Diazinone compounds for the control of invertebrate pests

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

[0001] Diazinone compounds for the control of invertebrate pests

[0002] Description

[0003] The invention relates to compounds of formula I wherein

[0004] R1is H, OH, NR12R13; C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6 - halocycloalkyl, C1-C5-alkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, C1-C4-alkyl-C3-C6- cycloalkyl, C3-C6-halocycloalkyl-C1-C4-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, which groups are unsubstituted, or partially or fully substituted with R11; or C(=N-R11)R12, C(O)R11a;

[0005] R10is H, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C3- C4-cycloalkyl-C1-C2-alkyl, C3-C4-halocycloalkyl-C1-C2-alkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4-haloalkyl, C(O)-C3-C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, SOm- C1-C4-alkyl, SOm-C1-C4-haloalkyl, SOm-C3-C6-cycloalkyl, or phenyl which is unsubstituted or partially or fully substituted with R3a;

[0006] R11is halogen, CN, NO2, NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; C1-C6-alkyl; C1-C6-haloalkyl; C2-C6-alkenyl; C2-C6-haloalkenyl; C2-C6-alkynyl; C2-C6-haloalkynyl; C3-C4-cycloalkyl-C1-C2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, 5- or 6- membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN;

[0007] R11ais NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; C1-C6-haloalkyl; C2- C6-alkenyl; C2-C6-haloalkenyl; C2-C6-alkynyl; C2-C6-haloalkynyl; C3-C4- cycloalkyl-C1-C2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN;

[0008] R12, R13are independently from each other H, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- haloalkoxy, C1-C4-haloalkyl, C3-C6-cycloalkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4- haloalkyl, C(O)-C3-C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, C(O)NH-C1-C4- alkyl, C(O)NH-C1-C4-haloalkyl, C(O)N(C1-C4-alkyl)-C1-C4-alkyl, C(O)N(C1-C4- haloalkyl)-C1-C4-alkyl, C(O)N(C1-C4-haloalkyl)-C1-C4-haloalkyl, C(O)NH-C1-C4- alkoxy, C(O)NH-C1-C4-haloalkoxy, C(O)NH-C1-C4-alkoxy-C1-C4-alkyl, C(O)NH- C1-C4-alkoxy-C1-C4-haloalkyl; C(O)NH-phenyl, C(O)NH-3-6-membered heterocyclyl or 5- or 6-membered hetaryl, C(O)NH-C1-C4-alkyl-phenyl, C(O)NH-C1-C4-alkyl-3-6-membered heterocyclyl or 5- or 6-membered hetaryl which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4-cycloalkyl, S(O)m-C3-C4- halocycloalkyl; 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3- haloalkyl, and / or CN; or or R12and R13together with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7-membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatomcontaining groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a; m is 0, 1 , or 2;

[0009] R2is H, C1-C3-alkyl, C1-C3-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, or C2-C3- alkynyl; each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6- cycloalkyl, C1-C6-haloalkyl, C3-C6-halocycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1- C4-alkoxy, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C6-cycloalkyl, 3- to 6- membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, -N=S(O)R12aR13a; or two R3bound to two adjacent C-atoms can form a 4-, 5-, or 6-membered ring, which may contain one or two heteroatoms selected from N, O, and S as ring members, which ring is unsubstituted or substituted with halogen, CN, C1-C3-alkyl, or C1-C3- haloalkyl;

[0010] R12a, R13aare independently from each other C1-C4-alkyl, C1-C4-haloalkyl, C3-C6- cycloalkyl, unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; or R12aand R13atogether with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7-membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatomcontaining groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a;

[0011] R14is as defined for R10;

[0012] R15is H, C1-C4-alkyl, or C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, which carbon chains are unsubstituted or partially or fully substituted with R11; or 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with R3a;

[0013] R3ais halogen, CN, NO2, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkoxy, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, S(O)m-C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4-cycloalkyl, S(O)m-C3- C4-halocycloalkyl; n is 0, 1 , 2, or 3;

[0014] X is N, CH, or CR3c;

[0015] R3cis as defined for R3;

[0016] R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl-C1-C2-alkyl, C1-C2- alkyl-C3-C6-cycloalky, C3-C6-cycloalkyl, C1-C3-haloalkyl, C3-C6-halocycloalkyl which are unsubstituted or partially or fully substituted with R3;

[0017] HET is a group HA or HB wherein # is the bond to the CH(R2)amide spacer, and % is the bond to the diazinone ring;

[0018] R5is H, halogen, CN, C1-C3-alkyl, C1-C3-haloalkyl, or C3-C6-cycloalkyl;

[0019] R5a,R5b,R5care independently from each other a group R5;

[0020] Z is N, or CR5c;

[0021] R6,R7are independently from each other H, halogen, CN, Ci-Cs-alkyl, CCi-Cs aloalkyl, or C3-C6-cycloalkyl; or

[0022] R6and R7together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered saturated or unsaturated carbocycle, which is unsubstituted or substituted with one or more halogen, CN, C1-C4-alkyl, or C1-C4-haloalkyl;

[0023] Y is O, S, or N-RN;

[0024] RNis as defined for R4; and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.

[0025] The invention also provides agricultural compositions comprising at least one compound of formula I, a stereoisomer thereof and / or an agriculturally acceptable salt thereof and at least one liquid and / or solid carrier, especially at least one inert liquid and / or solid agriculturally acceptable carrier.

[0026] The invention also provides a veterinary composition comprising at least one compound of formula I, a stereoisomer thereof and / or a veterinarily acceptable salt thereof and at least one liquid and / or solid carrier, especially at least one inert veterinarily liquid and / or solid acceptable carrier. The invention also provides a method for controlling invertebrate pests which method comprises treating the pests, their food supply, their habitat or their breeding ground or a cultivated plant, plant propagation materials (such as seed), soil, area, material or environment in which the pests are growing or may grow, or the materials, cultivated plants, plant propagation materials (such as seed), soils, surfaces or spaces to be protected from pest attack or infestation with a pesticidally effective amount of a compound of formula I or a salt thereof as defined herein.

[0027] The invention also relates to plant propagation material, in particular seed, comprising at least one compound of formula I and / or an agriculturally acceptable salt thereof.

[0028] The invention further relates to a method for treating or protecting an animal from infestation or infection by parasites which comprises bringing the animal in contact with a parasiticidally effective amount of a compound of formula I or a veterinarily acceptable salt thereof. Bringing the animal in contact with the compound I, its salt or the veterinary composition of the invention means applying or administering it to the animal.

[0029] WO2023 / 037249, WO2023 / 072849, and W02023 / 200911 describe structurally closely related active compounds, wherein the diazinone ring is designed differently. These compounds are mentioned to be useful for combating invertebrate pests.

[0030] Nevertheless, there remains a need for highly effective and versatile agents for combating invertebrate pests. It is therefore an object of the invention to provide compounds having a good pesticidal activity and showing a broad activity spectrum against a large number of different invertebrate pests, especially against difficult to control pests, such as insects.

[0031] It has been found that these objects can be achieved by compounds of formula I as depicted and defined below, and by their stereoisomers, salts, tautomers and N-oxides, in particular their agriculturally acceptable salts.

[0032] Formula I correspond to formulae I. A and LB.

[0033] In formula I the groups R5a, R5b, and R5crepresent independently from each other a group R5, and Z represent N or C-R5c.

[0034] Compounds I. A with Y=O (formula I. Ao) can be prepared via an intramolecular O-alkylation of the amide compound II with suitable leaving groups X”. In formula II R1, R2, and R3have the meaning as in formula I, and X” is a nucleophilic leaving group, such as a halide, preferably Br or Cl. The alkylation can be carried out under conditions known from literature.

[0035] This transformation is usually carried out at temperatures of from 0°C to 100°C, preferably from 50°C to the boiling point of the solvent, in an inert solvent, in the presence of a base [cf. European Journal of Med. Chemistry 1988, Vol.23. p.441-451 ; W02020157201],

[0036] Suitable solvents are alcohols such as methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol, n-butanol, and tert.-butanol, moreover dimethyl sulphoxide (DMSO), dimethyl formamide (DMF), and dimethylacetamide (DMA), preferably EtOH and DMF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, alkali metal and alkaline earth metal carbonates, such as IJ2CO3, Na2CO3, K2CO3, and CaCOs, and also alkali metal bicarbonates, such as NaHCO3. Particular preferences are given to NaHCOs and K2CO3. The bases are generally employed in equimolar amounts or in excess.

[0037] Compounds II can be obtained from Compounds III via an acylation reaction. Suitable acylating reagents Illa are acyl halides (preferably acyl chlorides) or anhydrides. In formula Illa

[0038] Y” can be chloride or an alkoxy residue.

[0039] This transformation is usually carried out at temperatures of from 30°C to 50°C, preferably from 40°C to 45°C, in an inert solvent, in the presence of a base [W02006045587, Journal fur Praktische Chemie (Leipzig) (1985), 327(1), 109-16],

[0040] Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, or ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and tetrahydrofuran (THF), preferably methylene chloride or THF. Suitable bases are, in general, organic bases, for example tertiary amines, such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to TEA. The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent. The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of Illa, based on III.

[0041] Compounds III can be obtained from compounds IV via activation of the carbocyclic acid as acid chloride or via conventional amide coupling reagents.

[0042] The activation is usually carried out at temperatures of from 0°C to 100°C, preferably from 0°C to 25°C, in DMF or methylene chloride, in the presence of SOCh or oxalyl chloride [Journal of Catalysis (2023), 423, 19-25, Advanced Synthesis & Catalysis (2023), 365(1), 43-52],

[0043] The activation with amide coupling reagents is usually carried out at temperatures of from 0°C to 100°C, preferably at about 25°C, in DMF in the presence of 1-[bis(dimethylamin)methylen]- 1 H-1 ,2,3-triazol[4,5-b]pyridinium-3-oxid-hexafluorophosphate [WO2021163302],

[0044] The reaction with IVa is usually carried out at temperatures of from 0°C to 30°C, preferably at about 0°C in DMF, in the presence of a base [Organic Letters (2021), 23(3), 974-978],

[0045] Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, or ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and tetrahydrofuran (THF), preferably methylene chloride or THF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, organic bases, for example tertiary amines, such as trimethylamine (TMA), triethylamine (TEA), diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preferences are given to TEA and pyridine. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent. The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of IVa, based on IV.

[0046] Alternatively, compounds IV can be converted directly to compounds II with a suitable, substituted acyl hydrazine 11 lb under similar reaction conditions as described above.

[0047] Compounds I. A with Y=S (formula I. As) can be obtained via an acylation reaction and a subsequent intramolecular S-alkylation analogously to what is described for the O-derivative above. Therefore, the hydrazide carbonyl group in III is transformed to a thiocarbonyl group in compound V.

[0048] Compounds V can be obtained from compounds III via an O to S-exchange. This transformation is usually carried out at temperatures of from 45°C to 150°C, preferably from 80°C to 120°C, in an inert solvent, in the presence of sulfur-donating agents such as 2,4-bis(4- methoxyphenyl)-1 ,3,2,4-dithiadiphosphetan-2,4-disulfid, P2S5 [W02005077124, Journal of Heterocyclic Chemistry (1986), 23(2), 417-19], Suitable solvents are aromatic hydrocarbons such as toluene, o-, m-, and p-xylene and ethers such as diethylether, diisopropylether, tert.- butylmethylether, dioxane, anisole, and THF. It is also possible to use mixtures of the solvents mentioned.

[0049] Alternatively, compounds VII can be converted directly to compounds V with an unsubstituted or substituted methyl 2-sulfanylacetate Va via previous in situ bromination of VII. The subsequent substitution reaction yields the cyclized product I. A (Y=S). Compounds I. A with Y=N (formula I. An) can be obtained via an in situ bromination of VII with subsequent substitution reactions to obtain the cyclized product I. An. Optionally, established protecting group chemistry can be applied to improve the yield of the reaction sequence.

[0050] Compounds I. An can be obtained from compounds VII via an in situ two step procedure. In the first step an alpha-bromination of the hydrazone derivative VII is conducted. This transformation is usually carried out at temperatures of from -78°C to 30°C, preferably from 0°C to 30°C, in an inert solvent, in the presence of bromination regents such as N-bromosuccinimde (NBS) or Br2 in presence of an organic acid [WO2021222017; Chemische Berichte (1984), 117(3), 1194-214], Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, ethers such as diethylether, diisopropylether, tert.- butylmethylether, dioxane, anisole, and THF, moreover dimethyl sulphoxide (DMSO), dimethyl formamide (DMF), and dimethylacetamide (DMA), preferably THF and DMF. Suitable acids and acidic catalysts are in general organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluene sulphonic acid, benzene sulphonic acid, camphor sulphonic acid, citric acid, and trifluoro acetic acid (TFA).

[0051] In the second step the cyclisation to obtain compound I. An via nucleophilic substitution is conducted. This transformation is usually carried out at temperatures of from 0°C to 30°C, in an inert solvent, in the presence of an alpha amino carbonyl derivative bearing RNand a leaving group Z” such as an alkoxy residue or a halide and a base [Australian Journal of Chemistry (1996), 49(4), 463-468; Phosphorus, Sulfur and Silicon and the Related Elements (2011), 186(9), 1876-1884], Suitable solvents are alcohols such as methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol, n-butanol, and tert.-butanol, ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and THF, preferably THF. Suitable bases are, in general, organic bases, e.g. tertiary amines, such as TMA, TEA, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preference is given to MeOH and TEA. It is also possible to use mixtures of the solvents mentioned. The bases are generally employed in equimolar amounts or in excess, if appropriate, as solvent.

[0052] Compounds VII can be obtained via a condensation reaction with a hydrazine derivative Villa.

[0053] This transformation is usually carried out at temperatures of from 0°C to 80°C, preferably at about 30°C in an inert solvent, in the presence of a hydrazine derivative Villa. [Bioorganic & Medicinal Chemistry Letters (2006), 16(21), 5488-5492; Journal of Medicinal Chemistry (2015), 58(13), 5355-5360], Suitable solvents are alcohols such as MeOH, EtOH, n-propanol, isopropanol, n-butanol, and tert.-butanol, preferably MeOH or EtOH. It is also possible to use mixtures of the solvents mentioned.

[0054] Compounds VIII can be obtained from compounds VI I lb via ozonolysis.

[0055] This transformation is usually carried out at temperatures of -78°C, in an inert solvent, in the presence of O3 [Chemistry - A European Journal (2017), 23(57)]. Suitable solvents are alcohols such as MeOH, EtOH, n-propanol, isopropanol, n-butanol, and tert.-butanol, preferably MeOH. It is also possible to use mixtures of the solvents mentioned.

[0056] Compounds of formula VIII are novel.

[0057] The starting materials required for preparing the compounds I are commercially available or can be prepared according to cited literature WO2021170881 and W02023025602.

[0058] Compounds I.B with Y=O can be obtained via an intramolecular O-alkylation of the amide compound IX with suitable leaving groups X”, such as a halide, preferably Cl or Br.

[0059] This transformation is usually carried out at temperatures of from 0°C to 100°C, preferably from 40°C to 80°C, in an inert solvent, in the presence of a base [European Journal of Med. Chemistry 1988, Vol.23. p.441-451 ; W02020157201], Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, or ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and THF, preferably methylene chloride or THF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, alkali metal and alkaline earth metal carbonates, such as Li2CO3, Na2CO3, K2CO3, and CaCO3, and also alkali metal bicarbonates, such as NaHCCh. Particular preferences are given to NaHCCh and K2CO3. The bases are generally employed in equimolar amounts or in excess.

[0060] Compounds IX can be obtained from compounds X via an acylation reaction.

[0061] This transformation is usually carried out at temperatures of from 30°C to 50°C, preferably at 40°C to 45°C, in an inert solvent, in the presence of a base and a suitable acylating reagent Illa such as acyl halides or anhydrides [W02006045587, Journal fur Praktische Chemie (Leipzig) (1985), 327(1), 109-16], Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, or ethers such as diethylether, diisopropylether, tert.- butylmethylether, dioxane, anisole, and THF, preferably methylene chloride or THF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, organic bases, for example tertiary amines, such as TMA, TEA, diisopropylethylamine and N- methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4- dimethylaminopyridine, and also bicyclic amines. Particular preferences is given to TEA. The bases are generally employed in equimolar amounts or in excess.

[0062] Compounds X can be obtained from compounds XI via a nucleophilic substitution reaction of a carbamoyl chloride XI and a hydrazine derivative Villa.

[0063] This transformation is usually carried out at temperatures of from 0°C to 30°C, preferably at about 0°C, in an inert solvent, in the presence of a base [Organic Letters (2021), 23(3), 974- 978], Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene or ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and THF, preferably methylene chloride or THF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, organic bases, for example tertiary amines, such as TMA, TEA, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines. Particular preferences are given to TEA and pyridine. The bases are generally employed in equimolar amounts, excess or, if appropriate, as solvent.

[0064] Alternatively, compounds IX can be obtained from compounds XI via a nucleophilic substitution reaction of a carbamoyl chloride XI and a hydrazide derivative I lib.

[0065] This transformation is usually carried out at temperatures of from 20°C to 100°C, preferably at about 20°C, in an inert solvent, in the presence of a base [Organic Letters (2014), 16(9), 2342- 2345; Physical Chemistry Chemical Physics (2020), 22(36), 20602-20611], Suitable solvents are halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene, preferably methylene chloride. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, alkali metal and alkaline earth metal carbonates, such as U2CO3, Na2COs, K2CO3, and CaCO3, and also alkali metal bicarbonates, such as NaHCCh, or organic bases, for example tertiary amines, such as TMA, TEA, diisopropylethylamine and N- methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethyl- aminopyridine, and also bicyclic amines. Particular preferences are given to sodium carbonate and TEA. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent.

[0066] Compounds XI can be obtained from compounds XII via a nucleophilic substitution with phosgene.

[0067] This transformation is usually carried out at room temperature (20-25°C), in an inert solvent, such as halogenated hydrocarbons like methylene chloride, chloroform, and chlorobenzene, or aromatic hydrocarbons such as toluene, o-, m-, and p-xylene [W02005047253], It is also possible to use mixtures of the solvents mentioned.

[0068] Compound XII is known from WO2023285175.

[0069] Compounds X (Y=S) can be obtained via an acylation reaction and a subsequent intramolecular S-alkylation analogously to what is described for the O-derivative above. Therefore, the hydrazide carbonyl group in X is transformed to a thiocarbonyl group in compound Xb. Compounds Xb can be obtained from compounds X via an O to S-exchange as outlined above for compounds I. A.

[0070] This transformation is usually carried out at temperatures of from 45°C to 150°C, preferably from 80°C to 120°C, in an inert solvent, in the presence of a sulfur-donating regents such as 2,4-bis(4-methoxyphenyl)-1 ,3,2,4-dithiadiphosphetan-2,4-disulfid, P2S5 [W02005077124, Journal of Heterocyclic Chemistry (1986), 23(2), 417-19], Suitable solvents are aromatic hydrocarbons such as toluene, o-, m-, and p-xylene and ethers such as diethylether, diisopropylether, tert.-butylmethylether, dioxane, anisole, and THF. Particular preference is given to THF. It is also possible to use mixtures of the solvents mentioned.

[0071] Alternatively, compounds of formula I.B (with Y=S, R2= Me, and R5= H) could be synthesized as presented in the scheme below.

[0072] Compounds I.B (Y=NRN; formula I. Bn) can be obtained from compound XIII via an alkylation reaction.

[0073] This transformation is usually carried out at temperatures of from 0°C to 30°C, preferably at about 0°C, in an inert solvent, in the presence of an alkylating agent such as alkyl halides or dialkyl sulfates and a base [Heterocycles (1987), 25(1), 437-47); Angewandte Chemie, Int.Ed. (2022), 61 (9)]. Suitable solvents are ethers such as diethylether, diisopropylether, tert.- butylmethylether, dioxane, anisole, and THF moreover DMSO, DMF, and DMA, preferably THF and DMF. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH, and CaH2, preferably NaH. The bases are generally employed in equimolar amounts or in excess.

[0074] Compounds XIII can be prepared from intermediates XIV and hydrazines XV, as described in

[0075] WO2021 / 224323.

[0076] Hydrazines XV can be obtained from compounds XVI via an intramolecular cyclisation reaction.

[0077] This transformation is usually carried out at 20-25°C, in an inert solvent, in the presence of an acid [WO9744324], Suitable solvents are alcohols such as MeOH, EtOH, n-propanol, isopropanol, n-butanol, tert.-butanol and water, preferably water. It is also possible to use mixtures of the solvents mentioned. Suitable acids and acidic catalysts are in general anorganic acids such as HF, HCI, HBr, H2SO4, and HCIO4, preferably HCI. The acids are generally employed in equimolar amounts or in excess. Compounds XVI can be obtained from compound XVII via a nucleophilic substitution reaction with an amino acetic acid XVIII.

[0078] This transformation is usually carried out at temperatures of from 75°C to 80°C, in an inert solvent, in the presence of a base [Journal of Medicinal Chemistry (2001), 44(8), 1231-1248], Suitable solvents are alcohols such as MeOH, EtOH, n-propanol, isopropanol, n-butanol, and tert.-butanol and water, preferably water. It is also possible to use mixtures of the solvents mentioned. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH and Ca(OH)2, preferably NaOH. The bases are generally employed in equimolar amounts or in excess.

[0079] Alternatively, compounds of formula I. Bn (with R2= Me, and R5= H) could be synthesized as presented in the scheme below.

[0080] The starting materials required for preparing the compounds I are commercially available or known from literature [WO2021224323, WO2023285175],

[0081] The reaction mixtures are worked up in a customary manner, for example by mixing with water, extracting with an appropriate organic solvent, separating the phases and, if appropriate, chromatographic purification of the crude products. Some of the intermediates and end products are obtained in the form of colourless or slightly brownish viscous oils which are purified or freed from volatile components under reduced pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion.

[0082] If individual compounds I cannot be obtained by the routes described above, they can be prepared by derivatization of other compounds I.

[0083] However, if the synthesis yields mixtures of isomers, a separation is generally not necessarily required since in some cases the individual isomers can be interconverted during work-up for use or during application (for example under the action of light, acids or bases). Such conversions may also take place after use, for example in the treatment of plants in the treated plant, or in the pest to be controlled.

[0084] The organic moieties groups mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.

[0085] The term “partially or fully substituted” by a radical means that in general the group is substituted with same or different radicals.

[0086] The term “halogen” denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine.

[0087] The term "alkyl" as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of an alkyl group are methyl (Me), ethyl (Et), n-propyl (n-Pr), iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1 -methyl butyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, 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, and 1-ethyl-2-methylpropyl.

[0088] The term "haloalkyl" as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from Ci- Cs-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

[0089] The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.- butyloxy, and the like.

[0090] The term "alkoxyalkyl" as used herein refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually comprising 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH2OCH3, CH2-OC2H5, 2-(methoxy)ethyl, and 2-(ethoxy)ethyl.

[0091] The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1-C4- haloalkoxy, in particular C1-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2- chloro-2-fluoroethoxy, 2-chloro-2,2-difluoro-ethoxy, 2,2dichloro-2-fluorethoxy, 2,2,2- trichloroethoxy, pentafluoroethoxy and the like.

[0092] The term "alkylthio "(alkylsulfanyl: S-alkyl)" as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= C1-C4-alkylthio), more preferably 1 to 3 carbon atoms, which is attached via a sulfur atom.

[0093] The term "haloalkylthio" as used herein refers to an alkylthio group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and / or iodine.

[0094] The term "alkylsulfinyl" (alkylsulfoxyl: S(=O)-alkyl), as used herein refers to a straight-chain or branched saturated alkyl group (as mentioned above) having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= C1-C4-alkylsulfinyl), more preferably 1 to 3 carbon atoms bonded through the sulfur atom of the sulfinyl group at any position in the alkyl group.

[0095] The term "haloalkylsulfinyl" as used herein refers to an alkylsulfinyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and / or iodine.

[0096] The term "alkylsulfonyl" (S(=O)2-alkyl) as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (= C1-C4- alkylsulfonyl), preferably 1 to 3 carbon atoms, which is bonded via the sulfur atom of the sulfonyl group at any position in the alkyl group. The term "haloalkylsulfonyl" as used herein refers to an alkylsulfonyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and / or iodine.

[0097] The term "alkylcarbonyl" refers to an alkyl group as defined above, which is bonded via the carbon atom of a carbonyl group (C=O) to the remainder of the molecule.

[0098] The term "haloalkylcarbonyl" refers to an alkylcarbonyl group as mentioned above, wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and / or iodine.

[0099] The term "alkoxycarbonyl" refers to an alkylcarbonyl group as defined above, which is bonded via an oxygen atom to the remainder of the molecule.

[0100] The term "haloalkoxycarbonyl” refers to an alkoxycarbonyl group as mentioned above, wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and / or iodine.

[0101] The term "alkenyl" as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1 -propen- 1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3- buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en- 1-yl and the like.

[0102] The term "haloalkenyl" as used herein refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.

[0103] The term "alkynyl" as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1- pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.

[0104] The term "haloalkynyl" as used herein refers to an alkynyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.

[0105] The term "cycloalkyl" as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl (CC3H5), cyclobutyl (CC4H7), cyclopentyl (CC5H9), cyclohexyl (cCeHn), cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0106] The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above which is bonded via an alkylene group, such as a C1-C5-alkyl group or a C1-C4-alkyl group, in particular a methylene group CH2(=cycloalkylmethyl), to the remainder of the molecule.

[0107] The term "halocycloalkyl" as used herein and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least one, e.g. 1 , 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 1- and 2-flu- orocyclopropyl, 1 ,2-, 2,2- and 2,3-difluorocyclopropyl, 1 ,2,2-trifluorocyclopropyl, 2, 2,3,3- tetrafluorocyclpropyl, 1- and 2-chlorocyclopropyl, 1 ,2-, 2,2- and 2,3-dichlorocyclopropyl, 1 ,2,2- trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclpropyl, 1-,2- and 3-fluorocyclopentyl, 1 ,2-, 2,2-, 2,3-,

[0108] 3.3-, 3,4-, 2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1 ,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5- dichlorocyclopentyl and the like.

[0109] The term “halocycloalkenyl” as used herein and in the halocycloalkenyl moieties of halocycloalkenyloxy and halocycloalkenylthio denotes in each case a monocyclic singly unsaturated non-aromatic radical having usually from 3 to 10, e.g. 3 or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8 carbon atoms, wherein at least one, e.g. 1 , 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are

[0110] 3.3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.

[0111] The term "cycloalkenylalkyl" refers to a cycloalkenyl group as defined above which is bonded via an alkyl group, such as a C1-C5-alkyl group or a C1-C4-alkyl group, in particular a methylene group (= cycloalkenylmethyl), to the remainder of the molecule.

[0112] The term “carbocycle” or “carbocyclyl” includes in general a 3- to 12-membered, preferably a 3- to 8-membered or a 5- to 8-membered, more preferably a 5- or 6-membered mono-cyclic, non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above.

[0113] The term “heterocycle” or "heterocyclyl" includes in general 3- to 12-membered, preferably 3- to 6-membered, in particular 6-membered monocyclic heterocyclic non-aromatic radicals. The heterocyclic non-aromatic radicals usually comprise 1 , 2, 3, 4 or 5, preferably 1 , 2 or 3 heteroatoms selected from N, O, and S, wherein S-atoms as ring members may be present as S, SO, or SO2, and optionally one or two groups C(O) as ring members. Examples of 5- or 6-membered heterocyclic radicals comprise saturated or unsaturated, non-aromatic heterocyclic rings, such as oxiranyl, oxetanyl, thietanyl, thietanyl-S-oxid (S-oxothietanyl), thietanyl-S-dioxid (S- dioxothiethanyl), pyrrolidinyl, pyrrolinyl, pyrazolinyl, tetrahydrofuranyl, di hydrofuranyl, 1 ,3- dioxolanyl, thiolanyl, S-oxothiolanyl, S-dioxothiolanyl, dihydrothienyl, S-oxodihydrothienyl, S- dioxodihydrothienyl, oxazolidinyl, oxazolinyl, thiazolinyl, oxathiolanyl, piperidinyl, piperazinyl, pyranyl, di hydropyranyl, tetrahydropyranyl, 1 ,3- and 1 ,4-dioxanyl, thiopyranyl, S. oxothiopyranyl, S-dioxothiopyranyl, dihydrothiopyranyl, S-oxodihydrothiopyranyl, S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl, S-oxotetrahydrothiopyranyl, S-dioxotetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl and the like. Examples for heterocyclic ring also comprising 1 or 2 carbonyl groups as ring members comprise pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-onyl, and the like. The term "hetaryl" includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O, and S. Examples of 5- or 6-mem- bered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5- pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2- or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4- thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1 ,2,3-thiadiazol)yl, 3- or 5- (1 ,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or 3H-1 ,2,3-triazol-4-yl, 2H-triazol-3-yl, 1 H-, 2H-, or 4H-1 ,2,4-triazolyl and tetrazolyl, i.e. 1 H- or 2H-tetrazolyl. The term "hetaryl" also includes bicyclic 8 to 10-membered heteroaromatic radicals comprising as ring members 1, 2 or 3 heteroatoms selected from N, O, and S, wherein a 5- or 6-membered heteroaromatic ring is fused to a phenyl ring or to a 5- or 6-membered heteroaromatic radical. Examples of a 5- or 6- membered heteroaromatic ring fused to a phenyl ring or to a 5- or 6-membered heteroaromatic radical include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, chinolinyl, isochinolinyl, purinyl, 1,8- naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or pyridoimidazolyl and the like. These fused hetaryl radicals may be bonded to the remainder of the molecule via any ring atom of 5- or 6- membered heteroaromatic ring or via a carbon atom of the fused phenyl moiety.

[0114] The terms "heterocyclylalkyl" and "hetarylalkyl" refer to heterocyclyl or hetaryl, respectively, as defined above which are bonded via a C1-C5-alkyl group or a C1-C4-alkyl group, in particular a methylene group (= heterocyclylmethyl or hetarylmethyl, resp.), to the remainder of the molecule.

[0115] The term “arylalkyl” and "phenylalkyl" refer to aryl as defined above and phenyl, respectively, which are bonded via C1-C5-alkyl group or a C1-C4-alkyl group, in particular a methyl group (= arylmethyl or phenylmethyl), to the remainder of the molecule, examples including benzyl, 1- phenylethyl, 2-phenylethyl, 2-phenoxyethyl etc.

[0116] The terms “alkylene”, “cycloalkylene”, “heterocycloalkylene”, “alkenylene”, “cycloalkenylene”, “heterocycloalkenylene” and “alkynylene” refer to alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl and alkynyl as defined above, resp., which are bonded to the remainder of the molecule, via two atoms, preferably via two carbon atoms, of the respective group, so that they represent a linker between two moieties of the molecule.

[0117] In a particular embodiment, the variables of the compounds of the formula I have the following meanings, these meanings, both on their own and in combination with one another, being particular embodiments of the compounds of the formula I. Embodiments and preferred compounds of the invention for use in pesticidal methods and for insecticidal application purposes are outlined in the following paragraphs.

[0118] With respect to the variables, the particularly preferred embodiments of the intermediates correspond to those of the compounds of the formula I.

[0119] In a preferred embodiment, the compounds I are present in form of a mixture of compounds I.S and I.R, wherein compound I.S with S-configuration of the carbon atom neighboring the nitrogen is present in an amount of more than 50% by weight, in particular of at least 70% by weight, more particularly of at least 85% by weight, more particularly of at least 90% by weight, more particularly of at least 95% by weight, specifically of at least 99% by weight, based on the total weight of compounds I.S and I.R. Compounds of formula I.S are a particularly preferred embodiment of the invention.

[0120] In one particularly preferred embodiment of the invention, the method comprises the step of contacting the plant, parts of it, its propagation material, the pests, their food supply, habitat or breeding grounds with a pesticidally effective amount of a compound of formula I.S.

[0121] In one preferred embodiment the invention relates to compounds of formula I wherein

[0122] R1is H, OH, NR12R13; C1-C6-alkyl, C3-C6-cycloalkyl, C1-C5-alkoxy, C3-C6-cycloalkyl-C1-C4- alkyl, C1-C4-alkyl-C3-C6-cycloalkyl, C3-C6-halocycloalkyl-C1-C4-alkyl, C2-C6-alkenyl, C2-C6- alkynyl, which groups are unsubstituted, or partially or fully substituted with R11; or C(O)R11a;

[0123] R10is H, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C3-C4-cycloalkyl- C1-C2-alkyl, C3-C4-halocycloalkyl-C1-C2-alkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4-haloalkyl, C(O)-C3- C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, SOm-C1-C4-alkyl, SOm-C1-C4-haloalkyl, SOm-C3-C6- cycloalkyl, or phenyl which is unsubstituted or partially or fully substituted with R3a;

[0124] R11is halogen, CN, NO2, NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; 3- to 6- membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN;

[0125] R11ais NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; C1-C6-haloalkyl; C2-C6-alkenyl; C2-C6-haloalkenyl; C2-C6-alkynyl; C2-C6-haloalkynyl; C3-C4-cycloalkyl-C1-C2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; R12, R13are independently from each other H, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-haloalkyl, C3-C6-cycloalkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4-haloalkyl, C(O)-C3-C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, C(O)NH-C1-C4-alkyl, C(O)NH-C1-C4-haloalkyl, C(O)N(C1-C4-alkyl)- C1-C4-alkyl, C(O)N(C1-C4-haloalkyl)-C1-C4-alkyl, C(O)N(C1-C4-haloalkyl)-C1-C4-haloalkyl, C(O)NH-C1-C4-alkoxy, C(O)NH-C1-C4-haloalkoxy, C(O)NH-C1-C4-alkoxy-C1-C4-alkyl, C(O)NH- C1-C4-alkoxy-C1-C4-haloalkyl; C(O)NH-phenyl, C(O)NH-3-6-membered heterocyclyl or 5- or 6- membered hetaryl, C(O)NH-C1-C4-alkyl-phenyl, C(O)NH-C1-C4-alkyl-3-6-membered heterocyclyl or 5- or 6-membered hetaryl which rings are unsubstituted or substituted with halogen, C1-C3- haloalkyl, and / or CN; S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4-cycloalkyl, S(O)m-C3-C4- halocycloalkyl; 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; or

[0126] R12and R13together with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7- membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom-containing groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a; m is 0, 1 , or 2;

[0127] R2is H, C1-C3-alkyl, C1-C3-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, or C2-C3-alkynyl; each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6-cycloalkyl, C2- Ce-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C6-cycloalkyl, 3- to 6-membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, - N=S(O)R12aR13a; or two R3bound to two adjacent C-atoms can form a 4-, 5-, or 6-membered ring, which may contain one or two heteroatoms selected from N, O, and S as ring members, which ring is unsubstituted or substituted with halogen, CN, C1-C3-alkyl, or C1-C3-haloalkyl;

[0128] R12a, R13aare independently from each other C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; or R12aand R13atogether with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7- membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatom-containing groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a;

[0129] R14is as defined for R10;

[0130] R15is H, C1-C4-alkyl, or C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, which carbon chains are unsubstituted or partially or fully substituted with R11; or 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with R3a; R3ais halogen, CN, NO2, OH, S(O)m-C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4- cycloalkyl, or S(O)m-C3-C4-halocycloalkyl; n is 0, 1 , 2, or 3;

[0131] X is N, CH, or CR3c;

[0132] R3cis as defined for R3;

[0133] R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl-C1-C2-alkyl, C1-C2-alkyl-C3- C6-cycloalky, C3-C6-cycloalkyl, which are unsubstituted or partially or fully substituted with halogen, CN, NO2, OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15;

[0134] HET is a group HA or HB wherein # is the bond to the CH(R2)amide spacer, and % is the bond to the diazinone ring;

[0135] R5is H, halogen, CN, C1-C3-alkyl, C1-C3-haloalkyl, or C3-C6-cycloalkyl;

[0136] R5a,R5b,R5care independently from each other a group R5;

[0137] Z is N;

[0138] R6,R7are independently from each other H, halogen, CN, C1-C3-alkyl, C1-C3-haloalkyl, or C3- Ce-cycloalkyl; or

[0139] R6and R7together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6- membered saturated or unsaturated carbocycle, which is unsubstituted or substituted with one or more halogen, CN, C1-C4-alkyl, or C1-C4-haloalkyl;

[0140] Y is O, S, or N-RN; and

[0141] RNis as defined for R4; and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.

[0142] In various embodiments, R1is H, OH, NR12R13; C1-C6-alkyl, C3-C6-cycloalkyl, C1-C5-alkoxy, C3- C6-cycloalkyl-C1-C4-alkyl, C1-C4-alkyl-C3-C6-cycloalkyl, C3-C6-halocycloalkyl-C1-C4-alkyl, C2-C6- alkenyl, Cs-Ce-alkynyl, which groups are unsubstituted, or partially or fully substituted with R11; or C(O)R11a, preferably C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C3- C6-cycloalkyl-C1-C4-alkyl, or C1-C4-alkyl-C3-C6-cycloalkyl; more preferably H, CH3, CH2-CH3, CH2-O-CH3, CH(CH3)2, or CH2-CC3H5.

[0143] In various embodiments, R1is H, C1-C3-alkyl, Cs-Ce-alkenyl, Cs-Ce-alkynyl, C3-C6-cycloalkyl, or C3-C6-cycloalkyl-C1-C4-alkyl, preferably H, CH3, C2H5, CH2cC3H5, CH2CH=CH2, or CH2CECH, more preferably H, CH3 or CH2CC3H5. Particularly for compounds I. A is R1preferably H, C1-C3- alkyl, C2-C6-alkenyl, Cs-Ce-alkynyl, C3-C6-cycloalkyl, or C3-C6-cycloalkyl-C1-C4-alkyl, more preferably H, CH3, C2H5, CH2-O-CH3, CH2CC3H5, particularly H, CH3 or CHscCsHs. In various embodiments, R2is CH3.

[0144] In various embodiments, each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkoxy, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6- alkyl-C3-C6-cycloalkyl, 3- to 6-membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, -N=S(O)R12aR13a.

[0145] In various embodiments, each R3is independently selected from halogen, CN, C1-C4-alkyl, wherein alkyl is unsubstituted or substituted with one or more CN, C1-C4-haloalkyl, C1-C4- haloalkoxy, C3-C4-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one or more CN or halogen, S(O)m-C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, OS(O)m-C1-C4-alkyl, OS(O)m-C1-C4- haloalkyl, S(O)m-phenyl, wherein phenyl is unsubstituted or substituted with one or more halogen.

[0146] In various embodiments, at least one R3group in (R3)nis selected from R3d: C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3- Ce-cycloalkyl, which are unsubstituted or substituted with R3a; NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, OS(O)m-R15, and -N=S(O)R12aR13a.

[0147] In various embodiments, each R3is independently selected from F, Cl, Br, CF3, CCIF2, CF2CH3, CN, SCH3, OCH3, S-CH2-CN, S-CF3, SO2CF3, SOCF3, SO2(4-F-C6H4), SO2-(2-F-C6H4), SO2-(4- Br-C6H4), SO2-CH(CH3)2, SO2-CC3H5, SO2-CH3, O-SO2-CF3, 1-CN-cC3H4, C(CH3)2CN, 2-CI2- CC3H3, C(CH2)-CC3H5, CH(OCH3)-CC3H5, C(O)-CC3H5, CCH, C(CH3)3, CH(CI)2, CF2H, OCF3or OCF2H.

[0148] In various embodiments, each R3is independently selected from SCH3, S-CH2-CN, SO2CF3, SOCF3, SO2(4-F-C6H4), SO2-(2-F-C6H4), SO2-(4-Br-C6H4), SO2-CH(CH3)2, SO2-cC3H5, SO2-CH3, O-SO2-CF3, 1-CN-CC3H4, C(CH3)2CN, 2-CI2-CC3H3, C(CH2)-CC3H5, CH(OCH3)-CC3H5, C(O)- CC3H5, or CCH

[0149] In various embodiments of (R3)n, index n is 2 and R3is in positions 3 and 5, preferably wherein R3is selected from 3,5-(CF3)2; 3-CF3, 5-CI; 3-(2-CI2-cC3H3), 5-CI; 3-(1-CN-cC3H4), 5-OCHF2; 3- C(CH2)-CC3H5, 5-CI; 3-S-CF3, 5-CN; 3-SO2-(2-F-C6H4), 5-CI; 3-SO2-(4-Br-C6H4), 5-CI; 3- CH(OCH3)-CC3H5, 5-CI; 3-CH(OCH3)-cC3H5, 5-CI; 3-C(O)-cC3H5, 5-CI; 3-SO2-CH(CH3)2, 5-CI; 3- SO2-(4-F-C6H4), 5-CI; 3-S(O)-CF3, 5-CI; 3-O-SO2-CF3, 5-CF3; 3-SO2-CF3, 5-CI; 3-C(CH3)2-CN, 5- Br; 3-SO2-CC3H5, 5-CI; 3-SO2-CH3, 5-CI; 3-O-CF3, 5-CI; 3-F, 5-OCH3; 3,5-Br2; 3-Br, 5-CI; 3-Br, 5- F; 3-F, 5-CCH; 3-Br, 5-CN; 3-CI, 5-CN; 3-F, 5-CN; 3-OCF3, 5-CN; 3-(1-CN-cC3H4), 5-Br; 3,5-CI2; 3-CI, 5-F; 3,5-F2; 3-OCF3, 5-Br; 3-OCF3, 5-F; 3-OCF2H, 5-CI; 3-OCF2H, 5-Br; 3-CF2H, 5-CI; 3-(1- CN-CC3H4), 5-OCF3; 3-CF3, 5-CN; 3-CF2H, 5-Br; 3-SCH3, 5-Br; 3-C(CH3)3, 5-CI; 3-OCF3, 5- OCF2H; 3-OCF2H, 5-CN; 3-CF2CH3, 5-F; 3-OCF2H, 5-OCF2H; 3-S-CH2-CN, 5-CI; 3-CI, 5- CH(CI)2; 3-CI, 5-CCIF2; or 3,5-(OCF3)2.

[0150] In various embodiments, index m in R3is 1 or 2.

[0151] In various embodiments, R3ais halogen, CN, NO2, OH, S(O)m-C1-C4-alkyl, S(O)m-C1-C4- haloalkyl, S(O)m-C3-C4-cycloalkyl, or S(O)m-C3-C4-halocycloalkyl.

[0152] In various embodiments, R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, -cycloalkyl-CCi-3-C6 C2-alkyl, C1-C2-alkyl-C3-C6-cycloalky, -cycClo3a-Clk6yl, which are unsubstituted or partially or fully substituted with halogen, CN, or C(O)NH2; preferably R4is CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CC3H5, CH2CN, CH2C=CH or CH2OCH3, CHF2, CH2CF3, 1-CN-cC3H4, CH2cC3H5, C(H)=CH2, CH2CH2CN, more preferably H or CH3.

[0153] In various embodiments, R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, -cycloalkyl-CCi-3-C6 C2-alkyl, C1-C2-alkyl-C3-C6-cycloalky, -cycClo3a-Clk6yl, which are unsubstituted or partially or fully substituted with halogen, CN, NO2, OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15.

[0154] In various embodiments, R5is H, halogen, C1-C4-alkyl, or -cycloalCky3-l,C p6referably H, F, Cl, CH3, or CC3HS, more preferably H or cC3Hs. R5being H is particularly preferred.

[0155] In various embodiments, R5a, R5band R5care H.

[0156] In various embodiments, R6and R7are independently from each other H, CH3, CH2CH3, CH(CH3)2or CH2CH2CH3, preferably H or CH3. In various embodiment, R6and R7are both H; or R6is H and R7is CH3; or R6is CH3and R7is CH3.

[0157] In various embodiments, R6and R7form together with the atom to which they are bound a carbocyclic ring, preferably a cyclopropyl ring.

[0158] In various embodiments, R11is halogen, CN, NO2, NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN. In various embodiments, Y is S or N-RN, when HET is HB; and Y is O, S, or N-RN, when HET is HA. In various embodiments, Y is S, when HET is HB; and Y is O or S, preferably O, when HET is HA.

[0159] In various embodiments, HET is HB; and Y is S or N-RN; preferably Y is S.

[0160] In various embodiments, HET is HA; and Y is O, S, or N-RN; preferably Y is S or O; further preferably Y is O.

[0161] In various embodiments, Z is N.

[0162] In various embodiments, X is CH or CR3, preferably CH. Such compounds correspond to

[0163] Formula 1.1

[0164] In various embodiments, X is N. Such compounds correspond to formula 1.2.

[0165] In various embodiments, HET is a group HA. Such compounds correspond to formula I. A.

[0166] In various embodiments, HET is a group HA and Z is preferably N. Such compounds correspond to formula I.A.N. In various embodiments of formula I.A.N, the groups R5a, R5b, and R5crepresent independently from each other a group R5. In various embodiments, R5a, R5b, and R5care preferably H. In various embodiments, HET is a group HA, Z is preferably N, X is preferably CH, and Y is preferably O. Such compounds correspond to formula I.A.N.O.

[0167] In various embodiments, HET is HB. Such compounds correspond to formula I.B. In various embodiments of formula I.B, R5is preferably H.

[0168] In various embodiments, the invention relates to compounds of formula I.A.N.1*, I.A.N.Ia*, I.A.N.2*, I.A.N.2b*, I.A.N.2c*, I.A.N.2S*, I.A.N.1S*, I.A.N.1 R*, I.A.N.3*, or l.A.N.3a*

[0169] and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.

[0170] In one preferred embodiment, the invention relates to compounds of Table I. In various embodiments, the invention relates to intermediate compounds of formula lnt-1 p, Int-

[0171] 2p, lnt-3p or VIII, and N-oxides, stereoisomers, and salts, preferably agriculturally or veterinarily acceptable salts, thereof, wherein the variables are as defined herein.

[0172] In various embodiments, the intermediate compounds of formula lnt-1 p are selected from

[0173] 2-(3-acetylpyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one

[0174] 2-(3-acetylpyrazin-2-yl)-4H-1 ,3,4-oxadiazin-5-one

[0175] 2-(3-acetylpyrazin-2-yl)-4,6-dimethyl-1 ,3,4-oxadiazin-5-one 2-(3-acetylpyrazin-2-yl)-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one

[0176] 2-(3-acetylpyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one In various embodiments, the intermediate compounds of formula lnt-2p are selected from

[0177] 2-[3-(1-aminoethyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one

[0178] 2-[3-(1-aminoethyl)pyrazin-2-yl]-4 / 7-1 ,3,4-oxadiazin-5-one

[0179] 2-[3-(1-aminoethyl)pyrazin-2-yl]-4,6-dimethyl-1 ,3,4-oxadiazin-5-one

[0180] 2-[3-(1-aminoethyl)pyrazin-2-yl]-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one

[0181] 2-[3-[1-(methylamino)ethyl]pyrazin-2-yl]-4 / 7-1 ,3,4-oxadiazin-5-one

[0182] 4-methyl-2-[3-[1-(methylamino)ethyl]pyrazin-2-yl]-1 ,3,4-oxadiazin-5-one

[0183] 2-[3-[(1R)-1-aminoethyl]pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one

[0184] 2-[3-(1-aminoethyl)pyrazin-2-yl]-6,6-dimethyl-4 / 7-1 ,3,4-oxadiazin-5-one

[0185] In various embodiments, the intermediate compound of formula lnt-3p is 2-[3-[(1 S)-1-aminoethyl]pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one

[0186] In particular with a view to their use, preference is given to the compounds of formula I com- piled in the tables below. Each of the groups mentioned for a substituent in the tables is furthermore per se, independently of the combination in which it is mentioned, a particularly preferred aspect of the substituent in question.

[0187] Table 1 : Compounds of formula I.A.N.1* in which Y is O, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0188] Table 2 : Compounds of formula I.A.N.1* in which Y is O, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0189] Table 3 : Compounds of formula I.A.N.1* in which Y is O, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0190] Table 4 : Compounds of formula I.A.N.1* in which Y is S, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A Table 5 : Compounds of formula I.A.N.1* in which Y is S, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0191] Table 6 : Compounds of formula I.A.N.1* in which Y is S, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0192] Table 7 : Compounds of formula I.A.N.1* in which Y is NH, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0193] Table 8 : Compounds of formula I.A.N.1* in which Y is NH, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0194] Table 9 : Compounds of formula I.A.N.1* in which Y is NH, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0195] Table 10 : Compounds of formula I.A.N.1* in which Y is NCH3, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0196] Table 11 : Compounds of formula I.A.N.1* in which Y is NCH3, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0197] Table 12 : Compounds of formula I.A.N.1* in which Y is NCH3, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0198] Table 13 : Compounds of formula I.A.N.Ia* in which Y is O, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0199] Table 14 : Compounds of formula I.A.N.Ia* in which Y is O, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0200] Table 15 : Compounds of formula I.A.N.Ia* in which Y is O, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0201] Table 16 : Compounds of formula I.A.N.Ia* in which Y is S, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0202] Table 17 : Compounds of formula I.A.N.Ia* in which Y is S, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0203] Table 18 : Compounds of formula I.A.N.Ia* in which Y is S, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0204] Table 19 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A Table 20 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0205] Table 21 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0206] Table 22 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0207] Table 23 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0208] Table 24 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0209] Table 25 : Compounds of formula I.A.N.Ia* in which Y is O, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0210] Table 26 : Compounds of formula I.A.N.Ia* in which Y is O, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0211] Table 27 : Compounds of formula I.A.N.Ia* in which Y is O, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0212] Table 28 : Compounds of formula I.A.N.Ia* in which Y is S, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0213] Table 29 : Compounds of formula I.A.N.Ia* in which Y is S, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0214] Table 30 : Compounds of formula I.A.N.Ia* in which Y is S, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0215] Table 31 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A Table 32 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0216] Table 33 : Compounds of formula I.A.N.Ia* in which Y is NH, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0217] Table 34 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0218] Table 35 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0219] Table 36 : Compounds of formula I.A.N.Ia* in which Y is NCH3, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0220] Table 37 : Compounds of formula I.A.N.2* in which Y is O, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0221] Table 38 : Compounds of formula I.A.N.2* in which Y is O, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0222] Table 39 : Compounds of formula I.A.N.2* in which Y is O, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0223] Table 40 : Compounds of formula I.A.N.2* in which Y is S, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0224] Table 41 : Compounds of formula I.A.N.2* in which Y is S, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0225] Table 42 : Compounds of formula I.A.N.2* in which Y is S, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0226] Table 43 : Compounds of formula I.A.N.2* in which Y is NH, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0227] Table 44 : Compounds of formula I.A.N.2* in which Y is NH, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0228] Table 45 : Compounds of formula I.A.N.2* in which Y is NH, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0229] Table 46 : Compounds of formula I.A.N.2* in which Y is NCH3, R4is H, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0230] Table 47 : Compounds of formula I.A.N.2* in which Y is NCH3, R4is CH3, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A Table 48 : Compounds of formula I.A.N.2* in which Y is NCH3, R4is CH2C=CH, and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0231] Table 49 Compounds of formula I.A.N.2a* in which Y is O, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0232] Table 50 : Compounds of formula I.A.N.2a* in which Y is O, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0233] Table 51 : Compounds of formula I.A.N.2a* in which Y is O, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0234] Table 52 : Compounds of formula I.A.N.2a* in which Y is S, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0235] Table 53 : Compounds of formula I.A.N.2a* in which Y is S, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0236] Table 54 : Compounds of formula I.A.N.2a* in which Y is S, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0237] Table 55 : Compounds of formula I.A.N.2a* in which Y is NH, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0238] Table 56 : Compounds of formula I.A.N.2a* in which Y is NH, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0239] Table 57 : Compounds of formula I.A.N.2a* in which Y is NH, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0240] Table 58 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is H, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0241] Table 59 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is CH3, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0242] Table 60 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is CH2C=CH, R6is H, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A Table 61 : Compounds of formula I.A.N.2a* in which Y is O, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0243] Table 62 : Compounds of formula I.A.N.2a* in which Y is O, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0244] Table 63 : Compounds of formula I.A.N.2a* in which Y is O, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0245] Table 64 : Compounds of formula I.A.N.2a* in which Y is S, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0246] Table 65 : Compounds of formula I.A.N.2a* in which Y is S, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0247] Table 66 : Compounds of formula I.A.N.2a* in which Y is S, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0248] Table 67 : Compounds of formula I.A.N.2a* in which Y is NH, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0249] Table 68 : Compounds of formula I.A.N.2a* in which Y is NH, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0250] Table 69 : Compounds of formula I.A.N.2a* in which Y is NH, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0251] Table 70 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is H, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0252] Table 71 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is CH3, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0253] Table 72 : Compounds of formula I.A.N.2a* in which Y is NCH3, R4is CH2C=CH, R6is CH3, R7is CH3and the combination of R1and (R3)nfor a compound corresponds in each case to one row of Table A

[0254] Table A

[0255] The term “compound(s) of the invention” refers to compound(s) of formula I, or “compound(s) I”, and includes their salts, tautomers, stereoisomers, and N-oxides.

[0256] The invention also relates to agrochemical compositions comprising an auxiliary and at least one compound I.

[0257] An agrochemical composition comprises a pesticidally effective amount of a compound I.

[0258] The compounds I can be converted into customary types of agro-chemical compositions, e.g. solutions, emulsions, suspensions, dusts, powders, pastes, granules, pressings, capsules, and mixtures thereof. Examples for composition types are suspensions (e.g. SC, OD, FS), emulsifiable concentrates (e.g. EC), emulsions (e.g. EW, EO, ES, ME), capsules (e.g. CS, ZC), pastes, pastilles, wettable powders or dusts (e.g. WP, SP, WS, DP, DS), pressings (e.g. BR, TB, DT), granules (e.g. WG, SG, GR, FG, GG, MG), insecticidal articles (e.g. LN), as well as gel formulations for the treatment of plant propagation materials e.g. seeds (e.g. GF). These and further compositions types are defined in the “Catalogue of pesticide formulation types and international coding system”, Technical Monograph No. 2, 6th Ed. May 2008, CropLife International. The compositions are prepared in a known manner, e.g. described by Mollet and Grubemann, Formulation technology, Wiley VCH, Weinheim, 2001 ; or Knowles, New developments in crop protection product formulation, Agrow Reports DS243, T&F Informa, London, 2005.

[0259] Suitable auxiliaries are solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetters, adjuvants, solubilizers, penetration enhancers, protective colloids, adhesion agents, thickeners, humectants, repellents, attractants, feeding stimulants, compatibilizers, bactericides, anti-freezing agents, anti-foaming agents, colorants, tackifiers and binders.

[0260] Suitable solvents and liquid carriers are water and organic solvents. Suitable solid carriers or fillers are mineral earths.

[0261] Suitable surfactants are surface-active compounds, e.g. anionic, cationic, nonionic, and amphoteric surfactants, block polymers, polyelectrolytes. Such surfactants can be used as emusifier, dispersant, solubilizer, wetter, penetration enhancer, protective colloid, or adjuvant. Surfactants are listed in McCutcheon’s, Vol.1: Emulsifiers & Detergents, McCutcheon’s Directories, Glen Rock, USA, 2008 (International or North American Ed.). Suitable anionic surfactants are alkali, alkaline earth, or ammonium salts of sulfonates, sulfates, phosphates, carboxylates. Suitable nonionic surfactants are alkoxylates, N-subsituted fatty acid amides, amine oxides, esters, sugar-based surfactants, polymeric surfactants. Suitable cationic surfactants are qua-ternary surfactants.

[0262] The agrochemical compositions generally comprise between 0.01 and 95%, preferably between 0.1 and 90%, and most preferably between 0.5 and 75%, by weight of active substance. The active substances are employed in a purity of from 90% to 100%, preferably from 95% to 100%.

[0263] Various types of oils, wetters, adjuvants, or fertilizer may be added to the active substances or the compositions comprising them as premix or, if appropriate not until immediately prior to use (tank mix). These agents can be admixed with the compositions according to the invention in a weight ratio of 1 : 100 to 100: 1.

[0264] The user applies the composition according to the invention usually from a predosage device, a knapsack sprayer, a spray tank, a spray plane, or an irrigation system. Usually, the agrochemical composition is made up with water, buffer, and / or further auxiliaries to the desired application concentration and the ready-to-use spray liquor or the agrochemical composition according to the invention is thus obtained. Usually, 20 to 2000 liters, of the ready-to-use spray liquor are applied per hectare of agricultural useful area.

[0265] The compounds I are suitable for use in protecting crops, plants, plant propagation materials, e.g. seeds, or soil or water, in which the plants are growing, from attack or infestation by animal pests. Therefore, the invention also relates to a plant protection method, which comprises contacting crops, plants, plant propagation materials, e.g. seeds, or soil or water, in which the plants are growing, to be protected from attack or infestation by animal pests, with a pesticidally effective amount of a compound I.

[0266] The compounds I are also suitable for use in combating or controlling animal pests. Therefore, the invention also relates to a method of combating or controlling animal pests, which comprises contacting the animal pests, their habitat, breeding ground, or food supply, or the crops, plants, plant propagation materials, e.g. seeds, or soil, or the area, material or environment in which the animal pests are growing or may grow, with a pesticidally effective amount of a compound I.

[0267] The compounds I are effective through both contact and ingestion to any and all developmental stages, such as egg, larva, pupa, and adult.

[0268] The compounds I can be applied as such or in form of compositions comprising them.

[0269] The application can be carried out both before and after the infestation of the crops, plants, plant propagation materials by the pests.

[0270] The term "contacting" includes both direct contact (applying the compounds / compositions directly on the animal pest or plant) and indirect contact (applying the compounds / compositions to the locus).

[0271] The term “animal pest” includes arthropods, gastropods, and nematodes. Preferred animal pests according to the invention are arthropods, preferably insects and arachnids, in particular insects.

[0272] The term “plant” includes cereals, e.g. durum and other wheat, rye, barley, triticale, oats, rice, or maize (fodder maize and sugar maize I sweet and field corn); beet, e.g. sugar beet, or fodder beet; fruits, e.g. pomes, stone fruits, or soft fruits, e.g. apples, pears, plums, peaches, nectarines, almonds, cherries, papayas, strawberries, raspberries, blackberries or gooseberries; leguminous plants, e.g. beans, lentils, peas, alfalfa, or soybeans; oil plants, e.g. rapeseed (oilseed rape), turnip rape, mustard, olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms, ground nuts, or soybeans; cucurbits, e.g. squashes, pumpkins, cucumber or melons; fiber plants, e.g. cotton, flax, hemp, or jute; citrus fruit, e.g. oranges, lemons, grape-fruits or mandarins; vegetables, e.g. eggplant, spinach, lettuce (e.g. iceberg lettuce), chicory, cabbage, asparagus, cabbages, carrots, onions, garlic, leeks, tomatoes, potatoes, cucurbits or sweet peppers; lauraceous plants, e.g. avocados, cinnamon, or camphor; energy and raw material plants, e.g. corn, soybean, rapeseed, sugar cane or oil palm; tobacco; nuts, e.g. walnuts; pistachios; coffee; tea; bananas; vines; hop; sweet leaf (Stevia); natural rubber plants or ornamental and forestry plants, , shrubs, broad-leaved trees or evergreens, eucalyptus; turf; lawn; grass. Preferred plants include potatoes sugar beets, tobacco, wheat, rye, barley, oats, rice, corn, cotton, soybeans, rapeseed, legumes, sunflowers, coffee, or sugar cane; fruits; vines; ornamentals; or vegetables, e.g. cucumbers, tomatoes, beans or squashes.

[0273] The term “seed” embraces seeds and plant propagules including true seeds, seed pieces, suckers, corms, bulbs, fruit, tubers, grains, cuttings, cut shoots, and means preferably true seeds.

[0274] "Pesticidally effective amount" means the amount of active ingredient needed to achieve an observable effect on growth, including the effects of necrosis, death, retardation, prevention, and removal, destruction, or otherwise diminishing the occurrence and activity of the target organism. The pesticidally effective amount can vary for the various compounds / compositions used in the invention. A pesticidally effective amount of the compositions will also vary according to the prevailing conditions e.g. desired pesticidal effect and duration, weather, target species, locus, mode of application.

[0275] For use in treating crop plants, e.g. by foliar application, the rate of application of the active ingredients of this invention may be in the range of 0.0001 g to 4000 g per hectare, e.g. from 1 g to 2 kg per hectare or from 1 g to 750 g per hectare, desirably from 1 g to 100 g per hectare.

[0276] The invention also relates to a seed comprising a compound or a composition according to the invention, preferably in an amount of from 0.1 g to 10 kg per 100 kg of seed.

[0277] The compounds I are also suitable for use against non-crop insect pests. For use against said non-crop pests, compounds I can be used as bait composition, gel, general insect spray, aerosol, as ultra-low volume application and bed net (impregnated or surface applied).

[0278] The term “non-crop insect pest” refers to pests, which are particularly relevant for non-crop targets, e.g. ants, termites, wasps, flies, ticks, mosquitoes, bed bugs, crickets, or cockroaches, such as: Aedes aegypti, Musca domestica, Tribolium spp.; termites such as Reticulitermes flavipes, Coptotermes formosanus; roaches such as Blatella germanica, Periplaneta Americana; ants such as Solenopsis invicta, Linepithema humile, and Camponotus pennsylvanicus.

[0279] The bait can be a liquid, a solid or a semisolid preparation (e.g. a gel). For use in bait compositions, the typical content of active ingredient is from 0.001 wt% to 15 wt%, desirably from 0.001 wt% to 5 wt% of active compound.

[0280] The compounds I and its compositions can be used for protecting wooden materials such as trees, board fences, sleepers, frames, artistic artifacts, etc. and buildings, but also construction materials, furniture, leathers, fibers, vinyl articles, electric wires and cables etc. from ants, termites and / or wood or textile destroying beetles, and for controlling ants and termites from doing harm to crops or human beings (e.g. when the pests invade into houses and public facilities or nest in yards, orchards or parks).

[0281] Customary application rates in the protection of materials are, e.g., from 0.001 g to 2000 g or from 0.01 g to 1000 g of active compound per m2treated material, desirably from 0.1 g to 50 g per m2.

[0282] Insecticidal compositions for use in the impregnation of materials typically contain from 0.001 to 95 wt%, preferably from 0.1 to 45 wt%, and more preferably from 1 to 25 wt% of at least one repellent and / or insecticide.

[0283] The compounds of the invention are especially suitable for efficiently combating animal pests e.g. arthropods, and nematodes including: insects from the sub-order of Auchenorrhyncha, e.g. Amrasca biguttula, Empoasca spp., Nephotettix virescens, Sogatella furcifera, Mahanarva spp., Laodelphax striatellus, Nilaparvata lugens, Diaphorina citri;

[0284] Lepidoptera, e.g. Helicoverpa spp., Heliothis virescens, Lobesia botrana, Ostrinia nubilalis, Plutella xylostella, Pseudoplusia includens, Scirpophaga incertulas, Spodoptera spp., Trichoplusia ni, Tuta absoluta, Cnaphalocrocis medialis, Cydia pomonella, Chilo suppressalis, Anticarsia gemmatalis, Agrotis ipsilon, Chrysodeixis includens;

[0285] True bugs, e.g. Lygus spp., Stink bugs such as Euschistus spp., Halyomorpha halys, Nezara viridula, Piezodorus guildinii, Dichelops furcatus;

[0286] Thrips, e.g. Frankliniella spp., Thrips spp., Dichromothrips corbettii;

[0287] Aphids, e.g. Acyrthosiphon pisum, Aphis spp., Myzus persicae, Rhopalosiphum spp., Schizaphis graminum, Megoura viciae;

[0288] Whiteflies, e.g. Trialeurodes vaporariorum, Bemisia spp.;

[0289] Coleoptera, e.g. Phyllotreta spp., Melanotus spp., Meligethes aeneus, Leptinotarsa decimlineata, Ceutorhynchus spp., Diabrotica spp., Anthonomus grandis, Atomaria linearia, Agriotes spp., Epilachna spp.;

[0290] Flies, e.g. Delia spp., Ceratitis capitate, Bactrocera spp., Liriomyza spp.;

[0291] Coccoidea, e.g. Aonidiella aurantia, Ferrisia virgate;

[0292] Anthropods of class Arachnida (Mites), e.g. Penthaleus major, Tetranychus spp.;

[0293] Nematodes, e.g. Heterodera glycines, Meloidogyne spp., Pratylenchus spp., Caenorhabditis elegans.

[0294] The compounds I are suitable for use in treating or protecting animals against infestation or infection by parasites. Therefore, the invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or protection of animals against infestation or infection by parasites. Furthermore, the invention relates to a method of treating or protecting animals against infestation and infection by parasites, which comprises orally, topically or parenterally administering or applying to the animals a parasiticidally effective amount of a compound I.

[0295] The invention also relates to the non-therapeutic use of compounds of the invention for treating or protecting animals against infestation and infection by parasites. Moreover, the invention relates to a non-therapeutic method of treating or protecting animals against infestation and infection by parasites, which comprises applying to a locus a parasiticidally effective amount of a compound I.

[0296] The compounds of the invention are further suitable for use in combating or controlling parasites in and on animals. Furthermore, the invention relates to a method of combating or controlling parasites in and on animals, which comprises contacting the parasites with a parasitically effective amount of a compound I. The invention also relates to the non-therapeutic use of compounds I for controlling or combating parasites. Moreover, the invention relates to a non-therapeutic method of combating or controlling parasites, which comprises applying to a locus a parasiticidally effective amount of a compound I.

[0297] The compounds I can be effective through both contact (via soil, glass, wall, bed net, carpet, blankets or animal parts) and ingestion (e.g. baits). Furthermore, the compounds I can be applied to any and all developmental stages.

[0298] The compounds I can be applied as such or in form of compositions comprising them.

[0299] The term "locus" means the habitat, food supply, breeding ground, area, material or environment in which a parasite is growing or may grow outside of the animal.

[0300] As used herein, the term “parasites” includes endo- and ectoparasites. In some embodiments of the invention, endoparasites can be preferred. In other embodiments, ectoparasites can be preferred. Infestations in warm-blooded animals and fish include lice, biting lice, ticks, nasal bots, keds, biting flies, muscoid flies, flies, myiasitic fly larvae, chiggers, gnats, mosquitoes and fleas.

[0301] The compounds of the invention are especially useful for combating the following parasites: Cimex lectularius, Rhipicephalus sanguineus, and Ctenocephalides felis.

[0302] As used herein, the term “animal” includes warm-blooded animals (including humans) and fish. Preferred are mammals, such as cattle, sheep, swine, camels, deer, horses, pigs, poultry, rabbits, goats, dogs and cats, water buffalo, donkeys, fallow deer and reindeer, and also in furbearing animals such as mink, chinchilla and raccoon, birds such as hens, geese, turkeys and ducks and fish such as fresh- and salt-water fish such as trout, carp and eels. Particularly preferred are domestic animals, such as dogs or cats.

[0303] The compounds I may be applied in total amounts of 0.5 mg / kg to 100 mg / kg per day, preferably 1 mg / kg to 50 mg / kg per day.

[0304] For oral administration to warm-blooded animals, the compounds I may be formulated as animal feeds, animal feed premixes, animal feed concentrates, pills, solutions, pastes, suspensions, drenches, gels, tablets, boluses and capsules. For oral administration, the dosage form chosen should provide the animal with 0.01 mg / kg to 100 mg / kg of animal body weight per day of the compounds I, preferably with 0.5 mg / kg to 100 mg / kg of animal body weight per day.

[0305] Alternatively, the compounds I may be administered to animals parenterally, e.g., by intraruminal, intramuscular, intravenous or subcutaneous injection. The compounds I may be dispersed or dissolved in a physiologically acceptable carrier for subcutaneous injection. Alternatively, the compounds I may be formulated into an implant for subcutaneous administration. In addition the compounds I may be transdermally administered to animals. For parenteral administration, the dosage form chosen should provide the animal with 0.01 mg / kg to 100 mg / kg of animal body weight per day of the compounds I. The compounds I may also be applied topically to the animals in the form of dips, dusts, powders, collars, medallions, sprays, shampoos, spot-on and pour-on formulations and in ointments or oil-in-water or water-in-oil emulsions. For topical application, dips and sprays usually contain 0.5 ppm to 5,000 ppm and preferably 1 ppm to 3,000 ppm of the compounds I. In addition, the compounds I may be formulated as ear tags for animals, particularly quadrupeds e.g. cattle and sheep.

[0306] Oral solutions are administered directly.

[0307] Solutions for use on the skin are trickled on, spread on, rubbed in, sprinkled on or sprayed on. Gels are applied to or spread on the skin or introduced into body cavities.

[0308] Pour-on formulations are poured or sprayed onto limited areas of the skin, the active compound penetrating the skin and acting systemically. Pour-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtures.

[0309] Emulsions can be administered orally, dermally or as injections.

[0310] Suspensions can be administered orally or topically / dermally.

[0311] Semi-solid preparations can be administered orally or topically / dermally.

[0312] For the production of solid preparations, the active compound is mixed with suitable excipients, if appropriate with addition of auxiliaries, and brought into the desired form.

[0313] The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound I.

[0314] Ready-to-use preparations contain the compounds acting against parasites, preferably ectoparasites, in concentrations of 10 ppm to 80% by weight, preferably from 0.1 to 65% by weight, more preferably from 1 to 50% by weight, most preferably from 5 to 40% by weight.

[0315] Preparations which are diluted before use contain the compounds acting against ectoparasites in concentrations of 0.5 to 90% by weight, preferably of 1 to 50% by weight.

[0316] Furthermore, the preparations comprise the compounds of formula I against endoparasites in concentrations of 10 ppm to 2% by weight, preferably of 0.05 to 0.9% by weight, very particularly preferably of 0.005 to 0.25% by weight.

[0317] Solid formulations which release compounds of the invention may be applied in total amounts of 10 mg / kg to 300 mg / kg, preferably 20 mg / kg to 200 mg / kg, most preferably 25 mg / kg to 160 mg / kg body weight of the treated animal in the course of three weeks.

[0318] A. Preparation examples

[0319] The compounds were characterized by melting point determination, by NMR spectroscopy or by the mass-to-charge ratio ([m / z]) and retention time (RT; [min.]), as determined by mass spectrometry (MS) coupled with HPLC analysis (HPLC-MS = high performance liquid chromatography-coupled mass spectrometry), LC analysis (LC-MS = liquid chromatography- coupled mass spectrometry) or chiral SFC (SFC = supercritical fluid chromatography).

[0320] Method A: LC-MS: SHIMADZU LCMS-2020 ESI; Column: Diamonsil plus 5 pm 30*3.0mm; Mobile Phase: A: 0.05% TFA; B: ACN; Temperature: 40°C; Flow: 2.0 mL / min; MS: ESI positive; Mass range (m / z): 100-1000.

[0321] Method B: Agilent 1200 & G6130A; Column: Diamonsil Plus, C-18, 5 pm, 30*4.6 mm; Mobile Phase: A: 0.05% TFA; B: ACN; Temperature: 40°C; Flow: 2.0 mL / min; MS: ESI positive; Mass range (m / z): 100-1000.

[0322] Method C: LC: Shimadzu LC-30AD, ESI; Column: Kinetex EVO C18.5pm 2.1x30mm; Mobile phase: A: water + 0.04% TFA; B: ACN + 0.02% TFA; Temperature: 40°C; Gradient: 5% B to 100% B in 2.5 min; 100% B to 5% B in 0.02min; 5% B for 0.5min; Flow: 0.8mL / min; MS: ESI positive; Mass range: 100-2000.

[0323] Method D: LC: Shimadzu LC-30AD, ESI; Column: Xbridge C18, 5pm 4.6*30mm; mobile phase: B (ACN) A (0.05%TFA aq.); gradient (B%), Gradient: 20% B to 95% B in 7 min. MS: ESI positive; Mass range: 100-1000.

[0324] Method E: LC: Shimadzu LC-20AD MSD: LCMS-2020, Mobile Phase A: 0.04% TFA in H2O, Mobile Phase B: 0.02% TFA In CAN, Total Flow: 0.8 mL / min in 3 min, Oven Temperature: 40 °C.

[0325] Chiral SFC: Instrument: CAS-TJ-ANA-SFC-M (Water UPCC with SQ Detector 2); Column: Chiralpak IG-3 100x4.6mm I.D.,3pm, Mobile phase: A: CO2, B: IPA(0.2%NH3(7M in MeOH), v / v; Gradient: 10%B to 90% B in 4 min; Flow rate: 3.4 mL, Column temp: 35 °C, ABPR: 2000psi

[0326] Example 1 : Synthesis of N-(1-(3-(4-Methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-1):

[0327] Step 1 : (Z)-N-(1-(3-((2-(4-Methoxybenzyl)hydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide:

[0328] A mixture of (4-methoxybenzyl)hydrazine (58mg, 0.38mmol) and N-[1-(3-formylpyrazin-2- yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (150mg, 0.38mmol) in MeOH (4mL) was stirred at 30°C for 1 hr. The mixture was concentrated to afford N-(1 -(3-(4-methyl-6-oxo-1 , 4,5,6- tetrahydro-1 ,2,4-triazin-3-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (160mg, 79% yield) as a yellow solid. LC-MS (ES) m / z=526.4 (M+H)+.

[0329] Step 2: N-(1-(3-(1-(4-Methoxybenzyl)-4-methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide:

[0330] To a mixture of N-(1-(3-(4-Methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (160mg, 0.30mmol) in THF (2mL) was added dropwise a solution of NBS (54mg, 0.30mmol) in THF (2mL) at 0°C. The mixture was stirred at 0°C for 0.5hr. Methyl 2-(methylamino)acetate hydrochloride (64mg, 0.46mmol) in MeOH (1mL) was added dropwise to the mixture at 0°C. Then (154mg, 1.52mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 hr. The mixture was warmed to 30°C and stirred for 6hrs. The mixture was concentrated. The residue was purified by column chromatography (PE / EtOAc = 1 / 1) to afford N-(1-(3-(1-(4-methoxybenzyl)-4-methyl-6-oxo-1 ,4,5,6-tetrahydro- 1,2,4-triazin-3-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (132mg, 73% yield) as a yellow solid. LC-MS (ES) m / z (M+H)+=595.5.

[0331] Step 3: N-(1-(3-(4-methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide:

[0332] To a mixture of N-(1-(3-(1-(4-methoxybenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydro-1,2,4-triazin- 3-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (130mg, 0.22mmol) in TFA (4mL) was added TfOH (0.4mL) at 0°C. The mixture was stirred at 0°C for 0.5hr. The mixture was diluted with EtOAc (10mL). The mixture was adjusted pH=10-11 with sat. aq. NaHCCh. The mixture was extracted with EtOAc (10mLx3). The organic layer was concentrated. The residue was purified by column chromatography (PE / EtOAc=1 / 4) to afford the crude title compound. Then the crude compound was purified by reverse flash (C-18) (5-95% ACN in water) to afford N-(1- (3-(4-methyl-6-oxo-1,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (72.1 mg, 69% yield) as a white solid. LC-MS (ES) m / z = 475.1 (M+H)+.

[0333] 1H-NMR (400MHz, DMSO-d6) δ [ppm] 10.63 (s, 1 H), 9.51 (d, J=6.4Hz, 1H), 8.72 (d, J=2.4Hz, 1H), 8.63 (d, J=2.4Hz, 1H), 8.53 (s, 2H), 8.31 (s, 1 H), 5.41-5.38 (m, 1 H), 3.93-3.82 (m, 2H), 2.67 (s, 3H), 1.59 (d, J=6.8Hz, 3H).

[0334] Example 2: Synthesis of N-(1-(3-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-4)

[0335] Step 1 : tert-butyl 2-(3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1-carboxylate:

[0336] A mixture of 3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (550mg, 1.35mmol), tert-butyl 1-methylhydrazine-1-carboxylate (296mg, 2.02mmol), 1-[bis(dimethyl- amin)methylen]-1 H-1 ,2,3-triazol[4,5-b]pyridinium-3-oxid-hexafluorophosphat (770mg, 2.02mmol) and diisopropyl ethyl amine (524mg, 4.05mmol) in dichloromethane (DCM ; 6mL) was stirred at 20-25°C for 16hrs under N2. The mixture was diluted with DCM (20mL), washed with saturated brine (10mL), dried over Na2SO4, filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc= 100 / 0 to 0 / 100) to afford tert-butyl 2-(3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1 -carboxylate (150mg, 21% yield) as a yellow solid. LC-MS (ES) m / z=480.4 (M+H-tBu)+.

[0337] Step 2: N-(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benz- amide hydrochloride:

[0338] A mixture of tert-butyl 2-(3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1 -carboxylate (150mg, 0.28mmol) and HCI / Et2O (3mL) was stirred at 20-25°C for 2hrs. The mixture was concentrated to afford crude N-(1-(3-(2-methylhydrazine-1-carbo- nyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide hydrochloride (132mg, 100% yield) as a yellow solid which was used directly for the next step without further purification. LC-MS (ES) m / z=436.4 (M+H-HCI)+.

[0339] Step 3: N-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5-bis(tri- fluoromethyl)benzamide:

[0340] To a solution of N-(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoro- methyl)benzamide hydrochloride (150mg, 0.32mmol) and TEA (96mg, 0.95mmol) in DCM (2mL) was added a solution of 2-chloroacetyl chloride (29mg, 0.25mmol) in DCM (1mL) dropwise at 0°C under N2. The reaction mixture was stirred at 20-25°C for 2hrs. The mixture was concentrated to afford crude N-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazinecarbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (150mg, 92% yield) as a yellow oil which was used directly for the next step without further purification. LC-MS (ES) m / z=512.3 (M+H)+.

[0341] Step 4: N-(1-(3-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide:

[0342] A mixture of N-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (150mg, 0.29mmol) and K2CO3 (81mg, 0.59mmol) in EtOH (2mL) was stirred at 80°C under N2for 3hrs. The mixture was filtered. The filtrate was purified by prep- HPLC to afford N-(1-(3-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (35.4mg, 25% yield) as a white solid. LC-MS (ES) m / z=475.9 (M+H)+.

[0343] 1H-NMR (400MHz, DMSO-d6) δ [ppm] 9.52 (d, J=6.8Hz, 1 H), 8.76 (d, J=2.4Hz 1 H), 8.65 (d, J=2.4Hz 1 H), 8.52 (s, 2H), 8.32 (s, 1 H), 5.82-5.78 (m, 1 H), 4.92-4.84 (m, 2H), 3.23 (s, 3H), 1.62 (d, J=7.2Hz, 3H).

[0344] Compound VII lb: Synthesis of N-[1-(3-formylpyrazin-2-yl)ethyl]-3,5 bis(trifluoromethyl)benz- amide:

[0345] A solution of 3,5-bis(trifluoromethyl)-N-(1-(3-vinylpyrazin-2-yl)ethyl)benzamide (30g, 0.077mol) in MeOH (300mL) was cooled to -78°C in a dry ice-acetone bath. O3 was bubbled into the solution for 30min at this temperature, and then N2 was bubbled to the solution for 20min, and (CHS)2S (28.59g, 0.4602mol) was added dropwise. The mixture was added H2O (50mL) and extracted with EtOAc (50mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatograph (PE / EtOAc = 95:5) to give the compound N-[1-(3-formylpyrazin-2-yl)ethyl]-3,5- bis(trifluoromethyl)benzamide (20g, 46.4%) as a yellow solid, which was about 95% purity by LCMS, but not pure by1H-NMR.

[0346] LCMS [mobile phase: from 95% water (0.1 % TFA) and 5% CH3CN to 95% CH3CN and 5% water in 3min, kept for 3 min.], Rt= 1.62min; MS calcd.: 391.27; MS found: 392.2 (M+1)+.1H-NMR (400MHz, DMSO-d6) δ [ppm] 10.22 (s, 1 H), 9.55 (d, J=8.0Hz, 1 H), 8.87 (d, J=4.0Hz, 1 H), 8.84 (d, J=4.0Hz, 1 H), 6.34 (s, 2H), 6.29 (s, 1 H), 6.07-6.00 (m, 1 H), 1.56-1.55 (d, J=4.0 Hz, 3H).

[0347] Example 3 : Synthesis of 3-chloro-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-5- (trifluoromethyl)benzamide (I-5)

[0348] Step 1 : 1-(3-chloropyrazin-2-yl)- / V-(2,4-dimethoxybenzyl)ethan-1 -amine :

[0349] To a solution of 1-(3-chloropyrazin-2-yl)ethanone (5.00 g, 31.94 mmol), (3,4- dimethylphenyl)methanamine (16.02 g, 95.80 mmol) in MeOH (70 mL) was added titanium(IV) isopropoxide (13.60 g, 47.90 mmol) at rt. Then the mixture was stirred at rt for 16 hrs. Then NaBH4 (2.36 g, 63.87 mmol) was added to the mixture. The reaction mixture was stirred at rt for 2 hrs. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 1-(3-chloropyrazin-2-yl)- / V-(2,4-dimethoxybenzyl)ethan- 1-amine (7.00 g, 71 % yield)) as a yellow oil. LC-MS (ES) m / z = 308.2 (M+H)+.

[0350] Step 2: 1 Tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(2,4-dimethoxybenzyl)carbamate:

[0351] To a solution of 1-(3-chloropyrazin-2-yl)- / V-(2,4-dimethoxybenzyl)ethan-1-amine (9.00 g, 29.24 mmol), TEA (8.86 g, 87.73 mmol) in THF (100 mL) was added (Boc)2O (9.57 g, 43.86 mmol) at rt. The reaction mixture was stirred at 30 °C for 2 hrs. Then the reaction mixture was concentrated with silica gel and purified by chromatography on silica gel (PE / EtOAC = 5 / 1) to afford the tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(2,4-dimethoxybenzyl)carbamate (11.0 g, 61 % yield) as a yellow oil. LC-MS (ES) m / z = 308.2 (M+H-Boc)+.

[0352] Step 3: 2-(Diethylamino)ethyl 3-(1-((tert-butoxycarbonyl)(2,4- dimethoxybenzyl)amino)ethyl)pyrazine-2-carboxylate :

[0353] A solution of tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(2,4-dimethoxybenzyl)carbamate (11.00 g, 26.97 mmol), 2-(diethylamino)ethan-1-ol (6.32 g, 53.94 mmol) and Pd(PPh3)2Cl2 (946 mg, 1.35 mmol) in NMP (80 mL) was stirred at 120 °C for 16 hrs. The mixture was washed with water (100 mL), extracted with EtOAc (200 mL *3). The organic layer was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2-(diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(2,4-dimethoxybenzyl)amino)ethyl)pyrazine-2-carboxylate (11.0 g, 79% yield) as a yellow oil. LC-MS (ES) m / z = 517.0 (M+H)+.

[0354] Step 4: 2-(Diethylamino)ethyl 3-(1-aminoethyl)pyrazine-2-carboxylate :

[0355] A solution of 2-(diethylamino)ethyl 3-(1-((tert-butoxycarbonyl)(2,4- dimethoxybenzyl)amino)ethyl)pyrazine-2-carboxylate (6.00 g, 11.61 mmol) in EtOAc (30 mL) and HCI / EtOAc (30 mL) was stirred at rt for 16 hrs. The reaction was concentrated to afford 2- (diethylamino)ethyl 3-(1-aminoethyl)pyrazine-2-carboxylate (3.00 g, 78% yield) as a yellow solid. LC-MS (ES) m / z = 267.0 (M+H)+. Step 5: 2-(Diethylamino)ethyl 3-(1-(3-chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2- carboxylate :

[0356] To a solution of 2-(diethylamino)ethyl 3-(1-aminoethyl)pyrazine-2-carboxylate (2.20 g, 8.26 mmol), 3-chloro-5-(trifluoromethyl)benzoyl chloride (2.41 g, 9.91 mmol) in DMF (30 mL) was added TEA (2.50 g, 24.78 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction was diluted with water (30 mL), extracted with DCM (20 mL *2). Then the organic layer was washed with brine (30 mL *2) and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2- (diethylamino)ethyl 3-(1-(3-chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (3.00 g, 77% yield) as a yellow oil. LC-MS (ES) m / z = 473.3 (M+H)+.

[0357] Step 6: 3-(1-(3-Chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid :

[0358] A solution of 2-(diethylamino)ethyl 3-(1-(3-chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine- 2-carboxylate (3.00 g, 6.34 mmol), LiOH.H2O (1.60 g, 38.06 mmol) in THF / H2O (3 / 1 , 50 mL) was stirred at rt for 5 hrs. The reaction was diluted with water and extracted with EtOAc (10 mL). Then the water phase was acidified with 1 M HCI to adjust pH = 2, extracted with EtOAc (20 mL *3). The organic layer was washed with brine (30 mL *2), dried over Na2SO4, filtered and concentrated to afford 3-(1-(3-chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (1.00 g, 41% yield) as a yellow solid. LC-MS (ES) m / z = 374.2 (M+H)+.

[0359] Step 7: 3-Chloro- / V-(1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide :

[0360] A solution of 3-(1-(3-chloro-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (1.20 g, 3.21 mmol), 2-chloroacetohydrazide (453 mg, 4.17 mmol), HATU (1.83 g, 4.82 mmol) and TEA (973 mg, 9.63 mmol) in DCM (20 mL) was stirred at rt for 3 hrs. The reaction was washed with water (30 mL), extracted with DCM (20 mL *2). The organic layer was washed with brine (30 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford 3-chloro- / V-(1-(3-(2-(2- chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (1.20 g, 81 % yield) as a yellow solid. LC-MS (ES) m / z = 464.2 (M+H)+.

[0361] Step 8: 3-Chloro- / V-(1-(3-(5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide :

[0362] A mixture of 3-chloro- / V-(1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide (1.00 g, 2.15 mmol), K2CO3 (892 mg, 6.46 mmol) and Nal (323 mg, 2.15 mmol) in DMF (30 mL) was stirred at 80 °C for 2 hrs. The reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford 3-chloro- / V-(1-(3-(5-oxo-5,6-dihydro-4 / 7- 1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (151 mg, 16% yield) as a white solid. LC-MS (ES) m / z = 428.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.37 (d, J = 6.8 Hz, 1 H), 8.74 (d, J = 2.4 Hz, 1 H), 8.63 (d, J = 2.0 Hz, 1 H), 8.24 (s, 1 H), 8.19 (s, 1 H), 8.06 (s, 1 H), 6.06 (s, 1 H), 5.83-5.76 (m, 1 H), 4.86 (s, 2H), 1.57 (d, J = 6.8 Hz, 3H).

[0363] Example 4: Synthesis of / V-methyl- / \ / -(1-(3-(5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-6) :

[0364] Step 1 : tert- butyl 2-(2-chloroacetyl)hydrazine-1 -carboxylate :

[0365] To a solution of tert-butyl hydrazinecarboxylate (5.00 g, 37.80 mmol) and TEA (7.64 mg, 75.67 mmol) in DCM (60 mL) was added 2-chloroacetyl chloride (4.70 g, 41.62 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 hrs. The reaction was diluted with water (100 mL), extracted with DCM (50 mL *3). The organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford tert-butyl 2-(2-chloroacetyl)hydrazine-1-carboxylate (5.00 g, 58% yield) as a white solid. LC-MS (ES) m / z = 152.9 (M+H-fBu)+.

[0366] Step 2: 2-Chloroacetohydrazide :

[0367] A solution of tert-butyl 2-(2-chloroacetyl)hydrazine-1-carboxylate (5.00 g, 23.96 mmol) in EtOAc (25 mL) and HCI / EtOAc (25 mL) was stirred at rt for 2 hrs. The reaction mixture was concentrated to afford 2-chloroacetohydrazide (2.50 g, 96% yield) as a white solid. LC-MS (ES) m / z = 108.8 (M+H)+.

[0368] Step 3: 1-(3-Chloropyrazin-2-yl)- / V-methylethan-1-amine :

[0369] To a solution of 1-(3-chloropyrazin-2-yl)ethanone (5.00 g, 31.93 mmol), methanamine (9.92 g, 95.80 mmol, 30 wt.% in EtOH) in MeOH (100 mL) was added Titanium(IV) isopropoxide (13.60 g, 47.90 mmol) at rt. The reaction mixture was stirred at rt for 16 hrs. The mixture was added sodium borohydride (1 .81 g, 47.9 mmol). Then the mixture was stirred at rt for 2 hrs. The reaction was concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH=20 / 1) to afford 1-(3-chloropyrazin-2-yl)- / V-methylethan-1 -amine (4.50 g, 82% yield) as yellow oil. LC-MS (ES) m / z = 172.0 (M+H)+.

[0370] Step 4: Tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate :

[0371] To a solution of 1-(3-chloropyrazin-2-yl)- / V-methylethan-1-amine (3.60 g, 20.98 mmol), TEA (6.37 g, 62.93 mmol) in THF (50 mL) was added (Boc)2O (6.87 g, 31.46 mmol). The reaction mixture was stirred at 30 °C for 2 hrs. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL *3). The organic layer was washed with brine (30 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate (5.00 g, 88% yield) as yellow oil.1H NMR (400 MHz, CDCI3) δ [ppm] 8.48 (s, 1 H), 8.30 (s, 1 H), 5.79- 5.58 (m, 1 H), 2.84-2.72 (m, 3H), 1.55-1.53 (m, 3H), 1.40-1.20 (m, 9H).

[0372] Step 5 : 2-(Diethylamino)ethyl 3-(1-((tert-butoxycarbonyl)(methyl)amino)ethyl)pyrazine-2- carboxylate : A solution of tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate (5.50 g, 20.24 mmol), 2-(diethylamino)ethanol (4.74 g, 40.48 mmol) and Pd(PPh3)2CI2(710 mg, 1.01 mmol) in NMP (70 mL) was stirred at 120 °C for 16 hrs. Then the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL *3). The organic layer was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2-(diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(methyl)amino)ethyl)pyrazine-2-carboxylate (6.00 g, 78% yield) as yellow oil. LC-MS (ES) m / z = 381.0 (M+H)+.

[0373] Step 6: 2-(Diethylamino)ethyl 3-(1-(methylamino)ethyl)pyrazine-2-carboxylate :

[0374] A solution of 2-(diethylamino)ethyl 3-(1-((tert-butoxycarbonyl)(methyl)amino)ethyl)pyrazine-2- carboxylate (4.00 g, 10.51 mmol) in EtOAc (20 mL) and HCI / EtOAc (20 mL) was stirred at rt for 16 hrs. The reaction was concentrated to afford 2-(diethylamino)ethyl 3-(1- (methylamino)ethyl)pyrazine-2-carboxylate (3.50 g, 83% yield) as a yellow solid. LC-MS (ES) m / z = 281.0 (M+H)+.

[0375] Step 7: 2-(Ethyl(methyl)amino)ethyl 3-(1-( / V-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate :

[0376] To a solution of 2-(diethylamino)ethyl 3-(1-(methylamino)ethyl)pyrazine-2-carboxylate (2.20 g, 7.85 mmol), 3,5-bis(trifluoromethyl)benzoyl chloride (2.60 g, 9.42 mmol) in DMF (50 mL) was added TEA (2.38 mg, 23.54 mmol). The reaction mixture was stirred at rt for 2 hrs. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL *2). The organic layer was washed with brine (20 mL *2) and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2- (ethyl(methyl)amino)ethyl 3-(1-( / V-methyl-3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2- carboxylate (4.00 g, 75% yield) as yellow oil. LC-MS (ES) m / z = 521.1 (M+H)+.

[0377] Step 8: 3-(1-( / V-Methyl-3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid :

[0378] A solution of 2-(ethyl(methyl)amino)ethyl 3-(1-( / V-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (4.50 g, 8.65 mmol), LiOH.H2O (1.09 g, 25.94 mmol) in THF / H2O = 3 / 1 (60 mL) was stirred at rt for 2 hrs. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL *3). The water layer was acidified with 1 M HCI to adjust pH = 2, extracted with EtOAc (20 mL *3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford 3-(1-( / V-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (2.20 mg, 60% yield) as a yellow solid. LC-MS (ES) m / z = 422.3 (M+H)+.

[0379] Step 9: / \ / -(1-(3-(2-(2-Chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / -methyl-3,5- bis(trifluoromethyl)benzamide :

[0380] A solution of 3-(1-( / V-methyl-3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (1.10 g, 2.61 mmol), 2-chloroacetohydrazide (368 mg, 3.39 mmol), HATU (1.49 g, 3.92 mmol) and TEA (791 mg, 7.83 mmol) in DCM (20 mL) was stirred at rt for 16 hrs. The reaction was diluted with water (30 mL) and extracted with DCM (20 mL *2). Then the organic layer was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (PE / EtOAc = 5 / 1) to afford / \ / -(1-(3-(2-(2- chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / -methyl-3,5- bis(trifluoromethyl)benzamide (1.20 g, 81% yield) as a yellow solid. LC-MS (ES) m / z = 512.3 (M+H)+.

[0381] Step 10: / V-Methyl- / V-(1-(3-(5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0382] A mixture of / V-(1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / -methyl-3,5- bis(trifluoromethyl)benzamide (700 mg, 1.40 mmol), K2CO3 (566 mg, 4.10 mmol) and Nal (205 mg, 1.40 mmol) in DMF (30 mL) was stirred at rt for 2 hrs. The reaction was diluted with water (20 mL) and extracted with EtOAc (30 mL *3). Then the organic layer was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford / V-methyl- / \ / -(1-(3-(5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (151 mg, 16% yield) as a white solid. LC-MS (ES) m / z = 476.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.79 (d, J = 2.4 Hz, 1 H), 8.70-8.67 (m, 1H), 8.21-8.13 (m, 1H), 8.04-7.62 (m, 2H), 6.29-5.43 (m, 1 H), 4.91-4.45 (m, 2H), 3.29-2.85 (m, 3H), 1.64 (d, J = 6.8 Hz, 3H).

[0383] Example 5 : Synthesis of 3-chloro- / V-methyl- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (I-9) :

[0384] Step 1 : 2-(Diethylamino)ethyl 3-(1-(3-chloro- / V-methyl-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate :

[0385] To a solution of 3-chloro-5-(trifluoromethyl)benzoyl chloride (6.49 g, 26.70 mmol) and TEA (5.39 g, 53.40 mmol) in DCM (50 mL) was added a solution of 2-(diethylamino)ethyl 3-(1- (methylamino)ethyl)pyrazine-2-carboxylate (5.00 g, 17.80 mmol) in DMF (10 mL) dropwise. The reaction mixture was stirred at rt for 2 hrs. The reaction was washed with saturated brine (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc =100 / 0 to 0 / 100) to afford 2-(diethylamino)ethyl 3-(1-(3-chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (3.70 g, 43% yield) as a yellow solid. LC-MS (ES) m / z = 487.2 (M+H)+.

[0386] Step 2: 3-(1-(3-Chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid :

[0387] A mixture of 2-(diethylamino)ethyl 3-(1-(3-chloro- / V-methyl-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (3.90 g, 8.00 mmol) and LiOH.H2O (0.67 g, 16.00 mmol) in THF / H2O = 3 / 1 (40 mL) was stirred at 30 °C for 16 hrs. The mixture was diluted with water (30 mL), extracted with EtOAc (20 mL). The aqueous layer was acidified with 1 M HCI to adjust pH = 3, extracted with EtOAc (30 mL *3). The organic layer was washed with saturated brine (30 mL), dried over Na2SC>4, filtered and concentrated to afford 3-(1-(3-chloro- / V- methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (3.00 g, 96% yield) as a yellow solid. LC-MS (ES) m / z = 387.8 (M+H)+.

[0388] Step 3: Tert-butyl 2-(3-(1-(3-chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2- carbonyl)-1-methylhydrazine-1 -carboxylate :

[0389] A mixture of 3-(1-(3-chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (1.50 g, 3.90 mmol), tert-butyl 1-methylhydrazine-1-carboxylate (0.86 g, 5.85 mmol), HATLI (2.22 g, 5.85 mmol) and TEA (1.18 g, 11.70 mmol) in DCM (20 mL) was stirred at 30 °C for 16 hrs. The reaction mixture was diluted with DCM (30 mL), washed with saturated brine (20 mL). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 100 / 0 to 90 / 10) to afford tert-butyl 2-(3- (1-(3-chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1-carboxylate (1.60 g, 80% yield) as a yellow solid. LC-MS (ES) m / z = 516.3 (M+H)+.

[0390] Step 4: 3-Chloro- / V-methyl- / \ / -(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide :

[0391] A solution of tert-butyl 2-(3-(1-(3-chloro- / V-methyl-5-(trifluoromethyl)benzamido)ethyl)pyrazine- 2-carbonyl)-1-methylhydrazine-1-carboxylate (1.80 g, 3.49 mmol) in EtOAc (20 mL) and HCI / EtOAc (20 mL) was stirred at rt for 16 hrs. The reaction was concentrated to afford 3- chloro- / V-methyl- / \ / -(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide (1.00 g, 69% yield) as yellow solid. LC-MS (ES) m / z = 416.2 (M+H)+.

[0392] Step 5: 3-Chloro- / V-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / V-methyl-5-(trifluoromethyl)benzamide :

[0393] To a solution of 3-chloro- / V-methyl- / \ / -(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- 5-(trifluoromethyl)benzamide (1.00 g, 2.41 mmol), TEA (729 mg, 7.22 mmol) in DCM (20 mL) was added 2-chloroacetyl chloride (326 mg, 2.89 mmol) in DCM (2 mL) dropwise at rt. The reaction mixture was stirred at rt for 2 hrs. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL *3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to afford 3-chloro- / V-(1-(3-(2-(2-chloroacetyl)-2- methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / -methyl-5-(trifluoromethyl)benzamide (1 .00 g, 85% yield) as a yellow solid. LC-MS (ES) m / z = 492.2 (M+H)+

[0394] Step 6: 3-Chloro- / V-methyl- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide :

[0395] A mixture of 3-chloro- / V-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazine-1-carbonyl)pyrazin-2- yl)ethyl)- / V-methyl-5-(trifluoromethyl)benzamide (1.00 g, 2.03 mmol), K2CO2(841 mg, 6.10 mmol) and Nal (305 mg, 2.03 mmol) in ACN (30 mL) was stirred at 80 °C for 2 hrs. The reaction was diluted with water (30 mL *2) and extracted with EtOAc (20 mL *3). The organic layer was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford 3-chloro- / V-methyl- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5- (trifluoromethyl)benzamide (400 mg, 43% yield) as a white solid. LC-MS (ES) m / z = 456.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.81 (s, 1 H), 8.74-8.69 (m, 1 H), 7.98-7.91 (m, 1 H), 7.74-7.30 (m, 2H), 6.34-5.67 (m, 1 H), 4.97-4.65 (m, 2H), 3.33-3.05 (m, 3H), 2.73-2.51 (m, 3H), 1.62 (d, J = 6.8 Hz, 3H).

[0396] Example 6: Synthesis of 3-chloro- / V-(cyclopropylmethyl)- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro- 4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (I-8) :

[0397] Step 1 : 1-(3-Chloropyrazin-2-yl)- / V-(cyclopropylmethyl)ethan-1 -amine :

[0398] To a solution of 1-(3-chloropyrazin-2-yl)ethanone (2.0 g, 12.78 mmol), cyclopropylmethanamine (2.73 g, 38.32 mmol) in MeOH (30 mL) was added Titanium(IV) isopropoxide (4.72 g, 16.61 mmol) at rt. Then the mixture was stirred at rt for 16 hrs. Then NaBH4 (724 mg, 19.16 mmol) was added at rt. The reaction mixture was stirred at rt for 2 hrs. The reaction was concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 1-(3-chloropyrazin-2-yl)- / V-(cyclopropylmethyl)ethan-1-amine (1.80 g, 67% yield) as yellow oil. LC-MS (ES) m / z = 212.1 (M+H)+.

[0399] Step 2: Tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(cyclopropylmethyl)carbamate :

[0400] To a solution of 1-(3-chloropyrazin-2-yl)- / V-(cyclopropylmethyl)ethan-1 -amine (6.0 g, 28.30 mmol), (BOC)2O (9.26 g, 42.45 mmol) in DCM (60 mL) was added TEA (8.57 g, 84.85 mol) dropwise. The reaction mixture was stirred at rt for 4 hours. The reaction was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford tert- butyl (1-(3-chloropyrazin-2-yl)ethyl)(cyclopropylmethyl)carbamate (7.0 g, 75% yield) as yellow oil. LC-MS (ES) m / z = 211.9 (M+H-Boc)+.

[0401] Step 3: 2-(Diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylate : A solution of tert- butyl (1-(3-chloropyrazin-2-yl)ethyl)(cyclopropylmethyl)carbamate (8.0 g, 25.72 mol), 2-diethylaminoethanol (8.56 g, 51.40 mol) and Pd(PPh3)2CI2(0.90 g, 1.29 mol) in NMP (80 mL) was stirred at 120 °C for 4 hours under CO atmosphere. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL*2). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford 2-(diethylamino)ethyl 3-(1- ((tert-butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylate (10.00 g, 49% yield) as brown oil. LC-MS (ES) m / z = 421.5 (M+H)+.

[0402] Step 4: 3-(1-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid : To a solution of 2-(diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylate (10.0 g, 23.8 mol) in THF (50 mL) was added a solution of LiOH.H2O (1 .5 g, 35.7 mol) in H2O (50 mL) at 0 °C. The reaction mixture was stirred at rt for 3 hours. The mixture was extracted with EtOAc (30 mL). The aqueous layer was acidified with 1 M HCI aqueous to adjust pH = 3 and extracted with EtOAc (50 mL *2). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 3-(1-((tert- butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid (4.0 g, 50% yield) as white solid. LC-MS (ES) m / z = 222.2 (M+H-Boc)+.

[0403] Step 5: 3-(1-((Cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid :

[0404] A solution of 3-(1-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid (2.00 g, 6.2 mol) in HCI / EtOAc (20 mL) was stirred at rt for 4 hours. The mixture was concentrated to afford 3-(1-((cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid (1.6 g, 100% yield) as a white solid. LC-MS (ES) m / z = 222.1 (M+H)+.

[0405] Step 6: 3-(1-(3-Chloro- / V-(cyclopropylmethyl)-5-(trifluoromethyl)benzamido)ethyl)pyrazine-2- carboxylic acid :

[0406] To a solution of 3-(1-((cyclopropylmethyl)amino)ethyl)pyrazine-2-carboxylic acid (1.0 g, 4.52 mmol), 3-chloro-5-(trifluoromethyl)benzoyl chloride (1.32 g, 5.42 mmol) in DCM (10 mL) was added TEA (1.37 g, 13.56 mmol) dropwise at 0°C under nitrogen. The reaction mixture was stirred at rt for 1 hour. The mixture was diluted with ice water (20 mL) and extracted with DCM (10 mL *2). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 3-(1-(3-chloro- / V-(cyclopropylmethyl)-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (1000 mg, 31% yield) as a yellow oil. LC-MS (ES) m / z = 428.2 (M+H)+.

[0407] Step 7: Tert-butyl 2-(3-(1-(3-chloro- / V-(cyclopropylmethyl)-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1-methylhydrazine-1-carboxylate : A solution of 3-(1-(3-chloro- / V-(cyclopropylmethyl)-5-(trifluoromethyl)benzamido)ethyl)pyrazine- 2-carboxylic acid (1.00 g, 2.33 mmol), (tert-butoxy)- / V-methylcarbohydrazide (409 mg, 2.80 mmol), HATU (1.15 g, 3.03 mmol) and TEA (708 mg, 7.00 mmol) in DCM (10 mL) was stirred at rt for 3 hours. The mixture was diluted with ice water (20 mL) and extracted with DCM (10 mL *2). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford tert-butyl 2-(3-(1-(3-chloro- / V-(cyclopropylmethyl)-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1-methylhydrazine-1-carboxylate (750 mg, 52% yield) as a white solid. LC-MS (ES) m / z = 556.2 (M+H)+.

[0408] Step 8: 3-Chloro- / V-(cyclopropylmethyl)- / \ / -(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-5-(trifluoromethyl)benzamide :

[0409] A solution of tert-butyl 2-(3-(1-(3-chloro- / V-(cyclopropylmethyl)-5- (trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1-methylhydrazine-1-carboxylate (800 mg, 1.43 mmol) in HCI / EtOAc (10 mL) was stirred at 30 °C for 4 hours. The mixture was concentrated to afford 3-chloro- / V-(cyclopropylmethyl)- / \ / -(1-(3-(2-methylhydrazine-1- carbonyl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (600 mg, 64% yield) as a white solid. LC-MS (ES) m / z = 456.3 (M+H)+.

[0410] Step 9: 3-Chloro- / V-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / - (cyclopropylmethyl)-5-(trifluoromethyl)benzamide :

[0411] To a solution of 3-chloro- / V-(cyclopropylmethyl)- / \ / -(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin- 2-yl)ethyl)-5-(trifluoromethyl)benzamide (600 mg, 1.31 mmol), TEA (398 mg, 3.94 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (223 mg, 1.97 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 2 hours. The mixture was diluted with ice water (20 mL) and extracted with DCM (10 mL *2). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 3-chloro- / V-(1-(3-(2-(2-chloroacetyl)-2- methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- / \ / -(cyclopropylmethyl)-5- (trifluoromethyl)benzamide (600 mg, 81% yield) as a white solid. LC-MS (ES) m / z = 531.7 (M+H)+.

[0412] Step 10: 3-Chloro- / V-(cyclopropylmethyl)- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide :

[0413] A solution of 3-chloro- / V-(1-(3-(2-(2-chloroacetyl)-2-methylhydrazine-1-carbonyl)pyrazin-2- yl)ethyl)- / V-(cyclopropylmethyl)-5-(trifluoromethyl)benzamide (600 mg, 1.13 mmol), K2CO3 (467 mg, 3.38 mmol) and Nal (186 mg, 1.24 mmol) in ACN (10 mL) was stirred at 80 °C for 2 hours. The mixture was diluted with ice water (20 mL) and extracted with DCM (10 mL *2). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse flash (C-18) (5-95% ACN in water) to afford 3-chloro- / V- (cyclopropylmethyl)- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl)ethyl)-5-(trifluoromethyl)benzamide (320 mg, 54% yield) as a white solid. LC-MS (ES) m / z = 496.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.80 -8.70 (m, 2H), 7.96 (s, 1 H), 7.70- 7.25 (m, 2H), 6.36-5.70 (m, 1 H), 4.87-4.50 (m, 2H), 3.83-3.52 (m, 1 H), 3.19-2.98 (m, 4H), 1.68 (d, J = 6.8 Hz, 3H), 1.25-1.15 (m, 1 H), 0.49-0.12 (m, 3H), (-0.27)-(-0.51) (m, 1 H).

[0414] Example 7: Synthesis of 3,5-bis(trifluoromethyl)- / \ / -(1-(3-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4 / 7- 1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)benzamide (1-16):

[0415] Step 1 : 3-(1-(3,5-Bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid :

[0416] To a solution of 3,5-bis(trifluoromethyl)-N-[1-(3-vinylpyrazin-2-yl)ethyl]benzamide

[0417] (CAS: 2700026-12-4) (1.0 g, 2.57 mmol) in acetone / HzO = 1 :1 (20 mL) was added KMnCL (1.23 g, 7.80 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with water (30 mL) and filtered. The filtrate was extracted with EtOAc (30 mL). The aqueous layer was acidified with 2 M HCI to adjust pH = 2, extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford 3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2- carboxylic acid (0.91 g, 69% yield) as a brown solid. LC-MS (ES) m / z = 408.3 (M+H)+. Step 2: Tert-butyl 2-(3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1-carboxylate :

[0418] To a solution of 3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylic acid (900 mg, 2.20 mmol), tert-butyl 1-methylhydrazine-1 -carboxylate (388 mg, 2.64 mmol) and HATLI (1.09 g, 2.86 mmol) in DMF (10 mL) was added TEA (333 mg, 2.30 mmol) dropwise. The reaction mixture was stirred at 25 °C for 12 hrs. The mixture was diluted with H2O (20 mL), then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO44 filtered and concentrated. The residue was purified by column chromatography on silica gel (CFhCh / MeOH = 20 / 1) to afford tert-butyl 2-(3-(1-(3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1-methylhydrazine-1-carboxylate (780 mg, 42% yield) as a yellow solid. LC-MS (ES) m / z = 536.3 (M+H)+.

[0419] Step 3: / V-(1-(3-(2-Methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0420] A mixture of tert-butyl 2-(3-(1-(3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carbonyl)-1- methylhydrazine-1 -carboxylate (780 mg, 1.45 mmol) in EtOAc (5 mL) and HCI / EtOAc (5 mL) stirred at 25 °C for 2 hrs. The mixture was concentrated to afford / V-(1-(3-(2-methylhydrazine-1- carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (703 mg, 89% yield) as a brown solid. LC-MS (ES) m / z = 436.3 (M+H)+

[0421] Step 4: / \ / -(1-(3-(2-(2-Chloro-2-methylpropanoyl)-2-methylhydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide :

[0422] To a mixture of / V-(1-(3-(2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (150 mg, 0.34 mmol) and NaHCCh (86 mg, 1.03 mmol) in THF (2.5 mL) was added 2-chloro-2-methylpropanoyl chloride (58 mg, 0.41 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 6 hrs. The mixture was diluted with H2O (5 mL), then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford / \ / -(1-(3-(2-(2-chloro-2- methylpropanoyl)-2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (146 mg, 67% yield) as a yellow solid. LC-MS (ES) m / z =540.3 (M+H)+.

[0423] Step 5: 3,5-Bis(trifluoromethyl)- / \ / -(1-(3-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin- 2-yl)pyrazin-2-yl)ethyl)benzamide :

[0424] A mixture of / \ / -(1-(3-(2-(2-chloro-2-methylpropanoyl)-2-methylhydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (245 mg, 0.45 mmol), Nal (68 mg, 0.45 mmol) and K2CO3 (188 mg, 1.36 mmol) in ACN (10 mL) was stirred in air at 80 °C for 8 hrs. The mixture was diluted with H2O (20 mL), then extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (5-95% ACN in water with 0.1 % NH4HCO3) to afford 3,5- bis(trifluoromethyl)- / \ / -(1-(3-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl)ethyl)benzamide (115 mg, 48% yield) as a white solid. LC-MS (ES) m / z = 504.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.54 (d, J = 6.8 Hz, 1 H), 8.76 (d, J = 2.4 Hz, 1 H), 8.67 (d, J = 2.4 Hz, 1 H), 8.51 (s, 2H), 8.32 (s, 1 H), 5.84-5.80 (m, 1 H), 3.28 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H), 1.50 (d, J = 7.6 Hz, 6H).

[0425] Example 8: Synthesis of / V-(1-(3-(4,6-Dimethyl-5-oxo-5,6-dihydro-4 / - / -1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-13):

[0426] Step 1 : / \ / -(1-(3-(2-(2-Chloropropanoyl)-2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0427] To a mixture of N-[1-[3-(methylaminocarbamoyl)pyrazin-2-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide (300 mg, 0.69 mmol) and NaHCCh (173 mg, 2.06 mmol) in THF (5 mL) was added 2-chloropropanoyl chloride (105 mg, 0.82 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 6 hrs. The mixture was diluted with H2O (10 mL), then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated to afford / \ / -(1-(3-(2-(2-chloropropanoyl)-2-methylhydrazine-1- carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (295 mg, 77% yield) as a yellow solid. LC-MS (ES) m / z = 525.8 (M+H)+.

[0428] Step 2: / V-(1-(3-(4,6-Dimethyl-5-oxo-5,6-dihydro-4 / - / -1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide :

[0429] A mixture of / V-(1-(3-(2-(2-chloropropanoyl)-2-methylhydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (295 mg, 0.56 mmol), Nal (84 mg, 0.56 mmol) and potassium carbonate (232 mg, 1.68 mmol) in ACN (10 mL) was stirred at 80 °C for 8 hrs. The mixture was diluted with H2O (20 mL), then extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (5-95% ACN in water with 0.1% NH4HCO3) to afford / \ / -(1-(3-(4,6- dimethyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (111.2 mg, 40% yield) as a white solid. LC-MS (ES) m / z = 490.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.55-9.52 (m, 1 H), 8.76 (d, J = 2.4 Hz, 1 H), 8.67-8.66 (m, 1 H), 8.55-8.51 (m, 2H), 8.32 (s, 1 H), 5.85-5.77 (m, 1 H), 5.10-5.05 (m, 1 H), 3.26 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.51-1.46 (m, 3H).

[0430] Example 9: Synthesis of / \ / -methyl- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-thiadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-17) :

[0431] Step 1 : tert-butyl N-[1-(3-chloropyrazin-2-yl)ethyl]carbamate :

[0432] A mixture of 1-(3-chloropyrazin-2-yl)ethanamine (CAS: 1379302-21-2) (5.0 g, 31.7 mmol), BOC2O (6.92 g, 31.7 mmol) and triethylamine (4.81 g, 47.6 mmol) in THF (30 mL) was stirred at 30 °C for 2 hrs. The mixture was diluted with H2O (30 mL), extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1) to afford the compound tert-butyl N-[1-(3-chloropyrazin-2-yl)ethyl]carbamate (7.28 g, 77% yield) as a white solid. LC-MS (ES) m / z = 258.3 (M+H)+.

[0433] Step 2 : Tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate :

[0434] To a solution of tert-butyl N-[1-(3-chloropyrazin-2-yl)ethyl]carbamate (1.5 g, 5.8 mmol) in DMF (20 mL) was slowly added sodium hydride (350 mg, 8.7 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then CH3I (2.47 g, 17.4 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 3 hrs. The reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL *2). The combined organic phase was concentrated to afford tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate (1.5 g, 95% yield) as yellow oil which was used directly for next step without further purification. LC-MS (ES) m / z = 171.9 (M+H-Boc)+.

[0435] Step 3: 1-(3-Chloropyrazin-2-yl)- / V-methylethan-1 -amine hydrochloride :

[0436] To a solution of tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate (1.5 g, 5.5 mmol) in HCI / EtOAc (20 mL) was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated to afford crude 1-(3-chloropyrazin-2-yl)- / V-methylethan-1-amine hydrochloride (1.08 g, 95% yield) as yellow oil which was used directly for next step without further purification. LC-MS (ES) m / z = 172.0 (M+H)+.

[0437] Step 4: / V-(1-(3-Chloropyrazin-2-yl)ethyl)- / V-methyl-3,5-bis(trifluoromethyl)benzamide :

[0438] To a solution of 1-(3-chloropyrazin-2-yl)- / V-methylethan-1-amine hydrochloride (1.08 g, 5.2 mmol) and triethylamine (1.59 g, 15.7 mmol) in THF (20 mL) was slowly added 3,5- bis(trifluoromethyl)benzoyl chloride (1.75 g, 6.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL *2). The combined organic phase was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 4:1) to afford / \ / -(1-(3-chloropyrazin-2-yl)ethyl)- / \ / - methyl-3,5-bis(trifluoromethyl)benzamide (1.2 g, 56% yield) as a yellow solid. LC-MS (ES) m / z = 412.2 (M+H)+.

[0439] Step 5: / V-Methyl-3,5-bis(trifluoromethyl)- / \ / -(1-(3-vinylpyrazin-2-yl)ethyl)benzamide :

[0440] A mixture of / V-(1-(3-chloropyrazin-2-yl)ethyl)- / V-methyl-3,5-bis(trifluoromethyl)benzamide (1.1 g, 2.7 mmol), Pinacol vinylboronate (0.83 g, 5.4 mmol), XPhosPdG3 (0.23 g, 0.27 mmol) and K2CO3 (0.75 g, 5.4 mmol) in 1 ,4-dioxane / water (10 mL / 2 mL) was stirred at 80 °C for 3 hrs under N2. The mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford / V-methyl-3,5-bis(trifluoromethyl)- / \ / -(1- (3-vinylpyrazin-2-yl)ethyl)benzamide (0.9 g, 74% yield) as a yellow solid. LC-MS (ES) m / z = 404.0 (M+H)+.

[0441] Step 6: / V-(1-(3-Formylpyrazin-2-yl)ethyl)- / V-methyl-3,5-bis(trifluoromethyl)benzamide :

[0442] To a mixture of / V-methyl-3,5-bis(trifluoromethyl)- / \ / -(1-(3-vinylpyrazin-2-yl)ethyl)benzamide (800 mg, 2.0 mmol) and K2OsO4.2H2O (37 mg, 0.10 mmol) in acetone (8 mL) was added NalCL (849 mg, 4.0 mmol) in H2O (4 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL *2). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1) to afford / \ / -(1-(3- formylpyrazin-2-yl)ethyl)- / V-methyl-3,5-bis(trifluoromethyl)benzamide (440 mg, 55% yield) as a yellow solid. LC-MS (ES) m / z = 406.3 (M+H)+.

[0443] Step 7: (Z)- / V-Methyl- / V-(1-(3-((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0444] To a mixture of / V-(1-(3-formylpyrazin-2-yl)ethyl)- / V-methyl-3,5-bis(trifluoromethyl)benzamide (400 mg, 1.0 mmol) in EtOH (8 mL) was added methylhydrazine (141 mg, 1.2 mmol) at 20 °C. The mixture was stirred at 50 °C for 2 hrs. The reaction mixture was diluted with sat. NaHCCh solution (5 mL) and extracted with EtOAc (10 mL *2). The combined organic phase was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford (Z)- / V-methyl- / V-(1-(3-((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (440 mg, 55% yield) as a yellow solid. LC-MS (ES) m / z = 434.3 (M+H)+.

[0445] Step 8: / V-Methyl- / V-(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-thiadiazin-2-yl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide :

[0446] To a mixture of (Z)- / V-methyl- / V-(1-(3-((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (350 mg, 0.8 mmol) in THF (6 mL) was added dropwise a solution of NBS (173 mg, 1.0 mmol) in THF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. A solution of methyl 2-sulfanylacetate (129 mg, 1.2 mmol) in MeOH (3 mL) was added dropwise to the mixture at 0 °C. Then TEA (409 mg, 4.0 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The mixture was warmed to 50 °C and stirred for 12 hrs. The mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford / \ / -methyl- / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4- thiadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (160 mg, 40% yield) as a white solid. LC-MS (ES) m / z = 506.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.77-8.69 (m, 2H), 8.21-8.19 (m, 1 H), 8.06 (s, 1 H), 7.64 (s, 1 H), 6.43-6.38 (m, 0.6H), 5.83-5.81 (m, 0.4H), 3.77-3.58 (m, 1.5H), 3.40 (s, 2H), 3.33 (s, 1 H), 3.22-3.18 (m, 0.5H), 3.09 (s, 1 H), 2.92 (s, 2H), 1.66-1.59 (m, 3H).

[0447] Example 10: Synthesis of / \ / -(1-(3-(4-methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-thiadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-14):

[0448] Step 1 : (Z)- / V-(1-(3-((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0449] To a mixture of N-[1-(3-formylpyrazin-2-yl)ethyl]-3,5 bis(trifluoromethyl)benzamide VI lib (1.00 g, 2.60 mmol) in MeOH (10 mL) was added methylhydrazine (40% in water, 0.36 g, 3.12 mmol). The mixture was stirred at 30 °C for 2 hrs. The mixture was concentrated to afford (Z)- / V-(1-(3- ((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1.05 g, 96% yield) as a yellow solid. LC-MS (ES) m / z = 420.4. (M+H)+.

[0450] Step 2: / V-(1-(3-(4-Methyl-5-oxo-5,6-dihydro-4 / - / -1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0451] To a mixture of (Z)- / V-(1-(3-((2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (200 mg, 0.48 mmol) in THF (5 mL) was added dropwise a solution of NBS (94 mg, 0.52 mmol) in THF (1 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Methyl 2-sulfanylacetate (76 mg, 0.72 mmol) in MeOH (2 mL) was added dropwise to the mixture at 0 °C. Then TEA (242 mg, 2.38 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The mixture was warmed to 50 °C and stirred for 2 hrs. The mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford / \ / -(1-(3-(4-Methyl-5-oxo-5,6-dihydro-4 / 7-1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (150 mg, 64% yield) as a white solid. LC-MS (ES) m / z = 492.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.55 (d, J = 6.8 Hz, 1 H), 8.71 (d, J = 2.4 Hz, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.55 (s, 2H), 8.31 (s, 1 H), 6.03-6.00 (m, 1 H), 3.71 (s, 2H), 3.47 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H).

[0452] Example 11 : Synthesis of N-(1-(3-(4-ethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-48)

[0453] Step 1 : N-(1-(3-Chloropyrazin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamide :

[0454] To a mixture of 1-(3-chloropyrazin-2-yl)-N-[(3,4-dimethoxyphenyl)methyl]ethanamine (6.00 g, 19.50 mmol) and TEA (3.95 g, 39.00 mmol) in DCM (60 mL) was added 3,5- bis(trifluoromethyl)benzoyl chloride (6.47 g, 23.40 mmol) at 0 °C. The reaction was stirred at 0 °C for 10 minutes. The reaction mixture was diluted with ice-water (100 mL) and extracted DCM (100 mL*2). The combined organic phase was concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 50 / 1) to afford N-(1-(3-chloropyrazin-2- yl)ethyl)-N-(2,4-dimethoxybenzyl)-3,5-bis(trifluoromethyl)benzamide (8.00 g, 81% yield) as yellow oil. LC-MS (ES) m / z = 548.1 (M+H)+.

[0455] Step 2: 2-(Diethylamino)ethyl 3-(1-(N-(2,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate :

[0456] A mixture of N-(1-(3-chloropyrazin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamide (15.3 g, 27.90 mmol), 2-(diethylamino)ethanol (9.81 g, 83.70 mmol) and Pd(PPh3)2Ch (1.96 g, 2.79 mmol) in NMP (160 mL) was stirred at 100 °C for 5 hours under CO (1 ATM). The reaction mixture was filtered through celite. The filter cake was washed with EtOAc (200 mL). The filtrate was diluted with brine (600 mL) and extracted with EtOAc (400 mL). The organic phase was washed with brine (300 mL*2) and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH=30 / 1) to afford 2- (diethylamino)ethyl 3-(1-(N-(2,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (7.00 g, 38% yield) as brown oil. LC- MS (ES) m / z = 657.3 (M+H)+.

[0457] Step 3: N-(3,4-dimethylbenzyl)-N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide :

[0458] A mixture of 2-(diethylamino)ethyl 3-(1-(N-(2,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (2.00 g, 3.00 mmol) and N2H4*H2O (0.75 g, 15.00 mmol) in THF (20 mL) was stirred at 25 °C for 3 hrs. The mixture was concentrated and the residue was purified by column chromatography (DCM / MeOH = 20 / 1) to afford N-(3,4-dimethylbenzyl)-N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (1.47 g, 87% yield) as a yellow solid. LC-MS (ES) m / z = 572.3 (M+H)+.

[0459] Step 4 : N-(1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-(3,4- dimethylbenzyl)-3,5-bis(trifluoromethyl)benzamide :To a mixture of N-(3,4-dimethylbenzyl)-N-(1- (3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (500.00 mg, 0.87 mmol) and NaHCCh (147.00 mg, 1.75 mmol) in THF (5 mL) was dropped a solution of 2- chloroacetyl chloride (119.00 mg, 1.05 mmol) in THF (5 mL) at 25 °C. The mixture was stirred at 25 °C for 3 hrs. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL*3). The organic layer was concentrated and the residue was purified by column chromatography (PE / EtOAc = 1 / 1) to afford N-(1-(3-(2-(2-chloroacetyl)hydrazine-1- carbonyl)pyrazin-2-yl)ethyl)-N-(3,4-dimethylbenzyl)-3,5-bis(trifluoromethyl)benzamide (561 mg, 99% yield) as a yellow solid. LC-MS (ES) m / z = 648.1 (M+H)+.

[0460] Step 5: N-(2,4-dimethoxybenzyl)-N-(1-(3-(4-ethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide :

[0461] A mixture of N-(1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-(3,4- dimethylbenzyl)-3,5-bis(trifluoromethyl)benzamide (460.00 mg, 0.71 mmol), K2CO3 (294.00 mg, 2.13 mmol), Nal (106.00 mg, 0.71 mmol) in DMF (5 mL) was stirred at 80 °C for 2 hrs. lodoethane (332.00 mg, 2.13 mmol) was added to the mixture and stirred at 50 °C for 16 hrs. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (20 mL*3) and concentrated. The residue was purified by column chromatography (PE / EtOAc = 1 / 1) to afford N-(2,4-dimethoxybenzyl)-N-(1-(3-(4-ethyl-5- oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (192 mg, 42% yield) as a white solid. LC-MS (ES) m / z = 640.3(M+H)+.

[0462] Step 6 : N-(1-(3-(4-ethyl-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (I-48) :

[0463] To a mixture of N-(2,4-dimethoxybenzyl)-N-(1-(3-(4-ethyl-5-oxo-5,6-dihydro-4H-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (192.00 mg, 0.30 mmol) in dioxane (5 mL) was added dioxane / HCI (5 mL, 4M) at 0 °C. The mixture was stirred at 25 °C for 16 hrs. The mixture was adjusted to pH = 9-10 with sat. Na2CO3. The mixture was extracted with EtOAc (30 mL*3) and the organic layer was concentrated. The residue was purified by column chromatography (PE / EtOAc = 1 / 3) to afford N-(1-(3-(4-ethyl-5-oxo-5,6-dihydro-4H- 1,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (103.6 mg, 71% yield) as a white solid. LC-MS (ES) m / z = 490.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.54 (d, J = 6.4 Hz, 1H), 8.76 (s, 1H), 8.66 (s, 1H), 8.53 (s, 2H), 8.32 (s, 1H), 5.88-5.81 (m, 1H), 4.90 (s, 2H), 3.78-3.64 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H),

[0464] Example 12: Synthesis of N-(1-(3-(7-methyl-8-oxo-4-oxa-6,7-diazaspiro[2.5]oct-5-en-5- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-68)

[0465] Step 1 : (E)-N-(1-(3-((2-(1-Hydroxycyclopropane-1-carbonyl)-2- methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide :

[0466] To a mixture of 1 -hydroxycyclopropane- 1 -carboxylic acid (0.67 g, 6.60 mmol) in DCM (10 mL) was added SOCh (2.36 g, 19.80 mmol) and a few drops of DMF (0.02 g, 0.33 mmol). The mixture was stirred at 50 °C for 1.5 hrs. The mixture was concentrated, and the residue was diluted with DCM (5 mL). The solution was dropped to N-[1-[3-[(E)- (methylhydrazono)methyl]pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (1.40 g, 3.30 mmol) and TEA (2.00 g, 19.80 mmol) in DCM (15 mL) at 0 °C. The mixture was stirred at 30 °C for 3 hrs. The mixture was quenched with water (30 mL) and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*3) and concentrated. The residue was purified by column chromatography (PE / EtOAc = 1 / 1) to afford 900 mg crude. The crude was purified by reverse phase column (ACN / water = 3 / 1) to afford (E)-N-(1-(3-((2-(1-hydroxycyclopropane-1- carbonyl)-2-methylhydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (528 mg, 30% yield) as a yellow solid. LC-MS (ES) m / z (M+H)+= 504.5. Step 2: To a mixture of (E)-N-(1-(3-((2-(1-hydroxycyclopropane-1-carbonyl)-2-methylhydrazineylidene)methyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (478 mg, 0.95 mmol) in THF (4 mL) was added a solution of NBS (338 mg, 1.90 mmol) in THF (4 mL) at 0 °C. The mixture was stirred at 50 °C for 2 hrs. NaH (152 mg, 3.80 mmol, 60% in oil) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 3 hrs. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL * 3). The organic layer was concentrated and the residue was purified by column chromatography (PE / EtOAc = 2 / 1) to afford 100 mg crude. The crude was purified by prep-TLC (PE / EtOAc = 2 / 1) to afford N-(1-(3-(7-methyl-8-oxo-4-oxa-6,7-diazaspiro[2.5]oct-5-en-5- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-68) (20.4 mg, 4% yield) as a white solid. LC-MS (ES) m / z = 502.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.55 (d, J = 6.8 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1 H), 8.52 (s, 2H), 8.33 (s, 1 H), 5.82 - 5.75 (m, 1 H), 3.28 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.38 - 1.36 (m, 2H), 1.27 - 1.24 (m, 2H). Example 13: Synthesis of N-[1-[3-(6-isopropylidene-4-methyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (1-71)

[0467] Step 1 : To a solution of 3-chloropyrazine-2-carboxylic acid (10 g, 63.07 mmol, 1 eq) in DCM (100 mL) was added DIEA (24.46 g, 189.22 mmol, 32.96 mL, 3 eq) at 0°C, and then was added PyBOP (42.67 g, 82.00 mmol, 1.3 eq) in DCM (40 mL) and tert-butyl N-amino-N-methyl- carbamate (13.83 g, 94.61 mmol, 1.5 eq) in DCM (60 mL) at the same time at 0°C, over 2hr. The mixture was stirred at 0-20°C for 2h. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (200 mL) at 0°C, and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc=100:0-74:26) to give tert-butyl N-[(3- chloropyrazine-2-carbonyl)amino]carbamate (16.6 g, yield: 91.79%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 9.42 - 8.92 (m, 1 H), 8.58 (d, J = 2.3 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1 H), 3.26 (s, 3H), 1.47 (br s, 9H)

[0468] Step 2: To a solution of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]carbamate (16.6 g, 57.90 mmol, 1 eq) in HCI / EtOAc (100 mL) at 25°C. The mixture was stirred at 25 °C for 2hr, under N2. TLC (PE: EtOAc= 1 : 1) showed the reaction was completed. The mixture was filtered, the filter cake was dried over vacuum to give 3-chloro-N'-methyl-pyrazine-2- carbohydrazide (10.5 g, yield: 97.19%) as a white solid was used into the next step without further purification. 1 H NMR (400 MHz, MeOD) δ [ppm] = 8.70 (s, 2H), 3.08 (s, 3H)

[0469] Step 3: To a solution of 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (10.5 g, 56.27 mmol, 1 eq) in DMF (180 mL) was added K2CO3 (19.44 g, 140.68 mmol, 2.5 eq) and 2-chloroacetyl chloride (7.63 g, 67.52 mmol, 5.38 mL, 1.2 eq) at 25°C, and stirred for 1 h at 25°C. LCMS showed 3-chloro-N'-methyl-pyrazine-2-carbohydrazide was consumed, and then the mixture was stirred at 45°C for 5hr. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (150 mL) at 0°C, and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with brine (150 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (40 mL) at 25°C for 30 min to give 2-(3-chloropyrazin-2-yl)-4-methyl-1,3,4-oxadiazin-5- one (8.9 g, Yield: 69.79%) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.60 (d, J = 2.1 Hz, 1 H), 8.48 (d, J = 2.3 Hz, 1 H), 4.84 (s, 2H), 3.44 (s, 3H)

[0470] Step 4 : To a solution of 2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (5 g, 22.06 mmol, 1 eq) in CCI4 (80 mL) was added NBS (7.85 g, 44.13 mmol, 2 eq) and AIBN (36.23 mg, 220.63 pmol, 0.01 eq). The mixture was stirred at 80°C for 16hr. TLC (PE: EtOAc=3:1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (40 mL) at 0°C, and extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtCAc=100:0~72:28) to give 6-bromo-2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (5.3 g, yield: 78.63%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.65 (d, J = 2.4 Hz, 1 H), 8.52 (d, J = 2.4 Hz, 1 H), 6.83 (s, 1 H), 3.54 (s, 3H)

[0471] Step 5 : To a solution of 6-bromo-2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (3 g, 9.82 mmol, 1 eq) in MeCN (40 mL) was added P(OEt)s (6.53 g, 39.28 mmol, 6.73 mL, 4 eq) at 25°C. The mixture was stirred at 80°C for 16hr, under N2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (80 mL) at 0°C, and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (120 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE~EtOAC=100:0-62:38) to give 2-(3- chloropyrazin-2-yl)-6-diethoxyphosphoryl-4-methyl-1 ,3,4-oxadiazin-5-one (3.5 g, yield: 98.27%) as colorless oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.60 (d, J = 2.4 Hz, 1 H), 8.48 (d, J = 2.3 Hz, 1 H), 5.19 (d, J = 13.9 Hz, 1 H), 4.32 - 4.25 (m, 4H), 3.47 (d, J = 1.4 Hz, 3H), 1.39 - 1.35 (m, 6H)

[0472] Step 6 : To a solution of 2-(3-chloropyrazin-2-yl)-6-diethoxyphosphoryl-4-methyl-1 ,3,4- oxadiazin-5-one (2 g, 5.51 mmol, 1 eq) in THF (30 mL) was added NaH (220.54 mg, 5.51 mmol, 60% purity, 1 eq) at 0°C, and stirred for 0.5 at 0°C. Then the acetone (352.28 mg, 6.07 mmol, 445.92 pL, 1.1 eq) in THF (0.5 mL) was added at 0°C. The mixture was stirred at 0°C~25°C for 2.5hr, under N2. TLC (PE: EtOAc=3:1) showed the reaction was completed. The reaction mixture was quenched with aq.NH4CI (15 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc=100:0-62:28) to give 2-(3-chloropyrazin-2-yl)-6- isopropylidene-4-methyl-1 ,3,4-oxadiazin-5-one (1.1 g, yield: 74.80%) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.53 (d, J = 2.4 Hz, 1 H), 8.41 (d, J = 2.4 Hz, 1 H), 3.34 (s, 3H), 2.24 (s, 3H), 1.84 (s, 3H)

[0473] Step 7 : To a solution of 2-(3-chloropyrazin-2-yl)-6-isopropylidene-4-methyl-1 ,3,4-oxadiazin-5- one (1.1 g, 4.12 mmol, 1 eq) in toluene (20 mL) was added Pd(PPh3)4 (476.64 mg, 412.47 pmol, 0.1 eq) and tributyl(1-ethoxyvinyl)stannane (1.79 g, 4.95 mmol, 1.67 mL, 1.2 eq). The mixture was stirred at 120 °C for 2hr, under N2. LCMS showed the reaction was completed. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]- 6-isopropylidene-4-methyl-1 ,3,4-oxadiazin-5-one (1.2 g, yield: 96.23%) as a brown oil was used into the next step without further purification.

[0474] Step 8: To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-6-isopropylidene-4-methyl-1 ,3,4- oxadiazin-5-one (1.2 g, 3.97 mmol, 1 eq) in MeCN (20 mL) was added HCI (2 M, 3.97 mL, 2 eq). The mixture was stirred at 20°C for 2hr. TLC (PE: EtOAc=3:1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (50 mL) at 0°C, and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE~EtOAc=100:0~70:30) to give 2-(3- acetylpyrazin-2-yl)-6-isopropylidene-4-methyl-1 ,3,4-oxadiazin-5-one (1.02 g, yield: 93.69%) as a white solid. 1H NMR (400 MHz, CDCI3) δ [ppm] = 8.75 (d, J = 2.4 Hz, 1 H), 8.66 (d, J = 2.4 Hz, 1H), 3.36 (s, 3H), 2.73 (s, 3H), 2.29 (s, 3H), 1.81 (s, 3H)

[0475] Step 9 : To a solution of 2-(3-acetylpyrazin-2-yl)-6-isopropylidene-4-methyl-1 ,3,4-oxadiazin-5- one (100 mg, 364.60 pmol, 1 eq) in THF (4 mL) was added 2-methylpropane-2-sulfinamide (88.38 mg, 729.20 pmol, 2 eq) and Ti(i-PrO)4 (259.06 mg, 911.49 pmol, 269.01 pL, 2.5 eq) at 25°C. The mixture was stirred at 80°C for 16hr, under N2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, and extracted with EtOAc (8 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EtOAc = 1:2) to give (NE)-N-[1-[3-(6-isopropylidene-4-methyl-5- oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethylidene]-2-methyl-propane-2-sulfinamide (70 mg, yield: 50.86%) as a white solid.

[0476] Step 10 : To a solution of (NE)-N-[1-[3-(6-isopropylidene-4-methyl-5-oxo-1,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethylidene]-2-methyl-propane-2-sulfinamide (740 mg, 1.96 mmol, 1 eq) in THF (15 mL) and MeOH (5 mL) was added NaBH4 (74.17 mg, 1.96 mmol, 1 eq) at 0°C. The mixture was stirred at 0 °C for 2hr, under N2. TLC (PE: EtOAc=2:1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (20 mL) at 0°C, and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc = 100: 0-24:76) to give N-[1-[3-(6- isopropylidene-4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2- sulfinamide (710 mg, yield: 95.44%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.69 - 8.50 (m, 2H), 5.46 - 5.23 (m, 1 H), 5.03 - 4.29 (m, 1H), 3.47 - 3.30 (m, 3H), 2.30 (s, 3H), 2.01 - 1.92 (m, 3H), 1.68 (d, J = 6.6 Hz, 2H), 1.53 (d, J = 6.8 Hz, 1 H), 1.27 - 1.16 (m, 9H)

[0477] Step 11 : To a solution of N-[1-[3-(6-isopropylidene-4-methyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2-sulfinamide (710 mg, 1.87 mmol, 1 eq) in EtOAc (2 mL) was added HCI / EtOAc (4 M, 2.5 mL, 5.34 eq) at 25°C. The mixture was stirred at 25 °C for 0.5hr. TLC (PE: EtOAc=1:1) showed the reaction was completed. The mixture was filtered, the filter cake was dried under vacuum to give 2-[3-(1-aminoethyl)pyrazin-2-yl]-6-isopropylidene-4- methyl-1,3,4-oxadiazin-5-one (400 mg, yield: 77.66%) was obtained as a white solid was used into the next step without further purification. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.82 - 8.50 (m, 2H), 5.23 (d, J = 6.1 Hz, 1 H), 3.39 - 3.26 (m, 3H), 2.15 (br s, 3H), 1.85 (br s, 3H), 1.56 (br d, J = 6.4 Hz, 3H) Step 12 : To a solution of 3,5-bis(trifluoromethyl)benzoic acid (400 mg, 1.45 mmol, 1 eq) in MeCN (6 mL) was added 2-[3-(1-aminoethyl)pyrazin-2-yl]-6-isopropylidene-4-methyl-1,3,4- oxadiazin-5-one (450.03 mg, 1.74 mmol, 1.2 eq) , TCFH (611.49 mg, 2.18 mmol, 1.5 eq) and NMI (357.87 mg, 4.36 mmol, 347.45 pL, 3 eq) at 0°C.The mixture was stirred at 0-25°C for 2hr. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (40 mL) at 0°C, and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc=100:~58:42) to give N-[1-[3- (6-isopropylidene-4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide (520 mg, yield: 69.44%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.72 - 8.61 (m, 2H), 8.26 (s, 2H), 8.03 (s, 1H), 7.70 - 7.57 (br d, 1H), 6.28 - 6.14 (m, 1 H), 3.47 (s, 3H), 2.32 (s, 3H), 1.98 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H)

[0478] Example 14: Synthesis of N-[1-[3-(6-isopropyl-4-methyl-5-oxo-1,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (I-64) :

[0479] To a solution of N-[1-[3-(6-isopropylidene-4-methyl-5-oxo-1,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (200 mg, 388.04 pmol, 1 eq) in EtOH (5 mL) was added Pd / C (206.48 mg, 194.02 pmol, 10% purity, 0.5 eq) at 25°C. The mixture was stirred at 25 °C for 2hr, under H2(1034 mbar). LCMS showed the reaction was completed. The mixture was filtered, the filtrated was concentrated. The residue was purified by prep-HPLC (HCI condition; column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H20(0.04% HCI)- ACN];gradient:25%-65% B over 8.0 min) to give Synthesis of N-[1-[3-(6-isopropyl-4-methyl-5- oxo-1,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (93 mg, yield: 46.32%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.73 - 8.60 (m, 2H), 8.26 (s, 2H), 8.03 (s, 1H), 7.58 (br d, J = 7.8 Hz, 1H), 6.19 (quin, J = 7.1 Hz, 1 H), 4.81 (d, J = 4.3 Hz, 1H), 3.49 (s, 3H), 2.49 (qd, J = 6.8, 11.3 Hz, 1 H), 1.66 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H)

[0480] Example 15: Synthesis of 3-bromo-5-(1-cyanocyclopropyl)-N-[1-[3-(4-methyl-5-oxo-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl]ethyl]benzamide (1-51) :

[0481] Step 1 : Deprotection of 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (I-2) : To a solution of 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (0.05 g, 147.31 pmol, 1 eq) in dioxane (0.5 mL) was added HCI / dioxane (8 M, 184.14 pL, 10 eq) at 0°C .The mixture was stirred at 10°C for 0.5hr. LC-MS showed that the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. 2-[3-(1-aminoethyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one (0.03 g, 110.41 pmol, 74.95% yield, HCI) was obtained as a yellow solid. LC-MS : desired mass : 235.1 , observed mass : 235.9.

[0482] Step 2: Amide-coupling: A mixture of 3-bromo-5-(1-cyanocyclopropyl)benzoic acid (1-1) (51.1 mg, 0.19 mmol, 1 eq.), 2-[3-(1-aminoethyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one (52.2 mg, 0.19 mmol, 1 eq.), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafluorophosphate (94.9 mg, 0.25 mmol, 1.3 eq.) and N-ethyl-N-isopropyl- porpan-2-amine (0.16 mL, 124 mg, 0.96 mmol, 5 eq.) in DMF (3 mL) was stirred for 20 h at room temperature. The solvent was removed under reduced pressure, redissolved in dichloromethane (40 mL), extracted with H2O and aqueous NH4CI solution, dried with MgSCL, filtered and the solvent was evapurated. The residue was purified by column chromatography on silica gel (eluting with cyclohexane / ethyl acetate) to afford 3-bromo-5-(1-cyanocyclopropyl)- N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]benzamide (67 mg, 0.14 mmol, 72%) as a solid. LC-MS : desired mass : 482.1 , observed mass : 482.9; 1 H NMR ppm (400 MHz, DMSO-d6) δ [ppm] 9.18 (d, J = 6.9 Hz, 1 H), 8.75 (d, J = 2.4, 1 H), 8.64 (d, J = 2.4 Hz, 1 H), 8.00 (t, J = 1.7 Hz, 1 H), 7.77 (t, J = 1.7 Hz, 1 H), 7.65 (t, J = 1.9 Hz, 1 H), 5.73 (p, J = 6.9 Hz, 1 H), 4.90 - 4.85 (m, 2H), 3.23 (s, 1 H), 1.83 - 1.76 (m, 2H), 1.64 - 1.58 (m, 2H), 1.58 (d, J = 6.9 Hz, 3H).

[0483] Exemplified amide coupling literature:

[0484] Albeiicio, F., Chinchilla, R., Dodsworth, D. J., & Najera, C. (2001). New trends in peptide coupling reagents. Organic Preparations and Procedures International, 33(3), 203-303. and / or Han, S. Y., & Kim, Y. A. (2004). Recent development of peptide coupling reagents in organic synthesis. Tetrahedron, 60(11), 2447-2467.

[0485] Example 16: Synthesis of N-[1-[3-[4-(cyanomethyl)-5-oxo-1 ,3,4-oxadiazin-2-yl]pyrazin-2- yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (I-49):

[0486] Step 1 : A mixture of tert-butyl N-[1-[3-[[(2-chloroacetyl)amino]carbamoyl]pyrazin-2-yl]ethyl]-N- (3,4-dimethoxyphenyl)carbamate (2.00 g, 3.94 mmol), K2CO3 (1.63 g, 11.81 mmol) and Nal (591 mg, 3.94 mmol) in DMF (40 mL) was stirred at 80 °C for 2 hours. Then 2-lodoacetonitrile (1 .31 mg, 7.87 mmol) was added at 80 °C. The reaction was stirred at 80 °C for 6 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford tert-butyl (1-(3-(4- (cyanomethyl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)(3,4- dimethylbenzyl)carbamate (1.2 g, 60% yield) as a yellow solid.

[0487] Step 2: A solution of tert-butyl (1-(3-(4-(cyanomethyl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)(3,4-dimethylbenzyl)carbamate (200 mg, 0.42 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at rt for 1 hour. The reaction was concentrated to afford 2-(2-(3-(1- aminoethyl)pyrazin-2-yl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-4-yl)acetonitrile (150 mg, crude >100% yield) as a yellow oil. LC-MS (ES) m / z = 261 (M+H)+.

[0488] Step 3: To a solution of 2-(2-(3-(1-aminoethyl)pyrazin-2-yl)-5-oxo-5,6-dihydro-4H-1 ,3,4- oxadiazin-4-yl)acetonitrile (200 mg, 0.77 mmol), NaHCCh (194 mg, 2.31 mmol) in THF (10 mL) was added 3-chloro-5-(trifluoromethyl)benzoyl chloride (255 mg, 0.92 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction was diluted with water (30 mL), extracted with EtOAc (20 mL * 2). Then the organic layer was washed with brine (30 mL * 2) and dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-HPLC to afford N-(1- (3-(4-(cyanomethyl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (95 mg, 25% yield) as a white solid. LC-MS (ES) m / z = 501.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.57 (d, J = 6.4 Hz, 1 H), 8.79 (s, 1 H), 8.68 (s, 1 H), 8.54 (s, 2H), 8.31 (s, 1 H), 5.86-5.79 (m, 1 H), 5.06 (s, 2 H), 4.97-4.86 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H).

[0489] Example 17: Synthesis of N-(1-(3-(4-(cyanomethyl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-50):

[0490] Step 1 : A solution of tert-butyl N-[1-[3-[4-(cyanomethyl)-5-oxo-1 ,3,4-oxadiazin-2-yl]pyrazin-2- yl]ethyl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (1.2 g, 2.35 mmol) in EtOAc (6 mL) and EtOAc / HCI (6 mL) was stirred at rt for 16 hrs. The reaction mixture was concentrated to afford 2- (2-(3-(1-aminoethyl)pyrazin-2-yl)-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-4-yl)acetamide (200 mg, 31 % yield) as a yellow oil. LC-MS (ES) m / z = 279.3 (M+H)+.

[0491] Step 2: To a solution of 2-(2-(3-(1-aminoethyl)pyrazin-2-yl)-5-oxo-5,6-dihydro-4H-1 ,3,4- oxadiazin-4-yl)acetamide (200 mg, 0.72 mmol), 3-chloro-5-(trifluoromethyl)benzoyl chloride (239 mg, 0.86 mmol) in DCM (5 mL) was added TEA (218 mg, 2.16 mmol). The reaction mixture was stirred at rt for 2 hrs. The reaction was diluted with water (30 mL), extracted with EtOAc (20 mL * 2). Then the organic layer was washed with brine (30 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford N-(1-(3-(4-(Cyanomethyl)-5-oxo- 5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (30 mg, 8% yield) as a white solid. LC-MS (ES) m / z = 519.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) 5 [ppm] 9.52 (d, J = 6.0 Hz, 1 H), 8.75 (s, 1 H), 8.65 (s, 1 H), 8.54 (s, 2H), 8.32 (s, 1 H), 7.67-7.48 (m, 1 H), 7.32-7.21 (m, 1 H), 6.14-5.68 (m, 1 H), 4.95-4.82 (m, 2H), 4.35-3.91(m, 2H),1.61 (d, J = 6.4 Hz, 3H).

[0492] Example 18: Synthesis of N-methyl-N-(1-(3-(6-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-66):

[0493] Step 1 : A mixture of N-[1-(3-chloropyrazin-2-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (4.1 g, 9.7 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 780 mg, 19.4 mmol) at 0 °C. After stirring 30 mins and the resulting mixture was added iodomethane (2.75 g, 19.4 mmol). The mixture was stirred at 25 °C for 2 hrs. The mixture was quenched with water (200 mL), extracted with EtOAc (120 mL * 3). The organic layer was washed with brine (100 mL * 3) and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1) to afford N-(1-(3-chloropyrazin-2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (3.7 g, 88% yield) as a white solid. LC-MS (ES) m / z = 412.0 (M+H)+.

[0494] Step 2: A solution of N-(1-(3-chloropyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (3.7 g, 8.5 mmol), 2-(diethylamino) ethan-1-ol (2.49 g, 21.2 mmol) and Pd(PPh3)2Ch (600 mg, 0.085 mmol) in NMP (50 mL) was stirred at 120 °C for 4 hrs. The mixture was washed with water (200 mL), extracted with EtOAc (200 mL * 3). The organic layer was washed with brine (150 mL * 3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford a brown oil. The oil was purified by reverse flash (C-18) (45-70% ACN in water 0.1% FA)) to afford 2- (diethylamino)ethyl 3-(1-(N-methyl-3,5-bis(trifluoromethyl)benzamido)ethyl)pyrazine-2- carboxylate (1.8 g, 80% purity, 33% yield) as a yellow oil. LC-MS (ES) m / z = 521.2 (M+H)+.

[0495] Step 3: To a solution of 2-(diethylamino)ethyl 3-(1-(N-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (1.8 g, 2.8 mmol) in THF (30 mL) was added Hydrazine hydrate (820 mg, 14.0 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction was quenched with water (3 mL) and concentrated. The residue was diluted in water (40 mL), extracted with DCM / MeOH (10:1 , 40 mL * 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford N-(1-(3-(hydrazinecarbonyl)pyrazin- 2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (1.5 g, 80% purity, 100% yield) as yellow oil. LC-MS (ES) m / z = 436.0 (M+H)+.

[0496] Step 4: To a solution of N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (1.7 g, 3.1 mmol), NaHCOs (520 mg, 6.2 mmol) in THF (20 mL) was added 2-chloroacetyl chloride (590 mg, 4.7 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. The mixture was diluted with water (20 mL), extracted with EtOAc (50 mL * 2). The organic layer was washed with brine (30 mL * 3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10-35% EtOAc / PE) to afford N-(1-(3-(2-(2-chloropropanoyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N- methyl-3,5-bis(trifluoromethyl)benzamide (1.3 g, 83% yield) as a yellow solid. LC-MS (ES) m / z = 526.0 (M+H)+.

[0497] Step 5: N-(1-(3-(2-(2-Chloropropanoyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (400 mg, 1.26 mmol) and DMF (4 mL) were added to a 20 mL microwave reaction tube. And the resulting mixture was charged with Nal (324 mg, 2.16 mmol) and triethylamine (291 mg, 2.88 mmol). Then the mixture was sealed and microwaved at 140 °C for 2 hours. The resulting mixture was poured into a water (30 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL * 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (EtOAc / DCM = 1 / 2 to 2 / 1) to give the crude. The crude was purified by Prep-HPLC (5 -95% ACN in water with 0.1 % NH4HCO3) to afford N-methyl-N-(1-(3-(6-methyl-5-oxo-5,6- dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (83.1 mg, 21% yield) as a white solid. LC-MS (ES) m / z = 490.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) 5 [ppm] 11.26 (s, 0.75H), 10.97 (s, 0.23H), 8.78 (s, 1 H), 8.71-8.70 (m, 1 H), 8.22 (s, 0.76H), 8.14- 8.08 (m, 0.25H), 8.03 (d, J = 6.4 Hz, 1.54H), 7.59 (d, J = 25.6 Hz, 0.45H), 6.25-6.22 (m, 0.76H), 5.45-5.38 (m, 0.22H), 5.08-4.96 (m, 0.75H), 4.68-4.56 (m, 0.22H), 3.30-3.28 (m, 0.77H), 2.89- 2.88 (m, 2.27H), 1.64-1.62 (m, 3H), 1.52-1.50 (m, 2.31 H), 1.35-1.28 (m, 0.77H).

[0498] Example 19: Synthesis of N-(1-(3-(4,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (I-65):

[0499] To a solution of N-methyl-N-(1-(3-(6-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (150 mg, 0.28 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 13 mg, 0.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. The resulting mixture was charged with iodomethane (51 mg, 0.36 mmol) and the reaction was stirred at 0 °C for 1 hour. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (20 mL * 3). The organic layer was washed with brine (30 mL * 3), dried over anhydrous Na2SC>4 and filtered and concentrated. The residue was purified by reverse flash (C-18) (45-70% ACN in water with 0.1 % HCOOH ) to afford N-(1-(3-(4,6-dimethyl-5-oxo- 5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (93.3 mg, 66% yield) as pale yellow solid. LC-MS (ES) m / z = 504.1 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 8.81-8.80 (m, 1 H), 8.74-8.69 (m, 1 H), 8.23 (s, 0.67H), 8.16-8.13 (m, 0.33H), 8.02-8.00 (m, 1.36H), 7.67-7.61 (m, 0.58H), 6.35-6.27 (m, 0.67H), 5.59-5.52 (m, 0.29H), 5.15-5.03 (m, 0.67H), 4.81-4.69 (m, 0.28H), 3.30 (s, 1 H), 3.21 (d, J = 2.8 Hz, 2H), 3.00 (s, 1 H), 2.78 (d, J = 9.6 Hz, 2H), 1.64-1.61 (m, 3H), 1.53-1.51 (m, 2H), 1.38-1.32 (m, 1 H).

[0500] Example 20: Synthesis of N-(1-(3-(6-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-67)

[0501] Step 1 : To a solution of / \ / -[(2,4-dimethoxyphenyl)methyl]- / \ / -[1-[3-(hydrazinecarbonyl)pyrazin- 2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide

[0502] (750 mg, 1 .39 mmol) in 4 M HCI in 1 ,4-dioxane (10 mL) at 0 oC under N2. After stirred at r for 1 hour. The reaction was concentrated to afford the compound N-(1-(3- (hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (600 mg, 98% yield) as a yellow solid. LC-MS (ES) m / z = 422.0 (M+H)+.

[0503] Step 2: To a solution of N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (500 mg, 0.97 mmol), TEA (300 mg, 2.91 mmol) in THF (20 mL) was added 2-chloropropanoyl chloride (135 mg, 1.06 mmol) at 0 °C under N2. After stirred at rt for 3hrs. The resulting mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL * 3). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica (DCM / EtOAc = 7 / 1 to 5 / 1) to afford the title compound N-(1-(3-(2-(2-chloropropanoyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (280 mg, 46% yield) as yellow solid. LC-MS (ES) m / z = 512.0 (M+H)+.

[0504] Step 3: To a solution of N-(1-(3-(2-(2-chloropropanoyl)hydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (280 mg, 0.45 mmol), TEA (180 mg, 1.79 mmol) in DMF (5 mL) was added Nal (170 mg, 1.12 mmol) at rt under N2. After stirred at 140 °C under microwave reactor for 2 hrs. The resulting mixture was diluted with EtOAc (50 mL), washed with brine (50 mL * 3). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica (DCM / EtOAc = 7 / 1 to 2 / 1) to afford N-(1-(3-(6-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (55 mg, 25% yield) as a white solid. LC-MS (ES) m / z = 476.0 (M+H)+. 1 HNMR (400 MHz, DMSO-d6) δ [ppm] 11.27 (d, J = 6.0 Hz, 1 H), 9.55-9.52 (m, 1 H), 8.74 (d, J = 2.4 Hz, 1 H), 8.64 (d, J = 2.0 Hz, 1 H), 8.52 (s, 2H), 8.31 (s, 1 H), 5.85-5.80 (m, 1 H), 5.05-5.00 (m, 1 H), 1.59 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.8 Hz, 3H).

[0505] Example 21 : Synthesis of 3-chloro-N-(1-(3-(5-oxo-4-(prop-2-yn-1-yl)-5,6-dihydro-4H-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (I-45) :

[0506] Step 1 : A solution of 2-(diethylamino)ethyl 3-[1-[tert-butoxycarbonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl]pyrazine-2-carboxylate (1.3 g, 2.70 mmol), hydrazine hydrate (0.68 g, 13.50 mmol) in THF (20 ml) was stirred at 50 oC for 16 hours. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (DCM / MeOH = 20 / 1) to afford tert-butyl (2,4-dimethoxybenzyl)(1-(3-(hydrazinecarbonyl)pyrazin-2- yl)ethyl)carbamate (1.00 g, 93% yield) as a yellow oil. LC-MS (ES) m / z = 432.5 (M+H)+.

[0507] Step 2: To a solution of tert-butyl (2,4-dimethoxybenzyl)(1-(3-(hydrazinecarbonyl)pyrazin-2- yl)ethyl)carbamate (1.1 g, 2.55 mmol), Na2CO3 (643 mg, 7.65 mmol) in THF (20 mL) was added 2-Chloroacetyl chloride (346 mg, 3.06 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 2 hours. The reaction was diluted with water (30 mL * 2), extracted with EtOAc (30 mL * 2). The organic layer was washed with brine (30 mL * 2), dried over Na2SO4, filtered and concentrated to afford crude tert-butyl (1-(3-(2-(2-chloroacetyl)hydrazine-1- carbonyl)pyrazin-2-yl)ethyl)(2,4-dimethoxybenzyl)carbamate (1.3 g, 100% yield) as a yellow solid. LC-MS (ES) m / z = 508.5 (M+H)+

[0508] Step 3: A mixture of tert-butyl (1-(3-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2- yl)ethyl)(2,4-dimethoxybenzyl)carbamate (1.1 g, 2.17 mmol), K2CO2(897 mg, 6.50 mmol) and Nal (325 mg, 2.17 mmol) in DMF (30 mL) was stirred at 80 °C for 2 hours. Then 3-bromoprop-1- yne (773 mg, 6.50 mmol) was added at 80 °C. The reaction was stirred at 80 °C for 6 hours. The reaction was diluted with water (30 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford tert-butyl (3,4- dimethylbenzyl)(1-(3-(5-oxo-4-(prop-2-yn-1-yl)-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl)ethyl)carbamate (600 mg, 54% yield) as a yellow solid. LC-MS (ES) m / z = 510.5

[0509] Step 4: A solution of tert-butyl (3,4-dimethylbenzyl)(1-(3-(5-oxo-4-(prop-2-yn-1-yl)-5,6-dihydro- 4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)carbamate (600 mg, 1.18 mmol) in EtOAc (5 mL) and HCI / EtOAc (5 mL) was stirred at rt for 16 hours. The reaction was concentrated to afford crude 2-(3-(1-aminoethyl)pyrazin-2-yl)-4-(prop-2-yn-1-yl)-4H-1 ,3,4-oxadiazin-5(6H)-one (500 mg, 100% yield) as a yellow solid. LC-MS (ES) m / z = 260 (M+H)+.

[0510] Step 5: To a solution of 2-(3-(1-aminoethyl)pyrazin-2-yl)-4-(prop-2-yn-1-yl)-4H-1 ,3,4-oxadiazin- 5(6H)-one (500 mg, 1.93 mmol), 3-chloro-5-(trifluoromethyl)benzoyl chloride (562 mg, 2.31 mmol) in DCM (10 mL) was added TEA (585 mg, 5.79 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction was diluted with water (30 mL), extracted with DCM (20 mL * 2). Then the organic layer was washed with brine (30 mL * 2) and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 3-chloro-N-(1-(3-(5-oxo-4-(prop-2-yn-1-yl)-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)benzamide (250 mg, 27% yield) as a white solid. LC-MS (ES) m / z = 466.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.38 (d, J = 6.8 Hz, 1 H), 8.76 (d, J = 2.0 Hz, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.23 (s, 1 H), 8.18 (s, 1 H), 8.05 (s, 1 H), 5.82-5.78 (m, 1 H), 4.98 (s, 2H), 4.55-4.84 (m, 2H), 3.26 (s, 1 H), 1.62 (d, J = 6.8 Hz, 3H).

[0511] Example 22: Synthesis of 3,5-bis(trifluoromethyl)-N-(1-(1-(4,6,6-trimethyl-5-oxo-5,6-dihydro- 4H-1 ,3,4-thiadiazin-2-yl)-1 H-1 ,2,4-triazol-5-yl)ethyl)benzamide (I-79) :

[0512] Step 1 : To a mixture of 1-(trimethylsilyl)-1 H-1 ,2,4-triazole (1.23 g, 8.70 mmol) in CCI4 (10 mL) was added a solution of thiophosgene (500 mg, 4.35 mmol) in CCI4 (2 mL) at 0 °C. The mixture was stirred at 20 °C for 10 hrs. The mixture was filtered. The filter cake was dried to afford di(1 H- 1 ,2,4-triazol-1-yl)methanethione (620 mg, 79% yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) 6 9.23 (s, 2H), 8.21 (s, 2H).

[0513] Step 2: To a mixture of tert-butyl 2-methylhydrazine-1 -carboxylate (2.0 g, 13.68 mmol) and NaHCO3 (3.45 g, 41.04 mmol) in THF (20 mL) was added 2-bromo-2-methylpropanoyl bromide (3.77 g, 16.42 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was diluted with H2O (30 mL), extracted with EtOAc (50 mL * 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford tert-butyl 2-(2-bromo-2- methylpropanoyl)-2-methylhydrazine-1 -carboxylate (3.58 g, 89% yield) as yellow oil. LC-MS (ES) m / z = 239.0 (M+H-tBu)+.

[0514] Step 3: A mixture of tert-butyl 2-(2-bromo-2-methylpropanoyl)-2-methylhydrazine-1- carboxylate (3.58 g, 0.012 mol) in EtOAc (30 mL) and HCI / dioxane (30 mL) was stirred at 25 °C for 1 hr. The mixture was filtered. The filter cake was dried to afford 2-bromo-N,2- dimethylpropanehydrazide hydrogen chloride (2.3 g, 82% yield) as a white solid. LC-MS (ES) m / z = 195.0 (M+H-HCI)+.

[0515] Step 4: To a mixture of di(1 H-1 ,2,4-triazol-1-yl)methanethione (2.33 g, 12.96 mmol) and TEA (2.62 g, 25.92 mmol) in THF (20 mL) was added 2-bromo-N,2-dimethylpropanehydrazide hydrogen chloride (2.0 g, 8.63 mmol) portions. The mixture was stirred at 25 °C for 2 hrs. The mixture was diluted with EtOAc (50 mL), washed with H2O (20 mL*2). The organic layer was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 10 / 1) to afford 4,6,6-trimethyl-2-(1 H-1 ,2,4-triazol-1-yl)-4H-1 ,3,4-thiadiazin-5(6H)-one (820 mg, 42.14% yield) as a yellow solid. LC-MS (ES) m / z = 226.1 (M+H)+.

[0516] Step 5: A mixture of 4,6,6-trimethyl-2-(1 H-1 ,2,4-triazol-1-yl)-4H-1 ,3,4-thiadiazin-5(6H)-one (820 mg, 3.64 mmol), dibromodifluoromethane (1.90 mg, 7.28 mmol) and t-BuOLi (874 mg, 10.92 mmol) in DMF (8 mL) was stirred at 25 °C for 1 hr. The mixture was diluted with H2O (15 mL), extracted with EtOAc (30 mL *2). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford 2-(5-bromo-1 H-1 ,2,4-triazol-1-yl)-4,6,6-trimethyl-4H-1 ,3,4- thiadiazin-5(6H)-one (450 mg, 40.64% yield) as yellow oil. LC-MS (ES) m / z = 306.0 (M+H)+.

[0517] Step 6: A mixture of 2-(5-bromo-1 H-1 ,2,4-triazol-1-yl)-4,6,6-trimethyl-4H-1 ,3,4-thiadiazin- 5(6H)-one (400 mg, 1.32 mmol), tributyl(1-ethoxyethenyl)stannane (570 mg, 1.58 mmol) and Pd(PPh3)4 (152 mg, 0.13 mmol) in 1 ,4-dioxane (4 mL) was stirred at 120 °C for 3 hrs under N2. The mixture was cooled to rt. The mixture was diluted with EtAOc (20 mL), washed with H2O (5 mL). The organic layer was concentrated. The residue was dissolved in THF (5 mL) and 2N HCI (5 mL). The mixture was stirred at 25 °C for 4 hrs. LCMS showed the reaction was OK. The mixture was basified with sat. Na2COs to adjust pH= 9, extracted with EtAOc (15 mL*2). The organic layer was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford the 2-(5-acetyl-1 H-1 ,2,4-triazol-1-yl)-4,6,6-trimethyl-4H-1 ,3,4- thiadiazin-5(6H)-one (260 mg, 73.96% yield) as a yellow solid. LC-MS (ES) m / z = 268.1 (M+H)+.

[0518] Step 7: A mixture of 2-(5-acetyl-1 H-1 ,2,4-triazol-1-yl)-4,6,6-trimethyl-4H-1 ,3,4-thiadiazin-5(6H)- one (260 mg, 0.97 mmol) and 2-methylpropane-2-sulfinamide (589 mg, 4.86 mmol) in THF (5 mL) was added Titanium tetraisopropanolate (1.38 g, 4.86 mmol) under N2. The mixture was stirred at 75 °C for 16 hrs. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was concentrated and the residue was purifed by column chromatography (PE / EtOAc = 3 / 1) to afford (E)-2-methyl-N-(1-(1-(4,6,6-trimethyl-5-oxo-5,6- dihydro-4H-1 ,3,4-thiadiazin-2-yl)-1 H-1 ,2,4-triazol-5-yl)ethylidene)propane-2-sulfinamide (235 mg, 65% yield) as a yellow solid. LC-MS (ES) m / z = 371.1 (M+H)+.

[0519] Step 8: To a mixture of (E)-2-methyl-N-(1-(1-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4- thiadiazin-2-yl)-1 H-1 ,2,4-triazol-5-yl)ethylidene)propane-2-sulfinamide (215 mg, 0.58 mmol) in MeOH (4 mL) was added NaBH4 (22 mg, 0.58 mmol) at -40 °C. The mixture was stirred at -40 °C for 1 hr. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL * 3). The organic layer was concentrated and the residue was purified by (EtOAc) to afford (E)-2- methyl-N-(1-(1-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)-1H-1,2,4-triazol-5- yl)ethylidene)propane-2-sulfinamide (130 mg, 60% yield) as a yellow solid. LC-MS (ES) m / z = 373.6 (M+H)+.

[0520] Step 9: To a mixture of (E)-2-methyl-N-(1-(1-(4,6,6-trimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4- thiadiazin-2-yl)-1H-1,2,4-triazol-5-yl)ethylidene)propane-2-sulfinamide (130 mg, 0.35 mmol) in EtOAc (2 mL) was added HOI / EtOAc (4 mL, 4 M) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The mixture was filtered and the filter cake was dried to afford 2-(5-(1-aminoethyl)-1H-1,2,4- triazol-1-yl)-4,6,6-trimethyl-4H-1 ,3,4-thiadiazin-5(6H)-one hydrogen chloride (100 mg, 94% yield) as a white solid. LC-MS (ES) m / z = 269.4 (M+H-HCI)+.

[0521] Step 10 : To a mixture of 2-(5-(1-aminoethyl)-1H-1 ,2,4-triazol-1-yl)-4,6,6-trimethyl-4H-1,3,4- thiadiazin-5(6H)-one hydrogen chloride (100 mg, 0.33 mmol) and TEA (100 mg, 0.98 mmol) in DCM (2 mL) was added 3,5-bis(trifluoromethyl)benzoyl chloride (91 mg, 0.33 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 minutes. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL * 3). The organic layer was concentrated. The residue was purified by reverse phase column (ACN / H2O = 1 / 1) to afford 3,5-bis(trifluoromethyl)-N-(1-(1-(4,6,6- trimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazi n-2-yl)- 1 H-1 ,2,4-triazol-5-yl)ethyl)benzamide (115.6 mg, 69% yield) as a white solid. LC-MS (ES) m / z = 509.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.61 (d, J = 7.2 Hz, 1H), 8.49 (s, 2H), 8.35 (s, 1H), 8.20 (s, 1H), 5.78-5.71 (m, 1 H), 3.33 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H), 1.46 (s, 3H), 1.41 (s, 3H).

[0522] Example 23: Synthesis of N-(1-(3-(5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2-yl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-26) :

[0523] Step 1 : To a mixture of (Z)-N-(1-(3-((2-(4-methoxybenzyl)hydrazineylidene)methyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (445 mg, 0.85 mmol) in THF (3 mL) was dropped a solution of NBS (166 mg, 0.93 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Methyl 2-mercaptoacetate (135 mg, 1.27 mmol) in MeOH (1.5 mL) was dropped to the mixture at 0 °C. Then TEA (428 mg, 4.23 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 hrs, and warmed to 70 °C. The mixture was stirred at 70 °C for 16 hrs. The mixture was concentrated. The residue was purified by column chromatography (PE / EtOAc = 2 / 1) to afford N-(1-(3-(4-(4-methoxybenzyl)-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2-yl)pyrazin- 2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (320 mg, 63% yield) as a yellow solid. LC-MS (ES) m / z (M+H)+= 598.0.

[0524] Step 2: To a solution of N-(1-(3-(4-(4-methoxybenzyl)-5-oxo-5,6-dihydro-4H-1,3,4-thiadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (320 mg, 0.54 mmol) in TFA (5 mL) was added TfOH (0.5 mL) at 0 °C. The mixture was warmed to 40 °C and stirred for 4 hrs. The mixture was diluted with EtOAc (20 mL) and quenched with sat.NH4CI to pH = 8-9. The mixture was extracted with EtOAc (30 mL * 3) and the organic layer was concentrated. The residue was purified by column chromatography (PE / EtOAc = 1 / 1) to afford 200 mg crude. The crude was triturated from (MeOH) to afford N-(1-(3-(5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (102.7 mg, 40% yield) as a white solid. LC-MS (ES) m / z = 477.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.88 (s, 1 H), 9.51 (d, J = 6.8 Hz, 1 H), 8.67 (s, 1 H), 8.62 (s, 1 H), 8.54 (s, 2H), 8.31 (s, 1 H), 6.03-5.96 (m, 1 H), 3.61 (s, 2H), 1.57 (d, J = 6.8 Hz, 3H).

[0525] Example 24: Synthesis of N-(1-(3-(6,6-dimethyl-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-81):

[0526] Step 1 : To a solution of N-[1-[3-(hydrazinecarbonyl)pyrazin-2-yl]ethyl]-3,5- bis(trifluoromethyl)benzamide (600 mg, 1.28 mmol) in EtOH (20 mL) was added 4- methoxybenzaldehyde (190 mg, 1.41 mmol) at room temperature. After stirred at 80°C for 6 hours. After stirred at room temperature for 1 hour. The reaction was concentrated and purified by column chromatography on silica (PE / EtOAc 9:1 to 3:1) to afford N-(1-(3-(2-(4- methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (700 mg, 98 % yield) as yellow solid. LC-MS (ES) m / z = 540.1 (M+H)+.

[0527] Step 2: To a solution of N-(1-(3-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (600 mg, 1.12 mmol) in MeOH (20 mL) was added 10% Pd / C (600 mg, 0.55 mmol) atmosphere of H2 at room temperature for 5 hours. The resulting mixture was filtered, and evaporated in vacuo to afford N-(1-(3-(2-(4- methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (600 mg, 95 % yield) as yellow oil. LC-MS (ES) m / z = 542.2 (M+H)+.

[0528] Step 3: To a solution of N-(1-(3-(2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (500 mg, 0.92 mmol) and NaHCCh (235 mg, 2.77 mmol) in THF (20 mL) was added 2-chloro-2-methylpropanoyl chloride (200 mg, 1.39 mmol) at 0 oC. After stirred at room temperature for 3 hours. The reaction mixture was diluted with brine (50 mL), extracted with EtOAc (50 mL * 2). The combined organic phase was concentrated and purified by column chromatography on silica gel (DCM / EA = 20 / 1) to afford N-(1-(3-(2-(2-chloro- 2-methylpropanoyl)-2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (850 mg, 95% yield) as a yellow solid. LC-MS (ES) m / z = 646.1 (M+H)+. 1 HNMR (400 MHz, DMSO-d6) δ [ppm] 11.20 (br s, 1H), 9.53 (br s, 1 H), 8.83 (d, J = 2.4 Hz, 1 H), 8.66 (d, J = 1.6 Hz, 1H), 8.53 (s, 2H), 8.31 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.91-5.84 (m, 1 H), 3.70 (s, 3H), 1.83 (s, 3H), 1.79 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

[0529] Step 4: To a mixture of N-(1-(3-(2-(2-chloro-2-methylpropanoyl)-2-(4- methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (420 mg, 0.65 mmol) in ACN (20 mL) were added Nal (390 mg, 2.6 mmol) and K2CO3 (360 mg, 2.6 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL * 2). The combined organic phase was concentrated. The residue was purified by reverse chromatography (70-82% ACN in water) to afford crude (210 mg, 53% yield, 92% purity). The crude (100 mg) was purified by Prep-HPLC (Chromatographic columns: Gemini-C18 150 x 21.2 mm, 63 -73% ACN in water with 0.1 % NH4HCO3) to afford N-(1-(3-(4-(4-methoxybenzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (36.1 mg) as a white solid. LC-MS (ES) m / z = 610.0 (M+H)+1 HNMR (400 MHz, DMSO-d6) δ [ppm] 9.46 (d, J = 6.4 Hz, 1 H), 8.72 (d, J = 2.4 Hz, 1 H), 8.63 (d, J = 2.4 Hz, 1 H), 8.50 (s, 2H), 8.31 (s, 1 H), 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.61-5.58 (m, 1 H), 4.87 (dd, J = 14.4 Hz, 36.8 Hz, 2H), 3.66 (s, 3H), 1.57 (s, 3H), 1.53 (s, 3H), 1.46 (d, J = 7.2 Hz, 3H).

[0530] Step 5: To a solution of N-(1-(3-(4-(4-methoxybenzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H- 1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (140 mg, 0.23 mmol) in TFA (4 mL) was added TfOH (1 mL) at 0 °C. The mixture was warmed to 60 °C and stirred for 1 hours. The mixture was diluted with EtOAc (20 mL) and quenched with sat. NaHCCh to pH = 8. The mixture was extracted with EtOAc (20 mL * 3). The combined organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by reversed phase column chromatography (ACN / H2O = 36%-42% ) to afford N-(1-(3-(6,6-dimethyl-5-oxo-5,6- dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (72 mg, 61 % yield) as white solid. LC-MS (ES) m / z = 490.0 (M+H)+.1HNMR (400 MHz, DMSO-d6) 6 [ppm] 11.25 (s, 1 H), 9.54 (d, J = 7.2 Hz, 1 H), 8.73 (d, J = 2.4 Hz, 1 H), 8.65 (d, J = 2.4 Hz, 1 H), 8.52 (s, 2H), 8.31 (s, 1 H), 5.85-5.81 (m, 1 H), 1.59 (d, J = 6.8 Hz, 3H), 1.53 (d, J = 5.2 Hz, 6H).

[0531] Example 25: Synthesis of N-(1-(3-(8-oxo-4-oxa-6,7-diazaspiro[2.5]oct-5-en-5-yl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-82):

[0532] Step 1 : A mixture of (4-methoxybenzyl)hydrazine (58 mg, 0.38 mmol) and N-[1-(3- formylpyrazin-2-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (150 mg, 0.38 mmol) in MeOH (4 mL) was stirred at 30 °C for 1 hr. The mixture was concentrated to afford N-[1-[3-[(E)-[(4- methoxyphenyl)methylhydrazono]methyl]pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (160 mg, 79% yield) as a yellow solid. LC-MS (ES) m / z = 526.4 (M+H)+.

[0533] Step 2: To a solution of 1-hydroxycyclopropane-1-carboxylic acid (4.82 g, 47.20 mmol) in DCM (60 mL) was added SOCI2 (16.85 g, 141.60 mmol) and a few drops of DMF. The mixture was stirred at 50 °C for 1.5 hours. The mixture was concentrated and the residue was diluted with DCM (50 mL). The solution was dropped to N-[1-[3-[(E)-[(4- methoxyphenyl)methylhydrazono]methyl]pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (12.40 g, 23.60 mmol) and TEA (14.33 g, 141.60 mmol) in DCM (130 mL) at 0 °C. The mixture was stirred at 30 °C for 2 hours. The mixture was quenched with water (100 mL) and extracted with DCM (100 mL * 3). The organic layer was concentrated and the residue was purified by column chromatography (PE / EtOAc = 3 / 1) to afford (E)-N-(1-(3-((2-(1-hydroxycyclopropane-1- carbonyl)-2-(4-methoxybenzyl)hydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (2.04 g, 14% yield) as a yellow solid. LC-MS (ES) m / z (M+H)+= 610.4.

[0534] Step 3: To a solution of (E)-N-(1-(3-((2-(1-hydroxycyclopropane-1-carbonyl)-2-(4- methoxybenzyl)hydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1.76 g, 2.90 mmol) in THF (20 mL) was added a solution of NBS (1.03 g, 5.80 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 50 °C for 2 hours. K2CO3 (0.80 g, 5.80 mmol) was added to the mixture at 0 °C and stirred at 0 °C for 4 hours. The mixture was quenched with aqueous of Na2S20s and extracted with EtOAc (50 mL * 3). The organic layer was concentrated and the residue was purified by column chromatography (PE / EtOAc = 3 / 1) to afford N-(1-(3-(7- (4-methoxybenzyl)-8-oxo-4-oxa-6,7-diazaspiro[2.5]oct-5-en-5-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (860 mg, 48% yield) as a yellow solid. LC-MS (ES) m / z = 608.1. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.48 (d, J = 6.4 Hz, 1 H), 8.72 (d, J = 2.4 Hz, 1 H), 8.61 (d, J = 2.4 Hz, 1 H), 8.51 (s, 2H), 8.31 (s, 1 H), 7.26 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.62 - 5.55 (m, 1 H), 4.91 - 4.76 (m, 2H), 3.66 (s, 3H), 1 .50 - 1 .32 (m, 7H).

[0535] Step 4: To a solution of N-(1-(3-(7-(4-methoxybenzyl)-8-oxo-4-oxa-6,7-diazaspiro[2.5]oct-5-en- 5-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (800.00 mg, 1.32 mmol) in TfOH (20 mL) was added TfOH (2 mL) at 0 °C. The mixture was stirred at 0 °C for 4 hours. The mixture was diluted with EtOAc (20 mL) and quenched with sat. Na2CO3 to pH = 9-10. The mixture was extracted with EtOAc (30 mL * 3) and the organic layer was concentrated. The residue was purified by column chromatography (PE / EtOAc = 2 / 1) to afford 500 mg crude. The crude was purified by reverse phase column (ACN / H2O = 3 / 1) to afford N-(1-(3-(8-oxo-4-oxa-6,7- diazaspiro[2.5]oct-5-en-5-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (300 mg, 47% yield) as a yellow solid. LC-MS (ES) m / z = 488.0. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 11.37 (s, 1 H), 9.55 (d, J = 6.4 Hz, 1 H), 8.74 (d, J = 2.4 Hz, 1 H), 8.63 (d, J = 2.4 Hz, 1 H), 8.53 (s, 2H), 8.32 (s, 1 H), 5.82 - 5.76 (m, 1 H), 1 .59 (d, J = 6.8 Hz, 3H), 1.43 - 1.37 (m, 2H), 1 .35 - 1 .23 (m, 2H).

[0536] Example 26: Synthesis of N-Methyl-3,5-bis(trifluoromethyl)-N-(1-(3-(4,6,6-trimethyl-5-oxo-5,6- dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)benzamide (I-88)

[0537] Step 1 : To a solution of 1-(3-chloropyrazin-2-yl)ethanone (10.0 g, 90% purity, 57.5 mmol), methanamine (20.9 mL, 68.97 mmol, 3.3 M in THF) in MeOH (140 mL) was added Titanium(IV) isopropoxide (24.5 g, 86.2 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. After completed, the mixture was added sodium borohydride (3.26 g, 86.2 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was directly concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford the 1-(3-chloropyrazin-2-yl)-N-methylethan-1 -amine (10.0 g, 74%, 75% yield) as yellow oil. LC-MS (ES) m / z = 172.0 (M+H)+. Step 2: To a solution of 1-(3-chloropyrazin-2-yl)-N-methylethan-1 -amine (10.0 g, 74% purity, 43.1 mmol), TEA (13.1 g, 129 mmol) in THF (120 mL) was added (Boc)2O (14.1 g, 64.7 mmol). The reaction mixture was stirred at 40 °C for 2 hours. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to afford tert-butyl (1-(3-chloropyrazin-2- yl)ethyl)(methyl)carbamate (11 g, 85% purity, 80% yield) as yellow oil. LC-MS (ES) m / z = 216.0 (M+H-56)+.

[0538] Step 3: A solution of Tert-butyl (1-(3-chloropyrazin-2-yl)ethyl)(methyl)carbamate (9.0 g, 85% purity, 28 mmol), 2-(diethylamino)ethanol (8.2 g, 70 mmol) and Pd(PPh3)2Cl2 (1.18 g, 1.68 mmol) in NMP (100 mL) was stirred at 120 °C for 16 hrs. Then the mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL *3). The organic layer was washed with brine (300 mL * 3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (DCM / MeOH = 20 / 1) to give the crude. The crude was subjected to C18 column (45-70% ACN / H2O) to afford 2-(Diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(methyl)amino)ethyl)Pyrazine-2-carboxylate (4.6 g, 95% purity, 41% yield) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] 8.63 - 8.62 (m, 1 H), 8.51 - 8.50 (m, 1 H), 5.94 - 5.61 (m, 1 H), 4.48 (s, 2H), 2.95 - 2.65 (m, 9H), 1.58 - 1.56 (m, 3H), 1.40 - 1.25 (m, 9H), 1.08 (s, 6H).

[0539] Step 4: A solution of 2-(diethylamino)ethyl 3-(1-((tert- butoxycarbonyl)(methyl)amino)ethyl)pyrazine-2-carboxylate (4.1 g, 95% purity, 10.2 mmol) in DCM (30 mL) was added 4M HCI / 1 ,4-dioxane (30 mL, 120 mmol) at 0°C and the mixture was stirred at 25°C for 2 hrs. The reaction was concentrated to afford 2-(diethylamino)ethyl 3-(1- (methylamino)ethyl)pyrazine-2-carboxylate hydrochloride (3.2 g, 90% purity, 95% yield) as a yellow solid. LC-MS (ES) m / z = 281.1 (M+H)+.

[0540] Step 5: To a solution of 2-(diethylamino)ethyl 3-(1-(methylamino)ethyl)pyrazine-2-carboxylate hydrochloride (3.2 g, 90% purity, 9.1 mmol), 3-chloro-5-(trifluoromethyl)benzoyl chloride (3.81 g, 13.7 mmol) in DMF (40 mL) was added TEA (4.61 g, 45.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 3 hrs. The reaction was diluted with water (120 mL), extracted with EtOAc (50 mL *3). Then the organic layer was washed with brine (50 mL *3) and dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2-(diethylamino)ethyl 3-(1-(N-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)Pyrazine-2-carboxylate (4.4 g, 81% purity, 60% yield) as yellow oil. LC-MS (ES) m / z = 521.2 (M+H)+.

[0541] Step 6: To a solution of 2-(diethylamino)ethyl 3-(1-(N-methyl-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (1.8 g, 80% purity, 2.8 mmol) in THF (20 mL) was added 85% w.t. hydrazine hydrate (596 mg, 14.0 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. The reaction was concentrated. The residue was diluted in water (10 mL), extracted with DCM / MeOH (10:1, 20 mL * 3), dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated to afford N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-N-methyl- 3,5-bis(trifluoromethyl)benzamide (1.3 g, 90% purity, 87% yield) as yellow oil. LC-MS (ES) m / z = 436.0 (M+H)+.

[0542] Step 7: To a solution of N-(1-(3-(hydrazinecarbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (1.1 g, 90% purity, 1.8 mmol) and 4-methoxybenzaldehyde (272 mg, 2.0 mmol) in EtOH (4 mL) was added acetic acid (11 mg, 0.18 mmol). The reaction mixture was stirred at 80°C for 4 hrs. The reaction was directly concentrated to give the crude. The crude was purified by silica gel chromatography (10-55% EtOAc / PE) to afford (E)-N-(1-(3-(2-(4- methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (1.4 g, 90% purity, 94% yield) as a yellow solid. LC-MS (ES) m / z = 554.1 (M+H)+.

[0543] Step 8: To a solution of (E)-N-(1-(3-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2- yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (1.3 g, 90% purity, 2.1 mmol) in MeOH (15 mL) was added Pd / C (1.11 g, 1.05 mmol) and the resulting mixture was evacuated and refilled with hydrogen (* 3) and then the mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness in vacuo to afford N-(1-(3-(2-(4- Methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (1.1 g, 90% purity, 78% yield) as a yellow solid. LC-MS (ES) m / z = 556.1 (M+H)+.

[0544] Step 9: To a solution of N-(1-(3-(2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- N-methyl-3,5-bis(trifluoromethyl)benzamide (900 mg, 90% purity, 1.46 mmol) and NaHCCh (366 mg, 4.38 mmol) in THF (10 mL) was added 2-chloro-2-methylpropanoyl chloride (268 mg, 1.90 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture combined was diluted with water (20 mL), extracted with EtOAc (30 mL *3). The organic layer was washed with brine (50 mL * 2), dried over Na2SC>4, filtered and concentrated. The residue was subjected to silica gel chromatography (10-45% EtOAc: PE) to afford N-(1-(3-(2-(2-chloro- 2-methylpropanoyl)-2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (900 mg, 90% purity, 84% yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] 9.69 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 7.91 - 7.82 (m, 3H), 7.26 - 7.06 (m, 2H), 6.84 - 6.82 (m, 2H), 6.49 - 6.47 (m, 1H), 4.92 (br s, 2H), 3.78 (s, 3H), 3.22 (s, 3H), 1.85 - 1.81 (m, 6H), 1.75 - 1.67 (m, 3H).

[0545] Step 10: A mixture of N-(1-(3-(2-(2-chloro-2-methylpropanoyl)-2-(4-methoxybenzyl)hydrazine- 1-carbonyl)pyrazin-2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (800 mg, 90% purity, 1.09 mmol), Nal (489 mg, 3.26 mmol, 60% purity) and K2COs (451 mg, 3.26 mmol) in ACN (10 mL) was stirred in air at 80°C for 48 hrs. The reaction mixture was cooled to 10°C and filtered. The filtrate was concentrated to dryness in vacuo to give the crude. The crude was purified by silica gel chromatography (10-45% EtOAc / PE) to afford N-(1-(3-(4-(4-methoxybenzyl)-6,6- dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-N-methyl-3,5- bis(trifluoromethyl)benzamide (700 mg, 85%, 88% yield) as a yellow solid. LC-MS (ES) m / z = 624.2 (M+H)+.

[0546] Step 11 : To a solution of N-(1-(3-(4-(4-methoxybenzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H- 1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (700 mg, 85% purity, 0.954 mmol) in TFA (2 mL) was added TfOH (0.2 mL) at 0 °C. The mixture was warmed to 60°C and stirred for 1 hrs. The mixture was diluted with EtOAc (20 mL) and quenched with sat. NaHCChto pH = 10-11. The mixture was extracted with EtOAc (30 mL * 3), and the organic layer was concentrated. The residue was purified by column chromatography (PE / EtOAc = 3 / 1) to afford the desired compound (500 mg, 90% purity, 94% yield) as a yellow solid. The solids (200 mg) were then subjected to Prep-HPLC (Xbridge prep C18 10um OBD 19*150mm / WELCH Xtimate C18 21.2*250mm 10um; 5 -95 % (v / v) acetrile / water (containing 0.1% NH4HCO3)) to afford N-(1-(3-(6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (I-89) (52.8 mg, 100% purity, 29% yield) as white solids. LC-MS (ES) m / z = 504.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) 5 [ppm] 11.24 (s, 0.72H), 10.95 (s, 0.21 H), 8.77 - 8.76 (m, 1 H), 8.71 - 8.70 (m, 1 H), 8.20 (s, 0.75H), 8.09 (s, 0.27H), 8.02 (s, 1.45H), 7.55 (s, 0.43H), 6.25 - 6.20 (m, 0.73H), 5.42 - 5.40 (m, 0.22H), 3.30 (s, 0.72H), 2.90 (s, 2.24H), 1.63 (d, J = 7.2 Hz, 3H), 1.53 - 1.26 (m, 6H).

[0547] Step 12: A mixture of N-(1-(3-(6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl)ethyl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (I-89) (150 mg, 0.27 mmol), K2CO3 (111 mg, 0.81 mmol) and iodomethane (46 mg, 0.32 mmol) in DMF (2 mL) was stirred in N2 at 60 °C for 3 hours. The mixture was diluted with H2O (10 mL), then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (Xbridge prep C18 10um OBD 19 * 150mm / WELCH Xtimate C18 21.2 * 250mm 10um; 5 -95 % (v / v) acetrile / water (containing 0.1 % NH4HCO3) to afford N-Methyl-3,5-bis(trifluoromethyl)-N-(1-(3-(4,6,6-trimethyl-5-oxo-5,6-dihydro- 4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)benzamide (82.5 mg, 59% yield) as white solids. LC- MS (ES) m / z = 518.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 8.80 - 8.79 (m, 1 H), 8.74 - 8.71 (m, 1 H), 8.22 (s, 0.67H), 8.12 (s, 0.30H), 7.99 (s, 1.33H), 7.61 (s, 0.58H), 6.35 - 6.30 (m, 0.68H), 5.58 - 5.56 (m, 0.29H), 3.32 (s, 1 H), 3.24 (s, 2H), 3.02 (s, 1 H), 2.79 (s, 2H), 1 .64 (d, J = 7.2Hz, 3H), 1.54 (s, 4H), 1.38-1.31 (m, 2H)

[0548] Example 27: Synthesis of N-(1-(3-(6,6-dimethyl-5-oxo-4-(prop-2-yn-1-yl)-5,6-dihydro-4H-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-90):

[0549] A mixture of N-[1-[3-(6,6-dimethyl-5-oxo-4-prop-2-ynyl-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]- 3,5-bis(trifluoromethyl)benzamide (60 mg, 0.12 mmol), 3-bromoprop-1-yne (14.5 mg, 0.12 mmol) and K2CO3 (33.8 mg, 0.24 mmol) in DMF (5 mL) was stirred at rt for 3 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layer was dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC (ACN / H2O, 10% to 20%) to afford N-(1-(3-(6,6-dimethyl-5-oxo-4-(prop-2-yn-1-yl)- 5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (40 mg, 62 % yield) as a white solid. LC-MS (ES) m / z = 528.0 (M+H)+. 1 H NMR [ppm] (400 MHz, DMSO-d6) δ [ppm] 9.55 (d, J = 6.8 Hz, 1 H), 8.76 (d, J = 2.4 Hz, 1 H), 8.67 (d, J = 2.4 Hz, 1 H), 8.52 (s, 2H), 8.30 (s, 1 H), 5.85-5.81 (m, 1 H), 4.60-4.46 (m, 2H), 3.32-3.27 (m, 1 H), 1.64 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 5.2 Hz, 6H).

[0550] Example 28: Synthesis of 3,5-bis(trifluoromethyl)-N-(1-(3-(4,6,6-trimethyl-5-oxo-5,6-dihydro- 4H-1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)benzamide (I-93):

[0551] Step 1 : To a solution of potassium thioacetate (10 g, 86 mmol) in DMF (15 mL) stirred under nitrogen at room temperature was added a solution of methyl 2-bromo-2-methyl-propanoate (31.1 g, 0.17 mol) in DMF (5 mL) dropwise. The reaction mixture was then heated at 60 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and was extracted with EtOAc (50 mL * 3). The combined organic phase was concentrated to afford methyl 2-(acetylthio)-2-methylpropanoate (13 g, 86.7 % yield) as a yellow solid.1HNMR (400 MHz, CDCI3) δ [ppm] 3.74 (s, 3H), 2.76 (s, 3H), 1.56 (s, 6H).

[0552] Step 2 : To a solution of methyl 2-(acetylthio)-2-methylpropanoate (13 g, 73.8 mmol) in dry MeOH (20 mL) stirred under nitrogen at room temperature was added a solution of (methylsulfanyl)sodium (5.17 mg, 73.8 mmol) in dry MeOH (10 mL) in one charge. The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with 0.1 N HCI and extracted with DCM. The organic phases were collected, washed with brine, dried over anhydrous Na2SO4 and concentrated under pressure to afford methyl 2- mercapto-2-methylpropanoate (6.9 g, 69.8%yield) as a yellow oil.1HNMR (400 MHz, CDCI3) 6 [ppm] 3.75 (s, 3H), 1.60 (s, 6H).

[0553] Step 3 : To a solution of 3,5-bis(trifluoromethyl)- / \ / -[1-(3-vinylpyrazin-2-yl)ethyl]benzamide

[0554] (5 g, 14.1 mmol) and K2OsC>4.2H2O (520 mg, 1.4 mmol) in acetone (100 mL) stirred at 0 °C was added a solution of NalCL (6.03 g, 28.2 mmol) in water (50 mL) in one charge. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL * 3). The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under pressure. The crude product was purified with silica gel chromatography (PE / EtOAc = 5 / 1) to afford N-(1-(3-formylpyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (3 g, 48.9% yield) as a yellow gum. LC-MS (ES) m / z = 392.1 (M+H)+.

[0555] Step 4: To a solution of N-(1-(3-formylpyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1 g, 2.6 mmol) in MeOH (20 mL) stirred at room temperature was added [(4- methoxyphenyl)methyl]hydrazine (470 mg, 3.1 mmol) in one charge. The reaction mixture was stirred at 30 °C for 3 hours. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL * 3). The organic layers were collected, dried over anhydrous Na2SC>4 and concentrated under pressure. The crude product was purified with silica gel chromatography (PE / EtOAc = 5 / 1) to afford (E)-N-(1-(3-((2-(4- methoxybenzyl)hydrazineylidene)methyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1g, 74.6% yield) as a yellow solid. LC-MS (ES) m / z = 526.1 (M+H)+.

[0556] Step 5: To a mixture of (E)-N-(1-(3-((2-(4-methoxybenzyl)hydrazineylidene)methyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (950 mg, 1.8 mmol) in THF (25 mL) was added dropwise a solution of NBS (386 mg, 2.17 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. A solution of methyl 2-methyl-2-sulfanylpropanoate (364 mg, 2.71 mmol) in MeOH (3 mL) was added dropwise to the mixture at 0 °C, followed by the addition of TEA (913 mg, 9.04 mmol). The mixture was stirred at 0 °C for 2 hours and was warmed to 50 °C for another 12 hours. After completion, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1) to afford N-(1-(3-(4-(4- methoxybenzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (386 mg, 34.1% yield) as a white solid. LC-MS (ES) m / z = 626.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.51 (d, J = 6.4 Hz, 1 H), 8.66 (d, J = 2.4 Hz, 1 H), 8.59 (d, J = 2.4 Hz, 1 H), 8.51 (s, 2H), 8.30 (s, 1 H), 7.23 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.87-5.84 (m, 1 H), 5.01 (dd, J = 14.4 Hz, 36.8 Hz, 2H), 3.67 (s, 3H), 1.50-1.46 (m, 9H).

[0557] Step 6: To a solution of N-[1-[3-[4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-5-oxo-1 ,3,4- thiadiazin-2-yl]pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (350 mg, 0.56 mmol) in TFA (4 mL) stirred at room temperature was added TfOH (1 mL) in one charge. The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under pressure. The resulting crude was diluted with water, neutralized with saturated NaHCCh solution and extracted with EtOAc (10 mL * 3). The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under pressure. The crude was purified with C18 column (30 - 40% ACN / Water ) to afford N-(1-(3-(6,6-dimethyl-5-oxo-5,6- dihydro-4H-1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-91) (180 mg, 63.4%yield) as a white solid. LC-MS (ES) m / z = 506.0 (M+H)+, 1 H NMR (400 MHz, DMSO- d6) δ [ppm] 11.90 (s, 1 H), 9.57 (d, J = 6.8 Hz, 1 H), 8.67 (d, J = 2.0 Hz, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.53 (s, 2H), 8.30 (s, 1 H), 6.02-5.99 (m, 1 H), 1.58 (d, J = 6.8 Hz, 3H), 1.47 (s, 6H).

[0558] Step 7: To a solution of N-(1-(3-(6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.2 mmol) in ACN (5 mL) stirred at room temperature was added K2CO3 (55 mg, 0.4 mmol) and Mel (57 mg, 0.4 mmol) in sequence. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EA (10 mL * 3). The organic layers were collected, dried over anhydrous Na2SC>4 and concentrated under pressure. The crude was purified by C18 column (40 - 50% ACN I Water ) to afford 3,5-bis(trifluoromethyl)-N-(1-(3-(4,6,6- trimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)pyrazin-2-yl)ethyl)benzamide (I-93) (89.1 mg, 86.5% yield) as a white solid. LC-MS (ES) m / z = 520.0 (M+H)+1 HNMR (400 MHz, DMSO- d6) δ [ppm] 9.57 (d, J = 6.8 Hz, 1 H), 8.69 (d, J = 2.0 Hz, 1 H), 8.61 (d, J = 2.0 Hz, 1 H), 8.52 (s, 2H), 8.30 (s, 1 H), 6.01-5.98 (m, 1 H), 3.49 (s, 3H), 1.64 (d, J = 6.0 Hz, 3H), 1.49 (s, 3H), 1.46 (s, 3H).

[0559] Example 29: Synthesis of N-(1-(1-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)-1 H- 1 ,2,4-triazol-5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (I-92):

[0560] Step 1 : To a solution of 4-methyl-2-(1 ,2,4-triazol-1-yl)-1 ,3,4-thiadiazin-5-one (200 mg, 1.01 mmol) in THF (5 ml) was added hydrazine hydrate (152 mg, 3.04 mmol, 98% purity). The reaction mixture was stirred at rt for 5 hrs and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to afford 2-hydrazineyl-4-methyl-4H-1 ,3,4- thiadiazin-5(6H)-one (80 mg, 49% yield) as yellow oil. LC-MS (ES) m / z = 161.0 (M+H)+.

[0561] Step 2: A solution of 2-hydrazineyl-4-methyl-4H-1 ,3,4-thiadiazin-5(6H)-one (60 mg, 0.37 mmol) in tert-butyl (E)-(1-(((dimethylamino)methylene)amino)-1-oxopropan-2-yl)carbamate (137 mg, 0.56 mmol) in AcOH (5 ml) was stirred at rt for 16 hrs. The reaction was concentrated and the residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford tertbutyl (1-(1-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)-1 H-1 ,2,4-triazol-5- yl)ethyl)carbamate (100 mg, 78% yield) as a colorless oil. LC-MS (ES) m / z = 341.3 (M+H)+.

[0562] Step 3: To a solution of Tert-butyl (1-(1-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)- 1 H-1 ,2,4-triazol-5-yl)ethyl)carbamate (100 mg, 0.29 mmol) in EtOAc (2 mL) was added HCI (g) in EtOAc (1 mL, 6 M). The reaction mixture was stirred at rt for 2 hrs and concentrated to afford 2-(5-(1-aminoethyl)-1 H-1 ,2,4-triazol-1-yl)-4-methyl-4H-1 ,3,4-thiadiazin-5(6H)-one hydrochloride (100 mg, crude) as a yellow oil. LC-MS (ES) m / z = 241.2 (M+H)+

[0563] Step 4: To a solution of 2-(5-(1-aminoethyl)-1 H-1 ,2,4-triazol-1-yl)-4-methyl-4H-1 ,3,4-thiadiazin- 5(6H)-one hydrochloride (100 mg crude, 0.29 mmol), TEA (126 mg, 1.25 mmol) in DCM (5 mL) was added 3,5-bis(trifluoromethyl)benzoyl chloride (138 mg, 0.50 mmol). The mixture was stirred at rt for 2 hrs and concentrated. The residue was purified by Prep-HPLC to afford N-(1- (1-(4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazi n-2-yl)- 1 H-1 ,2,4-triazol-5-yl)ethyl)-3, 5- bis(trifluoromethyl)benzamide (85 mg, 61% yield) as a white solid. LC-MS (ES) m / z = 481.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.60 (d, J = 7.2 Hz, 1 H), 8.52 (s, 2H), 8.34 (s, 1 H), 8.20 (s, 1 H), 5.79-5.72 (m, 1 H), 3.88 (d, J = 14.8 Hz, 1 H), 3.77 (d, J = 14.8 Hz, 1 H), 3.31 (s, 3H), 1.65 (d, J = 6.8 Hz, 3H).

[0564] Example 30: Synthesis of N-(1-(1-(6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)- 1 H-1 ,2,4-triazol-5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-127):

[0565] Step 1 : To a solution of tert-butyl N-aminocarbamate (1.00 g, 7.57 mmol), NaHCOs (1.9 g,

[0566] 22.70 mmol) in THF (20 ml) was added 2-bromo-2-methylpropanoyl bromide (1.9 g, 8.32 mmol] at 0°C. The reaction mixture was stirred at rt for 2hrs. The mixture was diluted with H2O (30 mL), extracted with EtOAc (30 mL *2). The organic layer was washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated to afford tert-butyl 2-(2-bromo-2-methylpropanoyl)hydrazine- 1-carboxylate (1.6 g, 75% yield) as yellow solid. LC-MS (ES) m / z = 181.0 (M+H-Boc)+.

[0567] Step 2: A solution of tert-butyl 2-(2-bromo-2-methylpropanoyl)hydrazine-1 -carboxylate (1.6 g, 5.69 mmol) in EtOAc (20 ml) EtOAc / HCI (10 ml) was stirred at rt for 2hrs. The mixture was concentrated to afford 2-bromo-2-methylpropanehydrazide hydrogen chloride (1 g, 97% yield) as white solid. LC-MS (ES) m / z = 182.9 (M+H)+.

[0568] Step 3: To a solution of bis(1 ,2,4-triazol-1-yl)methanethione (1 .74 g, 9.66 mmol), TEA (1.95 g, 19.31 mmol) in THF (20 ml) was added 2-bromo-2-methylpropanehydrazide hydrogen chloride (1.4 g, 6.44 mmol). The reaction was stirred at rt for 2hrs. The mixture was concentrated. The residue was purified by column chromatography on silica gel DCM / MeOH = (20 / 1) to afford 6,6- dimethyl-2-(1 H-1 ,2,4-triazol-1-yl)-4H-1 ,3,4-thiadiazin-5(6H)-one (1.00 g, 59% yield) as yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1 H), 8.96 (s, 1 H), 7.96 (s, 1 H), 1.99(s, 6H).

[0569] Step 4: To a solution of 6,6-dimethyl-2-(1 ,2,4-triazol- 1 -yl)-4 / 7- 1 ,3,4-thiadiazin-5-one

[0570] (500 mg, 2.36 mmol) in MeOH (10 ml) was added hydrazine hydrate (711 mg, 14.20 mmol, 98% purity). The reaction mixture was stirred at rt for 16 hrs. The reaction was concentrated and residue was purified by prep-HPLC to afford 2-hydrazineyl-6,6-dimethyl-4H-1 ,3,4-thiadiazin- 5(6H)-one (150 mg, 34% yield) as a white solid. LC-MS (ES) m / z = 174.9 (M+H)+.

[0571] Step y2: A solution of 2-hydrazineyl-6,6-dimethyl-4H-1 ,3,4-thiadiazin-5(6H)-one (80 mg, 0.46 mmol), N-[2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]-3,5- bis(trifluoromethyl)benzamide (137 mg, 0.56 mmol) in AcOH (5 ml) was stirred at rt for 16 hrs. The reaction was concentrated and the residue was purified by prep-HPLC to afford N-(1-(1- (6,6-dimethyl-5-oxo-5,6-dihydro-4H-1 ,3,4-thiadiazin-2-yl)-1 H-1 ,2 ,4-triazol-5-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (30 mg, 13% yield) as a white solid. LC-MS (ES) m / z = 495.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.52 (d, J = 7.2 Hz, 1 H), 8.55 (s, 2H), 8.31 (s, 1 H), 7.90 (s, 1 H), 5.23-5.19 (m, 1 H), 2.03 (s, 3H), 1.95 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H).

[0572] Example 31 : Synthesis of N-(1-(1-(6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)-1 H-1 ,2,4-triazol- 5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-183):

[0573] Step 1 : To a solution of 1 ,3-diaminothiourea (37.5 g, 353 mmol) in EtOH (300 mL) was added CH3I (55 g, 389 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered to afford the product Methyl (Z)-hydrazinecarbohydrazonothioate hydroiodide (62 g, 71 % yield) as a white solid which without further purification. 1 H NMR (400 MHz, DMSO-de) 5 [ppm] 9.62 (br s, 1 H), 5.17 (br s, 2H), 2.39 (s, 3H).

[0574] Step 2: To a solution of glycine (1 g, 13.3 mmol) in 2 N NaOH solution (8 mL, 16 mmol) was added Methyl (Z)-hydrazinecarbohydrazonothioate hydroiodide (3.6 g, 14.6 mmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated to give a crude product, which was purified with reverse chromatography (3% ACN in water) to afford the product 2- ((dihydrazineylmethylene)amino)acetic acid (2 g, crude) as a brown solid. LC-MS (ES) m / z = 148.1 (M+H)+.

[0575] Step 3: To a solution of 2-((dihydrazineylmethylene)amino)acetic acid (2 g crude) in 1 N HCI (20 mL) was stirred at 25 °C for 5 h. The reaction mixture was concentrated to give a crude product, which was purified with reverse chromatography (5% ACN in water) to afford 3- hydrazineyl-4,5-dihydro-1 ,2,4-triazin-6(1 H)-one hydrochloride (1 g crude) as a brown solid. LC- MS (ES) m / z = 130.1 (M+H)+.

[0576] Step 4: To a solution of 3-hydrazineyl-4,5-dihydro-1 ,2,4-triazin-6(1 H)-one hydrochloride (200 mg, 1.2 mmol) in AcOH (5 mL) was added N-(1-(((dimethyl-l4-azaneylidene)methyl)amino)-1- oxopropan-2-yl)-3,5-bis(trifluoromethyl)benzamide (507 mg, 1.3 mmol). The mixture was stirred at 25 °C for 18 h and concentrated to give a crude product, which was purified with silica gel chromatography hhO / MeCN (45%-60%) to afford N-(1-(1-(6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin- 3-yl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (32 mg, 6 %yield) as a white solid. LC-MS (ES) m / z = 450.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 10.52 (s, 1 H), 9.58 (d, J = 7.2 Hz, 1 H), 8.53 (s, 2H), 8.34 (s, 1 H), 8.13 (s, 1 H), 7.93 (s, 1 H), 5.78-5.74 (m, 1 H), 3.91-3.85 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H).

[0577] Example 32 and Example 33: Synthesis of N-(1-(1-(4-methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4- triazin-3-yl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-181) and N-(1-(1- (1 ,4-dimethyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazi n-3-yl)- 1 H-1 ,2,4-triazol-5-yl)ethyl)-3, 5- bis(trifluoromethyl)benzamide (1-186):

[0578] To a solution of N-(1-(1-(6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)-1 H-1 ,2,4-triazol-5-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (380 mg, 0.84 mmol) in DMF (5 mL) was added CH3I (185 mg, 1.3 mmol) and K2CO3 (348 mg, 2.5 mmol). The mixture was stirred at 25 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by prep-HPLC to afford N-(1-(1-(1 ,4-dimethyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin- 3-yl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (44 mg, 11 %yield) as a white solid and N-(1-(1-(4-methyl-6-oxo-1 ,4,5,6-tetrahydro-1 ,2,4-triazin-3-yl)-1 H-1 ,2,4-triazol-5- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (21 mg, 5 %yield) as a white solid.

[0579] 1-186 : LC-MS (ES) m / z = 478.1 (M+H)+

[0580] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.60 (d, J = 6.8 Hz, 1 H), 8.48 (s, 2H), 8.36 (s, 1 H), 8.21 (s, 1 H), 5.51-5.48 (m, 1 H), 4.01 (d, J = 16.0 Hz, 1 H), 3.83 (d, J = 16.0 Hz, 1 H), 3.06 (s, 3H), 2.61 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H).

[0581] 1-181 : LC-MS (ES) m / z = 464.0 (M+H)+.

[0582] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 10.68 (s, 1 H), 9.61 (d, J = 6.8 Hz, 1 H), 8.51 (s, 2H), 8.36 (s, 1 H), 8.18 (s, 1 H), 5.43-5.40 (m, 1 H), 3.99 (d, J = 15.6 Hz, 1 H), 3.84 (d, J = 15.6 Hz, 1 H), 2.59 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). Example 34: Synthesis of N-(1-(3-(6,6-difluoro-4-methyl-5-oxo-5,6-dihydro-4H-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-182):

[0583] Step 1 : N-[1-(3-chloropyrazin-2-yl)ethyl]-N-[(3,4-dimethoxyphenyl)methyl]-3,5- bis(trifluoromethyl)benzamide (3.5 g,6.8 mmol), 2-(diethylamino)ethanol (2.39 g, 20.3 mmol) and Pd(PPh3)2Ch (480 mg, 0.6 mmol) were dissolved in NMP (30 mL). The reaction mixture was extracted and backfilled with CO. The reaction mixture was heated at 100 °C for 12 hours under CO atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL), and was extracted with EtOAc (50 mL *3). The combined organic phase was concentrated, and the residue was purified with silica gel chromatography(DCM / MeOH = 5 / 1) to afford the product 2-(diethylamino)ethyl 3-(1-(N-(3,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (1.7 g, 35.3 % yield) as a yellow solid. LC-MS (ES) m / z =657.2 (M+H)+.

[0584] Step 2: To a solution of 2-(diethylamino)ethyl 3-(1-(N-(3,4-dimethoxybenzyl)-3,5- bis(trifluoromethyl)benzamido)ethyl)pyrazine-2-carboxylate (1.7 g, 2.9 mmol) in dioxane (30 mL) stirred at 25 °C was added Hydrazinium hydroxide solution (128 mg, 3.48 mmol). The reaction mixture was stirred at 90 °C for 2 hours. After cooing to room temperature, the reaction mixture was concentrated under pressure to remove the solvent. The residue was then washed with brine and extracted with EA. The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under pressure to afford N-(3,4-dimethoxybenzyl)-N-(1-(3- (hydrazinecarbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1.49 g, 90.2% yield) as a yellow solid. LC-MS (ES) m / z =594.1 (M+Na)+.

[0585] Step 3: To a solution of N-(3,4-dimethoxybenzyl)-N-(1-(3-(hydrazinecarbonyl)pyrazin-2- yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1.49 g, 2.6 mmol) in EtOH (50 mL) stirred at room temprature was added a solution of 4-methoxybenzaldehyde (571 mg, 4.2 mmol) in EtOH (5 mL) and a drop of AcOH. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL*3). The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under pressure. The crude product was purified with silica gel chromatography (PE / EtOA = 3 / 1) to afford (E)-N-(2,4- dimethoxybenzyl)-N-(1-(3-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)- 3,5-bis(trifluoromethyl)benzamide (950 mg, 52.8% yield) as a yellow solid. LC-MS (ES) m / z = 690.2 (M+H)+.

[0586] Step 4: To a solution of (E)-N-(2,4-dimethoxybenzyl)-N-(1-(3-(2-(4- methoxybenzylidene)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (950 mg, 1.76 mmol) in MeOH (20 mL) stirred under nitrogen at 25 °C was added Palladium / Carbon (190 mg, 20%wt). The reaction mixture was extracted and backfilled with H2 for 3 times. The reaction mixture was stirred at 25 °C for 12 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated under pressure. The crude product was purified with silica gel chromatography (PE / EtOA =3 / 1) to afford N-(2,4-dimethoxybenzyl)-N-(1- (3-(2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (880 mg, 92.4% yield) as a yellow solid. LC-MS (ES) m / z = 692.2 (M+H)+

[0587] Step 5: To a solution of N-(2,4-dimethoxybenzyl)-N-(1-(3-(2-(4-methoxybenzyl)hydrazine-1- carbonyl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (880 mg, 1.33 mmol) and NaHCOs (566 mg, 5.34 mmol) in DCM (10 mL) stirred at 0 °C was added a solution of 2-bromo- 2,2-difluoroacetyl chloride (516 mg, 2.67 mmol) in DCM (2 mL) dropwise. The reaction mixture was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford N-(1-(3- (2-(2-bromo-2,2-difluoroacetyl)-2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N- (2,4-dimethoxybenzyl)-3,5-bis(trifluoromethyl)benzamide (750 mg, 69.4% yield) as a yellow solid. LC-MS (ES) m / z = 850.1 (M+H)+

[0588] Step 6: A 20 mL microwave tube containing a mixture of N-(1-(3-(2-(2-bromo-2,2- difluoroacetyl)-2-(4-methoxybenzyl)hydrazine-1-carbonyl)pyrazin-2-yl)ethyl)-N-(2,4- dimethoxybenzyl)-3,5-bis(trifluoromethyl)benzamide (740 mg, 0.91 mmol), Nal (272 mg, 1.81 mmol) and TEA (183 mg, 1.81 mmol) in DMF (5 mL) was heated at 100 °C in microwave for 1 hour. After completion, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 2 / 1) to afford N-(1-(3-(6,6-Difluoro-4-(4- methoxybenzyl)-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-N-(2,4- dimethoxybenzyl)-3,5-bis(trifluoromethyl)benzamide (350 mg, 49.9% yield) as a pale yellow solid. LC-MS (ES) m / z = 790.2 (M+Na)+.

[0589] Step 7: To a solution of N-(1-(3-(6,6-difluoro-4-(4-methoxybenzyl)-5-oxo-5,6-dihydro-4H-1,3,4- oxadiazin-2-yl)pyrazin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-3,5-bis(trifluoromethyl)benzamide (350 mg, 0.48 mmol) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated and diluted with saturated Na2COs solution, and extracted with EtOA. The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under pressure. The crude was purified with silica- gel chromatography (PE / EtOAc=1 / 1), followed by reverse chromatography (40% ACN in water) to afford N-(1-(3-(6,6-difluoro-4-(4-methoxybenzyl)-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (197 mg, 66.4% yield) as a white solid. LC-MS (ES) m / z = 618.0 (M+H)+.1HNMR (400 MHz, DMSO-d6) δ [ppm] 9.47 (d, J = 6.4 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1 H), 8.71 (d, J = 2.4 Hz, 1H), 8.49 (s, 2H), 8.31 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.62-5.58 (m, 1 H), 5.01 (dd, J = 14.4 Hz, 36.8 Hz, 2H), 3.66 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H).

[0590] Step 8: To a solution of N-[1-[3-[6,6-difluoro-4-[(4-methoxyphenyl)methyl]-5-oxo-1,3,4- oxadiazin-2-yl]pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (280 mg, 0.41 mmol) in TFA (4 mL) stirred at 25 °C was added TfOH (1 mL) in one portion. The reaction mixture was stirred at 50 °C for 1 h. After completion, the reaction mixture was concentrated under pressure. The resulting crude was diluted with water, neutralized with saturated NaHCCh and extracted with EtOAc (30 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under pressure. The residue was purified with Prep-HPLC to afford N-(1-(3-(6,6- difluoro-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5- bis(trifluoromethyl)benzamide (1-185) (150 mg, 67%yield) as a white solid. LC-MS (ES) m / z = 498.0 (M+H)+1 H NMR (400 MHz, DMSO-d6) δ [ppm] 12.72 (s, 1 H), 9.55 (d, J = 6.8 Hz, 1 H), 8.83 (s, 1 H), 8.73 (s, 1 H), 8.51 (s, 2H), 8.31 (s, 1 H), 5.85-5.82 (m, 1 H), 1.60 (d, J = 6.8 Hz, 3H).

[0591] Step 9: To a mixture of N-(1-(3-(6,6-difluoro-5-oxo-5,6-dihydro-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-185) (110 mg, 0.22 mmol) and K2CO3 (61 mg, 0.44 mmol) in ACN (8 mL) at 25 °C was added a solution of CH3I (38 mg, 0.27 mmol) in ACN (2 mL) in one charge. The reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was concentrated under pressure. The crude product was purified with silica gel chromatography (PE / EA = 5 / 1) to afford N-(1-(3-(6,6-difluoro-4-methyl-5-oxo-5,6- dihydro-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl)ethyl)-3,5-bis(trifluoromethyl)benzamide (1-182) (52.3 mg, 45.0 %yield) as a yellow solid. LC-MS (ES) m / z = 512.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 9.57 (d, J = 6.8 Hz, 1 H), 8.85 (d, J = 1.2 Hz, 1 H), 8.87 (d, J = 1.2 Hz, 1 H), 8.50 (s, 2H), 8.33 (s, 1 H), 5.85-5.82 (m, 1 H), 3.43 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H).

[0592] Synthesis of the intermediats:

[0593] Amine intermediats:

[0594] Intermediate 1a : Synthesis of 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin- 2-yl]ethyl]propane-2-sulfinamide (I nt- 1a) :

[0595] Step 1 : To a solution of 3-chloropyrazine-2-carboxylic acid (50 g, 315.37 mmol, 1 eq) in DCM (500 mL) was added DIEA (122.28 g, 946.12 mmol, 164.79 mL, 3 eq) at 0°C, and then added tert-butyl N-amino-N-methyl-carbamate (69.16 g, 473.06 mmol, 1.5 eq) in DCM (200 mL) and PyBOP (213.35 g, 409.98 mmol, 1.3 eq) in DCM (400 mL) at the same time at 0°C dropwise over 4 hr. The mixture was stirred at 0-20 °C for 1 hr. LCMS showed the reaction was completed. The reaction mixture was quenched with H2O (300 mL), and then extracted with DCM (300 mL x 3). The combined organic layers were washed with aqueous NaCI (100 mL), dried over Na2SC>4, filtered and concentrated, purified by column (Petroleum ether / Ethyl acetate=10 / 1 to 2 / 1) to give tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]-N-methyl- carbamate (162 g, 565.02 mmol, 89.58% yield) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.89 - 9.45 (m, 1 H) 8.59 (d, J=2.13 Hz, 1 H) 8.51 (d, J=2.13 Hz, 1 H) 3.27 (s, 3 H) 1.48 (br s, 9 H)

[0596] Step 2 : To a solution of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]-N-methyl- carbamate (54 g, 188.34 mmol, 1 eq) in EtOAC / HCI (350 mL) .The mixture was stirred at 20°C for 2hr. LCMS showed the reaction was completed. The reaction mixture was filtrated and the filter cake was concentrated to give 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (104 g, 466.24 mmol, 82.52% yield, HCI) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.79 (d, J=2.50 Hz, 1 H) 8.76 (d, J=2.50 Hz, 1 H) 2.84 (s, 3 H)

[0597] Step 3 : To a solution of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]-N-methyl- carbamate (31 g, 138.98 mmol, 1 eq, HCI) in DMF (500 mL) was added K2CO3 (48.02 g, 347.44 mmol, 2.5 eq) and 2-chloroacetyl chloride (18.84 g, 166.77 mmol, 13.28 mL, 1.2eq) .The mixture was stirred at 20°C for 2.5hr, and then stirred at 45°C for 3hr. TLC (PE: EtOAc = 3:1) showed the reaction was completed. The reaction mixture was quenched with H2O (2000 mL), and then extracted with EtOAc (500 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5- one (total 104 g, 413.03 mmol, 99.06% yield, 90% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J=2.47 Hz, 1 H) 8.68 (d, J=2.35 Hz, 1 H) 4.92 (s, 2 H) 3.28 (s, 3 H)

[0598] Step 4 : To a solution of 2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (25 g, 110.32 mmol, 1 eq) in Tol. (1000 mL) was added Pd(PPh3)4 (6.37 g, 5.52 mmol, 0.05 eq) and tributyl(1- ethoxyvinyl)stannane (47.81 g, 132.38 mmol, 44.72 mL, 1.2 eq) .The mixture was stirred at 120°C for 12hr under N2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition aq.KF (1000 mL), and then filtered, and the filter cake was washed with EtOAc (300 mL x 4) and the filtrate was extracted with EtOAc (1200 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 2-[3-(1- ethoxyvinyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one (110 g, 419.42 mmol, 95.05% yield) as a brown oil and used directly.

[0599] Step 5 : To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one (110 g, 419.42 mmol, 1 eq) in MeCN (850 mL) was added HCI (2 M, 419.42 mL, 2 eq) at 0°C.The mixture was stirred at 0 °C for 1 hr . TLC (PE: EtOAc = 0:1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (1000 mL), and then extracted with EtOAc (1000 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated, triturating with MTBE (30 mL) to give 2-(3-acetylpyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (90 g, 384.27 mmol, 91 .62% yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.77 (d, J=2.47 Hz, 1 H) 8.68 (d, J=2.35 Hz, 1 H) 4.92 (s, 2 H) 3.28 (s, 3 H)

[0600] Step 6 : To a solution of 2-(3-acetylpyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (10 g, 42.70 mmol, 1 eq) in THF (120 mL) was added Ti(i-PrO)4 (30.34 g, 106.74 mmol, 31.50 mL, 2.5 eq) and 2-methylpropane-2-sulfinamide (10.35 g, 85.39 mmol, 2 eq) .The mixture was stirred at 80 °C for 16hr . TLC (EtOAc: MeOH = 10:1) showed the reaction was completed. The reaction mixture was quenched with H2O (100 mL), and then filtrated, washed with EtOAc (50 mL x 6) and extracted with EtOAc (300 mL), DCM: i-PrOH=3:1 (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated, the crude was triturated with EtOAc (100 mL), filtered to give (NE)-2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]propane-2-sulfinamide (40 g, 118.55 mmol, 92.56% yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.67 (dd, J=12.88, 1.88 Hz, 1 H) 8.58 (br d, J=5.00 Hz, 1 H)

[0601] 4.68 - 5.02 (m, 2 H) 3.39 (s, 3 H) 2.51 - 2.87 (m, 3 H) 1.22 (s, 9 H).

[0602] Step 7 : To a solution of (NE)-2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]propane-2-sulfinamide (5 g, 14.82 mmol, 1 eq) in THF (1000 mL) and MeOH (500 mL) was added NaBH4 (560.65 mg, 14.82 mmol, 1 eq) at 0°C under N2 .The mixture was stirred 0°C for 0.5hr under N2 . TLC (EtOAc: MeOH = 10:1) showed the reaction was completed. 8 reactions were combined for workup. The reaction mixture was quenched by addition H2O 1000 mL, and then extracted with EtOAc (1000 mL), DOM: i-PrOH=3:1 (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated, purified by prep-HPLC (neutral) to give 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (13 g, 38.30 mmol, 32.31 % yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.61 (d, J=2.25 Hz, 1 H) 8.56 (d, J=2.38 Hz, 1 H) 5.38 (dd, J=8.94,

[0603] 6.69 Hz, 1 H) 4.93 (br d, J=9.01 Hz, 1 H) 4.87 (s, 2 H) 3.46 (s, 3 H) 1 .53 (d, J=6.63 Hz, 3 H) 1.24 (s, 9 H) ; LC-MS : desired mass : 339.1 , observed mass : 340.1.

[0604] Intermediate 2a : Synthesis of 2-methyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (lnt-2a):

[0605] Step 1 : To a solution of 3-chloropyrazine-2-carboxylic acid (35 g, 220.76 mmol, 1 eq) in DOM (350 mL) was added TEA (67.02 g, 662.28 mmol, 92.18 mL, 3 eq), T4P (238.59 g, 331.14 mmol, 50% purity, 1.5 eq), and tert-butyl N-aminocarbamate (32.09 g, 242.84 mmol, 1.1 eq) at 20 °C and then stirred for 2 h at 20°C, the reaction mixture was quenched with aq.NaHCCh (200 mL), extracted with DCM (500 mL x 2), washed with aqueous NaCI (200 mL), dried over Na2SC>4, filtrated and concentrated to give product. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=3 / 1 to 1 / 1) to give tert-butyl N-[(3-chloropyrazine-2- carbonyl)amino]carbamate (98 g, 359.39 mmol, 81.40% yield) as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 9.18 (br s, 1 H) 8.59 (d, J=2.25 Hz, 1 H) 8.51 (d, J=2.25 Hz, 1 H) 6.71 (br s, 1 H) 1.51 (s, 9 H)

[0606] Step 2 : To a solution of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]carbamate (86 g, 315.38 mmol, 1 eq) in EtOAC / HCI (600 mL) was stirred at 25°C for 2hr. LCMS showed the reaction was completed. The reaction mixture was filtrated and the filter cake was concentrated to give 3-chloropyrazine-2-carbohydrazide (63 g, 301.39 mmol, 95.56% yield, HCI) as a yellow solid. 1 H NMR (400 MHz MeOD) δ [ppm] = 8.67 - 8.70 (m, 2 H)

[0607] Step 3 : To a solution of 3-chloropyrazine-2-carbohydrazide (20 g, 95.68 mmol, 1 eq, HCI) in MeCN (300 mL) was added K2CO3 (39.67 g, 287.04 mmol, 3 eq) and 2-chloroacetyl chloride (11.89 g, 105.25 mmol, 8.38 mL, 1.1 eq) at 25°C. The mixture was stirred at 25°C for 2hr. LCMS showed the reaction was completed. The reaction mixture was filtrated and the filter cake was washed with MeCN (50 mL x 3), the filtrate was concentrated to give 3-chloro-N'-(2- chloroacetyl)pyrazine-2-carbohydrazide (49.7 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 10.92 (s, 1 H) 10.71 (d, J=1.00 Hz, 1 H) 8.75 (d, J=2.50 Hz, 1 H) 8.69 (d, J=2.38 Hz, 1 H) 4.21 (s, 2 H)

[0608] Step 4 : To a solution of 3-chloro-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (12 g, 48.18 mmol, 1 eq) in DMF (120 mL) was added NaHCCh (40.47 g, 481.82 mmol, 18.75 mL, 10 eq) at 25°C. The mixture was stirred at 100°C for 1 ,5hr. LCMS showed the reaction was completed. The reaction mixture was quenched with H2O (300 mL), and then extracted with EtOAc (200 mL x 2) and DCM:i-PrOH=3:1 (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (25 mL) to give 2-(3-chloropyrazin-2-yl)-4H-1 ,3,4-oxadiazin-5-one (19 g, 89.37 mmol, 46.37% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 11.32 (s, 1 H) 8.76 (d, J=2.38 Hz, 1 H) 8.66 (d, J=2.38 Hz, 1 H) 4.86 (s, 2 H)

[0609] Step 5 : To a solution of 2-(3-chloropyrazin-2-yl)-4H-1 ,3,4-oxadiazin-5-one (2.9 g, 13.64 mmol, 1 eq) in dioxane (300 mL) was added Pd(PPh3)2Cl2 (957.46 mg, 1.36 mmol, 0.1 eq) and tributyl(1-ethoxyvinyl)stannane (6.40 g, 17.73 mmol, 5.99 mL, 1.3 eq). The mixture was stirred at 120 °C for 36hr under N2. LCMS showed the reaction was completed. The reaction mixture was quenched by addition aq. KF (500 mL), extracted with EtOAc (300 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ethergradient @ 150 mL / min) to give 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4H-1 ,3,4-oxadiazin-5-one (16 g crude) as a yellow solid and used directly.

[0610] Step 6 : To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4H-1 ,3,4-oxadiazin-5-one (8 g, 32.23 mmol, 1 eq) in MeCN (80 mL) was added HCI (2 M, 32.23 mL, 2 eq) at 0°C. The mixture was stirred at 0 °C for 1 hr under N2. TLC (PE: EtOAc = 1 :1) showed the reaction was completed. The reaction mixture was quenched by addition H2O (100 mL), and extracted with EtOAc (100 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by triturated and flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) to give 2-(3-acetylpyrazin-2-yl)-4H-1 ,3,4- oxadiazin-5-one (9 g, 40.87 mmol, 63.42% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.77 (d, J=2.38 Hz, 1 H) 8.70 (d, J=2.38 Hz, 1 H) 8.50 (br s, 1 H) 4.80 (s, 2 H) 2.74 (s, 3 H)

[0611] Step 7 : To a solution of 2-(3-acetylpyrazin-2-yl)-4H-1 ,3,4-oxadiazin-5-one (2 g, 9.08 mmol, 1 eq) in THF (30 mL) and 2-methylpropane-2-sulfinamide (1.65 g, 13.62 mmol, 1.5 eq) was added Ti(i-PrO)4 (6.45 g, 22.71 mmol, 6.70 mL, 2.5 eq) at 20°C under N2. The mixture was stirred 90°C for 12hr under N2. TLC (PE: EtOAc = 0:1) showed the reaction was completed. The reaction mixture was quenched with H2O (100 mL), and then filtrated, washed with EtOAc (100 mL x 3) and extracted with EtOAc (300 mL), DCM: i-PrOH=3:1 (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) to give (NE)-2-methyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethylidene]propane-2- sulfinamide (4 g, 12.37 mmol, 68.09% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.68 (dd, J=11 .88, 2.00 Hz, 1 H) 8.60 (br d, J=4.50 Hz, 1 H) 8.41 - 8.50 (m, 1 H) 4.74 - 5.08 (m, 2 H) 2.52 - 2.86 (m, 3 H) 1.23 - 1.24 (m, 9 H).

[0612] Step 8 : To a solution of (NE)-2-methyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]propane-2-sulfinamide (2 g, 6.18 mmol, 1 eq) in THF (36 mL) and MeOH (12 mL) was added NaBH4 (163.78 mg, 4.33 mmol, 0.7 eq) at 0°C under N2. The mixture was stirred at 0 °C for 0.5hr. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (40 mL) at 0 °C, extracted with EtOAc (30 mL x 2) and DCM:iPrOH=3:1 (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by triturated with EtOAc (3 mL) and prep-HPLC (neutral condition) to give 2-methyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (1.3 g, 4.00 mmol, 32.30% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 11.26 (s, 1 H) 8.74 (d, J=2.38 Hz, 1 H) 8.63 (d, J=2.38 Hz, 1 H) 5.56 (d, J=8.88 Hz, 1 H) 5.17 - 5.27 (m, 1 H) 4.85 (s, 2 H) 1.45 (d, J=6.75 Hz, 3 H) 1.07 (s, 9 H) LC-MS : desired mass : 325.1 , observed mass : 326.2.

[0613] Intermediate 3a: Synthesis of N-[1-[3-(4,6-dimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]-2-methyl-propane-2-sulfinamide (lnt-3a) :

[0614] Step 1 : To a solution of 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (10 g, 44.83 mmol, 1 eq, HCI) in MeCN (300 mL) was added K2CO3 (15.49 g, 112.08 mmol, 2.5 eq), 2- bromopropanoyl chloride (8.45 g, 49.31 mmol, 4.97 mL, 1.1 eq) at 0°C, The mixture was stirred at 0 °C for 1 hr. 3-chloro-N'-methyl-pyrazine-2-carbohydrazide was consumed, and then stirred at 60 °C for 1 hr. TLC (PE: EA= 3:1) showed that the starting material was consumed completely. The reaction mixture was quenched by addition H2O 600 mL at 0 °C, and then extracted with EtOAc 800 mL (400 mL x 2). The combined organic layers were washed with aqueous NaCI 500 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-35% ethyl acetate / petroleum ethergradient @ 100 mL / min) to give 2-(3-chloropyrazin-2-yl)-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (9.7 g, Yield: 89.91%) as yellow solid. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.61 (d, J=2.38 Hz, 1 H) 8.48 (d, J=2.38 Hz, 1 H) 4.98 (q, J=6.88 Hz, 1 H) 3.44 (s, 3 H) 1.70 (d, J=6.88 Hz, 3 H)

[0615] Step 2 : To a solution of 2-(3-chloropyrazin-2-yl)-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (14.6 g, 60.67 mmol, 1 eq) in toluene (150 mL) was added Pd(PPh3)4 (3.51 g, 3.03 mmol, 0.05 eq) and tributyl(1-ethoxyvinyl)stannane (26.29 g, 72.80 mmol, 24.60 mL, 1.2 eq). The mixture was stirred at 120 °C for 16hr under N2. TLC (PE: EA= 2:1) showed 2-(3-chloropyrazin-2-yl)-4,6- dimethyl-1 ,3,4-oxadiazin-5-one was consumed completely. The reaction mixture was quenched by addition KF aq 1500 mL at 0 °C, and then extracted with EtOAc 600 mL (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (16.7 g, Yield: crude) as brown oil.

[0616] Step 3 : To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (16.7 g, 60.44 mmol, 1 eq) in MeCN (200 mL) was added HCI (2 M, 60.44 mL, 2 eq) at 0°C. The mixture was stirred at 0~25 °C for 0.5hr. TLC (PE: EA= 1 :1) showed 2-[3-(1-ethoxyvinyl)pyrazin- 2-yl]-4,6-dimethyl-1 ,3,4-oxadiazin-5-one was consumed completely. The reaction mixture was quenched by addition H2O 500 mL at 0 °C, and then extracted with EA 600 mL (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-45% Ethyl acetate / Petroleum ethergradient @ 120 mL / min) to give 2-(3-acetylpyrazin-2-yl)-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (13.7 g, Yield: 91.31%) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.76 (d, J=2.38 Hz, 1 H) 8.66 (d, J=2.38 Hz, 1 H) 4.92 (q, J=6.75 Hz, 1 H) 3.40 (s, 3 H) 2.73 (s, 3 H) 1.65 (d, J=6.88 Hz, 3 H)

[0617] Step 4 : To a solution of 2-(3-acetylpyrazin-2-yl)-4,6-dimethyl-1 ,3,4-oxadiazin-5-one (5.1 g, 20.54 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (3.74 g, 30.82 mmol, 1.5 eq) in THF (50 mL) was added Ti(i-PrO)4 (14.60 g, 51.36 mmol, 15.16 mL, 2.5 eq). The mixture was stirred at 80 °C for 16hr. TLC (PE: EA= 0:1) showed that the starting material was consumed completely. The reaction mixture was quenched by addition H2O 500 mL at 0°C, and then extracted with EA 600 mL (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-25% (ethyl acetate / petroleum ether gradient @ 100 mL / min), and then purified by prep-HPLC (neutral condition) to give (NE)-N-[1-[3-(4,6-dimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethylidene]- 2-methyl-propane-2-sulfinamide (10.9 g, Yield: 75.49%) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.50 - 8.75 (m, 2 H) 4.87 - 5.14 (m, 1 H) 3.39 (s, 3 H) 2.52 - 2.88 (m, 3 H) 1.62 - 1.71 (m, 3 H) 1.22 - 1.25 (m, 9 H)

[0618] Step 5 : Three batches: to a solution of (NE)-N-[1-[3-(4,6-dimethyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethylidene]-2-methyl-propane-2-sulfinamide (3.1 g, 8.82 mmol, 1 eq) in THF (40 mL) and MeOH (10 mL) was added NaBH4(333.71 mg, 8.82 mmol, 1 eq) at 0°C. The mixture was stirred at 0 °C for 1 hr. LC-MS showed that the starting material was consumed completely. The reaction mixture was quenched by addition H2O 500 mL at 0 °C, and then extracted with EA 600 mL (200 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give two isomers, the peak 2 give N-[1-[3-(4,6-dimethyl-5-oxo-1 ,3,4- oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2-sulfinamide (P2) (2.7 g, Yield: 30.18%) as yellow solid, the peak 1 give 3 g crude and purified by prep-HPLC again to give N-[1-[3-(4,6- dimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2-sulfinamide (P1) (580 mg, Yield: 5.3%) as yellow solid.

[0619] P1 : 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J=1.98 Hz, 1 H) 8.65 (d, J=1.86 Hz, 1 H) 5.47 (d, J=8.04 Hz, 1 H) 5.24 - 5.37 (m, 1 H) 5.09 (q, J=6.72 Hz, 1 H) 3.30 (s, 3 H) 1.57 (d, J=6.68 Hz, 3 H) 1.51 (d, J=6.68 Hz, 3 H) 1.03 (s, 9 H) ; LC-MS : desired mass : 353.1 , observed mass : 354.2.

[0620] P2 : 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J=2.00 Hz, 1 H) 8.66 (d, J=2.25 Hz, 1 H) 5.55 (d, J=8.38 Hz, 1 H) 5.06 - 5.26 (m, 2 H) 3.31 (s, 3 H) 1.47 - 1 .55 (m, 6 H) 1.05 - 1.09 (m, 9 H) ; LC-MS : desired mass : 353.1 , observed mass : 354.1.

[0621] The stereocenters of the two diastereomers could not be assigned to the respective molecular structures.

[0622] Intermediate 4a: Synthesis of 2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (lnt-4a) :

[0623] Step 1 : To a solution of 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (20 g, 89.66 mmol, 1 eq, HCI) in MeCN (600 mL) was added K2CO3 (30.98 g, 224.16 mmol, 2.5 eq) and 2-chloro-2- methyl-propanoyl chloride (15.17 g, 107.59 mmol, 1.2 eq) at 0°C. The mixture was stirred at 0~30 °C for 2hr. TLC (PE: EA= 1 :1) showed that the starting material was consumed completely. The reaction mixture was quenched by addition H2O 500 mL at 0 °C, and then extracted with EA 600 mL (200 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give 3-chloro-N'-(2-chloro-2-methyl- propanoyl)-N'-methyl-pyrazine-2-carbohydrazide (27 g, Yield: crude) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 9.77 (br s, 1 H) 8.64 (d, J=2.13 Hz, 1 H) 8.56 (d, J=2.25 Hz, 1 H) 3.40 (br s, 3 H) 1.79 (s, 6 H)

[0624] Step 2 : To a solution of 3-chloro-N'-(2-chloro-2-methyl-propanoyl)-N'-methyl-pyrazine-2- carbohydrazide (27 g, 92.74 mmol, 1 eq) in DMSO (270 mL) was added NaHCCh (77.91 g, 927.41 mmol, 36.09 mL, 10 eq) .The mixture was stirred at 100 °C for 1 hr. TLC (PE: EA= 1 :1) showed 3-chloro-N'-(2-chloro-2-methyl-propanoyl)-N'-methyl-pyrazine-2-carbohydrazide was consumed completely. The reaction mixture was quenched by addition H2O 1000 mL at 0 °C, and then extracted with EA 800 mL (400 mL x 2). The combined organic layers were washed with aqueous NaCI 500 mL, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column,

[0625] Eluent of 0-40% ethyl acetate / petroleum ethergradient @ 120 mL / min) to give 2-(3- chloropyrazin-2-yl)-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one (20.6 g, 87.22%) as yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.60 (d, J=2.38 Hz, 1 H) 8.47 (d, J=2.38 Hz, 1 H) 3.43 (s, 3 H) 1.69 (s, 6 H)

[0626] Step 3 : To a solution of 2-(3-chloropyrazin-2-yl)-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one (10.3 g, 40.44 mmol, 1 eq) in toluene (200 mL) was added Pd(PPha)4 (2.34 g, 2.02 mmol, 0.05 eq) and tributyl(1-ethoxyvinyl)stannane (17.53 g, 48.53 mmol, 16.40 mL, 1.2 eq). The mixture was stirred at 110 °C for 16hr. TLC (PE: EA= 1 :1) showed 2-(3-chloropyrazin-2-yl)-4,6,6-trimethyl- 1,3,4-oxadiazin-5-one was consumed completely. The reaction mixture was quenched by addition KF aq 1000 mL at 0 °C, and then extracted with EA 700 mL (350 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one (23 g, Yield: crude) as yellow oil.

[0627] Step 4 : To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one (23 g, 79.22 mmol, 1 eq) in MeCN (200 mL) was added HCI (2 M, 79.22 mL, 2 eq) at 0°C. The mixture was stirred at 0~25 °C for 2hr. TLC (PE: EA= 1:1) showed 2-[3-(1-ethoxyvinyl)pyrazin-2- yl]-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one was consumed completely. The reaction mixture was quenched by addition H2O 400 mL at 0 °C, and then extracted with EA 500 mL (250 mL x 2). The combined organic layers were washed with aqueous NaCI 300 mL, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-45% Ethyl acetate / Petroleum ethergradient @ 120 mL / min) to give 2-(3-acetylpyrazin-2-yl)- 4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one (19.7 g, 75.12 mmol, 94.81% yield) as a yellow oil. 1 H NMR (400 MHz, CDCI3) δ [ppm] = 8.73 (d, J=2.50 Hz, 1 H) 8.62 (d, J=2.38 Hz, 1 H) 3.37 (s, 3 H) 2.71 (s, 3 H) 1.66 (s, 6 H)

[0628] Step 5 : To a solution of 2-(3-acetylpyrazin-2-yl)-4,6,6-trimethyl-1,3,4-oxadiazin-5-one (4 g, 15.25 mmol, 1 eq) and 2-methylpropane-2-sulfinamide (2.77 g, 22.88 mmol, 1.5 eq) in THF (80 mL) was added Ti(i-PrO)4 (10.84 g, 38.13 mmol, 11.25 mL, 2.5 eq). The mixture was stirred at 80 °C for 16hr. TLC (PE: EA= 0:1) showed 2-(3-acetylpyrazin-2-yl)-4,6,6-trimethyl-1 ,3,4- oxadiazin-5-one was consumed completely. The reaction mixture was quenched by addition H2O 200 mL at 0 °C, and then extracted with EA 300 mL (100 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MeCN at 25°C for 30 min, then triturated with EA at 25°C for 60 min to give (NE)-2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethylidene]propane-2-sulfinamide (13 g, Yield: 77.75%) as yellow solid. 1H NMR (400 MHz, CDCI3) δ [ppm] = 8.46 - 8.76 (m, 2 H) 3.39 (s, 3 H) 2.49 - 2.89 (m, 3 H) 1.65 (br d, J=4.95 Hz, 3 H) 1.61 (d, J=7.05 Hz, 3 H) 1.23 (d, J=4.45 Hz, 9 H)

[0629] Step 6 : To a solution of (NE)-2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo-1,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethylidene]propane-2-sulfinamide (3 g, 8.21 mmol, 1 eq) in THF (32 mL) and MeOH (8 mL) was added NaBH4 (310.55 mg, 8.21 mmol, 1 eq) at 0°C. The mixture was stirred at 0 °C for 1 hr. TLC (DCM: MeOH= 20:1) showed (NE)-2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo- 1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethylidene]propane-2-sulfinamide was consumed completely. The reaction mixture was quenched by addition H2O 300 mL at 0 °C, and then extracted with EA 600 mL (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) give two isomers:

[0630] The peak 1 give 2 g crude and then purified by prep-HPLC give 2-methyl-N-[1-[3-(4,6,6- trimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (P1) (1 g, Yield: 16.6%) as yellow solid.

[0631] The peak 2 give 2 g crude and then purified by column (PE in (EA :MeOH= 50:1)= 0-70%) to give 2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (P2) (1.6 g, Yield: 26.5%) as a white solid.

[0632] P1 : 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J=2.25 Hz, 1 H) 8.67 (d, J=2.38 Hz, 1 H) 5.49 (d, J=8.25 Hz, 1 H) 5.26 - 5.39 (m, 1 H) 3.31 (s, 3 H) 1.57 (d, J=6.75 Hz, 3 H) 1.53 (d, J=10.38 Hz, 6 H) 1.03 (s, 9 H); LC-MS : desired mass : 367.1 , observed mass : 368.1.

[0633] P2 : 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J=2.25 Hz, 1 H) 8.67 (d, J=2.25 Hz, 1 H) 5.53 (d, J=8.38 Hz, 1 H) 5.20 (dd, J=8.07, 6.94 Hz, 1 H) 3.32 (s, 3 H) 1.55 (d, J=10.13 Hz, 6 H) 1.50 (d, J=6.75 Hz, 3 H) 1.07 (s, 9 H); LC-MS : desired mass : 367.1 , observed mass : 368.1.

[0634] The stereocenters of the two diastereomers could not be assigned to the respective molecular structures.

[0635] Intermediate 5a: Synthesis of 2-methyl-N-[(1S)-1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (lnt-5a):

[0636] Step 1 : To a solution of 3-chloropyrazine-2-carboxylic acid (25 g, 157.69 mmol, 1 eq) in DCM (250 mL) was added DIEA (61.14 g, 473.06 mmol, 82.40 mL, 3 eq) at 0°C, and then added tertbutyl N-amino-N-methyl-carbamate (34.58 g, 236.53 mmol, 1.5 eq) in DCM (100 mL) and PyBOP (106.68 g, 204.99 mmol, 1.3 eq) in DCM (200 mL) were added drop-wise at the same time over 1 hr at 0°C. The mixture was stirred at 0-20°C for 2 hr. LCMS showed the reaction was completed. The reaction mixture was quenched with H2O (300 mL), and then extracted with DCM (300 mL x 3). The combined organic layers were washed with aqueous NaCI (100 mL), dried over Na2SC>4, filtered and concentrated, purified by column (EtOAc in PE = 0% -60%) to give tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]-N-methyl-carbamate (48.5 g, 152.24 mmol, 96.55% yield, 90% purity) as a yellow oil.

[0637] 1 H NMR: (400 MHz, CDCI3) δ [ppm] 8.91 - 9.45 (m, 1 H) 8.59 (d, J=2.13 Hz, 1 H) 8.51 (d, J=2.13 Hz, 1 H) 3.27 (s, 3 H) 1.48 (s, 9 H)

[0638] Step 2 : A mixture of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]-N-methyl-carbamate (33.5 g, 116.84 mmol, 1 eq) in HCI / EtOAc (300 mL) was stirred at 0 °C for 1 hr. TLC (PE: EtOAc = 1 :1) showed the reaction was completed. The reaction mixture was filtrated and the filter cake was concentrated to give 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (17 g, 76.21 mmol, 65.23% yield, HCI) as a white solid.

[0639] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] 11.50 - 12.74 (m, 1 H) 8.78 (dd, J= 12.32, 2.44 Hz, 2 H) 2.84 (s, 3 H)

[0640] Step 3 : Two batches: to a solution of 3-chloro-N'-methyl-pyrazine-2-carbohydrazide (12 g, 53.8 mmol, 1 eq, HCI) in DCM (200 mL) was added TEA (16.33 g, 161.39 mmol, 34.63 mL, 3 eq), and 2-chloroacetyl chloride (7.29 g, 64.56 mmol, 1.2 eq) added dropwise at 0°C over 30 min. The mixture was stirred at 0 °C for 30 min. TLC (PE: EtOAc = 1 :1) showed the reaction was completed. The reaction mixture was quenched with H2O (150 mL), and then extracted with DCM (200 mL x 2) and DCM:i-PrOH=3:1 (100 mL x 6). The combined organic layers were dried over Na2SC>4, filtered and concentrated to give 3-chloro-N'-(2-chloroacetyl)-N'-methyl-pyrazine- 2-carbohydrazide (20 g, 76.02 mmol, 70.66% yield) as a yellow solid.

[0641] 1 H NMR: (400 MHz, METHANOL-d4) δ [ppm] 8.71 (dt, J=5.11 , 2.53 Hz, 2 H) 4.24 - 4.55 (m, 2 H) 3.20 - 3.29 (m, 3 H)

[0642] Step 4 : To a solution of 3-chloro-N'-(2-chloroacetyl)-N'-methyl-pyrazine-2-carbohydrazide (10 g, 38.01 mmol, 1 eq) in MeCN (130 mL) was added K2CO3 (13.13 g, 95.03 mmol, 2.5 eq). The mixture was stirred at 80 °C for 24hr. LCMS showed the reaction was completed. The reaction mixture was quenched with H2O (200 mL), and then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with aqueous NaCI (100 mL), dried over Na2SO4, filtered and concentrated, purified by triturating with MTBE (50 mL) to give 2-(3-chloropyrazin-2-yl)-4- methyl-1 ,3,4-oxadiazin-5-one (12.1 g, 53.39 mmol, 70.23% yield) as a yellow solid.

[0643] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] 8.78 (d, J=2.38 Hz, 1 H) 8.68 (d, J=2.38 Hz, 1 H) 4.92 (s, 2 H) 3.28 (s, 3 H)

[0644] Step 5 : To a solution of 2-(3-chloropyrazin-2-yl)-4-methyl-1 ,3,4-oxadiazin-5-one (12.1 g, 53.39 mmol, 1 eq) in Tol. (120 mL) was added Pd(PPh3)4(3.08 g, 2.67 mmol, 0.05 eq) and tributyl(1-ethoxyvinyl)stannane (23.14 g, 64.07 mmol, 1.2 eq). The mixture was stirred at 120 °C for 12hr. LCMS showed the reaction was completed. The reaction mixture was quenched by addition aq.KF (100 mL), and then filtrated and the filter cake was washed with EtOAc (50 mL x 4) and the filtrate was extracted with EtOAc (100 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4-methyl- 1 ,3,4-oxadiazin-5-one (14 g crude) as a brown oil.

[0645] Step 6 : To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one (14 g crude) in MeCN (100 mL) was added HCI (2 M, 53.38 mL) at 0°C. The mixture was stirred at 0 °C for 3hr. LCMS showed the reaction was completed. The reaction mixture was quenched by addition H2O (200 mL), and then extracted with EtOAc (250 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated, purified by triturating with MTBE (30 mL) to give 2-(3-acetylpyrazin-2-yl)-4-methyl-1,3,4-oxadiazin-5-one (9.5 g, 40.56 mmol, 75.98% yield over two steps) as a yellow solid.

[0646] 1H NMR: (400 MHz, DMSO-d6) δ [ppm] 8.89 (d, J=2.38 Hz, 1 H) 8.86 (d, J=2.38 Hz, 1 H) 4.82 (s, 2 H) 3.23 (s, 3 H) 2.64 (s, 3 H)

[0647] Step 7 : 2 Batches:

[0648] To a solution of 2-(3-acetylpyrazin-2-yl)-4-methyl-1,3,4-oxadiazin-5-one (3.5 g, 14.94 mmol, 1 eq) in THF (50 mL) was added Ti(i-PrO)4 (10.62 g, 37.36 mmol, 11.03 mL, 2.5 eq) and (S)-2- methylpropane-2-sulfinamide (3.62 g, 29.89 mmol, 2 eq). The mixture was stirred at 80 °C for 16hr. TLC (EtOAc: MeOH = 10:1) showed the reaction was completed. The reaction mixture was quenched with H2O (400 mL), and then filtrated, the filter cake was washed with EtOAc (100 mL x 6) and then extracted with DCM: i-PrOH=3:1 (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (NE)-2-methyl-N-[1-[3-(4- methyl-5-oxo-1,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethylidene]propane-2-sulfinamide (11.1 g crude) as brown oil.

[0649] Step 8 : 2 Batches:

[0650] To a solution of (NE)-2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]propane-2-sulfinamide (2.5 g crude) in THF (50 mL) was added NaBH4(196.4 mg, 5.19 mmol) at 0°C under N2. The mixture was stirred 0°C for 0.5hr under N2. TLC (EtOAc: MeOH = 10:1) showed the reaction was completed. The reaction mixture was quenched by addition H2O 300 mL, and then extracted with DCM: i-PrOH=3:1 (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated, purified by column (PE in (EtOAc: EtOH=3 :1)= 0~ 50%), and then purified by prep-HPLC (neutral condition) to give Synthesis of 2-methyl-N-[(1S )-1-[3-(4-methyl-5-oxo-1,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (1.7 g, 5.01 mmol, 33.75% yield over two steps) as a yellow solid.

[0651] 1H NMR: (400 MHz, DMSO-d6) δ [ppm] 8.76 (d, J=2.25 Hz, 1 H) 8.64 (d, J=2.38 Hz, 1 H) 5.54 (d, J=8.38 Hz, 1 H) 5.16 - 5.26 (m, 1 H) 4.90 (s, 2 H) 3.30 (s, 3 H) 1.49 (d, J=6.75 Hz, 3 H) 1.08 (s, 9 H) LCMS: (Desired Mass: 339.1; Observed Mass: 340.2) ; chiral SFC : e.e : 99.66%

[0652] Intermediate 6a: Synthesis of N,2-dimethyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (lnt-6a) :

[0653] Step 1 : To a solution of 2,3-dichloropyrazine (165 g, 1.11 mol, 1 eq) in toluene (1650 mL) was added Pd(PPh3)4 (63.99 g, 55.38 mmol, 0.05 eq) and tributyl(1-ethoxyvinyl)stannane (479.99 g, 1.33 mol, 449.01 mL, 1.2 eq) at 25°C.The mixture was stirred at 120°C for 12h. TLC (petroleum ether / ethyl acetate = 5 / 1 , Rf= 0.45) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction mixture was quenched by KF aqueous (3000 mL) at 0°C, filtered and the filtrate was extracted with EtOAc (2000 mL x 2). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 2-chloro-3-(1- ethoxyviny I) pyrazine (230 g, crude) was obtained as black oil.

[0654] Step 2 : To a solution of 2-chloro-3-(1-ethoxyvinyl)pyrazine (230 g, 1.25 mol, 1 eq) in MeCN (1050 mL) was added HCI (2 M, 1.25 L, 2 eq) at 25°C. The mixture was stirred at 25°C for 2h . TLC (petroleum ether / ethyl acetate = 5 / 1 , Rf = 0.40) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction mixture was quenched by addition H2O (2000 mL), and then extracted with EtOAc (1000 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated with the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ethergradient @ 200 mL / min). Compound 1-(3-chloropyrazin-2-yl)ethanone (169 g, 1.08 mol, 86.64% yield) was obtained as a yellow solid.

[0655] 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J = 2.4 Hz, 1 H), 8.71 (d, J = 2.5 Hz, 1H), 2.64 (s, 3H)

[0656] Step 3 : To a solution of 1-(3-chloropyrazin-2-yl)ethanone (149 g, 951.65 mmol, 1 eq) in THF (1500 mL) was added Ti(OEt)4(540.95 g, 1.90 mol, 561.73 mL, 2 eq) and 2-methylpropane-2- sulfinamide (161.48 g, 1.33 mol, 1.4 eq) .The mixture was stirred at 50°C for 12h . TLC (petroleum ether / ethyl acetate = 5 / 1, Rf = 0.30) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction mixture was quenched with H2O (2000 mL), and then filtrated, the aueous layer was extracted with EtOAc (700 mL), the filter cake was washed with EtOAc (1000 mL x 6). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 2 Kg SepaFlash® Silica Flash Column, eluent of 0-50% ethyl acetate / petroleum ethergradient @ 200 mL / min). Compound (NE)-N-[1- (3-chloropyrazin-2-yl)ethylidene]-2-methyl-propane-2-sulfinamide (60 g, 162.61 mmol, 17.09% yield, 70.4% purity) was obtained as yellow oil. Desired MS: 260.3 Observed MS: 260.3

[0657] Step 4 : To a solution of (NE)-N-[1-(3-chloropyrazin-2-yl)ethylidene]-2-methyl-propane-2- sulfinamide (60 g, 230.99 mmol, 1 eq) in THF (400 mL) and MeOH (200 mL) was added NaBH4(6.12 g, 161.69 mmol, 0.7 eq) at 0°C. The mixture was stirred at 0 °C for 0.5h. LCMS showed the starting material was consumed completely and one main peak with desired Ms was detected. The reaction mixture was quenched by water (1000 mL) at 0°C, extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 1000 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 200 mL / min). Compound N-[1-(3- chloropyrazin-2-yl)ethyl]-2-methyl-propane-2-sulfinamide (43 g, 156.87 mmol, 67.91% yield, 95.5% purity) was obtained as yellow oil. LCMS: Desired MS: 262.3, Observed MS: 262.3, 1 H NMR : (400 MHz, DMSO-d6) 5 [ppm] = 8.68 - 8.65 (m, 1 H), 8.44 (d, J = 2.5 Hz, 1 H), 5.59 (d, J = 8.0 Hz, 1 H), 4.93 - 4.82 (m, 1 H), 1.54 (d, J = 6.8 Hz, 3H), 1.07 (s, 9H)

[0658] Step 5 : To a solution of N-[1-(3-chloropyrazin-2-yl)ethyl]-2-methyl-propane-2-sulfinamide (39 g, 148.99 mmol, 1 eq) in THF (390 mL) was added NaOH (11.92 g, 297.97 mmol, 2 eq)and Mel (63.44 g, 446.96 mmol, 27.82 mL, 3 eq) at 25°C. The mixture was stirred at 25°C for 12h. TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf= 0.50) indicated the starting material was consumed completely and one new spot with small polarity was formed. The reaction mixture was quenched by water (700 mL), extracted with EtOAc (350 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 200 mL / min). Compound N-[1-(3-chloropyrazin-2-yl)ethyl]-N,2-dimethyl- propane-2-sulfinamide (32.8 g, 118.93 mmol, 79.83% yield) was obtained as yellow oil.

[0659] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] = 8.70 (d, J = 2.3 Hz, 1 H), 8.49 (d, J = 2.3 Hz, 1 H), 5.03 (q, J = 6.9 Hz, 1 H), 2.42 (s, 3H), 1 .51 (br d, J = 6.8 Hz, 3H), 1.09 (s, 9H)

[0660] Step 6 : A mixture of N-[1-(3-chloropyrazin-2-yl)ethyl]-N,2-dimethyl-propane-2-sulfinamide (13 g, 47.14 mmol, 1 eq) and Pd(dppf)Ch (6.90 g, 9.43 mmol, 0.2 eq) and EfeN (9.54 g, 94.27 mmol, 13.12 mL, 2 eq) in MeOH (150 mL) was stirred at 50°C for 4 h under CO (3447.38 mbar). TLC (Petroleum ether / Ethyl acetate = 1 / 1 , Rf = 0.2) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction mixture was filtered and the filtrate was concentrated to give product. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 150 mL / min). Compound methyl 3-[1-[tert- butylsulfinyl(methyl)amino]ethyl]pyrazine-2-carboxylate (12 g, 40.08 mmol, 85.03% yield) was obtained as a black solid.

[0661] 1 H NMR: (400 MHz, DMSO-d6), 5 [ppm] = 8.87 (d, J = 2.4 Hz, 1 H), 8.69 (d, J = 2.4 Hz, 1 H), 5.35 (q, J = 6.9 Hz, 1 H), 3.92 (s, 3H), 2.42 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H), 1.04 (s, 9H)

[0662] Step 7 : To a solution of methyl 3-[1-[tert-butylsulfinyl(methyl)amino]ethyl]pyrazine-2- carboxylate (12 g, 40.08 mmol, 1 eq) in EtOH (120 mL) was added NH2NH2.H2O (15.65 g, 312.64 mmol, 15.17 mL, 7.8 eq) at 25°C. The mixture was stirred at 60°C for 2h. TLC (Petroleum ether / Ethyl acetate = 0 / 1 , Rf = 0.20) indicated the starting material was consumed completely and one new spot with large polarity was formed. The reaction was concentrated to give crude product. The reaction mixture was quenched by water (200 mL), extracted with DCM / IPA = 3 / 1 (350 mL x 4). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 150 mL / min). Compound N-[1-[3-(hydrazinecarbonyl)pyrazin-2-yl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (12 g, 34.87 mmol, 87.00% yield, 87% purity) was obtained as yellow oil. 1 H NMR: (400 MHz, DMSO-de)

[0663] 5 [ppm] = 9.99 (s, 1 H), 8.78 (d, J = 2.5 Hz, 1 H), 8.60 (d, J = 2.4 Hz, 1 H), 5.52 (q, J = 6.9 Hz, 1 H), 4.61 (br s, 2H), 2.40 (s, 3H), 1 .50 (d, J = 7.0 Hz, 3H), 1.02 (s, 9H)

[0664] Step 8 : To a solution of N-[1-[3-(hydrazinecarbonyl)pyrazin-2-yl]ethyl]-N,2-dimethyl-propane- 2-sulfinamide (10 g, 33.40 mmol, 1 eq) in DCM (100 mL) was added TEA (8.11 g, 80.16 mmol, 11.16 mL, 2.4 eq) and 2-chloroacetyl chloride (4.53 g, 40.08 mmol, 3.19 mL, 1.2 eq) at O°C. The mixture was stirred at 25°C for 1h. TLC (Petroleum ether / Ethyl acetate = 0 / 1 , Rf= 0.25) indicated the starting material was consumed completely and one new spot with small polarity was formed. The reaction was concentrated under reduced pressure to give a residue. The crude product was used for next step directly without purification. Compound N-[1-[3-[[(2- chloroacetyl)amino]carbamoyl]pyrazin-2-yl]ethyl]-N,2-dimethyl-propane-2-sulfinamide (12.7 g, 25.04 mmol, 74.96% yield, 74.1% purity) was obtained as black oil.

[0665] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] = 10.92 - 10.31 (m, 2H), 8.88 - 8.83 (m, 1 H), 8.66 (d, J = 2.3 Hz, 1 H), 5.41 (q, J = 6.9 Hz, 1 H), 4.22 (s, 2H), 2.46 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.02 (s, 9H)

[0666] Step 9 : To a solution of N-[1-[3-[[(2-chloroacetyl)amino]carbamoyl]pyrazin-2-yl]ethyl]-N,2- dimethyl-propane-2-sulfinamide (14 g, 37.25 mmol, 1 eq) in DMF (140 mL) was added NaHCOs (15.64 g, 186.23 mmol, 7.25 mL, 5 eq) at 25°C. The mixture was stirred at 100°C for 3h. LCMS showed the starting material was consumed completely and one main peak with desired Ms was detected. The reaction mixture was quenched by water (200 mL) at 25°C, extracted with DCM (70 mL x 4). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 150 mL / min) to give residue (21 g, 84.1 % purity). The residue was purified by prep-HPLC (column: Welch Xtimate C18 180*70mm#10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 8%-38% B over 18.0 min). Compound N,2-dimethyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (2.78 g, 8.18 mmol, 21.97% yield, 99.9% purity) was obtained as a white solid.

[0667] LCMS: Desired MS: 340.1 , Observed MS: 340.1 , 1 H NMR: (400 MHz, CDCI3)

[0668] 5 [ppm] = 8.69 (d, J = 2.4 Hz, 1 H), 8.57 (d, J = 2.3 Hz, 2H), 5.57 (q, J = 6.9 Hz, 1 H), 4.92 (d, J = 1.3 Hz, 2H), 2.63 (s, 3H), 1.62 (s, 3H), 1.15 (s, 9H)

[0669] Intermediate 7a: Synthesis of N,2-dimethyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (lnt-7a) :

[0670] Two batches: To a solution of 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]propane-2-sulfinamide (1 g, 2.95 mmol, 1 eq) and methanol (472.02 mg, 14.73 mmol, 596.13 pL, 5 eq) in Tol. (5 mL) was added 2-(tributyl-phosphanylidene)acetonitrile (2.13 g, 8.84 mmol, 3 eq). The mixture was stirred at 110 °C for 1 h under MW. After the completion of the reaction, the two batches were combined with another batch (0.3 g scale). The mixture was poured into H2O (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash Column, Eluent of 0-89% Ethylacetate / Petroleum ethergradient @ 100 mL / min) to give a residue. Then it was further purified by prep-HPLC (neutral condition) to afford the title compound N,2-dimethyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane- 2-sulfinamide (0.39 g, 97% purity) as a yellow solid.

[0671] LCMS: Desired MS: 353.1 , Observed MS: 354.1

[0672] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] = 8.77 (d, J = 2.4 Hz, 1 H), 8.67 (d, J = 2.4 Hz, 1 H), 5.44 (q, J = 6.8 Hz, 1 H), 4.90 (s, 2H), 3.30 (s, 3H), 2.53 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 0.97 (s, 9H)

[0673] Intermediate 8a: Synthesis of 2-methyl-N-[(1 R)-1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2- yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (lnt-8a) :

[0674] The synthesis protocol can be followed as described for “Intermediate 5a: Synthesis of 2- methyl-N-[(1S)-1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (lnt-5a) “ using the (R)-2-methylpropane-2-sulfinamide instead of the respective (S)- isomer in step 7.

[0675] Analytical date for lnt-8a: LCMS: Desired MS: 339.1 , Observed MS: 340.1

[0676] 1 H NMR: (400 MHz, DMSO-d6) δ [ppm] = 8.76 (d, J = 2.4 Hz, 1 H), 8.64 (d, J = 2.4 Hz, 1 H), 5.55 (d, J = 8.4 Hz, 1 H), 5.27 - 5.17 (m, 1 H), 4.90 (s, 2H), 3.30 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H), 1.08 (s, 9H)

[0677] Intermediate 9a: Synthesis of N-[1-[3-(6,6-dimethyl-5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]-2-methyl-propane-2-sulfinamide (lnt-9a):

[0678] Step 1 : To a solution of 3-chloropyrazine-2-carboxylic acid (70 g, 441.52 mmol, 1 eq) and tertbutyl N-aminocarbamate (89.34 g, 529.83 mmol, 1.2 eq, HCI) in DCM (700 mL) was added T4P (477.19 g, 662.28 mmol, 50% purity, 1.5 eq) and TEA (134.03 g, 1.32 mol, 184.36 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed 3-chloropyrazine-2-carboxylic acid was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, it was poured into sat. aq. NaHCOs (1000 mL), extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated in vacuum to afford the title compound tert-butyl N-[(3-chloropyrazine- 2-carbonyl)amino]carbamate (117 g, 399.03 mmol, 90.38% yield, 93% purity) as a brown oil, which was used to the next step without purification.

[0679] 1H NMR: (400 MHz, DMSO-d6)

[0680] 5 [ppm] = 10.61 - 10.30 (m, 1H), 9.15 (br s, 1 H), 8.78 - 8.62 (m, 2H), 1.43 (s, 9H)

[0681] Step 2: A solution of tert-butyl N-[(3-chloropyrazine-2-carbonyl)amino]carbamate (117 g, 429.06 mmol, 1 eq) in HCI / EtOAc (1 L) was stirred at 25 °C for 1 h. LCMS showed tert-butyl N- [(3-chloropyrazine-2-carbonyl)amino]carbamate was consumed completely and one major peak with desired mass was detected. After the completion of the reaction, it was concentrated in vacuum. The mixture was triturated with EtOAc (1000 mL) for 30 min, filtered. The filter cake was washed with EtOAc, and then concentrated in vacuum to afford the title compound 3- chloropyrazine-2-carbohydrazide (110 g, crude, HCI) as a gray solid.

[0682] Step 3: To a solution of 3-chloropyrazine-2-carbohydrazide (108 g, 516.66 mmol, 1 eq, HCI), NaOAc (63.57 g, 775.00 mmol, 1.5 eq), TsOH (133.45 g, 775.00 mmol, 1.5 eq) and 4- methoxybenzaldehyde (105.51 g, 775.00 mmol, 94.29 mL, 1.5 eq) in THF (1 L) was stirred at 25 °C for 1 h. Then NaBHsCN (64.93 g, 1.03 mol, 2 eq) was added at 0 °C. The mixture was stirred at 25 °C for another 11 h. LCMS showed 3-chloropyrazine-2-carbohydrazide was consumed completely and one peak with desired mass was detected. After the completion of the reaction, it was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-43% Ethylacetate / Petroleum ethergradient @ 150 mL / min). The residue was triturated with EtOAc (200 mL) for 30 min, filtered. The filter cake was washed with EtOAc (100 mL). Then the filtration was concentrated in vacuum. The product was dissolved with EtOAc, then it was washed with sat. aq. NaHCCh (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum to afford 3-chloro-N'- [(4-methoxyphenyl)methyl]pyrazine-2-carbohydrazide (89 g, 234.11 mmol, 65.89% yield, 77% purity) as a yellow oil.

[0683] 1H NMR: (400 MHz, DMSO-d6)

[0684] 5 [ppm] = 10.08 (d, J = 6.3 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1 H), 8.61 (d, J = 2.5 Hz, 1H), 7.33 - 7.28 (m, 2H), 6.91 - 6.87 (m, 2H), 5.63 - 5.54 (m, 1H), 3.93 (d, J = 5.1 Hz, 2H), 3.73 (s, 3H) Step 4: To a solution of 3-chloro-N'-[(4-methoxyphenyl)methyl]pyrazine-2-carbohydrazide (88 g, 231.48 mmol, 1 eq) and Pyridine (54.93 g, 694.45 mmol, 56.05 mL, 3 eq) in DCM (1 L) was added 2-chloro-2-methyl-propanoyl chloride (39.17 g, 277.78 mmol, 1.2 eq) at -40 °C. The mixture was stirred at -40 °C for 1 h. LCMS showed 3-chloro-N'-[(4- methoxyphenyl)methyl]pyrazine-2-carbohydrazide was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, it was combined with another batch (1 g scale). The mixture was poured into H2O (1 L), and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethylacetate / Petroleum ethergradient @ 150 mL / min) to afford 3-chloro-N'-(2-chloro-2-methyl- propanoyl)-N'-[(4-methoxyphenyl)methyl]pyrazine-2-carbohydrazide (61.8 g, 129.12 mmol, 55.78% yield, 83% purity) as a yellow solid.

[0685] 1H NMR: (400 MHz, DMSO-d6)

[0686] 5 [ppm] = 11.26 (s, 1 H), 8.76 (d, J = 2.5 Hz, 1 H), 8.69 (d, J = 2.5 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 5.51 - 4.10 (m, 2H), 3.73 (s, 3H), 1.80 (s, 6H)

[0687] Step 5: To a solution of 3-chloro-N'-(2-chloro-2-methyl-propanoyl)-N'-[(4- methoxyphenyl)methyl]pyrazine-2-carbohydrazide (60.8 g, 127.03 mmol, 1 eq) in EtOH (610 mL) was added K2CO3 (35.11 g, 254.06 mmol, 2 eq). The mixture was stirred at 50 °C for 12 h. LCMS showed 3-chloro-N'-(2-chloro-2-methyl-propanoyl)-N'-[(4- methoxyphenyl)methyl]pyrazine-2-carbohydrazide was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, it was combined with another batch (1 .0 g scale). The mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ethergradient @ 150 mL / min) to afford 2-(3- chloropyrazin-2-yl)-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1 ,3,4-oxadiazin-5-one (44.7 g, 93% purity) as a yellow oil.

[0688] 1H NMR: (400 MHz, DMSO-d6)

[0689] 5 [ppm] = 8.77 (d, J = 2.4 Hz, 1 H), 8.67 (d, J = 2.4 Hz, 1 H), 7.28 - 7.23 (m, 2H), 6.94 - 6.88 (m, 2H), 4.80 (s, 2H), 3.73 (s, 3H), 1.56 (s, 6H).

[0690] Step 6. To a solution of 2-(3-chloropyrazin-2-yl)-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl- 1 ,3,4-oxadiazin-5-one (44 g, 121.95 mmol, 1 eq) in Tol. (500 mL) was added Pd(PPh3)4 (7.05 g, 6.10 mmol, 0.05 eq) and tributyl(1-ethoxyvinyl)stannane (60.99 g, 168.88 mmol, 57.05 mL, 1.38 eq). The mixture was stirred at 120 °C for 12 h under N2. LCMS showed 2-(3-chloropyrazin-2- yl)-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1 ,3,4-oxadiazin-5-one was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, the reaction mixture was quenched by addition aq.KF (1 L), and then filtrated. The filter cake was washed with EtOAc (100 mL x 2) and the filtrate was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuum to afford 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1 ,3,4-oxadiazin-5- one (48.35 g, crude) as a brown oil.

[0691] Step 7: To a solution of 2-[3-(1-ethoxyvinyl)pyrazin-2-yl]-4-[(4-methoxyphenyl)methyl]-6,6- dimethyl-1 ,3,4-oxadiazin-5-one (48.35 g, 121.96 mmol, 1 eq) in MeCN (250 mL) was added HCI (2 M, 243.92 mL, 4 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed 2-[3-(1- ethoxyvinyl)pyrazin-2-yl]-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1 ,3,4-oxadiazin-5-one was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, the reaction mixture was poured into H2O (500 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-33% Ethylacetate / Petroleum ethergradient @ 60 mL / min) to afford 2-(3-acetylpyrazin-2-yl)-4- [(4-methoxyphenyl)methyl]-6,6-dimethyl-1,3,4-oxadiazin-5-one (39 g, 100.36 mmol, 82.29% yield, 94.8% purity) as a yellow oil.

[0692] 1H NMR: (400 MHz, DMSO-d6)

[0693] 5 [ppm] = 8.85 (d, J = 2.5 Hz, 1 H), 8.80 (d, J = 2.5 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.93 - 6.88 (m, 2H), 5.75 (s, 1H), 4.72 (s, 2H), 3.73 (s, 3H), 2.52 (d, J = 1.9 Hz, 3H), 1.53 (s, 6H)

[0694] Step 8: A solution of 2-(3-acetylpyrazin-2-yl)-4-[(4-methoxyphenyl)methyl]-6,6-dimethyl-1 ,3,4- oxadiazin-5-one (36 g, 97.72 mmol, 1 eq) in TFA (100 mL) and CF3SO3H (20 mL) was stirred at 25 °C for 1 h. LCMS showed 2-(3-acetylpyrazin-2-yl)-4-[(4-methoxyphenyl)methyl]-6,6- dimethyl-1 ,3,4-oxadiazin-5-one was remained and one main peak with desired mass was detected. After the completion of the reaction, the reaction mixture was added dropwise to sat. aq. NaHCOs (1.5 L), and then extracted with EtOAc (100 mL x 4). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-41% Ethylacetate / Petroleum ethergradient @ 150 mL / min). Then the product was triturated with MTBE (100 mL) for 10 min, filtered. The filter cake was washed with MTBE (80 mL), concentrated in vacuum to afford 2-(3-acetylpyrazin-2-yl)-6,6-dimethyl-4H- 1 ,3,4-oxadiazin-5-one (6.2 g, 24.79 mmol, 99.24% purity, yield: 25.3%) as a white solid.

[0695] LCMS: Desired MS: 248.1 , Observed MS: 249.1

[0696] 1H NMR: (400 MHz, DMSO-d6)

[0697] 5 [ppm] = 11.20 (s, 1 H), 8.87 (d, J = 2.4 Hz, 1 H), 8.81 (d, J = 2.4 Hz, 1 H), 2.60 (s, 3H), 1.51 (s, 6H))

[0698] Step 9: To a solution of 2-(3-acetylpyrazin-2-yl)-6,6-dimethyl-4H-1,3,4-oxadiazin-5-one (1.7 g, 6.85 mmol, 1 eq) in dioxane (20 mL) was added Ti(i-PrO)4 (4.87 g, 17.12 mmol, 5.05 mL, 2.5 eq) and 2-methylpropane-2-sulfinamide (1.66 g, 13.70 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h. LCMS showed 2-(3-acetylpyrazin-2-yl)-6,6-dimethyl-4H-1 ,3,4-oxadiazin-5-one was consumed completely and one main peak with desired mass was detected. After the completion of the reaction, it was poured into H2O (30 mL), and then filtered. The filtration was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-39% Ethylacetate / Petroleum ethergradient @ 60 mL / min). It was combined with another batch (7.0 g of product) to afford the (NE)-N-[1-[3-(6,6-dimethyl-5-oxo-4H-1,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]-2-methyl-propane-2-sulfinamide (8.6 g) as a brown oil.

[0699] 1H NMR (400 MHz, DMSO-d6) 5 [ppm] = 11.31 - 11.13 (m, 1 H), 8.82 (dd, J = 2.3, 11.0 Hz, 1 H), 8.67 (s, 1 H), 2.71 (s, 1 H), 2.47 (s, 2H), 1.49 (d, J = 2.1 Hz, 6H), 1 .13 (d, J = 16.3 Hz, 9H)

[0700] Step 10: To a solution of (NE)-N-[1-[3-(6,6-dimethyl-5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]-2-methyl-propane-2-sulfinamide (8.1 g, 23.05 mmol, 1 eq) in THF (100 mL) was added 9-BBN (0.5 M, 101.42 mL, 2.2 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS showed (NE)-N-[1-[3-(6,6-dimethyl-5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethylidene]-2-methyl-propane-2-sulfinamide was remained and one peak with desired mass was detected. MeOH (300 mL), acetone (20 mL) was added slowly to the reaction solution, and then stirred for 1 h. Then it was poured into H2O (1 L) and extracted with DCM (50 mL x 3). The combined organic layers were added 2% aq. NaCIO. Then the organic was washed with H2O (100 mL x 3), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethylacetate / Petroleum ethergradient (added 5% MeOH)@ 150 mL / min). Then 4 g of residue was further purified by prep-HPLC (neutral condition; column: Welch Xtimate C18 180*70mm#10um;mobile phase: [H2O(10mM NH4HCC>3)-ACN];gradient:10%-40% B over 17.0 min). It was combined with another batch (0.15 g of the product) to afford N-[1-[3- (6,6-dimethyl-5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2-sulfinamide (1.7763 g, 5.03 mmol, 21.80% yield, 100% purity) as a white solid.

[0701] LCMS: Desired MS: 353.1 , Observed MS: 354.1

[0702] 1H NMR: (400 MHz, DMSO-d6)

[0703] 5 [ppm] = 11.26 (br s, 1 H), 8.76 (d, J = 2.3 Hz, 1 H), 8.66 (d, J = 2.4 Hz, 1 H), 5.54 (d, J = 8.8 Hz, 1 H), 5.26 - 5.17 (m, 1 H), 1.53 (d, J = 10.9 Hz, 6H), 1.46 (d, J = 6.6 Hz, 3H), 1.07 (s, 9H)

[0704] Summary amine intermediats :

[0705] 2-methyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (I nt- 1a)

[0706] 2-methyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (Int- 2a)

[0707] N-[1-[3-(4,6-dimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2- sulfinamide (lnt-3a)

[0708] 2-methyl-N-[1-[3-(4,6,6-trimethyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (lnt-4a)

[0709] 2-methyl-N-[(1S)-1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (lnt-5a)

[0710] N,2-dimethyl-N-[1-[3-(5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2-sulfinamide (lnt-6a)

[0711] N,2-dimethyl-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (lnt-7a) 2-methyl-N-[(1 R)-1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]propane-2- sulfinamide (lnt-8a)

[0712] N-[1-[3-(6,6-dimethyl-5-oxo-4H-1 ,3,4-oxadiazin-2-yl)pyrazin-2-yl]ethyl]-2-methyl-propane-2- sulfinamide (lnt-9a)

[0713] Deprotection of the amine can be conducted as described in Example 15: Synthesis of 3- bromo-5-(1-cyanocyclopropyl)-N-[1-[3-(4-methyl-5-oxo-1 ,3,4-oxadiazin-2-yl)pyrazin-2- yl]ethyl]benzamide (1-51), to obtain the corresponding amine compounds lnt-2p and lnt-3p:

[0714] 2-[3-(1-aminoethyl)pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one 2-[3-(1-aminoethyl)pyrazin-2-yl]-4 / 7-1 ,3,4-oxadiazin-5-one 2-[3-(1-aminoethyl)pyrazin-2-yl]-4,6-dimethyl-1 ,3,4-oxadiazin-5-one 2-[3-(1-aminoethyl)pyrazin-2-yl]-4,6,6-trimethyl-1 ,3,4-oxadiazin-5-one 2-[3-[(1 S)-1-aminoethyl]pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one 2-[3-[1-(methylamino)ethyl]pyrazin-2-yl]-4 / 7-1 ,3,4-oxadiazin-5-one 4-methyl-2-[3-[1-(methylamino)ethyl]pyrazin-2-yl]-1 ,3,4-oxadiazin-5-one 2-[3-[(1R)-1-aminoethyl]pyrazin-2-yl]-4-methyl-1 ,3,4-oxadiazin-5-one 2-[3-(1-aminoethyl)pyrazin-2-yl]-6,6-dimethyl-4 / 7-1 ,3,4-oxadiazin-5-one

[0715] Carboxylic acid intermediats:

[0716] Intermediate 1c : Synthesis of 3-bromo-5-(1-cyanocyclopropyl)benzoic acid (lnt-1c) :

[0717] Step 1 : To a solution of methyl 3-bromo-5-(bromomethyl)benzoate (1 g, 3.24 mmol) in MeCN (10 mL), added TMSCN (647 mg, 6.5 mmol), TBAF (2 N) (2.43 mL, 4.86 mmol) at 0°C, and stirred at 0~15°C for 2 h. TLC (PE: EtOAc =3 :1) showed the reaction was completed. The reaction mixture was quenched with H2O (20 mL), extracted with EtOAc (10 mL*3), washed with brine (20 mL), dried over Na2SO4 and concentrated, purified by column (PE in EtOAc = 0-30%) to give methyl 3-bromo-5-(cyanomethyl)benzoate (600 mg, Yield: 72.9%) as white oil. 1 H NMR (400 MHz, methanol-d4) δ [ppm] = 8.09 - 8.12 (m, 1 H) 8.01 (s, 1 H) 7.81 (t, J=1.69 Hz, 1 H) 3.99 - 4.04 (m, 2 H) 3.93 (s, 3 H)

[0718] Step 2 : To a solution of 3-bromo-5-(cyanomethyl)benzoate (1 g, 3.94 mmol) in toluene (10 mL), added 1 ,2-dibromoethane (1.46 g, 7.88 mmol), TBAB (127 mg, 0.394 mmol) at 15°C, added NaOH (50%)(1 mL) at 0°C, and stirred at 0~15°C for 3 h. TLC (PE :EtOAc =3 :1) showed the reaction was completed. The reaction mixture was quenched with H2O (20 mL), extracted with EtOAc (10 mL*2), washed with brine (20 mL), dried over Na2SO4 and concentrated, purified by column (PE in EtOAc = 0-35%) to give methyl 3-bromo-5-(1-cyanocyclopropyl)benzoate (400 mg, Yield: 36.4%) as white solid. 1 H NMR (400 MHz, methanol-d4) δ [ppm] = 8.06 (t, J=1 .50 Hz, 1 H) 7.94 (t, J=1.56 Hz, 1 H) 7.72 (t, J=1.75 Hz, 1 H) 3.93 (s, 3 H) 1 .78 - 1 .82 (m, 2 H) 1.55 - 1.59 (m, 2 H) Step 3 : To a solution of methyl 3-bromo-5-(cyanomethyl)benzoate (400 mg, 1.5 mmol) in THF (5 mL), added H2O (1 mL), LiOH (126 mg, 3 mmol) at 0°C, and stirred at 0~15°C for 1 h. TLC (PE :EtOAc =3 :1) showed the reaction was completed. The reaction mixture was quenched with H2O (20 mL), adjust pH to 3, extracted with EtOAc (10 mL*2), washed with brine (20 mL), dried over Na2SO4 and concentrated to give 3-bromo-5-(1-cyanocyclopropyl)benzoic acid (300 mg, Yield: 78.9%) as yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 13.23 - 13.84 (m, 1 H) 7.96 (t, J=1.50 Hz, 1 H) 7.93 (t, J=1.44 Hz, 1 H) 7.69 (t, J=1.75 Hz, 1 H) 1 .79 - 1 .86 (m, 2 H) 1.63 - 1.70 (m, 2 H)

[0719] Intermediat 2c: Synthesis of 3-chloro-5-isopropylsulfonyl-benzoic acid (lnt-2c) :

[0720] Step 1 : To a solution of 3-chloro-5-nitro-benzoic acid (10 g, 49.75 mmol) in t-BuOH (100 mL) was added BOC2O (21 .7 g, 99.5 mmol) and DMAP (6.07 g, 49.75 mmol) at 25°C, stirred at 25°C for 2 hrs. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The mixture was concentrated, diluted with H2O (100 mL), extracted with EtOAc (100 mL x 2), washed with brine (100 mL x 2), dried over Na2SO4, filtrated, concentrated, purified by column (EtOAc in PE = 0% ~5%) to give tert-butyl 3-chloro-5-nitro-benzoate (total 21 g, Yield: 82%) as yellow solid.

[0721] 1 H NMR: (400 MHz, CDCI3) δ ppm 8.66 - 8.69 (m, 1 H) 8.37 (t, J=2.07 Hz, 1 H) 8.26 - 8.29 (m, 1 H) 1.63 (s, 9 H)

[0722] Step 2: To a solution of tert-butyl 3-chloro-5-nitro-benzoate (8 g, 31.13 mmol) in EtOH / H2O (90 mL / 30 mL) was added NH4CI (8.3 g, 155.64 mmol), Fe (8.7 g, 155.64 mmol) at 25°C, stirred at 80°C for 1 h. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The reaction mixture was filtered, the filter cake was washed with EtOAc (30 mL x 2), and the filtrate was quenched with H2O (200 mL), extracted with EtOAc (100 mL x 2), washed with brine (100 mL), dried over Na2SO4, filtrated and concentrated to give tert-butyl 3-amino-5-chloro-benzoate (13 g, Yield: 92%) as yellow solid. 1 H NMR: (400 MHz, CDCI3) δ ppm 7.34 (t, J=1.56 Hz, 1 H) 7.18 - 7.21 (m, 1 H) 6.83 (t, J=2.06 Hz, 1 H) 3.57 - 4.39 (br s, 2 H) 1 .58 (s, 9 H)

[0723] Step 3: To a solution of tert-butyl 3-amino-5-chloro-benzoate (6.81 g, 30 mmol) in EtOH (70 mL) was added HBF4 (40%) (13.2 g, 60 mmol) and t-BuONO (3.1 g, 60 mmol) at 0°C, stirred at 0°C for 1 h. Above mixture in MeCN (100 mL) was added to a solution of CuSCN (3.63 g, 30 mmol), KSCN (4.36 g, 45 mmol), CS2CO3 (9.78 g, 30 mmol) in MeCN (50 mL) at 0°C, stirred at 0°C for 1 hrs. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The reaction mixture was quenched with H2O (150 mL), extracted with EtOAc (150 mL x 3), washed with brine (100 mL), dried over Na2SO4, filtrated, concentrated and purified by column (EtOAc in PE = 0% ~ 6%) to give tert-butyl 3-chloro-5-thiocyanato-benzoate (4.6 g, Yield: 57%) as yellow oil. 1 H NMR: (400 MHz, CDCI3) δ [ppm] 7.97 - 8.01 (m, 2 H) 7.70 (t, J=1.75 Hz, 1 H) 1 .61 (s, 9 H)

[0724] Step 4: 5 Batches:

[0725] To a solution of tert-butyl 3-chloro-5-thiocyanato-benzoate (500 mg, 1.86 mmol) in THF (8 mL) was added bromo(isopropyl)magnesium (1.4 mL, 2.78 mmol) at 0°C under N2, and then stirred at 0°C~25°C for 2 hrs. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The reaction mixture was quenched with aq.NHUCI (30 mL), extracted with EtOAc (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, filtrated, concentrated and purified by column (EtOAc in PE = 0% ~ 3%) to give tert-butyl 3-chloro-5-isopropylsulfanyl-benzoate (total 2.3 g, Yield: 86%) as pale yellow solid. 1 H NMR: (400 MHz, CDCI3) δ ppm 7.85 (t, J=1.50 Hz, 1 H) 7.77 (t, J=1.69 Hz, 1 H) 7.49 (t, J=1.88 Hz, 1 H) 3.47 (dt, J=13.32, 6.72 Hz, 1 H) 1.60 (s, 9 H) 1.33 (d, J=6.63 Hz, 6 H)

[0726] Step 5: Two batches:

[0727] To a solution of tert-butyl 3-chloro-5-isopropylsulfanyl-benzoate (1.65 g, 5.77 mmol) in DOM (30 mL) was added m-CPBA (85%) (3.5 g, 17.31 mmol) at 0°C, stirred at 0°C~25°C for 12 hrs. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The reaction mixture was quenched with aq.Na2SO3(30 mL) and aq.NaHCO3(30 mL), extracted with DCM (30 mL x 2), washed with brine (50 mL), dried over Na3SO4, filtrated, concentrated and purified by column (EtOAc in PE = 0% ~ 5%) to give tert-butyl 3-chloro-5-isopropylsulfonyl-benzoate (total 3.5 g, Yield: 95%) as yellow solid.1 H NMR: (400 MHz, CDCI3) δ ppm 8.33 (t, J=1.50 Hz, 1 H) 8.22 (t, J=1.75 Hz, 1 H) 8.03 (t, J=1.88 Hz, 1 H) 3.25 (quin, J=6.85 Hz, 1 H) 1.62 (s, 9 H) 1.34 (d, J=6.88 Hz, 6 H)

[0728] Step 5: To a solution of tert-butyl 3-chloro-5-isopropylsulfonyl-benzoate (3.5 g, 11.0 mmol) in DCM (39 mL) was added TFA (15 mL) at 0°C, stirred at 0°C~25°C for 12 hrs. TLC (PE: EtOAc = 5:1) showed the reaction was completed. The reaction mixture was concentrated to give 3- chloro-5-isopropylsulfonyl-benzoic acid (2.6 g, Yield: 90%) as a white solid.1 H NMR: (400 MHz, METHANOL-d4) δ ppm 8.37 (t, J=1.50 Hz, 1 H) 8.31 (t, J=1.75 Hz, 1 H) 8.11 (t, J=1.88 Hz, 1 H) 3.43 (quin, J=6.85 Hz, 1 H) 1.28 (d, J=6.88 Hz, 6 H) LCMS: (Desired Mass: 262.0; Observed Mass: 261.0)

[0729] Intermediat 3c: Synthesis of 3-(4-bromophenyl)sulfonyl-5-chloro-benzoic acid (lnt-3c):

[0730] Step 1 : To a solution of 3-chloro-5-iodo-benzoic acid (3.3 g, 11.68 mmol) in MeOH (40 mL) was added SOCh (2.8 g, 23.36 mmol) at 25°C, stirred at 80°C for 2 hrs. TLC (PE: EtOAc = 5:1) showed the reaction was completed. The mixture was concentrated to give methyl 3-chloro-5- iodo-benzoate (3.5 g, Yield: crude) as yellow solid.

[0731] 1 H NMR: (400 MHz, CDCI3) 5 ppm 8.26 (s, 1 H) 7.98 (s, 1 H) 7.86 - 7.91 (m, 1 H) 3.94 (s, 3 H) Step 2: To a solution of methyl 3-chloro-5-iodo-benzoate (3.49 g, 11.79 mmol) in dioxane (50 mL) was added 4-bromobenzenethiol (2.23 g, 11.79 mmol), Cui (448 mg, 2.36 mmol), 1 , 10- phenanthroline (425 mg, 2.36 mmol), K3PO4 (5 g, 23.6 mmol) at 25°C, and then stirred at 110°C for 12 hrs. TLC (PE: EtOAc = 5:1) showed the reaction was completed. The reaction mixture was poured into H2O (100 mL), extracted with EtOAc (100 mL x 2), washed with brine (100 mL), dried over Na3SO4, filtrated and concentrated, purified by column (EtOAc in PE = 0% ~ 25%) to give methyl 3-(4-bromophenyl)sulfanyl-5-chloro-benzoate (3.18 g, Yield: 75.3%) as colorless oil. 1 H NMR: (400 MHz, CDCI3) δ ppm 7.86 (t, J=1.56 Hz, 1 H) 7.83 (t, J=1.50 Hz, 1 H) 7.48 - 7.53 (m, 2 H) 7.38 (t, J=1 .81 Hz, 1 H) 7.27 - 7.30 (m, 2 H) 3.91 (s, 3 H)

[0732] Step 3: To a solution of methyl 3-(4-bromophenyl)sulfanyl-5-chloro-benzoate (2.98 g, 8.37 mmol) in DCM (60 mL) was added m-CPBA (5.08 g, 85% purity, 25.11 mmol) at 0°C, stirred at 0°C~25°C for 12 hrs. TLC (PE: EtOAc = 10:1) showed the reaction was completed. The reaction mixture was quenched with aq.NaHCCh (50 mL) and aq.Na2SO3 (50 mL), extracted with DCM (50 mL x 2), washed with brine (50 mL), dried over Na2SO4, filtrated, concentrated and purified by column (EtOAc in PE = 0% ~ 8%) to give methyl 3-(4-bromophenyl)sulfonyl-5- ch loro- benzoate (2.65 g, Yield: 81.6%) as a white solid and methyl 3-(4-bromophenyl)sulfinyl-5- chloro-benzoate (250 mg, Yield: 8%) as colorless oil. 1 H NMR: (400 MHz, CDCI3)

[0733] 5 ppm 8.44 (t, J=1.56 Hz, 1 H) 8.21 (t, J=1.75 Hz, 1 H) 8.08 (t, J=1.88 Hz, 1 H) 7.80 - 7.86 (m, 2 H) 7.67 - 7.72 (m, 2 H) 3.97 (s, 3 H)

[0734] Step 4: To a solution of 3-(4-bromophenyl)sulfonyl-5-chloro-benzoate (2.65 g, 6.83 mmol) in THF / H2O (50 mL / 10 mL) was added LiOH*H2O (860 mg, 20.49 mmol) at 0°C, and then stirred at 25°C for 2 hrs. TLC (PE: EtOAc = 5:1) showed the reaction was completed. The reaction mixture was quenched with H2O (50 m...

Claims

Claims1) Compounds of formula IwhereinR1is H, OH, NR12R13; C1-C6-alkyl, C1-C6-haloalkyl, -cycloCa3lk-yCl6, - C3-C6 halocycloalkyl, C1-C5-alkoxy, -Ccy3-cClo6alkyl-C1-C4-alkyl, C1-C4-alkyl-C3-Ce- cycloalkyl, C3-C-h6alocycloalkyl-C1-C4-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, which groups are unsubstituted, or partially or fully substituted with R11; or C(=N-R11)R12, C(O)R11a;R10is H, C1-C4-alkyl, C1-C4-haloalkyl, -cCyc3-loCa6lkyl, -halocyCc3l-oCa6lkyl, C3- C4-cycloalkyl-C1-C2-alkyl, C3-C4-halocycloalkyl-C1-C2-alkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4-haloalkyl, C(O)-C3-C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, SOm- C1-C4-alkyl, SOm-C1-C4-haloalkyl, SOm-C3-C6-cycloalkyl, or phenyl which is unsubstituted or partially or fully substituted with R3a;R11is halogen, CN, NO2, NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; C1-C6-alkyl; C1-C6-haloalkyl; C2-C6-alkenyl; C2-C6-haloalkenyl; C2-C6-alkynyl; C2-C6-haloalkynyl; C3-C4-cycloalkyl-C1-C2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, 5- or 6- membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN;R11ais NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; C1-C6-haloalkyl; C2- Ce-alkenyl; C2-C6-haloalkenyl; C2-C6-alkynyl; C2-C6-haloalkynyl; O3-C4- cycloalkyl-C1-C2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN;R12, R13are independently from each other H, C1-C4-alkyl, C1-C4-alkoxy, C1-C4- haloalkoxy, C1-C4-haloalkyl, -cCy3c-Clo6alkyl, C(O)-C1-C4-alkyl, C(O)-C1-C4- haloalkyl, C(O)-C3-C4-cycloalkyl, C(O)-C3-C4-halocycloalkyl, C(O)NH-C1-C4- alkyl, C(O)NH-C1-C4-haloalkyl, C(O)N(C1-C4-alkyl)-C1-C4-alkyl, C(O)N(C1-C4- haloalkyl)-C1-C4-alkyl, C(O)N(C1-C4-haloalkyl)-C1-C4-haloalkyl, C(O)NH-C1-C4- alkoxy, C(O)NH-C1-C4-haloalkoxy, C(O)NH-C1-C4-alkoxy-C1-C4-alkyl, C(O)NH- C1-C4-alkoxy-C1-C4-haloalkyl; C(O)NH-phenyl, C(O)NH-3-6-membered heterocyclyl or 5- or 6-membered hetaryl, C(O)NH-C1-C4-alkyl-phenyl,C(O)NH-C1-C4-alkyl-3-6-membered heterocyclyl or 5- or 6-membered hetaryl which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4-cycloalkyl, S(O)m-C3-C4- halocycloalkyl; 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3- haloalkyl, and / or CN; or or R12and R13together with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7-membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatomcontaining groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a; m is 0, 1 , or 2;R2is H, C1-C3-alkyl, C1-C3-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, or C2-C3- alkynyl; each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6- cycloalkyl, C1-C6-haloalkyl, C3-C6-halocycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1- C4-alkoxy, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C6-cycloalkyl, 3- to 6- membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, -N=S(O)R12aR13a; or two R3bound to two adjacent C-atoms can form a 4-, 5-, or 6-membered ring, which may contain one or two heteroatoms selected from N, O, and S as ring members, which ring is unsubstituted or substituted with halogen, CN, C1-C3-alkyl, or C1-C3- haloalkyl;R12a, R13aare independently from each other C1-C4-alkyl, C1-C4-haloalkyl, C3-C6- cycloalkyl, unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; or R12aand R13atogether with the atom to which they are bound, form a 3-, 4-, 5-, 6-, or 7-membered saturated, partially or fully unsaturated heterocycle, which heterocycle may additionally contain 1 or 2 heteroatoms or heteroatomcontaining groups selected from N, O, S(O)m, and optionally one or two groups C(O) as ring members, and which heterocycle is unsubstituted or substituted with one or more R3a;R14is as defined for R10;R15is H, C1-C4-alkyl, or C1-C4-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, which carbon chains are unsubstituted or partially or fully substituted with R11; or 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with R3a;R3ais halogen, CN, NO2, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4- alkoxy-C1-C4-alkyl, C1-C4-haloalkoxy, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, S(O)m-C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4-cycloalkyl, S(O)m-C3- C4-halocycloalkyl; n is 0, 1 , 2, or 3;X is N, CH, or CR3c;R3cis as defined for R3;R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl-C1-C2-alkyl, C1-C2- alkyl-C3-C6-cycloalky, C3-C6-cycloalkyl, C1-C3-haloalkyl, C3-C6-halocycloalkyl which are unsubstituted or partially or fully substituted with R3;HET is a group HA or HBwherein # is the bond to the CH(R2)amide spacer, and % is the bond to the diazinone ring;R5is H, halogen, CN, C1-C3-alkyl, C1-C3-haloalkyl, or C3-C6-cycloalkyl;R5a,R5b,R5care independently from each other a group R5;Z is N, or CR5c;R6,R7are independently from each other H, halogen, CN, C1-C3-alkyl, C1-C3-haloalkyl, or C3-C6-cycloalkyl; orR6and R7together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered saturated or unsaturated carbocycle, which is unsubstituted or substituted with one or more halogen, CN, C1-C4-alkyl, or C1-C4-haloalkyl;Y is O, S, or N-RN;RNis as defined for R4; and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.2) Compounds of formula I according to claim 1 , whereinR1is H, OH, NR12R13; C1-C6-alkyl, C3-C6-cycloalkyl, C1-C5-alkoxy, C3-C6-cycloalkyl-Ci- C4-alkyl, C1-C4-alkyl-C3-C6-cycloalkyl, C3-C6-halocycloalkyl-C1-C4-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, which groups are unsubstituted, or partially or fully substituted with R11; or C(O)R11a;R11is halogen, CN, NO2, NR12R13, C(O)NH2, C(S)NH2, C(O)OH, OR10, Si(CH3)3; 3- to 6- membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C1-C3-haloalkyl, and / or CN; each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6- cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C3-Ce-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C6-cycloalkyl, 3- to 6-membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, -N=S(O)R12aR13a; or two R3bound to two adjacent C-atoms can form a 4-, 5-, or 6-membered ring, which may contain one or two heteroatoms selected from N, O, and S as ring members, which ring is unsubstituted or substituted with halogen, CN, C1-C3-alkyl, or C1-C3- haloalkyl;R4is H, C1-C3-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl-C1-C2-alkyl, C1-C2- alkyl-C3-C6-cycloalky, C3-C6-cycloalkyl, which are unsubstituted or partially or fully substituted with halogen, CN, NO2, OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15;R3ais halogen, CN, NO2, OH, S(O)m-C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, S(O)m-C3-C4- cycloalkyl, or S(O)m-C3-C4-halocycloalkyl; andZ is N.3) Compounds of formula I according to any one of claims 1 or 2, wherein R1is C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, or Ci- C4-alkyl-C3-C6-cycloalkyl.4) Compounds of formula I according to any one of claims 1 to 3, wherein R2is CH3.5) Compounds of formula I according to any one of claims 1 to 4, wherein each R3is independently selected from halogen, CN, C1-C4-alkyl, wherein alkyl is unsubstituted or substituted with one or more CN, C1-C4-haloalkyl, C1-C4-haloalkoxy, C3-C4-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one or more CN or halogen, S(0)m- C1-C4-alkyl, S(O)m-C1-C4-haloalkyl, OS(O)m-C1-C4-alkyl, OS(O)m-C1-C4-haloalkyl, S(0)m- phenyl, wherein phenyl is unsubstituted or substituted with one or more halogen.6) Compounds of formula I according to any of claim 1 to 4, wherein each R3is independently selected from halogen, CN, NO2; C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6- alkenyl, C2-C6-alkynyl, C1-C4-alkoxy, C3-C6-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C6- cycloalkyl, 3- to 6-membered heterocyclyl, which are unsubstituted or substituted with R3a; OR14, NR12R13, C(O)NR12R13, C(O)OR14, C(O)R15, S(O)m-R15, -N=S(O)R12aR13a; preferably wherein each R3is independently selected from F, Cl, Br, CF3, CCIF2, CF2CH3, CN, SCH3, OCH3, S-CH2-CN, S-CF3, SO2CF3, SOCF3, SO2(4-F-C6H4), SO2-(2-F-C6H4), SO2-(4-Br- C6H4), SO2-CH(CH3)2, SO2-CC3H5, SO2-CH3, O-SO2-CF3, 1-CN-CC3H4, C(CH3)2CN, 2-Ch- cC3H3, C(CH2)-CC3H5, CH(OCH3)-CC3H5, C(O)-CC3H5, CCH, C(CH3)3, CH(CI)2, CF2H, OCF3or OCF2H.7) Compounds of formula I according to any one of claims 1 to 6, wherein X is CH.8) Compounds of formula I according to any of claim 1 to 7, wherein R4is H, C1-C3-alkyl, C2- C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl-C1-C2-alkyl, C1-C2-alkyl-C3-C6-cycloalky, C3-C6- cycloalkyl, which are unsubstituted or partially or fully substituted with halogen, CN, C(O)NH2.9) Compounds of formula I according to any of claim 1 to 8, wherein n is 2 and R3is in positions 3 and 5.10) Compounds of formula I according to any one of claims 1 to 9, wherein a) R5is H; and / or b) R5a, R5band R5care H; and / or c) R6and R7are independently from each other H, CH3, CH2CH3, CH(CH3)2 or CH2CH2CH3; and / or d) R6and R7together with the carbon atom to which they are bound, form a cyclopropyl ring.11) Compounds of formula I according to any one of the preceding claims, which consist mainly of the isomer I.S.12) Compounds according to any one of the preceding claims, wherein the compounds are of formula I.A.N.1*, I.A.N.Ia*, I.A.N.2*, I.A.N.2b*, I.A.N.2c*, I.A.N.2S*, I.A.N.1S*, I.A.N.1 R*, I.A.N.3*, or LA. N.3a*and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.13) Compounds according to any one of the preceding claims, wherein the compounds are selected from6K09 ktSt391.£91and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.14) Intermediate compounds of formula lnt-1 p, lnt-2p, lnt-3p or VIII,or N-oxides, stereoisomers, and salts thereof, wherein the variables are as defined according to any of the preceding claims.15) An agricultural or veterinary composition comprising at least one compound according to any one of claims 1 to 13 and / or at least one agriculturally or veterinarily acceptable saltthereof, and at least one inert liquid and / or solid agriculturally or veterinarily acceptable carrier.16) An agricultural composition for combating animal pests comprising at least one compound as defined in any of claims 1 to 13 and at least one inert liquid and / or solid acceptable carrier and, if desired, at least one surfactant.17) A method for combating or controlling invertebrate pests, which method comprises contacting said pest or its food supply, habitat or breeding grounds with a pesticidally effective amount of at least one compound as defined in any one of claims 1 to 13.18) A method for protecting growing plants from attack or infestation by invertebrate pests, which method comprises contacting a plant, or soil or water in which the plant is growing, with a pesticidally effective amount of at least one compound as defined in any of claims 1 to 13.19) Seed comprising a compound as defined in any of claims 1 to 13, or the enantiomers, diastereomers or salts thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.20) A method for treating or protecting an animal from infestation or infection by invertebrate pests which comprises bringing the animal in contact with a pesticidally effective amount of at least one compound of the formula I as defined in any of claims 1 to 13, a stereoisomer thereof and / or at least one veterinarily acceptable salt thereof.