Diazine-amide compounds with pesticidal activity

Abstract

Compounds of formula I(1) wherein the substituents are as defined in claim 1, and agrochemically acceptable salts, stereoisomers, enantiomers, tautomers and N-oxides of those compounds can be used as insecticides.

Description

[0001] The present invention relates to pesticidally active, in particular insecticidal, diazine-amide compounds, processes for their preparation, compositions comprising these compounds, and their use for controlling animal pests, including arthropods and in particular insects or representatives of the order Acarina.

[0002] WO 2017192385 describes certain heteroaryl-1,2,4-triazole and heteroaryl-tetrazolyl compounds for use in controlling ectoparasites in animals (such as mammals and non-mammals).

[0003] Novel pesticidally active diazinonamide compounds have now been discovered.

[0004] Therefore, in a first aspect, the present invention relates to a compound having formula I

[0005]

[0006] in

[0007] R1 is H, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonylC1-C6 alkyl, hydroxycarbonylC1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilylC1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, C3-C4 cycloalkylC1-C2 alkyl- wherein the C3-C4 cycloalkyl group is substituted by 1 or 2 halogen atoms, oxetan-3-yl-CH2-, benzyl, or benzyl substituted by halo or C1-C6 haloalkyl;

[0008] A1 is N or CR 2c ;

[0009] R 2c is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy;

[0010] R 2aC3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 cycloalkyl substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen, C3-C6 cycloalkyloxy substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen, C3-C6 cycloalkylC1-C4 alkyl, C3-C6 cycloalkylC1-C4 alkoxy, substituted by one to five substituents independently selected from C C3-C6 cycloalkylC1-C4 alkyl substituted with a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen substituent, C3-C6 cycloalkylC1-C4 alkoxy substituted with one to five substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, or C1-C4 haloalkylsulfinyl;

[0011] R 2b is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylthio, C1-C3 alkoxy, C1-C3 haloalkoxy, SF5, or CN;

[0012] R3 is C1-C3 alkyl or C1-C3 haloalkyl;

[0013] A2 is CR 4b or N;

[0014] R 4b is hydrogen or a halogen;

[0015] R 4a is cyano, or C1-C3 haloalkoxy;

[0016] R 5a and R 5b are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy; or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer and N-oxide of the compound of formula I.

[0017] Compounds of formula I with at least one basic center can form acid addition salts, for example, with strong inorganic acids (such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid or hydrohalic acids), strong organic carboxylic acids (such as unsubstituted or, for example, halogen-substituted C1-C4-alkanecarboxylic acids, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid), or organic sulfonic acids (such as unsubstituted or, for example, halogen-substituted C1-C4-alkanesulfonic acids or arylsulfonic acids, for example methanesulfonic acid or p-toluenesulfonic acid). Compounds of formula I having at least one acidic group can, for example, form salts with bases, for example mineral salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts; or with ammonia or organic amines such as morpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines, for example ethylamine, diethylamine, triethylamine or dimethylpropylamine, or mono-, di- or trihydroxy-lower alkylamines, for example monoethanolamine, diethanolamine or triethanolamine.

[0018] In each case, the compounds of formula I according to the invention are in free form, in an oxidized form such as an N-oxide, or in salt form (eg an agronomically usable salt form).

[0019] N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen-containing heteroaromatic compounds. They are described, for example, in the book "Heterocyclic N-oxides" by A. Albini and S. Pietra, CRC Press, Boca Raton, 1991.

[0020] The compounds of formula I according to the invention also include hydrates which may be formed during salt formation.

[0021] As used herein, the term "C1-C n “Alkyl” refers to a saturated straight or branched chain hydrocarbon radical having 1 to n carbon atoms, attached via any carbon atom, such as any of the following: methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0022] As used herein, the term "C1-C n “Haloalkyl” refers to straight-chain or branched saturated alkyl groups (as mentioned above) having 1 to n carbon atoms, attached via any carbon atom, wherein some or all of the hydrogen atoms in these groups may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., for example, any of the following: chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoro The term "Ci-C2 fluoroalkyl" refers to a C1-C2 alkyl radical having 1, 2, 3, 4, or 5 fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl.

[0023] As used herein, the term "C1-C n "Alkoxy" refers to a straight-chain or branched saturated alkyl group (as mentioned above) having 1 to n carbon atoms, which is attached via an oxygen atom, i.e., for example, any of the following groups: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. As used herein, the term "halogenated C1-C n "Alkoxy" refers to C1-C n Alkoxy groups wherein one or more hydrogen atoms on the alkyl group are replaced by one or more halogen atoms which may be the same or different - examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.

[0024] As used herein, the term "C1-C n "Cyanoalkyl" refers to a straight or branched chain saturated C1-C nAlkyl groups (as mentioned above), wherein one of the hydrogen atoms in these groups is replaced by a cyano group: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, etc.

[0025] As used herein, the term "C3-C n "Cycloalkyl" refers to 3 to n-membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane. The term "C3-C n "Cycloalkoxy" refers to cycloalkyl groups (as mentioned above) which are attached to the remainder of the molecule via an oxygen atom.

[0026] As used herein, the term "C3-C n Cycloalkyl-C1-C n "Alkyl-" refers to a 3 to n membered cycloalkyl group having 1 to n alkyl groups attached to the remainder of the molecule. In the example, the C3-C4 cycloalkyl-C1-C2 alkyl- group is substituted, and the one or more substituents can be on the cycloalkyl group or the alkyl portion. The term "C3-C4 cycloalkyl-C1-C2 alkyl-" refers to a 3 to n membered cycloalkyl group having 1 to n alkyl groups attached to the remainder of the molecule. In the example, the C3-C4 cycloalkyl-C1-C2 alkyl- group is substituted, and the one or more substituents can be on the cycloalkyl group or the alkyl portion. n Cycloalkyl-C1-C n "Alkoxy-" refers to a cycloalkyl-alkyl substituent in which the alkyl group is attached to an oxygen atom which forms the attachment to the remainder of the molecule.

[0027] As used herein, the term "aminocarbonyl C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a CONH2 group.

[0028] As used herein, the term "hydroxycarbonyl C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a COOH group.

[0029] As used herein, the term "C1-C n "Nitroalkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a NO2 group.

[0030] As used herein, the term "C1-C n "Haloalkylthio" refers to a C1-C3 haloalkyl moiety attached through a sulfur atom.

[0031] As used herein, the term "trimethylsilane C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a -Si(CH3)3 group.

[0032] As used herein, the term "C2-C n"Alkenyl" refers to a straight or branched alkenyl chain having from 2 to n carbon atoms and one or two double bonds, for example vinyl, prop-1-enyl, but-2-enyl.

[0033] As used herein, the term "C2-C n "Haloalkenyl" refers to a C2-C4 group substituted by one or more halogen atoms which may be the same or different. n Alkenyl moiety.

[0034] As used herein, the term "C2-C n "Alkynyl" refers to a straight or branched alkynyl chain having from 2 to n carbon atoms and one triple bond, for example ethynyl, prop-2-ynyl, but-3-ynyl.

[0035] As used herein, the term "C2-C n "Haloalkynyl" refers to a C2-C6 substituted by one or more halogen atoms which may be the same or different. n Alkynyl moiety.

[0036] Halogen is typically fluorine, chlorine, bromine or iodine. This also applies correspondingly to halogen in combination with other meanings, such as haloalkyl.

[0037] As used herein, the term "control" means reducing the number of pests, eliminating pests and / or preventing further pest damage, thereby reducing damage to plants or plant-derived products.

[0038] Staggered lines as used herein, for example, in K-1 and L-1, indicate the point of connection / attachment to the rest of the compound.

[0039] As used herein, the term "pest" refers to insects and molluscs found in agriculture, horticulture, forestry, storage of products of plant origin (such as fruit, grain and wood); and those pests associated with damage to man-made structures. The term pest includes all stages of the pest life cycle.

[0040] As used herein, the term "effective amount" refers to an amount of a compound, or a salt thereof, that provides the desired effect after single or multiple administrations.

[0041] An effective amount is readily determined by one skilled in the art by using known techniques and observing the results obtained under similar circumstances. In determining an effective amount, many factors are considered, including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled and its life cycle; the specific compound to be applied; the type of application; and other relevant circumstances.

[0042] As will be understood by one of ordinary skill in the art, compounds having Formula I contain stereocenters, which are indicated by asterisks in the structures below:

[0043]

[0044] Among them, R1, R 2a 、R 2b , R3, R 4a 、R 5a 、R 5b , A1 and A2 are as defined in the first aspect.

[0045] The present invention encompasses both the racemates and the individual enantiomers.Compounds with preferred stereochemistry are described below.

[0046]

[0047] Particularly preferred compounds of the present invention are compounds having formula I'a:

[0048] Among them, R1, R 2a 、R 2b , R3, R 4a 、R 5a 、R 5b , A1 and A2 are as defined in the first aspect, as well as stereoisomers, enantiomers, tautomers and N-oxides of the compound of formula (I'a), and agrochemically acceptable salts thereof.

[0049] As used herein, the term "optionally substituted" means that the referenced group is unsubstituted or substituted with a specified substituent, for example, "C3-C4 cycloalkyl optionally substituted by 1 or 2 halogen atoms" means C3-C4 cycloalkyl, C3-C4 cycloalkyl substituted by 1 halogen atom, and C3-C4 cycloalkyl substituted by 2 halogen atoms.

[0050] As described below, embodiments according to the present invention are provided.

[0051] In an embodiment of each aspect of the invention, A1 is

[0052] AN; or

[0053] BC-R 2c , where R 2c is hydrogen or halogen (such as Cl, F, Br or I); preferably hydrogen.

[0054] In an embodiment of each aspect of the invention, R 2a yes

[0055] A. C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen, C3-C6 cycloalkyl substituted by one to five substituents independently selected from halogen and C1-C3 haloalkyl, C1-C4 alkyl, C1-C5 cyanoalkyl, C3-C6 cycloalkyloxy, C1-C4 haloalkylsulfonyl or C1-C4 haloalkylsulfinyl; or

[0056] B. C3-C4 cycloalkyl, C3-C4 cycloalkyloxy, C3-C4 cycloalkyl substituted by one to three substituents independently selected from C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, cyano, and halogen, C3-C4 cycloalkyl substituted by one to five substituents independently selected from halogen and C1-C3 haloalkyl, C1-C3 cyanoalkyl, C3-C4 cycloalkyloxy, C1-C3 haloalkylsulfonyl or C1-C3 haloalkylsulfinyl; or

[0057] C. cyclopropyl, cyclopropyl substituted by one to three substituents independently selected from methyl, trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted by one to five fluorine substituents, C1-C3 cyanoalkyl, cyclopropyloxy, trifluoromethylsulfonyl or trifluoromethylsulfinyl; or

[0058] D. cyclopropyl, cyclopropyl substituted by one to three substituents independently selected from methyl, trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted on the methyl portion by one or two fluorine substituents, C1-C3 cyanoalkyl, trifluoromethylsulfonyl or trifluoromethylsulfinyl; or

[0059] E. Cyclopropyl, cyclopropyl substituted by one to three substituents independently selected from trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted by one or two fluorine substituents on the methyl portion, C1-C3 cyanoalkyl, trifluoromethylsulfonyl.

[0060] In an embodiment of each aspect of the invention, R 2b yes

[0061] A. halogen, C1-C3 haloalkyl, C1-C3 haloalkylthio, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; or

[0062] B. halogen, C1-C3 haloalkyl, or C1-C3 haloalkoxy; or

[0063] C. chlorine, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy; or

[0064] D. Difluoromethyl or trifluoromethyl.

[0065] In an embodiment of each aspect of the invention, R1 is

[0066] A. hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HCH≡CCH2-; or

[0067] B. hydrogen, methyl, or cyclopropylmethyl; or

[0068] C. Hydrogen.

[0069] In an embodiment of each aspect of the invention, R3 is

[0070] A. C1-C3 alkyl or C1-C3 haloalkyl; or

[0071] B. Methyl.

[0072] In an embodiment of each aspect of the invention, A2 is

[0073] AN; or

[0074] BC-R 4b , where R 4b is hydrogen or halogen (such as Cl, F, Br and I); preferably R 4b It's hydrogen.

[0075] In an embodiment of each aspect of the invention, R 4a yes

[0076] A. cyano, or C1-C3 fluoroalkoxy; or

[0077] B. cyano, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, or 2,2-difluoroethoxy.

[0078] In an embodiment of each aspect of the invention, R 5a and R 5b independently selected from

[0079] A. hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy;

[0080] B. is selected from hydrogen, bromine, chlorine, methyl, methoxy; or

[0081] C. Hydrogen.

[0082] The present invention thus makes available compounds having the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R3 2a 、R 2b , R3, R 4a 、R 5a 、R 5b, A1 and A2 have a compound of formula I. Thus, for example, a compound of formula I can be obtained, wherein A1 is a compound belonging to the first aspect (ie, A1 is N or CR 2c , where R 2c is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy); R1 is Example B (i.e., hydrogen, methyl, cyclopropylmethyl); R 2a is Example C (i.e., cyclopropyl, cyclopropyl substituted by one to three substituents independently selected from methyl, trifluoromethyl, cyano, fluorine and chlorine, cyclopropylmethyl substituted by one to five fluorine substituents, C1-C3 cyanoalkyl, C3-C6 cyclopropyloxy, trifluoromethylsulfonyl or trifluoromethylsulfinyl); R 2b is Example B (ie, halogen, C1-C3 haloalkyl, or C1-C3 haloalkoxy); R3 is Example B (ie, methyl); A2 is Example B (ie, CR 4b , where R 4b is hydrogen or halogen (such as Cl, F, Br and I); preferably R 4b is hydrogen); R 4a is Example A (i.e., cyano, or C1-C3 fluoroalkoxy); and R 5a is embodiment B (ie, selected from hydrogen, bromine, chloride, methyl, methoxy); and R 5b is Example C (ie, hydrogen).

[0083] In one embodiment, the compound having Formula I can be represented as

[0084]

[0085] Among them, R1, R3, R 5a , and R 5b As defined in the first aspect, R2 is a compound containing A1 as defined in the first aspect and a substituent R 2a and R 2b and R4 is a cyclic group containing A2 and a substituent R as defined in the first aspect. 4a cyclic groups.

[0086] In embodiments of each aspect of the present invention, R2 (containing A1 and substituent R 2a and R 2b cyclic groups)

[0087] A. Select from K-1 to K-16

[0088]

[0089] B. selected from K-1, K-2, K-3, K-5, K-6, K-10, K-11, K-12, K-14, K-15 and K-16; or

[0090] C. Selected from K-1, K-2, K-6, K-10, K-12, K-14, K-15 and K-16; or

[0091] D. Selected from K-1, K-2, K-5, K-10, K-11, K-14, K-15 and K-16; or

[0092] E. selected from K-1, K-2, K-5, K-6, K-10, K-14, K-15 and K-16; or

[0093] F. selected from K-1, K-2, K-6, K-10, K-14, K-15 and K-16; or

[0094] G. Selected from K-2, K-6 and K-10; or

[0095] H. Selected from K-5, K-10, K-14 and K-15; or

[0096] I. Selected from K-2, K-6, K-14 and K-15.

[0097] In embodiments of each aspect of the present invention, R4 (containing A2 and substituent R 4a cyclic groups)

[0098] A. Selected from L-1 to L-9

[0099]

[0100] B. selected from L-1, L-2, L-7, L-8, and L-9; or

[0101] C. selected from L-3, L-5, L-6, L-7, L-8 and L-9; or

[0102] D. selected from L-5, L-7, L-8 and L-9; or

[0103] E. selected from L-3, L-5, L-7 and L-9; or

[0104] FL-8 and L-9; or

[0105] GL-5 and L-9; or

[0106] HL-7 or L-9; or

[0107] IL-1 or IL-9.

[0108] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl, or HCH≡CCH2- as R1; one of K-1 to K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0109] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1 to K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0110] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen as R1; one of K-1 to K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0111] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-3, K-5, K-6, K-10, K-11, K-12, K-14, K-15, and K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0112] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-5, K-10, K-11, K-14, K-15, and K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0113] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-5, K-10, K-11, K-14, K-15, and K-16 as R2; methyl as R3; one of L-1, L-2, L-7, L-8, and L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0114] In embodiments of each aspect of the invention, the compound of Formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-5, K-10, K-11, K-14, K-15, and K-16 as R2; methyl as R3; one of L-1, L-2, L-7, L-8, and L-9 as R4; and one of R-1, L-2, L-7, L-8, and L-9 as R 5a and R 5b of each hydrogen.

[0115] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-5, K-10, K-14, and K-15 as R2; methyl as R3; one of L-1 or L-9 as R4; and one of R-2, R-3, R-4, R-5, R-6, R-7, R-8, R-9, and R-10. 5a and R 5b of each hydrogen.

[0116] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-6, K-10, K-12, K-14, K-15, and K-16 as R2; methyl as R3; one of L-1 to L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0117] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-6, K-10, K-12, K-14, K-15, and K-16 as R2; methyl as R3; one of L-3, L-5, L-7, and L-9 as R4; and R independently selected from hydrogen, halogen, and methyl. 5a and R 5b .

[0118] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-1, K-2, K-6, K-10, K-12, K-14, K-15, and K-16 as R2; methyl as R3; one of L-3, L-5, L-7, and L-9 as R4; and one of R-1, R-2, R-6, K-10, K-12, K-14, K-15, and K-16 as R3. 5a and R 5b of each hydrogen.

[0119] In embodiments of each aspect of the invention, the compound of formula IA or I'-A has hydrogen, methyl, or cyclopropylmethyl as R1; one of K-2, K-6, K-14, and K-15 as R2; methyl as R3; one of L-1 or L-9 as R4; and one of R- 5a and R 5b of each hydrogen.

[0120] In a second aspect, the present invention makes available a composition comprising a compound of formula I as defined in the first aspect, one or more adjuvants and diluents, and optionally one or more other active ingredients.

[0121] In a third aspect, the present invention makes available a method for combating and controlling insects, acarines, nematodes or molluscs, which method comprises applying to the pest, the locus of the pest, or a plant susceptible to attack by the pest an insecticidal, acaricidal, nematicidal or molluscicidal effective amount of a compound as defined in the first aspect or a composition as defined in the second aspect.

[0122] In a fourth aspect, the present invention makes available a method for protecting plant propagation material from attack by insects, mites, nematodes or molluscs, said method comprising treating said propagation material or the site in which said propagation material is planted with an effective amount of a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.

[0123] In a fifth aspect, the present invention makes it possible to obtain a plant propagation material, such as a seed, comprising a compound of formula I as defined in the first aspect or a composition as defined in the second aspect, or treated with said compound or said composition or having said compound or said composition adhered thereto.

[0124] In another aspect, the present invention provides a method for controlling parasites in or on an animal in need thereof, the method comprising administering an effective amount of a compound of the first aspect. The present invention further provides a method for controlling external parasites on the surface of an animal in need thereof, the method comprising administering an effective amount of a compound having Formula I as defined in the first aspect. The present invention further provides a method for preventing and / or treating a disease transmitted by external parasites, the method comprising administering an effective amount of a compound having Formula I as defined in the first aspect to an animal in need thereof.

[0125] Compounds of Formula I can be prepared by those skilled in the art according to known methods. More specifically, compounds of Formula I and I'a and intermediates thereof can be prepared as described in the following schemes and examples. For the sake of clarity, certain stereocenters are left unspecified, but this is not intended to limit the teachings of the schemes in any way.

[0126] The processes according to the present invention for preparing compounds of formula I are carried out by methods known to those skilled in the art.

[0127] Compounds having formula I

[0128]

[0129] can be prepared by reacting an amine of formula II with a carboxylic acid derivative of formula III

[0130]

[0131] Among them, R1, R3, A2, R 4a 、R 5a and R 5b As described in Formula I,

[0132]

[0133] Among them, A1, R 2a and R 2b As described above under Formula I. The chemistry is described in more detail in Scheme 1.

[0134] Option 1:

[0135]

[0136] In Scheme 1, a compound of formula III (wherein A1, R 2a and R 2bis described in formula I) is activated to a compound of formula IIIa by methods known to those skilled in the art and described, for example, in Tetrahedron, 61(46), 10827-10852, 2005. For example, a compound wherein X0 is a halogen is formed by treating a compound of formula III with, for example, oxalyl chloride or thionyl chloride in the presence of a catalytic amount of DMF in an inert solvent such as dichloromethane or THF at a temperature between 20° C. and 100° C., preferably at 25° C. Optionally, the compound of formula II (wherein R1, R3, A2, R 4a 、R 5a and R 5b Treatment of IIIa with 1-(3-(3-dimethylaminopropyl)carbodiimide) (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in an inert solvent (e.g., pyridine or THF) optionally in the presence of a base (e.g., triethylamine) at temperatures between 50°C and 180°C gives compounds of formula I. 01 or X 02 Alternatively, the acid of formula III may be activated by coupling with a coupling agent such as propanephosphonic anhydride. or O-(7-aza-1-benzotriazolyl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU) reaction to provide wherein X0 is X 03 and X 04 Compounds of formula IIIa are prepared as described, for example, in Synthesis 2013, 45, 1569 and Journal Prakt. Chemie 1998, 340, 581. Subsequent reaction with an amine of formula II provides compounds of formula I.

[0137] An intermediate of formula II (wherein R1, R3, A2, R 4a 、R 5a and R 5b As defined in Formula I) can be prepared according to Scheme 2:

[0138] Option 2:

[0139]

[0140] In Scheme 2, a compound of Formula II (wherein R1, R3, A2, R 4a 、R 5a and R 5bAs defined in formula I) can be prepared by treating a compound of formula VI (wherein R3, A2, R4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A30, A31, A19, A22, A32, A40, A50, A60, A19, A22, A32, A19, A22, A33, A34, A35, A36, A37, A38, A39, A40, A41, A50, A51, A52, A61, A19, A22, A39, A39, A41, A51, A52, A61, A19, A22, A39, A39, A41, A51, A52, A61, A79, A79, A80, A9, A19, A20, A39, A39, A41, A51, A52, A61, A79, A19, A20 ... 4a 、R 5a and R 5b As defined in formula I). ​​Alternatively, another reagent system for reductive amination using a combination of Ti(i-OiPr)4 and NaBH4 in the presence of an amine of formula VII can also provide compounds of formula II (see Synthesis 2003(14), 2206).

[0141] A compound of formula VI (wherein R3, A2, R 4a 、R 5a and R 5b As defined in formula I) can be prepared by the Stille reaction in which a compound of formula IV (wherein X 05 is a leaving group such as chlorine, bromine, iodine, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate, and R3, R 5a and R 5b As defined in formula I) with a tin compound of formula V (wherein A2 and R 4a As defined in formula I), in the presence of a palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0) or (1,1'bis(diphenylphosphino)-ferrocene)palladium dichloride-dichloromethane (1:1 complex)), in an inert solvent (e.g., DMF, acetonitrile or dioxane), optionally in the presence of an additive (e.g., potassium fluoride, cesium fluoride or lithium chloride), and optionally in the presence of another catalyst (e.g., copper(I) iodide). Such Stiller coupling reactions are well known to those skilled in the art and have been described in the literature, for example, in J. Org. Chem., 2005, 70, 8601; J. Org. Chem., 2009, 74, 5599; Angew. Chem. Int. Ed., 2004, 43, 1132; Heterocycles 2010, 80, 1215 and J. Am. Chem. Soc. 2004, 126, 16433.

[0142] Alternatively, a compound of formula VI (wherein R3, A2, R 4a 、R 5a and R 5bAs defined in Formula I) can also be prepared by a Suzuki reaction (Scheme 3) which involves, for example, reacting a compound of Formula IV (wherein R3, R 5a and R 5b As defined in Formula I and X 05 The reaction can be carried out by reacting a compound of formula VIII (wherein W can be a boron-derived functional group, such as B(OH) 2 or pinacol borate) with a leaving group such as chlorine, bromine, iodine, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate. The reaction can be carried out by reacting a catalyst based on palladium (such as tetrakis(triphenylphosphine)-palladium or (1,1'-bis(diphenylphosphino)-ferrocene) palladium dichloride-dichloromethane (1:1 complex)) in the presence of a base (such as sodium carbonate or cesium fluoride) in a solvent or solvent mixture (such as a mixture of 1,2-dimethoxyethane and water, dioxane and water, or DMF and water), preferably under an inert atmosphere. The range of reaction temperature can preferably be from room temperature to the boiling point of the reaction mixture. Such Suzuki reactions are well known to those skilled in the art and have been reported in the following literature: for example, J. Organomet. Chem. 576, 1999, 147-168; Science of Synthesis 2010, 45b, 547; Eur. J. Org. Chem. 2012, (31), 6248 and Synthesis 2017, 49, 4372.

[0143] Option 3:

[0144]

[0145] Compounds of formula IV are generally commercially available.

[0146] Alternatively, a compound of formula VI (wherein R3, A2, R 4a 、R 5a , and R 5b as defined in Formula I) is outlined in Scheme 4.

[0147] Option 4:

[0148]

[0149] For example, a compound of formula VI (wherein R3, A2, R 4a 、R 5a , and R 5b As defined in formula I) can be prepared by: making a compound of formula IVa (wherein R3, R 5a and R5b As defined in formula I) with a compound of formula XI (wherein A2 and R 4a As defined in formula I) in a suitable solvent (preferably dioxane or DMF), in the presence of a Pd catalyst (preferably palladium acetate), a ligand (such as di-tert-butyl (methyl) phosphine) and a base (such as Cs2CO3), typically heated at a temperature between 120 ° C and 130 ° C. Such methods have been described, for example, in J.Am.Chem.Soc. [Journal of the American Chemical Society] 2018, 140, 15916.

[0150] The required intermediate of formula XI can be prepared from the intermediate of formula IX (wherein A2 and R 4a As defined for Formula I and X 06 Is a leaving group and represents a halogen and methyl sulfone) compounds are obtained by oxidation with propane-2-ene-1-thiol and subsequent oxidation with mCPBA. Such transformations are well known and reported in, for example, J.Am.Chem.Soc. [Journal of the American Chemical Society] 2018, 140, 15916.

[0151] Alternatively, a compound of formula VI (wherein R3, A2, R 4a 、R 5a , and R 5b as defined in Formula I) is outlined in Scheme 5.

[0152] A compound of formula VI (wherein R3, A2, R 4a 、R 5a , and R 5b As defined in formula I) can be prepared by treating a compound of formula XIV with a Grignard reagent R3MgBr (e.g. MeMgBr) in a suitable solvent such as THF or diethyl ether at relatively low temperatures (preferably between 0°C and 25°C).

[0153] Weinreb amides of formula XIV (wherein A2, R 4a 、R 5a , and R 5b As defined in formula I) can be prepared in three steps from a compound of formula XIII (wherein A2, R 4a 、R 5a , and R 5bAs defined in formula I and Z is C1-C6 alkyl). The compound of formula XIII is converted to a carboxylic acid by methods known in the art (see, for example, WO 2011 / 143365, page 138), and activated (see Scheme 1) and the subsequent carboxylic acid is then treated with N-methoxy-N-methylamine (according to Weinreb et al. Tet. Lett. [Tet. Lett.] 1981, 39, 3815) to produce a compound of formula XIV.

[0154] Compounds of formula XIII (wherein A2, R 4a 、R 5a , and R 5b As defined in formula I and Z is C1-C6 alkyl) can be prepared by: reacting a compound of formula XII (wherein R 5a and R 5b As defined in Formula I, Z is a C1-C6 alkyl group, and X 07 is a leaving group such as, for example, chloro, bromo, iodo) with a compound of formula V (Stiller reaction) or a compound of formula VIII (Suzuki-Miyaura reaction) in the presence of a palladium catalyst as described in detail in Schemes 2 and 3.

[0155] Option 5:

[0156]

[0157] In an alternative method (Scheme 6), a compound of Formula II (wherein R1, R3, A2, R 4a 、R 5a and R 5b As defined in formula I) can be prepared by: making a compound of formula XVI (wherein R3, A2, R 4a 、R 5a and R 5b As defined in Formula I and X 08 The nucleophilic substitution reaction is carried out by heating the amine having the formula VII in a suitable solvent (which may include, for example, acetonitrile or DMF) in the presence of a suitable base (such as sodium carbonate, potassium carbonate or cesium carbonate), typically at a temperature between room temperature and 200° C., preferably between 40° C. and the boiling point of the reaction mixture, optionally under microwave heating conditions.

[0158] The compound of formula XVI (wherein R3, A2, R 4a 、R 5a 、R 5b As defined in Formula I and X 08are OMs, OTs or OTf) can be prepared by activating an alcohol of formula XV (wherein R3, A2, R 4a 、R 5a and R 5b As defined in formula I). ​​Alcohols of formula XV can also be activated to alkyl halides XVI (wherein X is chlorine or bromine) by treatment with a phosphorus compound (e.g., P(X0)3, where X0 is chlorine or bromine) by methods known to those skilled in the art. 08 is Cl or Br). Such general functional group transformations are described, for example, in Organische Chemie. 4. Auflage [Organic Chemistry Edition], Wiley-VCH Verlag, Weinheim 2005, p. 393 et ​​seq. and Chem Commun. 2014, 50, 5756.

[0159] Compounds of formula XV (wherein R3, A2, R 4a 、R 5a and R 5b as defined in formula I) can be prepared by reducing ketone VI (wherein R3, A2, R 4a 、R 5a and R 5b as defined in Formula I).

[0160] Option 6:

[0161]

[0162] Yet another method for preparing compounds of general formula IIa is outlined in Scheme 7.

[0163]

[0164] Option 7:

[0165]

[0166] Thus, nucleophilic substitution reaction of a compound of Formula XVI with an amine of Formula VII provides a compound of Formula II (wherein R1, R3, A2, R 4a 、R 5a , and R 5bAs defined in formula I), as already described in detail in Scheme 6. Compounds of formula II equipped with a protecting group (e.g. R1 is benzyl) can be hydrogenated with hydrogen in the presence of palladium (on carbon) in a solvent such as MeOH or EtOH to give compounds of formula IIa (wherein R3, A2, R 4a 、R 5a , and R 5b As defined in formula I) (see, for example, Synlett [Synthesis Express], 2010, (18), page 2708). A compound of formula II (wherein R1 is allyl, and R3, A2, R 4a 、R 5a , and R 5b As defined in formula I) can also be converted to a compound of formula IIa by reacting with N'N' dimethylbarbituric acid in the presence of a Pd catalyst (preferably tetrakis(triphenylphosphine)-palladium(0)) in a suitable solvent (e.g., CH2Cl2) according to J.Org.Chem. 1993, 58, 6109 to provide a compound of formula IIa.

[0167] Compounds of formula V (wherein A2 and R 4a The formation of (as defined in Formula I) is outlined in Scheme 8.

[0168] Compounds of formula V (wherein A2 and R 4a As defined in formula I) can be prepared by treating a compound of formula IX with a palladium source (such as, for example, Pd(Ph3)4) and bis(tributyltin) in a suitable solvent (such as DMF), typically while heating at a temperature between 100°C and 130°C. Such methods have been described, for example, in Molecular Pharmacology, 90(3), 177-187; 2016. Alternatively, a compound of formula V can also be prepared by treating a compound of formula IX with n-butyllithium and tributyltin chloride in a suitable solvent (such as THF), typically at a lower temperature such as -78°C to 0°C. Such methods have been described, for example, in US20180273562.

[0169] Option 8:

[0170]

[0171] Compounds of formula IXa and IXaa (wherein A2 and R 4a As defined in Formula I and X 06 is a leaving group such as Cl, Br and Q is C1-C3 haloalkyl) are commercially available or can be prepared according to well-known methods as shown in Scheme 9.

[0172] Option 9:

[0173]

[0174] Thus, a compound of formula IXa (wherein A2 and R 4a As defined in Formula I, X 06 is a leaving group such as Cl or Br, and Q is C1-C3 haloalkyl) can be obtained by reacting a compound of formula XVIII (wherein Q is C1-C3 haloalkyl and X is a leaving group such as Cl or Br, and Q is C1-C3 haloalkyl) with a compound of formula XVIII (wherein Q is C1-C3 haloalkyl and X is a leaving group such as Cl or Br, and Q is C1-C3 haloalkyl) in the presence of a suitable base such as cesium carbonate or potassium carbonate in a solvent such as acetonitrile or DMF at a temperature between 20°C and 80°C. 09 is a leaving group such as Cl, Br, F, I, OSO2CF3, or OSO2CH3) to alkylate compound XVII. Such reactions are well known to those skilled in the art and have been reported, for example, in the following literature: see, for example, Med. Chem. Letts. [Medicinal Chemistry Express], 2017, 8(5), pp. 543-548 and Bio. Med. Chem. Letts. [Biological and Pharmaceutical Chemistry Express], 2017, 27(11), 2420-2423.

[0175] Compounds of formula IXaa (wherein A2 and R2 are substituted) can be prepared from compounds of formula XVII by treating with a difluorocarbene source (e.g., ClCF2CO2Na or CF2SO2OCHF2) in the presence of a base (e.g., KOH, potassium carbonate, etc.) in an inert solvent at a temperature between 20°C and 80°C. 4a As defined in Formula I, X 06 is a leaving group, such as Cl or Br). Such procedures are described, for example, in J. Fluor. Chem. 2017, 203, 155; and US 2013 / 0225552, page 128; and Org. Process Res. Dev. 2011, 15, 721.

[0176] Compounds of formula XVII are commercially available.

[0177] A carboxylic acid having formula IIIb (wherein R 2b and A1 are as defined in Formula I) are intermediates useful in preparing the final compounds (see Scheme 1) and can be prepared by the method shown in Scheme 10.

[0178] Option 10:

[0179]

[0180] Thus, a compound of formula IIIb (wherein R 2b and A1 are as defined in formula I) can be prepared by: making a compound of formula XXIII (wherein R 2b and A1 are as defined in formula I and Z1 is C1-C4 alkyl) with a suitable base (such as sodium hydroxide or lithium hydroxide) in a suitable solvent (like MeOH, THF and H2O or a mixture thereof), usually with heating at a temperature between room temperature and reflux. The compound of formula XXIII is prepared by oxidizing a compound of formula XXIIa (wherein R 2b and A1 are as defined in formula I and Z1 is C1-C4-alkyl). Such transformations are known to the person skilled in the art and are described, for example, in J. Med. Chem. 2008, 51, 6902 or WO 2004 / 9086, pp. 24-25.

[0181] Finally, the compound of formula XXIIa (wherein R 2b and A1 is as defined in formula I and Z1 is C1-C4 alkyl) can be prepared by: making a compound of formula XX (wherein R 2b and A1 are as defined in Formula I and X 10 is Br or Cl) with a suitable trifluoromethylthiolate copper reagent of formula XXI (ligand is, for example, 1,10-phenanthroline or 4,4'-di-tert-butylbipyridyl) in a suitable solvent (for example, acetonitrile or DMF) with heating generally at a temperature between 20°C and 150°C, preferably between 40°C and the boiling point of the reaction mixture. Such methods have been previously described, for example, in the following literature: Angew. Chem. Int. Ed. 2013, 52, 1548-1552; Angew. Chem. Int. Ed. 2011, 50, 3793; Org. Lett. 2014, 16, 1744; J. Org. Chem. 2017, 82, 11915.

[0182] Another carboxylic acid having formula IIIb (wherein R 2b and A1 are as defined in Formula I and R 2aAs defined in formula I, but excluding C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl, C1-C4-alkylsulfinyl, C1-C4-haloalkylsulfinyl) are generally known or can be easily prepared by those skilled in the art.

[0183] Compounds of formula IIIc (wherein R 2b and A1 are as defined in Formula I and R 2a A typical example of such a synthesis (as defined in Formula I, but excluding C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl, C1-C4-alkylsulfinyl, C1-C4-haloalkylsulfinyl) is shown in Scheme 11.

[0184] Option 11:

[0185]

[0186] For example, a compound of formula IIIc can be prepared by reacting a compound of formula XXV (wherein R 2a 、R 2b and A1 is as defined in Scheme 11 and Z1 is C1-C4 alkyl) with a suitable base such as sodium hydroxide or lithium hydroxide in a suitable solvent like MeOH, THF and H2O or a mixture thereof, typically with heating at a temperature between room temperature and reflux.

[0187] The compound of formula XXV (wherein R 2a 、R 2b , and A1 and Z1 are as defined in Scheme 11) can be prepared by: making a compound of formula XX (wherein R 2b and A1 is as defined in Scheme 11 and X 11 represents a leaving group (e.g., chloro, bromo, iodo, OMs, OTs, and OTf) and a compound of formula XXIV (wherein R 2a The reaction is carried out in the presence of a palladium catalyst (e.g., Pd(PPh 3 ) 4 ) in a suitable solvent (e.g., toluene / water, 1,4-dioxane / water) in the presence of a suitable base (e.g., sodium carbonate, potassium carbonate, or cesium carbonate or tripotassium phosphate), typically at temperatures between room temperature and 200° C., preferably between 20° C. and the boiling point of the reaction mixture, optionally under microwave heating conditions. Such methods have been previously described, for example, in Tetrahedron Letters 2002, 43, 6987-6990.

[0188] The compound of formula XXV (wherein R 2a 、R 2band A1 and Z1 are as defined in Scheme 11) can also be prepared by reacting a compound of Formula XXVII (wherein R 2b and A1 and Z1 are as defined in Scheme 11) and compounds of Formula XXVIII (wherein R 2a As defined in Scheme 11 and X 11 Is a leaving group, for example, bromine or iodine) in the presence of a palladium catalyst (e.g., PdCl2(dppf)), in a suitable solvent (which may include, for example, toluene / water, 1,4-dioxane / water), in the presence of a suitable base (such as sodium carbonate, potassium carbonate or cesium carbonate or tripotassium phosphate), typically at between room temperature and 200°C, preferably at a temperature between 20°C and the boiling point of the reaction mixture, optionally under microwave heating conditions. Such methods have previously been described, for example, in WO 12139775, page 73.

[0189] The compound of formula XXVII (wherein R 2b and A1 and Z1 are as defined in Scheme 11) can be prepared by: making a compound of formula XX (wherein R 2b and A1 and Z1 are as defined in Scheme 11 and X 11 is Cl, Br, I, OMs, OTs or OTf) with a compound of formula XXVI (e.g., bis(pinacolato)diboron (B2pin2)) in the presence of a palladium catalyst (e.g., PdCl2(dppf)), in a suitable solvent (which may include, for example, toluene / water, 1,4-dioxane / water), in the presence of a suitable base (e.g., sodium carbonate, potassium carbonate, or cesium carbonate or potassium acetate), typically at a temperature between room temperature and 200°C, preferably between 20°C and the boiling point of the reaction mixture, optionally under microwave heating conditions. Such methods have been previously described, for example, in the following literature: Bioorg. Med. Chem. Lett. [Biological Organic and Medicinal Chemistry Express] 2015, 25, 1730 and WO12139775, page 67.

[0190] A carboxylic acid having formula IIId (wherein R 2b and A1 are as defined in Formula I and R 2a is H, C1-C3 alkyl, C1-C3 haloalkyl, cyano or halogen) can be prepared as described in Scheme 12.

[0191] Option 12:

[0192]

[0193] Compounds of formula IIId can be prepared from analogs of compounds of formula XXX by treatment with, for example, aqueous LiOH, NaOH or KOH in a suitable solvent (which may include, for example, THF / MeOH mixtures), typically with heating at temperatures between room temperature and 100°C, preferably between 20°C and the boiling point of the reaction mixture.

[0194] A compound of formula XXX (wherein R 2a 、R 2b and A1 is as defined in Scheme 12 and Z1 is C1-C4 alkyl) can be prepared by reacting a compound of formula XXXI (e.g. (trifluoroethyl)-diphenyl-sulfonium trifluoromethanesulfonate (Ph2S)) with a base (preferably CsF) in the presence of an Fe catalyst and a base at a temperature between 0°C and 50°C, preferably 20°C, in DMA as solvent. + CH2CF3 - Compounds of formula XXIX (analogously to Org. Lett. 2016, 18, 2471) are commercially available or can be prepared by methods known to those skilled in the art (see, for example, Angew. Chem. Int. Ed. 2004, 43, 1132 and Pure Appl. Chem. 1985, 57, 1771) by treatment with 2-(2-(2-fluoro-1-oxo-2-yl)-1-oxo-2-oxo-3-oxo-4-oxo-5-nitropropene) (Tf)). Compounds of formula XXIX are obtained as a mixture of stereoisomers with the trans isomer being the predominant isomer.

[0195] For preparing a compound of formula XXX (wherein R 2a 、R 2b and A1 and Z1 are as defined in Scheme 12) (see Scheme 12) using trifluoroethylamine hydrochloride / NaNO2 / NaOAc in the presence of an Fe catalyst; the reaction is carried out at room temperature in H2O; or in a mixture of CH2Cl2 and H2O, see, for example, Angew.Chem.Int.Ed. [Applied Chemistry International Edition] 2010, 49, 938 and Chemm.Commun. [Chemical Communications] 2018, 54, 5110.

[0196] A carboxylic acid having formula IIIe (wherein R 2a 、R 2b and A1 are as defined in Scheme 12) can be prepared in a very analogous manner to that already shown in Scheme 12 (see Scheme 13).

[0197] Option 13:

[0198]

[0199] Thus, the compound of formula XXXI (wherein R 2a 、R 2b and A1 is as defined in Scheme 13 and Z1 is C1-C4 alkyl) are prepared by reacting a compound of formula XXIX (synthesized similarly to ACS Med. Chem. Lett. 2013, 4, 514 or Tetrahedron Lett. 2001, 42, 4083) with (bromodifluoromethyl)-trimethylsilane in NH4 + Br - The reaction is carried out in the presence of , in a suitable solvent, preferably THF or toluene, at a temperature between 70° C. and 110° C. Subsequent saponification of the ester intermediate XXXI provides compounds of formula IIIe (Scheme 13).

[0200] A carboxylic acid of formula IIIf (wherein R 2b and A1 are as defined in Formula I and R 2a is H, C1-C3 alkyl, C1-C3 haloalkyl, cyano or halogen) can also be prepared as described in Reaction Scheme 14.

[0201] Plan 14.

[0202]

[0203] Therefore, a compound of formula XXa (wherein R 2b and A1 is as defined in formula I, Z1 is C1-C4 alkyl and X 10 represents a leaving group (such as bromine or iodine) treated with iPrMgCl / LiCl-complex; subsequently reacted with CuCN and with cyclopropanecarbonyl chloride of formula XXXII (wherein R 2a (as defined above) provides a compound of formula XXXIII (analogous to WO 2006 / 067445, page 148). Fluorination of compound XXXIII with 2,2-difluoro-1,3-dimethylimidazoline in a solvent (e.g., in 1,2-dimethoxyethane) or in pure form (see Chem. Commun. 2002, (15), 1618) gives a compound of formula XXXIV. Subsequent hydrolysis using, for example, LiOH as already described gives a carboxylic acid of formula IIIf.

[0204] A carboxylic acid having formula IIIg (wherein R 2b and A1 are as defined in Formula I) can be prepared according to Reaction Scheme 15.

[0205] Option 15:

[0206]

[0207] A compound of formula XX (wherein R is 2-(di-benzylideneacetone)dipalladium(0)) is treated with trimethylsilyl-acetonitrile (TMCN) in the presence of zinc(II) fluoride (ZnF2) and a palladium(0) catalyst such as tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (Pd2(dba)3CHCl3) with a ligand such as Xantphos in an inert solvent such as N,N-dimethylformamide (DMF) at a temperature between 100°C and 180°C, optionally under microwave heating. 2b and A1 are as defined in Formula I, and X 11 is a leaving group such as a halogen or sulfonate, preferably chloro, bromo, iodo or trifluoromethanesulfonate, and Z1 is C1-C4 alkyl) to produce a compound of formula XXXV (wherein R 2b , Z1 and A1 are as defined in Scheme 15). Such chemical processes have been described in the literature, for example in Org. Lett. [Organic Letters] 16(24), 6314-6317, 2014.

[0208] Alternatively, the compound of formula XX is reacted with 4-isoxazoleboronic acid or 4-isoxazoleboronic acid pinacol ester in the presence of potassium fluoride (KF) and a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) in an inert solvent such as dimethyl sulfoxide (DMSO), optionally in a mixture with water, at a temperature between 40°C and 150°C, optionally under microwave heating to produce a compound of formula XXXVII (wherein R 2b , Z1 and A1 are as defined in Scheme 15). Compounds of formula XXXVII are reacted with aqueous potassium fluoride (KF concentration between 0.5 and 3 M, preferably 1 M) in an inert solvent such as dimethyl sulfoxide (DMSO) or methanol at a temperature between 20°C and 150°C, optionally under microwave heating, to produce compounds of formula XXXV (wherein R 2b , Z1 and A1 are as defined in Scheme 15). Such chemical processes have been described in the literature, for example in J. Am. Chem. Soc. [Journal of the American Chemical Society] 2011, 133, 6948-6951.

[0209] The compound of formula XXXV (wherein R 2b , Z1 and A1 are as defined in Scheme 15) can be further treated with a compound of formula XL (wherein X is a molecule of formula XL) in the presence of a base (such as sodium hydride, sodium carbonate, potassium carbonate K2CO3, or cesium carbonate Cs2CO3) in an inert solvent (such as N,N-dimethylformamide (DMF), acetone, or acetonitrile) at a temperature between 0°C and 120°C. 13is a leaving group, such as halogen (preferably chlorine, bromine or iodine), to give a compound of formula XXXVI (wherein R 2b and A1 is as defined in formula I and Z1 is C1-C4 alkyl).

[0210] Alternatively, compounds of formula XXXVI can be prepared directly from compounds of formula XX by treating them with compounds of formula XXXIII in the presence of a catalyst such as Pd2(dba)3 with a ligand (BINAP), a strong base such as lithium hexamethyldisilazane (LiHMDS), in an inert solvent such as tetrahydrofuran (THF) at temperatures between 30°C and 80°C. Such chemistry has been described, for example, in J. Am. Chem. Soc. [Journal of the American Chemical Society] 127(45), 15824-15832, 2005.

[0211] Yet another method for preparing a compound of formula XXXV from a compound of formula Xb is shown in Scheme 15. 2b , Z1 and A1 are as defined in Scheme 15, and wherein X 11 is a leaving group such as a halogen or sulfonate, preferably chloro, bromo, iodo or trifluoromethanesulfonate) with a reagent of formula XXXVIII wherein Z is C1-C4 alkyl in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate, or sodium hydride, sodium methoxide or sodium ethoxide, potassium tert-butoxide, optionally catalyzed by palladium (e.g. including Pd(PPh3)2Cl2) or copper (e.g. including CuI), in a suitable solvent such as, for example, toluene, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), optionally in the presence of a phase transfer catalyst PTC such as, for example, tetrabutylammonium bromide or triethylbenzylammonium chloride TEBAC, at a temperature between room temperature and 180°C to give a compound of formula XXXIX wherein R 2b and A1 are as defined in Formula 1, and Z1 and Z2 are each C1-C4 alkyl). Compounds of Formula XXXIX can be decarboxylated to give compounds of Formula XXXV using conditions such as the following: heating in wet DMSO, optionally in the presence of lithium chloride or sodium chloride, at temperatures between 50° C. and 180° C. Similar chemistry has been described, for example, in Synthesis 2010, 19, 3332-3338.

[0212] The compound of formula IIIg (wherein R is finally obtained from the compound of formula XXXVI) by treatment with, for example, aqueous LiOH, NaOH or KOH in a suitable solvent (which may include, for example, a THF / MeOH mixture), typically upon heating at a temperature between room temperature and 100° C., preferably between 20° C. and the boiling point of the reaction mixture. 2b and A1 are as defined in Formula I).

[0213] Compounds having formula I'a

[0214]

[0215] can be prepared by reacting an amine of formula IIb with a carboxylic acid derivative of formula III

[0216] Among them, R1, R3, A2, R 4a 、R 5a and R 5b is described in formula I'a, wherein A1, R 2a and R 2b As described above under Formula I.

[0217]

[0218] The chemistry is described in more detail in Scheme 16.

[0219] Option 16:

[0220]

[0221] Compounds of Formula IIb (wherein R1, R3, A2, R 4a 、R 5a , and R 5b As described in Formula I), a compound having Formula IIIa (wherein A1, R 2a 、R 2b and X0 are as described in Scheme 1), to give a compound of Formula I'a. The formation of a compound of Formula IIIa from a compound of Formula III is described in Scheme 1.

[0222] The formation of compounds of formula IIb is outlined in Scheme 17. Compounds of formula IIb can be prepared by treating a compound of formula IIc (wherein A2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R29, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, 4a 、R 5a , and R 5b is described in Formula I). ​​Alternatively, another reagent system for reductive amination uses a combination of Ti(i-OiPr)4 and NaBH4 (see Synthesis 2003(14), 2206).

[0223] Amines of formula IIc can be obtained by biocatalytic deracemization of amines of formula IIa. This can be achieved, for example, using a final immobilized form (e.g. 435), for example, Candida Antarctica lipase B or Pseudomonas fluorescens lipase, in the presence of an acyl donor, for example, ethyl methoxyacetate or vinyl acetate, in a suitable solvent, such as acetonitrile or methyl tert-butyl ether, at a temperature between 20° C. and 100° C. Such methods are described, for example, in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical outcome of such enzymatic deracemization is known to the person skilled in the art and is documented in the literature, for example in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

[0224] Option 17:

[0225]

[0226] In an alternative approach, compounds of formula IIc can be synthesized as described in Scheme 18 from XVa (wherein A2, R3, R 4a 、R 5a , and R 5b is described in Formula I).

[0227] Plan 18:

[0228]

[0229] Amines of formula IIc can be prepared from intermediates of formula XLII (wherein A2, R3, R 4a 、R 5a and R 5b is as described in formula I and Z3 is NPhth or NBoc2). Such intermediates can be obtained from alcohols of formula XVa by the Mitsunobu reaction, which involves treating the alcohol of formula XVa with diisopropyl azodicarboxylate in the presence of a phosphine (such as triphenylphosphine or tributylphosphine) and an amine (such as phthalimide or bis(tert-butyloxycarbonyl)amine). The Mitsunobu reaction is known to those skilled in the art for inverting stereocenters, as described, for example, in Chem. Rev. 2009, 109, 2551-2651. Amines of formula XLII can then be converted to amines of formula IIc by treatment with hydrazine (when Z3 = NPhth) or with TFA (when Z3 = NBoc2).

[0230] Alternatively, the amine of formula IIc can be treated with triphenylphosphine and water (Staudinger reaction) or by hydrogenation using a palladium catalyst in the presence of hydrogen to reduce the azide of formula XLIII (wherein A2, R3, R 4a 、R 5a , and R 5b The azide of formula XLIII can be obtained by treating an alcohol of formula XVa (wherein A2, R3, R 4a 、R 5a , and R 5b is described in formula I). ​​Such methods are known to those skilled in the art for inversion of stereocenters and are described in the literature, for example, in Adv. Synth. Catal. [Advanced Synthesis and Catalysis] 2018, 360, 2157-2165.

[0231] The alcohol of formula XVa can be prepared by reacting a ketone of formula VI (wherein A2, R3, R 4a 、R 5a , and R 5b(as described in Formula I) by enantioselective reduction. Such reduction can be carried out in the presence of a hydrogen donor system (such as, for example, HCOOH / Et3N or HCO2NH4) using a catalyst (e.g., a ruthenium or rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN] (mesitylene) or RuBF4[(R,R)-TsDPEN] (p-cymene)). Such methods are described in the literature, for example, in J.Org.Chem. 2017, 82, 5607.

[0232] Alternatively, compounds of formula IIc can also be prepared as outlined in Scheme 19.

[0233] Scheme 19:

[0234]

[0235] Amines of formula IIc can be prepared by treating an amine of formula LII (wherein A2, R3, R 4a 、R 5a , and R 5b The compound of formula LII can be prepared by deprotecting the compound of formula LI (wherein A2, R3 and R 4a is as described in Formula I and Z 5a and Z 5b are independently selected from R 5a 、R 5b , halogen, NH2 or OH). Such functional group interconversions are known to those skilled in the art and examples of such transformations are described in the literature, for example in Eur.J.Org.Chem. 2005, 19, 4141-4153 or J.Org.Chem. 2008, 73, 7481-7485. Compounds of formula LI can be obtained from compounds of formula L by, for example, alkylation using a base and an electrophilic reagent (e.g., chlorodifluoroacetic acid). Compounds of formula L can be obtained by hydroxylating compounds of formula XLIX (wherein A2 and R3 are as described in formula I, Z 4a Selected from R 4a , halogen or NH2, and Z 5a and Z 5b are independently selected from R 5a 、R 5b, halogen, NH2 or OH). The conversion of XLIX to L can be carried out according to the methods mentioned in the literature, such as Org. Lett. [Organic Letters] 2016, 18, 2244-2247 or Tetrahedron [Tetrahedron] 2009, 65, 757-764. The amine of formula XLIX can be obtained by reacting a diketone of formula XLVII (wherein A2 and R3 are as described in formula I, and Z 4a Selected from R 4a , halogen or NH2) is condensed with a diamine of formula XLVIII (wherein Z 5a and Z 5b are independently selected from R 5a 、R 5b , halogen, NH2 or OH). This condensation can occur in the presence of a suitable solvent (such as ethanol or isopropanol) in the presence of an oxidizing agent (such as air or DDQ). The diketone of formula XLVII can be obtained by oxidizing the hydroxyketone of formula XLVI (wherein A2 and R3 are as described in formula I, and Z 4a Selected from R 4a , halogen or NH2). This oxidation may involve, for example, SO3-pyridine in the presence of DMSO and a base (e.g., triethylamine), or sodium hypochlorite in the presence of a catalyst (e.g., TEMPO / Bu4NHSO4). Examples of such oxidations are found in the literature, e.g., Synlett [Synthesis Express], 2014, 25, 596 or J.Am.Chem.Soc. [Journal of the American Chemical Society] 1990, 112, 5290-5313. Hydroxyketones of formula XLVI may be prepared by reacting an aldehyde of formula XLIV (wherein A2 is a compound described in formula I and Z 4a Selected from R 4a The cross-benzoin condensation is carried out by reacting a base (e.g., potassium tert-butoxide or isopropyldiethylamine) with an aldehyde of formula XLV (e.g., DCM or THF) at a temperature between -20°C and the boiling point of the solvent and using an organic catalyst (e.g., a triazolium salt or a thiazolium salt). Examples of catalysts for such transformations have been described in the literature, for example in J. Am. Chem. Soc. [Journal of the American Chemical Society] 2014, 136, 7539-7542 or Org. Lett. [Organic Letters] 2016, 18, 4518-4521.

[0236] Compounds of formula LI can also be obtained directly from compounds of formula XLIX, for example, using transition metal catalysis or diazo chemistry. Such functional group interconversions are known to those skilled in the art and examples can be found in the literature, for example, in J. Am. Chem. Soc. [Journal of the American Chemical Society] 2019, 141, 19257-19262; Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2015, 54, 5736-5739 or Heterocycles [Heterocycles], 2004, 63, 2735-2746.

[0237] Compounds of formula LII can be prepared from compounds of formula LIV (wherein A2, R3, R 5a and R 5b The compound of formula LIV can be synthesized from the compound of formula XLIX by hydroxylation according to the method mentioned in the literature, for example, Org. Lett. [Organic Letters] 2016, 18, 2244-2247 or Tetrahedron [Tetrahedron] 2009, 65, 757-764. Alternatively, the compound of formula LII can be synthesized from the compound of formula LIII (wherein A2, R3, R 5a and R 5b is described in Formula I, and Z 4a Selected from R 4a , halogen or NH 2). Such functional group interconversions are known to those skilled in the art and examples can be found in the literature, for example, in J. Am. Chem. Soc. [Journal of the American Chemical Society] 2019, 141, 19257-19262; Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2015, 54, 5736-5739 or Heterocycles [Heterocycles], 2004, 63, 2735-2746.

[0238] Option 20:

[0239]

[0240] As shown in Scheme 20, compounds of formula I'a can alternatively be prepared by reacting a compound of formula LVI (wherein A1, R1, R 2a 、R 2b , R3, R 5a , and R 5b is defined in Formula I, and X 07is a leaving group like, for example, chloro, bromo, iodo) with a compound of formula V (Stiller reaction) or a compound of formula VIII (Suzuki-Miyaura reaction) in the presence of a palladium catalyst as detailed in Schemes 2 and 3.

[0241] Compounds of formula LVI can be prepared by reacting an amine of formula LVa (wherein R1, R3, R 5a , and R 5b is defined in Formula I, and X 07 is a leaving group, such as, for example, chloro, bromo, iodo) and a compound of formula IIIa (wherein A1, R 2a 、R 2b and X0 are as described in Scheme 1) are coupled under the conditions detailed in Scheme 1. Under the same conditions, if R1 = H, compounds of formula LVI can be obtained directly from compounds of formula LV.

[0242] Compounds of formula LVa can be prepared by treating a compound of formula LV with a compound of formula XLI (wherein R is as defined in formula I), for example, in the presence of NaBH(OAc) or NaBHCN in a suitable solvent, preferably acetic acid, at room temperature, analogously to WO 2002 / 088073, page 35. Alternatively, another reagent system for reductive amination uses a combination of Ti(i-OiPr) and NaBH (see Synthesis 2003 (14), 2206).

[0243] Amines of formula LV can be prepared by deracemization procedures involving, for example, the selective acylation of one enantiomer. Such an example is described in more detail in Scheme 21.

[0244] Option 21:

[0245]

[0246] Amines of formula LV can be biocatalytically deracemized to amines of formula LVb (wherein R3, R 5a , and R 5b is as described in Scheme 1 and X 07 is a leaving group such as bromine, chloride or iodine). This can be achieved, for example, using a final immobilized form (e.g. 435), such as Candida antarctica lipase B or Pseudomonas fluorescens lipase, in the presence of an acyl donor (e.g. ethyl methoxyacetate or vinyl acetate), in a suitable solvent (e.g. acetonitrile or methyl tert-butyl ether) at a temperature between 20° C. and 100° C. Such methods are described, for example, in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical consequences of such enzymatic deracemization are known to those skilled in the art and are documented in the literature, for example, in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

[0247] Alternatively, resolution of amines of formula LVb can be achieved using a chiral auxiliary as described in Scheme 22.

[0248] Plan 22

[0249]

[0250] Amines of formula LV can be prepared from intermediates of formula LVIII (wherein R3, R 5a , and R 5b is as described in Scheme 1, X 07 is a leaving group such as bromine, chloride or iodine and X 12 * is a chiral auxiliary). Amines of formula LVIII can be formed by reacting a chiral compound of formula LVII (wherein X0 is as described in Scheme 1 and X 12 * is a chiral moiety with known chirality) is coupled with an amine of formula LVb. The chiral auxiliary of formula LVII is derived, for example, from mandelic acid or (1R)-methylchloroformate. Examples of such deracemization methods are reported in the literature, for example, in J. Org. Chem. 2007, 72, 485-493.

[0251] Alternatively, an amine of formula LVc (wherein R3, R 5a , and R 5b is defined in Formula I, and X 05 is a leaving group, such as, for example, chloro, bromo, iodo) can be formed as described in Scheme 23.

[0252] Option 23:

[0253]

[0254] Amines of formula LVc can be prepared from intermediates of formula LIX (wherein R3, R 5a , and R 5b is described in Formula I, X 05 is a leaving group as described in Scheme 3 and Z3 is NPhth or NBoc2). Intermediates of formula LIX can be obtained from alcohols of formula LX (wherein R3, R 5a , and R 5b As described in Formula I and X 05 (where Z3 is a leaving group as described in Scheme 3) is obtained by the Mitsunobu reaction. This Mitsunobu reaction involves treating an alcohol of formula LX with diisopropyl azodicarboxylate in the presence of a phosphine (such as triphenylphosphine or tributylphosphine) and an amine (such as phthalimide or bis(tert-butyloxycarbonyl)amine). The Mitsunobu reaction is known to those skilled in the art for inverting stereocenters, as described, for example, in Chem. Rev. 2009, 109, 2551-2651. Amines of formula LIX can then be converted to amines of formula LVc by treatment with hydrazine (when Z3 = NPhth) or with TFA (when Z3 = NBoc2).

[0255] Alternatively, amines of formula LVc can be reacted by reducing azides of formula LXI (wherein R3, R 5a , and R 5b As described in Formula I and X 05 is a leaving group as described in Scheme 3). Azides of formula LXI can be obtained by treating an alcohol of formula LX with an azidating agent (such as diphenylphosphoryl azide) in a solvent (such as toluene or THF) in the presence of a base (such as DBU). Such methods are known to those skilled in the art for inversion of stereocenters and are described in the literature, for example, in Adv. Synth. Catal. [Advanced Synthesis and Catalysis] 2018, 360, 2157-2165.

[0256] Alcohols of formula LX can be prepared by reacting ketones of formula IV (wherein R3, R 5a , and R 5b As described in Formula I and X 05(a leaving group as described in Scheme 3) can be obtained by enantioselective reduction. Such reduction can be carried out in the presence of a hydrogen donor system (such as, for example, HCOOH / Et3N or HCO2NH4) using a catalyst (e.g., a ruthenium or rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN] (mesitylene) or RuBF4[(R,R)-TsDPEN] (p-cymene)). Such methods are described in the literature, for example, in J.Org.Chem. 2017, 82, 5607.

[0257] Depending on the procedure or reaction conditions, the reactants can be reacted in the presence of a base. Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxide and carbocyclic amines. Examples that may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0258] The reactants can react with each other as is, i.e. without adding a solvent or diluent. However, in most cases, it is advantageous to add an inert solvent or diluent or a mixture thereof. If the reaction is carried out in the presence of a base, an excess of the base (such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline) can also serve as a solvent or diluent.

[0259] The reaction is advantageously carried out in a temperature range of from about -80°C to about +140°C, preferably from about -30°C to about +100°C, in many cases in a range between ambient temperature and about +80°C.

[0260] Depending on the reaction conditions and starting materials chosen as appropriate in the respective case, it is possible, for example, to replace only one substituent by another substituent according to the invention in one reaction step or to replace several substituents by other substituents according to the invention in one and the same reaction step.

[0261] Salts of compounds of formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula I are obtained by treatment with a suitable acid or a suitable ion exchanger reagent, and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchanger reagent.

[0262] Salts of compounds of the formula I can be converted in a customary manner into the free compounds I, acid addition salts (for example by treatment with suitable basic compounds or with suitable ion exchange reagents) and salts with bases (for example by treatment with suitable acids or with suitable ion exchange reagents).

[0263] Salts of compounds of the formula I can be converted in a manner known per se into other salts, acid addition salts of compounds of the formula I, for example into other acid addition salts, for example by treating salts of inorganic acids (such as hydrochlorides) with suitable metal salts of the acid (such as sodium, barium or silver salts, for example with silver acetate) in a suitable solvent in which the inorganic salt formed (such as silver chloride) is insoluble and therefore precipitates from the reaction mixture.

[0264] Depending on the procedure or reaction conditions, compounds of formula I with salt-forming properties can be obtained in free form or in the form of salts.

[0265] Depending on the number of asymmetric carbon atoms present in the molecule, the absolute and relative configuration and / or depending on the configuration of non-aromatic double bonds present in the molecule, the compounds of the formula I and, where appropriate, their tautomers (in each case in free form or in salt form) may be present in the form of one of the possible isomers or as a mixture of these, for example in the form of pure isomers, such as enantiomers and / or diastereomers, or as isomer mixtures, such as enantiomeric mixtures, for example racemates, diastereomeric mixtures or racemic mixtures; the present invention relates to the pure isomers and also to all possible isomer mixtures, and this is to be understood in each case above and below, even when stereochemical details are not explicitly mentioned in each case.

[0266] Diastereomeric mixtures or racemic mixtures of compounds of formula I in free form or in salt form, which can be obtained according to the starting materials and procedures chosen, can be separated in a known manner into the pure diastereomers or racemates on the basis of the physicochemical differences of the components, for example, by fractional crystallization, distillation and / or chromatography.

[0267] Enantiomeric mixtures obtainable in an analogous manner (e.g. racemates) can be resolved into the optical enantiomers by known methods, for example by recrystallization from optically active solvents; by chromatography on chiral adsorbents, for example high performance liquid chromatography (HPLC) on acetylcellulose; by cleavage with specific immobilized enzymes with the aid of suitable microorganisms; via the formation of containing compounds, for example using chiral crown ethers, in which only one enantiomer is complexed; or by conversion into diastereomeric salts, for example by reacting the basic end product racemate with an optically active acid (e.g. a carboxylic acid, for example camphoric acid, tartaric acid or malic acid, or a sulfonic acid, for example camphorsulfonic acid) and separating the diastereomeric mixtures obtainable in this way, for example on the basis of their different solubilities, by fractional crystallization to give the diastereoisomers, from which the desired enantiomer can be freed by the action of suitable reagents, for example basic reagents.

[0268] Pure diastereomers or enantiomers can be obtained according to the invention not only by separation of the appropriate isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials having the appropriate stereochemistry.

[0269] N-oxides can be prepared by reacting a compound of formula I with a suitable oxidizing agent (e.g. H O / urea adduct) in the presence of an anhydride (e.g. trifluoroacetic anhydride). Such oxidations are known from the literature, for example from J. Med. Chem., 32 (12), 2561-73, 1989 or WO 2000 / 15615.

[0270] If the individual components have different biological activities, it is advantageous to isolate or synthesize the biologically more effective isomers, such as enantiomers or diastereomers or isomer mixtures, such as enantiomeric mixtures or diastereomeric mixtures, in each case.

[0271] If appropriate, the compounds of formula I and, where appropriate, their tautomers (in each case in free form or in salt form) can also be obtained in the form of hydrates and / or include other solvents, such as those which can be used for crystallization of compounds present in solid form.

[0272] The compounds of formula I according to the following tables A-1 to A-27 can be prepared according to the methods described above. The following examples are intended to illustrate the present invention and show preferred compounds of formula I in the form of compounds of formula Iaa.

[0273]

[0274] Table A-1 provides 16 compounds A-1.001 to A-1.016 of formula Iaa, wherein R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0275] For example, A-1.002 is

[0276]

[0277] Table Z: Definition of substituents for R2:

[0278]

[0279]

[0280]

[0281] Table A-2 Provided are 16 compounds A-2.001 to A-2.016 of formula Iaa wherein R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0282] Table A-3 Provided are 16 compounds A-3.001 to A-3.016 of formula Iaa wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0283] Table A-4 Provided are 16 compounds A-4.001 to A-4.016 of formula Iaa wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0284] Table A-5 Provided are 16 compounds A-5.001 to A-5.016 of formula Iaa, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0285] Table A-6 Provided are 16 compounds A-6.001 to A-6.016 of formula Iaa, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0286] Table A-7 Provided are 16 compounds A-7.001 to A-7.016 of formula Iaa, wherein R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0287] Table A-8 Provided are 16 compounds A-8.001 to A-8.016 of formula Iaa, wherein R1 is H, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0288] Table A-9 Provided are 16 compounds A-9.001 to A-9.016 of formula Iaa, wherein R1 is H, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0289] Table A-10 Provided are 16 compounds A-10.001 to A-10.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0290] Table A-11 Provided are 16 compounds A-11.001 to A-11.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0291] Table A-12 Provided are 16 compounds A-12.001 to A-12.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0292] Table A-13 Provided are 16 compounds A-13.001 to A-13.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0293] Table A-14 Provided are 16 compounds A-14.001 to A-14.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0294] Table A-15 Provided are 16 compounds A-15.001 to A-15.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0295] Table A-16Provided are 16 compounds A-16.001 to A-16.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0296] Table A-17 Provided are 16 compounds A-17.001 to A-17.016 of formula Iaa, wherein R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0297] Table A-18 Provided are 16 compounds A-18.001 to A-18.016 of formula Iaa, wherein R1 is CH3, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0298] Table A-19 Provided are 16 compounds A-19.001 to A-19.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0299] Table A-20 Provided are 16 compounds A-20.001 to A-20.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0300] Table A-21 Provided are 16 compounds A-21.001 to A-21.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0301] Table A-22 Provided are 16 compounds A-22.001 to A-22.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0302] Table A-23 Provided are 16 compounds A-23.001 to A-23.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0303] Table A-24Provided are 16 compounds A-24.001 to A-24.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0304] Table A-25 Provided are 16 compounds A-25.001 to A-25.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0305] Table A-26 Provided are 16 compounds A-26.001 to A-26.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0306] Table A-27 Provided are 16 compounds A-27.001 to A-27.016 of formula Iaa, wherein R1 is cyclopropyl-CH2-, R4 is (5-cyano-2-pyridinyl), and R2 is as defined in Table Z.

[0307] The compounds of formula I according to the following tables B-1 to B-27 can be prepared according to the methods described above. The following examples are intended to illustrate the present invention and show preferred compounds of formula I in the form of compounds of formula Iab.

[0308]

[0309] Table B-1 Provided are 16 compounds B-1.001 to B-1.016 of Formula Iab wherein R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0310] Table B-2 Provided are 16 compounds B-2.001 to B-2.016 of Formula Iab wherein R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0311] Table B-3 Provided are 16 compounds B-3.001 to B-3.016 of Formula Iab wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0312] Table B-4Provided are 16 compounds B-4.001 to B-4.016 of Formula Iab wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0313] Table B-5 Provided are 16 compounds B-5.001 to B-5.016 of Formula Iab wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0314] Table B-6 Provided are 16 compounds B-6.001 to B-6.016 of Formula Iab wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0315] Table B-7 Provided are 16 compounds B-7.001 to B-7.016 of Formula Iab wherein R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0316] Table B-8 Provided are 16 compounds B-8.001 to B-8.016 of Formula Iab wherein R1 is H, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0317] Table B-9 Provided are 16 compounds B-9.001 to B-9.016 of Formula Iab wherein R1 is H, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0318] Table B-10 Provided are 16 compounds B-10.001 to B-10.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0319] Table B-11 Provided are 16 compounds B-11.001 to B-11.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0320] Table B-12 Provided are 16 compounds B-12.001 to B-12.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0321] Table B-13 Provided are 16 compounds B-13.001 to B-13.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0322] Table B-14 Provided are 16 compounds B-14.001 to B-14.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0323] Table B-15 Provided are 16 compounds B-15.001 to B-15.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0324] Table B-16 Provided are 16 compounds B-16.001 to B-16.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0325] Table B-17 Provided are 16 compounds B-17.001 to B-17.016 of Formula Iab, wherein R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0326] Table B-18 Provided are 16 compounds B-18.001 to B-18.016 of Formula Iab, wherein R1 is CH3, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0327] Table B-19 Provided are 16 compounds B-19.001 to B-19.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0328] Table B-20 Provided are 16 compounds B-20.001 to B-20.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0329] Table B-21Provided are 16 compounds B-21.001 to B-21.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0330] Table B-22 Provided are 16 compounds B-22.001 to B-22.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0331] Table B-23 Provided are 16 compounds B-23.001 to B-23.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0332] Table B-24 Provided are 16 compounds B-24.001 to B-24.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0333] Table B-25 Provided are 16 compounds B-25.001 to B-25.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0334] Table B-26 Provided are 16 compounds B-26.001 to B-26.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0335] Table B-27 Provided are 16 compounds B-27.001 to B-27.016 of Formula Iab, wherein R1 is cyclopropyl-CH2-, R4 is (5-cyano-2-pyridinyl), and R2 is as defined in Table Z.

[0336] The compounds of formula I according to the following tables C-1 to C-27 can be prepared according to the methods described above. The following examples are intended to illustrate the present invention and show preferred compounds of formula I in the form of compounds of formula lac.

[0337]

[0338] Table C-1Provided are 16 compounds C-1.001 to C-1.016 of formula lac, wherein R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0339] Table C-2 Provided are 16 compounds C-2.001 to C-2.016 of formula lac, wherein R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0340] Table C-3 Provided are 16 compounds C-3.001 to C-3.016 of formula lac, wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0341] Table C-4 Provided are 16 compounds C-4.001 to C-4.016 of formula lac, wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0342] Table C-5 Provided are 16 compounds C-5.001 to C-5.016 of formula lac, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0343] Table C-6 Provided are 16 compounds C-6.001 to C-6.016 of formula lac, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0344] Table C-7 Provided are 16 compounds C-7.001 to C-7.016 of formula lac, wherein R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0345] Table C-8 Provided are 16 compounds C-8.001 to C-8.016 of formula lac, wherein R1 is H, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0346] Table C-9 Provided are 16 compounds C-9.001 to C-9.016 of formula lac, wherein R1 is H, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0347] Table C-10 Provided are 16 compounds C-10.001 to C-10.016 of formula lac, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0348] Table C-11 Provided are 16 compounds C-11.001 to C-11.016 of formula lac, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0349] Table C-12 Provided are 16 compounds C-12.001 to C-12.016 of formula lac, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0350] Table C-13 Provided are 16 compounds C-13.001 to C-13.016 of formula lac, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0351] Table C-14 Provided are 16 compounds C-14.001 to C-14.016 of formula lac, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0352] Table C-15 Provided are 16 compounds C-15.001 to C-15.016 of formula lac, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0353] Table C-16 Provided are 16 compounds C-16.001 to C-16.016 of Formula Iac, wherein R1 is CH3, R4 is [5-(difluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0354] Table C-17 Provided are 16 compounds C-17.001 to C-17.016 of formula lac, wherein R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0355] Table C-18Provided are 16 compounds C-18.001 to C-18.016 of formula lac, wherein R1 is CH3, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0356] Table C-19 Provided are 16 compounds C-19.001 to C-19.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0357] Table C-20 Provided are 16 compounds C-20.001 to C-20.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0358] Table C-21 Provided are 16 compounds C-21.001 to C-21.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0359] Table C-22 Provided are 16 compounds C-22.001 to C-22.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0360] Table C-23 Provided are 16 compounds C-23.001 to C-23.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0361] Table C-24 Provided are 16 compounds C-24.001 to C-24.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0362] Table C-25 Provided are 16 compounds C-25.001 to C-25.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0363] Table C-26Provided are 16 compounds C-26.001 to C-26.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0364] Table C-27 Provided are 16 compounds C-27.001 to C-27.016 of formula lac, wherein R1 is cyclopropyl-CH2-, R4 is (5-cyano-2-pyridinyl), and R2 is as defined in Table Z.

[0365] The compounds of formula I according to the following tables D-1 to D-27 can be prepared according to the methods described above. The following examples are intended to illustrate the present invention and show preferred compounds of formula I in the form of compounds of formula Iad.

[0366]

[0367] Table D-1 Sixteen compounds D-1.001 to D-1.016 of formula Iad are provided, wherein R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0368] Table D-2 Sixteen compounds D-2.001 to D-2.016 of formula Iad are provided wherein R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0369] Table D-3 Sixteen compounds D-3.001 to D-3.016 of formula Iad are provided wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0370] Table D-4 Sixteen compounds D-4.001 to D-4.016 of formula Iad are provided wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0371] Table D-5 Sixteen compounds D-5.001 to D-5.016 of formula Iad are provided, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0372] Table D-6Sixteen compounds D-6.001 to D-6.016 of formula Iad are provided wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0373] Table D-7 Sixteen compounds D-7.001 to D-7.016 of formula Iad are provided wherein R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0374] Table D-8 Sixteen compounds D-8.001 to D-8.016 of formula Iad are provided wherein R1 is H, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0375] Table D-9 Sixteen compounds D-9.001 to D-9.016 of formula Iad are provided, wherein R1 is H, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0376] Table D-10 Sixteen compounds D-10.001 to D-10.016 of formula Iad are provided, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0377] Table D-11 Sixteen compounds D-11.001 to D-11.016 of formula Iad are provided, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0378] Table D-12 Provided are 16 compounds D-12.001 to D-12.016 of formula Iad, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0379] Table D-13 Provided are 16 compounds D-13.001 to D-13.016 of formula Iad, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0380] Table D-14 Provided are 16 compounds D-14.001 to D-14.016 of formula Iad, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0381] Table D-15 Provided are 16 compounds D-15.001 to D-15.016 of formula Iad, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0382] Table D-16 Sixteen compounds D-16.001 to D-16.016 of formula Iad are provided, wherein R1 is CH3, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0383] Table D-17 Sixteen compounds D-17.001 to D-17.016 of formula Iad are provided, wherein R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0384] Table D-18 Sixteen compounds D-18.001 to D-18.016 of formula Iad are provided, wherein R1 is CH3, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0385] Table D-19 Provided are 16 compounds D-19.001 to D-19.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0386] Table D-20 Provided are 16 compounds D-20.001 to D-20.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0387] Table D-21 Provided are 16 compounds D-21.001 to D-21.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0388] Table D-22 Provided are 16 compounds D-22.001 to D-22.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0389] Table D-23Provided are 16 compounds D-23.001 to D-23.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0390] Table D-24 Provided are 16 compounds D-24.001 to D-24.016 of formula Iad, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0391] Table D-25 Sixteen compounds D-25.001 to D-25.016 of formula Iad are provided, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0392] Table D-26 Sixteen compounds D-26.001 to D-26.016 of formula Iad are provided, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0393] Table D-27 Sixteen compounds D-27.001 to D-27.016 of formula Iad are provided, wherein R1 is cyclopropyl-CH2-, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0394] The compounds of formula I according to the following tables D-1 to D-27 can be prepared according to the methods described above. The following examples are intended to illustrate the present invention and show preferred compounds of formula I in the form of compounds of formula Iae.

[0395]

[0396] Table E-1 Provided are 16 compounds E-1.001 to E-1.016 of formula lae, wherein R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0397] Table E-2 Provided are 16 compounds E-2.001 to E-2.016 of formula lae wherein R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0398] Table E-3Provided are 16 compounds E-3.001 to E-3.016 of formula lae, wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0399] Table E-4 Provided are 16 compounds E-4.001 to E-4.016 of formula lae, wherein R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0400] Table E-5 Provided are 16 compounds E-5.001 to E-5.016 of formula lae, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0401] Table E-6 Provided are 16 compounds E-6.001 to E-6.016 of formula lae, wherein R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0402] Table E-7 Provided are 16 compounds E-7.001 to E-7.016 of formula lae, wherein R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0403] Table E-8 Provided are 16 compounds E-8.001 to E-8.016 of formula lae, wherein R1 is H, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0404] Table E-9 Provided are 16 compounds E-9.001 to E-9.016 of formula lae, wherein R1 is H, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0405] Table E-10 Provided are 16 compounds E-10.001 to E-10.016 of formula lae, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0406] Table E-11 Provided are 16 compounds E-11.001 to E-11.016 of formula lae, wherein R1 is CH3, R4 is [5-(trifluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0407] Table E-12 Provided are 16 compounds E-12.001 to E-12.016 of formula lae, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0408] Table E-13 Provided are 16 compounds E-13.001 to E-13.016 of formula lae, wherein R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0409] Table E-14 Provided are 16 compounds E-14.001 to E-14.016 of formula lae, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0410] Table E-15 Provided are 16 compounds E-15.001 to E-15.016 of formula lae, wherein R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0411] Table E-16 Provided are 16 compounds E-16.001 to E-16.016 of formula lae, wherein R1 is CH3, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in Table Z.

[0412] Table E-17 Provided are 16 compounds E-17.001 to E-17.016 of formula lae, wherein R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridinyl] and R2 is as defined in Table Z.

[0413] Table E-18 Provided are 16 compounds E-18.001 to E-18.016 of formula lae, wherein R1 is CH3, R4 is (5-cyano-2-pyridinyl) and R2 is as defined in Table Z.

[0414] Table E-19 Provided are 16 compounds E-19.001 to E-19.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0415] Table E-20Provided are 16 compounds E-20.001 to E-20.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0416] Table E-21 Provided are 16 compounds E-21.001 to E-21.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0417] Table E-22 Provided are 16 compounds E-22.001 to E-22.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2-difluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0418] Table E-23 Provided are 16 compounds E-23.001 to E-23.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0419] Table E-24 Provided are 16 compounds E-24.001 to E-24.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0420] Table E-25 Provided are 16 compounds E-25.001 to E-25.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)pyrimidin-2-yl], and R2 is as defined in Table Z.

[0421] Table E-26 Provided are 16 compounds E-26.001 to E-26.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is [5-(difluoromethoxy)-2-pyridinyl], and R2 is as defined in Table Z.

[0422] Table E-27 Provided are 16 compounds E-27.001 to E-27.016 of formula lae, wherein R1 is cyclopropyl-CH2-, R4 is (5-cyano-2-pyridinyl), and R2 is as defined in Table Z.

[0423] It also makes available certain intermediate compounds (some of which are novel) of amines of formula IIaa to IIae, wherein R1 and R4 (corresponding to the amines of formula I with R 4a and A2) are as defined in the first aspect. Stereocenters are indicated with asterisks in the structures below; and thus the present invention makes it possible to obtain both racemates and individual enantiomers; particularly preferred are enantiomers having the same spatial arrangement at the stereocenter as depicted in Formula I'a.

[0424]

[0425] Specific examples of compounds having formulae IIaa to IIae are those wherein R1 and R4 are as defined in Tables A-1 to A27.

[0426] A specific example of a compound of formula IIIab is one in which R2 (corresponding to R 2a , A1 and R 2b The rings) are as defined in Table Z.

[0427]

[0428] It also makes available compounds of formula III, VI, XV, XVa, XLII, XLIII, XLVI, XLVII, XLIX, L, LI, LII, LIII, LIV, LV, LVa, LVc, LVI, LIX, LX, and LXI, wherein, where applicable, the substituents R1, A1, R 2a 、R 2b , R3, R 5a 、R 5b and R4 (corresponding to R 4a and A2 ring) are as defined in any row of Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27 and E-1 to E-27. Particularly preferred enantiomers of compounds of Formula III, VI, XV, XVa, XLII, XLIII, XLVI, XLVII, XLIX, L, LI, LII, LIII, LIV, LV, LVa, LVc, LVI, LIX, LX, and LXI are, where applicable, those having the same spatial arrangement at the stereocenter as depicted in Formula I'a.

[0429] The present invention also makes it possible to obtain

[0430] A compound of formula II, wherein A2, R1, R3, R 4a 、R 5a , and R 5b As defined for formula I; therefore, A2, R1, R3, R4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula II wherein A2, R1, R3, R 4a 、R 5a , and R 5b Preferred embodiment of;

[0431] Compounds of formula IIaa, IIab, IIac, IIad and IIae, wherein R1 is as defined for formula I and R4 is a compound containing A2 and a substituent R in formula I. 4a A cyclic group, wherein A2 and R 4a As defined for Formula I; therefore, R1, A2 and R of the compound of Formula I 4a Preferred embodiments are also compounds having R1, A2 and R of any of the formulae IIaa, IIab, IIac, IIad and IIae. 4a Preferred embodiment of;

[0432] A compound of formula III, wherein A1, R 2a and R 2b As defined for formula I; therefore, A1, R 2a and R 2b A preferred embodiment is also a compound having formula III wherein A1, R 2a and R 2b Preferred embodiment of;

[0433] A compound of formula VI, wherein A2, R3, R 4a 、R 5a , and R 5b As defined for formula I; therefore, A2, R3, R 4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula VI wherein A2, R3, R 4a 、R 5a , and R 5b Preferred embodiment of;

[0434] A compound of formula XV, wherein A2, R3, R 4a 、R 5a , and R 5b As defined for formula I; therefore, A2, R3, R 4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula XV wherein A2, R3, R 4a 、R 5a, and R 5b Preferred embodiment of;

[0435] A compound of formula XVa, wherein A2, R3, R 4a 、R 5a , and R 5b As defined for formula I; therefore, A2, R3, R 4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula XVa wherein A2, R3, R 4a 、R 5a , and R 5b Preferred embodiment of;

[0436] A compound of formula XLII, wherein A2, R3, R 4a 、R 5a , and R 5b As defined for formula I and Z3 is NPhth or NBoc2; therefore, A2, R3, R 4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula XLII wherein A2, R3, R 4a 、R 5a , and R 5b Preferred embodiment of;

[0437] Compounds of formula XLIII, wherein A2, R3, R 4a 、R 5a , and R 5b As defined for formula I; therefore, A2, R3, R 4a 、R 5a , and R 5b A preferred embodiment is also a compound having formula XLIII wherein A2, R3, R 4a 、R 5a , and R 5b Preferred embodiment of;

[0438] Compounds of formula XLVI, wherein A2 and R3 are as defined for formula I and Z 4a It is R 4a , halogen or NH2; therefore, A2, R3, and R of the compound of formula I 4a A preferred embodiment is also a compound having formula XLVI wherein A2, R3 and R 4a Preferred embodiment of;

[0439] Compounds of formula XLVII, wherein A2 and R3 are as defined for formula I and Z4a It is R 4a , halogen or NH2; therefore, A2, R3, and R of the compound of formula I 4a A preferred embodiment is also a compound having formula XLVII wherein A2, R3 and R 4a Preferred embodiment of;

[0440] Compounds of formula XLIX, wherein A2 and R3 are as defined for formula I, Z 4a It is R 4a , halogen or NH2, and Z 5a and Z 5b are independently selected from R 5a 、R 5b , halogen, NH2 and OH; therefore, A2, R3, R 4a 、R 5a and R 5b A preferred embodiment is also a compound having formula XLIX wherein A2, R3, R 4a 、R 5a and R 5b Preferred embodiment of;

[0441] A compound of formula L, wherein A2 and R3 are as defined for formula I, and Z 5a and Z 5b are independently selected from R 5a 、R 5b , halogen, NH2 and OH; therefore, A2, R3, R 5a and R 5b A preferred embodiment is also a compound having formula L wherein A2, R3, R 5a and R 5b Preferred embodiment of;

[0442] A compound of formula LI wherein A2, R3 and R 4a As defined for Formula I, and Z 5a and Z 5b are independently selected from R 5a 、R 5b , halogen, NH2 and OH; therefore, A2, R3, R 4a 、R 5a and R 5b A preferred embodiment is also a compound having formula LI wherein A2, R3, R 4a 、R 5a and R 5b Preferred embodiment of;

[0443] A compound of formula LII, wherein A2, R3, R4a 、R 5a and R 5b As defined for formula I; therefore, A2, R3, R 4a 、R 5a and R 5b A preferred embodiment is also a compound having formula LII wherein A2, R3, R 4a 、R 5a and R 5b Preferred embodiment of;

[0444] A compound of formula LIII, wherein A2, R3, R 5a and R 5b As defined for Formula I, and Z 4a It is R 4a , halogen or NH2; therefore, A2, R3, R 4a 、R 5a and R 5b A preferred embodiment is also a compound having formula LIII wherein A2, R3, R 4a 、R 5a and R 5b Preferred embodiment of;

[0445] A compound of formula LIV, wherein A2, R3, R 5a and R 5b As defined for Formula I, and Z 4a It is R 4a , halogen or NH2; therefore, A2, R3, R 4a 、R 5a and R 5b A preferred embodiment is also a compound having formula LIV wherein A2, R3, R 4a 、R 5a and R 5b Preferred embodiment of;

[0446] A compound of formula LV, wherein R3, R 5a and R 5b As defined for Formula I, and X 07 is a leaving group, such as chlorine, bromine, iodine; therefore, R3, R 5a and R 5b Preferred embodiments are also compounds of formula LV where R3, R 5a and R 5b Preferred embodiment of;

[0447] A compound of formula LVa, wherein R1, R3, R 5a and R 5bAs defined for Formula I, and X 07 is a leaving group, such as chlorine, bromine, iodine; therefore, R1, R3, R 5a and R 5b Preferred embodiments are also compounds having formula LVa wherein R1, R3, R 5a and R 5b Preferred embodiment of;

[0448] A compound of formula LVc, wherein R3, R 5a and R 5b As defined for Formula I, and X 05 is a leaving group, such as chloro, bromo, iodo, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate; therefore, R3, R 5a and R 5b Preferred embodiments are also compounds of formula LVc where R3, R 5a and R 5b Preferred embodiment of;

[0449] A compound of formula LVI, wherein A1, R 2a 、R 2b , R1, R3, R 5a and R 5b As defined for Formula I, and X 07 is a leaving group, such as chlorine, bromine, iodine; therefore, A1, R 2a 、R 2b , R1, R3, R 5a and R 5b A preferred embodiment is also a compound having formula LVI wherein A1, R 2a 、R 2b , R1, R3, R 5a and R 5b Preferred embodiment of;

[0450] A compound of formula LIX, wherein R3, R 5a and R 5b As defined for Formula I, Z3 is NPhth or NBoc2 and X 05 is a leaving group, such as chloro, bromo, iodo, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate; therefore, R3, R 5a and R 5b Preferred embodiments are also compounds having formula LIX where R3, R 5a and R 5b Preferred embodiment of;

[0451] A compound of formula LX, wherein R3, R5a and R 5b As defined for Formula I and X 05 is a leaving group, such as chloro, bromo, iodo, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate; therefore, R3, R 5a and R 5b Preferred embodiments are also compounds having formula LX where R3, R 5a and R 5b Preferred embodiments of; and

[0452] A compound of formula LXI, wherein R3, R 5a and R 5b As defined for Formula I and X 05 is a leaving group, such as chloro, bromo, iodo, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate; therefore, R3, R 5a and R 5b Preferred embodiments are also compounds having formula LXI where R3, R 5a and R 5b The preferred embodiment of .

[0453] The compounds of formula I according to the invention are active ingredients of preventive and / or therapeutic value in the field of pest control. Even at low application rates, they have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the invention act on all or individual developmental stages of normally sensitive but also resistant animal pests (such as insects or representatives of the order Acarina). The insecticidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i.e., destruction of the pest occurs immediately or only after a certain period of time (e.g., during molting); or indirectly, for example, by reducing egg laying and / or hatching rates.

[0454] Examples of the animal pests mentioned above are:

[0455] From the order Acarina, e.g.

[0456] Acalitus spp., Aculus spp., Acaricalus spp., Aceria spp., Acarus siro, Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia spp., Calipitrimerus spp., Chorioptes spp., Dermanyssus gallinae, Dermatophagoides spp., Eotetranychus spp., Eriophyes spp.), Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Olygonychus spp., Ornithodoros spp., Polyphagotarsone latus, Panonychus spp., Phyllocoptruta oleivora, Phytonemus spp., Polyphagotarsonemus spp., Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp.), Steneotarsonemus spp., Tarsonemus spp., and Tetranychus spp.;

[0457] From the order Anoplura, for example,

[0458] Haematopinus spp., Linognathus spp., Pediculus spp., Pemphigus spp., and Phylloxera spp.;

[0459] From the order Coleoptera, for example,

[0460] Agriotes spp., Amphimallon majale, Anomala orientalis, Anthonomus spp., Aphodius spp., Astylus atromaculatus, Ataenius spp., Atomaria linearis, Chaetocnema tibialis, Cerotomas spp., Conoderus spp., Cosmopolites spp., Cotinis nitida, Curculio spp., Cyclocephalas spp., Dermestes spp., Diabrotica spp.), Argentine beetle (Diloboderus abderus), herbivorous ladybirds (Epilachna spp.), Eremnus species, Heteronychus arator, Hypothenemus hampei, Lagria vilosa, Leptinotarsa ​​decemlineata, Lissorhoptrus spp., Liogenys species, Maecolaspis species, Maladera castanea, Megascelis spp., Melighetes aeneus, Melolontha spp., Myochrousarmatus, Orycaephilus spp., Otiorhynchus spp., Phyllophaga spp.), Phlyctinus spp., Popillia spp., Psylliodes spp., Rhyssomatus aubtilis, Rhizopertha spp., Scarabeidae, Sitophilus spp., Sitotroga spp.), Somaticus spp., Sphenophorus spp., Sternechus subsignatus, Tenebrio spp., Tribolium spp., and Trogoderma spp.;

[0461] From the order Diptera, for example,

[0462] Aedes spp., Anopheles spp., Antherigonas occata., Bactrocea oleae, Bibio hortulanus, Bradysia spp., Calliphora erythrocephala, Ceratitis spp., Chrysomyia spp., Culex spp., Cuterebra spp., Dacus spp., Delia spp., Drosophila melanogaster, Fannia spp., Gastrophilus spp., Geomyza tripunctata, Glossina spp.), Hypoderma spp., Hyppobosca spp., Liriomyza spp., Lucilia spp., Melanagromyza spp., Musca spp., Oestrus spp., Orseolia spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Rhagoletis spp., Riveria quadrifasciata, Scatella spp., Sciara spp., Stomoxys spp., Tabanus spp., Tannia spp.) and Tipula spp.;

[0463] From the order Hemiptera, for example,

[0464] Acanthocoris scabrator, Acrosternum spp., Adelphocoris lineolatus, Aleurodes spp., Amblypelta nitida, Bathycoelia thalassina, Acanthocoris spp., Cimex spp., Clavigrallatomentosicollis, Creontiades spp., Dichelops furcatus, Edessa spp., Euchistus spp., Eurydema pulchrum, Acrosternum spp., Brown-winged stink bug, Horciasno billellus), rice stink bugs, Lygus species, tropical scale bugs, Murgantia histrionic, Neomegalotomus spp., Nesidiocoris tenuis, green stink bugs, Nysius simulans, Oebalus insularis, skin stink bugs, wall stink bugs, red assassin bugs, Sahlbergella singularis, chestnut stink bugs, Scotinophara spp., Thyanta species, Triatominae species, and cassava web stink bugs;

[0465] Acyrthosium pisum, Adalges species, Agallina ensigera, Agonascena targionii, Aleurodicus spp., Aleurocanthus spp., Aleurolobus barodensis, Aleurothrixus floccosus, Aleyrodes brassicae, Amarascabiguttula, Amritodus atkinsoni, Aonidiella spp., Aphididae, Aphis spp., Aspidiotus spp., Aulacorthum solani), Bactericera cockerelli, Bemisia spp., Brachycaudus spp., Brevicoryne brassicae, Cacopsylla spp., Cavariella aegopodii Scop., Ceroplaster spp., Chrysomphalus aonidium, Chrysomphalus dictyospermi, Cicadella spp., Cofanaspectra, Cryptomyzus spp., Cicadulina spp., Coccus hesperidum, Dalbulus spp. maidis), Dialeurodes spp., Diaphorina citri, Diuraphis noxia, Dysaphis spp., Empoasca spp., Eriosoma larigerum, Erythroneura spp.), Gascardia species, Glycaspis brimblecombei, Hyadaphis pseudobrassicae, Hyalopterus spp., Hyperomyzus pallidus, Idioscopus clypealis, Jacobiasca lybica, Laodelphax spp., Lecanium corni, Lepidosaphes spp., Lopaphis erysimi, Lyogenys maidis, Macrosiphum spp., Mahanarva spp., Metcalfapruinosa, Metopolophium dirhodum, Myndus crudus), Myzus spp., Neotoxoptera sp., Nephotettix spp., Nilaparvata spp., Nippolachnus piri Mats, Odonaspis ruthae, Oregma lanigera Zehnter, Parabemisia myricae, Paratrioza cockerelli, Parlatoria spp., Pemphigus spp., Peregrinus maidis, Perkinsiella spp., Phorodon humuli, Phylloxera spp., Planococcus spp.), Pseudaulacaspis spp., Pseudococcus spp., Pseudatomoscelis seriatus, Psyllas spp., Pulvinaria aethiopica, Quadraspidiotus spp.), Quesadagigas, Recilia dorsalis, Rhopalosiphum spp., Saissetia spp., Scaphoideus spp., Schizaphis spp., Sitobion spp., Sogatella furcifera, Spissistilus festinus, Tarophagus proserpina, Toxoptera spp., Trialeurodes spp., Tridiscus sporoboli, Trionymus spp., Trioza erytreae, Unaspis citri, Zygina flammigera, Zyginidia scutellaris;

[0466] From the order Hymenoptera, for example,

[0467] Acromyrmex species, Arge spp., Atta spp., Cephus spp., Diprion spp., Diprionidae, Gilpinia polytoma, Hoplocampa spp., Lasius spp., Monomorium pharaonis, Neodiprions spp., Pogonomyrmex spp., Slenopsis invicta, Solenopsis spp., and Vespa spp.;

[0468] From the order Isoptera, for example,

[0469] Coptotermes spp., Corniternes cumulans, Incisitermes spp., Macrotermes spp., Mastotermes spp., Microtermes spp., Reticulitermes spp.; Tropical fire ants (Solenopsis geminate)

[0470] From the order Lepidoptera, for example,

[0471] Species of the genus Long-winged Roller Moth, species of the genus Brown-banded Roller Moth, species of the genus Clearwing Moth, species of the genus Noctua, cotton leafworm, species of the genus Amylois, species of the genus Mucuna, species of the genus Yellow Roller Moth, species of the genus Argyresthia, species of the genus Banded Roller Moth, species of the genus Spodoptera, species of the genus Cotton Miner, species of the genus Corn Armyworm, species of the genus Mesoderm, species of the genus Peach Fruit Borer, species of the genus Graminus, species of the genus Choristoneura, species of the genus Chrysoteuchia topiaria, species of the genus Graminus, species of the genus Leaf Roller, species of the genus Cloud Roller, species of the genus Sheath Moth, species of the genus Colias lesbia, species of the Cosmophila flava), grass borer species, cabbage borer, apple cyclops, boxwood moth, Cottonmouth species, boxwood borer, stem borer species, Sudan cotton bollworm, Spodoptera species, South American corn borer (Elasmopalpus lignosellus), sweet potato stem borer (Eldana saccharina), mealybug species, leaf roller species (Epinotias spp.), salt marsh moth (Estigmene acrea), Etiella zinckinella, flower roller species, ring-needle roller, yellow tussock moth species, root cutter species, Feltia jaculiferia, Grapholitas spp., clouded broad-winged roller (Hedya nubiferana), Heliothis species, cabbage borer, leaf cutter species (Herpetogramma spp.), American white moth, tomato codling moth, Lasmopalpus lignosellus, spiral leafminer, leafminer species, grape flower moth, Loxostege bifidalis, tussock moth species, miner species, Malacosoma spp., cabbage armyworm, tobacco hornworm, Mythimna spp., Noctua species, fall moth species, Orniodes indica, European corn borer, super-small tortoise species, brown tortoise species, small-eyed tortoise, stem borer, Pectinophora gossypiela, coffee leafminer, single-star armyworm, potato moth, cabbage butterfly, Pieris species, diamondback moth, white nest moth species, leaf moth species, mint ash moth (Rachiplusia nu), western bean groundworm (Richia albicosta), Scirpophaga spp.), species of the genus Noctua, species of the genus Longipalpis, species of the genus Spodoptera, species of the genus Cotton Leaf Roller, species of the genus Xingluo, species of the genus Heteroptera, species of the genus Leaf Roller, Trichoplusia ni, species of the tomato leafminer, and species of the genus Nidus;

[0472] From the order Mallophaga, for example,

[0473] Damalina spp. and Trichodectes spp.;

[0474] From the order Orthoptera, for example,

[0475] Blatta spp., Blattella spp., Gryllotalpa spp., Leucophaea maderae, Locusta spp., Neocurtilla hexadactyla, Periplaneta spp., Scapteriscus spp., and Schistocerca spp.;

[0476] From the order Psocoptera, for example,

[0477] Liposcelis spp.;

[0478] From the order Siphonaptera, for example,

[0479] Ceratophyllus spp., Ctenocephalides spp., and Xenopsylla cheopis;

[0480] From the order Thysanoptera, for example,

[0481] Calliothrips phaseoli, Frankliniella spp., Heliothrips spp., Hercinothrips spp., Parthenothrips spp., Scirtothrips aurantii, Sericothrips variabilis, Taeniothrips spp., Thrips spp.

[0482] From the order of the Thysanura, for example, Lepisma saccharina.

[0483] In another aspect, the present invention may also relate to a method for controlling damage to plants and parts thereof by phytoparasitic nematodes (endoparasitic, semi-endoparasitic and ectoparasitic nematodes), in particular the following plant-parasitic nematodes, such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other species of root knot nematodes; cyst-forming nematodes, Globodera rostochiensis and other species of Globodera; Heterodera avenae, Heteroderaglycines, Heterodera exigua and other species of Globodera; schachtii), Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Belonolaimus longicaudatus, and other Belonolaimus species; Pine nematodes, Bursaphelenchus xylophilus, and other Bursaphelenchus species; Ring nematodes, nematodes), Criconema species, Criconemella species, Criconemoides species, Mesocriconema species; Stemand bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci, and other Ditylenchus species; Awl nematodes, Dolichodorus species;Spiral nematodes, Heliocotylenchus multicinctus, and other species of the genus Helicotylenchus; Sheath and sheathoid nematodes, species of the genera Hemicycliophora, and species of the genera Hemicriconemoides; Hirshmanniella species; Lancenematodes, species of the genus Hoploaimus; False rootknot nematodes, species of the genus Nacobbus; Needle nematodes, Longidoruse longatus, and other species of the genus Longidorus; Pin nematodes, species of the genus Pratylenchus; Lesion nematodes. nematodes), Pratylenchus negletus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi, and other Pratylenchus species; Burrowing nematodes, Radopholus similis, and other Radopholus species; Reniform nematodes, Rotylenchus robustus, Rotylenchus reniformis, and other Rotylenchus species; Scutellonema species; Stubby root nematodes, Trichodorus primitivus) and other species of the genera Trichodorus and Paratrichodorus;Stunt nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius, and other Tylenchorhynchus species; Citrus nematodes, Tylenchulus species; Dagger nematodes, Xiphinema species; and other plant-parasitic nematode species, such as Subanguinas spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp., and Quinisulcius spp.

[0484] The compounds of the present invention may also have activity against mollusks. Examples include, for example, the Ampullariidae; the Arion genus (A. ater, A. circumscriptus, A. hortensis, A. rufus); the Bradybaenidae (Bradybaenidae); fruticum); Cepaea (C. hortensis, C. nemoralis); Ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (G. trunculata); Helicelia (H. itala, H. obvia); Helicidae (Helicigona arbustorum); Helicodiscus; Helix (H. aperta); Limax (L. cinereoniger, L. flavus, L. marginatus, L. maximus, L. Tenellus); Lymnaea; Milax (M. gagates, M. marginatus, M. sowerbyi); Opeas; Pomacea (P. canaticulata); Vallonia, and Zanitoides.

[0485] The active ingredients according to the invention can be used for controlling, i.e. suppressing or destroying harmful organisms of the above-mentioned type, which occur in particular on plants, in particular on useful and ornamental plants in agriculture, in horticulture and in forestry, or on organs of such plants, such as fruits, flowers, leaves, stems, tubers or roots, and in some cases even plant organs formed at a later point in time still remain protected against these harmful organisms.

[0486] Suitable target crops are, in particular, cereals such as wheat, barley, rye, oats, rice, maize or sorghum; beets such as sugar beets or fodder beets; fruits such as pome, stone or soft fruit such as apples, pears, plums, peaches, apricots, cherries or berries such as strawberries, raspberries or blackberries; leguminous crops such as beans, lentils, peas or soybeans; oilseed crops such as rapeseed, mustard, poppy, olives, sunflower, coconut, castor, cocoa or peanuts; melons Crops, such as pumpkin, cucumber or melon; fiber plants, such as cotton, flax, hemp or jute; citrus fruits, such as oranges, lemons, grapefruits or tangerines; vegetables, such as spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such as avocado, cinnamon (Cinnamonium) or camphor; and also tobacco, nuts, coffee, eggplant, sugarcane, tea, pepper, grapevines, hops, plantago and latex plants.

[0487] The compositions and / or methods of the present invention may also be used on any ornamental and / or vegetable crop, including flowers, shrubs, broadleaf trees, and evergreen plants.

[0488] For example, the present invention can be used with any of the following ornamental plant species: Ageratum species, Alonsoa species, Anemone species, Anisodontea capsenisis, Anthemis species, Antirrhinum species, Aster species, Begonia species (e.g., Rieger begonia, Begonia sempervirens, Begonia tubéreux), Bougainvillea species, Brachycome species, Brassica species (ornamental plants), Calceolaria species, Capsicum, Catharanthus roseus, Canna species, Centaurea species, Chrysanthemum species, Cineraria species (C. maritime), Coreopsis species, Crassula coccinea, Cupheaignea, Dahlia species, Delphinium species, Dicentra species, Dorotheantus species. spp.), Lisianthus, Forsythia species, Fuchsia species, Geranium gnaphalium, Gerbera species, Globe amaranth, Heliotrope species, Sunflower species, Hibiscus species, Hydrangea species, Hydrangea species, Rhododendron, Impatiens species (African balsam), Amaranth species (Iresines spp.), Kalanchoe species, Lantana, March flower, Lion's ear, Lilium species, Mesembryanthemum species, Physalis species, Monarda species, Dracaena species, Marigold species, Dianthus species (carnation), Canna species, Oxalis species, Daisy species, Pelargonium species (Shieldleaf Pelargonium, Horseshoe Pelargonium), Viola species (Viola tricolor), Petunia species, Phlox species, Plecthranthus species spp.), poinsettia species, creeper species (five-leaf creeper, Parthenocissus quinquefolia), primula species, ranunculus species, azalea species, Rosa species (roses), rudbeckia species, African violet species, salvia species, Scaevola aemola, Schizanthus wisetonensis, sedum species, Solanum species, Surfinia petunia species (Surfinia spp.), marigold species, Nicotiana species, verbena species, zinnia species, and other bedding plants.

[0489] For example, the present invention can be used with any of the following vegetable species: Allium species (garlic, onion, A. oschaninii, leek, shallot, scallion), fennel, celery (Apium graveolus), asparagus, beets, Brassica species (cabbage, Chinese cabbage, turnip), peppers, chickpeas, endive, chicory species (chicory, endive), watermelon (Citrillus lanatus), Cucumber species (cucumber, melon), Cucurbita species (zucchini, Indian pumpkin), Cyanara species (artichoke, cardoon), wild carrot, fennel, Hypericum species, lettuce, Lycopersicon species (tomato, cherry tomato), mint species, basil, parsley, Phaseolus species (bean, pea), peas, radish, edible rhubarb, Rosemary species, sage species, black salsify (Scorzonera hispanica), eggplant, spinach, new Valerian species (V. eriocarpa), and broad beans.

[0490] Preferred ornamental plant species include African violet, begonia, dahlia, gerbera, hydrangea, verbena, rose, kalanchoe, poinsettia, aster, cornflower, coreopsis, delphinium, monarda, phlox, rudbeckia, sedum, petunia, violet, impatiens, geranium, chrysanthemum, ranunculus, fuchsia, salvia, hydrangea, rosemary, sage, St. John's wort, mint, sweet pepper, tomato, and cucumber.

[0491] The active ingredients according to the invention are particularly suitable for controlling the bean aphid (Aphis craccivora), cucumber leaf beetle (Diabrotica balteata), tobacco budworm (Heliothis virescens), peach aphid (Myzus persicae), diamondback moth, and sea armyworm (Spodoptera littoralis) on cotton, vegetables, corn, rice, and soybean crops. The active ingredients according to the invention are also particularly suitable for controlling Mamestra (preferably on vegetables), codling moth (preferably on apples), green leafhopper (preferably on vegetables and vineyards), leaf beetles (Leptinotarsa) (preferably on potatoes), and striped stem borer (Chilo supressalis) (preferably on rice).

[0492] Compounds of formula I are particularly useful for controlling

[0493] pests of the order Hemiptera, for example one or more of the following species: Bemisia tabaci, Bean aphid, Green peach aphid, Rhopalosiphum padi, Brown rice hopper (Nilaparvata lugens), and Euschistus heros (preferably on vegetables, soybeans, and sugarcane);

[0494] Pests of the order Lepidoptera, for example one or more of the following species: Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Codling moth, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includesns, and Tomato leafminer (preferably on vegetables and corn);

[0495] pests of the order Thysanoptera, such as the family Thripidae, for example one or more of Thrips tabaci and Thrips occidentalis (preferably on vegetables); and

[0496] • Soil pests (e.g. of the order Coleoptera), for example species of Diabrotica spp., species of the genus Leptinotarsa ​​and potato beetles (preferably on vegetables and maize).

[0497] The term "crops" should be understood as also including crop plants which have been transformed by the use of recombinant DNA techniques such that they are able to synthesize one or more selectively acting toxins, such as are known, for example, from toxigenic bacteria, in particular those of the genus Bacillus.

[0498] Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, such as those from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as delta-endotoxins (e.g., Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1, or Cry9C), or vegetative insecticidal proteins (Vips) (e.g., Vip1, Vip2, Vip3, or Vip3A); or insecticidal proteins of nematode-parasitic bacteria, such as Photorhabdus species or Xenorhabdus species, such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals, such as scorpion toxins, spider toxins, wasp toxins, and other insect-specific neurotoxins; toxins produced by fungi, such as Streptomyces toxins; plant lectins, such as pea lectin, barley lectin, and lectin. Lectin or snowdrop agglutinin; lectins; protease inhibitors, such as trypsin inhibitor, serine protease inhibitor, potato storage protein (patatin), cysteine ​​protease inhibitor, papain inhibitor; ribosome inactivating protein (RIP), such as ricin, maize-RIP, abrin, luffain, saporin or bryophyllin; steroid metabolizing enzymes, such as 3-hydroxysteroid oxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidase, ecdysone inhibitor, HMG-COA-reductase; ion channel blockers, such as sodium channel or calcium channel blockers; juvenile hormone esterase; diuretic hormone receptor; stilbene synthase; bibenzyl synthase; chitinase and glucanase.

[0499] In the context of the present invention, δ-endotoxins (e.g., Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1, or Cry9C) or vegetative insecticidal proteins (Vips) (e.g., Vip1, Vip2, Vip3, or Vip3A) are understood to include, but are not limited to, mixed toxins, truncated toxins, and modified toxins. Mixed toxins are recombinantly produced by combining the different domains of those proteins (see, e.g., WO 02 / 15701). Truncated toxins, such as truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of a naturally occurring toxin are replaced. In such amino acid replacements, it is preferred that a non-naturally occurring protease recognition sequence be inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G recognition sequence is inserted into the Cry3A toxin (see WO 03 / 018810).

[0500] Examples of such toxins or transgenic plants capable of synthesizing such toxins are disclosed in, for example, EP-A-0 374 753, WO 93 / 07278, WO 95 / 34656, EP-A-0 427 529, EP-A-451 878 and WO 03 / 052073.

[0501] Methods for preparing such transgenic plants are generally known to those skilled in the art and are described, for example, in the publications mentioned above. CryI-type deoxyribonucleic acids and their preparation are known, for example, from WO 95 / 34656, EP-A-0 367474, EP-A-0 401 979 and WO 90 / 13651.

[0502] The toxins contained in the transgenic plants render the plants tolerant to harmful insects. Such insects can be found in any insect taxonomic group, but are particularly common among beetles (Coleoptera), two-winged insects (Diptera), and moths (Lepidoptera).

[0503] Transgenic plants containing one or more genes encoding insecticide resistance and expressing one or more toxins are known and some are commercially available. Examples of such plants are: (Zea mays variety expressing Cry1Ab toxin); YieldGard (maize variety expressing Cry3Bb1 toxin); YieldGard (Zea mays varieties expressing Cry1Ab and Cry3Bb1 toxins); (Zea mays variety expressing Cry9C toxin); Herculex (a maize variety expressing the Cry1Fa2 toxin and the enzyme phosphinothricin N-acetyltransferase (PAT) that confers tolerance to the herbicide glufosinate-ammonium); NuCOTN (cotton variety expressing Cry1Ac toxin); Bollgard (cotton variety expressing Cry1Ac toxin); Bollgard (cotton varieties expressing Cry1Ac and Cry2Ab toxins); (cotton variety expressing Vip3A and Cry1Ab toxins); (potato variety expressing Cry3A toxin); GT Advantage (GA21 glyphosate tolerance trait), CB Advantage (Bt11 corn borer (CB) trait) and

[0504] Further examples of such genetically modified crops are:

[0505] 1. Bt11 maize, from Syngenta Seeds SAS, Cheminde l'Hobit 27, F-31 790 St. Sauveur, France, registration number C / FR / 96 / 05 / 10. This genetically modified maize is resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia inermis) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenicly expresses the PAT enzyme to confer tolerance to the herbicide glufosinate-ammonium.

[0506] 2. Bt176 maize, from Syngenta Seeds, 27 Rue de Hobbitt, F-31 790 Saint-Sauveur, France, registration number C / FR / 96 / 05 / 10. This genetically modified maize is resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia inermis) by transgenic expression of the Cry1Ab toxin. Bt176 maize also transgenicly expresses the PAT enzyme to confer tolerance to the herbicide glufosinate-ammonium.

[0507] 3. MIR604 maize, from Syngenta Seeds, 27 Rue de Hobbit, F-31 790 Saint-Sauveur, France, registration number C / FR / 96 / 05 / 10. This maize plant is rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055, modified by insertion of a cathepsin G protease recognition sequence. The preparation of these transgenic maize plants is described in WO 03 / 018810.

[0508] 4. MON 863 maize, from Monsanto Europe SA, 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C / DE / 02 / 9. MON 863 expresses the Cry3Bb1 toxin and confers resistance to certain coleopteran insects.

[0509] 5. IPC 531 cotton, from Monsanto Europe SA, 270-272 Avenue Tervuren, B-1150 Brussels, Belgium, registration number C / ES / 96 / 02.

[0510] 6.1507 maize, from Pioneer Overseas Corporation, Avenue Tedesco, 7B-1160 Brussels, Belgium, registration number C / NL / 00 / 10. Genetically modified maize expressing the protein Cry1F for resistance to certain lepidopteran insects and the protein PAT for tolerance to the herbicide glufosinate.

[0511] 7. NK603×MON 810 maize, from Monsanto Europe, 270-272 Boulevard Tervuren, B-1150 Brussels, Belgium, registration number C / GB / 02 / M3 / 03. This is a conventionally bred hybrid maize variety, constructed by crossing the genetically modified varieties NK603 and MON 810. NK603×MON 810 maize transgenically expresses the protein CP4 EPSPS obtained from the Agrobacterium strain CP4, rendering it herbicide tolerant. (contains glyphosate), and also Cry1Ab toxin obtained from Bacillus thuringiensis subsp. kurstaki, which confers resistance to certain lepidopteran insects, including the European corn borer.

[0512] Transgenic crops of insect-resistant plants are also described in the BATS (Zentrum für Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) report 2003 ( http: / / bats.ch )middle.

[0513] The term "crop" should be understood as also including crop plants that have been transformed using recombinant DNA technology so that they can synthesize antipathogenic substances with selective action, such as, for example, so-called "pathogenesis-related proteins" (PRPs, see, for example, EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants that can synthesize such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95 / 33818, and EP-A-0 353 191. Methods for producing such transgenic plants are generally known to those skilled in the art and are described, for example, in the publications mentioned above.

[0514] Crops can also be modified to enhance resistance to fungal (eg, Fusarium, Anthracnose, or Phytophthora), bacterial (eg, Pseudomonas), or viral (eg, Potato Leaf Roll Virus, Tomato Spotted Wilt Virus, Cucumber Mosaic Virus) pathogens.

[0515] Crops also include those with enhanced resistance to nematodes, such as soybean cyst nematode.

[0516] Crops with tolerance to abiotic stress include those with enhanced tolerance to drought, high salinity, high temperature, cold, frost or light radiation, for example, through expression of NF-YB or other proteins known in the art.

[0517] Antipathogenic substances that can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers of sodium channels and calcium channels, for example viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; so-called "pathogenesis-related proteins" (PRPs, see, for example, EP-A-0 392 225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics which are involved in plant pathogen defense (see, for example, WO 95 / 33818) or protein or polypeptide factors (so-called "plant disease resistance genes", as described in WO 03 / 000906).

[0518] Further areas of use of the compositions according to the invention are the protection of stored goods and storage rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, in particular for the protection of humans, domestic animals and productive livestock against pests of the types mentioned.

[0519] The present invention provides a compound of the first aspect for use in therapy. The present invention provides a compound of the first aspect for use in controlling parasites in or on an animal. The present invention further provides a compound of the first aspect for use in controlling ectoparasites on an animal's body surface. The present invention further provides a compound of the first aspect for use in preventing and / or treating diseases transmitted by ectoparasites.

[0520] The present invention provides the use of the compound of the first aspect for the manufacture of a medicament for controlling parasites in or on an animal. The present invention further provides the use of the compound of the first aspect for the manufacture of a medicament for controlling ectoparasites on an animal's body surface. The present invention further provides the use of the compound of the first aspect for the manufacture of a medicament for preventing and / or treating diseases transmitted by ectoparasites.

[0521] The present invention provides a use of the compound of the first aspect in controlling parasites in or on an animal body. The present invention further provides a use of the compound of the first aspect in controlling ectoparasites on an animal body surface.

[0522] When used in the context of parasites in or on animals, the term "control" means reducing the number of pests or parasites, eliminating pests or parasites and / or preventing further infestation by pests or parasites.

[0523] When used in the context of parasites in or on animals, the term "treat" means to inhibit, slow, halt or reverse the progression or severity of existing symptoms or disease.

[0524] When used in the context of parasites in or on animals, the term "prevent" means avoiding symptoms or disease from developing in the animal.

[0525] When used in the context of parasites in or on animals, the term "animal" can refer to mammals and non-mammals, such as birds or fish. In the case of a mammal, it can be a human or a non-human mammal. Non-human mammals include, but are not limited to, livestock and companion animals. Livestock include, but are not limited to, cattle, camels, pigs, sheep, goats, and horses. Companion animals include, but are not limited to, dogs, cats, and rabbits.

[0526] A "parasite" is a harmful organism that lives in or on a host animal and benefits by obtaining nutrients at the host animal's expense. An "endoparasite" is a parasite that lives inside the host animal. An "ectoparasite" is a parasite that lives on the host animal's body. Ectoparasites include, but are not limited to, Acari, insects, and crustaceans (e.g., sea lice). The subclass Acari (or Acarina) includes ticks and mites. Ticks include, but are not limited to, members of the genera Rhipicaphalus, such as Rhipicaphalus microplus (Boophilus microplus) and Rhipicephalus sanguineus; Amblyomrna; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros. Mites include, but are not limited to, members of the genera: Dermonychia, such as Chorioptes bovis; Psoroptes, such as Psoroptes ovis; Cheyletiella; Dermanyssus, such as Dermanyssus gallinae; Ortnithonyssus; Demodex, such as Demodex canis; Sarcoptes, such as Sarcoptes scabiei; and Psorergates. Insects include, but are not limited to, members of the orders Siphonaptera, Diptera, Phthiraptera, Lepidoptera, Coleoptera, and Homoptera. Members of the order Siphonaptera include, but are not limited to, Ctenocephalides felis and Ctenocephatides canis. Members of the order Diptera include, but are not limited to, Musca species; skin flies, such as Gasterophilus intestinalis and Oestrus ovis; biting flies; horse flies, such as Haematopota spp. and Tabunus spp.; black horn flies, such as Haematobia irritans; biting flies; Lucilia; midges; and mosquitoes. Members of the order Pseudoptera include, but are not limited to, blood-sucking and chewing lice, such as Bovicola ovis and Bovicola bovis.

[0527] When used in the context of parasites in or on an animal, the term "effective amount" refers to the amount or dosage of a compound of the present invention or a salt thereof that provides the desired effect in or on the animal following administration to the animal in a single or multiple doses. An effective amount can be readily determined by the attending diagnostician, who is skilled in the art, using known techniques and by observing the results obtained under similar circumstances. In determining an effective amount, the attending diagnostician will consider a variety of factors, including, but not limited to: the species of mammal; its size, age, and general health; the parasite to be controlled and the degree of infestation; the specific disease or disorder involved; the degree of involvement or severity of the disease or disorder; the response of the individual; the specific compound to be administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; concomitant medications used; and other relevant circumstances.

[0528] The compounds of this invention can be administered to animals by any route having the desired effect, including but not limited to topical, oral, parenteral and subcutaneous administration. Topical administration is preferred. Suitable formulations for topical administration include, for example, solutions, emulsions and suspensions, and can be poured, dotted, sprayed, sprayed (spray race) or immersed in the form of. In an alternative embodiment, the compounds of this invention can be administered by ear tags or collars.

[0529] Salt forms of the compounds of the present invention include both pharmaceutically acceptable salts and veterinarily acceptable salts, which may be different from agrochemically acceptable salts. Pharmaceutically and veterinarily acceptable salts and common methods for preparing them are well known in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, RJ et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977). It will be appreciated by those skilled in the art that the compounds of this invention can be readily converted into salts using techniques and conditions known to those skilled in the art, and can be separated as salts (such as hydrochlorides). Additionally, it will be appreciated by those skilled in the art that the compounds of this invention can be readily converted into corresponding free alkalis from corresponding salts and can be separated as corresponding free alkalis converted from corresponding salts.

[0530] The present invention also provides a method for controlling pests (such as mosquitoes and other disease vectors; see also http: / / www.who.int / malaria / vector_control / irs / en / ). In one embodiment, the method for controlling pests comprises applying the composition of the present invention to the target pests, their locus, or a surface or substrate by brushing, rolling, spraying, coating, or dipping. By way of example, IRS (indoor residual spraying) application to surfaces (such as walls, ceilings, or floor surfaces) is contemplated by the methods of the present invention. In another embodiment, application of such compositions to substrates such as nonwoven or fabric materials in the form of (or that can be used in the manufacture of) netting, blankets, bedding, curtains, and tents is contemplated.

[0531] In one embodiment, the method for controlling this type of harmful organism comprises applying the composition of the present invention of pesticidal effective amount to target harmful organism, their place or surface or substrate, so that effective retained pesticidal activity is provided on this surface or substrate.This application can be carried out by brushing, rolling, spraying, coating or dipping pesticidal composition of the present invention.By way of example, it is envisaged that the IRS of surface (such as wall, ceiling or floor surface) is used by the method of the present invention, so that effective retained pesticidal activity is provided on this surface.In another embodiment, it is envisaged that this type of composition is used for the residual control of harmful organisms on substrate, and this substrate is as the fabric material of netting, covering, bedding, curtain and tent form (or can use in the manufacture of these articles).

[0532] The substrate to be treated (including nonwovens, fabrics or nettings) can be made of natural fibers such as cotton, raffia, jute, flax, sisal, burlap or wool, or synthetic fibers such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. Polyester is particularly suitable. Methods for textile treatment are known, for example WO 2008 / 151984, WO 2003 / 034823, US 5631072, WO 2005 / 64072, WO 2006 / 128870, EP 1724392, WO 2005113886 or WO 2007 / 090739.

[0533] A further area of ​​use of the compositions according to the invention is in the field of tree injection / trunk treatment of all ornamental trees as well as all kinds of fruit and nut trees.

[0534] In the field of tree injection / trunk treatment, the compounds according to the invention are particularly suitable for combating wood-boring insects from the orders Lepidoptera and from the orders Coleoptera mentioned above, in particular against the wood-boring insects listed in the following Tables A and B:

[0535] Table A. Examples of economically important exotic wood-boring insects.

[0536]

[0537] Table B. Examples of economically important native wood-boring insects.

[0538]

[0539]

[0540]

[0541] The present invention can also be used to control any insect pest that may be present in turfgrass, including, for example, beetles, caterpillars, fire ants, ground pearls, millipedes, woodlice, mites, mole crickets, scale insects, mealybugs, ticks, cicadas, southern wheat stink bugs, and white grubs. The present invention can be used to control insect pests at all stages of their life cycle, including eggs, larvae, nymphs, and adults.

[0542] In particular, the present invention can be used to control insect pests that feed on the roots of turfgrasses, including grubs (such as Cyclocephala spp. (e.g., labeled beetles, C. lurida), Rhizotrogus spp. (e.g., European beetles, European root-cutting gill beetles (R. majalis)), Cotinus spp. (e.g., Green June beetles, Green June flower beetles (C. nitida)), Popillia spp. (e.g., Japanese beetles, Japanese arc beetles (P. japonica)), Phyllophaga spp. (e.g., May / June beetles), Ataenius spp. (e.g., Black turfgrass ataenius, Black velvet beetles (A. spretulus)), Maladera spp. (e.g., Black turfgrass ataenius, Black velvet beetles (A. spretulus)), spp.) (e.g., Asiatic garden beetle, M. castanea, and Tomarus spp.), ground beetles (Margarodes spp.), mole crickets (tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana), and leatherjackets (European crane fly, Tipula spp.).

[0543] The present invention can also be used to control insect pests of turfgrass in thatched homes, including armyworms (such as the fall armyworm Spodoptera frugiperda and the common armyworm Pseudaletia unipuncta), cutworms, weevils (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and meadow moths (such as Crambus spp. and the tropical meadow moth, Herpetogramma phaeopteralis).

[0544] The present invention can also be used to control insect pests in turfgrasses that live above ground and feed on turfgrass leaves, including wheat stink bugs (such as the southern wheat stink bug, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), Gai's tiger tail mealybug (Antonina graminis), two-lined leafhopper (Propsapia bicincta), leafhoppers, cutworms (Noctuidae), and wheat aphids.

[0545] The present invention can also be used to control other pests in turfgrass, such as introduced fire ants (Solenopsis invicta) that create nests in lawns.

[0546] In the hygiene sector, the compositions according to the invention are effective against ectoparasites such as hard ticks, soft ticks, scabies, autumn mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.

[0547] Examples of such parasites are:

[0548] From the order of the Licea: Haemaphysalis species, Macrocephalus species, Pediculus species, Phtirus spp., Solenopotes spp.

[0549] From the order Trichophagus: Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp., and Felicola spp.

[0550] From the order Diptera and the suborders Nematocerina and Brachycerina, for example, Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp., Tabanus spp., Philipomyia spp., Braula spp., Musca domestica spp., Hydrotaea spp. spp.), biting flies, Haematobia spp., Morellia spp., toilet flies, Glossina spp., Calliphora spp., Lucilia spp., Chrysomelid spp., Wohlfahrtia spp., Sarcophaga spp., Botrytis spp., Dermatobia spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp., and Melophagus spp.

[0551] From the order of the Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllus spp.

[0552] From the order of the Heteropterida, for example, Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.

[0553] From the order of the Blattarida, for example, Blatta orientalis, Periplaneta americana, Blattelagermanica and Supella spp.

[0554] Subclass Acaria (family Acarida) and orders Meta-stigmata and Meso-stigmata, for example, Acropora spp., Ornithodoros spp., Ototrichum spp., Ixodes spp., Amblyomma spp., Boophilus spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Rhipicephalus spp., Dermatophytes spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp., and Varroa spp.

[0555] From the orders Actinedida (Prostigmata) and Acaridida (Astigmata), for example, Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Itch spp., Dermectin spp., Otodectes spp. spp.), Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp., and Laminosioptes spp.

[0556] The compositions according to the invention are also suitable for protecting materials in the case of, for example, wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and construction from infestation by insects.

[0557] The compositions according to the invention can be used, for example, to combat the following pests: beetles, such as the North American house beetle, the long-haired longhorn beetle, the furniture beetle, the red-haired beetle, the comb-horn beetle, Dendrobium pertinex, the pine twig beetle, Priobium carpini, the brown powder beetle, the African powder beetle, the southern powder beetle, the oak powder beetle, the soft-haired powder beetle, the breast powder beetle, the scale-haired powder beetle, the wood beetle species, the branch beetle species, the coffee black beetle, the oak beetle, the brown beetle, the two-spined beetle and the bamboo beetle; and also hymenoptera, such as the blue-black bumblebee, the giant bumblebee, the Taiga bumblebee and the Urocerus augur; and termites, such as the European wood termite (Kalotermes flavicollis), Coptotermes flavicollis, Heterotermes indica, Reticulitermes flavicris, Reticulitermes sant's, Reticulitermes euphorbiae, Macrotermes darwinii, Paleotermes nevadae, and Coptotermes formosanus; and borers, such as silverfish. The compounds of Formulae I and I'a, or their salts, are particularly useful for controlling one or more pests selected from the following families: Noctuidae, Plutellae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Pseudocypteridae, Meloidogyne, and Heteroderae. In a preferred embodiment of each aspect, compound TX (wherein the abbreviation "TX" means "a compound selected from the group consisting of the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27 and E-1 to E-27, and Table P") controls one or more pests selected from the following families: Noctuidae, Plutellae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Spodoptera, Meloidogyne, and Heteroderae.

[0558] The compounds of formula I and I'a, or salts thereof, are particularly suitable for controlling one or more pests selected from the following genera: Spodoptera species, Diamondback moth species, Thrips species, Thrips species, American stink bug species, Codling moth species, Nilaparvata species, Aphis species, Rootworm species, Aphis species, Spodoptera species, and Graminophora species. In preferred embodiments of each aspect, compound TX (wherein the abbreviation "TX" means "a compound selected from the group consisting of the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27 and E-1 to E-27, and Table P") controls one or more pests selected from the group consisting of Spodoptera species, Diamondback moth species, Thrips species, Thrips species, Stink bug species, Codling moth species, Nilaparvata species, Aphis species, Rootworm species, Aphis species, Spodoptera species, Geometridae species, and Graminophora species.

[0559] The compounds of formula I and I'a, or salts thereof, are particularly useful for controlling one or more of the following: Spodoptera littoralis, Plutella xylostella, western flower thrips, Thrips tabaci, American hero stink bug, codling moth, brown rice hopper, peach aphid, soybean looper, bean aphid, cucumber leaf beetle, cereal aphid, and striped stem borer.

[0560] In preferred embodiments of each aspect, compound TX (wherein the abbreviation "TX" means "a compound selected from the group consisting of the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27, and E-1 to E-27, and Table P") controls one or more of: Spodoptera littoralis, diamondback moth, western flower thrips, tabaci thrips, hero stink bug, codling moth, brown rice hopper, green peach aphid, soybean looper, bean aphid, cucumber leaf beetle, cereal aphid, and striped stem borer, such as Spodoptera littoralis+TX, diamondback moth+TX; western flower thrips+TX, tabaci thrips+TX, hero stink bug+TX, codling moth+TX, brown rice hopper+TX, green peach aphid+TX, soybean looper+TX, bean aphid+TX, cucumber leaf beetle+TX, cereal aphid+TX, and striped stem borer+TX.

[0561] In one embodiment of each aspect, a compound selected from the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27, and E-1 to E-27, and Table P is suitable for controlling Spodoptera littoralis, Plutella xylostella, Western Flower Thrips, Thrips tabaci, American stink bug, Codling moth, Brown rice hopper, Green peach aphid, Bean looper, Bean aphid, Cucumber leaf beetle, Grain aphid, and Chilo suppressalis on cotton, vegetables, corn, cereals, rice, and soybean crops.

[0562] In one embodiment, a compound selected from the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27 and E-1 to E-27, and Table P is suitable for controlling Spodoptera spp. (preferably on vegetables), Codling moth (preferably on apples), Empoasca spp. (preferably on vegetables, vineyards), Diabrotica spp. (preferably on potatoes) and Chilo suppressalis (preferably on rice).

[0563] The compounds according to the present invention may have any number of benefits, including, among others, favorable levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (e.g., higher biological activity, favorable activity spectrum, increased safety profile (against non-target organisms above and below ground, such as fish, birds, and bees), improved physico-chemical properties, or increased biodegradability). In particular, it has been unexpectedly discovered that certain compounds of Formula I can exhibit favorable safety profiles relative to non-target arthropods, particularly pollinators such as honey bees, solitary bees, and bumble bees. Most particularly, relative to the Italian honey bee (Apis mellifera).

[0564] The compounds according to the present invention can be used as pesticides in unmodified form, but they are usually formulated into compositions using formulation adjuvants such as carriers, solvents, and surfactants in a variety of ways. These formulations can be in different physical forms, for example, in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent compressed tablets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, flowable oils, aqueous dispersions, oily dispersions, suspoemulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or water-miscible organic solvents as carriers), impregnated polymer films, or in other known forms, for example, from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, 1st edition, second revision (2010). Such formulations can be used directly or diluted before use. Dilution can be performed with, for example, water, liquid fertilizers, micronutrients, biological organisms, oils or solvents.

[0565] The formulations can be prepared, for example, by mixing the active ingredient with formulation adjuvants to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredient can also be formulated with other adjuvants such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.

[0566] Active ingredient can also be contained in very fine microcapsules. Microcapsules contain active ingredient in a porous carrier. This enables the active ingredient to be released (e.g., slowly released) into the environment in a controlled amount. Microcapsules typically have a diameter of from 0.1 to 500 microns. The amount of active ingredient they contain is about 25% to 95% of the capsule weight by weight. The active ingredient can be in the form of a holistic solid, in the form of fine particles in a solid or liquid dispersion, or in the form of a suitable solution. The encapsulated membrane can include, for example, natural or synthetic rubber, cellulose, styrene / butadiene copolymer, polyacrylonitrile, polyacrylate, polyester, polyamide, polyurea, polyurethane or chemically modified polymers and starch xanthate or other polymers known to those skilled in the art. Alternatively, very fine microcapsules can be formed, in which the active ingredient is contained in the form of finely dispersed particles in a solid matrix of a base material, but these microcapsules themselves are not wrapped.

[0567] Formulation adjuvants suitable for preparing the compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol rosinate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethyl Formamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, dipropylene glycol, alkyl pyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, α-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, γ-butyrolactone, glycerol, glyceryl acetate, glyceryl diacetate, glyceryl triacetate, Hexadecane, hexanediol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, cumene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, dichloromethane, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, lactic acid propylene glycol Esters, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol and higher molecular weight alcohols such as amyl alcohol, tetrahydrofuranol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, etc.

[0568] Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, diatomaceous earth, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed hulls, wheat flour, soy flour, pumice, wood flour, ground walnut shells, lignin, and similar substances.

[0569] Many surface-active substances can be used advantageously in both solid and liquid formulations, especially those which can be diluted with a carrier before use. Surface-active substances can be anionic, cationic, nonionic or polymeric and they can act as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol / alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol / alkylene oxide addition products, such as tridecyl alcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; salts of dialkylsulfosuccinates, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary ammoniums, such as dodecyltrimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and dialkyl phosphates; as well as other substances described, for example, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood, MD. New Jersey[Ridgewood, New Jersey](1981).

[0570] Other adjuvants that can be used in pesticidal formulations include crystallization inhibitors, viscosity modifiers, suspending agents, dyes, antioxidants, foaming agents, light absorbers, mixing aids, defoamers, complexing agents, substances that neutralize or change the pH and buffers, corrosion inhibitors, fragrances, wetting agents, absorption enhancers, micronutrients, plasticizers, glidants, lubricants, dispersants, thickeners, antifreeze agents, microbicides, and liquid and solid fertilizers.

[0571] The composition according to the invention may contain additives comprising oils of plant or animal origin, mineral oils, alkyl esters of such oils or mixtures of such oils with oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01% to 10% based on the mixture to be applied. For example, the oil additive can be added to the spray tank in the desired concentration after the spray mixture has been prepared. Preferred oil additives include mineral oils or oils of plant origin, such as rapeseed oil, olive oil or sunflower oil; emulsified vegetable oils; alkyl esters of oils of plant origin, such as methyl derivatives; or oils of animal origin, such as fish oil or tallow. Preferred oil additives include C8-C 22 Alkyl esters of fatty acids, especially C 12 -C 18 Methyl derivatives of fatty acids, such as the methyl esters of lauric acid, palmitic acid, and oleic acid (methyl laurate, methyl palmitate, and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th edition, Southern Illinois University, 2010.

[0572] The compositions of the present invention generally contain from 0.1% to 99% by weight, especially from 0.1% to 95% by weight, of a compound of the present invention and from 1% to 99.9% by weight of formulation adjuvants, which preferably include from 0% to 25% by weight of surfactants. While commercial products may preferably be formulated as concentrates, the end user will generally use dilute formulations.

[0573] The application rate varies within a wide range and depends on the nature of the soil, the application method, the crop plants, the harmful organisms to be controlled, the prevailing climatic conditions, and other factors governed by the application method, the time of application and the target crop. In general, the compound can be applied at a rate of from 1 to 2000 l / ha, in particular from 10 to 1000 l / ha.

[0574] A preferred formulation may have the following composition (wt %):

[0575] Emulsifiable concentrates :

[0576] Active ingredient: 1% to 95%, preferably 60% to 90%

[0577] Surfactant: 1% to 30%, preferably 5% to 20%

[0578] Liquid carrier: 1% to 80%, preferably 1% to 35%

[0579] Dust Agent :

[0580] Active ingredient: 0.1% to 10%, preferably 0.1% to 5%

[0581] Solid carrier: 99.9% to 90%, preferably 99.9% to 99%

[0582] Suspension concentrate:

[0583] Active ingredient: 5% to 75%, preferably 10% to 50%

[0584] Water: 94% to 24%, preferably 88% to 30%

[0585] Surfactant: 1% to 40%, preferably 2% to 30%

[0586] wettable powder :

[0587] Active ingredient: 0.5% to 90%, preferably 1% to 80%

[0588] Surfactant: 0.5% to 20%, preferably 1% to 15%

[0589] Solid carrier: 5% to 95%, preferably 15% to 90%

[0590] Granules:

[0591] Active ingredient: 0.1% to 30%, preferably 0.1% to 15%

[0592] Solid carrier: 99.5% to 70%, preferably 97% to 85%

[0593] The following examples further illustrate (but do not limit) the present invention.

[0594] <![CDATA[ wettable powder ]]> a) b) c) Active ingredient 25％ 50％ 75％ Sodium lignin sulfonate 5％ 5％ - Sodium lauryl sulfate 3％ - 5％ Sodium diisobutylnaphthalenesulfonate - 6％ 10％ Phenol polyglycol ether (7-8 mol of ethylene oxide) - 2％ - Highly dispersed silicic acid 5％ 10％ 10％ Kaolin 62％ 27％ -

[0595] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable grinder to obtain a wettable powder which can be diluted with water to give a suspension of the desired concentration.

[0596] <![CDATA[ Powder for dry seed treatment ]]> a) b) c) Active ingredient 25％ 50％ 75％ Light mineral oil 5％ 5％ 5％ Highly dispersed silicic acid 5％ 5％ - Kaolin 65％ 40％ - talc - 20％

[0597] The combination is thoroughly mixed with adjuvants and the mixture is thoroughly ground in a suitable grinder to obtain a dust that can be used directly for seed treatment.

[0598]

[0599]

[0600] Emulsions of any desired dilution which can be used in plant protection can be obtained from these concentrates by dilution with water.

[0601] <![CDATA[ Dust agent ]]> a) b) c) Active ingredient 5％ 6％ 4％ talc 95％ - - Kaolin - 94％ - Mineral fillers - - 96％

[0602] Ready-to-use dusts are obtained by mixing the combination with a carrier and grinding the mixture in a suitable grinder. Such dusts can also be used for dry seed dressing.

[0603] <![CDATA[ Extruder pellets ]]> Active ingredient 15％ Sodium lignin sulfonate 2％ Carboxymethyl cellulose 1％ Kaolin 82％

[0604] The combination is mixed with adjuvants and ground, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

[0605] <![CDATA[ Coated granules ]]> Active ingredient 8％ Polyethylene glycol (molecular weight 200) 3％ Kaolin 89％

[0606] In a mixer, the finely ground combination is applied uniformly to the kaolin moistened with polyethylene glycol. In this way, dust-free coated granules are obtained.

[0607] Suspension concentrates

[0608] Active ingredient 40％ Propylene glycol 10％ Nonylphenol polyglycol ether (15 mol of ethylene oxide) 6％ Sodium lignin sulfonate 10％ Carboxymethyl cellulose 1％ Silicone oil (in the form of a 75% emulsion in water) 1％ water 32％

[0609] The finely ground combination is intimately mixed with adjuvants to give a suspension concentrate from which a suspension of any desired dilution can be obtained by dilution with water. Using such a dilution, living plants as well as plant propagation materials can be treated and protected from infection by microorganisms by spraying, pouring or immersion.

[0610] Flowable concentrate for seed treatment

[0611] Active ingredient 40％ Propylene glycol 5％ Copolymer butanol PO / EO 2％ Tristyrylphenol with 10-20 moles of EO 2％ 1,2-Benzisothiazolin-3-one (as a 20% solution in water) 0.5％ Monoazo-pigment calcium salt 5％ Silicone oil (in the form of a 75% emulsion in water) 0.2％ water 45.3％

[0612] The finely ground combination is intimately mixed with adjuvants to give a suspension concentrate from which a suspension of any desired dilution can be obtained by dilution with water. Using such a dilution, living plants as well as plant propagation materials can be treated and protected from infection by microorganisms by spraying, pouring or immersion.

[0613] Slow-release capsule suspension

[0614] 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of a toluene diisocyanate / polymethylene-polyphenyl isocyanate mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinyl alcohol, 0.05 parts of a defoamer, and 51.6 parts of water until the desired particle size is reached. To this emulsion is added a mixture of 2.8 parts of 1,6-hexanediamine in 5.3 parts of water. The mixture is stirred until the polymerization reaction is complete. The resulting capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersant. The capsule suspension formulation contains 28% active ingredient. The diameter of the medium capsules is 8-15 microns. The resulting formulation is applied to the seeds as an aqueous suspension in a device suitable for this purpose.

[0615] Formulation types include emulsion concentrates (EC), suspension concentrates (SC), suspoemulsions (SE), capsule suspensions (CS), water-dispersible granules (WG), emulsifiable granules (EG), water-in-oil emulsions (EO), oil-in-water emulsions (EW), microemulsions (ME), oil dispersions (OD), oil suspensions (OF), oil-soluble concentrates (OL), soluble concentrates (SL), ultra-low volume suspensions (SU), ultra-low volume concentrates (UL), finished products (TK), dispersible concentrates (DC), wettable powders (WP), soluble granules (SG), or any technically feasible formulation in combination with agriculturally acceptable adjuvants.

[0616] Preparation example:

[0617] LCMS method:

[0618] Method 1:

[0619] Spectra were recorded on a mass spectrometer from Agilent Technologies (6410 triple quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative ion, MS2 scan, capillary: 4.00 kV, fragmentor voltage: 100 V, desolvation temperature: 350°C, gas flow: 11 L / min, nebulizer gas: 45 psi, mass range: 110 to 1000 Da) and a 1200 series HPLC from Agilent: quaternary pump, heated column compartment and diode array detector. Column: KINETEX EVO C18, 2.6 μm, 50 x 4.6 mm, temperature: 40°C, DAD wavelength range (nm): 210 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.1% HCOOH, gradient: 0 min 0% B, 100% A; 0.9-1.8 min 100% B; flow rate (mL / min) 1.8.

[0620] Method 2:

[0621] Spectra were recorded on a mass spectrometer from Waters (SQD single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative, full scan, capillary: 3.00 kV, cone range: 41 V, source temperature: 150°C, desolvation temperature: 500°C, cone gas flow: 50 L / Hr, desolvation gas flow: 1000 L / Hr, mass range: 110 to 800 Da) and a Class H UPLC from Waters: binary pump, heated column compartment and diode array detector. Column: Waters UPLC HSS T3 C18, 1.8 μm, 30x2.1 mm, temperature: 40°C, DAD wavelength range (nm): 210 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.1% HCOOH, gradient: 0 min 10% B; 0.-0.2 min 10%-50% B; 0.2-0.7 min 50%-100% B; flow rate (mL / min) 0.8.

[0622] Chiral SFC Method 1: In the SFC from Waters Corporation (Waters Acquity UPC 2 Spectra were recorded on a SFC equipped with a PDA detector (Waters Acquity UPC 2 Column: Daicel SFC IC (3 μm, 0.3 cm x 10 cm, 40 ° C; mobile phase: A: CO2 B: MeOH isocratic: 10% B in 2.0 min; ABPR: 1800 psi; flow rate: 2.0 ml / min; detection: 220 nm; sample concentration: 1 mg / mL in ACN; injection: 1 μL

[0623] Chiral SFC Method 2: In the SFC from Waters Corporation (Waters Acquity UPC 2 Spectra were recorded on a SFC equipped with a PDA detector (Waters Acquity UPC 2 Column: Daicel SFC IG (3 μm, 0.3 cm x 10 cm, 40 ° C; mobile phase: A: CO2 B: MeOH isocratic: 15% B in 4.8 min; ABPR: 1800 psi; flow rate: 2.0 ml / min; detection: 270 nm; sample concentration: 1 mg / mL in ACN / MeOH (1:1); injection: 1 μL

[0624] Preparation of methyl 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (Intermediate I1)

[0625]

[0626] Sulfuric acid (2.46 mL, 44.3 mmol, 1.00 equiv) was added dropwise to a solution of 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid (CAS 796090-23-8, 10.0 g, 44.3 mmol) in methanol (266 mL) at room temperature. The reaction mixture was heated to 65° C. and stirred overnight. After cooling to room temperature, the reaction mixture was poured onto a saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to give the desired product (10.2 g, 42.70 mmol), which was used without further purification.

[0627] 1 H NMR (400 MHz, chloroform-d) δ ppm: 4.04 (s, 3H) 8.11 (s, 1H) 8.17 (d, J=1.10 Hz, 1H).

[0628] 2-Cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (Intermediate I2) and 2-cyclopropyl-6-(trifluoromethyl) Preparation of pyridine-4-carboxylic acid (intermediate I3)

[0629]

[0630] Cyclopropylboronic acid (1.43 g, 16.7 mmol, 2.00 equiv) and sodium bicarbonate (2.10 g, 25.1 mmol, 3.00 equiv) were added to a solution of methyl 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (Intermediate I1 prepared as described above) (2.00 g, 8.35 mmol) in 1,4-dioxane (20.9 mL) and water (8.35 mL), and the resulting suspension was flushed with argon for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.322 g, 0.417 mmol, 0.05 equiv) was added and the resulting suspension was stirred under argon at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated to give a first crude material which after purification by flash chromatography on silica gel (ethyl acetate in cyclohexane) gave the desired intermediate 12 (0.706 g, 2.88 mmol).

[0631] 1H NMR (400 MHz, chloroform-d) δ ppm: 1.04-1.23 (m, 4H) 2.14-2.28 (m, 1H) 4.00 (s, 3H) 7.88 (s, 1H) 7.95 (d, J = 1.47 Hz, 1H).

[0632] LC-MS (method 1): retention time 1.12 min, m / z 246 [M+H] + .

[0633] After acidification to pH 1, the aqueous layer was extracted twice more with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and evaporated to give a second crude material which, after purification by flash chromatography on silica gel (methanol in dichloromethane), gave intermediate I3 (0.166 g, 0.718 mmol).

[0634] 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 0.94-1.03 (m, 2H) 1.06-1.15 (m, 2H) 2.37-2.46 (m, 1H) 7.88 (d, J = 1.10 Hz, 1H) 8.05 (d, J = 0.73 Hz, 1H) 13.89-14.33 (m, 1H).

[0635] LC-MS (method 1): retention time 0.94 min, m / z 232 [M+H] + .

[0636] Preparation of 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylic acid (Intermediate I3)

[0637]

[0638] Lithium hydroxide monohydrate (0.147 g, 3.43 mmol, 1.20 equiv) was added to a solution of methyl 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylate (Intermediate I2 prepared as described above) in a 3:1 tetrahydrofuran / water mixture (24.5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated and the remaining aqueous phase was acidified to pH 1 by addition of 1 M aqueous hydrochloric acid solution (3.43 mL). The aqueous layer was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated to give 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylic acid.

[0639] 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 0.96-1.02 (m, 2H) 1.07-1.15 (m, 2H) 2.40 (tt, J1=8.12 Hz, J2=4.72 Hz, 1H) 7.88 (d, J=1.10 Hz, 1H) 8.04 (s, 1H) 13.90-14.36 (m, 1H)

[0640] LC-MS (method 1): retention time 0.94 min, m / z 232 [M+H] + .

[0641] Preparation of methyl 3-cyclopropyl-5-(trifluoromethyl)benzoate (Intermediate I4)

[0642]

[0643] Under argon, a solution of bromopropyne in toluene (80 weight %, 0.89g, 0.67mL) is added to a white suspension of 9-BBN dimer (3.0g, 12mmol) in 26mL anhydrous tetrahydrofuran to give a light yellow solution. The mixture is refluxed for 2 hours and then cooled to room temperature. Add the previously degassed sodium hydroxide 4M aqueous solution (4.4mL, 18mmol) to give a turbid colorless solution. Under argon, at room temperature, the mixture obtained is stirred for 1 hour. The very light yellow solution of gained is then added to a light yellow solution of previously degassed 3-bromo-5-(trifluoromethyl) benzoic acid methyl ester (187331-46-0,1.5g, 5.2mmol) and tetrakis (triphenylphosphine) palladium (0) (0.30g, 0.26mmol) in 52mL anhydrous tetrahydrofuran to give a light yellow solution. The resulting mixture is stirred under reflux for 19 hours. The mixture was cooled at room temperature, diluted with ethyl acetate, quenched with water (+ a few drops of brine) and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed once with brine, dried over sodium sulfate, filtered and evaporated in vacuo at 60 ° C. The crude product was purified by chromatography on silica gel to give methyl 3-cyclopropyl-5-(trifluoromethyl)benzoate as a colorless liquid.

[0644] 1 H NMR (400 MHz, chloroform-d) δ ppm: 0.76-0.85 (m, 2H) 1.06-1.15 (m, 2H) 2.03 (tt, J1=8.39 Hz, J2=5.00 Hz, 1H) 3.96 (s, 3H) 7.52 (s, 1H) 7.91 (s, 1H) 8.08 (d, J=0.73 Hz, 1H).

[0645] 19 F NMR (377 MHz, chloroform-d) δ ppm: -62.75 (s, 3F).

[0646] Preparation of 3-cyclopropyl-5-(trifluoromethyl)benzoic acid (Intermediate I5)

[0647]

[0648] 3-cyclopropyl-5-(trifluoromethyl)benzoic acid methyl ester (7.00g, 28.7mmol) is dissolved in tetrahydrofuran (57.3mL) and water (28.7mL). Then lithium hydroxide (1.21g, 28.7mmol) is added and the gained light yellow turbid solution is stirred at room temperature for 4 hours. The reaction mixture is diluted in ethyl acetate and water. The organic phase is washed twice with water. The combined aqueous layer is acidified to pH 1-2 with 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layer is washed once with salt water, dried over sodium sulfate, filtered and concentrated under reduced pressure at 60°C to obtain 3-cyclopropyl-5-(trifluoromethyl)benzoic acid, which is used without further purification.

[0649] 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 0.79-0.85 (m, 2H) 1.03-1.10 (m, 2H) 2.12-2.22 (m, 1H) 7.70 (s, 1H) 7.88 (s, 1H) 7.93 (s, 1H) 13.47 (br s, 1H).

[0650] LC-MS (method 1): retention time 0.99 min, m / z 229 [MH] - .

[0651] ^

[0652] Preparation of 3-(trifluoromethyl)-5-vinyl-benzoic acid methyl ester (Intermediate I6)

[0653]

[0654] In the three-necked flask under argon, 3-bromo-5-(trifluoromethyl) methyl benzoate (CAS:187331-46-0,20g, 69.24mmol) is dissolved in toluene (312mL).Then tributyl (vinyl) tin (25.56mL, 83.09mmol) is added and the resulting solution is degassed with argon for 10min. Tetrakis (triphenylphosphine) palladium (0) (0.816543g, 0.69mmol) is added, and the resulting mixture is stirred at 110 ℃ for 2 hours. After cooling at room temperature, the mixture is diluted with ethyl acetate (100mL), filtered through a diatomaceous earth pad, washed with ethyl acetate and the filtrate is concentrated in vacuo. Crude product is purified on silica gel by chromatography to obtain 3-(trifluoromethyl)-5-vinyl-methyl benzoate.

[0655] 1 H NMR (400 MHz, chloroform-d) δ ppm: 3.98 (s, 3H) 5.47 (d, J = 11.00 Hz, 1H) 5.93 (d, J = 17.61 Hz, 1H) 6.79 (dd, J1 = 17.42 Hz, J2 = 10.82 Hz, 1H) 7.82 (s, 1H) 8.19 (s, 1H) 8.24-8.29 (m, 1H).

[0656] Preparation of diphenyl (2,2,2-trifluoroethyl) sulfonium trifluoromethanesulfonate

[0657]

[0658] In an autoclave, diphenyl sulfide (36.43 mL, 211.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.207 mL, 42.22 mmol) were mixed. The mixture was stirred at room temperature for 2 min, then the autoclave was closed and heated at 150° C. for 20 hours. The reactants were cooled at room temperature and a white precipitate formed. 75 mL of ether was added, and the white solid was filtered. It was washed four times with 30 mL of ether and then dried under reduced pressure.

[0659] 1 H NMR (400 MHz, chloroform-d) δ ppm: 5.78 (d, J = 8.80 Hz, 2H) 7.89 (d, J = 8.07 Hz, 4H) 7.93-8.00 (m, 2H) 8.37 (dd, J1 = 8.62 Hz, J2 = 1.28 Hz, 4H).

[0660] 19 F NMR (377 MHz, chloroform-d) δ ppm: -78.91 (s, 3F) -61.26 (s, 3F).

[0661] Preparation of methyl 3-(trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoate (Intermediate I7)

[0662]

[0663] In a vial under argon, 3-(trifluoromethyl)-5-vinyl-benzoate (1.9 g, 8.3 mmol) and cesium fluoride (1.5 g, 9.9 mmol) were dissolved in dimethylacetamide (33 mL) to give a colorless solution, which was degassed under argon for 20 min. 5,10,15,20-tetraphenyl-21H,23H-porphyrin iron (III) chloride (0.31 g, 0.41 mmol) was added. The reaction became a green suspension and diphenyl (2,2,2-trifluoroethyl) sulfonium trifluoromethanesulfonic acid (3.8 g, 9.1 mmol) was also added in batches. The reaction was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane and then water was added. The organic layer was washed four times with water, dried over sodium sulfate, filtered and concentrated under reduced pressure at 40 ° C and 160 mbar. The crude material was purified by chromatography on silica gel to give methyl 3-(trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoate.

[0664] 1 H NMR (400 MHz, chloroform-d) δ ppm: 1.25-1.34 (m, 1H) 1.48-1.55 (m, 1H) 1.88-2.00 (m, 1H) 2.46-2.53 (m, 1H) 3.98 (s, 3H) 7.60 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H).

[0665] Preparation of 3-(trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoic acid (I8)

[0666]

[0667] 3-(Trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoate (1.43 g, 3.80 mmol) was dissolved in tetrahydrofuran (11.4 mL) and water (7.60 mL). Lithium hydroxide monohydrate (0.322 g, 7.60 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was cooled to 0°C and then acidified with 2M hydrochloric acid solution. The aqueous layer was extracted twice with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoic acid.

[0668] 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.40-1.47 (m, 2H) 2.53-2.60 (m, 1H) 2.72 (td, J1=7.70 Hz, J2=4.77 Hz, 1H) 7.87 (s, 1H) 8.02 (s, 1H) 8.05-8.08 (m, 1H) 13.54 (br s, 1H).

[0669] LC-MS (method 1): retention time 1.04 min, m / z 297 [MH] - .

[0670] Preparation of methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfanyl)benzoate (Intermediate I9)

[0671]

[0672] Under argon, (2,2'-bipyridine)(trifluoromethanethiol)copper (CAS1413732-47-4) (3.9 g, 12 mmol, 2.0 equivalents) was added to a solution of methyl 3-iodo-5-(trifluoromethyl)benzoate (2.0 g, 6.1 mmol) in acetonitrile (18 mL). The reaction mixture was heated to 90 ° C and stirred overnight. After cooling to room temperature, the reaction mixture was filtered through a celite pad and concentrated. The crude material was purified by two flash chromatography on silica gel (ethyl acetate in cyclohexane) to obtain the desired product (1.5 g, 4.9 mmol) as a yellow gum.

[0673] 1 H NMR (400 MHz, chloroform-d) δ ppm: 4.02 (s, 3H), 8.11 (s, 1H), 8.44 (s. 1H), 8.53 (s, 1H).

[0674] LC-MS (method 1): retention time 1.21 min, m / z 279 [M-MeO+H] + .

[0675] Preparation of methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate (Intermediate I10)

[0676]

[0677] 3-Chloroperbenzoic acid (2.3 g, 11 mmol, 2.1 equivalents) was added portionwise to a 0°C cooled solution of methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfanyl)benzoate (intermediate I13 prepared as described above) (1.8 g, 5.3 mmol) in dichloromethane (16 mL). After stirring at room temperature for 1 hour, more 3-chloroperbenzoic acid (2.3 g, 11 mmol, 2.1 equivalents) was added and the reaction mixture was stirred overnight. The formed precipitate was filtered. The filtrate was washed with a 10% aqueous solution of sodium thiosulfate and a saturated solution of NaHCO. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel to give methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate.

[0678] 1H NMR (400 MHz, chloroform) δ ppm 4.07 (s, 3H) 8.43-8.51 (m, 1H) 8.70-8.80 (m, 1H) 8.84-8.91 (m, 1H).

[0679] 19 F NMR (377 MHz, chloroform-d) δppm:-77.49 (s, 3F) -62.96 (s, 3F)

[0680] Preparation of 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoic acid (I11)

[0681]

[0682] Methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate (1.8 g, 5.4 mmol) was placed in a flask and dissolved in tetrahydrofuran (16 mL) and water (11 mL). To this mixture was added lithium hydroxide monohydrate (0.26 g, 11 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1 M hydrochloric acid and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and then concentrated to give 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoic acid, which was used without further purification.

[0683] 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 8.68 (s, 2H) 8.71-8.76 (m, 1H) 13.33-15.22 (m, 1H).

[0684] Preparation of methyl 3-(cyclopropanecarbonyl)-5-(trifluoromethyl)benzoate (Intermediate I12)

[0685]

[0686] Under argon, 3-iodo-5-(trifluoromethyl)benzoic acid methyl ester (10g, 28.78mmol) is dissolved in tetrahydrofuran (115mL).With dry ice / acetone bath, the gained light brown solution is cooled to-78 ℃.With syringe, the 1.3M Turbo Grignard reagent in tetrahydrofuran solution (31mL, 40.29mmol) is added dropwise over 20 minutes, directly provides dark solution, keeps the temperature lower than-65 ℃ simultaneously.The gained mixture is stirred at-78 ℃ for 15 minutes.Simultaneously, disposable addition cuprous cyanide (3.125g, 34.5mmol) and anhydrous lithium chloride (1.479g, 34.5mmol) provide dark suspension.The gained mixture is stirred at-78 ℃ for 15 minutes again.Finally, cyclopropanecarbonyl chloride (5.340mL, 57.5mmol) (temperature reaches-68 ℃ maximum value) is added dropwise over 5 minutes. The obtained mixture was stirred at -78 ° C for 1 hour, warmed to room temperature and stirred for 30 minutes to give a brown suspension. The reaction mixture was cooled to -78 ° C and slowly quenched with 20 ml of methanol. The obtained mixture was made to reach room temperature and the suspension obtained was filtered through diatomaceous earth. Saturated aqueous ammonium chloride and ethyl acetate were added to the filtrate. The water layer was extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure at 40 ° C. The crude material was purified by chromatography on silica gel to obtain 3-(cyclopropanecarbonyl)-5-(trifluoromethyl) methyl benzoate.

[0687] 1 H NMR (400 MHz, chloroform-d) δ ppm: 1.16-1.22 (m, 2H) 1.35 (quin, J = 3.76 Hz, 2H) 2.74 (tt, J1 = 7.84 Hz, J2 = 4.45 Hz, 1H) 4.02 (s, 3H) 8.45 (d, J = 0.73 Hz, 1H) 8.51 (d, J = 0.73 Hz, 1H) 8.86 (s, 1H).

[0688] Preparation of methyl 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoate (Intermediate I13)

[0689]

[0690] Under argon, 3-(cyclopropanecarbonyl)-5-(trifluoromethyl) methyl benzoate (5.5g, 20mmol) is dissolved in 2,2-difluoro-1,3-dimethyl-imidazolidine (36mL, 280mmol) to give a light yellow solution. The resulting mixture is stirred at 110°C for 5 hours to give a light brown solution. The reaction mixture is cooled to room temperature and added dropwise to 1.0L of saturated sodium bicarbonate aqueous solution (keeping the temperature below 10°C) stirred vigorously at 0°C. The resulting mixture (pH 8-9) is then extracted 3 times with ethyl acetate. The combined organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure at 50°C. The crude material is purified on silica gel by chromatography to obtain 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl) methyl benzoate.

[0691] 1 H NMR (400 MHz, chloroform-d) δ ppm: 0.73-0.79 (m, 2H) 0.82-0.89 (m, 2H) 1.47-1.60 (m, 1H) 8.00 (d, J=0.73 Hz, 1H) 8.39 (s, 1H) 8.42 (s, 1H).

[0692] 19 F NMR (377 MHz, chloroform-d) δ ppm: -98.40 (s, 3F) -62.81 (s, 2F).

[0693] Preparation of 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid (I14)

[0694]

[0695] 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid methyl ester (4.45g, 15.1mmol) was dissolved in tetrahydrofuran (30.3mL) and water (15.1mL). Lithium hydroxide monohydrate (0.833g, 19.7mmol) was added and the resulting colorless turbid solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed twice with water. The combined aqueous layer was acidified to pH 1-2 with 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic layer was washed once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure at 60°C to obtain 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid, which was used without further purification.

[0696] 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 0.62-0.84 (m, 4H) 1.65-1.97 (m, 1H) 7.93-8.23 (m, 1H) 8.23-8.51 (m, 2H) 13.24-14.48 (m, 1H).

[0697] LC-MS (method 1): retention time 1.03 min, m / z 279 [MH] - .

[0698] 2-(1-cyano-2-ethoxy-2-oxo-ethyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (intermediate Preparation of I15)

[0699]

[0700] 2-chloro-6-(trifluoromethyl)pyridine-4-methyl-formiate (1.05g, 4.40mmol) is dissolved in dimethyl sulfoxide (13.2mL).Then at room temperature continuously add ethyl 2-cyanoacetate (0.702mL, 6.60mmol), potassium carbonate (1.535g, 11.00mmol) and tetrabutylammonium bromide (0.145g, 0.440mmol).The gained suspension is stirred at 90 ℃ for 1 hour and then at room temperature stirred overnight.Reaction mass is diluted with 50mL water and 100mL ethyl acetate, is cooled to 0 ℃-10 ℃ and is slowly quenched with 1N hydrochloric acid via dropping funnel, until pH 3.Aqueous phase is extracted with ethyl acetate.The organic layer merged is dried over sodium sulfate and concentrated under reduced pressure at 50 ℃. The crude material was purified by chromatography on silica gel using ethyl acetate in cyclohexane to give methyl 2-(1-cyano-2-ethoxy-2-oxo-ethyl)-6-(trifluoromethyl)picolinate.

[0701] 1 H NMR (400 MHz, chloroform-d) δ ppm: 1.36-1.43 (m, 3H) 4.01 (s, 3H) 4.34 (q, J=7.58 Hz, 2H) 7.34 (s, 1H) 8.06 (s, 1H) 14.46-14.67 (m, 1H).

[0702] LC-MS (method 1): retention time 1.01 min, m / z 317 [M+H] + .

[0703] Preparation of methyl 2-(cyanomethyl)-6-(trifluoromethyl)pyridine-4-carboxylate (I16)

[0704]

[0705] To a solution of methyl 2-(1-cyano-2-ethoxy-2-oxo-ethyl)-6-(trifluoromethyl)picolinate (0.800 g, 2.53 mmol) in dimethyl sulfoxide (20 mL) was added sodium chloride (0.299 g, 5.06 mmol) in water (10 mL). The resulting mixture was stirred at 95 ° C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3*50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-(cyanomethyl)-6-(trifluoromethyl)picolinate, which was used without further purification.

[0706] 1 H NMR (400 MHz, chloroform-d) δ ppm: 4.05 (s, 3H) 4.13 (s, 2H) 8.24 (s, 1H) 8.26 (s, 1H).

[0707] LC-MS (method 1): retention time 0.89 min, m / z 243 [MH] - .

[0708] Preparation of 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (I17)

[0709]

[0710] 2-(cyanomethyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (0.05g, 0.20mmol) is dissolved in dimethylformamide (2mL). Sodium hydride (24mg, 0.61mmol) is added at room temperature and the colorless solution becomes a dark purple suspension. After 10min, 1,2-dibromoethane (0.02mL, 0.24mmol) is added and the resulting suspension is stirred at room temperature for 15min. The reaction mixture is quenched with saturated ammonium chloride solution at 0°C-5°C and diluted with ethyl acetate. The aqueous layer is acidified to pH 2-3 with 1N hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product is purified by reverse phase chromatography to obtain 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid.

[0711] 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 1.76-1.83 (m, 2H) 1.96-2.03 (m, 2H) 8.07 (d, J=1.10 Hz, 1H) 8.17 (s, 1H) 13.35-15.45 (m, 1H).

[0712] LC-MS (method 1): retention time 0.89 min, m / z 255 [MH]- .

[0713] Preparation of methyl 3-(cyanomethyl)-5-(trifluoromethyl)benzoate (Intermediate I18)

[0714]

[0715] 3-bromo-5-(trifluoromethyl) methyl benzoate (0.600g, 2.08mmol) is dissolved in DMF (4.2mL). (Trimethylsilyl) acetonitrile (0.862mL, 6.23mmol) is added dropwise with a syringe. The solution is degassed for 5min under Ar. ZnF2 (0.130g, 1.25mmol), Xantphos (0.0481g, 0.0831mmol) and Pd2(dba)3 (0.0384g, 0.0415mmol) are then added. The gained black suspension is stirred at 100°C for 22 hours and then cooled to room temperature. The mixture is concentrated under reduced pressure at 50°C. The crude material is purified by chromatography on silica gel with ethyl acetate in cyclohexane to obtain 3-(cyanomethyl)-5-(trifluoromethyl) methyl benzoate.

[0716] 1 H NMR (400 MHz, chloroform-d) δ = 8.30 (1H, s), 8.23 ​​(1H, s), 7.81 (1H, s), 3.99 (3H, s), 3.90 (2H, s) ppm.

[0717] LC-MS (method 1): retention time 0.92 min, m / z 242 [MH] - .

[0718] Preparation of methyl 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoate (Intermediate I19)

[0719]

[0720] 3-(cyanomethyl)-5-(trifluoromethyl) methyl benzoate (2.15g, 7.07mmol) is dissolved in DMF (32.3mL). Cesium carbonate (7.13g, 21.2mmol) is added to the stirred solution and the mixture is stirred at room temperature for 10min. 1,2-dibromoethane (0.68mL 7.78mmol) is added and the mixture is stirred at 60°C for 3 hours, then cooled to room temperature. Water (30mL) is added and the aqueous layer is extracted with ethyl acetate (60mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography (silica gel, ethyl acetate in hexane) to obtain 3-(1-cyanocyclopropyl)-5-(trifluoromethyl) methyl benzoate.

[0721] 1 H NMR (400 MHz, chloroform-d) δ = 8.23 ​​(1H, s), 8.09 (1H, s), 7.79 (1H, s), 3.98 (3H, s), 1.84-1.92 (2H, m), 1.47-1.57 (m, 2H) ppm.

[0722] Preparation of 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoic acid (Intermediate I20)

[0723]

[0724] Methyl 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoate (59 mg, 0.22 mmol) was dissolved in tetrahydrofuran (0.66 mL) and water (0.33 ml). Lithium hydroxide monohydrate (9.3 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 42 hours. 1N hydrochloric acid was added until pH = 2. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoic acid.

[0725] 1 H NMR (400 MHz, chloroform-d) δ = 8.60-9.90 (1H, br s), 8.29 (1H, s), 8.15 (1H, s), 7.84 (1H, s), 1.84-1.93 (2H, m), 1.50-1.60 (2H, m) ppm.

[0726] LC-MS (Method 1): retention time 0.86 min, m / z 254 [MH]-.

[0727] Preparation of 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanol

[0728]

[0729] Methylmagnesium bromide (1.00 M in THF, 63.2 mL, 63.2 mmol) was added to a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (8.00 g, 31.6 mmol) in tetrahydrofuran (100 mL) at 0 ° C under nitrogen. The resulting brown reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to obtain 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanol as a light yellow liquid.

[0730] 1H NMR (400MHz, DMSO-d) δppm: 7.78-7.88(m,2H),7.71(s,1H),5.52(d,1H),4.81(m,1H),1.35(d,3H).

[0731] Preparation of 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanone

[0732]

[0733] Pyridinium chlorochromate (5.05 g, 23.4 mmol) was added in batches to a stirred solution of 1- [3- bromo -5- (trifluoromethyl) phenyl] ethanol (7.00 g, 15.6 mmol) in dichloromethane (150 mL) at 0 ° C. The obtained brown reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluted with ethyl acetate in hexane) to give 1- [3- bromo -5- (trifluoromethyl) phenyl] ethyl ketone as a colorless oil.

[0734] 1 H NMR (400MHz, DMSO-d) δppm: 8.38 (1H, s), 8.26 (1H, s), 8.19 (1H, s), 2.69 (s, 1H).

[0735] Preparation of 1-[3-bromo-5-(trifluoromethyl)phenyl]cyclopropanol

[0736]

[0737] A solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanone (5.00 g, 18.3 mmol) in dichloromethane (30 mL) was treated with triethylamine (3.84 mL, 27.5 mmol) and trimethylsilyl trifluoromethanesulfonate (6.12 g, 27.5 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours.

[0738] The reaction mixture is quenched with saturated sodium bicarbonate solution (100mL). The water layer is extracted with dichloromethane. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude silyl enol ether is dissolved in dichloromethane and cooled to 0 ° C. Di-iodomethane (7.37g, 27.5mmol) and diethylzinc (1.00M in hexane, 27.5mL, 27.5mmol) are added dropwise and the mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with saturated ammonium chloride solution. The water layer is extracted with dichloromethane. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. At 0 ° C, the residue is dissolved in methanol and potassium carbonate (0.254g, 1.83mmol) is added. The gained light yellow reaction mixture is stirred at 0 ° C for 1 hour. The reaction mixture is concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate in hexanes) to provide 1-[3-bromo-5-(trifluoromethyl)phenyl]cyclopropanol as an off-white solid.

[0739] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm: 7.75 (1H, s), 7.65 (1H, s), 7.58 (1H, s), 6.30 (s, 1H), 1.15-1.25 (m, 2H), 1.05-1.15 (m, 2H).

[0740] Preparation of 1-bromo-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzene (I40)

[0741]

[0742] A solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]cyclopropanol (500 mg, 1.74 mmol) in tetrahydrofuran (2.0 mL) was added dropwise to a suspension of sodium hydride (60% in oil, 139 mg, 3.49 mmol) in tetrahydrofuran (2.0 mL). The mixture was stirred at 0 ° C for 10 minutes. Iodomethane (371 mg, 2.62 mmol) was added dropwise and the resulting mixture was stirred at 0 ° C for 1 hour. Saturated ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (gradient of ethyl acetate in hexane) to obtain 1-bromo-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzene as a colorless liquid.

[0743] 1 H NMR (400MHz, DMSO-d) δppm: 7.82(s,1H),7.69(s,1H),7.55(s,1H),3.27(s,3H),1.20-1.28(m,2H),1.09-1.18(m,2H).

[0744] Preparation of methyl 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoate (I38)

[0745]

[0746] 1-Bromo-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzene (1.50 g, 4.83 mmol), triethylamine (1.02 mL, 7.24 mmol) and methanol (30 mL) were charged into an autoclave. The reaction mixture was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (353 mg, 0.483 mmol) was added. The autoclave was placed under a carbon monoxide atmosphere (200 psi) and heated to 100 ° C for 16 hours. The autoclave was cooled to room temperature and filled with argon. The reaction mixture was filtered through diatomaceous earth. Water and ethyl acetate were added to the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude residue was purified on silica gel by flash chromatography (gradient of ethyl acetate in hexane) to obtain methyl 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoate as a light yellow liquid.

[0747] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.17 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 3.95 (s, 3H), 3.25 (s, 3H), 1.30 (t, 2H), 1.05 (t, 2H).

[0748] Preparation of 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid (I39)

[0749]

[0750] 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid methyl ester (1.00 g, 3.46 mmol) was dissolved in tetrahydrofuran (6.0 mL) and water (3.0 mL). Lithium hydroxide monohydrate (291 mg, 6.93 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and 2N hydrochloric acid was added at 0 ° C. The formed precipitate was filtered off, washed with water and dried to give 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid as a white solid.

[0751] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm: 13.4-13.7 (br. S, 1H), 8.00-8.10 (m, 2H), 7.72 (s, 1H), 3.19 (s, 3H), 1.25-1.35 (m, 2H), 1.08-1.15 (m, 2H).

[0752] Preparation of 2-chloro-5-(2,2-difluoroethoxy)pyrimidine

[0753]

[0754] 2-Chloropyrimidin-5-ol ([CAS: 4983-28-2] 5.00 g, 38.3 mmol) was dissolved in DMF (30.0 mL). Potassium carbonate (10.6 g, 76.6 mmol) and 1,1-difluoro-2-iodoethane (8.8 g, 46.0 mmol) were added. The resulting reaction mixture was stirred at 80 ° C for 12 h and then cooled to room temperature. It was then poured into the mixture in ice-cold water and extracted twice with ethyl acetate (200 mL each). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0%-50% ethyl acetate in hexane) to give 2-chloro-5-(2,2-difluoroethoxy)pyrimidine.

[0755] LC-MS (method 1): m / z 195.1 [M+H] + .

[0756] Preparation of tributyl-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]stannane

[0757]

[0758] 2-chloro-5-(2,2-difluoroethoxy)pyrimidine (2.00 g, 9.251 mmol) is dissolved in toluene (40.0 mL) and hexa-n-butylditin (8.05 g, 13.877 mmol) is added. The reaction mixture is purged with argon for 5 minutes, tetrakis(triphenylphosphine)palladium(0) (0.5345 g, 0.4626 mmol) is added, the reaction mixture is purged with argon for another 5 minutes and then stirred at 100 ° C for 16 h. It is filtered through a diatomaceous earth pad and the filtrate is concentrated in vacuo. The crude material is purified by neutral alumina chromatography (0%-20% ethyl acetate in hexane) to obtain tributyl-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]stannane.

[0759] 1 H NMR (400MHz, chloroform-d) δppm:0.87(t,9H)1.15(t,6H)1.30-1.35(q,6H)1.54-1.62(m,6H)4.21-4.30(dt,2H)5.95-6.26(br tt,1H)8.47(s,2H)

[0760] Preparation of 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ene ketone (I22)

[0761]

[0762] Tributyl-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]stannane (1.00 g, 2.00 mmol) was dissolved in toluene (15 mL) and 1-(3-chloropyrazin-2-yl)ethanone ([CAS: 121246-90-0] 0.439 g, 2.52 mmol) was added. The mixture was purged with argon for 5 minutes, and then copper (I) iodide (0.0763 g, 0.401 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.232 g, 0.200 mmol) were added and the resulting reaction mixture was stirred at 100 ° C for 4 h. After cooling to room temperature, it was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (combiflash, silica gel, 0% to 100% ethyl acetate in hexanes) to give 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone.

[0763] LC-MS (method 1): m / z 281.1 [M+H] + .

[0764] 1 H NMR (400MHz, DMSO-d6) δppm: 8.90 (s, 1H), 8.70-8.90 (m, 3H), 6.48 (t, 1H), 4.63 (td, 2H), 2.62 (s, 3H).

[0765] Preparation of 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (I28)

[0766]

[0767] 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (0.80 g, 0.285 mmol) was dissolved in a saturated solution of ammonium acetate in ethanol (10 mL). 30% ammonia solution and sodium cyanoborohydride (0.0538 g, 0.856 mmol) in water (5.0 mL) were added and the reaction mixture was stirred at reflux for 18 h. The reaction mixture was cooled to room temperature and washed with dichloromethane (50 mL). The aqueous layer was concentrated in vacuo to give the crude product, which was purified by reverse phase chromatography (C18 column, 0% to 50% acetonitrile in water) to give 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine.

[0768] LC-MS (method 1): m / z 282.1 [M+H] + .

[0769] 1H NMR(400MHz,DMSO-d6)δppm:8.80-9.00(m,4H),6.50(tt,1H),4.90(m,1H),4.78(td,2H),1.45(d,3H)

[0770] 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl Preparation of 6-(trifluoromethyl)pyridine-4-carboxamide (Compound P40)

[0771]

[0772] To a solution of 1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (80%, 50 mg, 0.142 mmol) in DMF (2 mL) was added 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (90%, 0.0486 g, 0.171 mmol), propanephosphonic anhydride (T3P, 0.136 g, 0.427 mmol), and N,N-diisopropylethylamine (0.0551 g, 0.427 mmol) at 0°C. After the addition, the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (30 mL) and extracted twice with dichloromethane (150 mL each). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by reverse phase chromatography (0% to 80% acetonitrile in water) to give 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-6-(trifluoromethyl)pyridine-4-carboxamide.

[0773] 1 H NMR(400MHz,DMSO-d6)δppm:1.62(d,3H)1.75(m,2H)1.93(m,2H)4.63(t,2H)5.66(t,1H)6.35-6.62(br t,1H)7.98(s,1H)8.11(s,1H)8.69(s,1H)8.78(s,1H)8.82(s,2H)9.48(d,1H)

[0774] LC-MS (method 1): retention time 7.32 min, m / z 520.2 [M+H] + .

[0775] Preparation of 2-chloro-5-(difluoromethoxy)pyrimidine

[0776]

[0777] 2-Chloropyrimidin-5-ol ([CAS: 4983-28-2] 5.00 g, 38.3 mmol) was dissolved in DMF (20.0 mL). Potassium carbonate (10.6 g, 76.6 mmol) and sodium 2-chloro-2,2-difluoroacetate (8.76 g, 57.5 mmol) were added. The resulting reaction mixture was stirred at 80 ° C for 4 h, then cooled to room temperature and diluted with ethyl acetate. This organic layer was washed twice with cold water (100 mL each), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (combiflash, silica gel, 0%-50% ethyl acetate in hexane) to give 2-chloro-5-(difluoromethoxy)pyrimidine.

[0778] 1 H NMR (400 MHz, chloroform-d) δ ppm: 6.45-6.82 (br t, 1H) 8.55 (s, 2H)

[0779] Preparation of tributyl-[5-(difluoromethoxy)pyrimidin-2-yl]stannane

[0780]

[0781] To a solution of 2-chloro-5-(difluoromethoxy)pyrimidine (2.70 g, 13.5 mmol) in toluene (50 mL) was added bis(tributyltin) (10.2 mL, 20.2 mmol). The reaction mixture was purged with argon for 5 minutes, then tetrakis(triphenylphosphine)palladium(0) (778 mg, 0.673 mmol) was added and the reaction mixture was purged with argon for 2 minutes again. The resulting reaction mixture was stirred at 100 ° C for 16 h. The reaction mixture was cooled to 0 ° C, diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to obtain tributyl-[5-(difluoromethoxy)pyrimidin-2-yl]stannane.

[0782] 1 H-NMR (400MHz, CDCl3): δ=8.60(s,1H),7.26(s,1H),6.57(t,1H),1.50-1.70(m,6H),1.25-1.40(m,6H),1.10-1.20(m,6H),0.88(m,9H)ppm.

[0783] Preparation of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (I23)

[0784]

[0785] To a mixture of tributyl-[5-(difluoromethoxy)pyrimidin-2-yl]stannane (3.20 g, 6.62 mmol) in toluene (50.0 mL) was added 1-(4-chloropyrimidin-5-yl)ethanone (1267 mg, 7.28 mmol). The reaction mixture was purged with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (382 mg, 0.331 mmol) and copper iodide (252 mg, 1.32 mmol) were added to the reaction mixture and purged with argon for another 2 minutes. The resulting reaction mixture was stirred at 100 ° C for 16 h. The reaction mixture was cooled to 0 ° C, diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in hexanes) to afford l-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]eneketone as a light brown solid.

[0786] 1 H NMR(400MHz,DMSO-d6)δppm:8.80-9.00(m,4H),7.50(t,1H),2.65(s,3H)

[0787] Preparation of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (I29)

[0788]

[0789] To a solution of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (1.70 g, 6.39 mmol) in a saturated solution of ammonium acetate in ethanol (130 mL) was added sodium cyanoborohydride (1.19 g, 19.2 mmol) and 30% aqueous ammonia (50 mL). The mixture was stirred at reflux for 16 h, cooled to room temperature, and concentrated in vacuo. The crude material was purified by reverse phase chromatography (C18 column, gradient of acetonitrile in water) to give 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine as a light brown gum.

[0790] 1 H NMR(400MHz,DMSO-d6)δppm:8.80-9.10(m,4H),7.51(t,1H),4.88(m,1H),1.50(d,3H)

[0791] 3-cyclopropyl-N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-5-(trifluoromethoxy) Preparation of 4-(4-amino)benzamide (Compound P7)

[0792]

[0793] To a stirred solution of 3-cyclopropyl-5-(trifluoromethyl)benzoic acid (90%, 0.0861 g, 0.337 mmol) in toluene (5 mL) was added thionyl chloride (0.0737 mL, 1.01 mmol) dropwise. The reaction mixture was stirred at reflux for 2 h, then cooled to room temperature and concentrated in vacuo to afford the corresponding acid chloride.

[0794] To a solution of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (90%, 0.100 g, 0.337 mmol) in dichloromethane (2 mL) and triethylamine (0.284 mL, 0.202 mmol) was added the previously prepared solution of the acid chloride in dichloromethane (3 mL) dropwise over 5 minutes. After the addition, the reaction mixture was stirred at room temperature for 2 hours. It was cooled to 0°C, quenched with water (10 mL), and extracted twice with ethyl acetate (50 mL each). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (combiflash, silica gel, 0%-100% ethyl acetate in hexanes) to give 3-cyclopropyl-N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-5-(trifluoromethyl)benzamide.

[0795] 1 H NMR (400 MHz, chloroform-d) δ ppm: 0.75-0.82 (m, 2H) 1.02 (d, 2H) 1.30 (d, 3H) 2.03-2.12 (m, 1H) 5.54-5.62 (m, 1H) 7.29-7.67 (br t, 1H) 7.61 (d, 2H) 7.80 (s, 1H) 8.70 (s, 1H) 8.79 (s, 1H) 8.94 (s, 2H) 9.06 (d, 1H)

[0796] LC-MS (method 1): retention time 7.65 min, m / z 480.1 [M+H] + .

[0797] 3-[Cyclopropyl(difluoro)methyl]-N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl Preparation of 5-(trifluoromethyl)benzamide (P29)

[0798]

[0799] To a solution of 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid (4.72 mg, 0.0168 mmol) in toluene (2.0 mL) was added thionyl chloride (0.0037 mL, 0.051 mmol) dropwise at room temperature. The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The crude material was dissolved in dichloromethane (1 mL), and a solution of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (5.0 mg, 0.017 mmol) in dichloromethane (2.0 mL) was added, followed by triethylamine (0.0071 mL, 0.051 mmol). The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0°C. Water was added, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of ethyl acetate in hexanes) to give 3-[cyclopropyl(difluoro)methyl]-N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-5-(trifluoromethyl)benzamide as an off-white solid.

[0800] 1 H-NMR (400MHz, chloroform-d)δ=0.65-0.75(m,4H),1.10(t,1H),1.63(d,3H),1.70-1.90(m,1H),5.61(m,1 H),7.48(t,1H),7.95(s,1H),8.20(d,2H),8.70(m,1H),8.79(m,1H),8.92(m,2H),9.28(d,1H)ppm

[0801] N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-3-(trifluoromethyl)-5-(trifluoromethyl) Preparation of (methylsulfonyl)benzamide (P19)

[0802]

[0803] To a solution of 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoic acid (121 mg, 0.337 mmol) in toluene (2.0 mL) was added thionyl chloride (0.0737 mL, 1.01 mmol) dropwise at room temperature. The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The crude acid chloride was dissolved in dichloromethane (10 mL), and a solution of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (100.0 mg, 0.337 mmol) in dichloromethane (10.0 mL) was added, followed by triethylamine (0.142 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0°C. Water was added, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of ethyl acetate in hexanes) to afford N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzamide as an off-white solid.

[0804] 1 H-NMR (400 MHz, chloroform-d) δ=1.63 (d, 3H), 5.61 (m, 1H), 7.48 (t, 1H), 8.52 (s, 1H), 8.65-8.73 (m, 3H), 8.79 (d, 1H), 8.92 (s, 2H), 9.57 (s, 1H) ppm

[0805] Preparation of 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine

[0806]

[0807] To a solution of 6-bromopyridine-3-ol (20.0 g, 115 mmol) and potassium carbonate (31.8 g, 230 mmol) in acetonitrile (200 mL) stirred at room temperature for 5 min, trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (29.3 g, 126 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with salt water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to obtain 2-bromo-5-(2,2,2-trifluoroethoxy) pyridine.

[0808] 1 H-NMR (400MHz, CDCl3): δ=8.15(d,1H),7.45(d,1H),7.2(dd,1H),4.4(q,2H)ppm.

[0809] Preparation of tributyl-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]stannane

[0810]

[0811] To a solution of 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine (9.00 g, 31.6 mmol) in toluene (300 mL) was added bis(tributyltin) (20.7 mL, 41.1 mmol). The reaction mixture was purged with argon for 20 minutes, then tetrakis(triphenylphosphine)palladium(0) (2.74 g, 2.37 mmol) was added and the reaction mixture was purged with argon for another 2 minutes. The resulting reaction mixture was stirred at 100 ° C for 48 h. The reaction mixture was cooled to 0 ° C, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to obtain tributyl-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]stannane.

[0812] 1 H-NMR (400MHz, CDCl3): δ=8.55(d,1h),7.4(dd,1H),7.15(m,1H),4.4(q,2H),1.55(m,6H),1.35(m,6H),1.15(m,6H),0.95(m,9H)ppm.

[0813] Preparation of 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazin-2-yl]ethanone (I25)

[0814]

[0815] To a solution of tributyl-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]stannane (550 mg, 1.06 mmol) in toluene (20 mL) was added 1-(3-chloropyrazin-2-yl)ethanone (203 mg, 1.17 mmol) and copper (I) iodide (40.4 mg, 0.212 mmol). The reaction mixture was purged with argon for 10 min and tetrakis(triphenylphosphine)palladium(0) (61.4 mg, 0.0531 mmol) was added. The reactants were stirred at 100 ° C for 2 h. The reaction mixture was cooled to 0 ° C, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to give 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazin-2-yl]ethanone.

[0816] 1H-NMR (400MHz, DMSO-d6): δ=8.85(d,1H),8.7(m,1H),8.45(s,1H),8.25(d,1H),7.75(d,1H),5(q,2H),2.6(s,3H)ppm.

[0817] Preparation of 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazin-2-yl]ethanamine (I31)

[0818]

[0819] To a solution of 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazine-2-yl]ethanone (1.80 g, 5.45 mmol) in a saturated solution of ammonium acetate in ethanol (120 mL) was added sodium cyanoborohydride (1.01 g, 16.4 mmol) and ammonia (30% in water, 50 mL) at room temperature. The reaction mixture was stirred under reflux for 18 hours. After cooling to room temperature, it was concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (eluting with acetonitrile in water) to obtain 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazine-2-yl]ethanamine.

[0820] 1 H-NMR (400MHz, DMSO-d6): δ=8.8(s,2H),8.65(d,1H),8.15(d,1H),7.8(m,1H),7.45(br s,2H),7.25(m,1H),7.15(m,1H),5.2(br s,1H),5(q,2H),1.5(m,3H)ppm.

[0821] 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]pyrazin-2-yl]ethyl Preparation of 6-(trifluoromethyl)pyridine-4-carboxamide (Compound P23)

[0822]

[0823] To a solution of 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (85.9 mg, 0.302 mmol) in toluene (5 mL) was added thionyl chloride (66 μL, 0.0905 mmol) dropwise at 0 ° C. The reaction mixture was stirred at 90 ° C for 20 hours. After cooling to room temperature, it was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 mL) and added to a solution of 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazine-2-yl]ethylamine (100 mg, 0.302 mmol) and triethylamine (0.127 mL, 0.905 mmol) in dichloromethane (10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in n-hexanes) to give 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridinyl]pyrazin-2-yl]ethyl]-6-(trifluoromethyl)pyridine-4-carboxamide.

[0824] 1 H-NMR (400MHz, DMSO-d6): δ = 9.5 (d, 1H), 8.75 (dd, 2H), 8.55 (m, 1H), 8.15 (s, 1H), 8.05 (d, 1h) ),8(s,1H),7.75(dd,1H),5.9(t,1H),5(q,2H),1.95(m,2H),1.75(m,2H),1.65(dd,3H)ppm.

[0825] Preparation of 2-chloro-5-(2,2,2-trifluoroethoxy)pyrimidine

[0826]

[0827] To a solution of 2-chloropyrimidine-5-ol (1.0 g, 7.7 mmol) in N, N-dimethylformamide (7.7 mL) was added cesium carbonate (3.2 g, 10 mmol). 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.2 g, 9.2 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The combined organic layers were washed four times with water and then washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to obtain 2-chloro-5-(2,2,2-trifluoroethoxy) pyrimidine as a light yellow oil.

[0828] 1H NMR (400 MHz, chloroform) δ ppm 4.46-4.52 (m, 2H) 8.40 (s, 2H)

[0829] 19 F NMR (377 MHz, chloroform) δ ppm-73.74 (s)

[0830] Preparation of tributyl-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]stannane

[0831]

[0832] To a solution of 2-chloro-5-(2,2,2-trifluoroethoxy) pyrimidine (1.00 g, 4.70 mmol) in toluene (10 mL) was added bis(tributyltin) (4.09 g, 7.06 mmol). The reaction mixture was purged with argon for 5 minutes, tetrakis(triphenylphosphine)palladium(0) (0.544 g, 0.470 mmol) was then added and the reaction mixture was purged with argon for 5 minutes. The resulting reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on neutral alumina (eluted with ethyl acetate in n-hexane) to obtain tributyl-[5-(2,2,2-trifluoroethoxy) pyrimidin-2-yl] tin alkane.

[0833] 1 H-NMR (400MHz, CDCl3): δ=8.50(s,1H),8.40(s,1H),4.43(m,2H),4.12(q,2H), 1.50-1.70(m,6H),1.20-1.45(m,6H),1.10-1.20(m,6H),0.83-0.98(m,9H)ppm.

[0834] Preparation of 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (I24)

[0835]

[0836] To a solution of tributyl-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]stannane (1.00 g, 2.14 mmol) in toluene (20 mL) was added 1-(3-chloropyrazin-2-yl)ethanone (0.402 g, 2.57 mmol). The reaction mixture was purged with argon for 5 min, and then copper (I) iodide (0.0815 g, 0.428 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.57 g, 2.14 mmol) were added. The reactants were stirred at 100 ° C for 4 hours. The reaction mixture was cooled to 0 ° C, filtered through celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in n-hexane) to give 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone.

[0837] m / z=299.1[M+H] +

[0838] Preparation of 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (I30)

[0839]

[0840] To a solution of 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (700 mg, 1.88 mmol) in a saturated solution of ammonium acetate in ethanol (100 mL) was added sodium cyanoborohydride (0.354 g, 5.63 mmol) and ammonia (30% in water, 30 mL) at room temperature. The reaction mixture was stirred at reflux for 18 hours. After cooling to room temperature, the mixture was washed with dichloromethane. The aqueous layer was concentrated in vacuo. The crude material was purified by reverse phase chromatography (eluting with acetonitrile in water) to give 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine.

[0841] 1 H-NMR (400MHz, DMSO-d6): δ=8.95(s,2H),8.60-9.00(m,2H),7.8-8.30(br s,2H),5.08-5.20(m,2H),4.95-5.05(m,1H),1.5(m,3H)ppm.

[0842] 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl Preparation of 6-(trifluoromethyl)pyridine-4-carboxamide (Compound P34)

[0843]

[0844] To a stirred solution of 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (30.0 mg, 0.100 mmol) in N,N-dimethylformamide (2.0 mL) at 0°C were added 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (0.0257 g, 0.100 mmol), propanephosphonic anhydride, and 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine (30.0 mg, 0.100 mmol). To the product of 4-nitropropane-2-ol (0.050g, 0.1mmol) and 4-nitropropane-2-ol (0.050g, 0.1mmol).(0.0957g, 0.301mmol) and N, N-diisopropylethylamine (0.0389g, 0.301mmol).The mixture is stirred at room temperature for 5h.The reaction mixture is diluted with water (30mL) and extracted twice with dichloromethane.The combined organic layer is washed with salt water (30mL), dried over sodium sulfate and concentrated in vacuo.The crude material is purified by reverse phase chromatography (C18 columns, gradient of acetonitrile in water) to obtain 2- (1- cyanocyclopropyl) -N- [1- [3- [5- (2,2,2- trifluoroethoxy) pyrimidine -2- bases] pyrazine -2- bases] ethyl] -6- (trifluoromethyl) pyridine -4- formamide as off-white solid.

[0845] 1 H-NMR (400MHz, DMSO-d6): δ=9.45(d,1H),8.82-8.90(m,2H),8.75-8.80(m,1H),8.68-8.75(m,1H),8.16-8.22(m,1H), 7.95-8.15(m,1H),5.60-5.70(m,1H),5.00-5.15(m,2H),1.90-1.98(m,2H),1.70-1.80(m,2H),1.56-1.65(d,3H)ppm.

[0846] Preparation of 6-tributylstannylpyridine-3-carbonitrile

[0847]

[0848] To a solution of 6-chloropyridine-3-carbonitrile (250mg, 1.80mmol) in toluene (10mL), six n-butyl ditin (1.00mL, 1.98mmol) is added. The reaction mixture is purged with argon for 2 minutes. Then tetrakis (triphenylphosphine) palladium (0) (146mg, 0.126mmol) is added and purged with argon for 2 minutes again. The gained reaction mixture is heated to 130 ℃ and stirred for 16 hours. After cooling to room temperature, the reaction mixture is filtered through diatomite. The filtrate is concentrated under reduced pressure. Purification of crude material by neutral alumina flash chromatography (eluting with ethyl acetate in hexane) obtains 6-tributyl stannyl pyridine-3-carbonitrile.

[0849] 1H-NMR (400MHz, CDCl3): δ=8.90-9.00(m,1H),7.65-7.75(m,1H),7.50-7.60(m,1H),7.25-7 .40(m,2H),1.45-1.65(m,4H),1.25-1.40(m,7H),1.10-1.20(m,5H),0.80-0.95(m,9H)ppm.

[0850] Preparation of 6-(3-acetylpyrazin-2-yl)pyridine-3-carbonitrile (I21)

[0851]

[0852] To a solution of 6-tributylstannylpyridine-3-carbonitrile (24.0g, 48.8mmol) in toluene (600mL), 1-(4-chloropyrimidine-5-yl) ethyl ketone (9.18g, 52.7mmol) and copper iodide (I) (1.86g, 9.77mmol) are added. The reaction mixture is purged with argon for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (2.82g, 2.44mmol) is then added. The reaction mixture is heated to 95°C and stirred for 5 hours. After being cooled to room temperature, it is filtered through diatomite and the filtrate is concentrated under reduced pressure. Purification of crude material on silica gel (eluting with ethyl acetate in hexane) is performed by flash chromatography to obtain 6-(3-acetylpyrazine-2-yl) pyridine-3-carbonitrile.

[0853] 1 H-NMR (400MHz, d6-DMSO): δ = 9.1 (m, 2H), 8.92 (m, 1H), 8.83 (m, 1H) 8.53 (d, 1H) 8.32 (d, 1H) 2.65 (s, 3H) ppm.

[0854] Preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]pyridine-3-carbonitrile (I27)

[0855]

[0856] At room temperature to 6-(3-acetyl pyrazine-2-yl) pyridine-3-carbonitrile (0.200g, 0.803mmol) in the ethanol saturated solution of ammonium acetate (30mL), add ammoniacal liquor (20mL) and sodium cyanoborohydride (154mg, 2.41mmol).Reaction mixture is heated to reflux and stirred 12 hours.After being cooled to room temperature, it is concentrated under reduced pressure.By reversed-phase chromatography (using the acetonitrile wash-out in water) purification of crude material, 6-[3-(1-aminoethyl) pyrazine-2-yl] pyridine-3-carbonitrile is obtained.

[0857] 1H-NMR (400MHz, d6-DMSO): δ=9.22(s,1H),8.85-8.95(m,2H),8.50-8.60(m,1H) ),8.30-8.40(m,1H)7.80-8.10(br.s,2H),5.25-5.35(m,1H),1.52(d,3H)ppm.

[0858] 3-(1-cyanocyclopropyl)-N-[1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]-5-(trifluoromethyl)- Preparation of 4-(2-amino)benzamide (P25)

[0859]

[0860] To a solution of 3-[cyano(cyclopropyl)methyl]-5-(trifluoromethyl)benzoic acid (0.130g, 0.459mmol) in toluene (20mL) was added dropwise thionyl chloride (0.134mL, 1.83mmol) at 0°C. The reaction mixture was heated to 90°C and stirred for 20 hours. After cooling to room temperature, it was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (10mL) and added to a solution of 6-[3-(1-aminoethyl)pyrazine-2-yl]pyridine-3-carbonitrile (0.126g, 0.505mmol) and triethylamine (0.258mL, 1.83mmol) in dichloromethane (5mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in hexanes) to give 3-(1-cyanocyclopropyl)-N-[1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]-5-(trifluoromethyl)benzamide.

[0861] 1 H-NMR (400MHz, d6-DMSO): δ=9.28(d,1H),9.15-9.20(m,1H),8.72-8.80(d,1H),8.65-8.72(d,1H),8.45-8.55(m ,1H),8.19(d,1H),8.06(s,1H),7.95(s,1H),7.75(s,1H),5.78(t,1H),1.80-1.87(m,2H),1.60-1.75(m,5H)ppm.

[0862] 2-(1-cyanocyclopropyl)-N-[1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]-6-(trifluoromethyl)- Preparation of 4-(2-amino-4-pyridine)-4-carboxamide (Compound P16)

[0863]

[0864] Under argon, thionyl chloride (0.14mL, 1.93mmol) is added dropwise to a stirred solution of 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (I17, 130mg, 0.482mmol) in toluene (20mL) at 0°C. The solution is heated at 90°C for 2h, and the reaction mixture is then concentrated in vacuo. The residue is diluted in dichloromethane (10mL) and added to a stirred solution of 6-[3-(1-aminoethyl)pyrazine-2-yl]pyridine-3-carbonitrile (121mg, 0.482mmol) and triethylamine (0.271mL, 1.93mmol) in dichloromethane (10mL) at 0°C. The reaction mixture is stirred at room temperature for 2 hours, then diluted with dichloromethane and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (C18 column, gradient of acetonitrile in water) to give 2-(1-cyanocyclopropyl)-N-[1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]-6-(trifluoromethyl)pyridine-4-carboxamide as a white solid.

[0865] 1 H-NMR (400MHz, d6-DMSO): δ=9.55(d,1H),9.18(m,1H),8.78(d,1H),8.71(d,1H),8.52(dd,1H),8. 20(d,1H),8.11(s,1H),7.96(s,1H),5.81(m,1H),1.91(m,2H),1.71-1.80(m,2H),1.67(d,3H)ppm.

[0866] 19 F NMR(377MHz,d6-DMSO)δ=-66.70(s)ppm

[0867] N-[1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]-3-(1-methoxycyclopropyl)-5-(trifluoromethyl) Preparation of 4-(2-amino-4-methyl)benzamide (P50)

[0868]

[0869] At 0 ℃, thionyl chloride (0.108mL, 1.48mmol) is added dropwise to a stirred solution of 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid (I39, 130mg, 0.493mmol) in toluene (3mL). The reaction mixture is heated to 90 ℃ and stirred for 2 hours. After cooling to room temperature, it is concentrated under reduced pressure. The gained residue is dissolved in dichloromethane (2mL) and added to a solution of 6-[3-(1-aminoethyl)pyrazine-2-yl]pyridine-3-carbonitrile (0.125g, 0.542mmol) and triethylamine (0.208mL, 1.48mmol) in dichloromethane (2mL). The reaction mixture is stirred at room temperature for 2 hours. It is then diluted with dichloromethane and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (C18 column, gradient of acetonitrile in water) to afford N-[1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzamide as an off-white solid.

[0870] 1H-NMR (400MHz, d6-DMSO): δ=9.12-9.35(m,2H),8.75-8.80(d,1H),8.68-8.75(d,1H),8.46-8.52(m,1H),8.19(d,1H),7.9 7(s,1H),7.82(s,1H),7.66(s,1H),5.71-5.82(m,1H),3.13(s,3H),1.68(d,2H),1.20-1.28(m,2H),1.08-1.12(m,2H)ppm.

[0871] Preparation of 1-(3-chloropyrazin-2-yl)ethylamine

[0872]

[0873] To a solution of 1-(3-chloropyrazine-2-yl)ethanone (0.200 g, 1.28 mmol) in methanol (4.5 mL) was added ammonium acetate (0.995 g, 12.8 mmol) and sodium cyanoborohydride (0.0591 g, 0.894 mmol) at room temperature. The resulting suspension was stirred at room temperature for 18 hours and then concentrated in vacuo. The crude material was purified by reverse phase chromatography (C18 column, gradient of acetonitrile in water) to give 1-(3-chloropyrazine-2-yl)ethanamine.

[0874] 1H NMR (400MHz, CDCl3)δ=8.49(d,1H),8.26(d,1H),4.56(q,1H),1.95(br s,2H),1.44(d,3H)ppm

[0875] Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethylamine (I34)

[0876]

[0877] To a solution of 1-(3-chloropyrazin-2-yl)ethanamine (202.2 mg, 1.20 mmol) in tert-butyl methyl ether (11 mL) was added To the mixture of 435 (240 mg), ethyl methoxyacetate (1.44 mL, 12.0 mmol) was added. The mixture was stirred at 40 ° C for 5.5 hours. The reaction mixture was diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with a gradient of methanol in dichloromethane) to give (1S)-1-(3-chloropyrazin-2-yl)ethanamine.

[0878] 1 H NMR (400MHz, CDCl3)δ=8.49(d,1H),8.27(d,1H),4.56(q,1H),1.73(br s,2H),1.44(d,3H)ppm

[0879] [α] D 20 :-32.3°(c:1.157,CHCl3)

[0880] Preparation of (1R)-1-(3-chloropyrazin-2-yl)ethanol (I26)

[0881]

[0882] 1-(3-chloropyrazine-2-yl) ethyl ketone (157mg, 1.00mmol) is dissolved in dichloromethane (10.0mL) and the flask is evacuated and backfilled three times with argon.Then RuBF4[(R,R)-TsDPEN](p-cymene) (0.0362g, 0.0526mmol) is added. The cooling solution of triethylamine (0.348mL, 2.50mmol) and formic acid (0.160mL, 4.29mmol) is added dropwise to the reaction mixture, which is stirred at room temperature for 4 hours. The reaction mixture is concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (gradient elution with ethyl acetate in cyclohexane) to obtain (1R)-1-(3-chloropyrazine-2-yl) ethanol.

[0883] 1H-NMR (400MHz, CDCl3)δ=8.49(d,1H),8.34(d,1H),5.18(m,1H),3.81(d,1H),1.52(d,3H)ppm

[0884] Chiral SFC (Method 2): 1.98 min (minor enantiomer), 2.55 min (major enantiomer); ee = 85%

[0885] Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethylamine (I34)

[0886]

[0887] (1R) -1- (3- chloropyrazine -2- base) ethanol (87.8 mg, 0.554 mmol) is dissolved in tetrahydrofuran (1.9 mL). Then, 1,8- diazabicyclo [5.4.0] undec-7-ene (0.10 mL, 0.66 mmol) is added dropwise to the reaction mixture, followed by diphenylphosphine azide (0.130 mL, 0.585 mmol). The reaction mixture is stirred at room temperature for 19 hours. Tetrahydrofuran (1.4 mL) is added, followed by triphenylphosphine (179.4 mg, 0.677 mmol). The reaction mixture is stirred at room temperature for 2 hours. Water (0.15 mL) is added, and the reaction mixture is stirred at room temperature for 46 hours. The reaction mixture is concentrated to a volume of 1 mL and then diluted with dichloromethane. 1 M hydrochloric acid is added, and the water layer is then washed with dichloromethane. The water layer is alkalized to pH = 14 with 4 M sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo.The crude material was purified by flash chromatography on silica gel (eluting with a gradient of methanol in dichloromethane) to afford (1S)-1-(3-chloropyrazin-2-yl)ethanamine.

[0888] 1 H NMR (400MHz, CDCl3)δ=8.49(d,1H),8.27(d,1H),4.56(q,1H),1.84(s,2H),1.44(d,3H)ppm

[0889] [α] D 20 :-26.0°(c:0.960,CHCl3)

[0890] Preparation of (2R)-N-[(1S)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide

[0891]

[0892] To a solution of 1-(3-chloropyrazin-2-yl)ethanamine; hydrochloride (700 mg, 3.61 mmol) in dichloromethane (18 mL) was added (R)-(-)-mandelic acid (610 mg, 3.97 mmol), N-ethyldiisopropylamine (1.26 mL, 7.21 mmol), 1-hydroxybenzotriazole (50.8 mg, 0.361 mmol) and N,N'-dicyclohexylcarbodiimide (844 mg, 3.97 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with methanol in dichloromethane) to give (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide and (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide. The relative stereochemistry of (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide was determined by X-ray crystallography (crystallization from acetonitrile / water).

[0893] Analytical data for (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide:

[0894] LCMS: Rt 0.74, m / z=291(M+H + )

[0895] Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethanamine; hydrochloride

[0896]

[0897] A solution of (2R)-N-[(1S)-1-(3-chloropyrazine-2-yl)ethyl]-2-hydroxy-2-phenyl-acetamide (0.93g, 3.2mmol) in hydrochloric acid (32% in water, 13mL) was heated to reflux and stirred for 2 hours. After cooling to room temperature, the reaction mixture was alkalized with 3N sodium hydroxide and diluted and extracted with ethyl acetate. The water layer was freeze-dried overnight and the gained solid was suspended in acetone. The suspension was filtered and the filtrate was concentrated under reduced pressure. The gained oil was dissolved in ethyl acetate and 1N hydrochloric acid was added. A precipitate was produced, which was filtered and dried under reduced pressure to obtain the desired product.

[0898] LCMS: Rt 0.19, m / z=158 (M+H+).

[0899] Preparation of (1S)-1-(3-chloropyrazin-2-yl)-N-(cyclopropylmethyl)ethanamine (I35)

[0900]

[0901] Sodium triacetoxyborohydride (59.4 mg, 0.267 mmol) was added to a stirred solution of (1S)-1-(3-chloropyrazin-2-yl)ethanamine (30.0 mg, 0.190 mmol), cyclopropanecarboxaldehyde (15.0 mg, 0.209 mmol) and acetic acid (0.0109 mL, 0.190 mmol) in 1,2-dichloroethane (0.95 mL). The mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium carbonate solution was added and the aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to give (1S)-1-(3-chloropyrazin-2-yl)-N-(cyclopropylmethyl)ethanamine. 1 H NMR (400 MHz, solvent) δ = -0.03-0.10 (m, 2H) 0.38-0.52 (m, 2H) 0.83-1.00 (m, 1H) 1.40 (d, 3H) 2.07 (dd, 1H) 2.15-2.29 (m, 1H) 2.53 (dd, 1H) 4.39 (q, 1H) 8.26 (d, 1H) 8.51 (d, 1H) ppm

[0902] [α] D 20 =-54°(c 0.327,CHCl3)

[0903] N-[(1S)-3-(5-bromo-2-pyridyl)-2-hydroxy-1-methyl-3-oxo-propyl]carbamic acid tert-butyl ester preparation

[0904]

[0905] Prepare N-[(1S)-1-methyl-2-oxo-ethyl] carbamic acid tert-butyl ester (CAS 79069-50-4, 1.07g, 6.18mmol) in dichloromethane (12mL) in a round-bottom flask. The flask is evacuated and refilled with argon three times. Then, 2-(3-benzyl-4-methyl-thiazole-3-ium-5-yl) ethanol is added continuously; Bromide (0.388g, 1.24mmol), 5-bromopyridine-2-carboxaldehyde (CAS 31181-90-5, 1.81g, 9.27mmol) and dichloromethane (6mL), followed by N, N-diisopropylethylamine (2.16mL, 12.4mmol). The reaction mixture is stirred at room temperature for 1 hour. It is quenched with saturated aqueous ammonium chloride and extracted three times with dichloromethane. The combined organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to afford tert-butyl N-[(1S)-3-(5-bromo-2-pyridinyl)-2-hydroxy-1-methyl-3-oxo-propyl]carbamate as an orange gum.

[0906] LCMS: Rt 0.98, m / z=359-361(M+H + )(bromine mode); 1 H-NMR (400MHz, CDCl3) δ = 1.37-1.40 (m, 3H) 1.43-1.44 (m, 9H) 4.34-4.69 (m, 2H) 5.22-5.36 (m, 1H) 7.86-8.08 (m, 2H) 8.73 (d, J = 2.20Hz, 1H) ppm.

[0907] Preparation of tert-butyl N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxo-propyl]carbamate

[0908]

[0909] To a solution of tert-butyl N-[(1S)-3-(5-bromo-2-pyridyl)-2-hydroxy-1-methyl-3-oxo-propyl]carbamate (15.2 g, 42.3 mmol) in dichloromethane (100 mL) and dimethyl sulfoxide (20 mL) was added N,N-diisopropylethylamine (21.8 mL, 127 mmol, 3.00 equiv) and sulfur trioxide pyridine complex (13.9 g, 84.6 mmol, 2.00 equiv) in two batches at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. It was quenched with water and diluted with dichloromethane and 1N hydrochloric acid. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to afford tert-butyl N-[(1S)-3-(5-bromo-2-pyridinyl)-1-methyl-2,3-dioxo-propyl]carbamate as an orange oil.

[0910] 1H-NMR (400MHz, CDCl3) δ = 1.36-1.41 (m, 9H) 1.45-1.48 (m, 3H) 4.82-4.96 (m, 1H) 5.10 (br s,1H)7.91-8.00(m,1H)8.01-8.11(m,1H)8.79(d,J=1.83Hz,1H)ppm.

[0911] Preparation of tert-butyl N-[(1S)-1-[3-(5-bromo-2-pyridyl)pyrazin-2-yl]ethyl]carbamate (I33)

[0912]

[0913] To a solution of N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxo-propyl] tert-butyl carbamate (375 mg, 1.05 mmol) in ethanol (22 mL) was added ethylenediamine (0.36 mL, 5.24 mmol). The reaction mixture was stirred at room temperature for 60 hours in the presence of air. It was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in cyclohexane) to obtain tert-butyl N-[(1S)-1-[3-(5-bromo-2-pyridyl)pyrazine-2-yl]ethyl]carbamate as a colorless gum.

[0914] LCMS: Rt 1.09, m / z=379-381 (M+H+) (bromine mode);

[0915] 1H-NMR (400MHz, CDCl3) δ = 1.33-1.45 (m, 9H) 1.52-1.56 (m, 3H) 5.65-5.83 (m, 2H) 7.96-8.02 (m, 2H) 8.53-8.60 (m, 2H) 8.79 (dd, J = 2.20, 1.10Hz, 1H) ppm.

[0916] Chiral SFC (Method 1): 1.80 min (major enantiomer), 1.11 min (minor enantiomer); ee = 92%

[0917] Tert-butyl N-[(1S)-1-[6-amino-3-(5-bromo-2-pyridyl)pyrazin-2-yl]ethyl]carbamate (I37) Preparation

[0918]

[0919] To N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxo-propyl] carboxylamine tert-butyl ester (500mg, 0.894mmol) in isopropyl alcohol (13.4mL) solution, add 2-aminoacetamidine dihydrobromide (1.21g, 4.11mmol).Add potassium acetate (266mg, 2.68mmol).In the presence of air, reaction mixture is stirred at room temperature for 2.5 hours.Reactant is quenched with water and aqueous layer is extracted with ethyl acetate.The organic layer merged is washed with salt water, dried over magnesium sulfate, filtered and concentrated under reduced pressure.By reverse phase chromatography (C18, eluted with ACN in water) purification of crude material obtains N-[(1S)-1-[6-amino-3-(5-bromo-2-pyridyl) pyrazine-2-yl] ethyl] carboxylamine tert-butyl ester.

[0920] LCMS: Rt 1.00, m / z=394-396(M+H + )(bromine mode); 1 H-NMR (600MHz, CDCl3) δ = 1.45 (brs, 9H) 1.47 (d, J = 6.7Hz, 3H) 4.84 (br s, 2H) 5.66-5.74 (m, 1H) 5.89 (br s, 1H) 7.86-7.88 (m, 1H) 7.89 (br d,J=2.0Hz,1H)7.90(s,1H)8.72(s,1H)ppm

[0921] Preparation of tert-butyl N-[(1S)-1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]carbamate (I36) Preparation

[0922]

[0923] At room temperature, under argon, degassed 1,4-dioxane (9.20 mL) was added to a mixture of tert-butyl N-[(1S)-1-[3-(5-bromo-2-pyridyl)pyrazin-2-yl]ethyl]carbamate (1.396 g, 3.681 mmol), potassium ferricyanide (1.224 g, 3.681 mmol), tBuXPhos Pd-G3 (0.151 g, 0.184 mmol) and tBuXPhos (0.082 g, 0.18 mmol). A degassed solution of potassium acetate (0.05 M in water, 9.20 mL, 0.500 mmol) was added and the mixture was stirred at 100 ° C for 5 hours. The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to give tert-butyl N-[(1S)-1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]carbamate as a white solid.

[0924] 1 H-NMR (400MHz, CDCl3) δ = 1.38 (br s,9H),1.55(d,3H),5.66-5.78(m,2H),8.11(dd,1H),8.30(d,1H),8.59(d,1H),8.63(d,1H),8.93-9.04(m,1H)ppm.

[0925] Preparation of 6-[3-[(1S)-1-aminoethyl]pyrazin-2-yl]pyridine-3-carbonitrile (I32)

[0926]

[0927] Trifluoroacetic acid (0.69 mL, 8.7 mmol) was added to a solution of tert-butyl N-[(1S)-1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]carbamate (0.520 g, 1.60 mmol) in dichloromethane (3.5 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, then washed with saturated aqueous sodium carbonate, dried over magnesium sulfate, and concentrated in vacuo to give 6-[3-[(1S)-1-aminoethyl]pyrazin-2-yl]pyridine-3-carbonitrile.

[0928] LCMS (method 1): Rt 0.28, m / z=226 [M+H] +

[0929] 1H-NMR (400MHz, CDCl3) δ = 1.48 (d, J = 6.60Hz, 3H) 1.96 (s, 2H) 4.74 (q, J = 6.60Hz, 1H) 8.09-8.14 (m, 1 H)8.19-8.23(m,1H)8.55(d,J=2.57Hz,1H)8.65(d,J=2.20Hz,1H)8.97(dd,J=2.20,0.73Hz,1H)ppm

[0930] Preparation of 6-[3-[(1S)-1-(cyclopropylmethylamino)ethyl]pyrazin-2-yl]pyridine-3-carbonitrile (I33)

[0931]

[0932] To a solution of 6-[3-[(1S)-1-aminoethyl]pyrazine-2-yl]pyridine-3-carbonitrile (0.200 g, 0.888 mmol) in 1,2-dichloroethane (4.4 mL) was added cyclopropanecarboxaldehyde (0.0745 mL, 0.977 mmol), acetic acid (0.051 mL, 0.89 mmol) and sodium triacetoxyborohydride (0.277 g, 1.24 mmol). The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium carbonate was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluted with ethyl acetate in cyclohexane) to give 6-[3-[(1S)-1-(cyclopropylmethylamino)ethyl]pyrazine-2-yl]pyridine-3-carbonitrile as a yellow oil.

[0933] 1 H-NMR (400MHz, CDCl3)δ=-0.05(dd,2H)0.39(td,2H)0.81-0.94(m,1H)1.50(d,3H)1.98(dd,1H)2.44(dd,1H )2.49-2.89(m,1H)4.73(q,1H)8.11-8.18(m,1H)8.20-8.27(m,1H)8.57(d,1H)8.69(d,1H)9.00(dd,1H)ppm

[0934] N-[(1S)-1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]-3-[cyclopropyl(difluoro)methyl]-N- Preparation of (cyclopropylmethyl)-5-(trifluoromethyl)benzamide (P43)

[0935]

[0936] Oxalyl chloride (0.0375mL, 0.428mmol) is added to a solution of 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid (0.0800g, 0.286mmol) in dichloromethane (0.87mL) containing a drop of N,N-dimethylformamide. After one hour, the reaction mixture is concentrated in vacuo. The crude acid chloride is dissolved in ethyl acetate (1.1mL) and 6-[3-[(1S)-1-(cyclopropylmethylamino)ethyl]pyrazine-2-yl]pyridine-3-carbonitrile (0.0797g, 0.286mmol) and aqueous sodium bicarbonate (1N, 1.14mL, 1.14mmol) are added. The mixture is stirred at room temperature for 45 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to give N-[(1S)-1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]-3-[cyclopropyl(difluoro)methyl]-N-(cyclopropylmethyl)-5-(trifluoromethyl)benzamide.

[0937] 1 H NMR(400MHz,TFA-d1)δ=-0.23-0.05(m,2H)0.35-0.57(m,2H)0.60-0.78(m,3H)0.76-1.04(m,2H)1.14-1.31(m,1H)1.32-1.47(m,1H)1.53-1.6 8(m,1H)2.03-2.17(m,3H)3.29-3.46(m,1H)3.54-3.73(m,1H)6.32-6. 50(m,1H)7.67-7.83(m,2H)7.90-8.06(m,1H)8.61-8.82(m,2H)9.08(br s, 1H) 9.18-9.38 (m, 2H) ppm; LCMS (method 1): Rt 1.21, m / z=542 [M+H] + ; [α] D 20 :+152°(c:0.477,CHCl3)

[0938] N-[(1S)-1-[3-(5-cyano-2-pyridyl)pyrazin-2-yl]ethyl]-3-[cyclopropyl(difluoro)methyl]-5- Preparation of (trifluoromethyl)benzamide (P42)

[0939]

[0940] Oxalyl chloride (0.0375mL, 0.428mmol) is added to a solution of 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid (0.0800g, 0.286mmol) in dichloromethane (0.87mL) containing a drop of N,N-dimethylformamide. After one hour, the reaction mixture is concentrated in vacuo. The crude acid chloride is dissolved in ethyl acetate (1.1mL) and 6-[3-[(1S)-1-aminoethyl]pyrazine-2-yl]pyridine-3-carbonitrile (0.0643g, 0.286mmol) and aqueous sodium bicarbonate (1N, 1.14mL, 1.14mmol) are added. The mixture is stirred at room temperature for 45 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) to give N-[(1S)-1-[3-(5-cyano-2-pyridinyl)pyrazin-2-yl]ethyl]-3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzamide.

[0941] 1 H NMR (400MHz, CDCl3) δ = 0.71-0.79 (m, 2H) 0.81-0.88 (m, 2H) 1.47-1.60 (m, 1H) 1.72 (d, 3H) 6.27-6.37 (m, 1H) 7.63 (br d,1H)7.93(s,1H)8.10(s,1H)8.15(s,1H)8.17-8.22(m,1H)8.38(dd,1H)8.69(q,2H)9.08(dd,1H)ppm; LCMS (method 1): Rt 1.13, m / z=488[M+H] + ; [α] D 20 :+145°(c:0.707,CHCl3)

[0942] Table P: Examples of compounds of formula I

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955] Table I: Table of intermediates

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966] 1)1 H NMR (400 MHz, chloroform-d) δ ppm: 4.04 (s, 3H) 8.11 (s, 1H) 8.17 (d, J=1.10 Hz, 1H).

[0967] 2)1 H NMR (400 MHz, chloroform-d) δ ppm: 0.76-0.85 (m, 2H) 1.06-1.15 (m, 2H) 2.03 (tt, J1=8.39 Hz, J2=5.00 Hz, 1H) 3.96 (s, 3H) 7.52 (s, 1H) 7.91 (s, 1H) 8.08 (d, J=0.73 Hz, 1H).

[0968] 19 F NMR (377 MHz, chloroform-d) δ ppm: -62.75 (s, 3F).

[0969] 3)1 H NMR (400 MHz, chloroform-d) δ ppm: 3.98 (s, 3H) 5.47 (d, J = 11.00 Hz, 1H) 5.93 (d, J = 17.61 Hz, 1H) 6.79 (dd, J1 = 17.42 Hz, J2 = 10.82 Hz, 1H) 7.82 (s, 1H) 8.19 (s, 1H) 8.24-8.29 (m, 1H).

[0970] 4)1 H NMR (400 MHz, chloroform-d) δ ppm: 1.25-1.34 (m, 1H) 1.48-1.55 (m, 1H) 1.88-2.00 (m, 1H) 2.46-2.53 (m, 1H) 3.98 (s, 3H) 7.60 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H).

[0971] 5)1 H NMR (400 MHz, chloroform-d) δ ppm: 4.02 (s, 3H), 8.11 (s, 1H), 8.44 (s. 1H), 8.53 (s, 1H).

[0972] 6)1 H NMR (400 MHz, chloroform) δ ppm 4.07 (s, 3H) 8.43-8.51 (m, 1H) 8.70-8.80 (m, 1H) 8.84-8.91 (m, 1H).

[0973] 19 F NMR (377 MHz, chloroform-d) δppm:-77.49 (s, 3F) -62.96 (s, 3F)

[0974] 7)1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm: 8.68 (s, 2H) 8.71-8.76 (m, 1H) 13.33-15.22 (m, 1H).

[0975] 8)1 H NMR (400 MHz, chloroform-d) δ ppm: 1.16-1.22 (m, 2H) 1.35 (quin, J = 3.76 Hz, 2H) 2.74 (tt, J1 = 7.84 Hz, J2 = 4.45 Hz, 1H) 4.02 (s, 3H) 8.45 (d, J = 0.73 Hz, 1H) 8.51 (d, J = 0.73 Hz, 1H) 8.86 (s, 1H).

[0976] 9)1H NMR (400 MHz, chloroform-d) δ ppm: 0.73-0.79 (m, 2H) 0.82-0.89 (m, 2H) 1.47-1.60 (m, 1H) 8.00 (d, J=0.73 Hz, 1H) 8.39 (s, 1H) 8.42 (s, 1H).

[0977] 19 F NMR (377 MHz, chloroform-d) δ ppm: -98.40 (s, 3F) -62.81 (s, 2F).

[0978] 10)1 H NMR (400 MHz, chloroform-d) δ ppm: 4.05 (s, 3H) 4.13 (s, 2H) 8.24 (s, 1H) 8.26 (s, 1H).

[0979] 11)1 H NMR (400 MHz, chloroform-d) δ ppm: 8.30 (1H, s), 8.23 ​​(1H, s), 7.81 (1H, s), 3.99 (3H, s), 3.90 (2H, s).

[0980] 12)1 H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.23 ​​(1H, s), 8.09 (1H, s), 7.79 (1H, s), 3.98 (3H, s), 1.84-1.92 (2H, m), 1.47-1.57 (m, 2H).

[0981] 13)1 H NMR (400 MHz, chloroform-d) δ ppm: 8.60-9.90 (1H, br s), 8.29 (1H, s), 8.15 (1H, s), 7.84 (1H, s), 1.84-1.93 (2H, m), 1.50-1.60 (2H, m)

[0982] 14)1 H NMR (400MHz, DMSO-d6) δppm: 8.90 (s, 1H), 8.70-8.90 (m, 3H), 6.48 (t, 1H), 4.63 (td, 2H), 2.62 (s, 3H).

[0983] 15)1 H NMR(400MHz,DMSO-d6)δppm:8.80-9.00(m,4H),7.50(t,1H),2.65(s,3H)

[0984] 16)1H-NMR(400MHz,DMSO-d6):δppm 8.85(d,1H),8.70(m,1H),8.45(s,1H),8.25(d,1H),7.75(d,1H),5(q,2H),2.6(s,3H)。

[0985] 17)1 H-NMR(400MHz,DMSO-d6):δppm 9.22(s,1H),8.85-8.95(m,2H),8.50-8.60(m,1H),8.30-8.40(m,1H)7.80-8.10(br.s,2H),5.25-5.35(m,1H),1.52(d,3H)

[0986] 18)1 H NMR(400MHz,DMSO-d6)δppm:8.80-9.00(m,4H),6.50(tt,1H),4.90(m,1H),4.78(td,2H),1.45(d,3H)

[0987] 19)1 H NMR(400MHz,DMSO-d6)δppm:8.80-9.10(m,4H),7.51(t,1H),4.88(m,1H),1.50(d,3H)

[0988] 20)1 H-NMR(400MHz,DMSO-d6):δppm:8.95(s,2H),8.60-9.00(m,2H),7.8-8.30(brs,2H),5.08-5.20(m,2H),4.95-5.05(m,1H),1.5(m,3H)

[0989] 21)1 H-NMR(400MHz,DMSO-d6):δppm:8.8(s,2H),8.65(d,1H),8.15(d,1H),7.8(m,1H),7.45(br s,2H),7.25(m,1H),7.15(m,1H),5.2(br s,1H),5(q,2H),1.5(m,3H)

[0990] 22)1H NMR(400MHz, chloroform-d)δppm-0.05(dd,2H)0.39(td,2H)0.81-0.94(m,1H)1.50(d,3H)1.98(dd,1H)2.44(dd,1 H)2.49-2.89(m,1H)4.73(q,1H)8.11-8.18(m,1H)8.20-8.27(m,1H)8.57(d,1H)8.69(d,1H)9.00(dd,1H)

[0991] 23)1 H NMR (400 MHz, chloroform-d) δ ppm 1.38 (br s, 9H), 1.55 (d, 3H), 5.66-5.78 (m, 2H), 8.11 (dd, 1H), 8.30 (d, 1H), 8.59 (d, 1H), 8.63 (d, 1H), 8.93-9.04 (m, 1H)

[0992] 24)1 H NMR (400 MHz, chloroform-d) δ ppm: 13.4-13.7 (br. s, 1H), 8.00-8.10 (m, 2H), 7.72 (s, 1H), 3.19 (s, 3H), 1.25-1.35 (m, 2H), 1.08-1.15 (m, 2H).

[0993] 25)1 H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.17 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 3.95 (s, 3H), 3.25 (s, 3H), 1.30 (t, 2H), 1.05 (t, 2H).

[0994] 26)1 H NMR (400MHz, DMSO-d) δppm: 7.82(s,1H),7.69(s,1H),7.55(s,1H),3.27(s,3H),1.20-1.28(m,2H),1.09-1.18(m,2H).

[0995] By adding other insecticides, acaricides and / or fungicidal active ingredients, the activity of the composition according to the present invention can be significantly widened and adapted to prevailing conditions. Mixtures of compounds of Formula I with other insecticides, acaricides and / or fungicidal active ingredients can also have other unexpected advantages, which can also be described as synergistic in a wider sense. For example, better tolerance of plants, reduced phytotoxicity, insects can be controlled at their different developmental stages, or better behavior during their production (e.g., during grinding or mixing, during their storage or during their use).

[0996] Suitable active ingredients for addition here are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.

[0997] The following mixtures of a compound of formula I and an active ingredient are preferred (wherein the abbreviation "TX" means "a compound selected from the group consisting of the compounds defined in Tables A-1 to A-27, B-1 to B-27, C-1 to C-27, D-1 to D-27 and E-1 to E-27, and Table P"):

[0998] Auxiliary agent, the auxiliary agent is selected from the group consisting of: petroleum (alias) (628) + TX,

[0999] Insect control active substances, the insect control active substances are selected from Abamectin + TX, Acetoquin + TX, Acetamiprid + TX, Acetaminophen + TX, Acynonapyr + TX, Bifenapyr + TX, Afolan + TX, Doxorubicin + TX, Allethrin + TX, Cis-cypermethrin + TX, Alpha-cypermethrin + TX, Sulfamycin + TX, Mefenamic Acid + TX, Azofenoxan + TX, Cyclohexidine + TX, Cyprodinil + TX, Benazir + TX, Benzpyrimoxan + TX, β-Cyfluthrin + TX, β-Cypermethrin + TX, Bifenazate + TX, Bifenthrin + TX, Binamit + TX, Bioallethrin + TX, Bioallethrin (S)-cyclopentyl isomer +TX, bio-resmethrin +TX, bistrifluan +TX, brofenapyr (Broflanilide) +TX, bromothrin +TX, bromophos-ethyl +TX, buprofezin +TX, butacarb +TX, cadusafos +TX, carbaryl +TX, butacarb +TX, batan +TX, CAS No.: 1472050-04-6 +TX, CAS No.: 1632218-00-8 +TX, CAS No.: 1808115-49-2 +TX, CAS No.: 2032403-97-5 +TX, CAS No.: 2044701-44-0 +TX, CAS No.: 2128706-05-6 +TX, CAS No.: 2249718- 27-0+TX, chlorantraniliprole+TX, chlordane+TX, chlorfenapyr+TX, chlorfenapyr+TX, chlorpromazine+TX, clenpyr+TX, chlorfenapyr+TX, clothianidin+TX, 2-chlorophenyl N-methylcarbamate (CPMC)+TX, benzonitrile+TX, cyantraniliprole+TX, cyclobromofenapyr+TX, Cyclobutrifluram+TX, pyrethroids+TX, cycloxanil+TX, cycloxanil+TX, cytoxanil+TX, cyhalodiamide+TX, trifluorochloride Cypermethrin + TX, cypermethrin + TX, cyromazine + TX, deltamethrin + TX, cypermethrin + TX, cypermethrin + TX, chlorfenapyr + TX, dibrom + TX, Diclomezotiaz + TX, fluazifop + TX, diflubenzuron + TX, dimpropyridaz + TX, diclofenac + TX, dinotefuran + TX, vegetable phosphorus + TX, emamectin + TX, dextran + TX, ε-momfluorothrin + TX, ε-methofluthrin + TX, cypermethrin + TX, ethion + TX, ethiprole + TX, etoxazole + TX, fenamiphos + TX,Fluphenazine + TX, Fenitrothion + TX, Fenbucarb + TX, Fenthiocarb + TX, Fenoxycarb + TX, Fenpropathrin + TX, Fenpyroxymate + TX, Fensulfuron + TX, Fenthion + TX, Fenvalerate + TX, Fipronil + TX, Flometoquin + TX, Flonicamid + TX, Fifenpyram + TX, Fluazaindolizine + TX, Fifoxazolidinone + TX, Flubendiamide + TX, Flucitrinate + TX , Flufenacet+TX, Flucythrin+TX, Fluthiazolin+TX, Flumethrin+TX, Flumethrin+TX, Butylene Flubendiamide+TX, Fluhexafon+TX, Flucythrin+TX, Flupyramid+TX, Flupentiofenox+TX, Flupyrimin+TX, Fluralaner+TX, Fluvalinate+TX, Fluxametamide+TX, Thiazophos+TX, γ-Cyhalothrin+TX, Gossyplure, TM+TX, Penpyramid +TX, Chlorfenapyr +TX, Chlorfenapyr +TX, Halofenprox +TX, Heptafluthrin +TX, Hexythiazox +TX, Hydrahydrazone +TX, Imicyafos +TX, Imidacloprid +TX, Imidazolidin +TX, Indoxacarb +TX, Iodomethane +TX, Iprodione +TX, Isocycloseram +TX, Isosulfuron +TX, Ivermectin +TX, κ-Bifenthrin +TX, κ-Tefluthrin +TX, λ-Cyhalothrin +TX, Lepidomectin +TX, Chlorfenuron +TX, Metaflumizone +TX, Metaldehyde +TX, Metamex +TX, Methoxyfenozide +TX, TX, Metofluthrin + TX, Metoclopramide + TX, Zikewei + TX, Cypermethrin + TX, Momfluorothrin + TX, Methionin + TX, Nitenpyram + TX, Nithiothiazide + TX, Oxydemeton + TX, Oxamyl + TX, Oxazosufyl + TX, Parathion-ethyl + TX, Permethrin + TX, Phenothrin + TX, Phosphamidon + TX, Piperonyl butoxide + TX, Pirimicarb + TX, Pyrimidophos-ethyl + TX, Polyhedrosis virus + TX, Promethrin + TX, Profenofos + TX, Profenofos + TX, Profluthrin + TX, Propargite + TX, Afenacet + TX, Proxorbide + TX, Prothiophos + TX, Protrifenbute +TX, Pyflubumide +TX, Pymetrozine +TX, Pyraclofos +TX, Pyrafluprole +TX, Pyridaben +TX, Pyridalyl +TX, Pyrifluquinazon +TX, Pyrimidine +TX, Pyrimostrobin +TX, Pyriprole +TX, Pyriproxyfen +TX, Resmethrin +TX, Sarolaner +TX, Selamectin +TX, Silafluthrin +TX, Spinetoram +TX, Spinosad +TX, Spirodiclofen +TX, Spiromesifen +TX, Spiropyrim +TX, Spiropyrim +TX, Spiropidion +TX, Spirotetramat +TX, Sulfonamidin +TX, Tebufenazol+TX, Tebufenpyrad+TX, Tebupirimiphos+TX, Tefluthrin+TX, Temephos+TX, Tetrachloraniliprole+TX, Tetradiphon+TX, Tetramethrin+TX, Tetrafluthrin+TX, Tetramethrin+TX, Acaricide+TX, Flucyrantel+TX, θ-Cypermethrin+TX, Thiacloprid+TX, Thiamethoxam+TX, Cypermethrin+TX, Thiamethoxam+TX, Cypermethrin+TX, Thiamethoxam+TX, Thiocyclam+TX, Thiodicarb+TX, Longxiaowei+TX, Methylsulfonate+TX, Cyprodinil+TX, Tioxazafen+TX, Tolfenpyrad+TX, Toxaphene+TX, Tralomethrin+TX, Transfluthrin+TX, Triazolam+TX,Triazophos + TX, Trichlorfon + TX, Chlorpheniramine + TX, Trichlorfon + TX, Triflumezopyrim + TX, Tyclopyrazoflor + TX, ζ-Cypermethrin + TX, Seaweed extract and fermentation products derived from sugar acyl + TX, Seaweed extract and fermentation products derived from sugar acyl (containing urea + TX, amino acids + TX, potassium and molybdenum, and EDTA-chelated manganese + TX,) Seaweed extract and fermented plant products + TX, Seaweed extract and fermented plant products (containing plant hormones + TX, vitamins + TX, EDTA-chelated copper + TX, zinc + TX, and iron + TX), Azadirachtin + TX, Bacillus aizawai + TX, Bacillus chitinosporus AQ746 (NRRL Accession No. B-21 618)+TX, Bacillus firmus+TX, Bacillus kurstaki+TX, Bacillus mycoides AQ726 (NRRL Accession No. B-21664)+TX, Bacillus pumilus (NRRL Accession No. B-30087)+TX, Bacillus pumilus AQ717 (NRRL Accession No. B-21662)+TX, Bacillus species AQ178 (ATCC Accession No. 53522)+TX, Bacillus species AQ175 (ATCC Accession No. 55608)+TX, Bacillus species AQ177 (ATCC Accession No. 55609)+TX, unspecified Bacillus subtilis+TX, Bacillus subtilis AQ153 (ATCC accession number 55614) + TX, Bacillus subtilis AQ30002 (NRRL accession number B-50421) + TX, Bacillus subtilis AQ30004 (NRRL accession number B-50455) + TX, Bacillus subtilis AQ713 (NRRL accession number B-21661) + TX, Bacillus subtilis AQ743 (NRRL accession number B-21665) + TX, Bacillus thuringiensis AQ52 (NRRL accession number B-21619) + TX, Bacillus thuringiensis BD#32 (NRRL accession number B-21530) + TX, Bacillus thuringiensis subsp. Kurstaki BMP 123+TX, Beauveria bassiana+TX, D-limonene+TX, Granulovirus+TX, Harpin+TX, Helicoverpa armigera nuclear polyhedrosis virus+TX, Helicoverpa virescens nuclear polyhedrosis virus+TX, Helicoverpa virescens nuclear polyhedrosis virus+TX, Helicoverpa virescens nuclear polyhedrosis virus+TX, Metarhizium species+TX, Muscodor albus 620 (NRRL accession number 30547)+TX, Muscodor roseus A3-5 (NRRL accession number 30548)+TX, Neem-based products+TX, Paecilomyces fumosorum+TX,Paecilomyces lilacinus + TX, Pasteuria szawanensis + TX, Pasteuria penetrans + TX, Pasteuria thornei + TX, Pasteuria thornei + TX, p-cymene + TX, Plutella xylostella granulosis virus + TX, Plutella xylostella nuclear polyhedrosis virus + TX, polyhedrosis virus + TX, pyrethrum + TX, QRD 420 (terpenoid blend) + TX, QRD 452 (terpenoid blend) + TX, QRD 460 (terpenoid blend) + TX, Quillaja sapodilla + TX, Rhodococcus sphaeroides AQ719 (NRRL Accession No. B-21663) + TX, Spodoptera frugiperda nuclear polyhedrosis virus + TX, Streptomyces flavus (NRRL Accession No. 30232) + TX, Streptomyces species (NRRL Accession No. B-30145) + TX, terpenoid blend + TX, and Verticillium species,

[1000] Algaecide, the algaecide being selected from the group consisting of bethoxazin [CCN] + TX, copper dioctanoate (IUPAC name) (170) + TX, copper sulfate (172) + TX, cybutryne [CCN] + TX, dichloronaphthoquinone (1052) + TX, dichlorophen (232) + TX, endoxan (295) + TX, triphenyltin (347) + TX, slaked lime [CCN] + TX, mancozeb (566) + TX, quinoclamine (714) + TX, quinonamid (1379) + TX, simazine (730) + TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347) + TX,

[1001] An anthelmintic selected from the group consisting of: avermectin (1) + TX, clofosinate (1011) + TX, cyclobutrifluram + TX, doramectin (alias) [CCN] + TX, emamectin (291) + TX, emamectin benzoate (291) + TX, eprinomectin (alias) [CCN] + TX, ivermectin (alias) [CCN] + TX, milbemycin oxime (alias) [CCN] + TX, moxidectin (alias) [CCN] + TX, piperazine [CCN] + TX, selamectin (alias) [CCN] + TX, spinosad (737) and thiophanate (1435) + TX,

[1002] Avicide selected from the group consisting of chloralose (127) + TX, endrin (1122) + TX, fenthion (346) + TX, pyridin-4-amine (IUPAC name) (23) and strychnine (745) + TX,

[1003] Bactericide, the bactericide is selected from the group consisting of: 1-hydroxy-1H-pyridine-2-thione (IUPAC name) (1222) + TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748) + TX, 8-hydroxyquinoline sulfate (446) + TX, bronopol (97) + TX, copper dioctanoate (IUPAC name) (170) + TX, copper hydroxide (IUPAC name) (169) + TX, cresol [CCN] + TX, dichlorophen (232) + TX, dipyrithione (1105) + TX, dodesine (1112) + TX, fenaminosulf (1144) + TX )+TX, formaldehyde (404)+TX, mercurophen (alias) [CCN]+TX, kasugamycin (483)+TX, kasugamycin hydrochloride hydrate (483)+TX, nickel bis(dimethyldithiocarbamate) (IUPAC name) (1308)+TX, trichloromethylpyridine (580)+TX, octhilamide (590)+TX, oxolinic acid (606)+TX, oxytetracycline (611)+TX, potassium hydroxyquinoline sulfate (446)+TX, thiabendazole (658)+TX, streptomycin (744)+TX, streptomycin sesquisulfate (744)+TX, chlorpheniramine (766)+TX, and thimerosal (alias) [CCN]+TX,

[1004] Biological agent, the biological agent is selected from the group consisting of: GV of cotton brown banded moth (alias) (12) + TX, Radibacterium radiobacterium (alias) (13) + TX, Amblyseius spp. (alias) (19) + TX, NPV of celery budworm (alias) (28) + TX, Anagrus atomus (alias) (29) + TX, Aphelinus abdominalis (alias) (33) + TX, Aphidius colemani (alias) (34) + TX, Aphidoletes aphidimyza (alias) (35) + TX, NPV of lucerne budworm (alias) (38) + TX, Bacillus firmus (alias) (48) + TX, Bacillus sphaericus Neide)(scientific name)(49)+TX、Bacillus thuringiensis Berliner)(scientific name)(51)+TX、Bacillus thuringiensis subsp. aizawai)(scientific name)(51)+TX、Bacillus thuringiensis subsp. israelensis)(scientific name)(51)+TX、Bacillus thuringiensis subsp. japonensis)(scientific name)(51)+TX、Bacillus thuringiensis subsp. kurstak(scientific name)(51)+TX、Bacillus thuringiensis subsp. tenebrionis(scientific name)(51)+TX、Beauveria bassiana)(other name)(53)+TX、Beauveria bassiana brongniartii)(alias)(54)+TX, Chrysoperlacarnea)(alias)(151)+TX, Cryptolaemus montrouzieri)(alias)(178)+TX, GV (alias)(191)+TX, Dacnusa sibirica)(alias)(212)+TX, Diglyphus isaea)(alias)(254)+TX, Encarsia formosa)(scientific name)(293)+TX, Eretmocerus eremicus)(alias)(300)+TX, NPV (alias)(431)+TX, Heterorhabditis bacteriophora and H.megidis)(alias)(433)+TX、Hippodamia convergens)(alias)(442)+TX、Leptomastix dactylopii)(alias)(488)+TX、Macrolophus caliginosus)(alias)(491)+TX、NPV of cabbage looper(alias)(494)+TX、Metaphycus helvolus)(alias)(522)+TX、Metarhizium anisopliae var. acridum)(scientific name)(523)+TX、Metarhizium anisopliae var. anisopliae)(scientific name)(523)+TX、Neodiprion serrata sertifer)NPV and N.leconteiNPV (alias) (575) + TX, species of the genus N. (alias) (596) + TX, Paecilomyces fumosoroseus (alias) (613) + TX, Phytoseiulus persimilis (alias) (644) + TX, Spodoptera exigua multicapsid nuclear polyhedrosisvirus (scientific name) (741) + TX, Steinernema bibionis (alias) (742) + TX, Steinernema carpocapsae (alias) (742) + TX, Steinernema sutchuenensis (alias) (742) + TX, Steinernema sutchuenensis (alias) (742) + TX, Steinernema sutchuenensis (alias) (742) + TX, Steinernema sutchuenensis (alias) (742) + TX, Steinernema sutchuenensis (alias) glaseri) (alias) (742) + TX, Steinernema riobrave (alias) (742) + TX, Steinernema riobravis (alias) (742) + TX, Steinernema capterisci (alias) (742) + TX, Steinernema spp. (alias) (742) + TX, Trichogramma spp. (alias) (826) + TX, Typhlodromus occidentalis (alias) (844) and Verticillium lecanii (alias) (848) + TX.

[1005] Soil disinfectant selected from the group consisting of iodomethane (IUPAC name) (542) and bromomethane (537) + TX,

[1006] A chemical sterilant selected from the group consisting of: apholanate [CCN] + TX, bis(aziridine) methylaminophosphine sulfide (bisazir) (alias) [CCN] + TX, busulfan (alias) [CCN] + TX, diflubenzuron (250) + TX, dimatif (alias) [CCN] + TX, hemel [CCN] + TX, hempa [CCN] + TX, metepa [CCN] + TX, methiotepa [CCN] + TX, methyl apholanate [CCN] + TX, methyl thiote ... apholate) [CCN] + TX, morzid [CCN] + TX, penfluron (another name) [CCN] + TX, tepa [CCN] + TX, thiohempa (another name) [CCN] + TX, thiohexamethylenetepa (another name) [CCN] + TX, trotamide (another name) [CCN] and urethaneimide (another name) [CCN] + TX,

[1007] Insect pheromone, the insect pheromone is selected from the group consisting of: (E)-dec-5-en-1-yl acetate and (E)-dec-5-en-1-ol (IUPAC name) (222) + TX, (E)-tridec-4-en-1-yl acetate (IUPAC name) (829) + TX, (E)-6-methylhept-2-en-4-ol (IUPAC name) (541) + TX, (E,Z)-tetradec-4,10-dien-1-yl acetate (IUPAC name) (779) + TX, (Z)-dodec-7-en-1-yl acetate (IUPAC name) (285) + TX, (Z)-hexadecan-11-enal (IUPAC name) (436) + TX, (Z)-hexadecan-11-en-1-yl acetate (IUPAC name) (437) +TX, (Z)-hexadec-13-en-11-yn-1-yl acetate (IUPAC name) (438) +TX, (Z)-eicos-13-en-10-one (IUPAC name) (448) +TX, (Z)-tetradec-7-en-1-al (IUPAC name) (782) +TX, (Z)-tetradec-9-en-1-ol (IUPAC name) (783) +TX, (Z)-tetradec-9-en-1-yl acetate (IUPAC name) (784) +TX, (7E,9Z)-dodec-7,9-dien-1-yl acetate (IUPAC name) (283) +TX, (9Z,11E)-tetradec-9,11-dien-1-yl acetate (IUPAC name) (780) +TX, (9Z,12E)-tetradec-9,12-Dien-1-yl acetate (IUPAC name) (781) + TX, 14-methyloctadec-1-ene (IUPAC name) (545) + TX, 4-methylnonan-5-ol and 4-methylnonan-5-one (IUPAC name) (544) + TX, alpha-multistriatin (alias) [CCN] + TX, western pine beetle gathering pheromone (brevicomin) (alias) [CCN] + TX, codlelure (alias) [CCN] + TX, codlemon mone)(alias)(167)+TX、cuelure)(alias)(179)+TX、disparlure)(277)+TX、1-dodecane-8-en-1-yl acetate(IUPAC name)(286)+TX、1-dodecane-9-en-1-yl acetate(IUPAC name)(287)+TX、10-10-dien-1-yl acetate(IUPAC name)(284)+TX、dominicalure(alias)[CCN]+TX、ethyl 4-methyloctanoate(IUPAC name) C name) (317) + TX, eugenol (alias) [CCN] + TX, southern pine beetle gathering pheromone (frontalin) (alias) [CCN] + TX, gossyplure (alias) (420) + TX, grandlure (421) + TX, grandlure I (alias) (421) + TX, grandlure II (alias) (421) + TX, grandlure III (alias) (421) + TX, grandlure IV (alias) (421) + TX, hexalure )[CCN]+TX、ipsdienol(alias)[CCN]+TX、ipsenol(alias)[CCN]+TX、japonilure(alias)(481)+TX、lineatin(alias)[CCN]+TX、litlure(alias)[CCN]+TX、looplure(alias)[CCN]+TX、medlure[CCN]+TX、megatomoic acid(alias)[CCN]+TX、methyl eugenol(alias)(540)+TX、muscalure(563)+TX、octadeca-2,13-dien-1-yl acetate(IUPAC name)(588)+TX、octadeca-3,13-Dien-1-yl acetate (IUPAC name) (589) + TX, orfralure (alias) [CCN] + TX, oryctalure (alias) (317) + TX, ostramone (alias) [CCN] + TX, siglure [CCN] + TX, sordidin (alias) (736) + TX, sulcatol (alias) [ CCN] + TX, tetradec-11-en-1-yl acetate (IUPAC name) (785) + TX, Mediterranean fruit fly attractant (trimedlure) (839) + TX, Mediterranean fruit fly attractant A (synonym) (839) + TX, Mediterranean fruit fly attractant B1 (synonym) (839) + TX, Mediterranean fruit fly attractant B2 (synonym) (839) + TX, Mediterranean fruit fly attractant C (synonym) (839) and trunc-call (synonym) [CCN] + TX,

[1008] An insect repellent selected from the group consisting of 2-(octylthio)ethanol (IUPAC name) (591) + TX, butopyronoxyl (933) + TX, butoxy(polypropylene glycol) (936) + TX, dibutyl adipate (IUPAC name) (1046) + TX, dibutyl phthalate (1047) + TX, dibutyl succinate (IUPAC name) (1048) + TX, DEET [CCN] + TX, dimethyl carbate) [CCN] + TX, dimethyl phthalate [CCN] + TX, ethyl hexanediol (1137) + TX, hexamide [CCN] + TX, methoquin-butyl (1276) + TX, methylneodecanamide [CCN] + TX, oxamate [CCN] and picaridin [CCN] + TX,

[1009] Molluscicide selected from the group consisting of: di(tributyltin) oxide (IUPAC name) (913) + TX, bromoacetamide [CCN] + TX, calcium arsenate [CCN] + TX, cloethocarb (999) + TX, copper acetyl arsenite [CCN] + TX, copper sulfate (172) + TX, triphenyltin (347) + TX, iron phosphate (IUPAC name) (352) + TX, metaldehyde (518) + TX, methiocarb (530) + TX, niclosamide (576) + TX, niclosamide-ethyl Alcoholamine (576) + TX, pentachlorophenol (623) + TX, sodium pentachlorophenoxide (623) + TX, tazimcarb (1412) + TX, thiodicarb (799) + TX, tributyltin oxide (913) + TX, trifenmorph (1454) + TX, trimethacarb (840) + TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347) + TX, pyraclostrobin [394730-71-3] + TX,

[1010] A nematicide selected from the group consisting of: AKD-3088 (compound code) + TX, 1,2-dibromo-3-chloropropane (IUPAC / Chemical Abstracts name) (1045) + TX, 1,2-dichloropropane (IUPAC / Chemical Abstracts name) (1062) + TX, 1,2-dichloropropane and 1,3-dichloropropene (IUPAC name) (1063) + TX, 1,3-dichloropropene (233) + TX, 3,4-dichlorotetrahydrothiophene 1,1-dioxide (IUPAC / Chemical Abstracts name) (1 065)+TX, 3-(4-chlorophenyl)-5-methylrhodanine (IUPAC name) (980)+TX, 5-methyl-6-thioxo-1,3,5-thiadiazin-3-yl acetic acid (IUPAC name) (1286)+TX, 6-isopentenylaminopurine (alias) (210)+TX, avermectin (1)+TX, acetofenamide [CCN]+TX, cotton bell carb (15)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, AZ 60541 (compound code) + TX, benclothiaz [CCN] + TX, benomyl (62) + TX, butylpyridaben (alias) + TX, cadusafos (109) + TX, carbofuran (118) + TX, carbon disulfide (945) + TX, carbofuran (119) + TX, chloropicrin (141) + TX, chlorpyrifos (145) + TX, diamidafos (999) + TX, Cyclobutrifluram + TX, cytokinins (alias) (210) + TX, dazomet (216) + TX, DBCP (1045) + TX, DCIP (218) + TX, diamidafos (1044) + TX, Dichlofenthion (1051) + TX, dicliphos (alias) + TX, dimethoate (262) + TX, doramectin (alias) [CCN] + TX, emamectin (291) + TX, emamectin benzoate (291) + TX, eprinomectin (alias) [CCN] + TX, ethoprophos (312) + TX, dibromoethane (316) + TX, fenamiphos (326) + TX, fenpyrad (alias) + TX, fensulfuron (1158) + TX, fosthiazate (408) + TX, fosthietan (1196) + TX, furfural (alias) [CCN] + TX, GY-81 (research code) (423) + TX, fenthiophos [CCN] + TX,Iodomethane (IUPAC name) (542) + TX, isamidophos (1230) + TX, isazofos (1231) + TX, ivermectin (alias) [CCN] + TX, kinetin (alias) (210) + TX, mecarphon (1258) + TX, metamectin (519) + TX, metamectin potassium salt (alias) )(519)+TX, sodium salt of methamphetamine (519)+TX, methyl bromide (537)+TX, methyl isothiocyanate (543)+TX, milbemycin oxime (alias) [CCN]+TX, moxidectin (alias) [CCN]+TX, verrucous mycorrhizal composition (alias) (565)+TX, NC-184 (compound code)+TX, oxamyl (602)+TX, methyl parathion (636)+TX, phosphamidon (639)+TX, phosphamidon Phosphocarb [CCN] + TX, sebufos (alias) + TX, selamectin (alias) [CCN] + TX, spinosad (737) + TX, terbam (alias) + TX, terbufos (773) + TX, tetrachlorothiophene (IUPAC / Chemical Abstracts name) (1422) + TX, thiafenox (alias) + TX, thionazin (1434) + TX, triazophos (820) + TX, triazuron (alias) + TX, xylenol [CCN] + TX, YI-5302 (compound code) and zeatin (alias) (210) + TX, fluensulfone [318290-98-1] + TX, fluopyram + TX,

[1011] A nitrification inhibitor selected from the group consisting of potassium ethylxanthate [CCN] and nitrapyrin (580) + TX,

[1012] A plant activator, the plant activator being selected from the group consisting of: acibenzolar (6) + TX, acibenzolar-S-methyl (6) + TX, thiabendazole (658) and Reynoutria sachalinensis extract (alias) (720) + TX,

[1013] Rodenticide, the rodenticide is selected from the group consisting of: 2-isovaleryl indane-1,3-dione (IUPAC name) (1246) + TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748) + TX, α-chlorohydrin [CCN] + TX, aluminum phosphide (640) + TX, antoconazole (880) + TX, arsenic trioxide (882) + TX, barium carbonate (891) + TX, dithiocarbamide (912) + TX, brodifacoum (89) + TX, bromodisulfuron (89) + TX, Diclofenac (91) + TX, Bromodimethalin (92) + TX, Calcium Cyanide (444) + TX, Chloralose (127) + TX, Chlorodipine (140) + TX, Cholecalciferol (alias) (850) + TX, Chlorodimethalin (1004) + TX, Cholecalciferol (1005) + TX, Cytodextrin (175) + TX, Cytodextrin (1009) + TX, Cytodextrin (246) + TX, Cytodextrin (249) + TX, Diclofenac (273) + TX, Calcifedol (301) + TX, Fluorine Felocell (357) + TX, fluoroacetamide (379) + TX, flufenacet (1183) + TX, flufenacet hydrochloride (1183) + TX, γ-HCH (430) + TX, HCH (430) + TX, hydrogen cyanide (444) + TX, iodomethane (IUPAC name) (542) + TX, lindane (430) + TX, magnesium phosphide (IUPAC name) (640) + TX, methyl bromide (537) + TX, fosfomycin (1318) + TX, fosfomycin (13 36)+TX, phosphine (IUPAC name) (640)+TX, phosphorus [CCN]+TX, warfarin (1341)+TX, potassium arsenite [CCN]+TX, warfarin (1371)+TX, scilla glycoside (1390)+TX, sodium arsenite [CCN]+TX, sodium cyanide (444)+TX, sodium fluoroacetate (735)+TX, strychnine (745)+TX, thallium sulfate [CCN]+TX, warfarin (851) and zinc phosphide (640)+TX,

[1014] A synergist selected from the group consisting of 2-(2-butoxyethoxy)ethyl piperate (IUPAC name) (934) + TX, 5-(1,3-benzodioxol-5-yl)-3-hexylcyclohex-2-enone (IUPAC name) (903) + TX, farnesol with nerolidol (alias) (324) + TX, MB-599 (research code) (498) + TX, MGK264 (research code) (296) + TX, piperonyl butoxide (649) + TX, piprotal (1343) + TX, propyl isomer (1358) + TX, S421 (research code) (724) + TX, sesamex (1393) + TX, sesasmolin (1394) and sulfoxide (1406) + TX,

[1015] An animal repellent selected from the group consisting of anthraquinone (32) + TX, chloralose (127) + TX, copper cyclohexane [CCN] + TX, copper oxychloride (171) + TX, diazinon (227) + TX, dicyclopentadiene (chemical name) (1069) + TX, guazatine (422) + TX, guazatine acetate (422) + TX, methiocarb (530) + TX, pyridin-4-amine (IUPAC name) (23) + TX, salamine (804) + TX, thiamethoxam (840) + TX, zinc cyclohexane [CCN], and ziram (856) + TX,

[1016] A virucide selected from the group consisting of: imipenem (also known as) [CCN] and ribavirin (also known as) [CCN] + TX,

[1017] A wound protective agent, which is selected from the group consisting of mercuric oxide (512) + TX, octhilinone (590) and methyl thiophanate (802) + TX,

[1018] A biologically active substance, wherein the biologically active substance is selected from the following substance group: 1,1-bis(4-chloro-phenyl)-2-ethoxyethanol+TX, 2,4-dichlorophenylbenzenesulfonate+TX, 2-fluoro-N-methyl-N-1-naphthylacetamide+TX, 4-chlorophenylphenylsulfone+TX, acetofenapyr+TX, aldisulfonyl+TX, sirox+TX, fomanphos+TX, amitriptyline+TX, amitriptyline hydrogen oxalate+TX, amitraz+TX, cypermethrin+TX, arsenic trioxide+TX, azobenzene+TX, azophos+TX, benomyl+TX, benoxafos+TX, benzyl benzoate+TX, bixafenthion+TX, bromethrin+TX, bromothiophene+TX, bromophos+TX , bromopyralid + TX, buprofezin + TX, butanone carbendazim + TX, butanone carbendazim + TX, butylpyridaben + TX, calcium polysulfide + TX, octachlorocamphene + TX, chlormethoxam + TX, trithion + TX, cypermethrin + TX, cypermethrin + TX, cypermethrin + TX, chlordimeform + TX, chlordimeform hydrochloride + TX, chlorfenapyr + TX, chlorfenapyr + TX, chlorfenapyr + TX, chlorfenapyr + TX, ethyl chlorfenapyr + TX, chlormebuform (chloromebuform) + TX, chlorfenapyr + TX, propyl chlorfenapyr + TX, chlorfenapyr + TX, chlorfenapyr I + TX, chlorfenapyr II + TX, chlorfenapyr + TX, closantel + TX, coumaphos + TX, crotamiton + TX, baclofos + TX, thiamethoxam + TX, cypermethrin + T X, DCPM+TX, DDT+TX, tanafon+TX, tanafon-O+TX, tanafon-S+TX, demeton-methyl+TX, demeton-O+TX, demeton-O-methyl+TX, demeton-S+TX, demeton-S-methyl+TX, demeton-S-methyl+TX, demeton-S-methyl+TX, demeton-S-methylsulfon+TX, bacteriostatic+TX, dichlorvos+TX, dichlorvos+TX, dichlorvos+TX, dimethoate+TX, dimethoate+TX, dinex+TX, dinex-diclexine+TX, dinocap-4+TX, dinocap-6+TX, o-dimethoate+TX, nitropentyl+TX, nitrooctyl acaricide+TX, nitrobutyl+TX, dimethoate Phosphorus + TX, sulfodiphenyl + TX, disulfiram + TX, DNOC + TX, dofenapyn + TX, doramectin + TX, indophos + TX, eprinomectin + TX, phosphine + TX, ethiopthion + TX, anti-mite + TX, fenbutatin + TX, fenthiocarb + TX, fenpyrad + TX, fenpyroximate + TX, fenamipyrazone + TX, fentrifanil + TX, fluazifop + TX, flufenoxam + TX, fluazifop + TX, FMC1137 + TX, fluazifop + TX, fluazifop hydrochloride + TX, formparanate + TX, γ-HCH + TX,Fructidin + TX, benzyl azomethanone + TX, hexadecyl cyclopropane carboxylate + TX, isocarbophos + TX, jasmonate I + TX, jasmonate II + TX, iodonium + TX, lindane + TX, propanil + TX, cypermethrin + TX, dithiophos + TX, methylthiophene + TX, cypermethrin + TX, methyl bromide + TX, cypermethrin + TX, milbemid + TX, propylamine + TX, monocrotophos + TX, maoguo + TX, moxidectin + TX, naled + TX, 4-chloro-2-(2-chloro-2-methyl-propyl)-5-[(6-iodo-3-pyridyl)methoxy]pyridazin-3-one + TX, fluazifop + TX, nikkomycin + TX, penbufenac + TX, penbufenac 1: 1. Zinc chloride complex + TX, omethoate + TX, isothiophos + TX, sulfamethoxam + TX, pp'-DDT + TX, parathion + TX, permethrin + TX, fenthion + TX, phosalone + TX, thiophanate + TX, phosphamidon + TX, polychloroterpenes + TX, polynactins + TX, prochlorperazine + TX, cypermethrin + TX, propoxur + TX, ethidium azate + TX, pyrethrin I + TX, pyrethrin II + TX, pyrethrin + TX, pyrimethoxam + TX, pyrimithiophos + TX, quinalphos + TX, quintiofos + TX X, R-1492+TX, glyphosate+TX, rotenone+TX, octamidine+TX, clomartin+TX, selamectin+TX, thion+TX, SSI-121+TX, sulfilam+TX, sulfluramid+TX, sulfotep+TX, sulfur+TX, flumethrin+TX, τ-fluvalinate+TX, TEPP+TX, terbucarb+TX, tetrachlorvinphos+TX, thiafenox+TX, thiafenox+TX, pyrimidine+TX, long-lasting cypermethrin+TX, methyl sulfophos+TX, chlorpyrifos+TX, thiamethoxam+TX, thiafenox+TX, thiamethoxam ... Vaniliprole + TX, chloranil + TX, copper dioctanoate + TX, copper sulfate + TX, cybutryne + TX, dichloronaphthoquinone + TX, dichlorophen + TX, endoxan + TX, triphenyltin + TX, slaked lime + TX, sodium mancozeb + TX, quinone + TX, quinone + TX, simazine + TX, triphenyltin acetate + TX, triphenyltin hydroxide + TX, fusulin + TX, piperazine + TX, thiophanate + TX, chloralose + TX, fenthion + TX, pyridin-4-amine + TX, strychnine + TX, 1-hydroxy-1H-pyridine-2-thione + TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide + TX, 8-hydroxyquinoline sulfate + TX, bronopol + TX,Copper hydroxide + TX, cresol + TX, dipyrithione + TX, dodixin + TX, sodium disulfide + TX, formaldehyde + TX, mercurophenicol + TX, kasugamycin + TX, kasugamycin hydrochloride hydrate + TX, nickel bis(dimethyldithiocarbamate) + TX, trichloromethylpyridine + TX, octhiazide + TX, oxolinic acid + TX, oxytetracycline + TX, potassium hydroxyquinoline sulfate + TX, thiabendazole + TX, streptomycin + TX, streptomycin sesquisulfate + TX, chlorothiazol + TX, thimerosal + TX, cotton brown-banded tormenter GV + TX, Agrobacterium radiobacterium + TX, Amblyseius species + TX, celery budworm NPV + TX, original cherry-winged tassel wasp + TX, short-spurred aphid wasp + TX, cotton aphid parasitoid + TX, aphid-eating gall midge + TX, lucerne budworm NPV + TX, sphaeridium + TX, Bacillus sphaeridium + TX, Beauveria bassiana + TX, common lacewings + TX, Cryptochilus monzii + TX, codling moth GV + TX, Siberian sibirica + TX, pea leafminer + TX, beautiful aphid wasp + TX, aphid wasp + TX, bacteriotrophic Heterorhabditis elegans and Heterorhabditis elegans + TX, spotted long-legged ladybird + TX, citrus mealybug parasitoid + TX, blind bug + TX, cabbage looper NPV + TX, yellow-stalked jumping wasp + TX, yellow green Metarhizium + TX, Metarhizium anisopliae microspore variant + TX, European new pine sawfly NPV and red-headed new pine sawfly NPV + TX, small flower stink bug species + TX, fumosomolus + TX, Chilean microseiid mite + TX, hairy nematode + TX, small-rolled moth nematode + TX, noctuid nematode + TX, Grill's nematode + TX, sharp-sided nematode + TX, Steinernema riobravis+TX, mole cricket Steinernema+TX, Steinernema species+TX, Trichogramma species+TX, western blind mite+TX, Verticillium lecanii+TX, oxazolidinone+TX, bis(aziridine)methylaminophosphonium sulfide+TX, busulfan+TX, dimethivin+TX, hexamethylmelamine+TX, hexamethylphosphonium+TX, methyl tibazol+TX, methylthiotibazol+TX, methyloxazolidinone+TX, infertilil+TX, thiofluanid+TX, tibazol+TX, hexamethylphosphonium thioate+TX, thiotibazol+TX, trothamide+TX, urethaneimide+TX, (E)-dec-5-en-1-yl acetate and (E)-dec-5-en-1-ol +TX, (E)-tridec-4-en-1-yl acetate +TX, (E)-6-methylhept-2-en-4-ol +TX, (E,Z)-tetradec-4,10-dien-1-yl acetate +TX, (Z)-dodec-7-en-1-yl acetate +TX, (Z)-hexadec-11-enal +TX, (Z)-hexadec-11-en-1-yl acetate +TX, (Z)-hexadec-13-en-11-yn-1-yl acetate +TX, (Z)-eicos-13-en-10-one +TX, (Z)-tetradec-7-en-1-al +TX, (Z)-tetradec-9-en-1-ol +TX,(Z)-tetradec-9-en-1-yl acetate + TX, (7E,9Z)-dodec-7,9-dien-1-yl acetate + TX, (9Z,11E)-tetradec-9,11-dien-1-yl acetate + TX, (9Z,12E)-tetradec-9,12-dien-1-yl acetate + TX, 14-methyloctadec-1-ene + TX, 4-methylnon-5-ol and 4-methylnon-5-one + TX, α-polystyrene + TX, western pine beetle gathering pheromone + TX, dodecadienol + TX, caldoxime + TX, pyrrolidone + TX, epoxynonadecane + TX, dodec-8-en-1-yl acetate + TX, dodecadienol + TX, caldoxime + TX, pyrrolidone + TX, epoxynonadecane + TX, dodec-8-en-1-yl acetate + TX, dodec -9-en-1-yl acetate + TX, dodecan-8 + TX, 10-dien-1-yl acetate + TX, dominicalure + TX, 4-methyloctanoic acid ethyl ester + TX, eugenol + TX, southern pine beetle gathering pheromone + TX, trapping ene mixture + TX, trapping ene mixture I + TX, trapping ene mixture II + TX, trapping ene mixture III + TX, trapping ene mixture IV + TX, hexane attractant + TX, tooth beetle dienol + TX, small beetle alcohol + TX, scarab sex attractant + TX, trimethyldioxytricyclononane + TX, litlure + TX, cabbage looper sex attractant + TX, trapping ester + TX, megatomoic acid+TX, entophore+TX, entophore+TX, octadec-2,13-dien-1-yl acetate+TX, octadec-3,13-dien-1-yl acetate+TX, Hekangbi+TX, coconut rhinoceros beetle aggregation pheromone+TX, feilekang+TX, entophore+TX, sordidin+TX, fungivorous acetic acid+TX, tetradec-11-en-1-yl acetate+TX, Mediterranean fruit fly attractant+TX, Mediterranean fruit fly attractant A+TX, Mediterranean fruit fly attractant B1+TX, Mediterranean fruit fly attractant B2+TX, Mediterranean fruit fly attractant C+TX, trunc-call+TX, 2-(octylthio)-ethanol+TX, dimethoate+TX, butoxy(polypropylene glycol)+TX, dibutyl adipate+ TX, dibutyl phthalate + TX, dibutyl succinate + TX, DEET + TX, mosquito repellent + TX, dimethyl phthalate + TX, ethyl hexanediol + TX, hexyl urea + TX, mequindine + TX, methyl neodecylamide + TX, oxamate + TX, picaridin + TX, 1-dichloro-1-nitroethane + TX, 1,1-dichloro-2,2-bis(4-ethylphenyl)-ethane + TX, 1,2-dichloropropane and 1,3-dichloropropylene + TX, 1-bromo-2-chloroethane + TX, 2,2,2-trichloro-1-(3,4-dichloro-phenyl)ethyl acetate + TX, 2,2-dichlorovinyl 2-ethylsulfinylethyl methyl phosphate + TX, 2-(1,3-dithiolan-2-yl)phenyl dimethylcarbamate + TX,2-(2-Butoxyethoxy)ethyl thiocyanate + TX, 2-(4,5-dimethyl-1,3-dioxolan-2-yl)phenylmethylcarbamate + TX, 2-(4-chloro-3,5-xylyloxy)ethanol + TX, 2-chlorovinyldiethyl phosphate + TX, 2-imidazolidinone + TX, 2-isovalerylindan-1,3-dione + TX, 2-methyl(prop-2-ynyl)aminophenylmethylcarbamate + TX, 2-thiocyanatoethyl laurate + TX, 3-bromo-1-chloroprop-1-ene + TX, 3-methyl-1-phenylpyrazol-5-yldimethyl-amino TX, 4-methyl (prop-2-ynyl) amino-3,5-dimethylphenylmethylcarbamate + TX, 5,5-dimethyl-3-oxocyclohex-1-enyl dimethylcarbamate + TX, acethion + TX, acrylonitrile + TX, aldrin + TX, aloamicin + TX, chlorpyrifos + TX, α-deceprin + TX, aluminum phosphide + TX, chlorpyrifos + TX, neonicotinoids + TX, ethylthiothion (athidathion) + TX, methylpyrifos + TX, Bacillus thuringiensis δ-endotoxin + TX, barium hexafluorosilicate + TX, barium polysulfide + TX, Permethrin + TX, Bayer 22 / 190 + TX, Bayer 22408 + TX, β-cyfluthrin + TX, β-cypermethrin + TX, bioethanomethrin + TX, biopermethrin + TX, bis(2-chloroethyl) ether + TX, borax + TX, bromopheniramine + TX, bromo-DDT + TX, cypermethrin + TX, butathiofos + TX, butyl phosphate + TX, calcium arsenate + TX, calcium cyanide + TX, carbon disulfide + TX, carbon tetrachloride + TX, batan hydrochloride + TX, Cevadine + TX, Borneol + TX, Chlordane + TX, Chlordecone + TX, Chloroform + TX, Chloropicrin + TX, Chloranilide + TX, Chlorprazophos + TX, Cis-resmethrin + TX, Cis-resmethrin + TX, Clocythrin (alias) + TX, Copper acetylarensite + TX, Copper arsenate + TX, Copper oleate + TX, Coumithoate + TX, Cryolite + TX, CS 708+TX, benzonitrile+TX, cypermethrin+TX, cypermethrin+TX, cypermethrin+TX, d-cypermethrin+TX, DAEP+TX, dazomethon+TX, decarbofuran+TX, cypermethrin+TX, isochlorvinphos+TX, cypermethrin+TX, dicresyl+TX, cypermethrin+TX, dieldrin+TX, diethyl 5-methylpyrazol-3-yl phosphate+TX, dior+TX, tetrafluthrin+TX, dimethoate+TX,Permethrin + TX, methyl chlorpyrifos + TX, difenocarb + TX, propanol + TX, pentanophenol + TX, dinoseb + TX, fenpyroxen + TX, vegetable phosphate + TX, thiopyraphos + TX, DSP + TX, ecdysterone + TX, EI 1642 + TX, EMPC + TX, EPBP + TX, etaphos + TX, ethiofencarb + TX, ethyl formate + TX, dibromoethane + TX, dichloroethane + TX, ethylene oxide + TX, EXD + TX, fenpyroxen + TX, ethiofencarb + TX, fenitrothion + TX, fenoxacrim + TX, cypermethrin + TX, fenthion + TX, ethylfenthion + TX, flucofuron + TX, butylfenthion + TX, phosphamidon + TX, butylfenthion + TX, furathiocarb + TX, pyrethroid +TX, biguanide salt +TX, biguanide acetate +TX, sodium tetrathiocarbonate +TX, benzyl chlorpyrifos +TX, HCH +TX, HEOD +TX, heptachlor +TX, cypermethrin +TX, HHDN +TX, hydrogen cyanide +TX, quinolinic acid +TX, IPSP +TX, chlorfenapyr +TX, carbofuran +TX, isodrin +TX, isofenol +TX, transplanting spirit +TX, rice blast +TX, oxazophos +TX, juvenile hormone I +TX, juvenile hormone II +TX, juvenile hormone III +TX, chlorpentyl +TX, methoprene +TX, lead arsenate +TX, bromophenylphos + TX, acetamiprid + TX, thiamethoxam + TX, m-isopropyl methylcarbamate + TX, magnesium phosphide + TX, phosphorus azide + TX, methyl azoxystrobin + TX, chlorpyrifos + TX, mercurous chloride + TX, methyl sulfoxide + TX, metamifop + TX, metamifop potassium + TX, metamifop sodium + TX, methylsulfonyl fluoride + TX, butenamidophos + TX, methoprene + TX, methoxythrin + TX, methoxychlor + TX, methyl isothiocyanate + TX, methyl chloroform + TX, dichloromethane + TX, oxadiazine + TX, mirex + TX, naphthiophos + TX, naphthalene + TX, NC-1 70+TX, Nicotine+TX, Nicotine sulfate+TX, Nithiothiazine+TX, Pronicotine+TX, O-5-dichloro-4-iodophenyl O-ethylethylphosphonothioate+TX, O,O-diethyl O-4-methyl-2-oxo-2H-benzopyran-7-ylphosphonothioate+TX, O,O-diethyl O-6-methyl-2-propylpyrimidin-4-ylphosphonothioate+TX, O,O,O',O'-tetrapropyl dithiopyrophosphate+TX, Oleic acid+TX, p-dichlorobenzene+TX, Methyl parathion+TX, Pentachlorophenol+TX, Pentachlorophenyl laurate+TX, PH 60-38+TX, fenthion+TX, parachlorothion+TX, phosphine+TX, methyl phoxim+TX, methamidophos+TX, polychlorinated dicyclopentadiene isomers+TX, potassium arsenite+TX, potassium thiocyanate+TX, precocious I+TX, precocious II+TX,Precocious hormone III + TX, amimidophos + TX, fluthrin + TX, fenvalerate + TX, prothiophos + TX, pyraclostrobin + TX, anti-pyrethroid + TX, quassia extract + TX, quinalphos-methyl + TX, fenvalerate + TX, iodoxamide + TX, resmethrin + TX, rotenone + TX, thiamethoxam + TX, ryanodine + TX, sabadilla + TX, octamethrin + TX, clostridium + TX, SI-0009 + TX, thiaprolin + TX, sodium arsenite + TX, sodium cyanide + TX, sodium fluoride + TX, sodium hexafluorosilicate + TX, sodium pentachlorophenol + TX, sodium selenate + TX, sodium thiocyanate + TX, sulfofensulfuron (su TX, sulfoanil sodium + TX, sulfuryl fluoride + TX, sulfoanil + TX, tar + TX, thiabendazim + TX, TDE + TX, butylpyrimidophos + TX, dimethophos + TX, cyclopentyl thiocarb + TX, tetrachloroethane + TX, thiochlorvos + TX, cyclohexane + TX, cyclohexane oxalate + TX, cypermethrin + TX, cypermethrin + TX, cypermethrin sodium + TX, tralomethrin + TX, permethrin + TX, triazolam + TX, trichlormetaphos-3 + TX, chlorpyrifos + TX, tolprocarb + TX, chlorpyrifos + TX, methoprene+TX, veratridine+TX, veratridine+TX, XMC+TX, zetamethrin+TX, zinc phosphide+TX, tolfenphos+TX, and chlorfluanidine+TX, tetrafluanidine+TX, bis(tributyltin)oxide+TX, bromoac...

Claims

1. A compound having formula I in R1 is hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HC≡CCH2-; A1 is N or CR 2c ; R 2c is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy; R 2a C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen, C3-C6 cycloalkyloxy substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen, C3-C6 cycloalkylC1-C4 alkyl, C3-C6 cycloalkylC1-C4 alkoxy, substituted by one to five substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen C3-C6 cycloalkylC1-C4 alkyl substituted with a C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen substituent, C3-C6 cycloalkylC1-C4 alkoxy substituted with one to five substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, or C1-C4 haloalkylsulfinyl; R 2b is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylthio, C1-C3 alkoxy, C1-C3 haloalkoxy, SF5, or CN; R3 is methyl; A2 is CR 4b or N; R 4b is hydrogen or a halogen; R 4a is cyano, or C1-C3 haloalkoxy; R 5a and R 5b are independently selected from hydrogen, halogen and methyl; or an agrochemically acceptable salt, stereoisomer, enantiomer and tautomer of the compound of formula I.

2. The compound according to claim 1, wherein A1 is N.

3. The compound according to claim 1, wherein A1 is CR 2c , where R 2c is hydrogen or a halogen.

4. The compound according to any one of claims 1 to 3, wherein R 2a It is C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and halogen, C3-C6 cycloalkyl substituted by one to five substituents independently selected from halogen and C1-C3 haloalkyl, C1-C4 alkyl, C1-C5 cyanoalkyl, C3-C6 cycloalkyloxy, C1-C4 haloalkylsulfonyl or C1-C4 haloalkylsulfinyl.

5. The compound according to any one of claims 1 to 3, wherein R 2b It is halogen, C1-C3 haloalkyl, C1-C3 haloalkylthio, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN.

6. The compound according to any one of claims 1 to 3, wherein R 4a It is cyano or C1-C3 fluoroalkoxy.

7. The compound according to any one of claims 1 to 3, wherein A2 is N.

8. The compound according to any one of claims 1 to 3, wherein A2 is CH.

9. A composition comprising a compound as defined in any one of claims 1 to 3, one or more adjuvants and diluents, and optionally one or more other active ingredients.

10. A method for preventing and controlling insects, acarines, nematodes or molluscs for non-therapeutic purposes, which method comprises applying an insecticidal, acaricidal, nematicidal or molluscicidal effective amount of a compound as defined in any one of claims 1 to 3 or a composition as defined in claim 9 to the pest, the locus of the pest, or a plant susceptible to attack by the pest.

11. A method for protecting plant propagation material from attack by insects, mites, nematodes or molluscs, the method comprising treating the propagation material or the site in which the propagation material is planted with an effective amount of a compound as defined in any one of claims 1 to 3 or a composition as defined in claim 9.

12. Use of a compound as defined in any one of claims 1 to 3 or a composition as defined in claim 9 for the preparation of a medicament for controlling parasites in or on an animal in need thereof.

13. A compound having formula IIaa to IIae wherein R1 is as defined in claim 1, and R4 is a substituent R in formula I as claimed in claim 1 4a A2 and R 4a As defined in any one of claims 1, 6, 7 and 8.

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