by stereoselective oxidation followed by stereospecific imination.

[0004] The present invention relates to formula (I): [ka] This provides a novel enantioselective synthesis of similar sulfoximines, yielding the compound: R 1 is a halogen, a C1-C6 haloalkyl, a cyano-C1-C6 alkyl, a cyano-C1-C6 alkoxy, a cyano-C3-C6 cycloalkyl, or an aryl, wherein the aryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogens, C1-C3 alkyl, or C1-C3 alkoxy; R 2 These are C1-C4 alkyl groups; R 3 is hydrogen or a C1-C4 alkyl group; R 4 is hydrogen, halogen or C1-C4 haloalkyl; S * is a stereogenic sulfur atom having R- or S-configuration; X 1 and X 2 are each independently CH or N, with the proviso that at least one of X 1 and X 2 is nitrogen, said process comprises reacting a compound of formula (V) or a compound of formula (VI)

Chemical Formula

Chemical Formula

[0005] In a previously published patent application (International Publication No. WO 2022 / 253841), this type of compound was prepared for specific examples as shown in Scheme 1 Scheme 1

Chemical Formula

[0006] The fully formed sulfide analog was first synthesized (described in International Publication No. 2019 / 234158), and in the final step, the sulfide was enantioselectively oxidized and then stereospecifically iminated with sulfur. While this method is quite applicable for synthesizing a wide variety of analogs, it is not ideal for large-scale synthesis. Firstly, the oxidation conditions must be adjusted for each substrate, and even then, the resulting enantiomeric excess is not always sufficient. More importantly, the reagents used for imination must be synthesized separately, making large-scale use difficult due to safety concerns. [Overview of the project] [Means for solving the problem]

[0007] Therefore, there is a need for atom-efficient approaches for the synthesis of enantiomerically pure or enriched chiral sulfoximine compounds, particularly large-scale ones. Such processes are advantageous in that they improve impurity profiles, reduce commercial manufacturing costs, and enhance efficiency and atom economy.

[0008] Surprisingly, the inventors have found that the sulfoximine compound of formula (I) can be converted from the corresponding sulfide compound via a cyclic sulfoximine intermediate, as shown in Scheme 2. We discovered that it could be prepared. [ka] Scheme 2 Compound of formula (II) (wherein R 1 and R 2 The compound of formula (III) (wherein R is defined as follows for the compound of formula (I)) is first oxidized in an enantioselective manner to obtain the compound of formula (III) (wherein R is defined as follows for the compound of formula (I)). 1 , R 2 , and *We obtain the compound of formula (IV) by nucleophilic addition of hydroxylamine (NH2OH) to the cyano moiety. The sulfonyl chloride compound of formula (IX) (wherein R 5 Activation of the amidine oxime with a base (selected from C1-C4 alkyl or phenyl, wherein the phenyl is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, or methyl) provides an intermediate of formula (V) in the presence of a base. Heating this intermediate yields the cyclic iminosulfoximine compound of formula (VI) as a sulfonate. Such intramolecular imination is surprising and has not been reported before. The compound of formula (VI) is then converted to the compound of formula (VII) (wherein R 3 , R 4 , X 1 , and X 2 It can be obtained by reacting it with (as defined for the compound of formula (I)) via the intermediate of formula (VIII), which can then be converted to the compound of formula (I). The compound of formula (VI) can be isolated, but in many cases it is advantageous to proceed directly to the compound of formula (I) by heating a mixture of the compound of formula (V) and the compound of formula (VII).

[0009] The condensation of compound (VI) to obtain an intermediate of formula (VIII) that can be isolated in certain cases and subsequently rearranged to obtain compound (I) represents a novel approach in this class of compounds, as there are no precedents in recent literature.

[0010] The present invention relates to formula (I) [ka] (In the formula, R 1is a halogen, a C1-C6 haloalkyl, a cyano-C1-C6 alkyl, a cyano-C1-C6 alkoxy, a cyano-C3-C6 cycloalkyl, or an aryl, wherein the aryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogens, C1-C3 alkyl, or C1-C3 alkoxy; R 2 These are C1-C4 alkyl groups; R 3 is hydrogen or a C1-C4 alkyl group; R 4 These are hydrogen, halogens, or C1-C4 haloalkyls; S * This is a stereogenic sulfur atom with an R- or S- configuration; X 1 and X 2 Each is independently CH or N, except X 1 and X 2 (At least one of them is nitrogen.) A process for preparing sulfoximines in an enantiomerically pure or enantiomerically enriched form, A) Equation (II) [ka] (In the formula, R 1 and R 2 The sulfanyl compound of formula (I) is stereoselectively oxidized in the presence of an oxidizing agent, a chiral reagent or catalyst, optionally in the presence of a suitable acid additive, and in a suitable solvent (or diluent). Formula (III) [ka] (In the formula, R 1 , R 2 , and S * This is achieved by generating a sulfinyl compound of formula (I), as defined for the compound of formula (I). And, B) Equation (III) [ka] (In the formula, R 1 , R 2 , and S * The compound of formula (as previously defined) is reacted with hydroxylamine in a suitable solvent at a suitable temperature to obtain formula (IV). [ka] (In the formula, R 1 , R 2 , and S * This is achieved by producing a compound of formula (I), as defined for the compound of formula (I). And, C) Equation (IV) [ka] (In the formula, R 1 , R 2 、 and S * The sulfinyl compound of formula (IX) is defined as follows for the compound of formula (I) [ka] (In the formula, R 5 is a C1-C4 alkyl or phenyl, wherein the phenyl is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, or methyl; preferably, R 5 This includes a sulfonyl chloride (selected from methyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-cyanophenyl, 4-nitrophenyl, or 2,4-dinitrophenyl), The reaction is carried out in the presence of a suitable base and in a suitable solvent, resulting in formula (V). [ka] (In the formula, R 1 , R 2 , and S * This is defined for compounds of formula (I), and R 5This is achieved by generating a compound of formula (IX), as defined for the compound of formula (IX). And, D) Equation (V) [ka] (In the formula, R 1 , R 2 , and S * This is defined for compounds of formula (I), and R 5 The compound of formula (IX) is thermally rearranged in a solvent to obtain formula (VI). [ka] (In the formula, R 1 , R 2 , and S * This is defined for compounds of formula (I), and R 5 This is defined for compounds of formula (IX) (optionally, formula (VIa) [ka] (In the formula, R 1 , R 2 , and S * A compound of formula (I) may be produced by adding a suitable base and used in step (E), And, E) Equation (VI) [ka] (In the formula, R 1 , R 2 , and S * This is defined for compounds of formula (I), and R 5 The compound of formula (VII) is defined as follows for the compound of formula (IX) [ka] (In the formula, R 3 , R 4 , X1 , and X 2 are as defined for the compound of formula (I)), is reacted with a compound of formula (I)

Chemical Formula

[0011] This condensation and rearrangement proceeds via formula (VIII)

Chemical Formula

[0012] Optionally, formula (V)

Chemical Formula

Chemical Formula

[0013] In one embodiment of the present invention, this condensation of the compound of formula (VI) to obtain the intermediate of formula (VIII) may be carried out in the presence of an acidic additive. In one embodiment of the present invention, the condensation reaction may be carried out in the presence of citric acid.

[0014] Furthermore, it has surprisingly been found that the compounds of formula (I) have a practically very advantageous level of pesticidal activity, in particular insecticidal activity, and are used for controlling animal pests, including arthropods and in particular insects. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] [Figure 1] Fig. 1 shows a single crystal X-ray structure of a compound according to one embodiment of the present invention. MODE FOR CARRYING OUT THE INVENTION

[0016] As used herein, the term "hydroxyl" or "hydroxy" refers to a -OH group. As used herein, the term "nitro" refers to a -NO2 group. Cyano, as used herein, refers to a -CN group. As used herein, the term "halogen" or "halo" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine. This accordingly also applies to halogen in combinations with other meanings, such as haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, halocycloalkyl and the like.

[0017] As used herein, the term "C1~C n"-alkyl" refers to any one of the saturated linear or branched hydrocarbon groups having 1 to n carbon atoms attached via any carbon atom, such as methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0018] The term "C3~C" as used in this specification n "Cycloalkyl" refers to 3-membered to n-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0019] Terms used in this specification "C1~C n "Alkoxy" refers to any one of the following linear or branched saturated alkyl groups having 1 to n carbon atoms (as described above) attached via an oxygen atom, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy, and 1,1-dimethylethoxy groups. The term "C2-C" as used herein is used in this specification. n "-Alkenyloxy" refers to a linear or branched saturated alkenyl chain having 2 to n carbon atoms (as described above) attached via oxygen atoms.

[0020] Terms used in this specification "C1~C n"-Haloalkyl" refers to a linear or branched saturated alkyl group attached via any of the carbon atoms having 1 to n carbon atoms (as described above), where some or all of the hydrogen atoms in these groups may be replaced by fluorine, chlorine, bromine and / or iodine, for example, but not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, and 3-bromopropyl.

[0021] The term "cyano-C1~C" as used herein n -alkyl refers to a linear or branched saturated C1-C chain (as described above) substituted with a cyano group. n - Refers to alkyl groups, such as cyanomethylene, cyanoethylene, 1,1-dimethylcyanomethyl, cyanoisopropyl, cyanomethyl, cyanoethyl, and 1-dimethylcyanomethyl. This term is "C1~C n- It can be used interchangeably with "cyanoalkyl" compounds.

[0022] Terms used in this specification: cyano-C1~C n -Alkoxy is a saturated C1-C1 chain (as described above) that is substituted with a cyano group, either linear or branched. n - Refers to an alkyloxy group. This term is "C1~C n- It can be used interchangeably with "cyanoalkoxy".

[0023] The term "cyano-C3~C" as used hereinn "C3-C" refers to a 3- to 6-membered cycloalkyl group (as described above) that is substituted with a cyano group. n - Can be used interchangeably with "cyanocycloalkyl".

[0024] The term "aryl" refers to monocyclic, bicyclic, or polycyclic aromatic systems having preferably 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, where both the aryl and alkyl moieties may be further substituted with the same or different substituents. Benzyl and phenylethyl are examples of such arylalkyls.

[0025] Unless otherwise defined, the term “optionally substituted” means that the group in question may be substituted from zero to a maximum number of substituents with groups independently selected from: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropyl, 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, and phenyl.

[0026] The term "enantiomerically enriched" means that one enantiomer of a compound is present in excess compared to the other enantiomer. This excess is hereafter referred to as enantiomerically enriched or ee. ee can be determined by chiral GC, HPLC, or SFC analysis. ee is equal to the difference between the amounts of enantiomers divided by the total amount of enantiomers, and this quotient can be expressed as a percentage after multiplying by 100. ee can also be referred to as the absolute difference between the mole fractions of each enantiomer in the mixture. For example, if there is an isomer with an enantiomer excess (ee) of 40%, this means that the mole fraction (or percentage) of such an excess isomer is 70%. Therefore, in one embodiment, the term “enantiomerically enriched” also refers to an enantiomer excess (ee) of at least 40%, for example, 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%.

[0027] As used herein, the terms “room temperature,” “RT,” “rt,” or “ambient temperature” refer to temperatures between approximately 15°C and approximately 35°C. For example, rt may refer to temperatures between approximately 20°C and approximately 30°C. As used herein, the term "condensation" refers to a reaction in which two molecules combine to form a single molecule.

[0028] As used herein, the term "suitable solvent" refers to a solvent that is appropriate or suitable for a particular reaction step. The term "suitable solvent" may be used interchangeably with the term "suitable solvent" or "dilutant."

[0029] As used herein, the term "appropriate temperature" refers to a temperature that is appropriate or suitable for a particular reaction step. The term "appropriate temperature" may be used interchangeably with the term "appropriate temperature for".

[0030] The R group used in the Marcush structure of the present invention as used herein is R xor R x This can be disclosed interchangeably as follows, where x is used to label the R group.

[0031] The process of the present invention may be carried out in separate process steps in which intermediate compounds can be isolated at each stage. Alternatively, the process may be carried out as a one-pot synthesis in which the resulting intermediate compounds are not isolated. Thus, the process of the present invention can be carried out in batch or continuous form.

[0032] The following list refers to the substituent R of the compounds of formula (I), (II), (III), and (IV) of the present invention. 1 , R 2 , R 3 , R 4 , R 5 , R 6 The following definitions are provided, including preferred definitions for X. Any of these substituents may be combined with any other substituent definitions provided below or elsewhere in this specification.

[0033] In one embodiment of the present invention, R 1 is a halogen, a C1-C4 haloalkyl, a cyano-C1-C4 alkyl, a cyano-C1-C4 alkoxy, a cyano-C3-C6 cycloalkyl, or an aryl; any of the aryls is either unsubstituted or substituted with one, two, or three substituents independently selected from halogens, C1-C3 alkyls, or C1-C3 alkoxys. Preferably, R 1 The substituent is a halogen, a C1-C2-haloalkyl, a cyano-C1-C3-alkyl, a cyano-C1-C3-alkoxy, a cyano-C3-C6-cycloalkyl, or a phenyl, wherein the phenyl is either unsubstituted or substituted with one or two substituents independently selected from the halogens.

[0034] In one embodiment of the present invention, R 2 is a C1-C4 alkyl group. Preferably, R 2is a C1-C3 alkyl group. More preferably, R 2 is methyl or ethyl. More preferably, R 2 It is ethyl.

[0035] In one embodiment of the present invention, R 3 is hydrogen or a C1-C4 alkyl group. Preferably, R 3 R is hydrogen or a C1-C3 alkyl group. More preferably, 3 is hydrogen or methyl. In one embodiment, R 3 is hydrogen. In another embodiment, R 3 is methyl. Preferably, R 3 It is methyl.

[0036] In one embodiment of the present invention, R 4 is hydrogen, halogen, or C1-C4 alkyl. Preferably, In one embodiment of the present invention, S * is a stereoisomerized sulfur atom in a (R)- or (S)- configuration. In a preferred embodiment of the present invention, S * is a stereogenic sulfur atom in the (R)-stereoconfiguration. In another preferred embodiment of the present invention, S * This is a stereoisomerized sulfur atom in the (S)- configuration.

[0037] In one embodiment of the present invention, X 1 and X 2 Each is independently CH or N, except X 1 and X 2 At least one of them is nitrogen. Preferably, X 1 is N and X 2 Is it CH or X? 1 is CH and X 2 Is it N; or X 1 is N and X 2 is N. More preferably, X 1 is N and X 2 Is it CH or X? 1 is CH and X2 It is N.

[0038] One embodiment of step (A) of the present invention is: Oxidation of the sulfanyl compound of formula (II) in the presence of an oxidizing agent, a metal derivative, a chiral ligand, a suitable solvent (or diluent), and optionally a suitable acid additive. Includes.

[0039] Suitable and preferred oxidizing agents include inorganic peroxides such as hydrogen peroxide, or organic peroxides such as tert-butyl hydroperoxide. Preferably, the oxidizing agent is hydrogen peroxide. The ratio of oxidizing agents used, based on the amount of the sulfanil compound of formula (II), is in the range of 8:1 to 0.8:1, preferably 5:1 to 1:1, and more preferably 3:1 to 1:1.

[0040] Suitable and preferred metal derivatives include vanadium salts and iron salts. Preferably, iron salts are used. Suitable examples include, but are not limited to, VOCl2, VO(acac)2, Fe(acac)3, and Fe(acac)2. The amount of metal catalyst used, based on the amount of the sulfanil compound of formula (II), is in the range of 0.1 mol% to 50 mol%. Preferably, it is 0.5 mol% to 10 mol%.

[0041] Examples of suitable and preferred chiral ligands are selected from Schiff bases formed from salicylaldehyde derivatives and chiral amines.

[0042] In a preferred embodiment of the present invention, the metal derivative is selected from iron, and the chiral ligand is a salicylaldehyde derivative and formula (X) [ka] (In the formula, R 6(where is a halogen, and the carbon marked with * represents an enantioenriched chiral center in either the (R)- or (S)- configuration) is a Schiff base formed from a chiral amino alcohol. Preferably, R 6 These are chloroform, iodine, or bromoform. Chiral ligands are used as enantioenriched compounds. The enantiomer ratio of the ligand is 80:20 to 100:0 [R]:[S] or [S]:[R], preferably 90:10 to 100:0 [R]:[S] or [S]:[R].

[0043] Based on the amount of the sulfanyl compound of formula (II), the amount of ligand used is in the range of 0.1 to 30 mol%, preferably 1 to 15 mol%, and most preferably 2 to 10 mol%. Optionally, ligands may be formed in situ during the reaction by adding a suitable salicylaldehyde derivative and a suitable amino alcohol. Alternatively, ligands may be prepared at a separate stage.

[0044] Examples of suitable and preferred acid additives include carboxylic acids. Preferably, the acid additive is benzoic acid, optionally monosubstituted, disubstituted, or trisubstituted with methyl, ethyl, isopropyl, methoxy, or dimethylamino, optionally in the form of a lithium, sodium, or potassium salt. More preferably, the additive is methoxybenzoic acid or dimethylaminobenzoic acid (optionally in the form of a lithium, sodium, or potassium salt), and even more preferably 4-methoxybenzoic acid. The amount of acid additive used compared to the sulfanil compound of formula (II) is in the range of 0.1 to 10 mol%, most preferably 0.5 to 5 mol%.

[0045] In the most preferred embodiment, the oxidizing agent is hydrogen peroxide; the metal salt is Fe(acac)3; and the ligands are (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimeth Selected from ru-butan-1-ol, (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, or (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol; the additive is 4-methoxybenzoic acid.

[0046] Suitable and preferred solvents (or diluents) include esters, nitriles, alcohols, ethers, and aliphatic, aromatic, or halogenated hydrocarbons. Examples include, but are not limited to, ethyl acetate, isopropyl acetate, acetonitrile, butyronitrile, ethanol, methanol, isopropanol, n-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, t-butyl methyl ether, diethyl ether, 1,4-dioxampentane, hexane, cyclohexane, heptane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or mixtures thereof.

[0047] Preferably, the solvent is an aromatic or halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or a mixture thereof.

[0048] More preferably, the solvent is selected from dichloromethane, toluene, xylene, chlorobenzene, methoxybenzene, or a mixture thereof.

[0049] The enantiomer ratio of the generated product is [R]:[S] or [S]:[R] in the range of 50.5:49.5 to 100:0. Preferably, the enantiomer ratio of the product is [R]:[S] or [S]:[R] in the range of 70:30 to 100:0, and more preferably [R]:[S] or [S]:[R] in the range of 90:10 to 100:0. The enantiomer ratio of the product may be lower or higher than the enantiomer ratio of the chiral ligand used in the reaction.

[0050] The ratio of the resulting enantiomers can be increased by crystallization as needed. Such methods are known to those skilled in the art and include crystallization from organic solvents, mixtures of organic solvents, or mixtures of organic solvents with water.

[0051] X-ray crystallography has demonstrated that a chiral ligand of formula (X) rich in R enantiomers provides an enantioenriched sulfoxide of formula (I) rich in R enantiomers (see Example 8). Accordingly, a chiral ligand of formula (X) rich in S enantiomers yields an enantioenriched sulfoxide of formula (I) rich in S enantiomers.

[0052] Process (B) is given by equation (III) [ka] (In the formula, R 1 , R 2 , and S* The process involves reacting a compound of formula (I) with an aqueous solution of hydroxylamine in a suitable solvent at a suitable temperature. The ratio of hydroxylamine used to the compound of formula (III) is in the range of 2:1 to 1:1, preferably 1.5:1 to 1:1.

[0053] Optionally, instead of hydroxylamine, a free base of hydroxylamine hydrochloride or hydroxylamine sulfate may be used in combination with one equivalent (relative to the hydroxylamine salt) of a suitable base. Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.

[0054] Examples of suitable and preferred solvents (or diluents) for step B include alcohols, ethers, and aliphatic hydrocarbons, aromatic hydrocarbons, or halogenated hydrocarbons.

[0055] Examples include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,2-dichloroethane, chlorobenzene, toluene, anisole, xylene, t-butyl methyl ether, fluorobenzene, ethanol, methanol, and isopropanol.

[0056] The reaction is advantageously carried out in a temperature range of -20°C to 80°C. The preferred temperature range is 0°C to 30°C.

[0057] Process (C) is, The method comprises reacting a compound of formula (IV) with a compound of formula (IX) in a suitable solvent (or diluent) in the presence of a suitable base. The ratio of the compound of formula (IX) used to the compound of formula (IV) 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.

[0058] Examples of suitable and preferred bases for step C include 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 (IX) is 1.5:1 to 1:1, more preferably 1.2:1 to 1:1.

[0059] Examples of suitable and preferred solvents (or diluents) for step C include esters, nitriles, ethers, and aliphatic hydrocarbons, aromatic hydrocarbons, or halogenated hydrocarbons.

[0060] 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.

[0061] Preferably, the solvent is an ether, nitrile, or halogenated hydrocarbon, such as tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, and chlorobenzene.

[0062] Process (D) is, This method involves thermally rearranging the compound of formula (V) to the compound of formula (VI) in a suitable solvent (or diluent) at a suitable temperature.

[0063] Suitable solvents (or diluents) are polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates, and ethers, or mixtures thereof.

[0064] 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, n-propanol, 2-methoxyethanol, chlorobenzene, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, anisole, N,N-dimethylformamide, N-methylpyrrolidine, sulfolane, 2,5-dimethylisosorbide, dimethylacetamide, silene, or mixtures thereof.

[0065] More preferably, the solvent (or diluent) is N-methylpyrrolidine, sulfolane, acetonitrile, ethylene glycol, ethanol, n-propanol, or a mixture thereof.

[0066] The rearrangement preferably occurs within a temperature range of 0°C to 150°C. The preferred temperature is R 5 It depends on the electronic properties of the substituent. 5 If the reaction is highly electron-withdrawing (e.g., 2,4-dinitrophenyl), the appropriate reaction temperature is in the range of 0°C to 40°C, but R 5 If the solution is neutral (e.g., methyl) or moderately electron-withdrawing (e.g., tosyl), the preferred temperature is 60°C to 100°C.

[0067] In one embodiment of a process according to the present invention for producing a compound of formula (VI), steps (C) and (D) can be advantageously carried out in a one-pot process without isolating an intermediate compound of formula (V). This is most preferred when R5 in the sulfonyl chloride of formula (IX) is highly electron-withdrawing (e.g., 2,4-dinitrophenyl).

[0068] Process (E) is, The process involves reacting a compound of formula (VI) with a compound of formula (VII) in a suitable solvent (or diluent) at a suitable temperature to produce a compound of formula (I) via an intermediate compound of formula (VIII). The ratio of the compound of formula (VII) used to the compound of formula (VI) is in the range of 2:1 to 1:1, preferably 1.5:1 to 1:1, and more preferably 1.2:1 to 1:1.

[0069] Suitable solvents (or diluents) include polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates, and ethers, or mixtures thereof.

[0070] Examples of suitable and preferred solvents include, but are not limited to, acetonitrile, butyronitrile, benzonitrile, ethylene glycol, methanol, ethanol, n-butanol, n-propanol, 2-methoxyethanol, 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.

[0071] The condensation rearrangement cascade favorably occurs within a temperature range of 20°C to 150°C. The preferred temperature range is 60°C to 100°C.

[0072] In one embodiment of a process according to the present invention for producing a compound of formula (I), steps D and E can be advantageously carried out in a one-pot process without isolating intermediate compounds of formulas (VI) and (VIII).

[0073] In another embodiment relating to a process according to the present invention for producing the compound of formula (I), steps D and E can be advantageously carried out in a one-pot process in the presence of a suitable acidic additive. The most preferred additive is citric acid. The preferred molar percentage of the acidic additive relative to the product of step C is 1 to 10 mol%.

[0074] The chiral center at sulfur is completely conserved throughout the entire sequence (after step A), starting from the chiral sulfoxide. By comparing the compound prepared in experimental procedure 43 with the same compound prepared in international publication 2022 / 253841, whose absolute configuration has been established by X-ray crystallography, it has been proven that no inversion occurs; that is, the R sulfoxide of formula (III) yields the R compound of formula (I), and vice versa.

[0075] A particular preferred embodiment according to the present invention is provided as described below. Embodiment 1 provides a process for preparing an enantiomerically enriched sulfoximine of formula (I) as defined above. The compounds of formula (I) described in accordance with the present invention are active ingredients that are beneficial preventively and / or therapeutically even at low application rates in the field of pest control, possess a very favorable biocidal spectrum, and are well tolerated by warm-blooded animal species, fish, and plants. [Examples]

[0076] The following examples further illustrate the present invention, but do not limit it. Those skilled in the art will quickly be able to understand appropriate modifications from the procedures, both in terms of reactants, reaction conditions, and technique.

[0077] When typical process conditions for producing the compounds of the present invention (e.g., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, minor modifications to these process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the reactants or solvent used, but such conditions can be determined by a general optimization procedure by those skilled in the art, provided the reagents are the same. Abbreviation CDCl3 (deuterated chloroform) CPME Cyclopentyl Methyl Ether DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) HCl ethyl acetate HCl (hydrochloric acid) h / hrs time LC-MS Liquid Chromatography Mass Spectrometry (LC-MS, LCMS, or LC / MS) MeCN acetonitrile (MeCN or ACN) min MeTHF 2-methyltetrahydrofuran NaHCO3 (sodium bicarbonate) Na2CO3 (sodium carbonate) Sodium sulfate (Na2SO4) rt room temperature Rt retention time sat. saturation TEA (Triethylamine, or Et3N) THF (Tetrahydrofuran)

[0078] Preparation example Compounds of formula (I) according to the present invention can be prepared using the synthetic techniques described above and below. Throughout this specification, temperatures are expressed in degrees Celsius (°C), and "mp" indicates the melting point. LC / MS stands for liquid chromatography-mass spectrometry. As used herein, the terms “room temperature,” “RT,” “rt,” or “ambient temperature” refer to temperatures between approximately 15°C and approximately 35°C. For example, rt may refer to temperatures between approximately 20°C and approximately 30°C.

[0079] 1 1H NMR and 19 F NMR measurements were performed using a Bruker 400 MHz spectrometer. Chemical shifts were obtained using TMS. 1 H) and CFCl3( 19 F) Values ​​are shown in ppm relative to the standard. Spectra were measured in a deuterated solvent as described. Synthesis of sulfide starting materials:

[0080] Example 1: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carboxamide [ka] A few drops of DMF were added to a suspension of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carboxylic acid (1.00 g, 98% purity, 3.68 mmol) in HCl (9.0 mL). Oxalyl chloride (0.360 mL, 4.05 mmol) was added dropwise to this reaction mixture over 2 hours at rt. The acid chloride solution thus prepared was slowly added to a two-phase mixture of NaHCO3 (0.372 g, 4.42 mmol), water (2.7 mL), HCl (2.5 mL), and ammonium hydroxide in water (4.31 g, 36.9 mmol), and cooled to 0°C. After addition, the reaction mixture was stirred for a further 1 hour at rt. The phases were separated, and the aqueous layer was extracted with HCl. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the title compound (1.00 g, 83% purity, 85% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.18(d,J=2.3Hz,1H),7.99(s,1H),7.54(m,2H),2.89(q,J=7.3Hz,2H),1.77(s,6H),1.27(t,J=7.3Hz,3H).

[0081] Example 2: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carbonitride [ka] 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carboxamide (10.0 g, 87.5% purity, 33.0 mmol) and TEA (18 mL, 132 mmol) were dissolved in THF (100 mL), to which trifluoroacetic anhydride (14.1 mL, 80.42 mmol) was added dropwise over 15 minutes at 0°C. After the addition was complete, the reaction mixture was warmed to rt. After stirring for 1 hour, water and saturated NaHCO3 were slowly added. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude substance was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (8.98 g, 82% purity, 90% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.38(d,J=2.4Hz,1H),7.74(d,J=2.4Hz,1H),3.20(q,J=7.3Hz,2H),1.81(s,6H),1.29(t,J=7.3Hz,3H).

[0082] Example 3: Preparation of 5-(3-fluorophenyl)-3-methylsulfanylpyridine-2-carbonitride [ka] Sodium methanethiolate (2.6 g, 35.2 mmol) was added to a solution of 3-chloro-5-(3-fluorophenyl)pyridine-2-carbonitrile (3.47 g, 94.5% purity, 14.1 mmol) in tetrahydrofuran (17 mL). The reaction mixture was stirred at 60°C for 2 hours, then cooled to rt and quenched with ice water. The resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using ethyl acetate and cyclohexane as eluents to obtain the title compound (2.60 g, 94% purity, 71% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.83(d,J=2.0Hz,1H),8.13(d,J=1.83Hz,1H),7.78-7.83(m,1H),7.73(d,J=7.5Hz,1H),7.56-7.63(m,1H),7.35(d,J=2.6Hz,1H),2.74(s,3H)

[0083] Example 4: Preparation of 5-chloro-3-ethylsulfanylpyridine-2-carbonitride [ka] To a solution of 5-chloro-3-ethylsulfanylpyridine-2-carboxamide (15.0 g, 97% purity, 67.0 mmol) and TEA (23.5 mL, 167.5 mmol) in dry THF (255 mL), trifluoroacetic anhydride (11.3 mL, 80.4 mmol) was added over 15 min while maintaining the internal temperature below 5°C. The reaction mixture was heated to rt and stirred for a further 2 hours. Most of the THF was evaporated under reduced pressure, and water (45 mL) was slowly added. The resulting brown precipitate was filtered and washed on the filter with cold water. The precipitate was dissolved in acetone (60 mL), and the solution was slowly added to water (150 mL) while vigorously stirring. The resulting light brown precipitate was filtered and dried under reduced pressure to obtain the title compound (13.25 g, 97% purity, 97% yield). 1H NMR(400MHz,CDCl3)δ 8.38(d,J=2.1Hz,1H),7.66(d,J=2.1Hz,1H),3.07(q,J=7.3Hz,2H),1.41(t,J=7.4Hz,3H).

[0084] Example 5: Preparation of 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate [ka] To a solution of 5-chloro-3-ethylsulfanylpyridine-2-carbonitrile (20.0 g, 97% purity, 97.6 mmol) in dry DMF (100 mL), powdered potassium carbonate (34.4 g, 244 mmol) was added. The resulting suspension was then heated to 100 °C, and ethyl cyanoethyl (15.9 mL, 146 mmol) was added over 1 hour. After completely consuming the starting materials, the reaction mixture was cooled to rt, diluted with ethyl acetate, and the precipitate (inorganic salt) was filtered off. The filtrate was neutralized with 2N aqueous HCl, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SO₄, and evaporated under reduced pressure. Using ethyl acetate and cyclohexane as eluents, the crude residue was purified by silica gel chromatography to obtain the title compound (19.12 g, 95.5% purity, 87% yield) as a gray solid. 1 H NMR(400MHz,CD3CN)δ 8.50(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),5.21(s,1H),4.23(q,J=7.1H z,2H),3.14(q,J=7.4Hz,2H),1.34(t,J=7.3Hz,3H),1.24(t,J=7.1Hz,3H).

[0085] Example 6: Preparation of 5-(cyanomethyl)-3-ethylsulfanylpyridine-2-carbonitride [ka] Sodium chloride (5.07 g, 86.3 mmol) was added to a solution of ethyl 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl) acetate (10.00 g, 95% purity, 34.51 mmol) in a mixture of acetic acid (44 mL) and water (22.5 mL). The reaction mixture was then stirred at 100°C until all the starting materials were consumed. The reaction mixture was cooled to rt and cold water (100 mL) was added. The resulting mixture was then neutralized by adding solid NaHCO3 in small amounts with vigorous stirring, and the neutralized solution was extracted with siRNA. The combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was dissolved in acetone (20 mL) and slowly added to water (100 mL) at 0°C with vigorous stirring. The resulting grayish-white precipitate was filtered off, washed with water (50 mL) on the filter, and dried under reduced pressure to obtain the title compound (7.17 g, 93% purity, 95% yield) as a grayish-white powder. 1 H NMR(400MHz,DMSO-d6)δ 8.50(d,J=1.8Hz,1H),8.04(d,J=1.7Hz,1H),4.21(s,2H),3.18(q,J=7.3Hz,2H),1.30(t,J=7.3Hz,3H).

[0086] Example 7: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanylpyridine-2-carbonitrile [ka] To a solution of 5-(cyanomethyl)-3-ethylsulfanylpyridine-2-carbonitrile (10.00 g, 96% purity, 47.23 mmol) in MeCN (150 mL), Cs2CO3 (47.1 g, 141.7 mmol), followed by iodomethane (6.0 mL, 94.5 mmol), was added, and the reaction mixture was stirred at 80°C for 1 hour. After completely consuming the starting materials, the reaction mixture was cooled to rt and quenched by adding water. The resulting mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Using cyclohexane and ethyl acetate as eluents, the crude substance was purified by silica gel chromatography to obtain the title compound (11.45 g, 85% purity, 89% yield) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 8.69(d,J=2.1Hz,1H),8.03(d,J=2.2Hz,1H),3.25(q,J=7.3Hz,2H),1.78(s,6H),1.29(t,J=7.3Hz,3H).

[0087] Preparation of racemic sulfoxides for the development of chiral analytical methods: Racemic samples of sulfoxides were prepared according to the following general procedure. One equivalent of sulfide was dissolved in acetic acid (5 mL / mmol), and hydrogen peroxide (1.05 equivalents, 30% by mass) was added at rt. The reaction mixture was stirred at 40°C for 20 hours, or until complete consumption of the starting material was observed by LC-MS. Aqueous sodium bicarbonate solution was added dropwise to the reaction mixture, followed by dropwise addition of ethyl acetate. The phases were separated, and the aqueous phase was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to obtain the desired sulfoxide. This substance was used directly for the development of the chiral HPLC method.

[0088] Preparation of enantioenriched sulfoxides Example 8: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-bromo-3-ethylsulfanylpyridine-2-carbonitrile (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 30% aq H2O2 (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 transformation of the starting materials), the reaction was quenched by adding crushed ice (4 g) and 40% aq NaHSO3 (2.6 mL). After warming to rt, the mixture was diluted with siRNA (8 mL) and treated with 1 M aqueous H2SO4 (0.83 mL). After stirring for 30 min, the phases were separated, the organic phase was washed with aqueous sodium bicarbonate (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 to the desired 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile. The crude product was purified by reverse-phase HPLC (MeCN / water / 0.1% formic acid mobile phase) to obtain the title compound (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: Waters Acquity UPC 2 / QDa;PDA Detector Waters Acquity UPC 2Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3 μm, 0.3 cm × 10 cm, 40°C; Mobile phase: A: CO2, B: IPA; Gradient: 20-60% B over 2 min; ABPR: 1800 psi; Flow rate: 2.0 mL / min; Detection: 240 nm; Sample concentration: 1 mg / mL in MeCN; Injection: 2 μL result: [Table 1] For X-ray data analysis, single crystals grown from diisopropyl ether were selected. The crystal sample used measured 0.4 mm × 0.3 mm × 0.3 mm and was a colorless prismatic crystal. Data was acquired at 293 K using a Rigaku Oxford Diffraction Supernova diffractometer. The unit cell was found to be orthorhombic (space group P212121), and the structure was found to contain one molecule within the crystal asymmetric unit (Figure 1, chirality marked and represented by thin rods. Figure 1 was created using the Flare software package). Stereochemistry was clearly determined to be R isomer by the Flack parameter of 0.02 + / - 0.03. Crystallographic data are summarized in Table 1, and the selected geometric parameters are shown in Table 2.

[0089] [Table 2-1] [Table 2-2] 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)

[0090] [Table 3]

[0091] Example 9a: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile [ka] 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) were dissolved in PhMe (4.0 mL), to which 30% aq H2O2 (0.20 ml, 2.00 mmol) was added at rt. 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 aqNaHCO3. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude substance 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); 13 C NMR(101MHz,d6-DMSO)δ=165.7,146.0,144.4,142.8,136.0,131.1,121.2,48.9,19.2,12.0,6.3. Chiral SFC method: Waters Acquity UPC 2 / QDa;PDA Detector Waters Acquity UPC 2Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C; Mobile phase: A: CO2, B: IPA; Gradient: 20-60% B over 1.8 min; ABPR: 1800 psi; Flow rate: 2.0 mL / min; Detection: DAD 210-500 nm; Sample preparation: Dissolve in MeOH; Injection: 2 μL result: [Table 4]

[0092] Example 9b: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitrile (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), 30% aq H2O2 (0.23 ml, 2.11 mmol) was added over 1 hour at 0°C using a syringe pump. The resulting reaction mixture was then stirred at the same temperature for a further 20 hours. The reaction mixture was poured into ELISA (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 aqNaHCO3. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product 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 Example 9a result: [Table 5]

[0093] Example 9c: 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-dibromophenol (1.281 g, 97% purity, 3.30 mmol) in anisole (46 mL), 30% aq H2O2 (7.8 ml, 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 40% aq NaHSO3 (10.6 mL) and diluted with anisole (53 mL). The phases were separated, and the organic phase was washed with 1 M H2SO4 (21 mL), aq saturated NaHCO3 (21 mL), and brine (21 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product 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: Waters Acquity UPC 2 / QDa;PDA Detector Waters Acquity UPC 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 over 9.8 min; ABPR: 1800 psi; Flow rate: 2.0 mL / min; Detection: 238 nm; Sample preparation: 1 mg / mL in MeCN; Injection: 2 μL result: [Table 6]

[0094] Example 10: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carbonitrile (2.00 g, 82% purity, 6.64 mmol), iron(III) acetylacetonate (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-anisic acid (51 mg, 0.332 mmol) were mixed in toluene (13 mL) and 30% aq H2O2 (1.36 ml, 50.1 mmol) over 1 hour at rt. The reaction mixture was stirred for a further 5 hours and then quenched by adding aqueous sodium thiosulfate at 0°C. The organic layer was separated, the aqueous layer was extracted with SiO2, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude substance was purified by silica gel chromatography using cyclohexane and SiO2 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=2.75Hz,1H)3.28-3.33(m,1H)2.96-3.02(m,1H),1.84(s,6H),1.09(t,J=7.3Hz,3H). Chiral analysis method: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IA (4.6 mm × 250 mm) 5 μm; Mobile phase: A: TBME B: IPA; Uniform concentration: 20% B at 13 min; Flow rate: 1.0 ml / min; Detection: 240 nm; Sample preparation: 1 mg / mL in EtOH; Injection: 2 μL result: [Table 7]

[0095] Example 11: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanylpyridine-2-carbonitrile (6.00 g, 96.5% purity, 25.0 mmol), iron(III) acetylacetonate (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) were dissolved in toluene (90 mL), to which 30% aqueous hydrogen peroxide (2.0 equivalents, 50.1 mmol) was added dropwise over 1 hour at 0°C. The reaction mixture was stirred at 24°C for 2 hours, and then quenched by adding saturated Na2S2O3 at 0°C. The organic layers were separated, the aqueous layer was extracted with ELISA, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude substance was purified by column chromatography using cyclohexane and SiO2 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) Chiral analysis method: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IC (4.6 mm × 250 mm) 5 μm; Mobile phase: A: n-hexane B: EtOH; Uniform concentration: 30% B at 30 min; Flow rate: 1.0 ml / min; Detection: 255 nm; Sample preparation: 1 mg / mL in EtOH; Injection: 2 μL result: [Table 8]

[0096] Example 12: Preparation of 5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(3-fluorophenyl)-3-methylsulfanylpyridine-2-carbonitrile (0.800 g, 90% purity, 2.95 mmol), iron(III) acetylacetonate (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-anisic acid (11.3 mg, 0.0737 mmol) in toluene (6.0 mL), 30% aq H2O2 (0.6 ml, 5.9 mmol) was added dropwise over 15 min, and the reaction mixture was continued to stir for another hour. The reaction mixture was quenched with saturated sodium thiosulfate, the resulting mixture was extracted with dimethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The title compound (0.73 g, 94% purity, 97% ee, 89% yield) was obtained by purification by silica gel chromatography using cyclohexane and dimethyl acetate as eluents. 1H 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) Chiral analysis method: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IA (4.6 mm × 250 mm) 5 μm; Mobile phase: A: TBME B: IPA; Uniform concentration: 30% B at 30 min; Flow rate: 1.0 ml / min, Detection: 255 nm; Sample preparation: 1 mg / mL in EtOH; Injection: 2 μL result: [Table 9]

[0097] Example 13: 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 30% aq H2O2 (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% aq NaHSO3 (0.30 ml). After warming to rt, the mixture was diluted with SiO4 (10 ml) and treated with concentrated H2SO4 (50 μl). After stirring for 30 min, the phases were separated, and the aqueous layer was further extracted with SiO4 (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 silica gel chromatography (cyclohexane / SiO4 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;PDA Detector Waters Acquity UPC 2; Column: Daicel SFC CHIRALPAK® IC, 3 μm, 0.3 cm×10 cm, 40°C; Mobile phase: A: CO₂ B: MeOH, isocratic 3% B for 2 min; ABPR: 1800 psi; Flow rate: 2.0 mL / min; Detection: 270 nm; Sample concentration: 1 mg / mL in MeOH; Injection: 1 μL Result: [Table 10]

[0098] Preparation of Enantioenriched Amidine Oxime Example 14: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine [Chemical Formula] 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) was added 50% aqueous NH₂OH (0.37 mL, 5.98 mmol) in two portions over 10 min. After stirring for an additional 20 min, most of the solvent was evaporated under reduced pressure (approximately 1.2 mL remaining). CPME (2.7 mL) was added slowly, resulting in precipitation. The precipitate was filtered, washed on the filter with CPME / MeTHF (7:3, 1.5 mL), and dried in vacuo to give the title compound (0.713 g, 95% purity, 78% yield) as a white powder. 1 H NMR (400 MHz, CDCl₃) δ 1.27 (t, J=7.45 Hz, 3H), 2.93 (dq, J=13.1, 7.4 Hz, 1H), 3.32 (dq, J=13.1, 7.5 Hz, 1H), 5.58 (br s, 2H), 7.55 (s, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H).

[0099] Example 15: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine

Chemical Formula

[0100] The previously prepared chiral sulfoxide solution (54.4 g) was packed into a 100 ml reactor while being mechanically stirred. In a separate flask, a 4.7 M NH2OH solution was prepared by treating an NH2OH·HCl solution with 50% aq NaOH 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 rt. After stirring for a further 2 hours (white crystals in an orange liquid), the precipitate was filtered off and washed on a filter with PhOMe (23 ml) and water (2 × 23 ml). 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) on the filter, and dried overnight under high vacuum to obtain the title compound (10.42 g, 97% assay, >99.5% ee, 80% isolation yield over two 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;PDA Detector Waters Acquity UPC 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C; Mobile phase: A: CO2 B: MeOH; Gradient: 20-60% over 1.8 min; ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: 227 nm; Sample preparation: 1 mg / mL in MeOH; Injection: 2 μL result: [Table 11]

[0101] Example 16: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine [ka] 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile (167.1 mg, 95% purity, 97% ee, 0.648 mmol) was suspended in ethanol (1.3 ml), to which 50% aqNH2OH (0.062 ml, 1.01 mmol) was added. The resulting concentrated 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: See Example 15. result: [Table 12]

[0102] Example 17: 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), 50% aqueous hydroxylamine (1.00 equivalent, 1.84 mmol) was added at 0°C, and the reaction mixture was stirred at rt for a further 2 hours. An additional portion of 50% aq hydroxylamine (0.20 equivalent, 0.368 mmol) was added, and the reaction mixture was stirred for a further 1 hour. RINKAN was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with RINKAN. 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)

[0103] Example 18: 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), 50% aqueous hydroxylamine (0.52 ml, 8.49 mmol) was added at rt. After stirring at rt for 1 hour, an additional portion of 50% aqueous hydroxylamine (0.20 ml, 3.4 mmol) was added. Immediately after the 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 on the filter with water and dried under high vacuum to obtain the title compound (1.78 g, 93% purity, 81% yield). 1¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 6.06 (s, 2H), 3.21-3.31 (m, 1H), 2.78 (m, 1H), 1.79 (s, 6H), 1.15 (t, J=7.4 Hz, 3H)

[0104] Example 19: Preparation of 5-(3-fluorophenyl)N'-hydroxy-3-[(R)-methylsulfinyl]pyridine-2-carboxamidine

Chemical Formula

[0105] Example 20: 3-[(R)-ethylsulfinyl]-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine

Chemical Formula

[0106] Example 21: Preparation of (Z)-[[amino-[5-bromo-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [ka] The reaction mixture was stirred at rt for 3 hours. 18 ml of butyl was added, and the resulting reaction mixture was washed with water (3.5 ml), 1 M aqHCl (2.5 ml), aqNaHCO3 (3.5 ml), and brine (5 ml). An additional 58 ml of butyl 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).

[0107] Example 22: 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), TEA (523 μl, 3.75 mmol) was added, followed by nosyl chloride (763 mg, 3.44 mmol). The reaction mixture was stirred at rt for 7 hours, and then diluted with water (20 ml) and HCl (15 ml). The phases were separated, and the aqueous phase was further extracted with HCl (2 × 15 mL). The combined organic phase was washed with 1 N aq. HCl (20 ml) and brine (20 ml). By drying on 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)

[0108] Example 23: Preparation of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]-methylene]-amino]4-methylbenzenesulfonate [ka] TEA (13.8 ml, 98.8 mmol) was added to a MeCN (50 ml) suspension of 5-(1-cyanocyclopropyl)-3-(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (14.817 g, 94% purity, 49.9 mmol). After stirring for 10 minutes, p-toluenesulfonyl chloride (pTsCl) (10.13 g, 53.15 mmol) was added in five portions over 20 minutes. After stirring at rt for 2 hours, the reaction mixture was diluted with ELISA (200 ml). The resulting solution was washed with 1 M HCl (3 × 40 ml), aq saturated NaHCO3 (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 on a filter with ELISA (20 ml), and dried under high vacuum to obtain the title compound (14.00 g, 97% purity, 90% yield) as a gray crystalline solid. 1 H 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

[0109] Example 24: 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), 2.76 ml of TEA (19.8 mmol) was added, followed by 2.309 g of 4-nitrobenzenesulfonyl chloride (10.42 mmol) in three portions over 10 minutes. After stirring at rt for 1.5 hours, the reaction 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 sat. 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 on the filter with MTBE, and dried under high vacuum to obtain the title compound (3.961 g, 93% purity, 85% yield) as a grayish-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)

[0110] Example 25: Preparation of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate [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), TEA (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 sat.NaHCO3 (10 ml). The phases were separated, and 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)

[0111] Example 26: 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 Me-THF (10 mL), TEA (0.83 mL, 5.92 mmol) and p-toluenesulfonyl chloride (0.624 g, 3.11 mmol) were added at rt. The reaction mixture was stirred for 2 hrs and quenched by adding water (10 mL). The layers were separated, the organic phase was washed with 2N HCl and water, and 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)

[0112] Example 27: 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-MeTHF (3.0 mL), TEA (0.42 mL, 3.0 mmol) and p-toluenesulfonyl chloride (0.318 g, 1.58 mmol) were added. The reaction mixture was stirred at rt 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)

[0113] Example 28: Preparation of [(Z)-[amino-[5-(3-fluorophenyl)-3-[(S)-methylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate [ka] 5-(3-fluorophenyl)-N'-hydroxy3-[(S)-methylsulfinyl]pyridine-2-carboxamidine (1.6 g, 86% purity, 4.69 mmol) and TEA (1.31 mL, 9.38 mmol) were stirred in 2-Me-THF (9.4 mL), to which 4-nitrobenzenesulfonyl chloride (1.21 g, 4.93 mmol) was added at rt. After stirring for 4 hours, the reaction mixture was quenched by adding water (10 mL), the organic layer was separated, washed with 2N aq. HCl (5 mL) followed by saturated NaHCO3 solution (10 mL), the combined organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain the title compound (2.01 g, 92% purity, 82% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:9.11(d,J=2.3Hz,1H),8.57(d,J=2.3Hz,1H),8.47-8.52(m,2H),8.26-8.32(m,2H),7.8 0-7.85(m,1H),7.73-7.80(m,1H),7.66-7.71(m,1H),7.60(td,J=7.9,6.0Hz,2H),7.31-7.38(m,1H),2.68(s,3H)

[0114] Example 29: 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-MeTHF (5.0 mL), TEA (0.45 mL, 3.21 mmol) and 4-nitrobenzenesulfonyl chloride (0.393 g, 1.68 mmol) were added at rt. The reaction mixture was stirred for 2 hours and quenched by adding water (5 mL) and 2-MeTHF (5 mL). The phases were separated, the organic phase was washed with 2N HCl and water, and the combined organic phase was further washed with sat. aqueous sodium bicarbonate solution (10 mL). 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).

[0115] Example 30: 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 MeCN (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 substance 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 a grayish-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).

[0116] Example 31: Preparation of 2-[(1R)-1-ethyl-3-imino-1-oxoisothiazolo[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 MeCN (10 mL) was stirred at 80°C for 18 hours, then cooled to rt and concentrated under reduced pressure. A saturated aqueous NaHCO3 solution was added to the resulting residue, and the resulting mixture was extracted with EtOAC. The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography using tert-butyl methyl ether and methanol as eluents to obtain the title compound (0.25 g, 85% purity, 50% yield) as a brown solid. 1H 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)

[0117] Example 32: Preparation of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropane-carbonitride 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 MeCN (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

[0118] Example 33: Preparation of (1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate [ka] A solution of [5-bromo-3-[(S)-ethylsulfinyl]pyridine-2-carboximidoyl]amino]4-nitrobenzenesulfonate (0.50 g, 1.04 mmol, 99% purity) in MeCN (4.2 mL) was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound (0.40 g, 99% purity, 81% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:11.05(br s,2H),9.45(d,J=4.3Hz,2H),8.17-8.22(m,2H),7.83(d,J=7.8Hz,2H),4.24-4.42(m,2H),1.44(t,J=7.27Hz,3H)

[0119] Example 34: Preparation of (1R)-1-ethyl-1-oxo-6-(trifluoromethyl)isothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate [ka] A solution of [3-[(S)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carboxyimidoyl]amino]4-nitrobenzenesulfonate (1.0 g, 83% purity, 1.78 mmol) in MeCN (1.78 mL) was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound (1.01 g, 55% purity, 67% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ:11.21(brs,1H),11.18(br s,1H),9.76(s,1H),9.67(d,J=1.4Hz,1H),8.17-8.22(m,2H),7.80-7.86(m,2H),4.39-4.48(m,1H),4.26-4.35(m,1H),1.47(t,J=7.3Hz,2H)

[0120] Example 35: Preparation of (1R)-6-(3-fluorophenyl)-1-methyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzene sulfonate [ka] A solution of [(Z)-[amino-[5-(3-fluorophenyl)-3-[(S)-methylsulfinyl]-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate (1.0 g, 92% purity, 1.92 mmol) in MeCN (1.92 mL) was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound (0.48 g, 82% purity, 43% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ:11.00(s,1H),10.93(s,1H),9.64(d,J=2.0Hz,1H),9.45(d,J=2.0Hz,1H),8.18-8.22(m,2H) ,7.93-7.95(m,1H),7.91-7.92(m,1H),7.81-7.86(m,3H),7.70(td,J=8.1,6.1Hz,1H),7.43-7.51(m,1H),4.21(s,3H)

[0121] Example 36a: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] To a MeCN (0.45 mL) stirred solution of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitrilate 4-methylbenzenesulfonate (0.100 g, 97% purity, 0.23 mmol) was mixed with N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.050 g, 0.25 mmol) at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified by neutral silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (0.060 g, 98% purity, >99.5% ee, 61% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.93(d,J=2.4Hz,1H),8.40(d,J=2.3Hz,1H),8.28(s,1H),4.56(s,1H) ),3.80(s,3H),3.58(dt,J=15.04,7.30Hz,2H),2.00-2.05(m,2H),1.85-1.94(m,2H),1.15(t,J=7.4Hz,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 272 nm; Analysis time: 15 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 13] result: [Table 14]

[0122] Example 36b: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (500 mg, 99% purity, 1.14 mmol) in dry MeCN (2.3 ml) was heated at 80°C for 8 hours. Then, a solution of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (240 mg, 1.25 mmol) in dry MeCN (1.1 ml) was added, and the resulting reaction mixture was heated at the same temperature for a further 20 hours. The solution was evaporated under reduced pressure to obtain the crude title compound (0.791 g, 41% purity, 65% yield). The crude product was purified by silica gel chromatography using toluene and cyclohexane as eluents to obtain the title compound (355 mg, 84% purity, >99% ee, 60% yield) as a grayish-white foam.

[0123] Example 36c: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] Step 1: To a suspension of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (7.89 g, 96.8% purity, 27.4 mmol) in dry THF (27.4 mL), TEA (4.2 mL, 30.2 mmol) was added at rt under an argon atmosphere. A solution of p-toluenesulfonyl chloride (5.50 g, 28.0 mmol) in THF (27.4 mL) was slowly added over 5 min while maintaining the temperature below 20°C. The resulting suspension was stirred at rt for 16 hours. The precipitate (Et3N·HCl) was filtered on Celite and washed with a small amount of dry THF. A filtrate (58.17 g) containing [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (19 w / w%, 93% chemical yield) was used in the next step without any purification. Step 2: The solution prepared in Step 1 was concentrated under reduced pressure to approximately 1 / 3 of its volume. Dry MeCN (20 ml) was added, and approximately half of the volume was evaporated under reduced pressure. This procedure was repeated once more. Next, N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (6.03 g, 30.6 mmol) and citric acid (0.25 g, 1.28 mmol) were added. Solvent exchange with MeCN was performed again, and finally the amount of MeCN was adjusted to a concentration of approximately 1 M for the product from Step 1. The resulting dilute suspension was stirred at 67°C for 17 hours, and then at 74°C for a further 8 hours. The resulting concentrated suspension was diluted with MeCN (12.5 ml) and cooled to 50°C. At this temperature, the precipitate (NH4OTs) was filtered off, and the filtrate was evaporated under reduced pressure to obtain the crude title compound (65% purity, 80% chemical yield from the product from Step 1). The crude substance was suspended in n-PrOH (152 ml), and the mixture was heated under reflux (97°C) to dissolve all the substances. After 10 min, the solution was slowly cooled to 50°C over 40 min, seed crystals were added, and the mixture was stirred for a further 30 min, then cooled to rt over 1 h. The precipitate was filtered and washed on the filter with n-PrOH (2 × 20 mL). The precipitate was then dried under high vacuum to obtain the title compound (7.93 g, 97% purity, >99.5% ee, 69% isolation yield from the product of step 1) as a beige solid.

[0124] Example 37: R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-ethyl-imino-oxo-λ 6 - Preparation of sulfane [ka] (1R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.100 g, 99% purity, 0.22 mmol) was stirred in MeCN (0.45 mL), to which N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.047 g, 0.24 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.045 g, 94% purity, 99% ee, 43% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.22(d,J=2.1Hz,1H),8.87(d,J=1.5Hz,1H),8.65(dd,J=8.6,1.9Hz,2H),3.73(s,3H),3.54-3.71(m,2H),1.18(t,J=7.4Hz,3H)

[0125] Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 290 nm; Analysis time: 20 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 15] result: [Table 16]

[0126] Example 38: R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-ethyl-imino-oxo-λ 6 - Preparation of sulfane [ka] (1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.100 g, 99% purity, 0.22 mmol) was stirred in MeCN (0.45 mL), to which N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.049 g, 0.25 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.060 g, 98% purity, 95% ee, 60% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ:9.27(s,1H),9.22(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H ),8.28(s,1H),4.60(s,1H),3.82(s,3H),3.51-3.68(m,2H),1.15(t,J=7.4Hz,3H) Method of chiral analysis: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; flow: 1 ml / min; λMax.: 274 nm; running time: 20 min; sample preparation: 1 mg / mL in EtOH; Inj.Vol.: 4 μL [Table 17] result: [Table 18]

[0127] Example 39: R-ethyl-imino-[2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridine-2-yl]-5-(trifluoromethyl-3-pyridyl]-oxo-λ 6 - Preparation of sulfane [ka] (1R)-1-ethyl-1-oxo-6-(trifluoromethyl)isothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.500 g, 70% purity, 0.75 mmol) was mixed with N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.14 g, 0.75 mmol) at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and ethyl acetate as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.070 g, 94% purity, 99% ee, 20% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:9.51(dd,J=2.06,0.81Hz,1H),8.91(dd,J=2.0 0.63Hz,1H),8.75(d,J=1.6Hz,1H),8.69-8.72(m,1H),4.70(s,1H),3.76(s,3H),3.67-3.75(m,2H),1.10-1.22(m,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm, Flow rate: 1 ml / min, λ Max.: 294 nm, Analysis time: 10 min, Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 19] result: [Table 20]

[0128] Example 40: R-ethyl-imino-[2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine-2-yl]-5-(trifluoromethyl)-3-pyridyl]-oxo-λ 6 - Preparation of sulfane [ka] [3-[(S)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carboxyimidoyl]amino]4-nitrobenzenesulfonate (0.100 g, 70% purity, 0.15 mmol) was stirred in MeCN (0.6 mL), to which N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.029 g, 0.15 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.042 g, >99% ee, 60% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.51(d,J=1.2Hz,1H),9.31(s,1H),8.74(d,J=1.8Hz,1H ),8.32(s,1H),4.70(s,1H),3.86(s,3H),3.59-3.74(m,2H),1.18(t,J=7.4Hz,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 270 nm; Analysis time: 15 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 21] result: [Table 22]

[0129] Example 41: Preparation of R-2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]-2-methyl-propanenitrile 4-methylbenzenesulfonate (0.200 g, 68% purity, 0.31 mmol) was added to a stirred solution of MeCN (0.63 mL) with N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.070 g, 0.35 mmol) at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.11 g, 98% purity, >99.5% ee, 78% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.23(d,J=2.3Hz,1H),8.87(d,J=1.3Hz,1H),8.65(d,J=1.5Hz,1H),8.56(d ,J=2.3Hz,1H),4.56(s,1H),3.73(s,3H),3.55-3.71(m,2H),1.89(d,J=5.3Hz,6H),1.14-1.17(m,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 290 nm; Analysis time: 40 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 23] result: [Table 24]

[0130] Example 42: Preparation of R-2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]-2-methyl-propanenitrile 4-methylbenzenesulfonate (0.200 g, 68% purity, 0.31 mmol) was added to a stirred solution of MeCN (0.63 mL) with N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.070 g, 0.35 mmol) at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.070 g, 98% purity, >99.5% ee, 50% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.28(s,1H),9.24(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.29(s,1 H),4.56(s,1H),3.83(s,3H),3.52-3.70(m,2H),1.89(d,J=5.1Hz,5H),1.17(t,J=7.4Hz,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 290 nm; Analysis time: 40 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 25] result: [Table 26]

[0131] Example 43: Preparation of R-2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzenesulfonate (0.200 g, 79% purity, 0.33 mmol) was added to a MeCN (2 mL) stirred solution with N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.080 g, 0.36 mmol) at rt, and the reaction mixture was heated to 80°C. After stirring for 24 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified by neutral silica gel chromatography using cyclohexane and siRNA as eluents to obtain the title compound (0.060 g, 95% purity, >99.5% ee, 38% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:8.86-8.90(m,2H),8.64(d,J=1.6Hz,1H),8.29(d,J=2.7Hz,1H ),4.58(s,1H),3.73(s,3H),3.58-3.71(m,2H),1.88(d,J=2.7Hz,6H),1.14-1.18(m,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow rate: 1 ml / min; λ Max.: 290 nm; Analysis time: 10 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 5 μL [Table 27] result: [Table 28]

[0132] Example 44: Preparation of R-2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] To a MeCN (2 mL) stirred solution of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzenesulfonate (0.200 g, 79% purity, 0.33 mmol), N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.080 g, 0.36 mmol) was added at rt. The reaction mixture was heated to 80°C and stirred for 24 hours, and the reaction mixture was concentrated under reduced pressure. The crude substance was purified by neutral silica gel chromatography using cyclohexane and siRNA as eluents to obtain the title compound (0.070 g, 99% purity, 99% ee, 47% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.26(s,1H),8.89(d,J=2.6Hz,1H),8.26-8.30(m,2H),4. 56(s,1H),3.82(s,3H),3.52-3.69(m,2H),1.88(d,J=2.9Hz,6H),1.12-1.19(m,3H) Chiral analysis method: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; Flow: λ Max.: 274 nm; Time: 12 min; Sample preparation: Inj. Vol.: 2 μL [Table 29] result: [Table 30]

[0133] Example 45: R-[5-(3-fluorophenyl)-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-imino-methyl-oxo-λ 6 - Preparation of sulfane [ka] (1R)-6-(3-fluorophenyl)-1-methyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.200 g, 99% purity, 0.42 mmol) was stirred in MeCN (1.7 mL), to which N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.080 g, 0.42 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 7 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.080 g, 99% purity, 97% ee, 40% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.39(d,J=2.1Hz,1H),8.88(d,J=1.4Hz,1H),8.75(d,J=2.3Hz,1H),8.6 6(d,J=1.5Hz,1H),7.85-7.91(m,1H),7.81(d,J=8.5Hz,1H),7.67(td,J=8.0,6.2Hz,1H),7.41(br d,J=2.5Hz,1H),4.53-4.56(m,1H),3.78(s,3H),3.47-3.52(m,3H) Chiral analysis method: Column: Cellulose LUX (4.6 mm × 250 mm) 3 μm; Flow rate: 0.7 ml / min; λ Max.: 294 nm; Analysis time: 25 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 10 μL [Table 31] result: [Table 32]

[0134] Example 46: R-[5-(3-fluorophenyl)-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-imino-methyl-oxo-λ 6 - Preparation of sulfane [ka] (1R)-6-(3-fluorophenyl)-1-methyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.200 g, 99% purity, 0.42 mmol) was stirred in MeCN (1.7 mL), to which N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.080 g, 0.42 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.075 g, 99% purity, 99% ee, 40% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.39(d,J=2.08Hz,1H),9.29(s,1H),8.75(d,J=2.20Hz,1H),8.29(s,1H),7.88(br d,J=9.9Hz,1H),7.81(d,J=7.8Hz,1H),7.67(d,J=6.1Hz,1H),7.41(br d,J=2.6Hz,1H),4.03(d,J=7.0Hz,1H),3.87(s,3H),3.47(s,3H) Chiral analysis method: Column: Cellulose LUX (4.6 mm × 250 mm) 3 μm; Flow rate: 0.7 ml / min; λ Max.: 275 nm; Analysis time: 22 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 10 μL [Table 33] result: [Table 34]

[0135] Example 47: Preparation of R-2-[[6-(6-chloro-3-methylimidazo[4,5-b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzene sulfonate (0.200 g, 85% purity, 0.35 mmol) was stirred in MeCN (1.4 mL), to which 5-chloro-N2-methylpyridine-2,3-diamine (0.062 g, 0.38 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 7 hours, the reaction mixture was concentrated under reduced pressure, and the crude substance was purified by neutral silica gel chromatography using cyclohexane and siRNA as eluents to obtain the title compound (0.900 g, 99% purity, 99.2% ee, 60% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:8.88(d,J=2.7Hz,1H),8.52(d,J=2.2Hz,1H),8.37(d,J=2.2Hz,1H),8. 28(d,J=2.7Hz,1H),4.56(s,1H),3.58-3.71(m,5H),1.88(d,J=3.0Hz,6H),1.16(t,J=7.4Hz,3H) Chiral analysis method: Column: Chiralpack-Lux-cellulose (4.6 mm × 250 mm) 3-5 μm; Flow rate: 1 ml / min; λ Max.: 306 nm; Analysis time: 30 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 10 μL [Table 35] result: [Table 36]

[0136] Example 48: R-[5-bromo-2-(3-ethylimidazo[4,5-b]pyridin-2-yl)-3-pyridyl]-ethyl-imino-oxo-λ 6 - Preparation of sulfane [ka] (1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine;4-nitrobenzenesulfonic acid (0.100 g, 99% purity, 0.44 mmol) was stirred in MeCN (0.90 mL), to which N2-ethylpyridine-2,3-diamine (0.070 g, 0.49 mmol) was added at rt, and the reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the crude substance was purified by neutral silica gel chromatography using cyclohexane and ethylacetal as eluents to obtain the title compound (0.065 g, 96% purity, >99% ee, 40% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ:9.20(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H),8.47(dd,J=4.8,1.50Hz,1H),8.16(dd,J=8.0,1.44Hz,1H) ,7.38(dd,J=8.0,4.7Hz,1H),4.59(s,1H),4.13-4.24(m,2H),3.72(q,J=7.1Hz,2H),1.31(t,J=7.2Hz,3H),1.18(t,J=7.4Hz,3H) Method of chiral analysis: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; flow: 1 ml / min; λMax.: 294 nm; running time: 25 min; sample preparation: 1 mg / mL in EtOH; Inj.Vol.: 7 μL [Table 37] result: [Table 38]

[0137] Example 49: Preparation of R-2-[[6-(3-ethylimidazo[4,5-b]pyridine-2-yl)-5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] To a MeCN (1.0 mL) stirred solution of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]oxy-2-methyl-propanenitrile;4-nitrobenzenesulfonic acid (0.100 g, 80% purity, 0.17 mmol), N2-ethylpyridine-2,3-diamine (0.025 g, 0.18 mmol) was added at rt, and the reaction mixture was heated to 80°C. After stirring for 7 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.045 g, 99% purity, 99.3% ee, 68% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ:8.86(d,J=2.7Hz,1H),8.46(dd,J=4.7,1.41Hz,1H),8.29(d,J=2.7Hz,1H),8.14(dd, J=8.0,1.3Hz,1H),7.36(dd,J=7.9,4.8Hz,1H),4.54(s,1H),4.13-4.23(m,2H),3.63-3.76(m,2H),1.87(d,J= 6.0Hz,6H),1.30-1.35(m,3H),1.14-1.18(m,3H) Chiral analysis method: Column: Chiralpack-Lux-cellulose (4.6 mm × 250 mm) 3-5 μm; Flow rate: 1 ml / min; λ Max.: 295 nm; Analysis time: 30 min; Sample preparation: 1 mg / mL in EtOH; Inj. Vol.: 4 μL [Table 39] result: [Table 40]

[0138] Example 50: Preparation of 4-[(Z)-[(1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-ylidene]amino]-N-methyl-6-(trifluoromethyl)pyridine-3-amine [ka] (1R)-6-bromo-1-ethyl-1-oxoisothiazolo[4,5-b]pyridine-3-imine 4-nitrobenzenesulfonate (0.100 g, 99% purity, 0.22 mmol) was stirred in MeCN (0.45 mL), to which N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.047 g, 0.24 mmol) was added at rt, and the reaction mixture was heated to 50°C. After stirring for 8 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and siRNA as eluents, the crude substance was purified by neutral silica gel chromatography to obtain the title compound (0.020 g, 99% purity, 43% yield) as a grayish-white solid. 1 H NMR(400MHz,CDCl3)δ:8.93(d,J=2.1Hz,1H),8.90(s,1H),8.65(d,J=2.3Hz,1H),8.03(s,1H),3.80(s,3H),3.57-3.78(m,2H),2.64(br s,1H),1.30(t,J=7.4Hz,3H)

[0139] Example 51: R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-ethyl-imino-oxo-λ 6 - Preparation of sulfane [ka] A solution of 4-[(Z)-[(1R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridine-3-ylidene]amino]-N-methyl-6-(trifluoromethyl)pyridine-3-amine (0.040 g, 99% purity) in MeCN (1.0 mL) was heated to 80°C. After stirring for 8 hours, the reaction mixture was concentrated under reduced pressure. Using cyclohexane and ethyl acetate as eluents, the crude product was purified by neutral silica gel chromatography to obtain the title compound (0.025 g, 99% purity, 99.5% ee, 63% yield) as a grayish-white solid. 1H NMR(400MHz,DMSO-d6)δ 9.27(s,1H),9.22(d,J=2.1Hz,1H),8.63(d,J=2.1Hz,1H),8.28(s,1H),4.61(s,1H),3.81(s,3H),3.54-3.67(m,2H),1.15(t,J=7.4Hz,3H) Method of chiral analysis: Column: Chiralpack-IG (4.6 mm × 250 mm) 5 μm; flow: 1 ml / min; λMax.: 274 nm; running time: 25 min, sample preparation: 1 mg / mL in EtOH; Inj.Vol.: 5 μL [Table 41] result: [Table 42]

[0140] Example 52a: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] Step 1: TEA (1.53 ml, 10.95 mmol) was added to a suspension of 5-(1-cyanocyclopropyl)-3-(R)-ethylsulfinyl]-N'-hydroxypyridine-2-carboxamidine (2.995 g, 97% purity, >99.5% ee, 10.4 mmol) in dry THF (13.2 ml). To this suspension, a 2.0 M solution of pTsCl in dry THF (5.2 ml, 10.5 mmol) was slowly added at rt. After stirring for 24 hours, the formed precipitate (Et3N·HCl) was filtered off and washed on the filter with a minimum amount of THF. The intermediate [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate was obtained as a 19.4% solution in THF (approximately 95% yield), which could be stored and used in the next step without isolation (see Example 23 for isolation as a solid). Step 2: To a solution of the intermediate prepared in Step 1 (11.16 g, 19.4% concentration, 5.00 mmol), dry sulfolane (5.0 ml) was added. Then, THF was removed under reduced pressure (40°C, 20 mbar), and methanol (5.0 ml) was added, followed by N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (1.06 g, 99% purity, 5.50 mmol). The resulting brown solution was stirred at 70°C for 22 hours. Then, methanol was removed under reduced pressure (50°C, 20 mbar), and the residual mixture was cooled to rt. Water (11 ml) was added while stirring vigorously. After stirring for 2 hours and further aging for 1 hour, the precipitate was filtered and washed on the filter with sulfolane / water 3:7 (5 ml) and water (2 × 5 ml). The precipitate was then dried under high vacuum to obtain the title compound (1.605 g, 95% purity, >99.5% ee, 70% yield) as a gray powder. Another 0.48 g (22% yield) of the title compound remained in the mother liquor and washing solution. 1H NMR (400MHz, solvent) δ 1.36(t,J=7.3Hz,3H),1.61-1.70(m,2H),1.97-2.08(m,2H),3.82-3.98(m,4H),8.31 (d,J=1.45Hz,1H),8.34(d,J=2.2Hz,1H),8.76(d,J=1.1Hz,1H),8.98(d,J=2.2Hz,1H) Method of chiral analysis: Column: Chiralpack-IG (0.46 cm × 10 cm) 3 μm; flow: 2 ml / min; λMax.: 290 nm; sample preparation: 1 mg / mL in MeOH; Inj.Vol.: 2 μL [Table 43] result: [Table 44]

[0141] Example 52b: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] Using a procedure similar to that of Example 52a, step 2 can be carried out under the following alternative conditions: Anisole / MeOH (1:1), 80°C, 16h: 92% yield Benzonitrile / MeOH (1:1), 80°C, 12h: 91% yield Sulfolane / nPrOH (1:1), 80°C, 10h: 85% yield Anisole / ethylene glycol (1:1), 80°C, 22h: 91% yield

[0142] Example 52c: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (1.108 g, 97% purity, >99.5% ee, 2.49 mmol) and N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.523 g, 98% purity, 2.68 mmol) in MeCN (5.0 ml) was heated at 80°C for 6 hours. The reaction mixture was cooled to rt, and the formed precipitate (TsOH·NH3) was filtered off and washed on the filter with MeCN. The filtrate was evaporated under reduced pressure to obtain the title compound (1.21 g, 75% purity, >99.5% ee, 84% yield).

[0143] Example 52d: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] A solution of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitride 4-methylbenzene sulfonate (88.8 mg, 97% purity, 0.200 mmol) and N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (41.6 mg, 99% purity, 0.216 mmol) in dry MeCN (0.40 ml) was heated at 80°C for 16 hours. The reaction mixture was then cooled to rt and the solvent was removed under reduced pressure. Analysis of the crude residue by quantitative NMR using trimethoxybenzene as an internal standard showed the formation of the title compound (78.9 mg, 91% yield).

[0144] Example 53: Preparation of 1-[(1R,3Z)-1-ethyl-3-[[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl]imino]-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]cyclopropanecarbonitride [ka] 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridine-6-yl]cyclopropanecarbonitriel 4-methylbenzenesulfonate (0.220 g, 0.509 mmol) and N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.115 g, 0.598 mmol) were dissolved in dried sulfolane (1.1 ml), to which TEA (13 ml, 0.097 mmol) was added. The resulting solution was heated at 60°C for 3 hours. The reaction mixture was cooled to rt and quenched by adding aqueous saturated NaHCO3 and iPrOAc. The organic layer was separated, washed with water, and dried on anhydrous Na2SO4. The solution was evaporated under reduced pressure, and the crude product was purified by reverse-phase HPLC (water / MeCN as mobile phase) to obtain the title compound (0.182 g, 95% purity, 78% yield) as a white, fluffy solid. 1 H NMR(400MHz,d6-DMSO)δ 9.11(d,J=2.2Hz,1H),8.80(d,J=2.2Hz,1H),8.14(dd,J=1.1,2.2Hz,1H),8.01(d,J=2.2Hz,1H),6.60(q,J=4.7Hz,1H),4 .26-4.02(m,2H),2.95(d,J=4.7Hz,3H),2.05-1.96(m,2H),1.92-1.85(m,1H),1.85-1.79(m,1H),1.15(t,J=7.3Hz,3H); 13 C NMR(101MHz,d6-DMSO)δ 156.50,155.87,154.50,154.21,140.94-140.39(m,1C),135.27,130.72,130.16,128.44,125.16(d,J=271.3Hz,1C),123.05(br d,J=3.0Hz,1C),121.16,112.04(q,J=31.2Hz,1C),47.92,27.86,19.48,18.95,11.93,7.00

[0145] Example 54: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (201 mg, 95% purity, 0.441 mmol) and N3-methyl-6-(trifluoromethyl)pyridazine-3,4-diamine (102 mg, 0.529 mmol) in MeCN (0.9 ml) was heated at 80°C for 23 hours. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. Using ethyl acetate and cyclohexane as eluents, the crude residue was purified by silica gel chromatography to obtain the title compound (52.7 mg, 27% yield) as a gray powder. 1 H NMR(400MHz,CDCl3)δ 1.38(td,J=7.27,1.82Hz,3H),1.71(br s,2H),2.07(br s,2H),3.61-3.93(m,2H),4.04(s,3H),8.18(d,J=1.82Hz,1H),8.37(br d,J=1.82Hz,1H),9.02(br d,J=1.82Hz,1H)

[0146] Example 55: Preparation of 1-[5-(ethylsulfonimidoyl)-6-[6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-ethylsulfinyl-2-pyridyl]methylene]amino]4-nitrobenzenesulfonate (259.5 mg, 89% purity, 0.499 mmol) and N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (102.6 mg, 95% purity, 0.550 mmol) in dry MeOH (1.0 ml) was heated in a sealed vial at 90°C for 4 hours. The reaction mixture was cooled to rt, the resulting precipitate was filtered off, and dried under high vacuum to obtain the title compound (204 mg, 77% purity, 75% yield) as a gray powder. For analytical purposes, a small portion was purified to >95% purity via reverse-phase HPLC (water / MeCN as eluent). 1 H NMR(600MHz, methanol-d4)δ 1.35(t,J=7.4Hz,3H)1.71-1.79(m,2H)1.96-2.04(m,2H)3.80-4.17(m,2H)8.35(br s,1H)8.39(d,J=2.4Hz,1H)8.73(s,1H)8.98(d,J=2.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ 7.5(s,1 C)11.7(s,1 C)19.1(d,J=15Hz,1 C)51.2(s,1 C)120.1(q,J=32Hz,1 C)121.2(s,1 C)124.5(q,J=272Hz,1 C)134.5(s,1 C)136.7(s,1 C)139.5(s,1 C)141.5(s,1 C)146.3(s,1 C)148.7(s,1 C)152.7-155.2(m,1 C)

[0147] Example 56: Preparation of R-1-[6-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3-pyridyl]cyclopropanecarbonitride [ka] A solution of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene]amino]4-methylbenzenesulfonate (203 mg, 95% purity, 0.445 mmol) and 2,3-diamino-5-bromopyridine (104 mg, 97% purity, 0.534 mmol) in MeCN (0.9 ml) was heated in a sealed vial at 80°C for 36 hours. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. Using ethyl acetate and cyclohexane as eluents, the crude residue was purified by silica gel chromatography to obtain the title compound (99 mg, 83% purity, 43% yield) as a gray powder. 1 H NMR(400MHz, methanol-d4)δ 1.30(t,J=7.3Hz,3H),1.77-1.89(m,2H),1.97-2.08(m,2H),3.87-4.16(m,2H),7.77 (d,J=2.2Hz,1H),8.47(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),9.13(d,J=2.2Hz,1H)

[0148] Table P: Compound of formula (I) prepared according to the present invention [Table 45-1] [Table 45-2] [Table 45-3]

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R 1 represents halogen, C 1 to C 6 -haloalkyl, cyano-C 1 to C 6 -alkyl, cyano-C 1 to C 6 -alkoxy, cyano-C 3 to C 6 -cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, C 1 to C 3 -alkyl, or C 1 to C 3 -alkoxy; R 2 C 1 ~C 4 It is alkyl; R 3 is hydrogen or C 1 ~C 4 It is alkyl; R 4 is hydrogen, halogen, or C 1 ~C 4 It is a haloalkyl; S * This is a stereogenic sulfur atom with an R- or S- configuration; X 1 and X 2 Each is independently CH or N, except X 1 and X 2 (At least one of them is nitrogen.) A method for preparing enantiomerically enriched sulfoximines, The above method involves a compound of formula (V) or a compound of formula (VI). 【Chemistry 2】 (In the formula, R 1 , R 2 , and S * This is defined as for the compound of formula (I), and R 5 C 1 ~C 4 - Selected from alkyl or phenyl, wherein the phenyl is either unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, or methyl) - Formula (VII) 【Transformation 3】 (In the formula, R 3 , R 4 , X 1 , and X 2 A method comprising reacting a compound of formula (I) (as defined for the compound of formula (I)) with a solvent suitable for producing the compound of formula (I) at a suitable temperature.

2. The compound of formula (VI) is reacted with the compound of formula (VII) to obtain the compound of formula (VIII). 【Chemistry 4】 (In the formula, R 1 , R 2 S * , R 3 , R 4 , X 1 , and X 2 The method according to claim 1, wherein a compound of formula (I) is obtained via an intermediate of (as defined for the compound of formula (I)).

3. Formula (IV) 【Transformation 5】 (In the formula, R 1 , R 2 , and S * The compound of formula (IX) is defined as follows for the compound of formula (I) 【Transformation 6】 (In the formula, R 5 C 1 ~C 4 - A sulfonyl chloride (selected from alkyl or phenyl, wherein the phenyl is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, or methyl) is reacted in a solvent in the presence of a base to form formula (V) 【Transformation 7】 The method according to claim 1, which produces the compound.

4. Formula (III) 【Transformation 8】 (In the formula, R 1 , R 2 , and S * The method according to claim 1, wherein a sulfinyl compound of formula (I) is reacted with hydroxylamine in a solvent at a suitable temperature to produce a compound of formula (IV).

5. Formula (II) 【Chemistry 9】 (In the formula, R 1 and R 2 The sulfanyl compound of formula (I) is stereoselectively oxidized in a solvent (or diluent) in the presence of an oxidizing agent, a chiral reagent or catalyst, and optionally a suitable acid additive, to obtain formula (III). 【Chemistry 10】 The method according to claim 1, which produces a sulfinyl compound.

6. The method according to claim 1, wherein the ratio of the compound of formula (VII) used to the compound of formula (VI) is in the range of 2:1 to 1:

1.

7. The method according to claim 5, wherein the solvent (or diluent) is selected from polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates, and ethers, and mixtures thereof.

8. The method according to claim 1, wherein the reaction of the compound of formula (V) or the compound of formula (VI) with the compound of formula (VII) is carried out in a temperature range of 20°C to 150°C.

9. The method according to claim 3, wherein the ratio of the compound of formula (IX) used to the compound of formula (IV) is in the range of 3:1 to 1:

1.

10. The method according to claim 3 or 9, wherein the base is selected from 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.

11. The method according to any one of claims 3, 9, or 10, wherein the ratio of the base used to the sulfonyl chloride of formula (IX) is 1.5:1 to 1:

1.

12. The method according to any one of claims 3, 9, 10, or 11, wherein the solvent (or diluent) is selected from esters, nitriles, ethers, and aliphatic hydrocarbons, aromatic hydrocarbons, or halogenated hydrocarbons.

13. The method according to claim 4, wherein the reaction is carried out using an aqueous solution of hydroxylamine in a suitable solvent at a suitable temperature.

14. The method according to claim 4 or 13, wherein the ratio of the hydroxylamine used to the compound of formula (III) is in the range of 2:1 to 1:

1.

15. The method according to claim 4, wherein instead of hydroxylamine, a free base hydroxylamine hydrochloride or hydroxylamine sulfate is used in combination with one equivalent (relative to the hydroxylamine salt) of a suitable base.

16. The method according to claim 15, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.

17. The method according to any one of claims 4, 13, 14, 15, or 16, wherein the solvent (or diluent) is selected from alcohols, ethers, and aliphatic hydrocarbons, aromatic hydrocarbons, or halogenated hydrocarbons.

18. The method according to any one of claims 4, 13, 14, 15, 16, or 17, wherein the reaction is carried out within a temperature range of -20°C to 80°C.

19. Formula (IV) 【Chemistry 11】 (In the formula, R 1 is halogen, C 1 ~C 6 - Haloalkyl, cyano-C 1 ~C 6 -Alkyl, cyano-C 1 ~C 6 -alkoxy, cyano-C 3 ~C 6 - A cycloalkyl or aryl group, wherein the aryl group is unsubstituted or a halogen, C 1 ~C 3 - Alkyl, or C 1 ~C 3 - Substituted with one, two, or three substituents independently selected from the alkoxy; R 2 C 1 ~C 4 It is alkyl; S * (This refers to a stereogenic sulfur atom with an R- or S- configuration.) A method for preparing the compound, Formula (III) 【Chemistry 12】 (In the formula, R 1 , R 2 , and S * A method comprising reacting the compound of formula (IV), as defined for the compound of formula (IV), with hydroxylamine in a suitable solvent at a suitable temperature to produce the compound of formula (IV).

20. Formula (VIII) 【Chemistry 13】 (In the formula, R 1 is halogen, C 1 ~C 6 - Haloalkyl, cyano-C 1 ~C 6 -Alkyl, cyano-C 1 ~C 6 -alkoxy, cyano-C 3 ~C 6 - A cycloalkyl or aryl group, wherein the aryl group is unsubstituted or a halogen, C 1 ~C 3 - Alkyl, or C 1 ~C 3 - Substituted with one, two, or three substituents independently selected from the alkoxy; R 2 is C 1 to C 4 alkyl; R 3 is hydrogen or C 1 ~C 4 It is alkyl; R 4 represents hydrogen, halogen, or C 1 to C 4 haloalkyl; S * This is a stereogenic sulfur atom with an R- or S- configuration; X 1 and X 2 Each is independently CH or N, except X 1 and X 2 A compound of which at least one of the elements is nitrogen.

21. Equation (VI) 【Chemistry 14】 (In the formula, R 1 is halogen, C 1 ~C 6 - Haloalkyl, cyano-C 1 ~C 6 -Alkyl, cyano-C 1 ~C 6 -alkoxy, cyano-C 3 ~C 6 - A cycloalkyl or aryl group, wherein the aryl group is unsubstituted or a halogen, C 1 ~C 3 - Alkyl, or C 1 ~C 3 - Substituted with one, two, or three substituents independently selected from the alkoxy; R 2 C 1 ~C 4 It is alkyl; R 5 C 1 ~C 4 - Alkyl or phenyl, wherein the phenyl is unsubstituted or substituted with one or two substituents selected from halogen, cyano, nitro, or methyl; S * A compound of which is a stereogenic sulfur atom with an R- or S- configuration.

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