Synthesis of sulfoximines containing a benzimidazole moiety

Abstract

A process for the preparation of enantiomerically enriched sulfoximines of formula (I) is provided, wherein R1, R2, S*, R3, R4, X and X2 are as defined in the description.

Description

[0001]83034 FF -1- SYNTHESIS OF SULFOXIMINES CONTAINING A BENZIMIDAZOLE MOIETY The present invention relates to the enantioselective synthesis of sulfoximines containing a benzimidazole moiety. Such compounds are useful as active ingredients, which have pesticidally activity, in particular insecticidally activity and are used for controlling animal pests, including arthropods and in particular insects. Pesticidally active heterocyclic sulfoximine derivatives have previously been described in the literature, for example, in WO2015 / 071180, WO2016 / 039441, WO2018 / 206348, WO2019 / 219689, WO2019 / 229089, WO2019 / 234158, WO2020 / 084075 and WO2020 / 141136. WO2022 / 253841 discloses the stereoselective synthesis of sulfoximines by means of a stereoselectiveoxidation, followed by a stereospecific imination reaction.The present invention provides a novel enantioselective synthesis of a similar class of sulfoximines leading to a compound of formula (I): * wherein: R1is halogen, C1-C6-haloalkyl, cyano-C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2is C1-C4-alkyl; R3is hydrogen or C1-C4-alkyl; R4is hydrogen, halogen, or C1-C4-haloalkyl; S* is a stereogenic sulfur atom which is in R- or S-configuration; and X1and X2are independently selected from CH or N, with the proviso that at least one of X1and X2isnitrogen,wherein said process comprises reacting a compound of formula (V) or a compound of formula (VI) * 83034 FF -2- wherein R1, R2and S* are as defined for compounds of formula (I), and R5selected from C1-C4-alkyl or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, or methyl; with a compound of formula (VII) , wherein R3, R4, X1and X2are as (I), in an appropriate solvent at an appropriate temperature to produce a compound of formula (I). In previously published patent application (WO2022 / 253841) compounds of this sort were prepared as shown in Scheme 1 for a specific example. Scheme 1 cat. Fe cat.4- acid The fully formed sulfide analogue was first synthesized (as described in WO2019 / 234158) and in the last steps the sulfide underwent enantioselective oxidation followed by a stereospecific imination at sulfur. This method is fully amenable for making a wide variety of analogues however for a large-scale synthesis this method is not ideal. First, oxidation conditions have to be adjusted for every substrate and even then enantiomeric excess obtained is not always sufficient. Even more importantly the reagent used for imination must be synthesized separately and is difficult to use on a large scale due to safety concerns. Therefore, there is a need for an atom-efficient approach for the synthesis of enantiomerically pure or enriched chiral sulfoximine compounds, especially those at scale. Such processes are advantageous in that they will improve the impurity profile, lower commercial manufacturing costs, and improve efficiency and atom economy. Surprisingly, we have now found that sulfoximine compounds of formula (I) can be prepared from the corresponding sulfide compounds via cyclic sulfoximine intermediates as shown in Scheme 2. 83034 FF -3- * A compound of formula (II), wherein R1and R2are as defined for a compound of formula (I), is first oxidized in an enantioselective manner to yield a compound of formula (III), wherein R1, R2and *S are as defined for a compound of formula (I). Nucleophilic addition of hydroxylamine (NH2OH) to the cyano moiety then provides a compound of formula (IV). Activation of amidine oxime with a sulfonyl chloride compound of formula (IX), wherein R5is selected from C1-C4-alkyl or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, or methyl; in the presence of a base, provides an intermediate of formula (V). Heating of this intermediate provides a cyclic imino sulfoximine compound of formula (VI) as asulfonic acid salt. Such intramolecular imination is surprising and has not been previously reported. Thecompound of formula (VI) is then reacted with a compound of formula (VII), wherein R3, R4, X1and X2are as defined for a compound of formula (I), to yield via an intermediate of formula (VIII), which can be converted to a compound of formula (I). A compound of formula (VI) may be isolated, but in many cases, it is advantageous to proceed immediately to a compound of formula (I) by heating a mixture of a compound of formula (V) and a compound of formula (VII). The condensation of a compound of formula (VI) to yield an intermediate of formula (VIII) which could in certain cases be isolated followed by rearrangement to yield a compound of formula (I) has no close literature precedents and constitutes a novel approach in this class of compounds. The present invention provides a process for the preparation of sulfoximines of formula (I) in an enantiomerically pure or enantiomerically enriched form 83034 FF -4- * cyano-C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2is C1-C4-alkyl; R3is hydrogen or C1-C4-alkyl; R4is hydrogen, halogen, or C1-C4-haloalkyl; S* is a stereogenic sulfur atom which is in R- or S-configuration; and X1and X2are independently selected from CH or N, with the proviso that at least one of X1and X2is nitrogen, by A) stereoselective oxidation of a sulfanyl compound of formula (II) defined for compounds of formula (I); in the presence of an oxidant, in the presence of a chiral reagent or catalyst, optionally in the presence of a suitable acid additive, in an appropriate solvent (or diluent); to produce a sulfinyl compound of formula (III) as defined for compounds of formula (I); and B) reacting the compound of formula (III) 83034 FF -5- wherein R1, R2and S* are as defined previously with hydroxylamine in an appropriate solvent at an appropriate temperature to produce a compound of formula (IV) * defined for a compound of formula (I); and C) reaction of the sulfinyl compound of formula (IV) * defined for compounds of formula (I) with a sulfonyl chloride of formula (IX) or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents nitro, or methyl; preferably R5is selected from methyl, phenyl, 4-methylphenyl, 4-nitrophenyl, or 2,4-dinitrophenyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (V) for compounds of formula (I) and R5is as defined for a compound of ; and D) thermally rearranging the compound of formula (V) 83034 FF -6- * for compounds of formula (I) and R5is as defined for a compound of ; a a compound of formula (VI) * as defined for compounds of formula (I) and R5is as defined for a compound of formula (IX), optionally a compound of formula (VIa) could be produced by adding an appropriate base and used in step (E) * defined for compounds of formula (I); and E) reacting a compound of formula (VI) * for compounds of formula (I) and R5is as defined for a compound of , a formula (VII) X2are as defined for a compound of formula (I); in an appropriate solvent at an appropriate temperature to produce a compound of formula (I) 83034 FF -7- are as previously defined. and rearrangement proceeds via an intermediate of formula (VIII) defined for a compound of formula (I). slower than the condensation step the compound of formula (VIII) could be isolated. Optionally a compound of formula (V) * as defined for compounds of formula (I), and R5is as defined for a compound of ; is reacted in an appropriate solvent at an appropriate temperature with a compound of formula (VII) are as defined for a compound of formula (I), to directly produce a compound of a isolate either a compound of formula (VI) or a compound of formula (VIII). In one embodiment of the invention, this condensation of a compound of formula (VI) to yield and intermediate of formula (VIII) may be carried out in the presence of an acidic additive. In one embodiment of the invention, said condensation reaction may be carried out in the presence of citric acid. 83034 FF -8- Further it has been surprisingly found that the compounds of formula (I) have, for practical purposes, a very advantageous level pesticidal activity, in particular insecticidally activity and are used for controlling animal pests, including arthropods and in particular insects. As used herein, the term “hydroxyl” or “hydroxy” means an -OH group. As used herein, the term “nitro” means a -NO2-group. As used herein, cyano means 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 also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, and halocycloalkyl.As used herein, the term "C1-Cn-alkyl” refers to a saturated straight-chain or branched hydrocarbon radicalattached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals 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. As used herein, the term “C3-Cn-cycloalkyl” refers to three (3) to n membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term "C1-Cn-alkoxy" refers to a straight-chain or branched saturated alkyl radical having one (1) to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy, and 1,1-dimethylethoxy. The term “C2-Cn-alkenyloxy” as used herein refers to a straight-chain or branched alkenyl chain having two (2) to n carbon atoms (as mentioned above) which is attached via an oxygen atom. As used herein, the term "C1-Cn-haloalkyl" refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., 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, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl. As used herein, the term “cyano-C1-Cn-alkyl”, refers to a straight chain or branched saturated C1-Cn-alkyl radicals (as mentioned above) which is substituted by a cyano group, for example cyanomethylene, cyanoethylene, 1,1-dimethylcyanomethyl, cyanoisopropyl, cyanomethyl, cyanoethyl, and 1- dimethylcyanomethyl. This term can be used interchangeably with “C1-Cn-cyanoalkyl”. 83034 FF -9- As used herein, the term cyano-C1-Cn-alkoxy refers to a straight chain or branched saturated C1-Cn-alkoxy radicals (as mentioned above) which is substituted by a cyano group. This term can be used interchangeably with “C1-Cn-cyanoalkoxy”. The term “cyano-C3-Cn-cycloalkyl” as used herein refers to a 3-6 membered cycloalkyl group (as mentioned above) which is substituted by a cyano group. This term can be used interchangeably with “C3-Cn- cyanocycloalkyl”. The term "aryl" represents a mono-, bi- or polycyclical aromatic system with preferably 6 to 14, more preferably 6 to 10 ring-carbon atoms, for example phenyl, naphthyl, anthryl, phenanthrenyl, preferably phenyl. "Aryl" also represents polycyclic systems, for example tetrahydronaphtyl, indenyl, indanyl, fluorenyl, biphenyl. Arylalkylsare examples of substituted aryls, which may be further substituted with the same or different substituents bothat the aryl or alkyl part. benzyl and phenylethyl are examples of such arylalkyls. Where not otherwise defined the term “optionally substituted” means that the group in question can be substituted with zero up to the maximum number of substituents with groups independently selected from: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, nitro, cyano, hydroxy, sulfhydryl, acetyl, acetoxy, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, amino, methlamino, dimethylamino, phenyl. The term "enantiomerically enriched" means that one of the enantiomers of the compound is present in excess in comparison to the other enantiomer. This excess will hereafter be referred to as enantiomeric excess or ee. The ee may be determined by chiral GC, HPLC or SFC analysis. The ee is equal to the difference between amounts of enantiomers divided by the sum of the amounts of the enantiomers, which quotient can be expressed as a percentage after multiplication by 100. The ee can also be referred to as the absolute difference between the mole fraction of each enantiomer in the mixture. For example, when there is an isomer with an enantiomeric excess (e.e.) of 40% this means that the mole fraction (or percent) of such excess isomer is 70%. Accordingly, in one embodiment, the term "enantiomerically enriched" also refers to an enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%. As used herein, the term “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15°C to about 35°C. For example, rt can refer to a temperature of about 20°C to about 30°C.As used herein the term “condensation” refers to a reaction in which two molecules combine to form a singlemolecule. As used herein the term “appropriate solvent” refers to a solvent that is suitable or fitting for a particular reaction step. The term "appropriate solvent” can be used interchangeably with the term “suitable solvent" or “dilutent” As used herein the term “appropriate temperature” refers to a temperate that is suitable or fitting for a particular reaction step. The term “appropriate temperature” can be used interchangeably with the term “temperature suitable for”. 83034 FF -10- As used herein, the R-groups as used in the Markush-structures of the present invention can be interchangeably disclosed as Rx or Rx, wherein the x is used to label the R-group. The process of the present invention can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out as a one-pot synthesis wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise or continuous fashion. The following list provides definitions, including preferred definitions, for substituents R1, R2, R3, R4, R5, R6, and X with reference to the compounds of formula (I), (II), (III) and (IV) of the present invention. For any one ofthese substituents, any of the definitions given below may be combined with any definition of any othersubstituent given below or elsewhere in this document. In one embodiment of the present invention, R1is halogen, C1-C4-haloalkyl, cyano-C1-C4-alkyl, cyano-C1-C4- alkoxy, cyano-C3-C6-cycloalkyl, or aryl; wherein said any of said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently from each other selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy. Preferably, R1is halogen, C1-C2-haloalkyl, cyano-C1-C3-alkyl, cyano-C1-C3-alkoxy, cyano-C3-C6-cycloalkyl, or phenyl; wherein said phenyl is unsubstituted or substituted with 1, or 2 substituents independently from each other selected from halogen. In one embodiment of the present invention, R2is C1-C4-alkyl. Preferably, R2is C1-C3-alkyl. More preferably, R2is methyl, or ethyl. Even more preferably, R2is ethyl. In one embodiment of the present invention, R3is hydrogen or C1-C4-alkyl. Preferably, R3is hydrogen or C1- C3-alkyl. More preferably, R3is hydrogen or methyl. In one embodiment, R3is hydrogen. In another embodiment, R3is methyl. Preferably, embodiment, R3is methyl. In one embodiment of the present invention, R4is hydrogen, halogen, or C1-C4-haloalkyl. Preferably, In one embodiment of the present invention, S* is a stereogenic sulfur atom which is in (R)- or (S)-configuration. In a preferred embodiment of the present invention, S* is a stereogenic sulfur atom which is in (R)-configuration. In another preferred embodiment of the present invention, S* is a stereogenic sulfur atom which is in (S)- configuration. In one embodiment of the present invention, X1and X2are independently selected from CH or N, with the proviso that at least one of X1and X2is nitrogen. Preferably, X1is N, and X2is CH; or X1is CH, and X2is N; orX1 is N, and X2 is N. More preferably, X1 is N, and X2 is CH; or X1 is CH, and X2 is N.In one embodiment of the invention step (A) comprises: 83034 FF -11- Oxidizing a sulfanyl compound of formula (II), in the presence of an oxidant, in the presence of a metal derivative, in the presence of a chiral ligand, in an appropriate solvent (or diluent) and optionally in the presence of a suitable acid additive. Examples of suitable and preferred oxidants are inorganic peroxides, such as hydrogen peroxide or organic peroxides, such as tert-butyl hydroperoxide. Preferably the oxidant is hydrogen peroxide. The ratio of the oxidant used, based on the amount of the sulfanyl compound of formula (II), is in the range from 8:1 to 0.8:1, preferably between 5:1 and 1:1, more preferably between 3:1 and 1:1. Example of suitable and preferred metal derivatives are salts of vanadium and iron. Preferably iron salts are used. Suitable examples include but are not limited to VOCl2, VO(acac)2, Fe(acac)3, Fe(acac)2. The amount ofmetal catalyst used, based on the amount of the sulfanyl compounds of formula (II) is in the range from 0.1mol% to 50 mol%. Preferably between 0.5 mol % and 10 mol%. Examples of suitable and preferred chiral ligands are selected from Schiff bases formed from salicylaldehyde derivatives and chiral amines. In a preferred embodiment of the invention the metal derivative is selected from iron and the chiral ligand is a Schiff base formed from salicylaldehyde derivatives and chiral amino-alcohols represented by a compound of formula (X), * the carbon marked with a * represents an enantioenriched chiral center in either (R)- or (S)-configuration. Preferably, R6is chloro, iodo or bromo.The chiral ligand is used as an enantioenriched compound. The enantiomeric ratio of the ligand is from 80:20to 100:0 [R]:[S] or [S]:[R], preferably the enantiomeric ratio of the ligand is from 90:10 to 100:0 [R]:[S] or [S]:[R]. The amount of the ligand used, based on the amount of the sulfanyl compound of formula (II), is in the range from 0.1 to 30 mol %, preferably from 1 to 15 mol%, most preferably from 2 to 10 mol%. Optionally, the ligand can be formed in situ in the reaction by adding the appropriate salicylaldehyde derivative and an appropriate amino alcohol. Alternatively, the ligand can be prepared in a separate step. Example of suitable and preferred acid additives are carboxylic acids. Preferably the acid additive is a benzoic acid, optionally mono-, di- or tri-substituted by methyl, ethyl, isopropyl, methoxy or dimethylamino, optionally in form of a lithium, sodium or potassium salt. More preferably the additive is a methoxybenzoic acid or a dimethylaminobenzoic acid (optionally in form of a lithium, sodium or potassium salt), even more preferably 4- 83034 FF -12- methoxybenzoic acid. The amount of the acid additive used, compared to the sulfanyl compound of formula (II), is in the range from 0.1 to 10 mol %, most preferably from 0.5 to 5 mol %. In the most preferred embodiment, the oxidizing agent is hydrogen peroxide; the metal salt is Fe(acac)3; the ligand is selected from (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)- (3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5- dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-dibromophenyl)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; and the additive is 4-methoxybenzoic acid. Examples of suitable and preferred solvents (or diluents) are esters, nitriles, alcohols, ethers, and aliphatic,aromatic or halogenated hydrocarbons. Examples include but are not limited to: ethyl acetate, isopropylacetate, acetonitrile, butyronitrile, ethanol, methanol, isopropanol, n-propanol, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, 1,4-dioxane pentane, hexane, cyclohexane, heptane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or mixtures thereof. Preferably the solvent is an aromatic or halogenated hydrocarbon, for example: dichloromethane, 1,2- dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or mixtures thereof. More preferably the solvent is selected from dichloromethane, toluene, xylene, chlorobenzene, methoxybenzene, or mixtures thereof. The ratio of enantiomers produced is from 50.5:49.5 to 100:0 [R]:[S] or [S]:[R]. Preferably the enantiomeric ratio of the product is from 70:30 to 100:0 [R]:[S] or [S]:[R], even more preferably 90:10 to 100:0 [R]:[S] or [S]:[R] The enantiomeric ratio of the product can be either lower or higher than the enantiomeric ratio of the chiral ligand used in the reaction. The ratio of enantiomers produced can be increased by crystallization if required. Such methods are known to those skilled in the art and include crystallization from an organic solvent, a mixture of organic solvents or a mixture of organic solvents with water. It has been proven by X-ray crystallography (see Example 8) that the chiral ligand of formula (X) enriched in Renantiomer provides an enantioenriched sulfoxide of formula (I) enriched in R enantiomer. Correspondingly,the chiral ligand of formula (X) enriched in S enantiomer yields enantioenriched sulfoxide of formula (I) enriched in S enantiomer. Step (B) comprises reacting a compound of formula (III) 83034 FF -13- as defined for a compound of formula (I); with an aqueous solution of hydroxylamine an at an appropriate temperature. The ratio of hydroxylamine used compared to a compound of formula (III) is in the range between 2:1 and 1:1, preferably between 1.5:1 and 1:1. Optionally in place of hydroxylamine free base hydroxylamine hydrochloride or hydroxylamine sulfate could be used in combination with 1 eq (relative to hydroxylamine salt) of an appropriate base. Appropriate bases include but are not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate. Examples of suitable and preferred solvents (or diluents) for step B are alcohols, ethers, and aliphatic, aromatic or halogenated hydrocarbons. Examples include but are not limited to: tetrahydrofuran, 2-methyl tetrahydrofuran, dichloromethane, 1,2- dichloroethane, chlorobenzene, toluene, anisole, xylenes, t-butylmethyl ether, fluorobenzene, ethanol, methanol and isopropanol. The reaction is advantageously carried out in a temperature range from -20°C to 80°C. The preferred temperature is between 0°C and 30°C. Step (C) comprises Reacting a compound of formula (IV) with a compound of formula (IX) in the presence of an appropriate base in an appropriate solvent (or diluent). The ratio of the compound of formula (IX) used, compared to the compound of formula (IV), is in the range from 3:1 to 1:1, preferably between 1.5:1 and 1:1, more preferably between 1.2:1 and 1:1. Example of suitable and preferred bases for step C are trialkylamines such as triethylamine and tributylamine, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxide such as potassium hydroxide and sodium hydroxide. Preferably the base is a trialkylamine, more preferably triethylamine. The ratio of a base used, compared to sulfonyl chloride of formula (IX), is from 1.5:1 to 1:1, more preferably between 1.2:1 and 1:1. Examples of suitable and preferred solvents (or diluents) for step C are esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons. Examples include but are not limited to: tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylenes, dioxane, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, anisole, fluorobenzene. 83034 FF -14- Preferably the solvent is an ether, nitrile or a halogenated hydrocarbon, for example: tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dichloromethane and chlorobenzene. Step (D) comprises A thermal rearrangement of compounds of formula (V) to compounds of formula (VI) in a suitable solvent (or diluent) at an appropriate temperature. Suitable solvents (or diluents) are polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatic hydrocarbons, carbonates and ethers or mixtures thereof. Examples of appropriate and preferred solvents include but are not limited to: acetonitrile, butyronitrile, benzonitrile, ethylene glycol, methanol, ethanol, methyl isobutyl ketone, nitrobenzene, trifluorotoluene,polyethelene glycol, n-propanol, 2-methoxyethanol, chlorobenzene, tetrahydrofuran, 2-methyl-tetrahydrofuran,1,4-dioxane, anisole, N,N-dimethyl formamide, N-methyl pyrrolidine, sulfolane, 2,5-dimethyl isosorbide, dimethyl acetamide, cyrene, or mixture thereof. More preferably the solvent (or diluent) is N-methyl pyrrolidine, sulfolane, acetonitrile, ethylene glycol, ethanol, n-propanol, or mixtures thereof. The rearrangement is advantageously carried out in a temperature range from 0°C to 150°C. The preferred temperature is dependent on the electronic nature of R5substituent. If R5is highly electron withdrawing (for example 2,4-dinitro phenyl) the appropriate reaction temperature is in the range from 0°C to 40°C. Whereas, if R5is neutral (for example methyl) or moderately electron withdrawing (for example tosyl) the preferred temperature is between 60°C and 100°C. In one embodiment related to the process according to the invention of making compounds of formula (VI), steps (C) and (D) could be advantageously carried out in one pot without isolating intermediate compound of formula (V). This is most preferable when R5 in sulfonyl chloride of formula (IX) is highly electron withdrawing (for example 2,4-dinitrophenyl). Step (E) comprises Reacting a compound of formula (VI) with a compound of formula (VII) in an appropriate solvent (or diluent) at an appropriate temperature to produce a compound of formula (I) via an intermediate compound of formula (VIII). The ratio of the compound of formula (VII) used, compared to the compound of formula (VI), is in the range from 2:1 to 1:1, preferably between 1.5:1 and 1:1, more preferably between 1.2:1 and 1:1. Suitable solvents (or diluents) are polar aprotic solvents, nitriles, esters, ketones, alcohols, aromatichydrocarbons, carbonates, and ethers, or mixtures thereof.Examples of appropriate 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, polyethelene glycol, chlorobenzene, tetrahydrofuran, 2-methyl- 83034 FF -15- tetrahydrofuran, 1,4-dioxane, anisole, N,N-dimethyl formamide, N-methyl pyrrolidine, sulfolane, 2,5-dimethyl isosorbide, dimethyl acetamide, cyrene, or mixture thereof. The condensation rearrangement cascade is advantageously carried out in a temperature range from 20°C to 150°C. The preferred temperature is between 60°C and 100°C. In one embodiment related to the process according to the invention of making compounds of formula (I) steps D and E could be advantageously carried out in one pot without isolating intermediate compounds of formula (VI) and (VIII). In another embodiment related to the process according to the invention of making compounds of formula (I) steps D and E could be advantageously carried out in one pot in the presence of an appropriate acidic additive.The most preferred additive is citric acid. The preferred molar percentage of acidic additive versus the productof step C is between 1 and 10 mol%. The chiral center at sulfur is fully preserved during the entire sequence starting from chiral sulfoxide (after step A). It has been proven that no inversion takes place, that is R sulfoxide of formula (III) leads to R compound of formula (I) and vice versa, by comparing the compound made in experimental procedure 43 with the same compound prepared in WO2022 / 253841 where its absolute configuration has been established by X-ray crystallography. Certain preferred embodiments according to the invention are provided as set out below. Embodiment 1 provides a process for the preparation of enantiomerically enriched sulfoximines of formula (I) as defined above. The compounds of formula (I) described according to the invention are preventively and / or curatively valuable active ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish, and plants. EXAMPLES The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. Where typical process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given to make the compounds of the present invention, minor modifications to theseprocess conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with thereactant or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures as long as the reagents stay the same. ABBREVIATIONS CDCl3 deuterated chloroform 83034 FF -16- CPME cyclopentylmethylether DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate HCl hydrochloric acid h / hrs hour / hours LC-MS Liquid Chromatography Mass Spectrometry (LC-MS, LCMS or LC / MS) MeCN acetonitrile (MeCN or ACN) min minutes MeTHF 2-methyl tetrahydrofuranNaHCO3 sodium hydrogencarbonate Na2CO3 sodium carbonate Na2SO4 sodium sulphate rt room temperature Rt retention time sat. saturated TEA triethylamine (TEA or Et3N) THF tetrahydrofuran PREPARATION EXAMPLES The compound of formula (I) according to the invention may be prepared using the synthetic techniques described both above and below. Throughout this description, temperatures are given in degrees Celsius ][°C] and “m.p.” means melting point. LC / MS means Liquid Chromatography Mass Spectroscopy. As used herein, the term “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15°C to about 35°C. For example, rt can refer to a temperature of about 20°C to about 30°C. 1H NMR and19F NMR measurements were recorded on a Bruker 400MHz spectrometer, chemical shifts are given in ppm relevant to a TMS (1H) and CFCl3 (19F) standard. Spectra were measured in deuterated solvents as indicated. SYNTHESIS OF SULFIDE STARTING MATERIALSExample 1: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanyl-pyridine-2-carboxamide 83034 FF -17- To a suspension of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanyl-pyridine-2-carboxylic acid (1.00 g, 98% purity, 3.68 mmol) in EtOAc (9.0 mL) was added few drops of DMF. Oxalyl chloride (0.360 mL, 4.05 mmol) was added to this reaction mixture drop wise at rt over 2 hrs. Thus prepared acid chloride solution was slowly dosed to a biphasic mixture of NaHCO3 (0.372 g, 4.42 mmol), water (2.7 mL), EtOAc (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 further 1 h at rt. Phases were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound (1.00 g, 83% purity, 85% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J=2.3 Hz, 1H), 7.99 (s, 1H), 7.54 (m, 2H), 2.89 (q, J=7.3 Hz, 2H), 1.77 (s, 6H), 1.27 (t, J=7.3 Hz, 3H).Example 2: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanyl-pyridine-2-carbonitrile 1-methyl-ethoxy)-3-ethylsulfanyl-pyridine-2-carboxamide (10.0 g, 87.5% purity, 33.0 mmol) and TEA (18 mL, 132 mmol) in THF (100 mL) was added trifluoro acetic anhydride (14.1 mL, 80.42 mmol) dropwise over the period of 15 minutes at 0°C. After complete addition the reaction mixture was allowed to warm to rt. After 1 h of stirring water and saturated NaHCO3 was slowly added. The aqueous layer was extracted with EtOAc, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using cyclohexane and EtOAc as an eluent to yield the title compound (8.98 g, 82% purity, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J=2.4 Hz, 1 H), 7.74 (d, J=2.4 Hz, 1H), 3.20 (q, J=7.3 Hz, 2 H), 1.81(s, 6H), 1.29 (t, J=7.3 Hz, 3H). Example 3: Preparation of 5-(3-fluorophenyl)-3-methylsulfanyl-pyridine-2-carbonitrile (3.47 g, 94.5% purity, 14.1 mmol) in tetrahydrofuran (17 mL) was added sodium methanethiolate (2.6 g, 35.2 mmol). The reaction mixture was stirred at 60°C for 2 hrs followed cooling to rt and quenching with ice cold water. The resulting mixture was extracted with EtOAc, the combined organic layers washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using EtOAc and cyclohexane as an eluent to yield the title compound (2.60 g, 94% purity, 71% yield) as a brown solid. 83034 FF -18- 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=2.0 Hz, 1H), 8.13 (d, J=1.83 Hz, 1H), 7.78-7.83 (m, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.56 - 7.63 (m, 1H), 7.35 (d, J=2.6 Hz, 1H), 2.74 (s, 3H) Example 4: Preparation of 5-chloro-3-ethylsulfanyl-pyridine-2-carbonitrile 3-ethylsulfanyl-pyridine-2-carboxamide (15.0 g, 97% purity, 67.0 mmol) and TEA (23.5 mL, 167.5 mmol) in dry THF (255 mL) was added trifluoro acetic anhydride (11.3 mL, 80.4 mmol) over 15 min while keeping the internal temperature under 5°C. The reaction mixture was allowed to warm to rt and stirred for further 2 h. Most of THF was evaporated under reduced pressure and water (45 mL) was slowly added. The obtained brown precipitate was filtered and washed on filter with cold water. The precipitate was dissolved in acetone (60 mL) and the solution was slowly added to water (150 mL) under vigorous stirring. The obtainedlight brown colored precipitate was filtered and dried under reduced pressured to afford the title compound (13.25 g, 97% purity, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 3.07 (q, J=7.3 Hz, 2 H), 1.41 (t, cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl) acetate pyridine-2-carbonitrile (20.0 g, 97% purity, 97.6 mmol) in dry DMF (100 mL) was added powdered potassium carbonate (34.4 g, 244 mmol). The resulting suspension was then heated at 100°C and ethyl cyanoacetate (15.9 mL, 146 mmol) was dosed over a period of 1 h. After full consumption of starting material, the reaction mixture was cooled to rt, diluted with EtOAc and the precipitate (inorganic salts) was filtered off. The filtrate was neutralized using aqueous 2N HCl and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was purified using by silica gel chromatography using EtOAc and cyclohexane as an eluent to afford the title compound (19.12 g, 95.5% purity, 87% yield) as a gray solid. 1H NMR (400 MHz, CD3CN) δ 8.50 (d, J=2.0 Hz, 1H), 7.90 (d, J=2.0 Hz, 1 H), 5.21 (s, 1 H), 4.23 (q, J=7.1 Hz, 2 H), 3.14 (q, J=7.4 Hz, 2 H), 1.34 (t, J=7.3 Hz, 3 H), 1.24 (t, J=7.1 Hz, 3 H). Example 6: Preparation of 5-(cyanomethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile 83034 FF -19- 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) was added sodium chloride (5.07 g, 86.3 mmol). The reaction mixture was then stirred at 100°C until the full consumption of starting material. The reaction mixture was the cooled to rt and cold water (100 mL) was added. The resulting mixture was then neutralized by the portion wise addition of solid NaHCO3 under vigorous stirring and the neutralized solution was extracted with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was dissolved in acetone (20 mL) and slowly added into water (100 ml) at 0°C under vigorous stirring. The obtained off-white colored precipitate was filtered off, washed on filter with water (50 mL) and dried under reduced pressure to afford the title compound (7.17 g, 93% purity, 95% yield) as an off-white powder.1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=1.8 Hz, 1H), 8.04 (d, J=1.7 Hz, 1 H), 4.21 (s, 2 H), 3.18 (q, J=7.3 Hz, 2 H), . Example 7: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile -3-ethylsulfanyl-pyridine-2-carbonitrile (10.00 g, 96% purity, 47.23 mmol) in MeCN (150 ml) was added Cs2CO3 (47.1 g., 141.7 mmol) followed by iodomethane (6.0 mL, 94.5 mmol) and the reaction mixture was stirred at 80°C for 1 hr. After full consumption of starting material, the reaction mixturewas cooled to rt and quenched by addition of water. The resulting mixture was extracted with EtOAc, and thecombined organic layers washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using cyclohexane and EtOAc as an eluent to yield the title compound (11.45 g, 85% purity, 89% yield) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=2.1 Hz, 1 H), 8.03 (d, J=2.2 Hz, 1 H ), 3.25 (q, J=7.3 Hz, 2 H ), 1.78 (s, 6 H) , 1.29 (t, J=7.3 Hz, 3 H). PREPARATION OF RACEMIC SULFOXIDES FOR DEVELOPMENT OF CHIRAL ANALYTICAL METHODS: Racemic samples of sulfoxides were prepared according to the following general procedure: 83034 FF -20- Sulfide (1 eq) was dissolved in acetic acid (5 mL / mmol) and hydrogen peroxide (1.05 equiv, 30 mass%) was added at rt. The reaction mixture was stirred at 40°C for 20 h or until complete consumption of the starting material was observed by LCMS. Aqueous NaHCO3 was added dropwise to the reaction mixture followed by EtOAc. The phases were separated, and the aqueous phase was extracted with another portion of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to afford the desired sulfoxide. The material was used directly for the development of a chiral HPLC method. PREPARATION OF ENANTIOENRICHED SULFOXIDES Example 8: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile 3-ethylsulfanyl-pyridine-2-carbonitrile (2.157 g, 93% purity, 8.25 mmol) in anisole (8.3ml) was added (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-dibromo-phenol) (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). The resulting dark red solution was cooled to 10 ⁰C and 30% aq H2O2 (1.35 ml, 13.2 mmol) was added. The resulting biphasic mixture was stirred at 10 ⁰C for 22 h. At this stage (full conversion of starting material) the reaction was quenched by addition of crushed ice (4 g) and 40% aq NaHSO3 (2.6 ml). After warming to rt, the mixture was diluted with EtOAc (8 ml) and treated with 1M aqueous H2SO4 (0.83 ml). After stirring for 30 min, the phases were separated, organic phase washed with aqueous NaHCO3 (8 ml) and brine (8 ml), and the organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield a crude product. Quantitative NMR analysis using 1,3,5-trimethoxy benzene as an internal standard indicates a chemical yield of 91% for the desired 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile. The crude product was purified by a reverse phase HPLC (MeCN / water / 0.1% formic acid mobile phase) to yield the title compound (1.63 g, >99% purity, >99.5% ee, 76% isolated yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.45 Hz, 3 H), 2.99 (dq, J=14.0, 7.2 Hz, 1 H), 3.15 - 3.36 (m, 1 H), 8.50 (d, J=2.2 Hz, 1 H), 8.85 (d, J=2.2 Hz, 1 H) Chiral SFC method : Waters Acquity UPC2 / QDa; PDA Detector Waters Acquity UPC2;Column: Daicel SFC CHIRALPAK®IC, 3μm, 0.3cm x 10cm, 40°C; Mobile phase:A: CO2 B: IPA gradient: 20-60% B in 2 min; ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: 240 nm; Sample concentration: 1 mg / mL in MeCN; Injection: 2 µL Results: S enantiomer R enantiomer Retention time (min) ~ 1.14 Retention time (min) ~ 1.35 Enantiomeric excess: >99.5% (R enantiomer, S enantiomer below HPLC detection limits) A single crystal grown from di-isopropyl ether was selected for X-ray data analysis. The crystal sample mounted had dimensions of 0.4 mm x 0.3 mm x 0.3 mm and was a colorless prism. Data collection was performed on a 83034 FF -21- Rigaku Oxford Diffraction Supernova diffractometer at 293 K. The unit cell was determined to be orthorhombic (space group P212121), and the structure contained one molecule in the crystal asymmetric unit (Figure 1, a thin stick representation labelled by chirality. Figure 1 generated in Flare software package). The stereochemistry was unambiguously determined to be the R isomer, with a Flack parameter of 0.02 + / - 0.03. Crystallographic data is summarized in Table 1 and selected geometric parameters are listed in Table 2. Table 1. Crystal data and structure refinement for 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile Chemical formula C8H7BrN2OS Mr 259.13 Crystal system, space group Orthorhombic, P212121 Temperature (K) 293 a, b, c (Å) 6.7404 (2), 9.2441 (3), 15.8051 (5) V (Å3) 984.80 (6) Z 4 Radiation type Cu Kα µ (mm−1) 7.37 Crystal size (mm) 0.40 × 0.30 × 0.30 Data collection Diffractometer Oxford Diffraction SuperNova Absorption correction Multi-scan CrysAlis PRO, (Agilent, 2011) Tmin, Tmax0.11, 0.11 No. of measured, independent and 4140, 2032, 1962 observed [I > 2.0σ(I)] reflections Rint 0.037 (sin θ / λ)max (Å−1) 0.632 Refinement R[F2> 2σ(F2)], wR(F2), S 0.041, 0.117, 0.91 No. of reflections 2024 No. of parameters 120 H-atom treatment H-atom parameters constrained Δρmax, Δρmin (e Å−3) 0.40, −0.72 Absolute structure Flack (1983), 814 Friedel-pairs Absolute structure parameter 0.02 (3) 83034 FF -22- 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) Table 2. Selected geometric parameters (Å, º) Br1—C2 1.874 (4) S5—C7 1.806 (4) C2—C3 1.380 (5) C7—C8 1.510 (6) C2—C11 1.394 (6) C9—N10 1.341 (4) C3—C4 1.392 (5) C9—C12 1.436 (5) C4—S5 1.808 (3) N10—C11 1.328 (5) C4—C9 1.388 (5) C12—N13 1.153 (6) S5—O6 1.491 (3) Br1—C2—C3 121.0 (3) O6—S5—C7 107.64 (19) Br1—C2—C11 118.8 (2) S5—C7—C8 114.3 (3) C3—C2—C11 120.3 (3) C4—C9—N10 123.7 (3) C2—C3—C4 117.2 (3) C4—C9—C12 121.2 (3) C3—C4—S5 118.3 (3) N10—C9—C12 115.1 (3) C3—C4—C9 118.9 (3) C9—N10—C11 117.3 (3) S5—C4—C9 122.6 (3) C2—C11—N10 122.6 (3) C4—S5—O6 105.15 (17) C9—C12—N13 179.2 (4) C4—S5—C7 98.29 (15) Example 9a: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile -3-ethylsulfanyl-pyridine-2-carbonitrile (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- dimethyl-propyl]iminomethyl]-4,6-diiodo-phenol (48.8 mg, 97% purity, 0.100 mmol) inPhMe (4.0 ml) was added 30% aq H2O2 (0.20 ml, 2.00 mmol) at rt. After stirring vigorously for 2.5 h the reactionmixture was poured into EtOAc (23 ml) and quenched by addition of 1.0M Na2S2O3 (2.4 ml). Phases were separated and the organic phase was washed with 1.0M HCl (2.3 ml) and aq NaHCO3. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by a reverse phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to yield the title compound (234 mg, 97%ee, 95% yield) as a white powder. 83034 FF -23-1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 3.26 (dq, J = 13.6, 7.3 Hz, 1H), 3.04 (dq, J = 13.6, 7.3 Hz, 1H), 2.09 –1.79 (m, 4H), 1.12 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, 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 UPC2 / QDa; PDA Detector Waters Acquity UPC2; Column: Daicel SFCCHIRALPAK® IA, 3μm, 0.3cm x 10cm, 40°C; Mobile phase: A: CO2B: IPA gradient: 20-60% B in 1.8 min;ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: DAD 210-500 nm; Sample preparation: dissolved in MeOH; Injection: 2 μL Results: S enantiomer R enantiomer Retention time (min) ~ 0.59 Retention time (min) ~ 1.04 Enantiomeric excess: 97% (S enantiomer) Example 9b: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile -3-ethylsulfanyl-pyridine-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- dimethyl-propyl]iminomethyl]-4,6-dichloro-phenol (32.8 mg, 98% purity, 0.110 mmol) in PhOMe (1.0 ml) was added 30% aq H2O2 (0.23 ml, 2.11 mmol) at 0⁰C over 1 h using a syringe pump. The resulting reaction mixture was stirred for further 20 h at the same temperature. The reaction mixture was poured into EtOAc (23 ml) and quenched by addition of 1.0M NaHSO3 (2.4 ml). Phases were separated and the organic phase was washed with 1.0M HCl (2.3 ml) and aq NaHCO3. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by a reverse phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to yield the title compound (230 mg, >99.5%ee, 93% yield) as a white powder. Chiral SFC method: Identical to Example 9a Results: S enantiomer R enantiomer Retention time (min) ~ 0.59 Retention time (min) ~ 1.04 Enantiomeric excess: >99.5% (R enantiomer) Example 9c: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile 83034 FF -24- -3-ethylsulfanyl-pyridine-2-carbonitrile (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-dimethyl-propyl]iminomethyl]-4,6-dibromo-phenol (1.281 g, 97% purity, 3.30 mmol) in anisole (46 ml) was added 30% aq H2O2 (7.8 ml, 76.3 mmol) at 10⁰C over 2 h using a syringe pump. The resulting reaction mixture was stirred vigorously for further 22 h at the same temperature. The reaction was quenched by addition of 40% aq NaHSO3 (10.6 ml) and diluted with anisole (53 ml). Phase were separated and the organic phase was washed with 1M 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 material was purified by a reverse phase HPLC (water / MeCN as a mobile phase) to yield the titlecompound (10.44 g, >99.5% ee, 93% yield) as a white powder. Chiral SFC method: Waters Acquity UPC2 / QDa; PDA Detector Waters Acquity UPC2; Column: Daicel SFC CHIRALPAK®IA, 3μm, 0.3cm x 10cm, 40°C; Mobile phase: A:CO2 B: IPA, gradient: 5-20% B in 9.8 min; ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: 238 nm; Sample preparation: 1mg / mL in MeCN; Injection: 2 μL Results: S enantiomer R enantiomer Retention time (min) ~ 3.07 Retention time (min) ~ 5.73 Enantiomeric excess: >99.5% (R enantiomer) Example 10: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile 1-methyl-ethoxy)-3-ethylsulfanyl-pyridine-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- dimethyl-propyl]iminomethyl]phenol (0.602 g, 1.99 mmol), p-anisic acid (51 mg, 0.332 mmol) in toluene (13 mL) was added 30% aq H2O2 (1.36 ml, 50.1 mmol) at rt over 1h. The reaction mixture was stirred for further 5 h and then quenched by adding aqueous sat. sodium thiosulphate at 0°C. The organic layer was separated, aqueous layer extracted with EtOAc, and the combined organic layers washed with brine, dried over Na2SO4, concentrated under reduced pressure to get the crude compound. The crude material was purified by silica gelchromatography using cyclohexane and EtOAc as an eluent to yield the title compound (1.55 g, 89% purity, >99.5% ee, 79% yield). 83034 FF -25-1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.6 Hz, 1H) 8.02 (d, J=2.75 Hz, 1H) 3.28 - 3.33 (m, 1H) 2.96-3.02 (m, 1H), 1.84 (s, 6H), 1.09 (t, J=7.3 Hz, 3H). Method of chiral analysis: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IA (4.6mm x 250mm) 5µm; Mobile phase: A: TBME B: IPA isocratic: 20% B in 13 min; Flow rate: 1.0 ml / min; Detection: 240 nm; Sample preparation: 1mg / mL in EtOH; Injection: 2 μL Results: S enantiomer R enantiomer Retention time (min) ~ 5.32 Retention time (min) ~ 6.8 Enantiomeric excess: >99.5% (R enantiomer, opposite enantiomer below HPLC detection limits) Example 11: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile 1-methyl-ethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile (6.00 g, 96.5% purity, 25.0 mmol), iron(III) acetylacetonate (0.177 g, 0.5 mmol), 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl) -2,2-dimethyl- propyl]iminomethyl]phenol (1.47 g, 3.75 mmol) in toluene (90 mL) was added 30% aqueous hydrogen peroxide (2.0 equiv., 50.1 mmol) drop wise over 1h at 0°C. The reaction mixture was stirred for 2 h at 24°C and then quenched by adding saturated Na2S2O3 at 0°C. The organic layer was separated, the aqueous layer extracted with EtOAc, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by column chromatography using cyclohexane and EtOAc as an eluent to yield the title compound (5.48 g, 91% purity, 97% ee, 81% yield).1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=2.3 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 3.28 (m , 1H), 3.04 (m, 1H), 1.82 (d, J=1.9 Hz, 6H), 1.12 (t, J=7.3 Hz, 3H)Method of chiral analysis: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IC (4.6mm x 250mm)5µm; Mobile phase: A: n-hexane B: EtOH isocratic: 30% B in in 30 min; Flow rate: 1.0 ml / min; Detection: 225 nm; Sample preparation: 1mg / mL in EtOH ; Injection: 2 μL Results: R enatiomer S enantiomer Retention time (min) ~ 18.2 Retention time (min) ~ 21.8 Enantiomeric excess: 97% (R enantiomer)Example 12: Preparation of 5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carbonitrile 83034 FF -26- -3-methylsulfanyl-pyridine-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-dimethyl- propyl]iminomethyl]-4,6-diiodo-phenol (0.213 g, 0.442 mmol), p-anisic acid (11.3 mg, 0.0737 mmol) in toluene (6.0 ml) was added 30% aq H2O2 (0.6 mL, 5.9 mmol) drop wise over 15 min, and the reaction mixture was continued to stir for further 1 hr. The reaction mixture was quenched by saturated sodium thiosulphate, the resulting mixture extracted with EtOAc, and the combined organic layers washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get crude material. Purification by silica gel chromatography using cyclohexane and EtOAc as an eluent yielded the title compound (0.73 g, 94% purity, 97% ee, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=2.1 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H), 7.89 (m, 1 H), 7.80 (d, J=7.8Hz, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 3.04 (s, 3 H) Method of chiral analysis: Chiral HPLC: WATERS ACQUITY UPLC; Column: Chiralpack-IA (4.6mm x 250mm) 5µm; Mobile phase: A: TBME B: IPA isocratic: 30% B in 30 min; Flow rate: 1.0 ml / min; Detection: 225 nm; Sample preparation: 1mg / mL in EtOH; Injection: 2 μL Results: S enatiomer R enantiomer Retention time (min) ~ 11.0 Retention time (min) ~ 14.9 Enantiomeric excess: 97% (R enantiomer) Example 13: Preparation of 3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carbonitrile 3-(trifluoromethyl)pyridine-2-carbonitrile (0.237 g, 98% purity, 1.00 mmol) in anisole (1.0 ml) was added (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-dibromo- phenol) (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). The resulting dark red solution was cooled to 10⁰C and 30% aq H2O2 (0.136 ml, 1.6 mmol) was added. The resulting biphasic mixture was stirred at 10⁰C for 22 h. At this stage (full conversion of starting material) the reaction was quenched by addition of crushed ice (4 g) and 40% aq NaHSO3 (0.30 ml). After warming to rt, the mixture was diluted with EtOAc (10 ml) and treated with conc. H2SO4 (50 µl). After stirring for 30 min phases were separated and the aqueous layer was again extracted with EtOAc (15 ml). The combined organic layer was washed with sat. aq. NaHCO3(8 ml) and brine (8 ml). The organic layer was dried over 83034 FF -27- anhydrous MgSO4 concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Cyclohexane / EtOAc 100:0 to 60:40) to yield the title compound (127 mg, 98% purity, >99% ee, 50% yield) as a colourless solid.1H NMR (400 MHz, CDCl3) δ 1.27 - 1.40 (m, 3 H), 2.95 - 3.09 (m, 1 H), 3.21 - 3.37 (m, 1 H) 8.65 (d, J=1.45 Hz, 1 H), 9.06 (d, J=1.09 Hz, 1 H);19F NMR (377 MHz, CDCl3) δ -62.80 (s, 3 F) Chiral SFC method: SFC:Waters Acquity UPC2 / QDa; PDA Detector Waters Acquity UPC2; Column: Daicel SFC CHIRALPAK®IC, 3μm, 0.3cm x 10cm, 40°C; Mobile phase: A: CO2 B: MeOH isocratic 3% B in 2 min; ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: 270 nm; Sample concentration: 1 mg / mL in MeOH; Injection: 1 µL Results: S enantiomer R enantiomer Retention time (min) ~ 0.95 Retention time (min) ~ 1.26 Enantiomeric excess: >99 % (R enantiomer; S enantiomer below HPLC detection limits) PREPARATION OF ENANTIOENRICHED AMIDINE OXIMES Example 14: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine 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 further 20 min most of the solvent was evaporated under reduced pressure (ca 1.2 ml left). CPME (2.7 ml) was added slowly leading to precipitation. The precipitate was filtered, washed on filter with CPME / MeTHF (7:3, 1.5 ml) and dried in vacuum to yield the title compound (0.713 g, 95% purity, 78% yield) as a white powder.1H NMR (400 MHz, CDCl3) δ 1.27 (t, J=7.45 Hz, 3 H), 2.93 (dq, J=13.1, 7.4 Hz, 1 H), 3.32 (dq, J=13.1, 7.5 Hz, 1 H), 5.58 (br s, 2 H), 7.55 (s, 1 H), 8.59 (d, J=2.2 Hz, 1 H), 8.68 (d, J=2.2 Hz, 1 H). Example 15: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine stirring was charged with 5-(1-cyanocyclopropyl)-3-ethylsulfanyl-pyridine- 2-carbonitrile (10.60 g, 45.5 mmol, 98% assay), 4-methoxybenzoic acid (0.234 g, 1.54 mmol), Fe(acac)3 (0.153 83034 FF -28- g, 0.432 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-dibromo-phenol (1.30 g, 3.33 mmol, 97% assay) and anisole (45.5 ml). The resulting deep red solution was cooled to 10°C and 30% aq H2O2 (7.9 ml, 77.0 mmol) was dosed over 1 h via a syringe pump while stirring vigorously (300 rpm). After the end of dosing the reaction mixture was stirred at the same temperature for further 14 h (full conversion by LC / MS). The reaction was quenched by addition of aq 40% NaHSO3 (10.6 ml) in two portions (exothermic). After 15 min the reaction temperature was raised to 20 ⁰C and stirred vigorously (600 rpm) for 30 min (reaction color turns bright yellow). Phases were separated and 1M H2SO4 (10.6 ml) was added to the organic phase. The resulting mixture was stirred vigorously for 30 min. Phases were again separated and the organic phase was washed with brine (3 x 10 ml) until washings had a pH > 6. The organic phase was dried over Na2SO4.After filtration of the drying agent the obtained solution in PhOMe was telescoped to the next step. qNMRanalysis using 1,3,5-trimethoxybenzene as an internal standard indicates 92% chemical yield of the chiral sulfoxide as well as ca 3% of the corresponding sulfone (overoxidation). This solution also contains most of the ligand used for oxidation. A solution of the chiral sulfoxide prepared above (54.4 g) was charged in a 100 ml reactor with a mechanical stirring. In a separate flask a 4.7M solution of NH2OH was prepared by treating a solution of NH2OH.HCl with 50% aq NaOH at 0°C (exothermic). Thus, prepared solution (10.0 ml, 47.2 mmol) was dosed to the sulfoxide solution in PhOMe at rt over 1.5 h. After stirring for further 2 h (white crystals in an orange liquid) the precipitate was filtered off and washed on filter with PhOMe (23 ml) and water (2 x 23 ml). The resulting white powder was resuspended in water (51 ml) and stirred vigorously for 1.5 h to yield a stable white suspension. The precipitate was filtered, washed on filter with water (20 ml) and dried under high vacuum overnight to yield the title compound (10.42 g, 97% assay, >99.5% ee, 80% isolated yield over two steps) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 6.01 (s, 2H), 3.25 (dq, J = 13.0, 7.4 Hz, 1H), 2.77 (dq, J = 13.0, 7.4 Hz, 1H), 1.99 – 1.84 (m, 2H), 1.80 – 1.65 (m, 2H), 1.16 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, 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 UPC² / QDa; PDA Detector Waters Acquity UPC ^2; Column: Daicel SFC CHIRALPAK®IA, 3μm, 0.3cm x 10cm, 40°C; Mobile phase: A: CO2 B: MeOH gradient: 20-60% B in 1.8 min; ABPR: 1800 psi; Flow rate: 2.0 ml / min; Detection: 227 nm ; Sample preparation: 1mg / mL in MeOH; Injection: 2 μL Results: S enantiomer R enantiomer Retention time (min) ~ 0.85 Retention time (min) ~ 1.15 Enantiomeric excess: >99.5% (R enantiomer) Example 16: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine 83034 FF -29- -3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile (167.1 mg, 95% purity, 97% ee, 0.648 mmol) in ethanol (1.3 ml) was added 50% aq NH2OH (0.062 ml, 1.01 mmol). The resulting thick suspension was stirred for 1 h. The solvent was evaporated, and the residue dried under vacuum to yield the title compound (187.4 mg, 92% purity, 97% ee, 96% yield) as a white powder. Chiral SFC method: see Example 15 Results: S enantiomer R enantiomer Retention time (min) ~ 0.85 Retention time (min) ~ 1.15 Enantiomeric excess: 97% (S enantiomer) Example 17: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2- carboxamidine methyl-ethoxy)-3-ethylsulfinyl-pyridine-2-carbonitrile (0.500 g, 97% purity, 1.84 mmol) in ethanol (1.3 mL) was added at 0°C 50% aqueous hydroxylamine (1.00 equiv., 1.84 mmol) and the reaction was stirred for further 2 h at rt. An extra portion of 50% aq hydroxylamine (0.20 equiv., 0.368 mmol) was added and the reaction stirred for a further 1 h. EtOAc was added to the reaction mixture, the organic layer was separated, and aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to yield the title compound (0.54 g, 93% purity, 92% yield) 1H NMR (400 MHz, DMSO-d6) δ10.35 (s, 1H), 8.53 (d, J=2.7 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H), 6.02 (s, 2H), 3.18 - 3.29 (m, 1H), 2.85 (dd, J=13.1 Hz, 7.4 Hz, 1H), 1.78 (d, J=6.0 Hz, 6 H) 1.11 (t, J=7.4 Hz, 3 H) Example 18: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2- carboxamidine 83034 FF -30- 1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile (2.00 g, 91% purity, 7.38 mmol ) in ethanol (5.0 ml) was added 50% aqueous hydroxylamine (0.52 ml, 8.49 mmol) at rt. After stirring for 1 h at rt an additional portion of 50% aqueous hydroxylamine (0.20 ml, 3.4 mmol) was added. Upon full conversion of the starting material the reaction mixture was concentrated under reduced pressure and product collected via filtration. The product was washed on filter with water and dried under high vacuum to yield the title compound (1.78 g, 93% purity, 81% yield). 1H 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) Example 19: Preparation of 5-(3-fluorophenyl) N'-hydroxy-3-[(R)-methylsulfinyl]pyridine-2-carboxamidine -3-[(R)-methylsulfinyl]pyridine-2-carbonitrile (0.12 g, 94% purity, 0.434 mmol) into ethanol (0.5 mL) was added 50% aqueous hydroxylamine (0.030 mL, 0.434 mmol) at rt. The reaction mixture was stirred for 2 hrs, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield the title compound (0.11 g, 98% purity, 85% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1 H), 9.06 (d, J=2.2 Hz, 1 H), 8.61 (d, J=2.1 Hz, 1 H), 7.75 (dt, J=10.3, 2.2 Hz, 1 H), 7.67 - 7.71 (m, 1 H), 7.58 - 7.65 (m, 1 H), 7.34 (m, 1H), 6.07 (s, 2 H), 2.90 (s, 3 H) Example 20: 3-[(R)-ethylsulfinyl]-N'-hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine -5-(trifluoromethyl)pyridine-2-carbonitrile (800 mg, 3.16 mmol) in EtOH (25 ml) was added 50% aqueous NH2OH (300 µl, 4.9 mmol). The resulting colorless reaction mixture was stirred at rt for 14 h and was concentrated under reduced pressure to yield the title compound (892 mg, >99% yield) as a colorless solid. 83034 FF -31- 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.45 Hz, 3 H) 2.98 - 3.13 (m, 1 H) 3.33 - 3.49 (m, 1 H) 5.68 (s, 2 H) 8.50 - 8.70 (m, 1 H) 8.73 (d, J=1.8 Hz, 1 H) 8.91 (d, J=1.1 Hz, 1 H);19F NMR (376 MHz, CDCl3) δ -62.27 (s, 3 F) Example 21: Preparation of [(Z)-[amino-[5-bromo-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene] amino] 4- nitrobenzenesulfonate -ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (0.611 g, 95% purity, 1.99 mmol) in THF (4.0 ml) was added TEA (0.33 ml, 2.39 mmol) followed by NsCl (0.488 g, 2.20 mmol). The reaction mixture was stirred for 3 h at rt. EtOAc (18 ml) was added, and the resulting reaction mixture was washed with water (3.5 ml), 1 M aq HCl (2.5 ml), aq NaHCO3 (3.5 ml) and brine (5 ml). Additional EtOAc (58ml) was added to avoid precipitation. The combined organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield the title compound (1.024 g) in a crude form. This material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.4 Hz, 3H), 2.85 (dq, J=13.35, 7.3 Hz, 1 H), 3.27 (dq, J=13.26, 7.4 Hz, 1 H), 5.62 (br s, 1 H), 6.61 (br s, 1 H), 8.21 - 8.29 (m, 2 H), 8.39 - 8.48 (m, 2 H), 8.62 (d, J=2.2 Hz, 1 H), 8.69 (d, J=2.2 Hz, 1 H). Example 22: Preparation of [(Z)-[amino-[3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)-2-pyridyl]methylene]amino] 4- nitrobenzenesulfonate hydroxy-5-(trifluoromethyl)pyridine-2-carboxamidine (880 mg, 3.13 mmol) in THF (10 ml) was added TEA (523 µl, 3.75 mmol) followed by nosyl chloride (763 mg, 3.44 mmol). The reaction was stirred at rt for 7 h before being diluted with water (20 ml) and EtOAc (15 ml). Phases were separated and aqueous phase extracted with EtOAc (2 x 15 ml). The combined organic phase was washed with 1N aq. HCl (20 ml) and brine (20 ml). Drying over anhydrous MgSO4 and concentration under reduced pressure yielded the title compound (1.32 g, 91% yield) as a colorless foam. 83034 FF -32-1H NMR (400 MHz, DMSO-d6) δ 1.05 (t, J = 7.45 Hz, 3 H) 2.64 - 2.84 (m, 1 H) 2.92 - 3.13 (m, 1 H) 7.42 - 8.07 (m, 2 H) 8.27 (d, J = 8.7 Hz, 2 H) 8.42 - 8.55 (m, 3 H) 9.18 (d, J = 1.1 Hz, 1 H);19F NMR (376 MHz, DMSO-d6) δ -61.22 (s, 3 F) Example 23: Preparation of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]-methylene]- amino] 4-methylbenzenesulfonate -3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (14.817 g, 94% purity, 49.9 mmol) in MeCN (50 ml) was added TEA (13.8 ml, 98.8 mmol). After stirring for 10 min p- toluenesulfonyl chloride (pTsCl) (10.13 g, 53.15 mmol) was added in five portions over 20 min. After stirring for2 h at rt the reaction mixture was diluted with EtOAc (200 ml). The resulting solution was washed with 1M HCl(3 x 40 ml), aq saturated NaHCO3 (40 ml) and brine (40 ml). The organic layer was dried over anhydrous Na2SO4 and solvents partially evaporated at 50 ⁰C and 150 mbar to ca 20 ml. The resulting precipitate was filtered, washed on filter with EtOAc (20 ml) and dried under high vacuum to yield the title compound (14.00 g, 97% purity, 90% yield) as a grey crystalline solid.1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H), 5.68 (s, 1H), 3.18 (qd, J = 7.4, 13.3 Hz, 1H), 2.76 (qd, J = 7.3, 13.3 Hz, 1H), 2.44 (s, 3H), 1.96 - 1.87 (m, 2H), 1.58 (ddd, J = 1.6, 4.2, 5.4 Hz, 2H), 1.15 (t, J = 7.4 Hz, 3H);13C NMR (101 MHz, 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 Example 24: Preparation of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-2-pyridyl]methylene] amino] 4-nitrobenzenesulfonate -3-[(S)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (2.942 g, 94% purity, 9.92 mmol) in MeTHF (30 ml) was added TEA (2.76 ml, 19.8 mmol) followed by 4- nitrobenzenesulfonyl chloride (2.309 g, 10.42 mmol) in three portions over 10 min. After stirring at rt for 1.5 h the reaction was quenched by addition of water (11 ml). Phases were separated, organic phase washed with 1M HCl (2 x 11 ml) and sat. NaHCO3 (11 ml), and the organic phase dried over anhydrous Na2SO4 and 83034 FF -33- evaporated under reduced pressure (30⁰C, 50 mbar). The foamy residue was redissolved in MeTHF (9 ml) and aged for 1 h. During this time precipitate was formed which was filtered, washed on filter with MTBE and dried under high vacuum to yield the title compound (3.961 g, 93% purity, 85% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ 1.22 (t, J = 7.4 Hz, 3 H) 1.55 - 1.62 (m, 2 H) 1.90 - 1.99 (m, 2 H) 2.79 (dq, J=13.3, 7.3 Hz, 1 H) 3.18 - 3.33 (m, 1 H) 5.44 - 5.84 (m, 1 H) 6.49 - 6.90 (m, 1 H) 8.09 (d, J=2.5 Hz, 1 H) 8.21 - 8.27 (m, 2 H) 8.37 - 8.44 (m, 2 H) 8.83 (d, J=2.5 Hz, 1 H) Example 25: Preparation of [(Z)-[amino-[5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]-2-pyridyl]methylene] amino] 4-chlorobenzenesulfonate -3-[(S)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (111.5 mg, 97% purity, 0.390 mmol) in MeCN (0.4 ml) was added TEA (0.121 ml, 0.872 mmol) and 4- chlorobenzenesulfonyl chloride (103.3 mg, 90% purity, 0.442 mmol). After stirring for 1 h, the reaction mixture was partitioned between EtOAc (10 ml) and sat. NaHCO3 (10 ml). Phases were separated, the organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield the title compound (202 mg, 87% purity, 99% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.4 Hz, 3 H) 1.56 - 1.63 (m, 2 H) 1.88 - 1.96 (m, 2 H) 2.76 (dq, J=13.3, 7.4 Hz, 1 H) 3.15 - 3.29 (m, 1 H) 5.45 - 5.96 (m, 1 H) 6.46 (s, 1 H) 6.49 - 6.82 (m, 1 H) 7.51 - 7.58 (m, 2 H) 7.93 - 8.01 (m, 2 H) 8.08 (d, J=2.2 Hz, 1 H) 8.81 (d, J=2.5 Hz, 1 H) Example 26: Preparation of [(Z)-[amino-[5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene] g, 83% purity, 2.96 mmol) in Me-THF (10 mL) was added TEA (0.83 mL, 5.92 mmol) and p-toluenesulfonyl chloride (0.624 g, 3.11 mmol) at rt. The reaction mixture was stirred for 2 hrs and quenched by addition of water (10 mL). Layers were separated, the organic phase washed with 2 N HCl and water, and the combined organic layers dried over Na2SO4 and concentrated under reduced pressure to yield the title compound (1.63 g, 71.5% purity, 91% yield) as a brown solid. 83034 FF -34- 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=2.3 Hz, 1H), 8.36 (d, J=2.3 Hz, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 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) Example 27: Preparation of [(Z)-[amino-[5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]-2-pyridyl]methylene] amino] pyridine-2-carboxamidine (0.50 g, 89% purity, 1.51 mmol) in 2-MeTHF (3.0 mL) was added TEA (0.42 mL, 3.0 mmol) and p-toluenesulfonyl chloride (0.318 g, 1.58 mmol). The reaction mixture was stirred at rt for 4 hr and quenched by addition of water (10 mL). Layers were separated and the organic phase was washed with 2 N HCl and water. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to yield the title compound (0.685 g, 84% purity, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.76 (d, J=9.9 Hz, 1H), 7.65 - 7.71 (m, 1H), 7.62 (dd, J=8.0, 6.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.35 (br d, J=2.4 Hz, 1H), 2.65 (s, 3H), 2.42 (s, 3H) Example 28: Preparation of [(Z)-[amino-[5-(3-fluorophenyl)-3-[(S)-methylsulfinyl]-2-pyridyl]methylene]amino] 4- nitrobenzenesulfonate -N'-hydroxy-3-[(S)-methylsulfinyl]pyridine-2-carboxamidine (1.6 g, 86% purity, 4.69 mmol) and TEA (1.31 mL, 9.38 mmol) in 2-Me-THF (9.4 mL) was added at rt 4- nitrobenzenesulfonyl chloride (1.21 g, 4.93 mmol). After stirring for 4h the reaction mixture was quenched byadding water (10 mL), the organic layer was separated, washed with 2N aq. HCl (5mL) followed by saturated NaHCO3 solution (10mL), and the combined organic layer dried over Na2SO4, and concentrated under reduced pressure to yield the title compound (2.01 g, 92% purity, 82% yield) as pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (d, J=2.3 Hz, 1 H), 8.57 (d, J=2.3 Hz, 1 H), 8.47 - 8.52 (m, 2 H), 8.26 - 8.32 (m, 2 H), 7.80 - 7.85 (m, 1 H), 7.73 - 7.80 (m, 1 H), 7.66 - 7.71 (m, 1 H), 7.60 (td, J=7.9, 6.0 Hz, 2 H), 7.31 - 7.38 (m, 1 H), 2.68 (s, 3 H) 83034 FF -35- Example 29: Preparation of [(Z)-[amino-[5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]-2-pyridyl]methylene] -3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (0.500 g, 95% purity, 1.60 mmol) in 2-MeTHF (5.0 mL) was added TEA (0.45 mL, 3.21 mmol) and 4- nitrobenzenesulfonyl chloride (0.393 g, 1.68 mmol) at rt. The reaction mixture was stirred for 2 hrs and quenched by addition of 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 NaHCO3 solution (10 mL) and aqueous layer extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to yield the title compound (0.82 g, 81% purity, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=2.6 Hz, 1H), 8.46-8.50 (m, 2H), 8.24-8.28 (m, 2H), 8.07 (d, J=2.6 Hz, 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). Example 30: Preparation of (1R)-6-(1-cyano-1-methyl-ethoxy)-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3- ylidene]ammonium 4-nitrobenzenesulfonate -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 2h. After full consumption of starting material, the reaction mixture was evaporated under reduced pressure. The crude material was washed with tert-butyl methyl ether and residue dried under high vacuum to afford the titlecompound (0.470 g, 86% purity, 99% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (d, J=5.0 Hz, 2H), 9.04-9.05 (m, 2H), 8.18 – 8.22 (m, 2H), 7.82 – 7.86 (m, 2H), 4.46-4.53 (m, 1H), 4.27-4.32 (m, 1H), 1.90 (s, 6H), 1.41 (t, J=7.4 Hz, 3H). Example 31: Preparation of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]-2-methyl- propanenitrile 83034 FF -36- [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 h and then cooled down to rt and concentrated under reduced pressure. To the resulting residue was added aqueous saturated NaHCO3 solution and the resulting mixture was extracted with EtOAC. The combined organic layers were concentrated under reduced pressure and purified by silica gel column chromatography using tert-butyl methyl ether and methanol as an eluent to yield the title compound (0.25 g, 85% purity, 50% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J=2.1 Hz, 1H), 8.95 (d, J=2.1 Hz, 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 = 7.4 Hz, 3H)Example 32: Preparation of 1-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]cyclopropane- carbonitrile 4-methylbenzenesulfonic acid salt -3-[(R)-ethylsulfinyl]-2-pyridyl]methylene] amino] 4-methylbenzenesulfonate (1.99 g, 97% purity, 4.47 mmol) in dry MeCN (8.9 ml) was heated in a sealed tube at80°C for 18 h. The reaction mixture was evaporated under reduced pressure and the residue purified by a reverse phase silica gel chromatography (0.25-20% MeCN in water) to yield after lyophilization the title compound as a white solid (1.15 g, 85% purity, 51% yield)1H NMR (400 MHz, CD3CN) δ 10.19 (br s, 1H), 9.45 (br s, 1H), 9.07 (d, J = 1.8 Hz, 1H), 8.67 (d, J =1.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 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 = 7.4 Hz, 3H);13C NMR (101 MHz, 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 Example 33: Preparation of (1R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt 83034 FF -37- A solution of [5-bromo-3-[(S)-ethylsulfinyl]pyridine-2-carboximidoyl]amino] 4-nitrobenzene sulfonate (0.50g, 1.04 mmol, 99% purity) in MeCN (4.2 mL) was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure to yield the title compound (0.40 g, 99% purity, 81% yield) as pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 11.05 (br s, 2 H), 9.45 (d, J=4.3 Hz, 2 H), 8.17 - 8.22 (m, 2 H), 7.83 (d, J=7.8 Hz, 2 H), 4.24 - 4.42 (m, 2 H), 1.44 (t, J=7.27 Hz, 3 H) Example 34: Preparation of (1R)-1-ethyl-1-oxo-6-(trifluoromethyl)isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt pyridine-2-carboximidoyl]amino] 4-nitrobenzenesulfonate(1.0 g, 83% purity, 1.78 mmol) in MeCN (1.78 mL) was heated to 80°C. After stirring for 16h the reaction mixture was concentrated under reduced pressure to yield the title compound (1.01 g, 55% purity, 67% yield) as pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 11.21 (br s, 1 H), 11.18 (br s, 1 H), 9.76 (s, 1 H), 9.67 (d, J=1.4 Hz, 1 H), 8.17 - 8.22 (m, 2 H), 7.80 - 7.86 (m, 2 H), 4.39 - 4.48 (m, 1 H), 4.26 - 4.35 (m, 1 H), 1.47 (t, J=7.3 Hz, 2 H) Example 35: Preparation of (1R)-6-(3-fluorophenyl)-1-methyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt -3-[(S)-methylsulfinyl]-2-pyridyl]methylene]amino] 4- nitrobenzenesulfonate (1.0 g, 92% purity, 1.92 mmol) in MeCN (1.92mL) was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure to yield the title compound (0.48 g, 82% purity, 43% yield) as brown solid.1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1 H), 10.93 (s, 1 H), 9.64 (d, J=2.0 Hz, 1 H), 9.45 (d, J=2.0 Hz, 1 H), 8.18 - 8.22 (m, 2 H), 7.93 - 7.95 (m, 1 H), 7.91 - 7.92 (m, 1 H), 7.81 - 7.86 (m, 3 H), 7.70 (td, J=8.1, 6.1 Hz, 1 H), 7.43 - 7.51 (m, 1 H), 4.21 (s, 3 H) Example 36a: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5- c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile 83034 FF -38- 3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]cyclopropane carbonitrile 4- methylbenzenesulfonic acid salt (0.100 g, 97% purity, 0.23 mmol) in MeCN (0.45 mL) was added at rt N3- methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.050 g, 0.25 mmol), and the reaction mixture was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.060 g, 98% purity, >99.5% ee, 61% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ: 9.26 (s, 1 H), 8.93 (d, J=2.4 Hz, 1 H), 8.40 (d, J=2.3 Hz, 1 H), 8.28 (s, 1 H), 4.56 (s,1 H), 3.80 (s, 3 H), 3.58 (dt, J=15.04, 7.30 Hz, 2 H), 2.00 - 2.05 (m, 2 H), 1.85 - 1.94 (m, 2 H), 1.15 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 272 nm; Run Time: 15 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 5 uL Mobile Phase % A (n-Hexane) % B (EtOH) Composition 65 35 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 6.98 Retention time (min) ~ 5.70 Enantiomeric excess: >99.5% (1st eluting enantiomer) Example 36b: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5- c]pyridin-2-yl]-3-pyridyl]cyclopropanecarbonitrile [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 h. Asolution of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (240 mg, 1.25 mmol) in dry MeCN (1.1 ml) was then added and the resulting reaction mixture was heated at the same temperature for further 20 h. The solution 83034 FF -39- was evaporated under reduced pressure to yield the crude title compound (0.791 g, 41% purity, 65% yield). The crude product was purified via silica gel chromatography using EtOAc and cyclohexane as eluents to yield the title compound (355 mg, 84% purity, >99% ee, 60% yield) as an off-white foam. Example 36c: Preparation of (1R)-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5- - -3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (7.89 g, 96.8% purity, 27.4 mmol) in dry THF (27.4 mL) was added TEA (4.2 mL, 30.2 mmol) at rt under Argon. A solution of p-toluenesulfonyl chloride (5.50 g, 28.0 mmol) in THF (27.4 mL) was slowly added over 5 min while keeping the temperature below 20°C. The resulting suspension was stirred at rt for 16 h. The precipitate (Et3N.HCl) was filtered over celite and washed with a small amount of dry THF. The 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 for the next step without any purification. Step 2: A solution prepared in Step 1 was concentrated to about 1 / 3 volume under reduced pressure. Dry MeCN (20 ml) was added and about half of the volume was evaporated under reduced pressure. This procedure was repeated one more time. N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (6.03 g, 30.6 mmol) and citric acid (0.25 g, 1.28 mmol) were then added. The solvent swap with MeCN was carried out one more time and finally MeCN amount was adjusted to have ca 1M concentration for Step 1 product. The resulting light suspension was stirred at 67°C for 17 h and at 74°C for further 8 h. The resulting thick suspension was diluted with MeCN (12.5 ml) and allowed to cool to 50°C. At this temperature the precipitate (NH4OTs) was filtered off and the filtrate evaporated under reduced pressure to yield a crude title compound (65% purity, 80% chemical yield from step 1 product). The crude material was suspended in n-PrOH (152 ml) and the mixture heated to reflux (97°C) resulting in dissolution of all material. After 10 min the solution was slowly cooled to 50°C over 40 min, seed crystals were added, and the mixture was stirred for further 30 min before cooling to rt over 1 h. The precipitate was filtered and washed on filter with n-PrOH (2 x 20 mL). The precipitate was then dried under high vacuum to yield the title compound (7.93 g, 97% purity, >99.5% ee, 69% isolated yield from step 1 product) as a beige solid. Example 37: Preparation of R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]- 83034 FF -40- bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4-nitrobenzenesulfonic acid salt (0.100 g, 99% purity, 0.22 mmol) in MeCN (0.45 mL) was added at rt N2-methyl-5- (trifluoromethyl)pyridine-2,3-diamine (0.047 g, 0.24 mmol), and the reaction mixture was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.045 g, 94% purity, 99% ee, 43% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.22 (d, J=2.1 Hz, 1 H), 8.87 (d, J=1.5 Hz, 1 H), 8.65 (dd, J = 8.6, 1.9 Hz, 2 H), 3.73 (s, 3 H), 3.54 - 3.71 (m, 2 H), 1.18 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 290 nm; Run Time: 20 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 5 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH 1:1) Composition 70 30 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 8.22 Retention time (min) ~ 11.54 Enantiomeric excess: 98.5 % (1steluting enantiomer) Example 38: Preparation of R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]- ethyl-imino-oxo-λ⁶-sulfane -6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4-nitrobenzenesulfonic acid salt (0.100 g, 99% purity, 0.22 mmol) in MeCN (0.45 mL) was added at rt N3-methyl-6- (trifluoromethyl)pyridine-3,4-diamine (0.049 g, 0.25 mmol), and the reaction mixture was heated to 80°C. After stirring for 16h the reaction mixture was concentrated under reduced pressure. The crude material was purified 83034 FF -41- by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.060 g, 98% purity, 95% ee, 60% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ: 9.27 (s, 1 H), 9.22 (d, J=2.1 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H), 8.28 (s, 1 H), 4.60 (s, 1 H), 3.82 (s, 3 H), 3.51 - 3.68 (m, 2 H), 1.15 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 274 nm; Run Time: 20 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.:4 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH 1:1) Composition 70 30 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 10.4 Retention time (min) ~ 17.14 Enantiomeric excess: 95% (first eluting enantiomer) Example 39: Preparation of R-ethyl-imino-[2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-5- (trifluoromethyl)-3-pyridyl]-oxo-λ⁶-sulfane (1R)-1-ethyl-1-oxo-6-(trifluoromethyl)isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt (0.500 g, 70% purity, 0.75 mmol) in MeCN (3 mL) was added at rt N2-methyl-5- (trifluoromethyl)pyridine-2,3-diamine (0.14 g, 0.75 mmol), and the reaction mixture was heated to 80°C. After stirring for 16h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.070 g, 94% purity, 99% ee, 20% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 9.51 (dd, J=2.06, 0.81 Hz, 1 H), 8.91 (dd, J=2.00.63 Hz, 1 H), 8.75 (d, J=1.6 Hz, 1 H), 8.69 - 8.72 (m, 1 H), 4.70 (s, 1 H), 3.76 (s, 3 H), 3.67 - 3.75 (m, 2 H), 1.10 - 1.22 (m, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm, Flow: 1 ml / min, λMax.:294 nm, Run Time: 10 min, Sample Preparation: 1mg / mL in EtOH, Inj. Vol.: 5 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH 1:1) Composition 80 20 83034 FF -42- Results: First eluting enantiomer Second eluting enantiomer Retention time (min) ~ 6.34 Retention time (min) ~7.29 Enantiomeric excess: 99% (first eluting enantiomer) Example 40: Preparation of R-ethyl-imino-[2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-5- (trifluoromethyl)-3-pyridyl]-oxo-λ⁶-sulfane [3-[(S)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carboximidoyl]amino] 4- nitrobenzenesulfonate salt (0.100 g, 70% purity, 0.15 mmol) in MeCN (0.6 mL) was added at rt N3-methyl-6- (trifluoromethyl)pyridine-3,4-diamine (0.029 g, 0.15 mmol), and the reaction mixture was heated to 80°C. After stirring for 20h the reaction mixture was concentrated under reduced pressure. The crude material was purifiedby neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.042g, >99% ee, 60% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ: 9.51 (d, J=1.2 Hz, 1 H), 9.31 (s, 1 H), 8.74 (d, J=1.8 Hz, 1 H), 8.32 (s, 1 H), 4.70 (s, 1 H), 3.86 (s, 3 H), 3.59 - 3.74 (m, 2 H), 1.18 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 270 nm; Run Time: 15 min; Sample Preparation: 1mg / mL in ETOH; Inj. Vol.: 5 uL Mobile Phase % A (n-Hexane) % B (Ethanol+0.1%DEA) Composition 60 40 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 6.7 Retention time (min) ~10.3 Enantiomeric excess: >99% (1st eluting enantiomer) 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 83034 FF -43- 3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]-2-methyl-propanenitrile 4- methylbenzenesulfonic acid salt (0.200 g, 68% purity, 0.31 mmol) in MeCN (0.63 mL) was added at rt N2- methyl-5-(trifluoromethyl)pyridine-2,3-diamine (0.070 g, 0.35 mmol), and reaction mixture was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.11 g, 98% purity, >99.5 ee, 78 % yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.23 (d, J=2.3 Hz, 1 H), 8.87 (d, J=1.3 Hz, 1 H), 8.65 (d, J=1.5 Hz, 1 H), 8.56 (d, J=2.3 Hz, 1 H), 4.56 (s, 1 H), 3.73 (s, 3 H), 3.55 - 3.71 (m, 2 H), 1.89 (d, J=5.3 Hz, 6 H), 1.14 - 1.17 (m, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 290 nm; Run Time: 40 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.:5 uL Mobile Phase % A (n-Hexane) % B (EtOH) Composition 70 30 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 20.80 Retention time (min) ~27.45 Enantiomeric excess: >99.5% (1st eluting enantiomer, opposite enantiomer below HPLC detection limits) 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 3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]-2-methyl-propanenitrile 4- methylbenzenesulfonic acid salt (0.200 g, 68% purity, 0.31 mmol) in MeCN (0.63 mL) was added at rt N3- methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.070 g, 0.35 mmol), and reaction mixture was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure. The crude material was 83034 FF -44- purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.070 g, 98% purity, >99.5%ee, 50% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.28 (s, 1 H), 9.24 (d, J=2.3 Hz, 1 H), 8.56 (d, J=2.3 Hz, 1 H), 8.29 (s, 1 H), 4.56 (s, 1 H), 3.83 (s, 3 H), 3.52 - 3.70 (m, 2 H), 1.89 (d, J=5.1 Hz, 5 H), 1.17 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 290 nm, Run Time: 40 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.:5 uL Mobile Phase % A (n-Hexane) % B (EtOH) Composition 70 30 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 23.7 Retention time (min) ~29.60 Enantiomeric excess: >99.5% (1st eluting enantiomer, opposite enantiomer below HPLC detection limits) 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- ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzenesulfonic acid salt (0.200 g, 79% purity, 0.33 mmol) in MeCN (2 mL) was added at rt N2-methyl- 5-(trifluoromethyl)pyridine-2,3-diamine (0.080 g, 0.36 mmol), and reaction mixture was heated to 80°C. After stirring for 24h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.060 g, 95% purity, >99.5% ee, 38% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.86 - 8.90 (m, 2 H), 8.64 (d, J=1.6 Hz, 1 H), 8.29 (d, J=2.7 Hz, 1 H), 4.58 (s, 1 H), 3.73 (s, 3 H), 3.58 - 3.71 (m, 2 H), 1.88 (d, J=2.7 Hz, 6 H), 1.14 - 1.18 (m, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 290 nm; Run Time: 10 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.:5 uL Mobile Phase % A (TBME) % B (EtOH) Composition 95 5 83034 FF -45- Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 5.27 Retention time (min) ~4.64 Enantiomeric excess: >99.5% (1st eluting enantiomer, opposite enantiomer below HPLC detection limits) 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- 3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzenesulfonic acid salt (0.200 g, 79% purity, 0.33 mmol) in MeCN (2 mL) was added at rt N3-methyl- 6-(trifluoromethyl)pyridine-3,4-diamine (0.080 g, 0.36 mmol), and the reaction mixture was heated to 80°C, and stirred for 24h, and the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.070 g, 99% purity, 99% ee, 47% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.26 (s, 1 H), 8.89 (d, J=2.6 Hz, 1 H), 8.26 - 8.30 (m, 2 H), 4.56 (s, 1 H), 3.82 (s, 3 H), 3.52 - 3.69 (m, 2 H), 1.88 (d, J=2.9 Hz, 6 H), 1.12 - 1.19 (m, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: ; λMax.: 274 nm; Run Time: 12 min; Sample Preparation: Inj. Vol.: 2 uLMobile Phase % A (TBME) % B (Ethanol+0.1%DEA) Composition 90 10 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 5.73 Retention time (min) ~6.83 Enantiomeric excess: 99 % Example 45: Preparation of R-[5-(3-fluorophenyl)-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3- pyridyl]-imino-methyl-oxo-λ⁶-sulfane 83034 FF -46- -6-(3-fluorophenyl)-1-methyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt (0.200 g, 99% purity, 0.42 mmol) in MeCN (1.7 mL) was added at rt N2-methyl- 5-(trifluoromethyl)pyridine-2,3-diamine (0.080 g, 0.42 mmol), and reaction mixture was heated to 80°C. After stirring for 7 h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.080 g, 99%purity, 97% ee, 40% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.39 (d, J=2.1 Hz, 1 H), 8.88 (d, J=1.4 Hz, 1 H), 8.75 (d, J=2.3 Hz, 1 H), 8.66 (d, J=1.5 Hz, 1 H), 7.85 - 7.91 (m, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.67 (td, J=8.0, 6.2 Hz, 1 H), 7.41 (br d, J=2.5 Hz, 1 H), 4.53 - 4.56 (m, 1 H), 3.78 (s, 3 H), 3.47 - 3.52 (m, 3 H)Method of Chiral Analysis: Column: Cellulose LUX (4.6mm x 250mm) 3µm; Flow: 0.7 ml / min; λ Max.: 294 nm; Run Time: 25 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 10 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH) Composition 75 25 Results: First eluting enantiomer (S) Second eluting enantiomer (R) Retention time (min) ~ 9.0 Retention time (min) ~10.71 Enantiomeric excess: 97 % (2ndeluting enantiomer) Example 46: Preparation of R-[5-(3-fluorophenyl)-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3- pyridyl]-imino-methyl-oxo-λ⁶-sulfane -6-(3-fluorophenyl)-1-methyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4- nitrobenzenesulfonic acid salt (0.200 g, 99% purity, 0.42 mmol) in MeCN (1.7 mL) was added at rt N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (0.080 g, 0.42 mmol), and the reaction mixture was heated to 80°C. After stirring for 16 h the reaction mixture was concentrated under reduced pressure. The crude material was 83034 FF -47- purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.075 g, 99% purity, 99% ee, 40% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ: 9.39 (d, J=2.08 Hz, 1 H), 9.29 (s, 1 H), 8.75 (d, J=2.20 Hz, 1 H), 8.29 (s, 1 H), 7.88 (br d, J=9.9 Hz, 1 H), 7.81 (d, J=7.8 Hz, 1 H), 7.67 (d, J=6.1 Hz, 1 H), 7.41 (br d, J=2.6 Hz, 1 H), 4.03 (d, J=7.0 Hz, 1 H), 3.87 (s, 3 H), 3.47 (s, 3 H) Method of Chiral Analysis: Column: Cellulose LUX (4.6mm x 250mm) 3µm; Flow: 0.7 ml / min; λ Max.: 275 nm; Run Time: 22 min; Sample Preparation: 1mg / mL in ETOH; Inj. Vol.:10 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH) Composition 75 25 Results: First eluting enantiomer (S) Second eluting enantiomer (R) Retention time (min) ~ 11.65 Retention time (min) ~13.54 Enantiomeric excess: 99% (2ndeluting enantiomer) Example 47: Preparation of R-2-[[6-(6-chloro-3-methyl-imidazo[4,5-b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3- pyridyl]oxy]-2-methyl- -1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]oxy-2-methyl-propanenitrile 4-nitrobenzenesulfonic acid salt (0.200 g, 85% purity, 0.35 mmol) in MeCN (1.4 mL) was added at rt 5-chloro- N2-methyl-pyridine-2,3-diamine (0.062 g, 0.38 mmol), and the reaction mixture was heated to 80°C. After stirring for 7 h the reaction mixture was concentrated under reduced pressure, and the crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.900 g, 99% purity, 99.2% ee, 60% yield) as pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ: 8.88 (d, J=2.7 Hz, 1 H), 8.52 (d, J=2.2 Hz, 1 H), 8.37 (d, J=2.2 Hz, 1 H), 8.28 (d,J=2.7 Hz, 1 H), 4.56 (s, 1 H), 3.58 - 3.71 (m, 5 H), 1.88 (d, J=3.0 Hz, 6 H), 1.16 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-Lux-Cellulose (4.6mm x 250mm) 3-5µm; Flow: 1 ml / min; λMax.: 306 nm; Run Time: 30 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 10 uL Mobile Phase % A (TBME) % B (EtOH +0.1% DEA) Composition 95 5 83034 FF -48- Results: First eluting enantiomer (S) Second eluting enantiomer (R) Retention time (min) ~ 8.45 Retention time (min) ~11.59 Enantiomeric excess: 99.2 % (2ndeluting enantiomer) Example 48: Preparation of R-[5-bromo-2-(3-ethylimidazo[4,5-b]pyridin-2-yl)-3-pyridyl]-ethyl-imino-oxo-λ⁶- sulfane (1R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine;4-nitrobenzenesulfonic acid (0.100 g, 99% purity, 0.44 mmol) in MeCN (0.90 mL) was added at rt N2-ethylpyridine-2,3-diamine (0.070 g, 0.49 mmol), and the reaction mixture was stirred at 80°C for 24 h. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.065 g, 96% purity, >99% ee, 40% yield) as pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.20 (d, J=2.3 Hz, 1 H), 8.64 (d, J=2.3 Hz, 1 H), 8.47 (dd, J=4.8, 1.50 Hz, 1 H) , 8.16 (dd, J=8.0, 1.44 Hz, 1 H) , 7.38 (dd, J=8.0, 4.7 Hz, 1 H) , 4.59 (s, 1 H) , 4.13 - 4.24 (m, 2 H), 3.72 (q, J=7.1 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H) , 1.18 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 294 nm; Run Time: 25 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 7 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH 1:1) Composition 70 30 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 12.37 Retention time (min) ~16.57 Enantiomeric excess: 99.5% (1steluting enantiomer) Example 49: Preparation of R-2-[[6-(3-ethylimidazo[4,5-b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2- methyl-propanenitrile 83034 FF -49- of 2-[(1R)-1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]oxy-2-methyl- propanenitrile;4-nitrobenzenesulfonic acid (0.100 g, 80% purity, 0.17 mmol) in MeCN (1.0 mL) was added at rt N2-ethylpyridine-2,3-diamine (0.025 g, 0.18 mmol), and the reaction mixture was heated to 80°C. After stirring for 7 h the reaction mixture was concentrated under reduced pressure. The crude material was purified byneutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.045 g, 99% purity, 99.3% ee, 68% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.86 (d, J=2.7 Hz, 1 H), 8.46 (dd, J=4.7, 1.41 Hz, 1 H), 8.29 (d, J=2.7 Hz, 1 H), 8.14 (dd, J=8.0, 1.3 Hz, 1 H), 7.36 (dd, J=7.9, 4.8 Hz, 1 H), 4.54 (s, 1 H), 4.13-4.23 (m, 2 H), 3.63 - 3.76 (m, 2 H), 1.87 (d, J= 6.0 Hz, 6 H), 1.30 - 1.35 (m, 3 H), 1.14 - 1.18 (m, 3 H) Method of Chiral Analysis: Column: Chiralpack-Lux-Cellulose (4.6mm x 250mm) 3-5µm; Flow: 1 ml / min; λMax.:295 nm; Run Time: 30 min; Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 4 uL Mobile Phase % A (TBME) % B (EtOH + 0.1% DEA) Composition 95 5 Results: First eluting enantiomer (S) Second eluting enantiomer (R) Retention time (min) ~ 11.81 Retention time (min) ~13.14 Enantiomeric excess: 99.3 % (2ndeluting enantiomer) Example 50: Preparation of 4-[(Z)-[(1R)-6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-ylidene]amino]-N- methyl-6-(trifluoromethyl)pyridin-3-amine -6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-imine 4-nitrobenzenesulfonic acid salt (0.100 g, 99% purity, 0.22 mmol) in MeCN (0.45 mL) was added at rt N3-methyl-6- (trifluoromethyl)pyridine-3,4-diamine (0.047 g, 0.24 mmol), and the reaction mixture was heated to 50°C. After 83034 FF -50- stirring for 8 h, the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.020 g, 99% purity, 43% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ: 8.93 (d, J=2.1 Hz, 1 H), 8.90 (s, 1 H), 8.65 (d, J=2.3 Hz, 1H), 8.03 (s, 1 H), 3.80 (s, 3 H), 3.57 - 3.78 (m, 2 H), 2.64 (br s, 1 H), 1.30 (t, J=7.4 Hz, 3 H) Example 51: Preparation of R-[5-bromo-2-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]- ethyl-imino-oxo-λ⁶-sulfane -6-bromo-1-ethyl-1-oxo-isothiazolo[4,5-b]pyridin-3-ylidene]amino]-N-methyl-6- (trifluoromethyl)pyridin-3-amine (0.040 g, 99% purity) in MeCN (1.0 mL) was heated to 80°C. After stirring for8 h the reaction mixture was concentrated under reduced pressure. The crude material was purified by neutral silica gel chromatography using cyclohexane and EtOAc as eluent to yield the title compound (0.025 g, 99% purity, 99.5% ee, 63% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1 H), 9.22 (d, J=2.1 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H), 8.28 (s, 1 H), 4.61 (s, 1 H), 3.81 (s, 3 H), 3.54 - 3.67 (m, 2 H), 1.15 (t, J=7.4 Hz, 3 H) Method of Chiral Analysis: Column: Chiralpack-IG (4.6mm x 250mm) 5µm; Flow: 1 ml / min; λMax.: 274 nm; Run Time: 25 min, Sample Preparation: 1mg / mL in EtOH; Inj. Vol.: 5 uL Mobile Phase % A (n-Hexane) % B (EtOAc +EtOH 1:1) Composition 70 30 Results: First eluting enantiomer (S) Second eluting enantiomer (R) Retention time (min) ~ 10.4 Retention time (min) ~ 17.14 Enantiomeric excess: 99.5% (2ndeluting enantiomer) Example 52a: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo [4,5-b]pyridin- 2-yl]-3-pyridyl]cyclopropanecarbonitrile 83034 FF -51- 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]-N'-hydroxy-pyridine-2-carboxamidine (2.995 g, 97% purity, >99.5% ee, 10.4 mmol) in dry THF (13.2 ml) was added TEA (1.53 ml, 10.95 mmol). To this suspension was slowly added a 2.0 M solution of pTsCl in dry THF (5.2 ml, 10.5 mmol) at rt. After stirring for 24 h the formed precipitate (Et3N.HCl) was filtered off and washed on 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 (ca 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 intermediate prepared in Step 1 (11.16 g, 19.4% concentration, 5.00 mmol) was added dry sulfolane (5.0 ml). THF was then removed at 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 h. Methanol was then removed at reduced pressure (50°C, 20 mbar), the remaining mixture cooled to rt, and water (11 ml) added while stirring vigorously. After stirring for 2 h and aging for a further hr, the precipitate was filtered, washed on filter with sulfolane / water 3:7 (5 ml) and water (2 x 5 ml). The precipitate was then dried under high vacuum to yield the title compound (1.605 g, 95% purity, >99.5% ee, 70% yield) as a gray powder. Another 0.48 g of title compound (22% yield) remained in the mother and wash liquors.1H NMR (400 MHz, Solvent) δ 1.36 (t, J=7.3 Hz, 3 H), 1.61 - 1.70 (m, 2 H), 1.97 - 2.08 (m, 2 H), 3.82 - 3.98 (m, 4 H), 8.31 (d, J=1.45 Hz, 1 H), 8.34 (d, J=2.2 Hz, 1 H), 8.76 (d, J=1.1 Hz, 1 H), 8.98 (d, J=2.2 Hz, 1 H)Method of Chiral Analysis: Column: Chiralpack-IG (0.46cm x 10cm) 3µm; Flow: 2 ml / min; λMax.: 290 nm;Sample Preparation: 1mg / mL in MeOH; Inj. Vol.: 2 uL Mobile Phase % A (CO2) % B (MeOH) Composition 75 25 Results: First eluting enantiomer (R) Second eluting enantiomer (S) Retention time (min) ~ 2.35 Retention time (min) ~ 3.43 Enantiomeric excess: >99.5% (1steluting enantiomer, the other enantiomer below detection limits) Example 52b: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo [4,5-b]pyridin- 2-yl]-3-pyridyl]cyclopropanecarbonitrile 83034 FF -52- Example 52a Step 2 could be run under the following alternative conditions: Anisole / MeOH (1:1), 80°C, 16 h: 92% yield Benzonitrile / MeOH (1:1), 80°C, 12 h: 91% yield Sulfolane / nPrOH (1:1), 80°C, 10 h: 85% yield Anisole / ethylene glycol (1:1), 80°C, 22 h: 91% yield Example 52c: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo [4,5-b]pyridin- 2-yl]-3-pyridyl]cyclopropanecarbonitrile (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 h. The reaction mixture was cooled to rt and the formed precipitate (TsOH.NH3) was filtered off and washed on filter with MeCN. The filtrate was evaporated under reduced pressure to yield the title compound (1.21 g, 75% purity,>99.5% ee, 84% yield).Example 52d: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo [4,5-b]pyridin- 2-yl]-3-pyridyl]cyclopropanecarbonitrile 3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]cyclopropanecarbonitrile 4- methylbenzenesulfonic acid salt (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 h. The reaction mixture was then cooled to rt and solvent removed under reduced pressure. Analysis of crude residue with quantitative NMR using trimethoxybenzene as an internal standard indicated formation of the title compound (78.9 mg, 91% yield). 83034 FF -53- 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] -1-ethyl-3-imino-1-oxo-isothiazolo[4,5-b]pyridin-6-yl]cyclopropanecarbonitrile 4- methylbenzenesulfonic acid salt (0.220 g, 0.509 mmol) and N2-methyl-5-(trifluoromethyl) pyridine-2,3-diamine (0.115 g.0.598 mmol) in dry sulfolane (1.1 ml) was added TEA (13 ml, 0.097 mmol). The resulting solution was heated at 60°C for 3 h. The reaction mixture was cooled to rt and quenched by addition of aqueous saturated NaHCO3 and iPrOAc. The organic phase was separated, washed with water and dried over anhydrous Na2SO4. The solution was evaporated under reduced pressure and the crude product purified by reverse phase HPLC(water / MeCN as a mobile phase) to obtain the title compound (0.182 g, 95% purity, 78% yield) as a white fluffysolid.1H NMR (400 MHz, d6-DMSO) δ 9.11 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 1.1, 2.2 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 6.60 (q, J = 4.7 Hz, 1H), 4.26 - 4.02 (m, 2H), 2.95 (d, J = 4.7 Hz, 3H), 2.05 - 1.96 (m, 2H), 1.92 - 1.85 (m, 1H), 1.85 - 1.79 (m, 1H), 1.15 (t, J = 7.3 Hz, 3H);13C NMR (101 MHz, 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 = 271.3 Hz, 1C), 123.05 (br d, J = 3.0 Hz, 1C), 121.16, 112.04 (q, J = 31.2 Hz, 1C), 47.92, 27.86, 19.48, 18.95, 11.93, 7.00 Example 54: Preparation of R-1-[5-(ethylsulfonimidoyl)-6-[7-methyl-3-(trifluoromethyl)imidazo [4,5-c]pyridazin- 6-yl]-3-pyridyl]cyclopropanecarbonitrile (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 h. The reaction mixture was cooled to rt and solvent evaporated under reduced pressure. The crude residue was purified by silica gel chromatography using EtOAc and cyclohexane as eluents to yield the title compound (52.7 mg, 27% yield) as a gray powder.1H NMR (400 MHz, CDCl3) δ 1.38 (td, J=7.27, 1.82 Hz, 3 H), 1.71 (br s, 2 H), 2.07 (br s, 2 H), 3.61 - 3.93 (m, 2 H), 4.04 (s, 3 H), 8.18 (d, J=1.82 Hz, 1 H), 8.37 (br d, J=1.82 Hz, 1 H), 9.02 (br d, J=1.82 Hz, 1 H) 83034 FF -54- Example 55: Preparation of 1-[5-(ethylsulfonimidoyl)-6-[6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]-3- pyridyl]cyclopropanecarbonitrile [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 closed vial at 90°C for 4 h. The reaction mixture was cooled to rt and the resulting precipitated was filtered off and dried under high vacuum to yield 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 eluents).1H NMR (600 MHz, METHANOL-d4) δ 1.35 (t, J=7.4 Hz, 3 H) 1.71 - 1.79 (m, 2 H) 1.96 - 2.04 (m, 2 H) 3.80 -4.17 (m, 2 H) 8.35 (br s, 1 H) 8.39 (d, J=2.4 Hz, 1 H) 8.73 (s, 1 H) 8.98 (d, J=2.2 Hz, 1 H);13C NMR (151 MHz, DMSO-d6) δ 7.5 (s, 1 C) 11.7 (s, 1 C) 19.1 (d, J=15 Hz, 1 C) 51.2 (s, 1 C) 120.1 (q, J=32 Hz, 1 C) 121.2 (s, 1 C) 124.5 (q, J=272 Hz, 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) Example 56: Preparation of R-1-[6-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3- pyridyl]cyclopropanecarbonitrile (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 closed via at 80°C for 36 h. The reaction mixture was cooled to rt and solvent evaporated under reduced pressure. The crude residue was purified by silica gel chromatography using EtOAc and cyclohexane as eluents to yield the title compound (99 mg, 83% purity, 43% yield) as a gray powder.1H NMR (400 MHz, methanol-d4) δ 1.30 (t, J=7.3 Hz, 3 H), 1.77 - 1.89 (m, 2 H), 1.97 - 2.08 (m, 2 H), 3.87 - 4.16 (m, 2 H), 7.77 (d, J=2.2 Hz, 1 H), 8.47 (d, J=2.2 Hz, 1 H), 8.68 (d, J=2.2 Hz, 1 H), 9.13 (d, J=2.2 Hz, 1 H) Table P: Compounds of formula (I) prepared according to the present invention Entry IUPAC-name Structure 83034 FF -55- 1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-1 (trifluoromethyl)imidazo[4,5-c]pyridin-2- yl]-3-pyridyl]cyclopropanecarbonitrile [5-bromo-2-[3-methyl-6- P-2 (trifluoromethyl)imidazo[4,5-b]pyridin-2- yl]-3-pyridyl]-ethyl-imino-oxo-λ⁶-sulfane [5-bromo-2-[3-methyl-6- P-3 (trifluoromethyl)imidazo[4,5-c]pyridin-2- yl]-3-pyridyl]-ethyl-imino-oxo-λ⁶-sulfane ethyl-imino-[2-[3-methyl-6- (trifluoromethyl)imidazo[4,5-b]pyridin-2- P-4 yl]-5-(trifluoromethyl)-3-pyridyl]-oxo-λ⁶- sulfane ethyl-imino-[2-[3-methyl-6- (trifluoromethyl)imidazo[4,5-c]pyridin-2- P-5 yl]-5-(trifluoromethyl)-3-pyridyl]-oxo-λ⁶- sulfane 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-6 (trifluoromethyl)imidazo[4,5-b]pyridin-2- yl]-3-pyridyl]-2-methyl-propanenitrile 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-7 (trifluoromethyl)imidazo[4,5-c]pyridin-2- yl]-3-pyridyl]-2-methyl-propanenitrile 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-8 (trifluoromethyl)imidazo[4,5-b]pyridin-2- yl]-3-pyridyl]oxy]-2-methyl-propanenitrile 83034 FF -56- 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-9 (trifluoromethyl)imidazo[4,5-c]pyridin-2- yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [5-(3-fluorophenyl)-2-[3-methyl-6- (trifluoromethyl)imidazo[4,5-b]pyridin-2- P-10 yl]-3-pyridyl]-imino-methyl-oxo-λ⁶- sulfane [5-(3-fluorophenyl)-2-[3-methyl-6- (trifluoromethyl)imidazo[4,5-c]pyridin-2- P-11 yl]-3-pyridyl]-imino-methyl-oxo-λ⁶- sulfane 2-[[6-(6-chloro-3-methyl-imidazo[4,5- P-12 b]pyridin-2-yl)-5-(ethylsulfonimidoyl)-3- pyridyl]oxy]-2-methyl-propanenitrile [5-bromo-2-(3-ethylimidazo[4,5- P-13 b]pyridin-2-yl)-3-pyridyl]-ethyl-imino-oxo- λ⁶-sulfane 2-[[6-(3-ethylimidazo[4,5-b]pyridin-2-yl)- P-14 5-(ethylsulfonimidoyl)-3-pyridyl]oxy]-2- methyl-propanenitrile 1-[5-(ethylsulfonimidoyl)-6-[3-methyl-6- P-15 (trifluoromethyl)imidazo[4,5-b]pyridin-2- yl]-3-pyridyl]cyclopropanecarbonitrile 1-[5-(ethylsulfonimidoyl)-6-[7-methyl-3- P-16 (trifluoromethyl)imidazo[4,5-c]pyridazin- 6-yl]-3-pyridyl]cyclopropanecarbonitrile83034 FF

Claims

83034 FF -58- CLAIMS 1. A process for the preparation of enantiomerically enriched sulfoximines of formula (I) *R1is halogen, C1-C6-haloalkyl, cyano-C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2is C1-C4-alkyl; R3is hydrogen or C1-C4-alkyl; R4is hydrogen, halogen, or C1-C4-haloalkyl; S* is a stereogenic sulfur atom which is in R- or S-configuration; X1and X2are independently selected from CH or N, with the proviso that at least one of X1and X2is nitrogen, wherein said process comprises reacting a compound of formula (V) or a compound of formula (VI)from C1-C4-alkyl or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, or methyl; with a compound of formula (VII) ,defined for a compound of formula (I), in an appropriate solvent at an appropriate temperature to produce a compound of formula (I).83034 FF -59- 2. The process according to claim 1, wherein the compound of formula (VI) is reacted with a compound of formula (VII) to yield a compound of formula (I) via an intermediate of formula (VIII) , as defined for a compound of formula (I).

3. The process according to claim 1, wherein a compound of formula (IV) * , defined for a compound of formula (I), is reacted with a sulfonyl chloride(IX),is selected from C1-C4-alkyl or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, or methyl; in the presence of a base and in a solvent to produce a compound of formula (V)4. The process according to claim 1, wherein a sulfinyl compound of formula (III)83034 FF -60- ,defined for a compound of formula (I), is reacted with hydroxylamine in a solvent at an appropriate temperature to produce a compound of formula (IV).

5. The process according to claim 1, wherein a sulfanyl compound of formula (II) ;defined for compounds of formula (I); is stereoselectively oxidized in the presence of an oxidant, in the presence of a chiral reagent or catalyst, optionally in the presence of a suitable acid additive, in a solvent (or diluent); to produce a sulfinyl compound of formula (III) .

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

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

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

9. The process according to claim 3, wherein the ratio of the compound of formula (IX) used, compared to the compound of formula (IV), is in the range from 3:1 to 1:1.83034 FF -61- 10. The process according to claim 3 or claim 9, wherein the base is selected from trialkylamines such as triethylamine and tributylamine, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxide such as potassium hydroxide and sodium hydroxide.

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

1.

12. The process according to any one of claims 3, 9, 10 or 11, wherein the solvents (or diluents) are selected from esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.

13. The process according to claims 4, wherein the reaction is carried out with an aqueous solution of hydroxylamine in an appropriate solvent at an appropriate temperature.

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

1.

15. The process according to claims 4, wherein a free base hydroxylamine hydrochloride or hydroxylamine sulfate in combination with 1 eq (relative to hydroxylamine salt) of an appropriate base is used in place of hydroxylamine.

16. The process according to claims 15, wherein the bases is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.

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

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

19. A process for the preparation of a compound of formula (IV)83034 FF -62- C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl,or with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2 is C1-C4alkyl; andS* is a stereogenic sulfur atom which is in R- or S-configuration; which process comprises reacting the compound of formula (III) (III), wherein R1, R2and S* are as defined for compounds of formula (IV), withappropriate solvent at an appropriate temperature to produce a compound of formula (IV).

20. A compound of formula (VIII);R1is halogen, C1-C6-haloalkyl, cyano-C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2is C1-C4 alkyl; R3 is hydrogen or C1-C4 alkyl;R4is hydrogen, halogen, or C1-C4-haloalkyl; S* is a stereogenic sulfur atom which is in R- or S-configuration; and X1and X2are independently CH or N, with the proviso that at least one of X1and X2is nitrogen.83034 FF -63- 21. A compound of formula (VI) * whereinR1is halogen, C1-C6-haloalkyl, cyano-C1-C6-alkyl, cyano-C1-C6-alkoxy, cyano-C3-C6-cycloalkyl, or aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-C3-alkyl, or C1-C3-alkoxy; R2is C1-C4 alkyl; R5is C1-C4-alkyl or phenyl, wherein said phenyl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, cyano, nitro, or methyl; and S* is a stereogenic sulfur atom which is in R- or S-configuration.

Images