EA045353B1 - PESTICIDALLY ACTIVE DIAZINAMIDE COMPOUNDS - Google Patents

Description

The present invention relates to pesticidal active, in particular insecticidal active diazinamide compounds, methods for their preparation, compositions containing these compounds, and their use for the control of animal pests, including arthropods and, in particular, insects or members of the order Acarina.

WO 2017192385 describes certain heteroaryl-1,2,4-triazole and heteroaryl-tetrazole compounds for use in the control of ectoparasites in animals (such as mammal and non-mammalian animals).

Currently, new pesticide-active diazinamide compounds have been discovered.

The present invention accordingly relates, in a first aspect, to a compound of formula I

Where

R1 is H, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cyanoalkyl, aminocarbonyl-C ₁ -C ₆ -alkyl, hydroxycarbonyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -nitroalkyl, trimethylsilane -C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C2-C6alkenyl, C ₂ -C ₆ -haloalkenyl, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ -haloalkynyl, C ₃ -C ₄ -cycloalkyl-C ₁ -C ₂ -alkyl, C ₃ C ₄ -cycloalkyl-C ₁ -C ₂ -alkyl, where the C ₃ -C ₄ -cycloalkyl group is replaced by 1 or 2 halogen atoms, oxetan-3-yl-CH ₂ -, benzyl or benzyl substituted with halogen or C ₁ -C ₆ haloalkyl;

A1 is N or CR _2c ;

R _2c is H, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy or C 1 -C 3 -haloalkoxy;

R _2a represents C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkoxy, C ₃ -C ₆ -cycloalkyl, substituted with one to three substituents independently selected from C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C1-C3alkoxy, cyano and halogen, C ₃ -C ₆ -cycloalkoxy, substituted with one to three substituents independently selected from C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, cyano and halogen, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, C ₃ C ₆ -cycloalkyl-C ₁ -C ₄ -alkoxy, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, substituted with one to five substituents , independently selected from C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -alkoxy, cyano and halogen, C ₃ -C ₆ cycloalkyl-C ₁ -C ₄ -alkoxy substituted with one- five substituents independently selected from C1-C3alkyl, _C1 - _C3haloalkyl , cyano and halogen, _C1 - _C6cyanoalkyl , _C1 - _{C4alkylsulfonyl} , C1-C4haloalkylsulfonyl, _C1 - _{C4alkylsulfinyl} or C ₁ -C ₄ -haloalkylsulfinyl;

R _2b is H, halogen, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -haloalkylthio, C 1 -C 3 -alkoxy, C ₁ -C ₃ -haloalkoxy, SF ₅ or CN;

R ₃ represents C ₁ -C ₃ -alkyl or C ₁ -C ₃ -haloalkyl;

A ₂ represents CR _4b or N;

R _4b represents hydrogen or halogen;

R4 _a represents cyano or C ₁ -C ₃ haloalkoxy;

R _5a and R _5b are independently selected from hydrogen, halogen, CN, C ₁ -C ₃ alkyl,

C ₁ -C ₃ -haloalkyl, C ₃ -C ₄ -cycloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -haloalkoxy; or agrochemically acceptable salts, stereoisomers, enantiomers, tautomers and N-oxides of the compounds of formula I.

Compounds of formula I which contain at least one basic center can form, for example, 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 acid, with strong organic carboxylic acids, such as C ₁ -C ₄ -alkane carboxylic acids which are unsubstituted or substituted, for example with a halogen, 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 with organic sulfonic acids, such as C ₁ -C ₄ - alkanyl arylsulfonic acids which are unsubstituted or substituted, for example with halogen, for example methane or p-toluenesulfonic acid. Compounds of formula I which contain at least one acidic group can form, for example, salts with bases, for example mineral salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine such as morpholine, piperidine, pyrrolidine, a lower mono-, di- or trialkylamine such as ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a lower mono-, di- or trihydroxyalkylamine such as mono-, di- or triethanolamine .

- 1 045353

In each case, the compounds of formula I of the present invention are in free form, in oxidized form in the form of an N-oxide or in the form of a salt, for example in the form of an agronomically useful salt.

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.

The compounds of formula I according to the present invention also include hydrates, which can be formed during salt formation.

As used herein, the term C ₁ -C _n -alkyl refers to a straight or branched chain saturated hydrocarbon radical attached via any carbon atom, having from 1 to n carbon atoms, for example, any of the radicals methyl, ethyl , n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl , 2-methylpentyl, 3-methylpentyl, 4methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2 -ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl.

As used herein, the term C ₁ -C _n -haloalkyl refers to a straight or branched saturated alkyl radical attached via any carbon atom, having from 1 to n carbon atoms (as defined above), some or all of the hydrogen atoms in these radicals can be replaced by fluorine, chlorine, bromine and/or iodine, i.e. for example, any of 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, 2,3difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3, 3,3-pentafluoropropyl, heptafluoropropyl, 1(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4chlorobutyl, 4-bromobutyl or nonafluorobutyl. Accordingly, the term C ₁ -C ₂ -fluoroalkyl will refer to a C ₁ -C ₂ -alkyl radical which carries 1, 2, 3, 4 or 5 fluorine atoms, for example any of difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl , 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2tetrafluoroethyl or pentafluoroethyl.

As used herein, the term C ₁ -C _n -alkoxy refers to a saturated straight or branched chain alkyl radical having from 1 to n carbon atoms (as defined above) which is attached via an oxygen atom, i.e. for example, any of the radicals being methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. The term halogen-C ₁ -C _n -alkoxy as used herein refers to a C1Cn alkoxy radical where one or more hydrogen atoms in the alkyl radical are replaced by the same or different halogen atoms. Examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.

As used herein, the term C ₁ -C _n -cyanoalkyl refers to a saturated C 1 -C _n straight or branched chain alkyl radical having from 1 to n carbon atoms (as defined above), wherein one of the hydrogen atoms in these radicals is substituted to a cyano group, for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2cyanoethyl, 4-cyanobutyl, etc.

As used herein, the term C ₃ -C _n -cycloalkyl refers to 3-n-membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane. The term C ₃ -C _n cycloalkoxy refers to cycloalkyl groups (as defined above) that are attached via an oxygen atom to the rest of the molecule.

As used herein, the term C ₃ -C _n -cycloalkyl-C ₁ -C _n -alkyl refers to a 3-membered cycloalkyl group with an alkyl group of 1-n carbon atoms, where the alkyl group is attached to the rest of the molecule. In case the C ₃ -C 4 -cycloalkyl-C ₁ -C ₂ -alkyl group is substituted, the substituent(s) may be on the cycloalkyl group or alkyl moiety. The term C ₃ -C _n -cycloalkyl-C ₁ -C _n -αalkoxy refers to an alkyl group of a cycloalkylalkyl substituent attached to an oxygen atom, where the oxygen atom is attached to the rest of the molecule.

As used herein, the term aminocarbonyl-C ₁ -C _n -alkyl refers to an alkyl radical wherein one of the hydrogen atoms in the radical is replaced by a CONH2 group.

As used herein, the term hydroxycarbonyl-C ₁ -C _n -alkyl refers to an alkyl radical wherein one of the hydrogen atoms in the radical is replaced by a COOH group.

As used herein, the term C ₁ -C _n -nitroalkyl refers to an alkyl radical wherein one of the hydrogen atoms in the radical is replaced by a NO2 group.

As used herein, the term C ₁ -C _n -haloalkylthio refers to a C 1 -C3- 2 045353 haloalkyl moiety linked via a sulfur atom.

As used herein, the term trimethylsilane-C ₁ -C _n -alkyl'' refers to an alkyl radical wherein one of the hydrogen atoms in the radical is replaced by a -Si(CH ₃ ) ₃ group.

As used herein, the term C ₂ -C _n -alkenyl refers to a straight or branched alkenyl chain having from two to n carbon atoms and one or two double bonds, for example ethenyl, prop-1-enyl, but-2-enyl.

As used herein, the term C ₂ -C _n -haloalkenyl refers to a C ₂ -C _n -alkenyl moiety substituted with one or more halogen atoms, which may be the same or different.

As used herein, the term 'C ₂ -C _n -alkynyl' refers to a straight or branched alkynyl chain having two to n carbon atoms and one triple bond, for example ethynyl, prop-2-ynyl, but-3-ynyl,

As used herein, the term 'C ₂ -C _n -haloalkynyl' refers to a C ₂ -C _n alkynyl moiety substituted with one or more halogen atoms, which may be the same or different.

A halogen is typically fluorine, chlorine, bromine or iodine. This also applies correspondingly to halogen in combination with other terms, such as haloalkyl.

As used herein, the term control refers to the reduction of pests, the elimination of pests, and/or the prevention of further pest damage, thereby reducing damage to the plant or plant-derived product.

The zigzag line used herein, for example in K-1 and L-1, indicates the point of attachment/attachment to the rest of the connection.

As used herein, the term pest refers to insects and molluscs found in agriculture, horticulture, forestry, and the storage of plant products (such as fruits, grains, and lumber); as well as pests that cause damage to man-made structures. The term pest covers all stages of the pest's life cycle.

As used herein, the term effective amount refers to the amount of a compound or a salt thereof that, after single or multiple applications, provides the desired effect.

The effective amount will readily be determined by one skilled in the art by using known techniques and examining results obtained under similar circumstances. In determining the effective amount, a number of factors are considered, including, without limitation, the type of plant or product to which the application will be applied; the pest to be controlled and its life cycle; the specific compound used; type of application and other relevant circumstances.

One of ordinary skill in the art will recognize that compounds of formula I contain a stereogenic center, which is indicated by an asterisk in the structure below wherein R1, _R2a , _{R2b , R3} , R4a, _R5a , _R5b , A1 and A2 are as follows: , as defined in the first aspect.

The present invention contemplates both racemates and individual enantiomers. Compounds with preferred stereochemical configurations are presented below.

Particularly preferred compounds of the present invention are those of formula I'a:

wherein R1, _R2a , _R2b , _R3 , _R4a , R5a, _R5b , A1 and A2 are as defined in the first aspect, and stereoisomers, enantiomers, _tautomers and N-oxides of the compounds of formula (I'a) , as well as their agrochemically acceptable salts.

As used herein, the term optionally substituted means that the group is either unsubstituted or substituted with a designated substituent, for example C ₃ -C ₄ - 3 045353 cycloalkyl optionally substituted with 1 or 2 halogen means C ₃ -C ₄ -cycloalkyl, C ₃ - C ₄ cycloalkyl substituted with 1 halogen atom and C ₃ -C ₄ cycloalkyl substituted with 2 halogen atoms.

Embodiments according to the present invention are set forth below.

In one embodiment of each aspect of the present invention, A1 is

A. N or

B. CR _2c where R _2c represents hydrogen or halogen (such as Cl, F, Br and I); preferably hydrogen.

In one embodiment of each aspect of the present invention, R _2a is:

A. C ₃ -C ₆ -cycloalkyl, C ₃ -C6 -cycloalkoxy, C ₃ -C ₆ -cycloalkyl, substituted with one to three substituents independently selected from C ₁ -C ₃ -alkyl, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -αalkoxy, cyano and halogen, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, substituted with one to five substituents independently selected from halogen and C ₁ -C ₃ -haloalkyl, C ₁ - C ₅ -cyanoalkyl, C ₃ -C6 -cycloalkoxy, C ₁ -C ₄ -haloalkylsulfonyl or C ₁ -C ₄ -haloalkylsulfinyl; or

B. C ₃ -C ₄ -cycloalkyl, C ₃ -C ₄ -cycloalkoxy, C ₃ -C ₄ -cycloalkyl, substituted with one to three substituents independently selected from C ₁ -C ₂ -alkyl, C ₁ -C ₂ -haloalkyl , C ₁ -C ₂ -αalkoxy, cyano and halogen, C ₃ -C ₄ -cycloalkyl-C ₁ -C ₂ -alkyl, substituted with one to five substituents independently selected from halogen and C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -cyanoalkyl, C ₃ -C ₄ -cycloalkoxy, C ₁ -C ₃ -haloalkylsulfonyl or C ₁ -C ₃ -haloalkylsulfinyl; or

C. Cyclopropyl, cyclopropyl substituted with one to three substituents independently selected from methyl, trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted with one to five fluorine substituents, C ₁ -C ₃ -cyanoalkyl, cyclopropoxy, trifluoromethylsulfonyl or trifluoromethylsulfinyl; or

D. Cyclopropyl, cyclopropyl substituted with one to three substituents independently selected from methyl, trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted with one or two fluorine substituents on the methyl moiety, C ₁ -C ₃ -cyanoalkyl , trifluoromethylsulfonyl or trifluoromethylsulfinyl; or

E. Cyclopropyl, cyclopropyl substituted with one to three substituents independently selected from trifluoromethyl, methoxy, cyano, fluorine and chlorine, cyclopropylmethyl substituted with one or two fluorine substituents on the methyl moiety, C ₁ -C ₃ cyanoalkyl, trifluoromethylsulfonyl.

In one embodiment of each aspect of the present invention, R _2b is:

A) halogen, C ₁ -C ₃ -haloalkyl, C ₁ -C ₃ -haloalkylthio, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -haloalkoxy or CN; or

B) halogen, C ₁ -C ₃ -haloalkyl or C ₁ -C ₃ -haloalkoxy; or

C) chlorine, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy; or

D) difluoromethyl or trifluoromethyl.

In one embodiment of each aspect of the present invention, R1 is:

A) hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HCH^CCH ₂ -; or

B) hydrogen, methyl or cyclopropylmethyl; or

C) hydrogen.

In one embodiment of each aspect of the present invention, R ₃ is:

A) C ₁ -C ₃ -alkyl or C ₁ -C ₃ -haloalkyl or

B) methyl.

In one embodiment of each aspect of the present invention, A ₂ is: A. N or

B. C-R4b, where R4b is hydrogen or halogen (such as Cl, F, Br and I); preferably R4b is hydrogen.

In one embodiment of each aspect of the present invention, R4 _a is:

A) cyano or C ₁ -C ₃ -fluoroalkoxy; or

B) cyano, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy or 2,2-difluoroethoxy.

In one embodiment of each aspect of the present invention, R _5a and R _5b are independently selected from:

A) hydrogen, halogen, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy;

B) selected from hydrogen, bromine, chlorine, methyl, methoxy or

C) hydrogen.

The present invention accordingly provides a compound of formula I containing the substituents R1, _R2a , _R2b , _R3 , _R4a , _R5a , _R5b , A1 and _A2 as defined above, in all combinations/permutations. Accordingly, there is provided, for example, a compound of formula I, wherein A1 corresponds to the first aspect (i.e., A1 is N or CR _2c , where R _2c is H, halogen, C ₁ -C ₃ alkyl, C1C ₃ haloalkyl, C ₁ -C ₃ -alkoxy or C ₁ -C ₃ -haloalkoxy); R1 represents embodiment B (ie hydrogen, methyl, cyclopropylmethyl); R _2a is embodiment C (i.e., cyclopropyl, cyclopropyl substituted with one to three substituents independently selected from methyl, trifluoromethyl, cyano, fluorine and chlorine, cyclopropylmethyl substituted with one to five fluorine substituents , C ₁ -C ₃ -cyanoalkyl, C ₃ -C ₆ -cyclopropoxy, trifluoromethylsulfonyl or trifluoromethylsulfinyl); R2 _b is embodiment B (ie halogen, C ₁ -C ₃ haloalkyl or C ₁ -C ₃ haloalkoxy); R3 is embodiment B (ie methyl); A2 represents embodiment B (ie, C-R4 _b wherein R4 _b is hydrogen or a halogen (such as Cl, F, Br and I); preferably R4 _b is hydrogen); R _4a is embodiment A (ie, cyano or C ₁ -C ₃ -fluoroalkoxy) and R _5a is embodiment B (ie, selected from hydrogen, bromine, chlorine, methyl, methoxy); and R _5b is embodiment C (ie hydrogen).

In one embodiment, a compound of Formula I may be presented as

wherein Rb R ₃ , R _5a and R _5b are as defined in the first aspect, R2 is a cyclic group containing A ₁ and substituents R _2a and R _2b as defined in the first aspect, and R4 is a cyclic group containing A ₂ and substituent R4 _a as defined in the first aspect.

In one embodiment of each aspect of the present invention, R2 (a cyclic group containing A ₁ and substituents R _2a and R _2b )

A. Selected from K-1- K-16

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

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

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

E. Selected from K-1, K-2, K-5, K-6, K-10, K-14, K-15, and K-16; or

F. Selected from K-1, K-2, K-6, K-10, K-14, K-15 and K-16; or

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

N. Selected from K-5, K-10, K-14 and K-15; or

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

In one embodiment of each aspect of the present invention, R4 (a cyclic group containing A ₂ and a substituent R _4a )

A. selected from L-1- L-9

- 5 045353

B. Selected from L-1, L-2, L-7, L-8 and L-9; or

C. Selected from L-3, L-5, L-6, L-7, L-8 and L-9; or

D. Selected from L5, L-7, L-8 and L-9; or

E. Selected from L-3, L-5, L-7 and L-9; or

F. L-8 and L-9; or

G. L-5 and L-9; or

N. L-7 or L-9; or

I. L-1 or L-9.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A as R1 contains hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HCH=CCH ₂ -; as R ₂ contains one of K-1-K-16; contains methyl as _R3 ; as R4 contains one of L-1-L-9; and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1-K-16; contains methyl as _R3 ; as R ₄ contains one of L-1-L-9; and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen as R1; as R2 contains one of K-1-K-16; contains methyl as _R3 ; as R4 contains one of L-1-L-9; and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains 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; contains methyl as _R3 ; as R4 contains one of L-1-L-9; and R5a and R5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1, K-2, K-5, K-10, K-11, K-14; K-15 and K-16; contains methyl as _R3 ; as R4 contains one of L-1-L-9; and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1, K-2, K-5, K-10, K-11, K-14, K-15 and K-16; contains methyl as _R3 ; as R4 contains one of L-1, L-2, L-7, L-8 and L-9; and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1, K-2, K-5, K-10, K-11, K-14, K-15 and K-16; contains methyl as _R3 ; as R4 contains one of L-1, L-2, L-7, L-8 and L-9; and each of R _5a and R _5b is hydrogen.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-5, K-10, K-14 and K-15; contains methyl as _R3 ; as R4 contains one of L-1 or L-9; and each of R5a and R5b is hydrogen.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1, K-2, K-6, K-10, K-12, K-14, K-15 and K-16; contains methyl as _R3 ; as R4 contains one of L-1-L-9; and R5a and R5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A contains hydrogen, methyl or cyclopropylmethyl as R1; as R2 contains one of K-1, K-2, K-6, K-10, K-12, K-14, K-15 and K-16; contains methyl as _R3 ; as R4 contains one of L-3, L-5, L-7 and L-9 and R _5a and R _5b are independently selected from hydrogen, halogen and methyl.

In one embodiment of each aspect of the present invention, a compound of formula I- 6 045353

A or I'-A as R ₁ contains hydrogen, methyl or cyclopropylmethyl; as R2 contains one of K-1, K-2, K-6, K-10, K-12, K-14, K-15 and K-16; contains methyl as _R3 ; as R ₄ contains one of L-3, L-5, L-7 and L-9 and each of R _5a and R _5b represents hydrogen.

In one embodiment of each aspect of the present invention, the compound of formula IA or I'-A as R ₁ contains hydrogen, methyl or cyclopropylmethyl; as R ₂ contains one of K-2, K-6, K-14 and K-15; contains methyl as _R3 ; as R4 contains one of L-1 or L-9; and each of R5a and R5b is hydrogen.

In a second aspect of the present invention there is provided a composition comprising a compound of formula I as defined in the first aspect, one or more auxiliaries and a diluent, and optionally one other active ingredient.

A third aspect of the present invention provides a method for controlling or controlling insects, mites, nematodes, or molluscs, which includes applying to a pest, to a pest habitat, or to a plant susceptible to pest attack an insecticidal, acaricidal, nematocidal, or molluscicidal effective amount a compound as defined in the first aspect, or a composition as defined in the second aspect.

In a fourth aspect of the present invention, there is provided a method of protecting plant propagation material from attack by insects, mites, nematodes or molluscs, which comprises treating the propagation material or an area where the propagation material is planted with an effective amount of a compound of formula I as defined in the first aspect, or the composition defined in the second aspect.

In a fifth aspect of the present invention, there is provided a plant propagation material, such as a seed, containing or treated with or attached to a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.

In a further aspect of the present invention, there is provided a method of controlling parasites in or on an animal in need thereof, comprising administering an effective amount of a compound of the first aspect. The present invention further provides a method of controlling ectoparasites on an animal in need thereof, comprising administering an effective amount of a compound of Formula I as defined in the first aspect. The present invention further provides a method of preventing and/or treating diseases transmitted by ectoparasites, comprising administering an effective amount of a compound of Formula I as defined in the first aspect to an animal in need thereof.

The compounds of formula I can be prepared by those skilled in the art according to known methods. More specifically, the compounds of formulas I and I'a, as well as intermediate compounds, can therefore be prepared as described below in the schemes and examples. Specific stereogenic centers have been left unspecified for simplicity and are in no way intended to limit the presentation of the diagrams.

The process for preparing the compounds of formula I of the present invention is carried out using methods known to those skilled in the art.

Compounds of formula I

can be prepared by reacting the amine of formula II

where R _b R ₃ , A ₂ , R _4a , R _5a and R _5b are as described in formula I, with the carboxylic acid derivative of formula III

- 7 045353 where A1, R2 _a and R2 _b are as described above for formula I.

The chemical reactions are described in more detail in Scheme 1.

Scheme 1

In Scheme 1, the compounds of formula III, where A1, R2 _a and R2 _b are as described in formula I, are activated to compounds 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, compounds in which X ₀ represents a halogen are formed by treating compounds of formula III, for example, with oxalyl chloride or thionyl chloride in the presence of catalytic quantities of DMF in inert solvents such as methylene dichloride or THF, at a temperature of 20 up to 100°C, preferably 25°C. Treatment of IIIa with compounds of formula II, wherein R1, R3, A2, _R4a , _R5a and _R5b are as defined in formula I, optionally in the presence of a base, for example triethylamine or pyridine, produces compounds of formula I. Alternatively, compounds of formula I can be prepared by treating compounds of formula III with dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to produce activated molecules IIIa, wherein _X0 is X01 or _X02 , in an inert solvent, for example pyridine or THF, optionally in the presence of a base, for example triethylamine, at a temperature of 50-180°C. In addition, the acid of formula III can also be activated by reaction with a coupling reagent such as propanephosphonic anhydride (T3P®) or O-(7-aza-1benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU ), to obtain compounds of formula IIIa, where X ₀ represents X ₀₃ and X ₀₄ , as described, for example, in Synthesis 2013, 45, 1569 and Journal Prakt. Chemie 1998, 340, 581. Subsequent reaction with an amine of formula II gives compounds of formula I.

Intermediates of formula II, where R1, R3, A ₂ , R4 _a , R _5a and R _5b are as defined in formula I, can be prepared according to scheme 2.

Scheme 2

Xffi = a, Br, I, OMs, OTs or OTf

In Scheme 2, the compounds of formula II, where R1, R3, A2, R4 _a , R _5a and R _5b are as defined in formula I, can be prepared by treating the compounds of formula VI, where R3, A ₂ , R4 _a , R _5a and R _5b are as defined in formula I, compounds of formula VII (where R1 is as defined in formula I), for example in the presence of NaBH(OAc) ₃ or NaBH ₃ CN, preferably in the presence of NaBH ₃ CN in as a reducing reagent, in a suitable solvent, preferably acetic acid, at room temperature, similar to WO 2002/088073, page 35. Alternatively, using another reagent system for carrying out reductive amination, which uses a combination of Ti(i-OiPr) 4 and NaBH4 in the presence of an amine of formula VII, compounds of formula II can also be prepared (see Synthesis 2003 (14), 2206).

Compounds of formula VI, wherein R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, can be prepared by performing a Still reaction between compounds of formula IV,

- 8 045353 where X ₀₅ represents a leaving group such as chlorine, bromine, iodine, arisulfonate, alkyl sulfonate or trifluoromethanesulfonate, and R ₃ , R _5a and R _5b are as defined in formula I, and tin compounds of formula V (where A2 and R4 _a are as defined in formula I) in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0) or (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1 complex) , in an inert solvent such as DMF, acetonitrile or dioxane, optionally in the presence of an additive such as potassium, cesium fluoride or lithium chloride, and optionally in the presence of an additional catalyst such as copper(1) iodide. Such Still coupling reactions are well known to those skilled in the art and are described, 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.

Alternatively, the compounds of formula VI (wherein R ₃ , A ₂ , R | _a , R _5a and R _5b are as defined in formula I) can also be prepared by performing the Suzuki reaction (Scheme 3), which provides, for example, reacting compounds of formula IV (wherein R ₃ , R _5a and R 5b are as defined in formula I and X05 represents a leaving group such as, for example, chlorine, bromine, iodine, arisulfonate, alkyl sulfonate or trifluoromethanesulfonate) with compounds of formula VIII, where W may represent a boron-based functional group, such as, for example, B(OH) ₂ or boronic acid pinacol ester. The reaction can be catalyzed using a palladium catalyst, such as tetrakis(triphenylphosphine)palladium or (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1 complex), in the presence of a base such as sodium carbonate or fluoride cesium, in a solvent or mixture of solvents, such as, for example, a mixture of 1,2-dimethoxyethane and water, dioxane and water or DMF and water, preferably under an inert atmosphere. The reaction temperature may preferably be in the range from room temperature to the boiling point of the reaction mixture. Such Suzuki reactions are well known to those skilled in the art and are described, for example, in 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.

Scheme 3

Compounds of formula IV are generally commercially available.

Alternatively, compounds of formula VI wherein R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I are listed in Scheme 4.

Scheme 4

For example, compounds of formula VI, where R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, can be prepared by performing an allyl sulfone coupling reaction between compounds of formula IVa (where R 3 , R 5a and R5b are as defined in formula I) and compounds of formula XI, where A ₂ and R _4a are as defined in formula I, in suitable solvents, preferably dioxane or DMF, in the presence of a Pd catalyst, preferably palladium acetate, a ligand, for example di-tert-butyl(methyl)phosphane, and a base, for example Cs2CO3, usually when heated at a temperature of 120-130°C. Such methods have been described, for example, in J. Am. Chem. Soc. 2018, 140, 15916.

- 9 045353

The necessary intermediates of formula XI can be prepared from compounds of formula IX (where A2 and R _4a are as defined for formula I, and X ₀₆ is a leaving group and represents halogen and methyl sulfone) by nucleophilic substitution with prop-2-ene1-thiol and subsequent oxidation of mCPBA. Such transformations are widely known and are described, for example, in J. Am. Chem. Soc. 2018, 140, 15916.

Alternatively, compounds of formula VI wherein R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I are listed in Scheme 5.

Compounds of formula VI (where R ₃ , A ₂ , R 4 _a , R _5a and R _5b are as defined in formula I) can be prepared by treating compounds of formula XIV with a Grignard reagent R ₃ MgBr, for example MeMgBr, at lower values temperature, preferably 0-25°C, in a suitable solvent such as THF or diethyl ether.

Weinreb amides of formula XIV (where A ₂ , R _4a , R _5a and R _5b are as defined in formula I) can be prepared in three steps from compounds of formula XIII, where A ₂ , R _4a , R _5a and R _5b are as defined in formula I, and Z represents C ₁ -C ₆ -alkyl. Compounds of formula XIII are converted to carboxylic acids by methods known in the art (see, for example, WO 2011/143365, page 138), and activation (see Scheme 1) of the resulting carboxylic acids followed by treatment with N-methoxy-N-methylamine (according to Weinreb et al. Tet. Lett. 1981, 39, 3815) gives compounds of formula XIV.

Compounds of formula XIII, where A ₂ , R _4a , R _5a and R _5b are as defined in formula I, and Z represents C ₁ -C ₆ -alkyl, can be prepared by reacting compounds of formula XII (where R _5a and R _5b are as defined in formula I, Z represents C1-C6 alkyl and X ₀₇ represents a leaving group such as chlorine, bromine, iodine) with compounds of formula V (Still's reaction) or compounds of formula VIII (reaction Suzuki-Miyaura) in the presence of a palladium catalyst, as detailed in Schemes 2 and 3.

Scheme 5

In an alternative method (Scheme 6), compounds of formula II, where R1, R ₃ , A ₂ , R4 _a , R _5a and R _5b are as defined in formula I, can be prepared by performing a nucleophilic substitution reaction of a compound of formula XVI, where R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, and X ₀₈ is OMs, OTs or OTf, with amines of formula VII in suitable solvents, which may include, for example, acetonitrile or DMF, in the presence of a suitable base such as sodium, potassium or cesium carbonate, usually by heating at a temperature from room temperature to 200°C, preferably from 40°C to the boiling point of the reaction mixture, optionally under microwave heating conditions.

Compounds of formula XVI, where R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, and X ₀₈ represents OMs, OTs or OTf, can be prepared by activating alcohols of formula XV, where R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, compounds of formula XIII, where Y is CH ₃ , CF ₃ or p-CH ₃ -C ₆ H ₄ , in an inert solvent, preferably in methylene dichloride, and in the presence of a base, for example triethylamine. Alcohols of formula XV can also be activated to alkyl halides XVI (where X ₀₈ represents Cl or Br) by treatment with phosphorus compounds, for example, P(X ₀ ) ₃ , where X ₀ represents chlorine or bromine, by methods known to those skilled in the art. areas. Such general transformations of functional groups are described, for example, in Organische Chemie. 4. Auflage, Wiley-VCH Verlag, Weinheim 2005, p. 393 ff and

- 10 045353

Chem Commun. 2014, 50, 5756.

Compounds of formula XV, wherein R ₃ , A ₂ , R _4a , R _5a and R _5b are as defined in formula I, can be prepared by reduction of ketones VI (where R ₃ , A ₂ , R4 _a , R _5a and R _5b are as defined in formula I), for example using NaBH4, in the usual way (see for example WO

2012/082997, page 141), preferably in MeOH as solvent.

Scheme 6

Another method for obtaining compounds of general formula IIa is presented in Scheme 7.

Scheme 7

X^OMsOTf

OTs, Cl or Br

H^d/C solvent, e.g. MeOH or

Pd(PPh ₃ h, N,N-dimethylbarbituric acid solvent, for example, CH ₂ Clg

T = στ rt up to the reflux temperature, removal of the protective group

Thus, by performing a nucleophilic substitution reaction of compounds of formula XVI with amines of formula VII, compounds of formula II are obtained (wherein R1, _R3 , _A2 , _R4a , _R5a and _R5b are as defined in formula I), as already detailed described in Scheme 6. Compounds of formula II containing a suitable protecting group, for example where R1 is benzyl, can be hydrogenated with hydrogen in the presence of palladium (on carbon) in a solvent, for example MeOH or EtOH, to give compounds of formula IIa, where R ₃ , A ₂ , R 4 _a , R _5a and R _5b are as defined in formula I (see, for example, Synlett, 2010, (18), p. 2708). Compounds of formula II wherein R1 is allyl and _R3 , _A2 , _R4a , _R5a and _R5b are as defined in formula I can also be converted to compounds of formula IIa by reacting with N'N'dimethylbarbituric acid. acid in the presence of a Pd catalyst, preferably tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, for example CH ₂ Cl ₂ , to obtain compounds of formula IIa according to J. Org. Chem. 1993, 58, 6109.

Formation of compounds of formula V, where A ₂ and R4 _a are as defined in formula I,

- 11 045353 is shown in diagram 8.

The compounds of formula V, where A2 and R _4a are as defined in formula I, can be prepared by treating the compounds of formula IX with a source of palladium, such as, for example, Pd(Ph ₃ ) ₄ and bis(tributyltin), in a suitable solvent, such as DMF, usually when heated at a temperature of 100-130°C. Such methods have been described, for example, in Molecular Pharmacology, 90(3), 177187; 2016. Alternatively, compounds of formula V can also be prepared by treating compounds of formula IX with n-butyllithium and tributyltin chloride in a suitable solvent such as THF, typically at a lower temperature, such as -78 to 0°C. Such methods have been described, for example, in US 20180273562.

Scheme 8

R ₄ a Where is the source Rd, for example, Pd(Ph j,.

y |j (Bu _b Sn-Sn(Bu^, solvent y p

A ₂ N --------------------* a ₂ m or | BuLi, BusSnCI, solvent |

Χοθ SnBus

IX ν

Hob = Cl or Br

Compounds of formula IXa and IXaa, wherein A ₂ and R4 _a are as defined in formula I, and X ₀₆ represents a leaving group such as Cl, Br and Q represents C ₁ -C ₃ -haloalkyl, or are commercially available , or can be obtained according to widely known methods, as shown in Scheme 9.

Scheme 9

Q-X® XVIII solvent, AcCN or dioxane base, e.g. KOH

T = from 20°C to reflux temperature nucleophilic substitution

Λ06

1Ha he

*06

CICF ₂ CO ₂ Na

K2CO3 solvent, for example, DMF with difluorocarbene

IXaa

Thus, compounds of formula IXa, wherein A ₂ and R4a are as defined in formula I, X ₀₆ is a leaving group such as Cl or Br, and Q is a C1-C3 haloalkyl, can be prepared by alkylation of compounds XVII with using a compound of formula XVIII, where Q is a C ₁ -C ₃ haloalkyl and X ₀₉ is a leaving group such as Cl, Br, F, I, OSO2CF3 or OSO2CH3, in the presence of a suitable base, for example cesium or potassium carbonate, in a solvent such as acetonitrile or DMF at 20-80°C. Such reactions are widely known to those skilled in the art and have been described, for example, in Med. Chem. Letts., 2017, 8(5), p. 543-548 and Bio. Med. Chem. Letts., 2017, 27(11), 2420-2423.

Compounds of formula IXaa, wherein A ₂ and R4 _a are as defined in formula I, X ₀₆ representing a leaving group such as Cl or Br, can be prepared from compounds of formula XVII by treatment with a source of difluorocarbene, for example ClCF ₂ CO ₂ Na or CF2SO2OCHF2, in the presence of a base such as KOH, potassium carbonate, etc., in an inert solvent at a temperature of 20-80°C. Such procedures have been described, for example, in J. Fluor. Chem. 2017, 203, 155, and US 2013/0225552, p. 128, and Org. Process Res. Dev., 2011, 15, 721.

Compounds of formula XVII are commercially available.

Carboxylic acids of formula IIIb, where R _2b and A ₁ are as defined in formula I, are useful intermediates for the preparation of the final compounds (see Scheme 1) and can be prepared by the method shown in Scheme 10.

- 12 045353

Scheme 10

Accordingly, compounds of formula IIIb, wherein R2 _b and A ₁ are as defined in formula I, can be prepared by reacting compounds of formula XXIII (wherein R2 _b and A1 are as defined in formula I, and Z1 is C ₁ -C ₄ -alkyl) with a suitable base, such as sodium or lithium hydroxide, in a suitable solvent such as MeOH, THF and H ₂ O, or a mixture thereof, usually by heating at a temperature from room temperature to reflux. Compounds of formula XXIII are prepared by oxidation of compounds of formula XXIIa (where R2 _b and A1 are as defined in formula I and Z1 is C ₁ -C ₄ -alkyl), for example using m-CPBA or NaIO4/RuCl ₃ . in a solvent, preferably CH2Cl2, or CHCl ₃ , or a mixture of H2O, AcCN and CCl ₄ . Such transformations are known to those skilled in the art and are described, for example, in J. Med. Chem. 2008, 51, 6902 or WO 2004/9086, pp. 24-25.

Finally, compounds of formula XXIIa, wherein R2b and A1 are as defined in formula I, and Z1 is C ₁ -C ₄ -alkyl, can be prepared by reacting compounds of formula XX with a suitable copper-containing trifluoromethylthiolation reagent of formula XXI (where R _2b and A1 are as defined in formula I, and X ₁₀ represents Br or Cl), ligands such as 1,10-phenanthroline or 4,4'-di-tert-butylbipyridine, in suitable solvents, for example acetonitrile or DMF, usually by heating at a temperature of 20-150°C, preferably from 40°C to the boiling point of the reaction mixture. Such methods have been described previously, for example, in 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.

Additional carboxylic acids of formula IIIb, wherein R _2b and A ₁ are as defined in formula I, and R _2a is as defined in formula I, but excluding C 1 -C 4 -alkylsulfonyl, C ₁ -C ₄ -alogenalkylsulfonyl, C ₁ -C ₄ -alkylsulfinyl, C ₁ -C ₄ -haloalkylsulfinyl are generally known or can be easily prepared by one skilled in the art.

A typical example of such a synthesis is of compounds of formula IIIc, wherein _R2b and _A1 are as defined in formula I, and R2a is as defined in formula I, but excluding the C1-C4 alkylsulfonyl, _C1 - _C4 haloalkylsulfonyl, C ₁ -C ₄ -alkylsulfinyl, C ₁ -C ₄ -haloalkylsulfinyl, shown in Scheme 11.

Scheme 11

X11

R2b

XX

XXVI solvent, for example, toluene, water, base, for example, K3PO4 T = from rt to 200°C

Chi = Cl, Br, I, OMs OTs, OTf

Pd catalyst, for example, PdCI ₂ (dppf) solvent, for example, 1,4-dioxane base, for example, KOAc T = 50-120°C

R2a. HE

G ^ON XXIV

Pd catalyst, for example Pd(PPh _:t )4

X^Cl, Br, I, OMs

OTs, OTf xxvm _R2a - ^X11

Pd catalyst, for example, PdCI ₂ (dppf) solvent, for example, 1,4-dioxane base, for example, K ₂ CO ₃ T = from rt to 200°C

Z, = C^alkyl R2b _XXV ||

base, for example _R2a aq. LiOH or NaOH solvent, e.g. MeOH, THF

He

R2b

111s

R _2a is not C ₁ -C ₄ alkylsulfonyl, C -C ₄ haloalkylsulfonyl, C _g C ₄ alkylsulfinyl, C _G Sdaloalkylsulfinyl

For example, compounds of formula IIIc can be prepared by reacting compounds of formula XXV (wherein _R2a , _R2b and A1 are as defined in Scheme 11 and Z1 is C1-C4 alkyl) with a suitable base, such as sodium or lithium hydroxide, in a suitable solvent such as MeOH, THF and H2O, or a mixture thereof, usually by heating at a temperature from room temperature to reflux temperature.

Compounds of formula XXV, where R2 _a , R _2b and A1, and Z ₁ are as defined in scheme 11, can be prepared by reacting compounds of formula XX, where R _2b and A ₁ are as defined in scheme 11, and X11 represents a leaving group (such as chlorine, bromine, iodine, OMs, OTs and OTf), with compounds of formula XXIV, where R2 _a is as defined in scheme 11, in the presence of a palladium catalyst, for example Pd(PPh ₃ ) ₄ , in suitable solvents, for example toluene/water, 1,4-dioxane/water, in the presence of a suitable base such as sodium, potassium or cesium carbonate or tripotassium phosphate, usually when heated at a temperature from room temperature to 200°C, preferably from 20° C. to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such processes have been described previously, for example, in Tetrahedron Letters 2002, 43, 6987-6990.

Compounds of formula XXV, wherein R _2a , R _2b and A1, and Z ₁ are as defined in Scheme 11, can also be prepared by reacting compounds of formula XXVII, where R _2b and A1 and Z1 are as defined in Scheme 11, and compounds of formula XXVIII, wherein R2a is as defined in Scheme 11 and X11 is a leaving group, for example bromine or iodine, in the presence of a palladium catalyst, for example PdCl ₂ (dppf), in suitable solvents that can include, for example, toluene/water, 1,4-dioxane/water, in the presence of a suitable base such as sodium, potassium or cesium carbonate or tripotassium phosphate, usually when heated at a temperature from room temperature to 200°C, preferably from 20°C to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such methods have been described previously, for example in WO 12139775, page 73.

Compounds of formula XXVII wherein R _2b and A 1 and Z 1 are as defined in Scheme 11 can be prepared by reacting compounds of formula XX wherein R _2b and A ₁ and Z ₁ are as defined in Scheme 11, and X11 is Cl, Br, I, OMs, OTs or OTf, with a compound of formula XXVI, for example bis(pinacolato)diboron (B ₂ pin ₂ ), in the presence of a palladium catalyst, for example PdCl ₂ (dppf), in suitable solvents, which may include, for example, toluene/water, 1,4-dioxane/water, in the presence of a suitable base such as sodium, potassium or cesium carbonate or potassium acetate, typically when heated at a temperature from room temperature to 200°C , preferably from 20°C to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such methods have been described previously, for example, in Bioorg. Med. Chem. Lett. 2015, 25, 1730, and WO 12139775, page 67.

Carboxylic acids of formula IIId, wherein R _2b and A1 are as defined in formula I, and R _2a is H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, cyano or halogen, can be prepared by as described in diagram 12.

Scheme 12

Compounds of formula IIId can be prepared from analogues of the compound of formula XXX by treatment with, for example, aqueous LiOH, NaOH or KOH in suitable solvents, which may include, for example, a THF/MeOH mixture, typically by heating from room temperature to 100° C., preferably from 20°C to the boiling temperature of the reaction mixture.

Compounds of formula XXX, wherein R _2a , R _2b and A ₁ are as defined in Scheme 12 and Z ₁ is C ₁ -C ₄ alkyl, can be prepared by treating compounds of formula XXIX which are either 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) with a compound of formula XXXI, for example, (trifluoroethyl)diphenylsulfonium triflate (Ph ₂ S ⁺ CH ₂ CF ₃ 'OTf) in the presence of an Fe catalyst and a base, preferably CsF, at a temperature of 0-50°C, preferably 20°C, in DMA as a solvent (same as described in Org. Lett. 2016, 18, 2471). The compounds of formula XXIX are obtained as a mixture of stereoisomers, where the trans isomer is the main isomer.

An alternative method (see Scheme 12) for preparing compounds of formula XXX, where R _2a , R _2b , and A1 and Z1 are as defined in Scheme 12, uses trifluoroethylamine hydrochloride/NaNO ₂ /NaOAc in the presence of an Fe catalyst; this reaction is carried out at room temperature in H2O or in a mixture of CH ₂ Cl ₂ and H2O, see, for example, Angew. Chem. Int. Ed.2010, 49,

- 14 045353

938 and Chemm. Commun. 2018, 54, 5110.

Carboxylic acids of formula IIIe, where R _2a , R _2b and A1 are as defined in Scheme 12, can be prepared in a manner quite similar to the method already shown in Scheme 12 (see Scheme

13).

Scheme 13

Thus, compounds of formula XXXI, wherein R _2a , R _2b and A1 are as defined in Scheme 13 and Z 1 is C ₁ -C ₄ -alkyl, are prepared by reacting compounds of formula XXIX (synthesized as described in ACS Med Chem. Lett. 2013, 4, 514 or Tetrahedron Lett. 2001, 42, 4083) with (bromodifluoromethyl)trimethylsilane in the presence of NH4'Br- in a suitable solvent, preferably THF or toluene at a temperature of 70-110°C. Subsequent saponification of ester intermediates XXXI gives compounds of formula IIIe (Scheme 13).

Carboxylic acids of formula IIIf wherein R _2b and A1 are as defined in formula I and R _2a is H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, cyano or halogen can also be prepared according to reaction scheme 14.

Scheme 14

Thus, compounds of formula XXa, where R _2b and A1 are as defined in formula I, Z1 is C ₁ -C ₄ -alkyl and X ₁₀ is a leaving group (such as bromine or iodine), were treated with the iPrMgCl/ complex LiCl; subsequent reaction with CuCN and quenching with cyclopropanecarbonyl chlorides of formula XXXII, where R _2a is as defined above, provided compounds of formula XXXIII (similar to the description in WO 2006/067445, page 148). Subsequent fluorination of compounds XXXIII with 2,2-difluoro-1,3-dimethylimidazoline, either in a solvent such as 1,2-dimethoxyethane or in pure form (see Chem. Commun. 2002, (15), 1618) gave the compound of formula XXXIV. Subsequent hydrolysis with, for example, LiOH, as already described, gave the carboxylic acids of formula IIIf.

Carboxylic acids of formula IIIg, where R2b and A1 are as defined in formula I, can be prepared according to reaction scheme 15.

- 15 045353

Scheme 15

base, e.g. K ₂ CO ₅ , optional phase transfer catalyst, e.g. TEBAC solvent, e.g. DMSO

Treatment of compounds of formula XX wherein R _2b and A ₁ are as defined in formula I and Xz is a leaving group, for example a halogen or sulfonate, preferably chlorine, bromine, iodine or trifluoromethanesulfonate, and Z ₁ is C ₁ - C ₄ -alkyl, using trimethylsilylacetonitrile TMSCN in the presence of zinc(II) fluoride (ZnF2) and a palladium(0) catalyst such as the adduct of chloroform and tris(dibenzylideneacetone)dipalladium(0) (Pd ₂ (dba) ₃ CHCl ₃ ), using a ligand, for example Xantphos, in an inert solvent such as N,N-dimethylformamide (DMF), at a temperature of 100-180°C, optionally under microwave heating conditions, gives compounds of formula XXXV, where R2 _b , Z ₁ and A ₁ are as defined in Scheme 15. Such chemical reactions have been described in the literature, for example, in Org. Lett. 16(24), 6314-6317, 2014.

Alternatively, reacting compounds of formula XX 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(P) dichloride (Pd(PPh3)2Cl2) , in an inert solvent such as dimethyl sulfoxide DMSO, optionally mixed with water at a temperature of 40-150°C, optionally under microwave heating conditions, produces compounds of formula XXXVII, where R2b, Z1 and A1 are as defined in Scheme 15 Reacting compounds of formula XXXVII with an aqueous solution of potassium fluoride (KF concentration 0.5-3M, preferably 1M) in an inert solvent such as dimethyl sulfoxide DMSO or methanol at a temperature of 20-150°C, optionally under microwave heating conditions, results in to obtain compounds of formula XXXV, where R _2b , Z ₁ and A ₁ are as defined in scheme 15. Such chemical reactions have been described in the literature, for example, in J. Am. Chem. Soc. 2011, 133, 6948-6951.

Compounds of formula XXXV, where R2b, Z1 and A1 are as defined in Scheme 15, can be further treated with compounds of formula XL, where X13 is a leaving group such as a halogen (preferably chlorine, bromine or iodine), 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 of 0-120°C to give compounds of formula XXXVI, where R2b and A1 are as defined in formula I, and Z1 is C ₁ -C ₄ alkyl.

Alternatively, compounds of formula XXXVI can be prepared directly from compounds of formula XX by treating compounds of formula XXXIII in the presence of a catalyst such as Pd ₂ (dba) ₃ with a ligand such as BINAP, a strong base such as lithium hexamethyldisilazane (LiHMDS) , in an inert solvent such as tetrahydrofuran (THF), at a temperature of 30-80°C. Such chemical reactions have been described, for example, in J. Am. Chem. Soc. 127(45), 15824-15832, 2005.

Another method for preparing compounds of formula XXXV from compounds of formula Xb is shown in Scheme 15. Reaction of compounds of formula XX wherein R _2b , Z ₁ and A ₁ are as defined in Scheme 15 and where X ₁₁ represents a leaving group, e.g. , halogen or sulfonate, preferably chlorine, bromine, iodine or trifluoromethanesulfonate, with reagents of formula XXXVIII, where Z ₂ represents C ₁ -C ₄ -alkyl, in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate or sodium hydride, sodium methoxide or ethoxide, potassium tert-butoxide, optionally under catalytic conditions using palladium (eg using Pd(PPh ₃ ) ₂ Cl ₂ ) or copper (eg using CuI) in a suitable solvent such as, for example, toluene , dioxane,

- 16 045353 tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), optionally in the presence of a PTS phase transfer catalyst such as, for example, tetrabutylammonium bromide or triethylbenzylammonium chloride TEBAC, at a temperature from room temperature to 180°C leads to the preparation of compounds of formula XXXIX, where R _2b and A1 are as defined in formula 1, and each of Z ₁ and Z2 represents C ₁ -C ₄ - alkyl Compounds of formula XXXIX can be decarboxylated using conditions such as heating in wet DMSO, optionally in the presence of lithium or sodium chloride at a temperature of from 50 to 180°C to obtain compounds of formula XXXV. Similar reactions have been described, for example, in Synthesis 2010, No. 19, 3332-3338.

The compounds of formula IIIg, wherein R _2b and A1 are as defined in formula I, are finally prepared from the compound of formula XXXVI by treatment with, for example, aqueous LiOH, NaOH or KOH, in suitable solvents, which may include, for example, a mixture of THF/ MeOH, usually by heating from room temperature to 100°C, preferably from 20°C to the boiling point of the reaction mixture.

Compounds of formula I'a

can be prepared by reacting an amine of formula IIb

wherein R1, _R3 , _A2 , _R4a , _R5a and _R5b are as described in formula I'a, with the carboxylic acid derivative of formula III, wherein A1, _R2a and _R2b are as described above for formula I.

The chemical reaction is described in more detail in Scheme 16.

Scheme 16

Compounds of formula IIIa, where A1, R _2a , R _2b and X ₀ are as described in Scheme 1, can be treated with compounds of formula IIb, where R1, R ₃ , A ₂ , R4 _a , R _5a and R _5b are such as described in formula I, under the conditions detailed in scheme 1, to obtain compounds of formula I'a. The formation of compounds of formula IIIa from compounds of formula III is described in Scheme 1.

The formation of compounds of formula IIb is shown in Scheme 17. Compounds of formula IIb can be prepared by treating compounds of formula IIc, where A ₂ , R ₃ , R4 _a , R _5a and R _5b are as described in formula I, with compounds of formula XLI (where R ₁ is as defined in formula I), for example in the presence of NaBH(OAc) ₃ or NaBH ₃ CN, in a suitable solvent, preferably acetic acid at room temperature as described in WO 2002/088073, page 35. As alternatively, another reagent system uses Ti(i-OiPr) ₄ and NaBH4 to carry out reductive amination (see Synthesis 2003 (14), 2206).

Amines of formula IIc can be prepared by biocatalytic deracemization of amines

- 17 045353 formula IIa. This can be carried out, for example, using a lipase, for example Candida antarctica lipase B or Pseudomonas fluorescens lipase, sometimes in immobilized form (for example Novozym® 435), in the presence of an acyl donor, for example ethyl methoxy acetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at temperatures from 20 to 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 result of such enzymatic deracemization is known to those skilled in the art and has been documented in the literature, for example, in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

Scheme 17

In an alternative method, compounds of formula IIc can be prepared from XVa, where A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I, according to the synthesis method described in scheme 18.

Scheme 18

XLIII

Amines of formula IIc can be prepared from intermediates of formula XLII wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I and Z ₃ is NPhth or NBoc ₂ . Such intermediates can be prepared from alcohols of formula XVa by performing the Mitsunobu reaction, which involves treating alcohols 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-butoxycarbonyl)amine. Mitsunobu reactions are known to those skilled in the art as leading to stereocenter inversion, 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 if Z ₃ = NPhth, or TFA if Z ₃ = NBoc ₂ .

Alternatively, amines of formula IIc can be prepared by reduction of azides of formula XLIII, where A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I, by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation, for example using a palladium catalyst in the presence of hydrogen. Azides of formula XLIII can be prepared by treating alcohols of formula XVa, wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I, using an azidation reagent such as diphenylphosphoryl azide in a solvent such such as toluene or THF, in the presence of a base such as DBU. Such methods are known to those skilled in the art as leading to stereocenter inversion and are described in the literature, for example, in Adv. Synth. Catal. 2018, 360, 2157-2165.

Alcohols of formula XVa can be prepared by the enantioselective reduction of ketones of formula VI, where A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I. Such reduction can be carried out using a catalyst, for example, ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesilene) or RuBF4[(R,R)-TsDPEN](ncymene), in the presence of a hydrogen donor system such as, for example, HCOOH/Et ₃ N or HCO2NH4. Such methods are described in the literature, for example, in J. Org. Chem. 2017, 82, 5607.

Alternatively, compounds of formula IIc can also be prepared as indicated in Scheme 19.

- 18 045353

Scheme 19

Amines of formula IIc can be prepared by deprotection of amines of formula LII, where A2, R ₃ , R _4a , R _5a and R _5b are as described in formula I, for example, using an acid such as trifluoroacetic acid or hydrochloric acid . Compounds of formula LII can be synthesized from compounds of formula LI, wherein A2, _R3 and _R4a are as described in formula I, and _Z5a and _Z5b are independently selected from _R5a , _R5b , halogen, NH2 or HE. Such interconversions of functional groups are known to those skilled in the art, and examples of such transformations have been described in the literature, for example in Eur. J. Org. Chem. 2005, 19, 4141-4153 or in J. Org. Chem. 2008, 73, 7481-7485. Compounds of formula LI can be prepared from compounds of formula L by alkylation, for example using a base and an electrophile such as chlorodifluoroacetic acid. Compounds of formula L can be prepared by hydroxylation of compounds of formula XLIX, wherein A2 and R ₃ are as described in formula I, Z _4a is selected from R4 _a , 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 by the following methods mentioned in the literature, for example, in Org. Lett. 2016, 18, 2244-2247 or Tetrahedron 2009, 65, 757-764. Amines of formula XLIX can be prepared by the condensation of diamines of formula XLVIII, where Z _5a and Z _5b are independently selected from R _5a , R _5b , halogen, NH ₂ or OH, on diketones of formula XLVII, where A ₂ and R ₃ are such as described in Formula I, and Z _4a is selected from R4, halogen or NH2. This condensation may 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. Diketones of formula XLVII can be formed by oxidation of hydroxyketones of formula XLVI, where A ₂ and R ₃ are as described in formula I, and Z _4a is selected from R _4a , halogen or NH2. This oxidation may involve, for example, SO ₃ -pyridine in the presence of DMSO and a base, for example triethylamine, or also sodium hypochlorite in the presence of a catalyst such as TEMPO/Bu ₄ NHSO ₄ . Examples of such oxidation can be found in the literature, for example, Synlett, 2014, 25, 596 or J. Am. Chem. Soc. 1990, 112, 5290-5313. Hydroxyketones of formula XLVI can be synthesized via benzoin cross-condensation between aldehydes of formula XLIV, where A ₂ is as described in formula I, and Z _4a is selected from R _4a , halogen or NH ₂ , and aldehydes of formula XLV, where R ₃ is as described in formula I. Aldehydes of formula XLV are commercially available in chiral form, such as Boc-L-alaninal (CAS 79069-504) or tert-butyl-N-[(1S)-1-(cyclopropylmethyl) -2-oxoethyl]carbamate (CAS 881902-36-9). Benzoin cross-condensation is carried out in the usual way through the use of an organocatalyst,

- 19 045353 such as triazolium salt or thiazolium salt, in the presence of a base such as potassium tert-butoxide or isopropyldiethylamine, in a suitable solvent such as DCM or THF, at a temperature from 20°C to the boiling point of the solvent. Examples of catalysts for such transformations have been described in the literature, for example, in J. Am. Chem. Soc. 2014, 136, 7539-7542 or Org. Lett. 2016, 18, 45184521.

Compounds of formula LI can also be prepared directly from compounds of formula XLIX, for example by transition metal catalysis or diazonium chemistry. Such interconversions of functional groups are known to those skilled in the art, and examples can be found in the literature, for example, in J. Am. Chem. Soc. 2019, 141, 19257-19262, Angew. Chem. Int. Ed. 2015, 54, 5736-5739 or Heterocycles, 2004, 63, 2735-2746.

Compounds of formula LII can be prepared from compounds of formula LIV, wherein A ₂ , R ₃ , R _5a and R _5b are as described in formula I, by alkylation, for example using a base and an electrophile, for example chlorodifluoroacetic acid. Compounds of formula LIV can be synthesized from compounds of formula XLIX by carrying out a hydroxylation reaction, the following methods are mentioned in the literature, for example, in Org. Lett. 2016, 18, 2244-2247 or Tetrahedron 2009, 65, 757-764. Alternatively, compounds of formula LII can be prepared from compounds of formula LIII, wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as described in formula I and Z _4a is selected from R4 _a , halogen or NH ₂ . Such interconversions of functional groups are known to those skilled in the art, and examples can be found in the literature, for example, in J. Am. Chem. Soc. 2019, 141, 19257-19262, Angew. Chem. Int. Ed. 2015, 54, 5736-5739 or Heterocycles, 2004, 63, 2735-2746.

Scheme 20

As shown in Scheme 20, compounds of formula I'a can alternatively be prepared by reacting compounds of formula LVI (wherein A1, R1, _R2a , _R2b , _R3 , _R5a and _R5b are as defined in formula I, and X ₀₇ represents a leaving group, such as chlorine, bromine, iodine) with compounds of formula V (Still's reaction) or compounds of formula VIII (Suzuki-Miyaura reaction) in the presence of a palladium catalyst, as detailed in Schemes 2 and 3.

Compounds of formula LVI can be prepared by coupling amines of formula LVa (where R1, _R3 , _R5a and _R5b are as defined in formula I, and _X07 represents a leaving group such as chlorine, bromine, iodine) and compounds of formula IIIa, wherein A1, _R2a , _R2b and _X0 are as described in Scheme 1, under the conditions detailed in Scheme 1. Under the same conditions, if R1 = H, compounds of formula LVI can be prepared directly from compounds of formula LV.

Compounds of formula LVa can be prepared by treating compounds of formula LV with compounds of formula XLI (where R1 is as defined in formula I), for example in the presence of NaBH(OAc) ₃ or NaBH ₃ CN, in a suitable solvent, preferably acetic acid at room temperature, as described in WO 2002/088073, page 35. Alternatively, another reagent system uses Ti(iOiPr) ₄ and NaBH ₄ to carry out reductive amination (see Synthesis 2003 (14), 2206).

Amines of formula LV can be prepared by a deracemization procedure that involves, for example, selective acylation of one enantiomer. This example is described in more detail in Diagram 21.

- 20 045353

Amines of formula LV can be prepared by biocatalytic deracemization of amines of formula LVb, where R ₃ , R _5a and R _5b are as described in Scheme 1, and X ₀₇ represents a leaving group such as bromine, chlorine or iodine. This can be carried out, for example, using a lipase, for example Candida antarctica lipase B or Pseudomonas fluorescens lipase, sometimes in immobili. Scheme 21

enzymatic separation biological catalyst, e.g. lipase or protease acylating agent, e.g. ethyl methoxy acetate or vinyl acetate solvent, e.g. ACN or TBME T = 20-100°C

Xo7 = Cl, Br, I, OMs OTs or OTf zited form (e.g. Novozym® 435), in the presence of an acyl donor, e.g. ethyl methoxy acetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at a temperature of 20 to 100°C. Such methods are described, for example, in J. Org. Chem, 2007, 72, 69186923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical result of such enzymatic deracemization is known to those skilled in the art and has been documented in the literature, for example, in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

Alternatively, the resolution of amines of formula LVb can be accomplished using a chiral auxiliary as described in Scheme 22.

Scheme 22

Amines of formula LV can be prepared from intermediates of formula LVIII wherein R3, _R5a and _R5b are as described in Scheme 1, _X07 is a leaving group such as bromine, chlorine or iodine, and _X12 * is chiral auxiliary, by treatment with acids such as HCl or bases such as NaOH. Amines of formula LVIII can be formed by coupling a chiral compound of formula LVII, where X ₀ is as described in Scheme 1 and X ₁₂ * is a chiral moiety of known chirality, with amines of formula LVb, according to the conditions detailed in Scheme 1 The chiral auxiliaries of formula LVII are, for example, prepared from mandelic acid or (1R)menthyl chloroformate. Examples of such deracemization methods are given in the literature, for example, in J. Org. Chem. 2007, 72, 485-493.

Alternatively, amines of formula LVc (where R ₃ , R _5a and R _5b are as defined in formula I and X ₀₅ represents a leaving group such as chlorine, bromine, iodo) can be formed as described in diagram 23.

Scheme 23

LXI

Amines of formula LVc can be prepared from intermediates of formula LIX, where R ₃ , R _5a and R _5b are as described in formula I, X ₀₅ represents the leaving group described in scheme 3, and Z ₃ represents is NPhth or NBoc2. Intermediates of formula LIX can be prepared from alcohols of formula LX, where R ₃ , R _5a and R _5b are as described in formula I, and X ₀₅ represents the leaving group described in scheme 3, by performing the Mitsunobu reaction. This involves treating alcohols of formula LX with diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine or tributylphosphine and an amine such as phthalimide or 6is(tert-butoxycarbonyl)amine. Mitsunobu reactions are known to those skilled in the art as leading to stereocenter inversion, 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 if Z ₃ = NPhth, or TFA if Z ₃ = NBoc ₂ .

Alternatively, amines of formula LVc can be prepared by reduction of azides of formula LXI, where R ₃ , R _5a and R _5b are as described in formula I, and X ₀₅ is the leaving group described in scheme 3, by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation, for example using a palladium catalyst in the presence of hydrogen. Azides of formula LXI can be prepared by treating alcohols of formula LX using an azidation reagent 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 as leading to stereocenter inversion and are described in the literature, for example, in Adv. Synth. Catal. 2018, 360, 2157-2165.

Alcohols of formula LX can be prepared by the enantioselective reduction of ketones of formula IV, where R ₃ , R _5a and R _5b are as described in formula I, and X ₀₅ is the leaving group described in scheme 3. Such reduction can be carried out using catalysts, such as a ruthenium or rhodium catalyst, with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene), with the system acting as a hydrogen donor, such as HCOOH/Et ₃ N or HCO ₂ NH ₄ . Such methods are described in the literature, for example, in J. Org. Chem. 2017, 82, 5607.

Depending on the procedure or reaction conditions, reagents may react 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 carbonates or alkaline earth metals, dialkylamides of alkali metals or alkaline earth metals or alkylsilylamides of alkali metals or alkaline earth metals, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides 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, hydride calcium, 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).

The reagents can be reacted with each other as is, i.e. without adding solvent or thinner. 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, then bases that are used in excess, such as triethylamine, pyridine, N-methylmorpholine or N,Ndiethylaniline, can also act as solvents or diluents.

The reactions are preferably carried out at temperatures ranging from about -80°C to about +140°C, preferably from about -30°C to about +100°C, in many cases ranging from ambient temperature to about +80°C.

Depending on the choice of reaction conditions and starting materials suitable in each case, it is possible, for example, in one reaction step to replace only one substituent with another substituent according to the present invention, or in the same reaction step, it is possible to replace several substituents with other substituents according to the present invention .

Salts of the 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 exchange reagent, and salts with bases are obtained by treatment with a suitable base or a suitable ion exchange reagent.

Salts of compounds of formula I can be converted in the conventional manner into free compounds I, acid addition salts, for example by treatment with a suitable basic compound or a suitable ion exchange reagent, and salts with bases, for example by treatment with a suitable acid or a suitable ion exchange reagent.

Salts of compounds of formula I can be converted in a manner known per se to other salts of compounds of formula I, acid addition salts, for example, to other acid addition salts, for example, by treating an inorganic acid salt, for example a hydrochloride, with a suitable metal acid salt, such as a sodium, barium or silver salt, for example silver acetate, in a suitable solvent in which the inorganic salt that is formed, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.

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

The compounds of formula I and, where appropriate, their tautomers, in each case in free or salt form, may be present in the form of one of the possible isomers or as a mixture thereof, for example in the form of pure isomers such as antipodes and/or diastereomers, or in the form of mixtures of isomers, such as mixtures of enantiomers, for example racemates, mixtures of diastereomers or mixtures of racemates, depending on the number, absolute and relative configuration of asymmetric carbon atoms that are present in the molecule, and/or depending on the configuration of non-aromatic double bonds, which are in the molecule; however, the present invention relates to pure isomers, as well as to all possible mixtures of isomers, and should be understood in each case above and below herein in this sense, even if stereochemical details have not been specifically mentioned in each case.

Mixtures of diastereoisomers or mixtures of racemates of the compounds of formula I, in free form or in salt form, which can be obtained depending on which starting materials and procedures have been chosen, can be separated in a known manner into pure diastereoisomers or racemates on the basis of physicochemical differences components, for example, by fractional crystallization, distillation and/or chromatography.

Mixtures of enantiomers, such as racemates, which can be prepared in a similar manner, can be separated into optical antipodes using known methods, for example, by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example, by high performance liquid chromatography (HPLC) on cellulose acetate, with the help of suitable microorganisms, by cleavage with specific immobilized enzymes, by the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer participates in the complex formation, or by conversion to diastereomeric salts, for example by a racemate reaction the main end product with an optically active acid, such as a carboxylic acid, for example camphoric, tartaric or malic acid, or a sulfonic acid, for example camphorsulfonic acid, and separating the mixture of diastereomers that can be obtained in this way, for example, by fractional crystallization based on their different solubilities to produce diastereomers from which the desired enantiomer can be released by suitable means, eg basic agents.

Pure diastereomers or enantiomers can be obtained according to the present invention not only by separating suitable mixtures of isomers, but also by generally known diastereoselective or enantioselective synthetic methods, for example by carrying out the process of the present invention with starting materials of suitable stereochemical configuration.

N-oxides can be prepared by reacting a compound of formula I with a suitable oxidizing agent, eg an H ₂ O ₂ /urea adduct, in the presence of an acid anhydride, eg trifluoroacetic anhydride. These types of oxidation reactions are known from the literature, for example from J. Med. Chem., 32(12), 2561-73, 1989 or WO 2000/15615.

It is advantageous to isolate or synthesize in each case a biologically more effective isomer, for example an enantiomer or a diastereomer, or a mixture of isomers, for example a mixture of enantiomers or a mixture of diastereomers, if the individual components have different biological activities.

The compounds of formula I and, where appropriate, their tautomers, in each case in free or salt form, may also be obtained, if necessary, in the form of hydrates and/or may contain other solvents, for example, which could be used for crystallization compounds present in solid form.

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 as a compound of formula Iaa.

laa

In table A-1 represents 16 compounds A-1.001 to A-1.016 of formula Iaa, where R ₁ represents H, R ₄ represents [5-(trifluoromethoxy)pyrimidin-2-yl] and R 2 is as defined in table. Z.

For example, A-1.002 is

- 23 045353

In table A-2 presents 16 compounds A-2.001 to A-2.016 of formula Iaa, where R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridyl] and _R2 is as defined in

- 24 045353 table. Z.

In table A-3 presents 16 compounds A-3.001 to A-3.016 of formula Iaa, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and _R2 is such as defined in table. Z.

In table A-4 presents 16 compounds A-4.001 to A-4.016 of formula Iaa, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and _R2 is as defined in table Z.

In table A-5 presents 16 compounds A-5.001 to A-5.016 of formula Iaa, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table A-6 presents 16 compounds A-6.001 to A-6.016 of formula Iaa, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table A-7 presents 16 compounds A-7.001 to A-7.016 of formula Iaa, where R1 is H, _R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and _R2 is as defined in table. Z.

In table A-8 presents 16 compounds A-8.001 to A-8.016 of formula Iaa, where R1 is H, _R4 is [5-(difluoromethoxy)-2-pyridyl] and _R2 is as defined in table. Z.

In table A-9 presents 16 compounds A-9.001 to A-9.016 of formula Iaa, where R1 is H, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table A-10 presents 16 compounds A-10.001 to A-10.016 of formula Iaa, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table A-11 presents 16 compounds A-11.001 to A-11.016 of formula Iaa, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table A-12 represents 16 compounds A-12.001 to A-12.016 of formula Iaa, where R1 is _CH3 , _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table A-13 presents 16 compounds A-13.001 to A-13.016 of formula Iaa, where R1 is CH3, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table A-14 represents 16 compounds A-14.001 to A-14.016 of formula Iaa, where R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table A-15 presents 16 compounds A-15.001 to A-15.016 of formula Iaa, where R1 is CH ₃ , R ₄ is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R ₂ is , as defined in table. Z.

In table A-16 presents 16 compounds A-16.001 to A-16.016 of formula Iaa, where R1 is CH ₃ , R ₄ is [5-(difluoromethoxy)pyrimidin-2-yl] and R ₂ is as defined in table . Z.

In table A-17 presents 16 compounds A-17.001 to A-17.016 of formula Iaa, where R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table A-18 presents 16 compounds A-18.001 to A-18.016 of formula Iaa, where R1 is CH3, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table A-19 represents 16 compounds A-19.001 to A-19.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table A-20 represents 16 compounds A-20.001 to A-20.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table A-21 represents 16 compounds A-21.001 to A-21.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is , as defined in table. Z.

In table A-22 represents 16 compounds A-22.001 to A-22.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table A-23 presents 16 compounds from A-23.001 to A-23.016 of formula Iaa, where R1 represents cyclopropyl-CH ₂ -, R ₄ represents [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

- 25 045353

In table A-24 represents 16 compounds A-24.001 to A-24.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table A-25 presents 16 compounds A-25.001 to A-25.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table A-26 represents 16 compounds A-26.001 to A-26.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table A-27 presents 16 compounds A-27.001 to A-27.016 of formula Iaa, where R1 is cyclopropyl-CH ₂ -, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

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 as a compound of formula Iab.

lab

In table B-1 represents 16 compounds B-1.001 to B-1.016 of formula Iab, where R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table B-2 presents 16 compounds B-2.001 to B-2.016 of formula Iab, where R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table B-3 presents 16 compounds B-3.001 to B-3.016 of formula Iab, where R1 is H, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table B-4 presents 16 compounds B-4.001 to B-4.016 of formula Iab, where R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table B-5 represents 16 compounds B-5.001 to B-5.016 of formula Iab, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table B-6 represents 16 compounds B-6.001 to B-6.016 of formula Iab, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table B-7 presents 16 compounds B-7.001 to B-7.016 of formula Iab, where R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table B-8 presents 16 compounds B-8.001 to B-8.016 of formula Iab, where R1 is H, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table B-9 presents 16 compounds B-9.001 to B-9.016 of formula Iab, where R1 is H, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table B-10 represents 16 compounds B-10.001 to B-10.016 of formula Iab, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table B-11 represents 16 compounds B-11.001 to B-11.016 of formula Iab, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table B-12 represents 16 compounds B-12.001 to B-12.016 of formula Iab, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table B-13 represents 16 compounds B-13.001 to B-13.016 of formula Iab, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table B-14 represents 16 compounds B-14.001 to B-14.016 of formula Iab, where R1 is _CH3 , R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

- 26 045353

In table B-15 represents 16 compounds B-15.001 to B-15.016 of formula Iab, where R ₁ is CH ₃ , R 4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R ₂ is , as defined in table. Z.

In table B-16 represents 16 compounds B-16.001 to B-16.016 of formula Iab, where R1 is CH ₃ , R ₄ is [5-(difluoromethoxy)pyrimidin-2-yl] and R ₂ is as defined in table . Z.

In table B-17 represents 16 compounds B-17.001 to B-17.016 of formula Iab, where R1 is CH ₃ , R4 is [5-(difluoromethoxy)-2-pyridyl] and R ₂ is as defined in table. Z.

In table B-18 represents 16 compounds B-18.001 to B-18.016 of formula Iab, where R1 is CH ₃ , R4 is (5-cyano-2-pyridyl) and R ₂ is as defined in table. Z.

In table B-19 represents 16 compounds B-19.001 to B-19.016 of formula Iab, where R ₁ is cyclopropyl-CH ₂ -, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R ₂ is such as defined in table. Z.

In table B-20 represents 16 compounds B-20.001 to B-20.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(trifluoromethoxy)-2-pyridyl] and R ₂ is as defined in table Z.

In table B-21 represents 16 compounds from B-21.001 to B-21.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R ₂ is such as defined in table. Z.

In table B-22 represents 16 compounds from B-22.001 to B-22.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R ₂ is , as defined in table. Z.

In table B-23 presents 16 compounds from B-23.001 to B-23.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R ₂ is as defined in table. Z.

In table B-24 presents 16 compounds from B-24.001 to B-24.016 of formula Iab, where R1 represents cyclopropyl-CH ₂ -, R ₄ represents [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R ₂ is as defined in table. Z.

In table B-25 presents 16 compounds B-25.001 to B-25.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(difluoromethoxy)pyrimidin-2-yl] and R ₂ is such as defined in table. Z.

In table B-26 represents 16 compounds B-26.001 to B-26.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)-2-pyridyl] and R ₂ is as defined in table Z.

In table B-27 presents 16 compounds B-27.001 to B-27.016 of formula Iab, where R1 is cyclopropyl-CH ₂ -, R4 is (5-cyano-2-pyridyl) and R ₂ is as defined in table. Z.

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 as a compound of formula Iac.

lac

In table C-1 represents 16 compounds C-1.001 to C-1.016 of formula Iac, where R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and _R2 is as defined in table. Z.

In table C-2 represents 16 compounds C-2.001 to C-2.016 of formula Iac, where R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table C-3 represents 16 compounds C-3.001 to C-3.016 of formula Iac, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and _R2 is such as defined in table. Z.

In table C-4 represents 16 compounds C-4.001 to C-4.016 of formula Iac, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and _R2 is as defined in table Z.

In table C-5 represents 16 compounds from C-5.001 to C-5.016 of formula Iac, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table C-6 represents 16 compounds C-6.001 to C-6.016 of formula Iac, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined

- 27 045353 in the table. Z.

In table C-7 represents 16 compounds C-7.001 to C-7.016 of formula Iac, where R1 is H, _R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and _R2 is as defined in table. Z.

In table C-8 represents 16 compounds C-8.001 to C-8.016 of formula Iac, where R1 is H, _R4 is [5-(difluoromethoxy)-2-pyridyl] and _R2 is as defined in table. Z.

In table C-9 represents 16 compounds C-9.001 to C-9.016 of formula Iac, where R1 is H, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table C-10 represents 16 compounds from C-10.001 to C-10.016 of formula Iac, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table C-11 represents 16 compounds C-11.001 to C-11.016 of formula Iac, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table C-12 represents 16 compounds C-12.001 to C-12.016 of formula Iac, where R1 is _CH3 , _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table C-13 represents 16 compounds from C-13.001 to C-13.016 of formula Iac, where R1 is CH ₃ , R ₄ is [5-(2,2-difluoroethoxy)-2-pyridyl] and R ₂ is such as defined in table. Z.

In table C-14 represents 16 compounds from C-14.001 to C-14.016 of formula Iac, where R1 is CH3, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table C-15 represents 16 compounds C-15.001 to C-15.016 of formula Iac, where R1 is _CH3 , _R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and _R2 is , as defined in table. Z.

In table C-16 represents 16 compounds C-16.001 to C-16.016 of formula Iac, where R1 is _CH3 , _R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and _R2 is as defined in table . Z.

In table C-17 represents 16 compounds from C-17.001 to C-17.016 of formula Iac, where R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table C-18 represents 16 compounds C-18.001 to C-18.016 of formula Iac, where R1 is CH3, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table C-19 represents 16 compounds C-19.001 to C-19.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table C-20 represents 16 compounds C-20.001 to C-20.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table C-21 represents 16 compounds from C-21.001 to C-21.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table C-22 represents 16 compounds from C-22.001 to C-22.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table C-23 represents 16 compounds from C-23.001 to C-23.016 of formula Iac, where R1 represents cyclopropyl-CH ₂ -, R ₄ represents [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table C-24 represents 16 compounds from C-24.001 to C-24.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table C-25 represents 16 compounds from C-25.001 to C-25.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table C-26 represents 16 compounds from C-26.001 to C-26.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table C-27 represents 16 compounds from C-27.001 to C-27.016 of formula Iac, where R1 is cyclopropyl-CH ₂ -, R ₄ is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

- 28 045353

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 as a compound of formula Iad.

In table D-1 represents 16 compounds D-1.001 to D-1.016 of formula Iad, where R ₁ represents H, R 4 represents [5-(trifluoromethoxy)pyrimidin-2-yl] and R ₂ is as defined in table. Z.

In table D-2 represents 16 compounds D-2.001 to D-2.016 of formula Iad, where R1 is H, R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table D-3 represents 16 compounds D-3.001 to D-3.016 of formula Iad, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table D-4 represents 16 compounds D-4.001 to D-4.016 of formula Iad, where R1 is H, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table D-5 represents 16 compounds D-5.001 to D-5.016 of formula Iad, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table D-6 represents 16 compounds D-6.001 to D-6.016 of formula Iad, where R1 is H, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table D-7 presents 16 compounds D-7.001 to D-7.016 of formula Iad, where R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table D-8 presents 16 compounds D-8.001 to D-8.016 of formula Iad, where R1 is H, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table D-9 presents 16 compounds D-9.001 to D-9.016 of formula Iad, where R1 is H, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table D-10 represents 16 compounds D-10.001 to D-10.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table D-11 represents 16 compounds D-11.001 to D-11.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table D-12 represents 16 compounds D-12.001 to D-12.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table D-13 represents 16 compounds D-13.001 to D-13.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table D-14 represents 16 compounds D-14.001 to D-14.016 of formula Iad, where R1 is _CH3 , R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table D-15 represents 16 compounds D-15.001 to D-15.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table D-16 represents 16 compounds D-16.001 to D-16.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table D-17 represents 16 compounds D-17.001 to D-17.016 of formula Iad, where R1 is CH ₃ , R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table D-18 represents 16 compounds D-18.001 to D-18.016 of formula Iad, where R1 is CH3, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table D-19 represents 16 compounds D-19.001 to D-19.016 of formula Iad, where R1 is cyclopropyl-CH2-, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table D-20 represents 16 compounds D-20.001 to D-20.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table D-21 represents 16 compounds D-21.001 to D-21.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is , as defined in table. Z.

In table D-22 represents 16 compounds D-22.001 to D-22.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table D-23 represents 16 compounds from D-23.001 to D-23.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table D-24 represents 16 compounds D-24.001 to D-24.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table D-25 represents 16 compounds D-25.001 to D-25.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table D-26 represents 16 compounds D-26.001 to D-26.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table D-27 presents 16 compounds D-27.001 to D-27.016 of formula Iad, where R1 is cyclopropyl-CH ₂ -, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

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 as compounds of formula Iae.

In table E-1 represents 16 compounds E-1.001 to E-1.016 of formula Iae, where R1 is H, R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table E-2 represents 16 compounds E-2.001 to E-2.016 of formula Iae, where R1 is H, _R4 is [5-(trifluoromethoxy)-2-pyridyl] and _R2 is as defined in table. Z.

In table E-3 represents 16 compounds E-3.001 to E-3.016 of formula Iae, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and _R2 is such as defined in table. Z.

In table E-4 represents 16 compounds E-4.001 to E-4.016 of formula Iae, where R1 is H, _R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and _R2 is as defined in table Z.

In table E-5 represents 16 compounds E-5.001 to E-5.016 of formula Iae, where R1 is H, _R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and _R2 is , as defined in table. Z.

In table E-6 represents 16 compounds E-6.001 to E-6.016 of formula Iae, where R1 is H, _R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and _R2 is such as as defined in table. Z.

In table E-7 represents 16 compounds E-7.001 to E-7.016 of formula Iae, where R1 is H, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table E-8 represents 16 compounds E-8.001 to E-8.016 of formula Iae, where R1 is H, _R4 is [5-(difluoromethoxy)-2-pyridyl] and _R2 is as defined in table. Z.

In table E-9 represents 16 compounds E-9.001 to E-9.016 of formula Iae, where R1 is H, R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table E-10 represents 16 compounds from E-10.001 to E-10.016 of formula Iae, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table E-11 represents 16 compounds E-11.001 to E-11.016 of formula Iae, where R1 is CH ₃ , R4 is [5-(trifluoromethoxy)-2-pyridyl] and R ₂ is as defined in table. Z.

In table E-12 represents 16 compounds E-12.001 to E-12.016 of formula Iae, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table E-13 represents 16 compounds E-13.001 to E-13.016 of formula Iae, where R1 is CH ₃ , R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table E-14 represents 16 compounds E-14.001 to E-14.016 of formula Iae, where R1 is _CH3 , R4 is [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is such as defined in table. Z.

In table E-15 represents 16 compounds E-15.001 to E-15.016 of formula Iae, where R1 is _CH3 , _R4 is [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and _R2 is , as defined in table. Z.

In table E-16 represents 16 compounds E-16.001 to E-16.016 of formula Iae, where R1 is CH ₃ , R ₄ is [5-(difluoromethoxy)pyrimidin-2-yl] and R ₂ is as defined in table . Z.

In table E-17 represents 16 compounds E-17.001 to E-17.016 of formula Iae, where R1 is CH3, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table E-18 represents 16 compounds E-18.001 to E-18.016 of formula Iae, where R1 is CH ₃ , R4 is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

In table E-19 represents 16 compounds E-19.001 to E-19.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(trifluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table E-20 represents 16 compounds E-20.001 to E-20.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R ₄ is [5-(trifluoromethoxy)-2-pyridyl] and R2 is as defined in table Z.

In table E-21 represents 16 compounds from E-21.001 to E-21.016 of formula Iae, where

R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)pyrimidin2-yl] and R2 is as defined in table. Z.

In table E-22 represents 16 compounds from E-22.001 to E-22.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(2,2-difluoroethoxy)-2-pyridyl] and R2 is such as defined in table. Z.

In table E-23 represents 16 compounds from E-23.001 to E-23.016 of formula Iae, where R1 represents cyclopropyl-CH ₂ -, R ₄ represents [5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl] and R2 is as defined in table. Z.

In table E-24 represents 16 compounds from E-24.001 to E-24.016 of formula Iae, where R1 represents cyclopropyl-CH ₂ -, R ₄ represents [5-(2,2,2-trifluoroethoxy)-2-pyridyl] and R2 is as defined in table. Z.

In table E-25 represents 16 compounds E-25.001 to E-25.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)pyrimidin-2-yl] and R2 is as defined in table Z.

In table E-26 represents 16 compounds E-26.001 to E-26.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R4 is [5-(difluoromethoxy)-2-pyridyl] and R2 is as defined in table . Z.

In table E-27 represents 16 compounds E-27.001 to E-27.016 of formula Iae, where R1 is cyclopropyl-CH ₂ -, R ₄ is (5-cyano-2-pyridyl) and R2 is as defined in table. Z.

Also provided are certain amine intermediates of formulas IIaa to IIae, some of which are new, wherein R1 and R4 (corresponding to the ring containing R _4a and A ₂ in formula I) are as defined in the first aspect. The stereogenic center is indicated by an asterisk in the structures shown below; and accordingly, the present invention provides both racemates and individual enantiomers; Particularly preferred is the enantiomer having the same spatial grouping at the stereogenic center as depicted in formula I'a.

- 31 045353

Specific examples of compounds of formulas IIaa to IIae are compounds wherein R1 and R4 are as defined in table. A-1-A27.

Specific examples of compounds of formula IIIab are compounds wherein R2 (corresponding to the ring containing _R2a , A1 and _R2b ) is as defined in table. Z.

O

Also presented are compounds of formulas III, VI, XV, XVa, XLII, XLIII, XLVI, XLVII, XLIX, L, LI, LII, LIII, LIV, LV, LVa, LVc, LVI, LIX, LX and LXI, where, where appropriate, the substituents R1, A1, R _2a , R _2b , R ₃ , R _5a , R _5b and R4 (corresponding to the ring containing R _4a and A2) are as defined in any of the rows in the table. A-1-A-27, B-1-B-27, C-1-C-27, D-1-D-27 and E-1-E-27. A particularly preferred enantiomer of the compounds of formulas III, VI, XV, XVa, XLII, XLIII, XLVI, XLVII, XLIX, L, LI, LII, LIII, LIV, LV, LVa, LVc, LVI, LIX, LX and LXI, as appropriate, is an enantiomer having the same spatial grouping at the stereogenic center as depicted in formula I'a.

The present invention also provides a compound of formula II, wherein A ₂ , R 1 , R ₃ , R 4 _a , R _5a and R _5b are as defined for formula I; accordingly, preferred embodiments A ₂ , R1, R ₃ , R4 _a , R _5a and R _5b for a compound of formula I are also preferred embodiments A ₂ , R1, R ₃ , R4 _a , R _5a and R _5b for a compound of formula II ; a compound of formulas IIaa, IIab, IIac, IIab and IIae, where R1 is as defined in formula I, and R4 is a cyclic group containing A ₂ and the substituent R _4a in formula I, where A ₂ and R _4a are as follows as defined in Formula I; accordingly, preferred embodiments R1, A2 and R4 _a for a compound of formula I are also preferred embodiments R1, A ₂ and R4 _a for any of the compounds of formulas IIaa, IIab, IIac, IIab and IIae;

a compound of formula III, wherein A1, R _2a and R _2b are as defined for formula I; accordingly, preferred embodiments A1, R _2a and R _2b for a compound of formula I are also preferred embodiments A1, R _2a and R _2b for a compound of formula III; a compound of formula VI, wherein A2, R3, R4a, R5a and R5b are as defined for formula I; accordingly, preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula I are also preferred embodiments A2, R3, R4a, R5a and R5b for a compound of formula VI;

a compound of formula XV wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as defined for formula I; accordingly, preferred embodiments A2, R3, R4a, R5a and R5b for a compound of formula I are also preferred embodiments _A2 , _R3 , _R4a , _R5a and _R5b for a compound of formula XV;

a compound of formula XVa wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as defined for formula I; accordingly, preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula I are also preferred embodiments A2, R3, R4a, R5a and R5b for a compound of formula XVa;

a compound of formula XLII wherein A ₂ , R ₃ , R _4a , R _5a and R _5b are as defined for formula I and Z ₃ is NPhth or NBoc ₂ ; accordingly, preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula I are also preferred embodiments A2, R3, R4a, R5a and R5b for a compound of formula XLII; a compound of formula XLIII, wherein A2, R3, R4a, R _5a and R _5b are as defined for formula I; accordingly, preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula I are also preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula XLIII;

a compound of formula XLVI, wherein A ₂ and R ₃ are as defined for formula I, and Z _4a represents R4 _a , halogen or NH2; accordingly, preferred embodiments A ₂ , R ₃ and R _4a for a compound of formula I are also preferred embodiments A ₂ , R ₃ and R _4a for a compound of formula XLVI;

a compound of formula XLVII, wherein A ₂ and R ₃ are as defined for formula I, and Z _4a is R _4a , halogen or NH ₂ ; accordingly preferred embodiments

- 32 045353

A ₂ , R ₃ and R _4a for a compound of formula I are also preferred embodiments

A2, R ₃ and R4 _a for the compound of formula XLVII;

a compound of formula XLIX wherein A2 and R ₃ are as defined for formula I, Z _4a is R _4a , halogen or NH2, and Z _5a and Z _5b are independently selected from R _5a , R _5b , halogen, NH2 and he; accordingly, preferred embodiments A2, _R3 , _R4a , _R5a and _R5b for a compound of formula I are also preferred embodiments _A2 , _R3 , _R4a , _R5a and _R5b for a compound of formula XLIX;

a compound of formula L, wherein A2 and _R3 are as defined for formula I, and _Z5a and _Z5b are independently selected from _R5a , _R5b , halogen, NH2 and OH; accordingly, preferred embodiments A ₂ , R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments A ₂ , R ₃ , R _5a and R _5b for a compound of formula L; a compound of formula LI, wherein A ₂ , R ₃ and R 4 _a are as defined for formula I, and Z _5a and Z _5b are independently selected from R _5a , R _5b , halogen, NH 2 and OH; accordingly, preferred embodiments A ₂ , R ₃ , R4 _a , R _5a and R _5b for a compound of formula I are also preferred embodiments A2, R ₃ , R4 _a , R _5a and R _5b for a compound of formula LI; a compound of formula LII wherein A ₂ , R ₃ , R 4 _a , R _5a and R _5b are as defined for formula I; accordingly, preferred embodiments A2, _R3 , _R4a , _R5a and _R5b for a compound of formula I are also preferred embodiments _A2 , _R3 , _R4a , _R5a and _R5b for a compound of formula LII;

a compound of formula LIII wherein A ₂ , R ₃ , R _5a and R _5b are as defined for formula I and Z _4a is R _4a , halogen or NH ₂ ; accordingly, preferred embodiments A ₂ , R ₃ , R4 _a , R _5a and R _5b for a compound of formula I are also preferred embodiments A ₂ , R ₃ , R4 _a , R _5a and R _5b for a compound of formula LIII;

a compound of formula LIV wherein A ₂ , R ₃ , R _5a and R _5b are as defined for formula I and Z4a is R4a, halogen or NH2; accordingly, preferred embodiments A ₂ , R ₃ , R4 _a , R _5a and R _5b for a compound of formula I are also preferred embodiments A ₂ , R ₃ , R _4a , R _5a and R _5b for a compound of formula LIV;

a compound of formula LV, wherein R ₃ , R _5a and R _5b are as defined for formula I, and X ₀₇ represents a leaving group, for example chlorine, bromine, iodine; accordingly, preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula LV;

a compound of formula LVa, wherein R1, _R3 , _R5a and _R5b are as defined for formula I, and X07 represents a leaving group, for example chlorine, bromine, iodine; accordingly, preferred embodiments R1, _R3 , _R5a and _R5b for a compound of formula I are also preferred embodiments R1, _R3 , _R5a and _R5b for a compound of formula LVa; a compound of formula LVc wherein R ₃ , R _5a and R _5b are as defined for formula I and X ₀₅ represents a leaving group, for example chlorine, bromine, iodine, arisulfonate, alkylsulfonate or trifluoromethanesulfonate; accordingly, preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula LVc;

a compound of formula LVI, wherein A1, R _2a , R _2b , R1, R ₃ , R _5a and R _5b are as defined for formula I, and X ₀₇ represents a leaving group, for example, chlorine, bromine, iodine; accordingly, preferred embodiments A1, R _2a , R _2b , R1, R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments A1, R _2a , R _2b , R1, R ₃ , R _5a and R _5b for a compound of formula LVI;

a compound of formula LIX, wherein R ₃ , R _5a and R _5b are as defined for formula I, Z ₃ represents NPhth or NBoc ₂ , and X ₀₅ represents a leaving group, for example chlorine, bromine, iodine, arisulfonate, alkylsulfonate or trifluoromethanesulfonate; accordingly, preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula LIX;

a compound of formula LX, where R ₃ , R _5a and R _5b are as defined for formula I, and X ₀₅ represents a leaving group, for example, chlorine, bromine, iodine, arisulfonate, alkylsulfonate or trifluoromethanesulfonate; accordingly, preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula LX; and a compound of formula LXI, wherein R ₃ , R _5a and R _5b are as defined for formula I, and X ₀₅ represents a leaving group, for example, chlorine, bromine, iodine, arisulfonate, alkylsulfonate or trifluoromethanesulfonate; accordingly, preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula I are also preferred embodiments of R ₃ , R _5a and R _5b for a compound of formula LXI.

The compounds of formula I according to the present invention are active ingredients of importance in the field of pest control for prevention and/or treatment even at low application rates, which have a very suitable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the present invention act on all or individual stages of development of animal pests, such as insects or representatives of the order Acarina, with normal sensitivity as well as resistance. The insecticidal or acaricidal activity of the active ingredients according to the present invention can be manifested directly, i.e. in the destruction of pests, which occurs either immediately or over time, for example during molting, or indirectly, for example, in the form of a decrease in the number of eggs laid and/or hatching rate.

Examples of the above mentioned animal pests are:

from the order Acarina, for example 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.;

from the order Anoplura, for example Haematopinus spp., Linognathus spp., Pediculus spp., Pemphigus spp. and Phylloxera spp.;

from the order Coleoptera, for example Agriotes spp., Amphimallon majale, Anomala orientalis, Anthonomus spp., Aphodius spp, Astylus atromaculatus, Ataenius spp, Atomaria linearis, Chaetocnema tibialis, Cerotoma spp, Conoderus spp, Cosmopolites spp., Cotinis nitida, Curculio spp. , Cyclocephala spp., Dermestes spp., Diabrotica spp., Diloboderus abderus, Epilachna spp., Eremnus spp., Heteronychus arator, Hypothenemus hampei, Lagria vilosa, Leptinotarsa decemlineata, Lissorhoptrus spp., Liogenys spp, Maecolaspis spp, Maladera castanea, Megascelis spp , Melighetes aeneus, Melolontha spp., Myochrous armatus, 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.;

from the order Diptera, for example Aedes spp., Anopheles spp., Antherigona soccata, 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., Rivelia quadrifasciata, Scatella spp., Sciara spp., Stomoxys spp., Tabanus spp., Tannia spp. and Tipula spp.;

from the order Hemiptera, for example Acanthocoris scabrator, Acrosternum spp., Adelphocoris lineolatus, Aleurodes spp., Amblypelta nitida, Bathycoelia thalassina, Blissus spp., Cimex spp., Clavigralla tomentosicollis, Creontiades spp., Distantiella theobroma, Dichelops furcatus, Dysdercus spp., Edes sa spp, Euchistus spp., Eurydema pulchrum, Eurygaster spp., Halyomorpha Halys, Horcias Nobillas, Leptocorisa spp., Lygus spp, Margarodes spp, murgantia histering, neomegalotomus spp, nesidiocoris tenuis, nezara spp., Nysius Simulans, Oebalus Insularis, Piesma spp., Piezodorus spp., Rhodnius spp., Sahlbergella singularis, Scaptocoris castanea, Scotinophara spp., Thyanta spp., Triatoma spp., Vatiga illudens; Acyrthosium pisum, Adalges spp, Agalliana ensigera, Agonoscena targionii, Aleurodicus spp, Aleurocanthus spp., Aleurolobus barodensis, Aleurothrixus floccosus, Aleyrodes brassicae, Amarasca biguttula, Amritodus atkinsoni, Aonidiella spp., Aphididae, Aphis spp., As pidiotus spp., Aulacorthum solani, Bactericera cockerelli, Bemisia spp, Brachycaudus spp, Brevicoryne brassicae, Cacopsylla spp, Cavariella aegopodii Scop., Ceroplaster spp., Chrysomphalus aonidium, Chrysomphalus dictyospermi, Cicadella spp, Cofana spectra, Cryptomyzus spp, Cicadulina spp, Coccus hesperidum , Dalbulus maidis, Dialeurodes spp. , Diaphorina citri, Diuraphis noxia, Dysaphis spp, Empoasca spp., Eriosoma larigerum, Erythroneura spp., Gascardia spp., Glycaspis brimblecombei, Hyadaphis pseudobrassicae, Hyalopterus spp, Hyperomyzus pallidus, Idioscopus clypealis, Jacobiasca lybica, Lao delphax spp., Lecanium corni, Lepidosaphes spp., Lopaphis erysimi, Lyogenys maidis, Macrosiphum spp., Mahanarva spp., Metcalfa pruinosa, 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, Psylla spp., Pulvinaria aethi opica, Quadraspidiotus spp., Quezada Gigas, Recilia Dorsalis, Rhopalosiphum spp., Saissetia spp., Scaphoideus spp., Schizaphis spp., Sogatella Furcifera, Spis. sistilus festinus, tarophagus proserpina, toxoptera spp, trialeurodes spp, tridiscus sporoboli, Trionymus spp , Trioza erytreae, Unaspis citri, Zygina flammigera, Zyginidia scutellaris;

from the order Hymenoptera, e.g. Acromyrmex, Arge spp., Atta spp., Cephus spp., Diprion spp., Diprionidae, Gilpinia polytoma, Hoplocampa spp., Lasius spp., Monomorium pharaonis, Neodiprion spp., Pogonomyrmex spp., Slenopsis invicta, Solenopsis spp. . and Vespa spp.;

from the order Isoptera, for example Coptotermes spp, Corniternes cumulans, Incisitermes spp, Macrotermes spp, Mastotermes spp, Microtermes spp, Reticulitermes spp.; Solenopsis geminate from the order Lepidoptera, e.g. Acleris spp., Adoxophyes spp., Aegeria spp., Agrotis spp., Alabama argillaceae, Amylois spp., Anticarsia gemmatalis, Archips spp., Argyresthia spp., Argyrotaenia spp., Autographa spp., Bucculatrix thurberiella, Busseola fusca, Cadra cautella, Carposina nipponensis, Chilo spp., Choristoneura spp., Chrysoteuchia topiaria, Clysia am

- 34 045353 biguella, Cnaphalocrocis spp., Cnephasia spp., Cochylis spp., Coleophora spp., Colias lesbia, Cosmophila flava, Crambus spp., Crocidolomia binotalis, Cryptophlebia leucotreta, Cydalima perspectalis, Cydia spp., Diaphania perspectalis, Diatraea spp., Diparopsis castanea, Earias spp., Elasmopalpus lignosellus, Eldana saccharina, Ephestia spp., Epinotia spp, Estigmene acrea, Etiella zinckinella, Eucosma spp., Eupoecilia ambiguella, Euproctis spp., Euxoa spp., Feltia jaculiferia, Grapholita spp., Hedya n ubiferana , Heliothis spp., Hellula undalis, Herpetogramma spp, Hyphantria cunea, Keiferia lycopersicella, Lasmopalpus lignosellus, Leucoptera scitella, Lithocollethis spp., Lobesia botrana, Loxostege bifidalis, Lymantria spp., Lyonetia spp., Malacosoma spp., Mamestra brassicae, Manduc a sexta , Mythimna spp, noctua spp, operophtera spp., Orniodes indica, ostrinia nubilalis, Pammeen spp., Pandemis spp., Panolis Flammea, Papaipema Nebris, Pectinophor Gososy Piela, Perileucoptera Coffeella, Pseudaletia Unipuncta, Phthorimaea Opeerculella, Pieris Rapae, Pieris spp., Plutella xylostella, Prays spp., Pseudoplusia spp, Rachiplusia nu, Richia albicosta, Scirpophaga spp., Sesamia spp., Sparganothis spp., Spodoptera spp., Sylepta derogate, Synanthedon spp., Thaumetopoea spp., Tortrix spp., Trichoplusia ni, Tuta absoluta and Yponomeuta spp.; from the order Mallophaga, for example Damalinea spp. and Trichodectes spp.;

from the order Orthoptera, for example Blatta spp., Blattella spp., Gryllotalpa spp., Leucophaea maderae, Locusta spp., Neocurtilla hexadactyla, Periplaneta spp., Scapteriscus spp. and Schistocerca spp.;

from the order Psocoptera, for example Liposcelis spp.;

from the order Siphonaptera, for example Ceratophyllus spp., Ctenocephalides spp. and Xenopsylla cheopis;

from the order Thysanoptera, for example Calliothrips phaseoli, Frankliniella spp., Heliothrips spp., Hercinothrips spp., Parthenothrips spp., Scirtothrips aurantii, Sericothrips variabilis, Taeniothrips spp., Thrips spp;

from the order Thysanura, for example Lepisma saccharina.

In a further aspect, the present invention may also relate to a method for controlling damage to a plant and its parts by plant parasitic nematodes (endoparasitic, semi-endoparasitic and ectoparasitic nematodes), in particular plant parasitic nematodes such as root-knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica , Meloidogyne arenaria and other Meloidogyne species; cyst nematodes, Globodera rostochiensis and other Globodera species; Heterodera avenae, Heterodera glycines, Heterodera schachtii, Heterodera trifolii and other Heterodera species; seed root-knot nematodes, Anguina spp.; stem and leaf nematodes, Aphelenchoides spp.; sting nematodes, Belonolaimus longicaudatus and other Belonolaimus species; conifer nematodes, Bursaphelenchus xylophilus and other Bursaphelenchus species; ring nematodes, Criconema spp., Criconemella spp., Criconemoides spp., Mesocriconema spp.; stem and bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci and other Ditylenchus species; Spine-nosed nematodes, Dolichodorus spp.; spiral nematodes, Heliocotylenchus multicinctus and other Helicotylenchus species; tunicate and tunicate nematodes, Hemicycliophora spp. and Hemicriconemoides spp.; Hirshmanniella spp.; lanceolate nematodes, Hoploaimus spp.; false root-knot nematodes, Nacobbus spp.; needle nematodes, Longidorus elongatus and other Longidorus species; short-bodied nematodes, Pratylenchus spp.; wounding nematodes, Pratylenchus neglectus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi and other Pratylenchus species; burrowing nematodes, Radopholus similis and other Radopholus species; kidney nematodes, Rotylenchus robustus, Rotylenchus reniformis and other Rotylenchus species; Scutellonema spp.; short root nematodes, Trichodorus primitivus and other Trichodorus spp., Paratricodorus spp.; dwarf nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius and other Tylenchorhynchus species; citrus nematodes, Tylenchulus spp.; dagger nematodes, Xiphinema spp.; as well as other plant-parasitic nematode species, such as Subanguina spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp. and Quinisulcius spp.

The compounds of the present invention may also exhibit activity against shellfish. Examples of which include, for example, Ampullariidae; Arion (A. ater, A. circumscriptus, A. hortensis, A. rufus); Bradybaenidae (Bradybaena 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.

The active ingredients of the present invention can be used as a control, i.e. control or destruction of pests of the above type which occur in particular on plants, especially useful plants and ornamental plants in agriculture, horticulture and forestry, or on the organs of such plants, such as fruits, flowers, leaves, stems, tubers or roots, and in some cases even plant organs that form at a later point in time, remain protected from these pests.

Suitable target crops include, in particular, cereal crops such as wheat, barley, rye, oats, rice, maize or sorghum; beets such as sugar beets or fodder beets; fruit crops, for example pome, stone fruit or berry crops, such as apple, pear, plum, peach, almond, cherry or berry varieties, for example strawberry, raspberry or blackberry varieties; legumes such as varieties of beans, lentils, peas or soybeans; oilseeds such as oilseed rape, mustard, poppy varieties, olives, sunflowers, coconut palm,

- 35 045353 castor beans, cocoa or peanut varieties; melons, such as pumpkin, cucumber or melon varieties; fibrous plants such as cotton, flax, hemp or jute; citrus fruits such as orange, lemon, grapefruit or tangerine varieties; vegetables such as spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes or bell peppers; members of Lauraceae such as avocado, Cinnamonium or camphor; as well as tobacco, nuts, coffee, eggplant varieties, sugar cane, tea, pepper, cultivated grape varieties, hops, representatives of the plantain family and rubber plants.

The compositions and/or methods of the present invention can also be applied to any ornamental and/or vegetable crops, including flowers, shrubs, broadleaf trees and evergreens.

For example, the present invention can be applied to any of the following ornamental plant species: Ageratum spp., Alonsoa spp., Anemone spp., Anisodontea capsenisis, Anthemis spp., Antirrhinum spp., Aster spp., Begonia spp. (e.g. B. elatior, B. semperflorens, B. tubereux), Bougainvillea spp., Brachycome spp., Brassica spp. (ornamental species), Calceolaria spp., Capsicum annuum, Catharanthus roseus, Canna spp., Centaurea spp., Chrysanthemum spp., Cineraria spp. (C. maritime), Coreopsis spp., Crassula coccinea, Cuphea ignea, Dahlia spp., Delphinium spp., Dicentra spectabilis, Dorotheantus spp., Eustoma grandiflorum, Forsythia spp., Fuchsia spp., Geranium gnaphalium, Gerbera spp., Gomphrena globosa, Heliotropium spp., Helianthus spp., Hibiscus spp., Hortensia spp., Hydrangea spp., Hypoestes phyllostachya, Impatiens spp. (I. Walleriana), Iresines spp., Kalanchoe spp., Lantana camara, Lavatera trimestris, Leonotis leonurus, Lilium spp., Mesembryanthemum spp., Mimulus spp., Monarda spp., Nemesia spp., Tagetes spp., Dianthus spp. (clove), Canna spp., Oxalis spp., Bellis spp., Pelargonium spp. (P. peltatum, P. Zonale), Viola spp. (tricolor violet), Petunia spp., Phlox spp., Plecthranthus spp., Poinsettia spp., Parthenocissus spp. (P. quinquefolia, P. tricuspidata), Primula spp., Ranunculus spp., Rhododendron spp., Rosa spp. (rose), Rudbeckia spp., Saintpaulia spp., Salvia spp., Scaevola aemola, Schizanthus wisetonensis, Sedum spp., Solanum spp., Surfinia spp., Tagetes spp., Nicotinia spp., Verbena spp., Zinnia spp. and other plants for flower garden decoration.

For example, the present invention can be applied to any of the following vegetable crops: Allium spp. (A. sativum, A., sulfur, A. oschaninii, A. Porrum, A. ascalonicum, A. fistulosum), Anthriscus cerefolium, Apium graveolus, Asparagus officinalis, Beta vulgarus, Brassica spp. (B. Oleracea, B. Pekinensis, B. rapa), Capsicum annuum, Cieer arietinum, Cichorium endivia, Cichorum spp. (C. intybus, C. endivia), Citrillus lanatus, Cucumis spp. (C. sativus, C. melo), Cucurbita spp. (S. pepo, S. maxima), Cyanara spp. (C. scolymus, C. cardunculus), Daucus carota, Foeniculum vulgare, Hypericum spp., Lactuca sativa, Lycopersicon spp. (L. esculentum, L. lycopersicum), Mentha spp., Ocimum basilicum, Petroselinum crispum, Phaseolus spp. (P. vulgaris, P. coccineus), Pisum sativum, Raphanus sativus, Rheum rhaponticum, Rosemarinus spp., Salvia spp., Scorzonera hispanica, Solarium melongena, Spinacea oleracea, Valerianella spp. (V. locusta, V. eriocarpa) and Viciafaba.

Preferred ornamental plant species include Saintpaulia, Begonia, Dahlia, Gerbera, Hydrangea, Verbena, Rosa, Kalanchoe, Poinsettia, Aster, Centaurea, Coreopsis, Delphinium, Monarda, Phlox, Rudbeckia, Sedum, Petunia, Viola, Impatiens, Geranium, Chrysanthemum, Ranunculus , Fuchsia, Salvia, Hortensia, rosemary, sage, St. John's wort, mint, bell pepper, tomato and cucumber.

The active ingredients of the present invention are particularly suitable for the control of Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable crops, maize, rice and soybean. Moreover, the active ingredients according to the present invention are particularly suitable for the control of Mamestra (preferably on vegetable crops), Cydia pomonella (preferably on apple varieties), Empoasca (preferably on vegetable crops, vineyards), Leptinotarsa (preferably on potato varieties) and Chilo supressalis ( preferably on rice).

The compounds of formula I are particularly suitable for the control of a pest of the order Hemiptera, for example one or more of the species Bemisia tabaci, Aphis craccivora, Myzus persicae, Rhopalosiphum Padi, Nilaparvata lugens and Euschistus heros (preferably on vegetables, soybeans and sugar cane);

a pest from the order Lepidoptera, for example one or more of the species Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includens, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens and Tuta absoluta (preferably on vegetables and maize);

a pest from the order Thysanoptera, for example from the family Thripidae, for example one or more of the species Thrips tabaci and Frankliniella occidentalis (preferably on vegetable crops); and soil pests (for example, from the order Coleoptera), for example the species Diabrotica balteata, Agriotes spp. and Leptinotarsa decemlineata (preferably on vegetables and corn).

The term crops should be understood to also include crop plants that have been transformed by recombinant DNA techniques in such a way that they have acquired the ability to synthesize one or more selective toxins, such as those known, for example, from toxin-producing bacteria, e.g. , bacte

- 36 045353 riy of the genus Bacillus.

Toxins that may be expressed by such transgenic plants include, for example, insecticidal proteins, such as insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as 5-endotoxins, for example, Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example, Vip1, Vip2, Vip3 or Vip3A; or insecticidal proteins from bacteria colonizing nematodes, such as Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals such as scorpion toxins, arachnid toxins, wasp toxins and other specific insect neurotoxins; toxins produced by fungi such as Streptomycetes toxins, plant lectins such as pea lectins, barley lectins or snowdrop lectins; agglutinins; proteinase inhibitors such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors; ribosome inactivating proteins (RIPs), such as ricin, corn RIP, abrin, luffin, saporin or bryodin; steroid metabolic enzymes such as 3-hydroxysteroid oxidase, ecdysteroid UDP glycosyltransferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA reductase, ion channel blockers such as sodium or calcium channel blockers, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, dibenzyl synthase , chitinases and glucanases.

In the context of the present invention, 5-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A, should also be understood explicitly as hybrid toxins , truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by novel combinations of different domains of such proteins (see, for example, WO 02/15701). Truncated toxins are known, such as truncated Cry1Ab. In the case of modified toxins, one or more amino acids of a naturally occurring toxin are replaced. With such amino acid substitutions, sequences recognized by proteases that are not present in the natural toxin are preferably introduced into the toxin, for example, in the case of Cry3A055, a sequence recognized by cathepsin G is introduced into the Cry3A toxin (see WO 03/018810).

Examples of such toxins or transgenic plants capable of synthesizing such toxins are disclosed, for example, in EP-A-0374753, WO 93/07278, WO 95/34656, EP-A-0427529, EP-A-451878 and WO 03/052073.

Methods for producing such transgenic plants are generally known to one 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-0367474, EP-A-0401979 and WO 90/13651.

The toxin contained in transgenic plants gives the plants tolerance to harmful insects. Such insects can belong to any taxonomic group of insects, but are especially common among beetles (Coleoptera), dipterans (Diptera) and moths (Lepidoptera).

Transgenic plants containing one or more genes that encode insect resistance and express one or more toxins are known, and some of them are commercially available. Examples of such plants are: YieldGard® (a maize variety expressing the Cry1Ab toxin); YieldGard Rootworm® (a maize variety expressing the Cry3Bb1 toxin); YieldGard Plus® (maize variety expressing Cry1Ab and Cry3Bb1 toxin); Starlink® (a maize variety expressing the Cry9C toxin); Herculex I® (a maize variety expressing the Cry1Fa2 toxin and the enzyme phosphinothricin-Nacetyltransferase (PAT) with tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety expressing Cry1Ac toxin); Bollgard I® (cotton variety expressing the Cry1Ac toxin); Bollgard II® (cotton variety expressing Oy1Ac and Cry2Ab toxin); VipCot® (cotton variety expressing Vip3 A toxin and Cry1Ab); NewLeaf® (potato variety expressing the Cry3A toxin); NatureGard® Agrisure® GT Advantage (GA21 with glyphosate tolerance trait), Agrisure® CB Advantage (Bt11 with corn borer (CB) tolerance trait) and Protecta®.

Additional examples of such transgenic crops are the following.

1. Maize Bt11 from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790 Saint-Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays that has been rendered resistant to corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenically expresses the PAT enzyme to provide tolerance to the herbicide glufosinate ammonium.

2. Maize Bt176 from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790 Saint-Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays, which has been given resistance to corn borer (Ostrinia nubilalis and Sesamia nonagrioides) through transgenic

- 37 045353 expression of the CrylAb toxin. Bt176 maize also transgenically expresses the PAT enzyme to provide tolerance to the herbicide glufosinate ammonium.

3. Maize MIR604 from Syngenta Seeds SaS, Chemin de l'Hobit 27, F-31 790 Saint-Sauveur, France, registration number C/FR/96/05/10. Maize that has been rendered resistant to insects by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a sequence recognized by the protease cathepsin G. The production of such transgenic maize plants is described in WO 03/018810.

4. Maize MON 863 from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses the Cry3Bb1 toxin and is resistant to certain insects of the order Coleoptera.

5. Cotton plant IPC 531 from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/ES/96/02.

6. Maize 1507 from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-1160 Brussels, Belgium, registration number C/NL/00/10. Maize genetically modified to express the Cry1F protein, designed to provide resistance to certain insects in the order Lepidoptera, and the PAT protein, designed to provide tolerance to the herbicide glufosinate ammonium.

7. Maize NK603 x MON 810 from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of hybrid maize varieties obtained through traditional breeding by crossing genetically modified varieties NK603 and MON 810. Maize NK603 x MON 810 transgenically expresses the CP4 EPSPS protein, obtained from the CP4 strain of Agrobacterium sp., which provides tolerance to the herbicide Roundup® (contains glyphosate) , as well as the toxin Cry1Ab, derived from Bacillus thuringiensis subspecies kurstaki, which confers tolerance to certain members of the order Lepidoptera, including the corn borer.

Transgenic insect-resistant crop crops are also described in the BATS (Zentrum fur Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) report (http://bats.ch) 2003.

The term crops should be understood to also include crop plants that have been transformed by recombinant DNA techniques in such a way that they have acquired the ability to synthesize selective antipathogenic substances, such as, for example, the so-called pathogenesis-related proteins (PRPs, see ., for example, EP-A0392225). Examples of such antipathogenic substances and transgenic plants capable of synthesizing such antipathogenic substances are known, for example, from EP-A-0392225, WO 95/33818 and EP-A-0353191. Methods for producing such transgenic plants are well known to those skilled in the art and are described, for example, in the publications mentioned above.

Crops can also be modified to provide increased resistance to fungal (e.g., Fusarium, Anthracnose, or Phytophthora), bacterial (e.g., Pseudomonas), or viral (e.g., potato leafroll virus, tomato bronzing virus, cucumber mosaic virus) pathogens.

Agricultural crops also include crops that have increased resistance to nematodes, such as soybean cyst nematode.

Crops that have tolerance to abiotic stress include crops that have increased tolerance to drought, high salt, heat, cold, frost or light, for example through the expression of NF-YB or other proteins known in this field of technology.

Antipathogenic agents that may be expressed by such transgenic plants include, for example, ion channel blockers, such as sodium and calcium channel blockers, for example, the viral toxins KP1, KP4 or KP6; stilbene synthase; bibenzyl synthase; chitinases; glucanases; so-called pathogenesis-related proteins (PRP; see, for example, EP-A-0392225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics (see, for example, WO 95/33818) or protein or polypeptide factors involved in plant defense against pathogens (so-called plant disease resistance genes described in WO 03/ 000906).

Additional areas of application of the compositions according to the present invention are the protection of stored goods and storage areas and the protection of raw materials such as wood, fabrics, floor coverings or building materials, as well as applications in the field of sanitation, in particular the protection of humans, domestic animals and productive livestock from pests of the mentioned type.

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 the control of parasites in or on an animal. The present invention further provides a compound of the first aspect for use in the control of ectoparasites in an animal. The present invention further provides a compound of the first aspect for use in the prevention and/or treatment of diseases transmitted by ectoparasites.

The present invention provides the use of a compound of the first aspect for the manufacture of a medicament for the control of parasites in or on an animal. The present invention further provides the use of a compound of the first aspect for the manufacture of a medicament for the control of ectoparasites in an animal. The present invention further provides the use of a compound of the first aspect for the manufacture of a medicament for the prevention and/or treatment of diseases transmitted by ectoparasites.

The present invention provides the use of a compound of the first aspect for the control of parasites in or on an animal. The present invention further provides the use of a compound of the first aspect for the control of ectoparasites in an animal.

The term control, as used in the context of pests in or on an animal, refers to reducing the number of pests, eliminating pests or parasites, and/or preventing further pest damage or infestation.

The term treatment, as used in the context of parasites in or on an animal, refers to containing, slowing, stopping or reversing the progression or severity of an observed symptom or disease.

The term prevention, when used in the context of parasites in or on an animal, refers to preventing the animal from developing a symptom or disease.

The term animal, when used in the context of parasites in or on an animal, can refer to a mammal and a non-mammalian animal such as a bird or fish. In the case of a mammal, it may be a human or a non-human mammal. Non-human mammals include, but are not limited to, farm animals and domestic animals. Farm animals include, but are not limited to, cattle, camelids, swine, sheep, goats and horses. Pets include, but are not limited to, dogs, cats and rabbits.

A parasite is a pest that lives in or on a host animal and obtains nutrients at the expense of the host animal. An endoparasite is a parasite that lives inside a host animal. An ectoparasite is a parasite that lives on an animal host. Ectoparasites include, but are not limited to, mites, insects, and crustaceans (eg, sea louse). The subclass Acari (or Acarina) includes mites and microscopic mites. Ticks include, but are not limited to, members of the following genera: Rhipicaphalus, for example, Rhipicaphalus (Boophilus) microplus and Rhipicephalus sanguineus; Amblyomma; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius and Ornithodoros. Microscopic mites include, but are not limited to, members of the following genera: Chorioptes, for example Chorioptes bovis; Psoroptes, for example Psoroptes ovis; Cheyletiella; Dermanyssus; for example Dermanyssus gallinae; Ortnithonyssus; Demodex, for example Demodex canis; Sarcoptes, for example 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. Representatives of the order Diptera include, but are not limited to, Musca spp.; nasopharyngeal botfly, for example Gasterophilus intestinalis and Oestrus ovis., stinging flies; horseflies, such as Haematopota spp. and Tabunus spp.; Haematobia, for example Haematobia irritans; Stomoxys; Lucilia; midges and mosquitoes. Members of the class Phthiraptera include, but are not limited to, lice and lice, such as Bovicola ovis and Bovicola bovis.

The term effective amount, as used in the context of parasites in or on an animal, refers to an amount or dose of a compound of the present invention or a salt thereof which, when administered single or multiple doses to an animal, produces the desired effect in or on the animal. The effective amount can be easily determined by a diagnostician skilled in the art by applying known techniques and observing the results obtained under similar circumstances. In determining the effective amount, the diagnostician will consider a number of factors, including, but not limited to: the species of mammal; its size, age and general health; parasite to be controlled and degree of infestation; the specific disease or disorder being considered; the extent or affection or severity of the disease or disorder; the individual's response; the specific compound administered; method of administration; characteristics of the bioavailability of the administered drug; selected administration regimen; use of concomitant medications and other relevant circumstances.

The compounds of the present invention can be administered to an animal by any route that produces the desired effect, including, without limitation, topically, orally, parenterally, and subcutaneously. Local administration is preferred. Formulations suitable for topical administration include, for example, solutions, emulsions and suspensions, and may be in the form of a spreadable formulation, a spot-on formulation, a nebulizer, a split formulation, a spray or a dipping formulation. Alternatively, the compounds of the present invention can be administered using an ear tag or collar.

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Salt forms of the compounds of the present invention include both pharmaceutically acceptable salts and veterinary acceptable salts, which may differ from agrochemically acceptable salts. Pharmaceutically and veterinarily acceptable salts and conventional techniques for their preparation are well known in the art. See, for example, Gould, P. L., Salt selection for basic drugs, International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities, Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 66: 1-19, (1977). One skilled in the art of synthesis will appreciate that the compounds of the present invention are easily converted and can be isolated as a salt, such as a hydrochloride salt, using techniques and conditions well known to one of ordinary skill in the art. In addition, one skilled in the art of synthesis will appreciate that the compounds of the present invention are easy to convert and can be isolated as the free base from the corresponding salt.

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, a method of controlling pests includes applying the compositions of the present invention to a target pest, to its habitat, or to a surface or substrate by brushing, rolling, spraying, spreading, or dipping. As an example, the method of the present invention assumes IRS application (indoor residual spraying) to a surface such as a wall, ceiling or floor surface. Another embodiment contemplates the use of such compositions in relation to a substrate, such as a non-woven or woven material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.

In one embodiment, a method of controlling such pests includes applying a pesticide effective amount of the compositions of the present invention to the target pest, to its habitat, or to a surface or substrate, thereby providing an effective level of residual pesticide activity on the surface or substrate. Such application of the pesticide composition of the present invention can be carried out by brushing, rolling, spraying, spreading or dipping. By way of example, the method of the present invention involves application of IRS to a surface, such as a wall, ceiling or floor surface, to provide effective residual pesticide activity on the surface. Another embodiment contemplates the use of such compositions to control pests on a substrate, such as woven material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents, through residual action.

The substrates, including the non-woven fabrics, woven fabrics or mesh to be treated, can be made from natural fibers such as cotton, raffia, jute, linen, sisal, burlap or wool, or from synthetic fibers such as polyamide, polyester, polypropylene, polyacrylonitrile, etc. Polyesters are particularly suitable. Methods for treating fabrics are known, for example, from WO 2008/151984, WO 2003/034823, US 5631072, WO 2005/64072, WO 2006/128870, EP 1724392, WO 2005113886 or WO 2007/090739.

Other areas of application for the compositions of the present invention are for tree injection/trunk treatment of all ornamental trees and all varieties of fruit and nut trees.

In the field of tree injection/trunk application, the compounds of the present invention are particularly suitable against wood-boring insects from the order Lepidoptem mentioned above and from the order Coleoptera, especially against the wood-boring insects listed in the following tables. A and B.

Table A. Examples of introduced woodborers of economic importance

Family View Host or infected crop Buprestidae Agrilus planipennis Ash Cerambycidae Anoplura glabripennis Hardwood Scolytidae Xylosandrus crassiusculus Hardwood X. mutilatus Hardwood Tomicus piniperda Conifers

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Table B. Examples of native woodborers of economic importance

Family View Host or infected crop Buprestidae Agrilus anxius Birch Agrilus politus Willow, maple Agrilus sayi Waxwort, sweetroot Agrilus vittaticolllis Apple, pear, cranberry, shadberry, hawthorn Chrysobothris femorata Apple tree, apricot, beech, ash maple, cherry, chestnut, currant, elm, hawthorn, hackberry, hickory, horse chestnut, linden, maple, rowan, oak, pecan, pear, peach, persimmon, plum, poplar, quince, cercis, serviceberry, plane tree, walnut, willow Texania campestris Linden, beech, maple, oak, plane tree, willow, tulip tree Cerambycidae Goes pulverulentus Beech, elm, Nuttala spandex, willow, red oak, red swamp oak, black oak, sycamore Goes tigrinus Oak Neoclytus acuminatus Ash, hickory, oak, walnut, birch, beech, maple, eastern hornbeam, dogwood, persimmon, cercis, holly, hackberry, black locust, honey locust, tulip tree, chestnut, orange maclura, sassafras officinalis, lilac, cherry birch, pear, cherry, plum, peach, apple, elm, linden, amber wood Neoptychodes trilineatus Fig, alder, mulberry, willow, mesh frame Oberea ocellata Sumac, apple, peach, plum, pear, currant, blackberry Oberea tripunctata Dogwood, viburnum, elm, oxidendrum arborescens, blueberry, rhododendron, azalea, laurel, poplar, willow, mulberry Oncideres cingulata Hickory, pecan, persimmon, elm, oxidendrum arborescens, linden, honey locust, dogwood, eucalyptus, oak, hackberry, maple, fruit trees Saperda calcarata Poplar Strophiona nitens Chestnut, oak, hickory, walnut, beech, maple Scolytidae Corthylus columbianus Maple, oak, tulip tree, beech, ash maple, sycamore, birch, linden, chestnut, elm Dendroctonus frontalis Pine Dryocoetes betulae Birch, amberwood, wild cherry, beech, pear Monarthrum fasciatum Oak, maple, birch, chestnut, amber, eucalyptus, poplar, hickory, mimosa, apple, peach, pine Phloeotribus liminaris Peach, cherry, plum, sweet cherry, elm, mulberry,

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Sesiidae Pseudopityophthorus pruinosus Paranthrene simulans Sarmina uroceriformis Synanthedon exitiosa Synanthedon pictipes Synanthedon rubrofascia Rowan Oak, American beech, cherry, angustifolia plum, chestnut, maple, hickory, hornbeam, hop hornbeam Oak, American chestnut Persimmon Peach, plum, nectarine, cherry, apricot, almond, sweet cherry Peach, plum, cherry, beech, sweet cherry Nyssa Synanthedon scitula Dogwood, pecan, hickory, oak, chestnut, beech, birch, cherry, elm, rowan, viburnum, willow, apple tree, Japanese medlar, bladderwort, waxwort Vitacea polistiformis Grape

The present invention can also be used to control any insect pests that may be present in lawn grass, including, for example, beetles, caterpillars, fire ants, mealybugs, millipedes, wood lice, microscopic mites, mole crickets, scale insects, mealybugs, mites , pennits, southern earthen bugs and beetle larvae. The present invention can be used to control insect pests at various stages of their life cycle, including the eggs, larvae, nymphs and adults.

In particular, the present invention can be used to control insect pests that feed on the roots of lawn grass, including beetle larvae (such as Cyclocephala spp. (e.g., masked beetle, C. lurida), Rhizotrogus spp. (e.g., European beetle, R. majalis), Cotinus spp. (e.g. green beetle, C. nitida), Popillia spp. (e.g. Japanese beetle, P. japonica), Phyllophaga spp. (e.g. May/June beetle), Ataenius spp. ( for example, black root beetle of the genus Ataenius, A. spretulus), Maladera spp. (for example, Asian garden beetle M. castaned) and Tomarus spp.), scale insects (Margarodes spp.), mole crickets (dark yellow, southern and short-winged; Scapteriscus spp., Gryllotalpa africana) and larvae of long-legged mosquitoes (marsh long-legged mosquito, Tipula spp.).

The present invention can also be used to control insect pests of turf grass that live in thatch, including worms (such as the armyworm Spodoptera frugiperda and the armyworm Pseudaletia unipuncta), fall armyworm caterpillars, weevils (Sphenophorus spp., such as S . venatus verstitus and S. parvulus) and meadow moths (such as Crambus spp. and tropical meadow moths, Herpetogramma phaeopteralis).

The present invention can also be used to control turfgrass insect pests that live above ground and feed on turfgrass leaves, including turf bugs (such as turf bugs, Blissus insularis), Bermuda grass mite (Eriophyes cynodoniensis), Rhodes grass mealybug (Antonina graminis), two-striped pennies (Propsapia bicincta), leafhoppers, fall armyworm caterpillars (family Noctuidae) and cereal aphids.

The present invention can also be used to control other lawn grass pests, such as imported red fire ants (Solenopsis invicta), which create anthills on the surface of the lawn.

In the field of sanitation, the compositions of the present invention are characterized by activity against ectoparasites such as ixodid mites, argas mites, itch mites, red mites, flies (stinging and licking), parasitic fly larvae, lice, head lice, lice and fleas.

Examples of such parasites are the following.

From the order Anoplurida: Haematopinus spp., Linognathus spp., Pediculus spp. and Phtirus spp., Solenopotes spp.

From the order Mallophagida: Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp. and Felicola spp.

From the order Diptera and 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., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp. ., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp. and Melophagus spp.

From the order Siphonapterida, for example Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllus spp.

From the order Heteropterida, for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.

From the order Blattarida, such as Blatta orientalis, Periplaneta americana, Blattela germanica and Supella spp.

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From the subclass Acaria (Acarida) and the orders Meta- and Mesostigmata, for example, Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp., Boophilus spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp. , Rhipicephalus spp., Dermanyssus spp., Raillietia spp., Pneumonyssus spp., Stemostoma spp. and Varroa spp.

From the order Actinedida (Prostigmata) and Acaridida (Astigmata), for example Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergatesspp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp. ., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp. and Laminosioptes spp.

The compositions of the present invention are also suitable for protection against insect infestation in the case of materials such as wood, fabrics, plastics, adhesives, adhesives, paints, paper and cardboard, leather, floor coverings and building materials.

The compositions of the present invention can be used, for example, against the following pests: beetles, such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthesrugicollis, Xyleborus spec, Tryptodendron spec, Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec. and Dinoderus minutus, as well as hymenoptera insects such as Sirex juvencus, Urocerus gigas, Urocerus gigas taignus and Urocerus augur, and termites such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucifugus, Masto termes darwiniensis, Zootermopsis nevadensis and Coptotermes formosanus, and bristletails such as Lepisma saccharina. The compounds of formulas I and I'a or salts thereof are particularly suitable for the control of one or more pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae and Heteroderidae. In a preferred embodiment of each aspect, the compound TX (where the abbreviation TX means one compound selected from the compounds defined in Table A-1-A-27, B-1-B-27, C-1-C-27, D- 1-D-27 and E-1-E-27, as well as in Table P) controls one or more pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae and Heteroderidae.

The compounds of formulas I and I'a or salts thereof are particularly suitable for the control of one or more pests selected from the genus: Spodoptera spp, Plutella spp, Frankliniella spp, Thrips spp, Euschistus spp, Cydia spp, Nilaparvata spp, Myzus spp, Aphis spp , Diabrotica spp, Rhopalosiphum spp, Pseudoplusia spp and Chilo spp. In a preferred embodiment of each aspect, the compound TX (where the abbreviation TX means one compound selected from the compounds defined in Table A-1-A-27, B-1-B-27, C-1-C-27, D- 1-D-27 and E-1-E-27, as well as in Table P) controls one or more pests selected from the genus: Spodoptera spp, Plutella spp, Frankliniella spp, Thrips spp, Euschistus spp, Cydia spp, Nilaparvata spp, Myzus spp, Aphis spp, Diabrotica spp, Rhopalosiphum spp, Pseudoplusia spp and Chilo spp.

The compounds of formulas I and I'a or salts thereof are particularly suitable for the control of one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padi and Chilo suppressalis.

In a preferred embodiment of each aspect, the compound TX (where the abbreviation TX means one compound selected from the compounds defined in Table A-1-A-27, B-1-B-27, C-1-C-27, D- 1-D-27 and E-1-E-27, as well as in Table P) controls one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae , Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padi and Chilo suppressalis, such as Spodoptera littoralis + TX, Plutella xylostella + TX; Frankliniella occidentalis + TX, Thrips tabaci + TX, Euschistus heros + TX, Cydia pomonella + TX, Nilaparvata lugens + TX, Myzus persicae + TX, Chrysodeixis includens + TX, Aphis craccivora + TX, Diabrotica balteata + TX, Rhopalosiphum Padi + TX and Chilo suppressalis + TX.

In one embodiment of each aspect, one compound selected from the compounds defined in table. A-1- A-27, B-1- B-27, C-1- C-27, D-1- D-27 and E-1- E-27, as well as in table. P, is suitable for the control of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padi and Chilo suppressalis on cotton crops, vegetable plants , maize, cereals, rice and soybeans.

In one embodiment, one compound selected from the compounds defined in table. A-1- A-27, B-1- B-27, C-1- C-27, D-1- D-27 and E-1- E-27, as well as in table. P, is suitable for the control of Mamestra (preferably on vegetable crops), Cydia pomonella (preferably on apple varieties), Empoasca (preferably on vegetable crops, vineyards), Leptinotarsa (preferably on potato varieties) and Chilo supressalis (preferably on rice).

The compounds of the present invention may have any number of advantages, including, but not limited to, superior levels of biological activity for protecting plants from insects or superior properties for use as agrochemical active ingredients (e.g., higher biological activity, advantageous spectrum of activity, favorable safety profile (against non-target organisms living on and in soil (such as fish, birds and bees), improved physico-chemical properties or increased biodegradability) In particular, it has surprisingly been discovered that certain compounds of formula I can exhibit a favorable profile safety against non-target arthropods, particularly pollinators such as honeybees, solitary bees and bumblebees, most specifically Apis mellifera.

The compounds of the present invention can be used as pesticidal agents in unmodified form, but are typically formulated in various ways using formulation auxiliaries such as carriers, solvents and surfactants. The compositions may be present in various physical forms, for example, sprayable powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent tablets, emulsifiable concentrates, microemulsion concentrates, oil-in-water emulsions, oil-based pourable formulations, aqueous dispersions, oil dispersions, suspoemulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as a carrier), impregnated polymer films or in other forms known, for example, from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). Such formulations can either be applied directly or diluted before use. Dilutions can be carried out, for example, with water, liquid fertilizers, micronutrients, biological organisms, oil or solvents.

The compositions can be prepared, for example, by mixing the active ingredient with formulation auxiliaries to obtain compositions in the form of fine solids, granules, solutions, dispersions or emulsions. The active ingredients may also be formulated with other excipients, for example, fine solids, mineral oils, vegetable or animal oils, modified vegetable or animal oils, organic solvents, water, surfactants, or combinations thereof.

The active ingredients may also be contained in very small microcapsules. Microcapsules contain active ingredients in a porous carrier. This allows the active ingredients to be released into the environment in controlled quantities (eg slow release). Microcapsules typically have a diameter ranging from 0.1 to 500 microns. They contain active ingredients in amounts ranging from approximately 25 to 95% by weight of the capsule. The active ingredients may be in the form of a monolithic solid, in the form of fine particles in a solid or liquid dispersion, or in the form of a suitable solution. Encapsulating membranes may contain, for example, natural and synthetic rubbers, cellulose, styrene-butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to one skilled in the art. Alternatively, very fine microcapsules can be prepared in which the active ingredient is contained as fine particles in a solid matrix of the base material, but the microcapsules are not themselves encapsulated.

Formulation auxiliaries that are suitable for preparing the compositions according to the present invention are known per se. Liquid carriers that can be used include 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 esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate , diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerin, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane , n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichlorethylene, perchlorethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol and high molecular weight alcohols such as amyl alcohol, tetra-hydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerin, N-methyl-2pyrrolidone, etc.

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, soya flour, pumice, wood flour, ground shells walnuts, lignin and similar substances.

A large number of surfactants can be used successfully in both solid and liquid formulations, especially in those formulations that can be diluted with a vehicle before use. Surfactants may be anionic, cationic, nonionic, or polymeric, and may be used as emulsifiers, wetting agents or suspending agents, or for other purposes. Typical surfactants include, for example, alkyl sulfate salts such as diethanolammonium lauryl sulfate; alkylaryl sulfonate salts such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products such as nonylphenol ethyloxylate; alcohol/alkylene oxide addition products such as tridecyl alcohol ethoxylate; soaps such as sodium stearate; alkyl naphthalene sulfonate salts such as sodium dibutyl naphthalene sulfonate; dialkyl esters of sulfosuccinate salts such as sodium di(2ethylhexyl)sulfosuccinate; sorbitol esters such as sorbitolate; quaternary amines such as lauryltrimethylammonium chloride, polyethylene glycol fatty acid esters such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide and salts of mono- and dialkyl phosphate esters; as well as additional substances described, for example, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).

Additional excipients that may be used in pesticide formulations include crystallization inhibitors, viscosity modifiers, suspending agents, colorants, antioxidants, foaming agents, light absorbers, mixing aids, antifoams, complexing agents, neutralizing or pH-modifying agents, and buffers. corrosion inhibitors, fragrances, wetting agents, absorption enhancers, micronutrients, plasticizers, glidants, lubricants, dispersants, thickeners, antifreeze, microbicides, and liquid and solid fertilizers.

The compositions of the present invention may include an additive containing a vegetable or animal oil, mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the present invention is usually from 0.01 to 10% based on the mixture to be used. For example, an oil additive can be added to the sprayer reservoir at the required concentration after preparing the spray mixture. Preferred oil additives contain mineral or vegetable oils, such as canola oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of vegetable oils, such as methyl derivatives, or an animal oil, such as fish oil or beef tallow. Preferred oil additives contain alkyl esters of C ₈ -C ₂₂ fatty acids, in particular methyl derivatives of C ₁₂ -C ₁₈ fatty acids, such as methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively) . Many oil derivatives are known from Compendium of Herbicide Adjuvants, ^10th Edition, Southern Illinois University, 2010.

The compositions of the present invention generally contain from 0.1 to 99% by weight, in particular from 0.1 to 95% by weight of the compounds of the present invention and from 1 to 99.9% by weight of the formulation excipient which preferably includes from 0 to 25% by weight of surfactant. Since commercial products may preferably be formulated as concentrates, the end user will typically use diluted formulations.

Application rates vary widely and depend on soil properties, method of application, crop plant, pest being controlled, prevailing climatic conditions and other factors determined by application method, time of application and target crop. As a general guideline, the compounds can be applied at rates from 1 to 2000 l/ha, in particular from 10 to 1000 l/ha.

Preferred compositions may be characterized by the following compositions (wt.%).

Emulsifiable concentrates:

active ingredient: 1-95%, preferably 60-90%;

surfactant: 1-30%, preferably 5-20%;

liquid carrier: 1-80%, preferably 1-35%.

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Dust preparations:

active ingredient:

solid carrier:

Suspension concentrates: active ingredient:

water:

surface-active substance:

Wettable powders:

active ingredient:

surfactant: solid carrier:

Granules:

active ingredient:

0.1-10%, preferably 0.1-5%;

99.9-90%, preferably 99.9-99%.

5-75%, preferably 10-50%;

94-24%, preferably 88-30%;

1-40%, preferably 2-30%.

0.5-90%, preferably 1-80%;

0.5-20%, preferably 1-15%;

5-95%, preferably 15-90%.

0.1-30%, preferably 0.1-15%;

solid carrier: 9.5-70%, preferably 97-85%.

The following examples further illustrate, but do not limit, the present invention.

Wettable powders A) b) With) active ingredients 25% 50% 75% sodium lignosulfonate 5% 5% - sodium lauryl sulfate 3% - 5% sodium diisobutylnaphthalene sulfonate - 6% 10% phenol polyethylene glycol ether (7-8 mol ethylene oxide) - 2% - highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% -

The combination is thoroughly mixed with the excipients and the mixture is thoroughly ground in a suitable mill to obtain wettable powders which can be diluted with water to obtain suspensions of the required concentration.

The combination is thoroughly mixed with the excipients and the mixture is thoroughly ground in a suitable mill to obtain powders that can be used directly for seed treatment. ________________________________________________

Emulsifiable concentrate active ingredients 10% octylphenolpolyethylene glycol ether (4-5 mol ethylene oxide) 3% calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (3 5 mol ethylene oxide) 4% Cyclohexanone thirty% xylene mixture 50%

From this concentrate, by diluting with water, emulsions of any required dilution can be obtained, which can be used to protect plants.

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Dust preparations A) b) With) active ingredients 5% 6% 4% Talc 95% - - Kaolin - 94% - mineral filler - - 96%

Ready-to-use powdered preparations are prepared by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry seed dressing.

Extruded granules active ingredients 15 % sodium lignosulfonate 2% carboxymethylcellulose 1 % kaolin 82%

The combination is mixed and ground with excipients, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air. ______

Coated granules active ingredients 8% polyethylene glycol (molecular weight 3% 200) kaolin 89%

The finely ground combination in a mixing device is evenly applied to the kaolin moistened with polyethylene glycol. In this way, dust-free, coated granules are obtained.

Suspension concentrate:

active ingredients 40% Propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol ethylene oxide) 6% sodium lignosulfonate 10% Carboxymethylcellulose 1 % silicone oil (as a 75% emulsion in water) 1 % Water 32%

The finely ground combination is thoroughly mixed with excipients to obtain a suspension concentrate, from which suspensions of any required dilution can be obtained by dilution with water. With the help of such diluted solutions, living plants, as well as plant propagation material, can be treated and protected from contamination by microorganisms by spraying, watering or immersing.

Flowable seed treatment concentrate:

active ingredients 40% Propylene glycol 5% copolymer of butanol and PO/EO 2% tristyrenephenol with 10-20 moles of EO 2% 1,2-Benzisothiazolin-3-one (as a 20% solution in water) 0.5% calcium salt of monoazopigment 5% silicone oil (as a 75% emulsion in water) 0.2% Water 45.3%

The finely ground combination is thoroughly mixed with excipients to obtain a suspension concentrate, from which suspensions of any required dilution can be obtained by dilution with water. With the help of such diluted solutions, living plants, as well as plant propagation material, can be treated and protected from contamination by microorganisms by spraying, watering or immersing.

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Slow-release capsule suspension

Mix 28 parts of the combination with 2 parts of an aromatic solvent and 7 parts of a mixture of toluene diisocyanate/polymethylene polyphenyl isocyanate (8:1). This mixture is emulsified in a mixture of 1.2 parts polyvinyl alcohol, 0.05 parts defoamer and 51.6 parts water to obtain particles of the required size. To this emulsion is added a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts water. The mixture is stirred until the polymerization reaction is completed. The resulting capsule suspension is stabilized by adding 0.25 parts thickener and 3 parts dispersant. The composition of the capsule suspension contains 28% active ingredients. The average diameter of capsules is 8-15 microns. The resulting composition is applied to the seeds in the form of an aqueous suspension in a device suitable for the purpose.

Formulation types include emulsion concentrate (EC), suspension concentrate (SC), suspoemulsion (SE), capsule suspension (CS), water-dispersible granule (WG), emulsifiable granule (EG), water-in-oil emulsion (EO), emulsion type oil in water (EW), micro emulsion (ME), oil dispersion (OD), oil miscible fluid (OF), oil miscible liquid (OL), soluble concentrate (SL), ultra low volume suspension (SU ), ultra low volume liquid (UL), technical concentrate (TK), dispersible concentrate (DC), wettable powder (WP), soluble granule (SG) or any other technically feasible formulation in combination with agriculturally acceptable excipients .

Examples of receiving

LCMS methods.

Method 1.

Spectra were recorded on an Agilent Technologies mass spectrometer (6410 Triple Quadrupole Mass Spectrometer) equipped with an electrospray source (polarity: positive or negative ions, scan type MS2, capillary voltage: 4.00 kV, fragmentor voltage: 100 V, desolvation temperature: 350 °C, gas flow: 11 L/min, nebulizer gas: 45 psi, mass range: 110-1000 Da), and Agilent 1200 Series HPLC: quaternary pump, heated column space, and diode detector matrix. Column: KINETEX EVO C18, 2.6 µm, 50x4.6 mm, temp.: 40°C, DAD wavelength range (nm): 210-400, 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 (ml/min.) 1.8.

Method 2.

Spectra were recorded on a Waters mass spectrometer (SQD single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative ions, full scan, capillary voltage: 3.00 kV, cone voltage range: 41 V, source temperature: 150 °C, desolvation temperature: 500°C, cone gas flow: 50 l/h, desolvation gas flow: 1000 l/h, mass range: 110-800 Da) and H-Class UPLC from Waters: pump for two-component mixtures, a heated section of the column and a diode array detector. Column: Waters UPLC HSS T3 C18, 1.8 µm, 30x2.1 mm, temp.: 40°C, DAD wavelength range (nm): 210-400, 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 (ml/min.) 0.8.

Chiral SFC method 1. Spectra were recorded on a Waters SFC (Waters Acquity UPC ² /QDa) equipped with a Waters Acquity UPC ² PDA Detector. Column: Daicel SFC CHIRALPAK® IC, (3 µm, 0.3 cm x 10 cm, 40°C; mobile phase: A: CO2 B: MeOH, isocratic mode: 10% B in 2.0 min; ABPR: 1800 lb/ sq.in., Flow rate: 2.0 mL/min; Detection: at 220 nm; Sample concentration: 1 mg/mL in ACN; Injection volume: 1 μL

Chiral SFC 2 method. Spectra were recorded on a Waters SFC (Waters Acquity UPC ² /QDa) equipped with a Waters Acquity UPC ² PDA Detector. Column: Daicel SFC CHIRALPAK® IG, (3 µm, 0.3 cm x 10 cm, 40°C; mobile phase: A: CO2 B: MeOH, isocratic mode: 15% B in 4.8 min; ABPR: 1800 lb/ sq.in., Flow Rate: 2.0 mL/min, Detection: 270 nm, Sample Concentration: 1 mg/mL in ACN/MeOH (1:1), Injection Volume: 1 µL

Preparation of methyl 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (intermediate I1)

Sulfuric acid (2.46 mL, 44.3 mmol, 1.00 eq.) was added dropwise at room temperature to a solution of 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid (CAS 796090-23-8, 10.0 g, 44.3 mmol)

- 48 045353 in methanol (266 ml). The reaction mixture was heated to 65°C and stirred overnight. After cooling to room temperature, the reaction mixture was poured over a saturated aqueous sodium hydrogen carbonate 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.

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

Preparation of methyl 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylate (intermediate I2) and 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylic acid (intermediate I3)

Cyclopropylboronic acid (1.43 g,

16.7 mmol, 2.00 eq.) and sodium bicarbonate (2.10 g, 25.1 mmol, 3.00 eq.) were added to the solution of methyl 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (intermediate I1 prepared as above) (2.00 g, 8.35 mmol) in 1,4-dioxane (20.9 ml) and water (8.35 ml), and the resulting suspension was purged with argon for 10 min. [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.322 g, 0.417 mmol, 0.05 eq) was added and the resulting suspension was stirred at 100°C for 1 hour under argon. 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 the first crude material, which after purification by flash silica gel chromatography (ethyl acetate in cyclohexane) provided the desired intermediate I2 (0.706 g, 2.88 mmol).

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).

LC-MS (method 1): retention time 1.12 min, mass/charge 246 [M+H] ⁺ . After acidification to pH 1, the aqueous layer was again extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulfate, filtered and evaporated to give the second crude material, which after purification by flash chromatography on silica gel (methanol in dichloromethane) provided intermediate I3 (0.166 g, 0.718 mmol).

1H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) 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).

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

Preparation of 2-cyclopropyl-6-(trifluoromethyl)pyridine-4-carboxylic acid (intermediate I3)

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

¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ ppm: 0.96-1.02 (m, 2H), 1.07-1.15 (m, 2H), 2.40 (tt, J1=8 ,12 Hz, J ₂ =4.72 Hz, 1H), 7.88 (d, J=1.10 Hz, 1H), 8.04 (s, 1H), 13.90-14.36 (m, 1H). LC-MS (method 1): retention time 0.94 min, mass/charge 232 [M+H]+.

Preparation of methyl 3-cyclopropyl-5-(trifluoromethyl)benzoate (intermediate I4)

- 49 045353

A solution of propargyl bromide in toluene (80% by weight, 0.89 g, 0.67 ml) was added to a white suspension of 9-BBN dimer (3.0 g, 12 mmol) in 26 ml of dry tetrahydrofuran under argon to give a pale yellow solution. The mixture was refluxed for 2 hours and then cooled to room temperature. Pre-degassed 4 M aqueous sodium hydroxide solution (4.4 mL, 18 mmol) was added to obtain a cloudy, colorless solution. The resulting mixture was stirred for 1 hour at room temperature in an argon atmosphere. The resulting very pale yellow solution was then added to a pre-degassed light yellow solution of methyl 3-bromo-5(trifluoromethyl)benzoate (187331-46-0, 1.5 g, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0 ) (0.30 g, 0.26 mmol) in 52 ml of dry tetrahydrofuran to give a light yellow solution. The resulting mixture was stirred for 19 hours under reflux. The mixture was cooled at room temperature, diluted with ethyl acetate, quenched with water (+ a few drops of saline) 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 silica gel chromatography to give methyl 3-cyclopropyl-5-(trifluoromethyl)benzoate as a colorless liquid.

^1H NMR (400 MHz, chloroform-d) δ ppm: 0.76-0.85 (m, 2H), 1.06-1.15 (m, 2H), 2.03 (tt, J ₁ =8 .39 Hz, J ₂ =5.00 Hz, 1H), 3.96 (s, 3H), 7.52 (s, 1H), 7.91 (s, 1H), 8.08 (d, J= 0.73 Hz, 1H). ¹⁹ F NMR (377 MHz, chloroform-d) δ ppm: -62.75 (s, 3F).

Preparation of 3-cyclopropyl-5-(trifluoromethyl)benzoic acid (intermediate I5)

Methyl 3-cyclopropyl-5-(trifluoromethyl)benzoate (7.00 g, 28.7 mmol) was dissolved in tetrahydrofuran (57.3 ml) and water (28.7 ml). Lithium hydroxide (1.21 g, 28.7 mmol) was then added and the resulting pale yellow cloudy solution was stirred for 4 hours at room temperature. The reaction mixture was diluted in ethyl acetate and water. The organic phase was washed twice with water. The combined aqueous layers were acidified with 1 N. aqueous hydrochloric acid solution to pH 1-2 and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure at 60°C to give 3-cyclopropyl-5-(trifluoromethyl)benzoic acid, which was used without further purification.

^1H 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). LC-MS (method 1): retention time 0.99 min, mass/charge 229 [M-H] ^- .

Preparation of methyl 3-(trifluoromethyl)-5-vinylbenzoate (intermediate I6)

In a three-neck flask under argon, methyl 3-bromo-5-(trifluoromethyl)benzoate (CAS: 187331-46-0, 20 g, 69.24 mmol) was dissolved in toluene (312 ml). Tributyl(vinyl)tin (25.56 mL, 83.09 mmol) was then added and the resulting solution was degassed with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.816543 g, 0.69 mmol) was added and the resulting mixture was stirred at 110°C for 2 hours. After cooling at room temperature, the mixture was diluted with ethyl acetate (100 ml), filtered through a pad of celite , washed with ethyl acetate and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography to give methyl 3(trifluoromethyl)-5-vinyl benzoate.

^1H 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, J ₁ =17.42 Hz, J ₂ =10.82 Hz, 1H), 7.82 (s, 1H), 8.19 (s, 1H), 8, 24-8.29 (m, 1H).

Preparation of diphenyl(2,2,2-trifluoroethyl)sulfonium trifluoromethanesulfonate

Diphenyl sulfide (36.43 mL, 211.1 mmol) and 2,2,2 trifluoroethyl trifluoromethanesulfonate (6.207 mL, 42.22 mmol) were mixed in an autoclave. The mixture was stirred for 2 minutes at

- 50 045353 room temperature, then the autoclave was closed and heated at 150°C for 20 hours. The reaction mixture was cooled at room temperature, and a white precipitate formed. 75 ml of diethyl ether was added, then the white solid was filtered. It was washed four times with 30 ml of diethyl ether and then dried under reduced pressure.

1H 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, J ₂ =1.28 Hz, 4H).

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

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

In a vial under argon, 3-(trifluoromethyl)-5-vinylbenzoate (1.9 g, 8.3 mmol) and cesium fluoride (1.5 g, 9.9 mmol) were dissolved in dimethylacetamide (33 ml) to obtain a colorless solution , which was degassed in an argon atmosphere for 20 minutes. 5,10,15,20-tetraphenyl-21H,23Hporphine-iron(III) chloride (0.31 g, 0.41 mmol) was added. The reaction mixture became a green suspension and diphenyl(2,2,2-trifluoroethyl)sulfonium trifluoromethanesulfonic acid (3.8 g, 9.1 mmol) was added in portions. The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane, 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 at 160 mbar. The crude product was purified by silica gel chromatography to give methyl 3-(trifluoromethyl)-5-[2-(trifluoromethyl)cyclopropyl]benzoate.

1H 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 ), 2.462.53 (m, 1H), 3.98 (s, 3H), 7.60 (s, 1H), 7.98 (s, 1H), 8.19 (s, 1H).

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

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 for 3 hours 30 minutes at room temperature. The reaction mixture was cooled to 0°C, then it was acidified with 2 M hydrochloric acid solution. The aqueous layer was extracted twice with ethyl acetate, 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.

1H NMR (400 MHz, dimethyl sulfoxide-46) δ ppm 1.40-1.47 (m, 2H), 2.53-2.60 (m, 1H), 2.72 (td, J1=7.70 Hz , J ₂ =4.77 Hz, 1H), 7.87 (s, 1H), 8.02 (s, 1H), 8.05-8.08 (m, 1H), 13.54 (brs, 1H ). LC-MS (method 1): retention time 1.04 min, mass/charge 297 [M-H]'.

Preparation of methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfanyl)benzoate (intermediate I9)

(2,2'-Bipyridine)(trifluoromethanethiolato)copper (CAS 1413732-47-4) (3.9 g, 12 mmol, 2.0 eq.) was added to the methyl 3-iodo-5-(trifluoromethyl)benzoate solution (2.0 g, 6.1 mmol) in acetonitrile (18 ml) under argon. The reaction mixture was heated to 90°C and stirred overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and concentrated. The crude material was purified by two rounds of flash silica gel chromatography (ethyl acetate in cyclohexane) to give the desired product as a yellow gum (1.5 g, 4.9 mmol).

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

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

Preparation of methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate (intermediate I10)

3-Chloroperbenzoic acid (2.3 g, 11 mmol, 2.1 eq.) was added portionwise to a cooled 0°C 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 for 1 hour at room temperature, additional 3-chloroperbenzoic acid (2.3 g, 11 mmol, 2.1 eq.) was added and the reaction mixture was stirred overnight. The formed precipitate was filtered off. The filtrate was washed with 10% aqueous sodium thiosulfate and sat. NaHCO ₃ solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate.

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).

¹⁹ F NMR (377 MHz, chloroform-d) δ ppm: -77.49 (s, 3F), -62.96 (s, 3F).

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

Methyl 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoate (1.8 g, 5.4 mmol) was charged into a flask and dissolved in tetrahydrofuran (16 ml) and water (11 ml). Lithium hydroxide monohydrate (0.26 g, 11 mmol) was added to this mixture, and the reaction mixture was stirred for 1 hour at room temperature. 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.

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

Preparation of methyl 3-(cyclopropanecarbonyl)-5-(trifluoromethyl)benzoate (intermediate I12)

Methyl 3-iodo-5-(trifluoromethyl)benzoate (10 g, 28.78 mmol) was taken up with tetrahydrofuran (115 ml) under argon. The resulting pale brown solution was cooled to -78°C in a dry ice/acetone bath. Using a syringe, a 1.3 M solution of Turbo-Grignard in tetrahydrofuran (31 mL, 40.29 mmol) was added dropwise over 20 min to immediately obtain a dark solution while maintaining the temperature below -65°C. The resulting mixture was stirred at -78°C for 15 minutes. At the same time, copper cyanide (3.125 g, 34.5 mmol) and anhydrous lithium chloride (1.479 g, 34.5 mmol) were immediately added to obtain a dark suspension. The resulting mixture was stirred again at -78°C for 15 minutes. Finally, cyclopropanecarbonyl chloride (5.340 mL, 57.5 mmol) was added dropwise over 5 min (maximum temperature reached -68°C). The resulting mixture was stirred at -78°C for 1 hour, warmed to room temperature and stirred for 30 minutes to obtain a brown slurry. The reaction mixture was cooled to -78°C and slowly quenched with 20 ml of methanol. The resulting mixture was allowed to reach room temperature and the resulting suspension was filtered through celite. A saturated aqueous solution of ammonium chloride and ethyl acetate was added to the filtrate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure at 40°C. The crude material was purified by silica gel chromatography to give methyl 3-(cyclopropanecarbonyl)-5-(trifluoromethyl)benzoate.

1H NMR (400 MHz, chloroform-d) δ ppm: 1.16-1.22 (m, 2H), 1.35 (quin, J=3.76 Hz, 2H), 2.74 (tt, J ₁ =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).

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

Methyl 3-(cyclopropanecarbonyl)-5-(trifluoromethyl)benzoate (5.5 g, 20 mmol) was taken up with 2,2-difluoro-1,3-dimethylimidazolidine (36 ml, 280 mmol) under argon to give a light yellow solution. The resulting mixture was stirred for 5 hours at 110°C to obtain a light brown solution. The reaction mixture was cooled to room temperature and added dropwise to 1.0 L of vigorously stirred saturated aqueous sodium hydrogen carbonate solution at 0°C (temperature maintained below 10°C). The resulting mixture (pH 8-9) was then extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure at 50°C. The crude material was purified by silica gel chromatography to give methyl 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoate.

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).

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

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

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

1H NMR (400 MHz, dimethylsulfoxyg-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).

LC-MS (method 1): retention time 1.03 min, mass/charge 279 [M-H] ^- .

Preparation of methyl 2-(1-cyano-2-ethoxy-2-oxoethyl)-6-(trifluoromethyl)pyridine-4-carboxylate (intermediate I15)

Methyl 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (1.05 g, 4.40 mmol) was dissolved in dimethyl sulfoxide (13.2 ml). Ethyl 2-cyanoacetate (0.702 mL, 6.60 mmol), potassium carbonate (1.535 g, 11.00 mmol) and tetrabutylammonium bromide (0.145 g, 0.440 mmol) were then added sequentially at room temperature. The resulting suspension was stirred for 1 hour at 90°C and then stirred overnight at room temperature. The reaction mass was diluted with 50 ml of water and 100 ml of ethyl acetate, cooled to 0-10°C and slowly quenched with 1 N. hydrochloric acid using a dropping funnel to pH 3. The aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure at 50°C. The crude material was purified by silica gel chromatography with ethyl acetate in cyclohexane to give methyl 2-(1-cyano-2-ethoxy-2-oxoethyl)-6-(trifluoromethyl)pyridine-4-carboxylate.

1H 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).

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

Preparation of methyl 2-(cyanomethyl)-6-(trifluoromethyl)pyridine-4-carboxylate (116) o

(116)

Sodium chloride (0.299 g, 5.06 mmol) in water (10 ml). The resulting mixture was stirred for 4 hours at 95°C. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were dried over sodium sulfate, filtered and compacted under reduced pressure to give methyl 2-(cyanomethyl)-6-(trifluoromethyl)pyridine-4-carboxylate, which was used without further purification.

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

LC-MS (method 1): retention time 0.89 min, mass/charge 243 [M-H] ^- .

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

(P7)

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

^1H 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).

LC-MS (method 1): retention time 0.89 min, mass/charge 255 [M-H] ^- .

Preparation of methyl 3-(cyanomethyl)-5-(trifluoromethyl)benzoate (intermediate I18)

^F (US)

Methyl 3-bromo-5-(trifluoromethyl)benzoate (0.600 g, 2.08 mmol) was dissolved in N,N-dimethylformamide (4.2 ml). (Trimethylsilyl)acetonitrile (0.862 mL, 6.23 mmol) was added dropwise using a syringe. The solution was degassed under Ar atmosphere for 5 min. ZnF ₂ (0.130 g, 1.25 mmol), Xantphos (0.0481 g, 0.0831 mmol) and Pd ₂ (dba) ₃ (0.0384 g, 0.0415 mmol) were then added. The resulting black suspension was stirred at 100°C for 22 hours, then cooled to room temperature. The mixture was concentrated under reduced pressure at 50°C. The crude material was purified by silica gel chromatography using ethyl acetate in cyclohexane to give methyl 3-(cyanomethyl)-5(trifluoromethyl)benzoate.

1H 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)

- 54 045353 ppm.

LC-MS (method 1): retention time 0.92 min, mass/charge 242 [M-H] ^- .

Preparation of methyl 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoate (intermediate I19)

Methyl 3-(cyanomethyl)-5-(trifluoromethyl)benzoate (2.15 g, 7.07 mmol) was dissolved in N,N dimethylformamide (32.3 ml). Cesium carbonate (7.13 g, 21.2 mmol) was added to the stirred solution and the mixture was stirred at room temperature for 10 minutes. 1,2-dibromoethane (0.68 ml, 7.78 mmol) was added and the mixture was stirred at 60°C for 3 hours, then cooled to room temperature. Water (30 ml) was added, then the aqueous layer was extracted with ethyl acetate (60 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate in hexanes) to give methyl 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoate.

^1H 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.

Preparation of 3-(1-cyanocyclopropyl)-5-(trifluoromethyl)benzoic acid (intermediate I20)

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 was added. hydrochloric acid to 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.

^1H 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), 1.841.93 (2H, m), 1.50-1.60 (2H, m), ppm.

LC-MS (method 1): retention time 0.86 min, mass/charge 254 [M-H] ^- .

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

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 in nitrogen atmosphere. The resulting brown reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with a 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.

1H NMR (400 MHz, DMSO-d) δ ppm: 7.78-7.88 (m, 2H), 7.71 (s, 1H), 5.52 (d, 1H), 4.81 (m, 1H), 1.35 (d, 3H).

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

Pyridinium chlorochromate (5.05 g, 23.4 mmol) was added portionwise 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 resulting brown reaction mixture was stirred at room temperature for 2 hours.

- 55 045353

The reaction mixture was filtered through a pad of celite, then the filtrate was evaporated under reduced pressure. The crude residue was purified by flash silica gel chromatography (eluting with ethyl acetate in hexanes) to give 1-[3-bromo-5-(trifluoromethyl)phenyl]ethanone as a colorless oil.

1H NMR (400 MHz, DMSO-d) δ ppm: 8.38 (1H, s), 8.26 (1H, s), 8.19 (1H, s), 2.69 (s, 1H).

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

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

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

1H 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).

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

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. Methyl iodide (371 mg, 2.62 mmol) was added dropwise and the resulting mixture was stirred at 0°C for 1 hour. A 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 silica gel chromatography (ethyl acetate in hexanes gradient) to give 1-bromo-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzene as a colorless liquid.

^1H NMR (400 MHz, DMSO-d) δ ppm: 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).

Preparation of methyl-3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoate (I3 8)

The autoclave was charged with 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 ). The reaction mixture was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (353 mg, 0.483 mmol) was added.

The contents of the autoclave were 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 celite. 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 by flash chromatography

- 56 045353 on silica gel (gradient of ethyl acetate in hexanes) to obtain methyl 3-(1-methoxycyclopropyl)-5(trifluoromethyl)benzoate in the form of a pale yellow liquid.

^1H 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).

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

Methyl 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoate (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 2 N was added. hydrochloric acid at 0°C. The resulting precipitate was filtered off, washed with water and dried to obtain 3-(1-methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid as a white solid.

1H 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).

Preparation of 2-chloro-5-(2,2-difluoroethoxy)pyrimidine

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 hours before cooling to room temperature. It was then poured into a mixture of ice and cold water and extracted twice with ethyl acetate (200 ml in each case). 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 hexanes) to give 2-chloro-5-(2,2-difluoroethoxy)pyrimidine.

LC-MS (method 1): mass/charge 195.1 [M+H]+.

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

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

1H NMR (400 MHz, chloroform-d) δ ppm: 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).

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

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Tributyl-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]stannane (1.00 g, 2.00 mmol) was dissolved in toluene (15 ml), then 1-(3-chloropyrazin-2-yl) was added )ethanone ([CAS: 121246-90-0] 0.439 g, 2.52 mmol). The mixture was purged with argon for 5 min, 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 in for 4 hours. 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, 0-100% ethyl acetate in hexanes) to give 1-[3-[5-(2,2difluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone. LC-MS (method 1): mass/charge 281.1 [M+H] ⁺ .

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

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

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 in water (5.0 mL) and sodium cyanoborohydride (0.0538 g, 0.856 mmol) were added and the reaction mixture was stirred at reflux for 18 hours. 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, 0-50% acetonitrile in water) to give 1-[3-[5-(2,2-difluoroethoxy)pyrimidine-2- yl]pyrazin-2-yl]ethanamine. LCMS (method 1): mass/charge 282.1 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ ppm: 8.80-9.00 (m, 4H), 6.50 (tt, 1H), 4.90 (m, 1H), 4.78 (td, 2H), 1.45 (d, 3H).

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

To a stirred 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) at 0° C, 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,K- diisopropylethylamine (0.0551 g, 0.427 mmol). After addition, the reaction mixture was allowed to stir at room temperature for 5 hours. The reaction mixture was diluted with water (30 ml) and extracted twice with dichloromethane (150 ml in each case). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase chromatography (0-80% acetonitrile in water) to give 2-(1cyanocyclopropyl)-N-[1-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]pyrazine -2-yl]ethyl]-6-(trifluoromethyl)pyridin-4-carboxamide.

^1H NMR (400 MHz, DMSO-d6) δ ppm: 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).

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LC-MS (method 1): retention time 7.32 min, mass/charge 520.2 [M+H]+. Preparation of 2-chloro-5-(difluoromethoxy)pyrimidine

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 hours before cooling to room temperature and diluted with ethyl acetate. This organic layer was washed twice with cold water (100 ml in each case), 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 hexanes) to give 2-chloro-5-(difluoromethoxy)pyrimidine.

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

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

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 min, then tetrakis(triphenylphosphine)palladium(0) (778 mg, 0.673 mmol) was added and the reaction mixture was purged with argon again for an additional 2 min. The resulting reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to 0°C, diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (eluting with ethyl acetate in n-hexane) provided tributyl-[5-(difluoromethoxy)pyrimidin-2-yl] stannane.

1H NMR (400 MHz, CDCl ₃ ): 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.

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

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 min. Tetrakis(triphenylphosphine)palladium(0) (382 mg, 0.331 mmol) and copper iodide (252 mg, 1.32 mmol) were added to the reaction mixture and again purged with argon for another 2 min. The resulting reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to 0°C, diluted with water (100 ml) and extracted with ethyl acetate (2x100 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 ethyl acetate in hexanes) to give 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethenone as a light brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.80-9.00 (m, 4H), 7.50 (t, 1H), 2.65 (s, 3H).

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

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To a solution of 1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone (1.70 g, 6.39 mmol) in saturated ammonium acetate in ethanol (130 ml) was added cyanoborohydride sodium (1.19 g, 19.2 mmol) and 30% aqueous ammonia solution (50 ml). The mixture was stirred at reflux for 16 hours, 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.80-9.10 (m, 4H), 7.51 (t, 1H), 4.88 (m, 1H), 1.50 ( d, 3H).

Preparation of 3-cyclopropyl-N-[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-5-(trifluoromethyl)benzamide (compound P7)

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

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 ) a solution of the previously obtained acid chloride in dichloromethane (3 ml) was added dropwise over 5 minutes. After addition, the reaction mixture was stirred for 2 hours at room temperature. It was cooled to 0°C, quenched with water (10 ml) and extracted twice with ethyl acetate (50 ml in each case). 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.

1H 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).

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

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

To a solution of 3-[cyclopropyl(difluoro)methyl]-5-(trifluoromethyl)benzoic acid (4.72 mg, 0.0168 mmol) in toluene (2.0 ml), thionyl chloride (0.0037 ml, 0.051 mmol) was added dropwise at room temperature. The reaction mixture was stirred under 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) followed by the addition of triethylamine (0.0071 ml, 0.051

- 60 045353 mmol). The reaction mixture was stirred at room temperature for 2 hours, 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 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.

1H NMR (400 MHz, 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, 1H), 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.

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

To a solution of 3-(trifluoromethyl)-5-(trifluoromethylsulfonyl)benzoic acid (121 mg, 0.337 mmol) in toluene (2.0 mL), thionyl chloride (0.0737 mL, 1.01 mmol) was added dropwise at room temperature. The reaction mixture was stirred under 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) was added ml) followed by the addition of triethylamine (0.142 ml, 1.01 mmol). The reaction mixture was stirred at room temperature for 2 hours, 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 ethyl acetate in hexanes) to give N[1-[3-[5-(difluoromethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethyl]-3-(trifluoromethyl) -5-(trifluoromethylsulfonyl)benzamide as an off-white solid.

'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.

Preparation of 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine

To a solution of 6-bromopyridin-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, 2.2 ,2trifluoroethyltrifluoromethanesulfonate (29.3 g, 126 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (eluting with ethyl acetate in n-hexane) provided 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine.

1H NMR (400 MHz, CDCl ₃ ): δ = 8.15 (d, 1H), 7.45 (d, 1H), 7.2 (dd, 1H), 4.4 (q, 2H), ppm.

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

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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 again for another 2 minutes. The resulting reaction mixture was stirred at 100°C for 48 hours. 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. Purification of the crude material by flash chromatography on silica gel (eluting with ethyl acetate in n-hexane) provided tributyl-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]stannane.

1H NMR (400 MHz, CDCl ₃ ): 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.

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

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 reaction mixture was stirred at 100°C for 2 hours. 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. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in n-hexane) provided 1-[3-[5-(2,2,2-trifluoroethoxy)2-pyridyl]pyrazin-2-yl]ethanone.

1H NMR (400 MHz, 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.

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

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

1H NMR (400 MHz, 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.

Receipt

2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazin-2 yl]ethyl]-6-(trifluoromethyl)pyridin-4- carboxamide (compound P23)

To a solution of 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (85.9 mg,

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0.302 mmol) in toluene (5 ml), thionyl chloride (66 μl, 0.0905 mmol) was added 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 resulting residue was dissolved in dichloromethane (10 ml) and added at 0°C to a solution of 1-[3-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]pyrazin-2-yl]ethanamine (100 mg, 0.302 mmol) and triethylamine (0.127 ml, 0.905 mmol) in dichloromethane (10 ml). 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. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in n-hexane) provided 2-(1-cyanocyclopropyl)-N-[1-[3-[5(2,2,2-trifluoroethoxy)-2-pyridyl ]pyrazin-2-yl]ethyl]-6-(trifluoromethyl)pyridin-4-carboxamide.

^1H NMR (400 MHz, 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.

Preparation of 2-chloro-5-(2,2,2-trifluoroethoxy)pyrimidine

Cesium carbonate (3.2 g, 10 mmol) was added to a solution of 2-chloropyrimidin-5-ol (1.0 g, 7.7 mmol) in K,K-dimethylformamide (7.7 mL). 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, then extracted with ethyl acetate. The combined organic layers were washed with water four times, then with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in n-hexane) provided 2-chloro-5-(2,2,2trifluoroethoxy)pyrimidine as a light yellow oil.

1H NMR (400 MHz, Chloroform) δ ppm 4.46-4.52 (m, 2H), 8.40 (s, 2H), ¹⁹ F NMR (377 MHz, Chloroform) δ ppm -73.74 (s) .

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

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, then tetrakis(triphenylphosphine)palladium(0) (0.544 g, 0.470 mmol) was added and the reaction mixture was purged with argon again for another 5 minutes. The resulting reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the crude material by neutral alumina chromatography (eluting with ethyl acetate in n-hexane) provided tributyl-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]stannane.

1H NMR (400 MHz, CDCl ₃ ): 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

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

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

- 63 045353 argon for 5 min, then copper(1) iodide (0.0815 g, 0.428 mmol) and [1,1bis(diphenylphosphino)ferrocene]dichloropalladium(11) (1.57 g, 2.14 mmol) were added . The reaction mixture was 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. Purification of the crude material by silica gel flash chromatography (eluting with ethyl acetate in n-hexane) provided 1-[3-[5(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanone. mass/charge = 299.1 [M+N] ⁺ .

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

(130)

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) sodium cyanoborohydride (0.354 g, 5.63 mmol) and ammonia (30% in water, 30 ml) were added at room temperature. The reaction mixture was stirred under reflux for 18 hours. After cooling to room temperature, the mixture was washed with dichloromethane. The aqueous layer was concentrated in vacuo. Purification of the crude material by reverse phase chromatography (eluting with acetonitrile in water) provided 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2-yl]ethanamine.

1H NMR (400 MHz, 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.

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

(P34)

To a stirred solution of 1-[3-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]pyrazin-2yl]ethanamine (30.0 mg, 0.100 mmol) in N,N-dimethylformamide (2.0 ml) 2-(1cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (0.0257 g, 0.100 mmol), propanephosphonic anhydride (T3P®) (0.0957 g, 0.301 mmol) and N,N were added -diisopropylethylamine (0.0389 g, 0.301 mmol) at 0°C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (30 ml) and extracted twice with dichloromethane. The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo. Purification of the crude material by reverse phase chromatography (C18 column, gradient of acetonitrile in water) provided 2-(1-cyanocyclopropyl)-N-[1-[3-[5-(2,2,2trifluoroethoxy)pyrimidin-2-yl ]pyrazin-2-yl]ethyl]-6-(trifluoromethyl)pyridin-4-carboxamide as an off-white solid.

1H NMR (400 MHz, 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.

Preparation of 6-tributylstanylpyridine-3-carbonitrile

To a solution of 6-chloropyridine-3-carbonitrile (250 mg, 1.80 mmol) in toluene (10 ml) was added hexane-butyldithine (1.00 ml, 1.98 mmol). The reaction mixture was purged with argon for 2 min. Tetrakis(triphenylphosphine)palladium(0) (146 mg, 0.126 mmol) was then added and the mixture was again purged with argon for another 2 min. The resulting reaction mixture was heated to 130°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. Purification of the crude material by neutral alumina chromatography (eluting with ethyl acetate in hexane) provided 6-tributylstannylpyridine-3-carbonitrile.

1H NMR (400 MHz, 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.

Preparation of 6-(3-acetylpyrazin-2-yl)pyridin-3-carbonitrile (I21)

To a solution of 6-tributylstannylpyridin-3-carbonitrile (24.0 g, 48.8 mmol) in toluene (600 ml) was added 1-(4-chloropyrimidin-5-yl)ethanone (9.18 g, 52.7 mmol) and copper(I) iodide (1.86 g, 9.77 mmol). The reaction mixture was purged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (2.82 g, 2.44 mmol) was then added. The reaction mixture was heated to 95°C and stirred for 5 hours. After cooling to room temperature, it was filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (eluting with ethyl acetate in hexane) provided 6-(3acetylpyrazin-2-yl)pyridin-3-carbonitrile.

1H NMR (400 MHz, 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.

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

To a solution of 6-(3-acetylpyrazin-2-yl)pyridin-3-carbonitrile (0.200 g, 0.803 mmol) in a saturated solution of ammonium acetate in ethanol (30 ml) at room temperature was added an aqueous solution of ammonia (20 ml) and sodium cyanoborohydride (154 mg, 2.41 mmol). The reaction mixture was heated to reflux and stirred for 12 hours. After cooling to room temperature, it was concentrated under reduced pressure. Purification of the crude material by reverse phase chromatography (eluting with acetonitrile in water) provided 6-[3(1-aminoethyl)pyrazin-2-yl]pyridin-3-carbonitrile.

1H NMR (400 MHz, 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.

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

To a solution of 3-[cyano(cyclopropyl)methyl]-5-(trifluoromethyl)benzoic acid (0.130 g, 0.459 mmol) in toluene (20 mL), thionyl chloride (0.134 mL, 1.83 mmol) was added dropwise 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 (10 ml) and added at 0°C to a solution of 6-[3-(1-aminoethyl)pyrazin-2-yl]pyridin-3-carbonitrile (0.126 g, 0.505 mmol) and triethylamine (0.258 ml , 1.83 mmol) in dichloromethane (5 ml). 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. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in hexane) provided 3-(1-cyanocyclopropyl)-N-[1-[3-(5cyano-2-pyridyl)pyrazin-2-yl]ethyl]-5 -(trifluoromethyl)benzamide.

'H NMR (400 MHz, 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), 1.601.75 (m, 5H), ppm.

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

Under argon, thionyl chloride (0.14 mL, 1.93 mmol) was added dropwise to a stirred solution of 2-(1-cyanocyclopropyl)-6-(trifluoromethyl)pyridine-4-carboxylic acid (117, 130 mg, 0.482 mmol) in toluene (20 ml) at 0°C. The solution was heated at 90°C for 2 hours, then the reaction mixture was concentrated in vacuo. The residue was diluted in dichloromethane (10 ml) and added to a stirred solution of 6-[3-(1-aminoethyl)pyrazin-2-yl]pyridin-3-carbonitrile (121 mg, 0.482 mmol) and triethylamine (0.271 ml, 1.93 mmol) in dichloromethane (10 ml) at 0°C. The reaction mixture was stirred for 2 hours at room temperature, 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 reverse phase chromatography (C18 column, gradient of acetonitrile in water) to give 2-(1-cyanocyclopropyl)-N-[1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl] -6-(trifluoromethyl)pyridine-4-carboxamide as a white solid.

1H NMR (400 MHz, 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.

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

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

Ν

(Ρ50)

Thionyl chloride (0.108 ml, 1.48 mmol) was added dropwise to a stirred solution of 3-(1methoxycyclopropyl)-5-(trifluoromethyl)benzoic acid (139, 130 mg, 0.493 mmol) in toluene (3 ml) at 0°C. The reaction mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, it was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2 ml) and added to a solution of 6-[3-(1-aminoethyl)pyrazin-2-yl]pyridin-3-carbonitrile (0.125 g, 0.542 mmol) and triethylamine (0.208 ml, 1.48 mmol) in dichloromethane (2 ml). 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. Purification of the crude material by reverse phase chromatography (C18 column, gradient of acetonitrile in water) provided N-[1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl]-3-(1-methoxycyclopropyl) -5-(trifluoromethyl)benzamide as an off-white solid.

1H NMR (400 MHz, 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), 7.97 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H) , 5.71-5.82 (m, 1H), 3.13 (s, 3H), 1.68 (d, 2H), 1.201.28 (m, 2H), 1.08-1.12 (m , 2H), ppm.

- 66 045353

Preparation of 1-(3-chloropyrazin-2-yl)ethanamine

Ammonium acetate (0.995 g, 12.8 mmol) and sodium cyanoborohydride ( 0.0591 g, 0.894 mmol). 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-chloropyrazin-2-yl)ethanamine.

^1H NMR (400 MHz, CDCI3) δ = 8.49 (d, 1H), 8.26 (d, 1H), 4.56 (q, 1H), 1.95 (br s, 2H), 1. 44 (d, 3H), ppm.

Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethanamine (I34)

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 Novozym® 435 (240 mg), followed by ethyl methoxy acetate (1.44 ml, 12.0 mmol) at room temperature.

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 (elution with a gradient of methanol in dichloromethane) to give (1S)1-(3-chloropyrazin-2-yl)ethanamine.

^1H NMR (400 MHz, CDC13) δ = 8.49 (d, 1H), 8.27 (d, 1H), 4.56 (q, 1H), 1.73 (br s, 2H), 1. 44 (d, 3H), ppm.

[a]D ²⁰ : -32.3° (c: 1.157, CHCl ₃ ).

Preparation of (1R)-1-(3-chloropyrazin-2-yl)ethanol (I26) but ci

Ιί| (126)

1-(3-Chloropyrazin-2-yl)ethanone (157 mg, 1.00 mmol) was dissolved in dichloromethane (10.0 mL) and the flask was evacuated and filled with argon three times. RuBF4[(R,R)-TsDPEN](p-cymene) (0.0362 g, 0.0526 mmol) was then added. A cooled solution of triethylamine (0.348 ml, 2.50 mmol) and formic acid (0.160 ml, 4.29 mmol) were added dropwise to the reaction mixture, which was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo.

The crude material was purified by flash silica gel chromatography (ethyl acetate/cyclohexane gradient elution) to give (1R)-1-(3-chloropyrazin-2-yl)ethanol.

1H NMR (400 MHz, CDCl ₃ ) δ = 8.49 (d, 1H), 8.34 (d, 1H), 5.18 (m, 1H), 3.81 (d, 1H), 1.52 (d, 3H), ppm.

Chiral SFC (method 2): 1.98 min. (minor enantiomer), 2.55 min. (main enantiomer); ee = 85%

Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethanamine (I34)

(1R)-1-(3-chloropyrazin-2-yl)ethanol (87.8 mg, 0.554 mmol) was dissolved in tetrahydrofuran (1.9 ml). Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.66 mmol) was added dropwise to the reaction mixture, followed by the addition of diphenylphosphinazide (0.130 mL, 0.585 mmol). The reaction mixture was stirred at room temperature. over 19 hours. Tetrahydrofuran (1.4 ml) was added followed by triphenylphosphine (179.4 mg, 0.677 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (0.15 ml) was added and the reaction mixture was stirred at room temperature for 46 hours. The reaction mixture was concentrated to a volume of 1 ml, then diluted with dichloromethane. 1 M hydrochloric acid was added, then the aqueous layer was washed with dichloromethane. The aqueous layer was made alkaline 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 silica gel chromatography (elution with a gradient of methanol in dichloromethane) to give (1S)-1-(3-chloropyrazin-2yl)ethanamine.

1H NMR (400 MHz, CDCl,) δ = 8.49 (d, 1H), 8.27 (d, 1H), 4.56 (q, 1H), 1.84 (s, 2H), 1. 44 (d, 3H), ppm. [a]D ²⁰ : -26.0° (c: 0.960, CHCl ₃ ).

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

- 67 045353

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-ethyldiisoopropylamine (1.26 ml, 7.21 mmol), 1-hydroxybenzotriazole (50.8 mg, 0.361 mmol) and N,N-dicylohexylcarbodiimide (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 and extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (eluting with methanol in dichloromethane) provided (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2 phenylacetamide and ( 2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenylacetamide. The relative stereochemical configuration of (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2phenylacetamide was determined by X-ray crystallography (via crystallization from acetonitrile/water). Analytical data for (2R)-N-[(1R)-1-(3-chloropyrazin-2-yl)ethyl]-2hydroxy-2-phenylacetamide: LCMS: Rt 0.74, wt/charge = 291 (M+H +).

Preparation of (1S)-1-(3-chloropyrazin-2-yl)ethanamine hydrochloride

A solution of (2R)-N-[(1S)-1-(3-chloropyrazin-2-yl)ethyl]-2-hydroxy-2-phenylacetamide (0.93 g, 3.2 mmol) in hydrochloric acid (32% in water, 13 ml) was heated to reflux temperature and stirred for 2 hours. After cooling to room temperature, the reaction mixture was made alkaline with 3 N. sodium hydroxide and diluted and extracted with ethyl acetate. The aqueous layer was freeze-dried overnight and the resulting solid was suspended in acetone. The suspension was filtered and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in ethyl acetate and 1 N was added. hydrochloric acid. A precipitate appeared, it was filtered and dried under reduced pressure to obtain the desired product. LCMS: Rt 0.19, mass/charge = 158 (M+H+).

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

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), cyclopropanecarboxylaldehyde (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. A 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.

^1H 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.

[a]D ²⁰ = -54° (c 0.327, CHCl ₃ ).

Preparation of tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-2-hydroxy-1-methyl-3-oxopropyl]carbamate

A solution of tert-butyl-N-[(1S)-1-methyl-2-oxoethyl]carbamate (CAS 79069-50-4, 1.07 g, 6.18 mmol) in dichloromethane (12 ml) was prepared in a round bottom flask. The air was evacuated from the flask and filled with argon three times. 2-(3-Benzyl-4-methylthiazol-3-yl-5-yl)ethanol bromide (0.388 g, 1.24 mmol), 5-bromopyridine-2-carbaldehyde (CAS 31181-90-5, 1 .81 g, 9.27 mmol) and dichloromethane (6 ml) followed by N,N-diisopropylethylamine (2.16 ml, 12.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. It was extinguished by saturation. aq. ammonium chloride solution and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in cyclohexane) provided tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-2-hydroxy-1methyl- 3-oxopropyl]carbamate in the form of an orange resin. LCMS: Rt 0.98, mass/charge = 359-361 (M+H+) (bromine pattern);

^1H NMR (400 MHz, CDCl ₃ ) 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=2.20 Hz, 1H), ppm.

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

To a solution of tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-2-hydroxy-1-methyl-3-oxopropyl]carbamate (15.2 g, 42.3 mmol) in dichloromethane (100 ml) and dimethyl sulfoxide (20 ml) at 0°C, N,Ndiisopropylethylamine (21.8 ml, 127 mmol, 3.00 eq.) and sulfur trioxide pyridine complex (13.9 g, 84.6 mmol) were added , 2.00 eq.) as two servings. The reaction mixture was stirred at 0°C for 1 hour. It was quenched with water and diluted with dichloromethane and 1 N. 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. Purification of the crude material by flash chromatography on silica gel (eluting with ethyl acetate in cyclohexane) provided tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxopropyl ]carbamate in the form of an orange oil.

^1H NMR (400 MHz, CDCl ₃ ) 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=1.83 Hz, 1H), ppm.

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

To a solution of tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxopropyl]carbamate (375 mg, 1.05 mmol) in ethanol (22 ml ) ethylenediamine (0.36 mL, 5.24 mmol) was added. The reaction mixture was stirred at room temperature for 60 hours in the presence of air. It was concentrated under reduced pressure. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in cyclohexane) provided tert-butyl-N-[(1S)-1-[3-(5bromo-2-pyridyl)pyrazin-2-yl]ethyl]carbamate in in the form of a colorless resin. LCMS: Rt 1.09, mass/charge = 379-381 (M+H+) (bromine pattern);

^1H NMR (400 MHz, CDCl ₃ ) 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, 1.10 Hz, 1H), ppm.

Chiral SFC (method 1): 1.80 min. (main enantiomer), 1.11 min. (minor enantiomer); ee = 92%.

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

To a solution of tert-butyl-N-[(1S)-3-(5-bromo-2-pyridyl)-1-methyl-2,3-dioxopropyl]carbamate (500 mg, 0.894 mmol) in isopropanol (13.4 ml ) 2-aminoacetamidine dihydrobromide (1.21 g, 4.11 mmol) was added. Potassium acetate (266 mg, 2.68 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 hours in the presence of air. The reaction mixture was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the crude material by reverse phase chromatography (C18, eluting with ACN in water) provided tert-butyl-N-[(1S)-1-[6-amino-3-(5-bromo-2-pyridyl)pyrazine-2 - 69 045353 yl]ethyl]carbamate.

LCMS: Rt 1.00, mass/charge = 394-396 (M+H+) (bromine pattern);

'H NMR (600 MHz, CDCl ₃ ) δ = 1.45 (br s, 9H), 1.47 (d, J=6.7 Hz, 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=2.0 Hz, 1H) , 7.90 (s, 1H), 8.72 (s, 1H), ppm.

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

Degassed 1,4-dioxane (9.20 ml) was added to a mixture of tert-butyl-N-[(1S)-1-[3-(5-bromo-2pyridyl)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) at room temperature under argon. 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, 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-pyridyl)pyrazin-2yl]ethyl]carbamate in as a white solid.

'H NMR (400 MHz, CDCl ₃ ) 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.

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

Trifluoroacetic acid (0.69 ml, 8.7 mmol) was added to a solution of tert-butyl N-[(1S)-1-[3-(5cyano-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]pyridin-3-carbonitrile. LCMS (method 1): Rt 0.28, mass/charge = 226 [M+H] ⁺ .

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

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

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. A saturated aqueous sodium carbonate solution was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification of the crude material by flash silica gel chromatography (eluting with ethyl acetate in cyclohexane) provided 6-[3-[(1S)-1-(cyclopropylmethylamino)ethyl]pyrazin-2-yl]pyridin-3-carbonitrile as a yellow oil.

- 70 045353 ¹ H NMR (400 MHz, CDCl ₃ ) 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.

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

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

1H NMR (400 MHz, 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), 1.53-1.68 (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, mass/charge = 542 [M+H]+;

[a] _D ²⁰ : +152° (c: 0.477, CHCl ₃ ).

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

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

1H NMR (400 MHz, CDCl ₃ ) 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, mass/charge = 488 [M+H]+; [a] _D ²⁰ : +145° (c: 0.707, CHCl ₃ ).

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Table P. Examples of compounds of formula I

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P8 3-(1-cyano-1-methyl ethyl) -N- [ 1 - [3 [5 -(difluoromethoxy)pyrimidin2 -yl] pyrazin-2 -yl] ethyl] -5 (trifluoromethyl)benzamide F^O A ^{o n} iL· J F—I—F 130-140 P9 3 - (1 -cyano -1 -methyl ethyl) -N- [ 1 - [3 (5 -cyano -2 -pyridyl) pyrazin-2 yl] ethyl]-5 (trifluoromethyl)benzamide A F--F 135-140 PIO 3 - (1 -cyano -1 -methyl ethyl) -N- [ 1 - [3 [5-(2,2,2-trifluoroethoxy)-2pyridyl] pyrazin-2 -yl] ethyl] -5 (trifluoromethyl)benzamide fAf F—|— F F 120 -125 Pll M-[1-[3-[5-(difluoromethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-3 (trifluoromethyl)-5 (trifluoromethylsulfonyl)benzamide ^F ->-F ^o F O 180-190

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P16 2-(1-cyanocyclopropyl)-C-[1[3-(5-cyano-2-pyridyl)pyrazine2-i l] eti l]-6(trifluoromethyl)pyridine-4carboxamide 150-155 P17 M-[1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl]-2cyclopropyl-6(trifluoromethyl)pyridine-4carboxamide fXf ν ηΙ. DDT Dm 210-215 P18 M-[1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl]-3 [cyclopropyl(difluoro)methyl]-5(trifluoromethyl)benzamide Π from ^β 160 -165 P19 N-[l-[3-[5- (difluoromethoxy)pyrimidin-2yl] pyrazin-2 -yl] ethyl] -3 (trifluoromethyl) -5 - (trifluoromethylsulfonyl)benzamide γΎ F O 130-135

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P24 3 -(1-cyanocyclopropyl)-K-[1 [3-[5-(2,2,2-trifluoroethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide F^F fJ? it ⁿ md 140 -145 P25 3 -(1-cyanocyclopropyl)-C-[1[3-(5-cyano-2-pyridyl)pyrazin2-yl]ethyl]-5(trifluoromethyl)benzamide N II Xi F O X 170 -175 P26 3-cyclopropyl-K-[1-[3-[5-(2,2difluoroethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide 1 SH'TA'H'' Ξ—* \ 100 -105 P27 3-cyclopropyl-K-[1-[3-[5-(2,2,2trifluoroethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide F^F . F O X' 110-115

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P28 N-[l-[3-[5-(2,2difluoroethoxy)pyrimidin-2yl]pyrazin-2-yl]ethyl]-3 (trifluoromethyl)-5 (trifluoromethylsulfonyl)benzamide 185-188 P29 3 -[cyclopropyl (difluoro)methyl] N-[l-[3-[5- (difluoromethoxy)pyrimidin-2yl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide A vx ^F 120 -125 P30 3 -[cyclopropyl(difluoro)methyl] M-[1-[3-[5-(2,2-difluoroethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide F^F Λ F О VtAo ^F 130-135 P31 3 -[cyclopropyl(difluoro)methyl] - N-[l-[3-[5-(2,2,2- trifluoroethoxy)-2pyridyl] pyrazin-2 -yl] ethyl] -5 (trifluoromethyl)benzamide F^F ^_X-F F 130-135

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P32 3 -(1 -cyanocyclopropyl)-K-[1 [3-[5(difluoromethoxy)pyrimidin-2yl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide F^O A 100 -105 RZZ 3 -(1-cyanocyclopropyl)-K-[1 [3-[5-(2,2-difluoroethoxy)-2pyridyl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide %ό. 130-135 P34 2-(1-cyanocyclopropyl)-K-[1 [3-[5-(2,2,2- trifluoroethoxy)pyrimidin-2yl] pyrazin-2 -yl] ethyl] -6(trifluoromethyl)pyridine-4carboxamide fXf A NyJ ^H 68-72 P35 2-cyclopropyl-K-[1-[3-[5-(2,2difluoroethoxy)pyrimidin-2yl]pyrazin-2-yl]ethyl]-6(trifluoromethyl)pyridine-4carboxamide fAf 132-135

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P41 3-cyclopropyl-N-[1-[3-[5(difluoromethoxy)pyrimidin-2yl]pyrazin-2-yl]ethyl]-5 (trifluoromethyl)benzamide ό F ft T 90-95 P42 M-[(18)-1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl]-3 [cyclopropyl (difluoro)methyl]-5 (trifluoromethyl)benzamide y s ιΦ y ⁿ i 1.13 488.0 1 P43 K-[(18)-1-[3-(5-cyano-2pyridyl)pyrazin-2-yl]ethyl]-3 [cyclopropyl(difluoro)methyl]-N(cyclopropylmethyl)-5(trifluoromethyl)benzamide 9^7 v if 1.21 542.6 1 P44 3 -(1-cyanocyclopropyl)-C-[1[3-(5-cyano-2-pyridyl)pyrazin2-yl]ethyl]-5(difluoromethoxy)benzamide Ν II f Xlj n 140-150

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Table I. Table of intermediate compounds

(measured methyl-3-(trifluoromethyl)-5methyl-3-cyclopropyl-5(trifluoromethyl)benzoate

-cyclopropyl-6 (trifluoromethyl)pyridine-4carboxylic acid methyl-2-cyclopropyl-6(trifluoromethyl)pyridine-4carboxylate (trifluoromethyl)cyclopropyl benzoate

-cyclopropyl-5 (trifluoromethyl)benzoic methyl-3 -(trifluoromethyl)-5vinyl benzoate methyl-2-chloro-b(trifluoromethyl)pyridine-4carboxylate

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125 1-13-15-(2.2.2trifluoroethoxy)-2pyridyl]pyrazin-2yl]ethanone

126 (1C)-1-(3-chloropyrazin-2yl)ethanol

127 6-[3-(1-aminoethyl)pyrazin2 -yl]pyridin-3-carbonitrile

128 1-[3-[5-(2,2difluoroethoxy)pyrimidin-2yl]pyrazin-2-yl]ethanamine

0.40 159/160 1

[M+N] ⁺

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¹¹ 'H NMR (400 MHz, chloroform-d) δ ppm: 4.04 (s, 3H), 8.11 (s, 1H), 8.17 (d, J=1.10 Hz, 1H).

²⁾ 'H NMR (400 MHz, chloroform-d) δ ppm: 0.76-0.85 (m, 2H), 1.06-1.15 (m, 2H), 2.03 (tt, J' =8.39 Hz, J ₂ =5.00 Hz, 1 H3.96 (s, 3H), 7.52 (s, 1H), 7.91 (s, 1H), 8.08 (d, J= 0.73 Hz, 1H).

' ⁹ F NMR (377 MHz, chloroform-d) δ ppm: -62.75 (s, 3F).

³⁾ '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 ,6' Hz, 1H), 6.79 (dd, J'=17.42 Hz, J ₂ ='0.82 Hz, 1H), 7.82 (s, 'H), 8.19 (s, 1H), 8.24-8.29 (m, 'H).

⁴⁾ '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, 'H), 2.46-2.53 (m, 1H), 3.98 (s, 3H), 7.60 (s, 1H), 7.98 (s, 1H), 8.19 ( s, 1H).

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

⁶⁾ 'H NMR (400 MHz, Chloroform) δ ppm 4.07 (s, 3H), 8.43-8.51 (m, 'H), 8.70-8.80 (m, 'H), 8.84-8.91 (m, 1H).

' ⁹ F NMR (377 MHz, chloroform-d) δ ppm: -77.49 (s, 3F), -62.96 (s, 3F).

⁷⁾ 'H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ ppm: 8.68 (s, 2H), 8.71-8.76 (m, 1H), 13.33-15.22 (m, 1H ).

⁸⁾ 'H NMR (400 MHz, chloroform-d) δ ppm: '.16-1.22 (m, 2H), 1.35 (quin, J=3.76 Hz, 2H), 2.74 (tt , J'=7.84 Hz, J ₂ =4.45 Hz, 1H), 4.02 (s, 3H), 8.45 (d, J=0.73 Hz, 'H), 8.51 ( d, J=0.73 Hz, 1H), 8.86 (s, 'H).

⁹⁾ '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, 'H), 8.00 (d, J=0.73 Hz, 1H), 8.39 (s, 1H), 8.42 (s, 1H).

' ⁹ F NMR (377 MHz, chloroform-d) δ ppm: -98.40 (s, 3F), -62.81 (s, 2F).

' ⁰⁾ 'H NMR (400 MHz, chloroform-d) δ ppm: 4.05 (s, 3H), 4.13 (s, 2H), 8.24 (s, 1H), 8.26 (s, 1H).

^10'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).

' ²⁾ 'H NMR (400 MHz, chloroform-d) δ ppm: 8.23 ('H, s), 8.09 (1H, s), 7.79 (1H, s), 3.98 (3 H, s), 1.841.92 (2H, m), 1.47-1.57 (m, 2H).

' ³⁾ 'H NMR (400 MHz, chloroform-d) δ ppm: 8.60-9.90 ('H, br s), 8.29 ('H, s), 8.15 ('H, s ), 7.84 ('H, s), 1.84-1.93 (2H, m), '.50-1.60 (2H, m).

' ⁴⁾ 'H NMR (400 MHz, DMSO-d6) δ ppm: 8.90 (s, 'H), 8.70-8.90 (m, 3H), 6.48 (t, 1H), 4 .63 (td, 2H), 2.62 (s, 3H).

¹⁵⁾ 'H NMR (400 MHz, DMSO-d6) δ ppm: 8.80-9.00 (m, 4H), 7.50 (t, 1H), 2.65 (s, 3H).

' ⁶⁾ 'H NMR (400 MHz, DMSO-d6): δ ppm 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).

' ⁷⁾ 'H NMR (400 MHz, DMSO-d6): δ ppm 9.22 (s, 'H), 8.85-8.95 (m, 2H), 8.50-8.60 (m, 'H), 8.30-8.40 (m, 'H), 7.80-8.10 (br. s, 2H), 5.25-5.35 (m, 1H), '.52 ( d, 3H).

¹⁸⁾ 'H NMR (400 MHz, DMSO-d6) δ ppm: 8.80-9.00 (m, 4H), 6.50 (tt, 1H), 4.90 (m, 1H), 4.78 (td, 2H), 1.45 (d, 3H).

- 90 045353 ^{19) 1} H NMR (400 MHz, DMSO-d6) δ ppm: 8.80-9.10 (m, 4H), 7.51 (t, 1H), 4.88 (m, 1H), 1.50 (d, 3H).

^{20) 1H} NMR (400 MHz, DMSO-d6): δ ppm: 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).

^{21) 1H} NMR (400 MHz, DMSO-d6): δ ppm: 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).

^{22) 1H} NMR (400 MHz, chloroform-d) δ ppm -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).

²³⁾ 1H 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).

^{24) 1H} 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).

^{25) 1H} 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).

^{26) 1H} NMR (400 MHz, DMSO-d) δ ppm: 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).

The activity of the compositions according to the present invention can be significantly expanded and adapted to given circumstances by adding other insecticidal, acaricidal and/or fungicidal active ingredients. Mixtures of compounds of formula I with other insecticidal, acaricidal and/or fungicidal active ingredients may also have additional unexpected benefits, which may also be described more broadly as synergistic activity. For example, better plant tolerance, reduced phytotoxicity, the ability to control insects at different stages of their development or better parameters during their production, for example during grinding or mixing, during their storage or during their use.

Suitable additives to the active ingredients discussed herein 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, pyridylmethyleneamines derivatives, macrolides, neonicotinoids and preparations based on Bacillus thuringiensis.

The following mixtures of compounds of formula I with active ingredients are preferred (wherein the abbreviation TX means one 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 - D-27 and E-1 - E-27, as well as in Table P):

excipient selected from the group of substances consisting of petroleum oils (alternative name) (628) + TX, insect control active substance selected from abamectin + TX, acequinocyl + TX, acetamiprid + TX, acetoprol + TX, acrinatrine + TX, acinonapyra + TX, afidopyropene + TX, afoxolaner + TX, alanicarb + TX, allethrina + TX, alpha-cypermethrin + TX, alphamethrin + TX, amidoflumet + TX, aminocarb + TX, azocyclotine + TX, bensultap + TX, benzoximate + TX, benzpyrimoxane + TX, betacifluthrin + TX, beta-cypermethrin + TX, biphenazate + TX, bifenthrin + TX, binapacryl + TX, bioallethrin + TX, S)-cyclopentyl isomer bioallethrin + TX, bioresmethrin + TX, bistrifluron + TX, broflanilide + TX, broflutrinate + TX, bromophos-ethyl + TX, buprofezin + TX, butocarboxyme + TX, cadusafos + TX, carbaryl + TX, carbosulfan + TX, cartap + TX, CAS number: 1472050-04-6 + TX, CAS number: 1632218- 00-8 + TX, CAS number: 1808115-49-2 + TX, CAS number: 2032403-97-5 + TX, CAS number: 2044701-44-0 + TX, CAS number: 2128706-05-6 + TX, CAS number: 2249718-27-0 + TC, chlorantraniliprole + TC, chlordane + TC, chlorfenapyr + TC, chloroprallethrin + TC, chromafenozide + TC, clenpirine + TC, cloetocarb + TC, clothianidin + TC, 2-chlorophenyl-Nmethylcarbamate (CPMC) ) + TX, cyanophenphos + TX, cyantraniliprole + TX, cyclaniliprole + TX, cyclobutrifluram + TX, cycloprothrin + TX, cycloxapride + TX, cycloxapride + TX, cyenopyrafen + TX, cietpirafen (or etpirafen) + TX, cyflumetofen + TX, cyfluthrin + TX, cyhalodiamide + TX, cyhalothrin + TX, cypermethrin + TX, cyphenothrin + TX, cyromazine + TX, deltamethrin + TX, diafenthiuron + TX, dialifos + TX, dibrom + TX, dichloromesothiase + TX, difluvidazine + TX, diflubenzuron + TX, dimpropyridase + TX, dynactin + TX, dinocapa + TX, dinotefuran + TX, dioxabenzophos + TX, emamectin + TX, empentrin + TX, epsilon-momofluorothrin + TX, epsilonmetofluthrin + TX, esfenvalerate + TX, ethion + TX, ethiprole + TX, etofenprox + TX, etoxazole + TX, famfur + TX, phenazaquin + TX, fenfluthrin + TX, fenitrothion + TX, fenobucarb + TX, phenothiocarb + TX, fenoxycarb + TX, fenpropathrina + TX, fenpyroximate + TX, fensulfothion + TX, fenthion + TX, fentin acetate + TX, fenvalerate + TX, fipronil + TX, flometoquin + TX, flonicamid + TX, fluacripyrim + TX, fluazaindolizine + TX, fluazuron + TX, flubendiamide + TX, flubenzimine + TX, flucitrinate + TX, flucycloxuron + TX, flucitrinate + TX, fluensulfone + TX, flufenerim + TX, flufenprox + TX, flufiprol + TX, fluhexaphone + TX, flumethrin + TX,

- 91 045353 fluopyram + TX, flupentiophenox + TX, flupyradifuron + TX, flupirimine + TX, fluralaner + TX, fluvalinate + TX, fluxamethamide + TX, fosthiazate + TX, gamma-cyhalothrin + TX, Gossyplure™ + TX, guadipyra + TX, halofenozide + TX, halofenozide + TX, halofenprox + TX, heptafluthrin + TX, hexythiazox + TX, hydramethylnon + TX, imitsiaphos + TX, imidacloprid + TX, imiprotrin + TX, indoxacarb + TX, iodomethane + TX, iprodione + TX, isocycloseram + TX, isothioate + TX, ivermectin + TX, kappa-bifenthrin + TX, kappa-tefluthrin + TX, lambda-cyhalothrin + TX, lepimectin + TX, lufenuron + TX, metaflumizone + TX, metaldehyde + TX, metam + TX, methomyl + TX, methoxyfenozide + TX, metofluthrin + TX, metolcarb + TX, mexacarbate + TX, milbemectin + TX, momfluorotrin + TX, niclosamide + TX, nitenpyram + TX, nithiazine + TX, omethoate + TX, oxamyl + TX, oxazosulfyl + TX, parathion-ethyl + TX, permethrin + TX, phenothrin + TX, phosphocarb + TX, piperonyl butoxide + TX, pirimicarb + TX, pirimifos-ethyl + TX, polyhedrosis virus + TX, prallethrin + TX, profenofos + TX, profenophos + TX, profluthrin + TX, propargita + TX, propetamphos + TX, propoxura + TX, prothiophos + TX, protrifenbuta + TX, pyflubumide + TX, pymetrozine + TX, pyraclophos + TX, pirafluprol + TX, pyridabene + TX, pyridalyl + TX, pyrifluquinazone + TX , pyrimidifene + TX, pyriminostrobin + TX, pyriprol + TX, pyriproxyfen + TX, resmethrin + TX, sarolaner + TX, selamectin + TX, silafluofen + TX, spinetoram + TX, spinosad + TX, spirodiclofen + TX, spiromesifen + TX, spiropidione + TX, spirotetramate + TX, sulfoxaflor + TX, tebufenozide + TX, tebufenpyrad + TX, tebupyrimphos + TX, tefluthrin + TX, temephos + TX, tetrachloraniliprole + TX, tetradiphone + TX, tetramethrin + TX, tetramethylfluthrin + TX, tetranactin + TX , tetraniliprole + TX theta-cypermethrin + TX, thiacloprid + TX, thiamethoxam + TX, thiocyclam + TX, thiodicarb + TX, thiophanox + TX, thiometon + TX, thiosultap + TX, thioxazafen + TX, tolfenpyrad + TX, toxaphene + TX, tralomethrin + TX, transfluthrin + TX, triazamate + TX, triazophos + TX, trichlorfon + TX, trichloronate + TX, trichlorfon + TX, triflumesopyrim + TX, ticlopyrazoflor + TX, zeta-cypermethrin + TX, seaweed extract and fermentation product obtained from molasses + TC, seaweed extract and fermentation product obtained from molasses containing urea + TC, amino acids + TC, potassium, and molybdenum, and manganese EDTA chelate + TC, seaweed extract and fermented products of plant origin + TC, extract seaweed and fermented products of plant origin, containing plant growth regulators + TX, vitamins + TX, EDTA-chelate copper + TX, zinc + TX, and iron + TX, azadirachtin + TX, Bacillus aizawai + TX, Bacillus chitinosporus AQ746 (accession number in NRRL B-21 618) + TX, Bacillus firmus + TX, Bacillus kurstaki + TX, Bacillus mycoides AQ726 (NRRL accession number B-21664) + TX, Bacillus pumilus (NRRL accession number B-30087) + TX, Bacillus pumilus AQ717 (NRRL accession number B-21662) + TX, Bacillus sp. AQ178 (ATCC accession number 53522) + TX, Bacillus sp. AQ175 (ATCC accession number 55608) + TX, Bacillus sp. AQ177 (ATCC accession number 55609) + TX, Bacillus subtilis unspecified + TX, Bacillus subtilis AQ153 (ATCC accession number 55614) + TX, Bacillus subtilis AQ30002 (NRRL accession number B-50421) + TX, Bacillus subtilis AQ30004 (accession number accession to NRRL B-50455) + TX, Bacillus subtilis AQ713 (accession number to NRRL B21661) + TX, Bacillus subtilis AQ743 (accession number to NRRL B-21665) + TX, Bacillus thuringiensis AQ52 (accession number to NRRL B-21619) + TX, Bacillus thuringiensis BD#32 (NRRL accession number B-21530) + TX, Bacillus thuringiensis subspec. kurstaki BMP 123 + TX, Beauveria bassiana + TX, D-limonene + TX, Granulovirus + TX, harpin + TX, nuclear polyhedrosis virus Helicoverpa armigera + TX, nuclear polyhedrosis virus Helicoverpa zea + TX, nuclear polyhedrosis virus Heliothis virescens + TX, virus nuclear polyhedrosis Heliothis punctigera + TX, Metarhizium spp. + TX, Muscodor albus 620 (NRRL accession number 30547) + TX, Muscodor roseus A3-5 (NRRL accession number 30548) + TX, Melia indian products + TX, Paecilomyces fumosoroseus + TX, Paecilomyces lilacinus + TX, Pasteuria nishizawae + TX, Pasteuria penetrans + TX, Pasteuria ramosa + TX, Pasteuria thornei + TX, Pasteuria usgae + TX, p-cymene + TX, granulosa virus Plutella xylostella + TX, nuclear polyhedrosis virus Plutella xylostella + TX, polyhedrosis virus + TX, pyrethrum + TX, QRD 420 (terpenoid mixtures) + TX, QRD 452 (terpenoid mixtures) + TX, QRD 460 (terpenoid mixtures) + TX, Quillaja saponaria + TX, Rhodococcus globerulus AQ719 (NRRL accession number B-21663) + TX , nuclear polyhedrosis virus Spodoptera frugiperda + TX, Streptomyces galbus (NRRL accession number 30232) + TX, Streptomyces sp. (NRRL accession number B-30145) + TX, mixtures of terpenoids + TX, and Verticillium spp., an algaecide selected from the group of substances consisting of betoxazin [CCN] + TX, copper dioctanoate (IUPAC name) (170) + TX , copper sulfate (172) + TC, cibutrin [CCN] + TC, dichlon (1052) + TC, dichlorophen (232) + TC, endothal (295) + TC, fentin (347) + TC, slaked lime [CCN] + TC, nabama (566) + TC, quinoclamine (714) + TC, quinonamide (1379) + TC, simazine (730) + TC, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347 ) + TX, an anthelmintic selected from the group of substances consisting of abamectin (1) + TX, crufomate (1011) + TX, cyclobutrifluram + TX, doramectin (alternative name) [CCN] + TX, emamectin (291) + TX, emamectin benzoate (291) + TX, eprinomectin (alternative name) [CCN] + TX, ivermectin (alternative name) [CCN] + TX, milbemycin oxime (alternative name) [CCN] + TX, moxidectin (alternative name) [CCN ] + TX, piperazine [CCN] + TX, selamectin (alternative name) [CCN] + TX, spinosa- 92 045353 yes (737) and thiophanate (1435) + TX, avicid, selected from the group of substances consisting of chloralose (127 ) + TC, endrin (1122) + TC, fenthion (346) + TC, pyridine-4-amine (IUPAC name) (23) and strychnine (745) + TC, a bactericide selected from the group of substances consisting of 1- hydroxy-spiridin-2-thione (IUPAC name) (1222) + TX, 4-(quinoxalin-2ylamino)benzenesulfonamide (IUPAC name) (748) + TX, 8-hydroxyquinoline sulfate (446) + TX, bronopol (97 ) + TC, copper dioctanoate (IUPAC name) (170) + TC, copper hydroxide (IUPAC name) (169) + TC, cresol [CCN] + TC, dichlorophen (232) + TC, dipyrithione (1105) + TC , dodicine (1112) + TX, fenaminosulfate (1144) + TX, formaldehyde (404) + TX, hydrargafen (alternative name) [CCN] + TX, kasugamycin (483) + TX, kasugamycin hydrochloride hydrate (483) + TX, bis (dimethyldithiocarbamate) nickel (IUPAC name) (1308) + TX, nitrapyrine (580) + TX, octylinone (590) + TX, oxolinic acid (606) + TX, oxytetracycline (611) + TX, potassium hydroxyquinoline sulfate (446) + TX, probenazole (658) + TX, streptomycin (744) + TX, streptomycin sesquisulfate (744) + TX, teclophthalam (766) + TX and thiomersal (alternative name) [CCN] + TX, a biological agent selected from the group of substances consisting of Adoxophyes orana GV (alternative name) (12) + TX, Agrobacterium radiobacter (alternative name) (13) + TX, Amblyseius spp. (alternative name) (19) + TX, Anagrapha falcifera NPV (alternative name) (28) + TX, Anagrus atomus (alternative name) (29) + TX, Aphelinus abdominalis (alternative name) (33) + TX, Aphidius colemani ( alternative name) (34) + TX, Aphidoletes aphidimyza (alternative name) (35) + TX, Autographa californica NPV (alternative name) (38) + TX, Bacillus firmus (alternative name) (48) + TX, Bacillus sphaericus Neide ( scientific name) (49) + TX, Bacillus thuringiensis Berliner (scientific name) (51) + TX, Bacillus thuringiensis subspecies aizawai (scientific name) (51) + TX, Bacillus thuringiensis subspecies israelensis (scientific name) (51) + TX, Bacillus thuringiensis subspecies japonensis (scientific name) (51) + TX, Bacillus thuringiensis subspecies kurstaki (scientific name) (51) + TX, Bacillus thuringiensis subspecies tenebrionis (scientific name) (51) + TX, Beauveria bassiana (alternative name) (53 ) + TX, Beauveria brongniartii (alternative name) (54) + TX, Chrysoperla carnea (alternative name) (151) + TX, Cryptolaemus montrouzieri (alternative name) (178) + TX, Cydia pomonella GV (alternative name) (191) + TX, Dacnusa sibirica (alternative name) (212) + TX, Diglyphus isaea (alternative name) (254) + TX, Encarsia formosa (scientific name) (293) + TX, Eretmocerus eremicus (alternative name) (300) + TX , Helicoverpa zea NPV (alternative name) (431) + TX, Heterorhabditis bacteriophora and H. megidis (alternative name) (433) + TX, Hippodamia convergens (alternative name) (442) + TX, Leptomastix dactylopii (alternative name) (488 ) + TX, Macrolophus caliginosus (alternative name) (491) + TX, Mamestra brassicae NPV (alternative name) (494) + TX, Metaphycus helvolus (alternative name) (522) + TX, Metarhizium anisopliae acridum spp. (scientific name) ( 523) + TX, Metarhizium anisopliae species anisopliae (scientific name) (523) + TX, Neodiprion sertifer NPV and N. lecontei NPV (alternative name) (575) + TX, Orius spp. (alternative name) (596) + TX, Paecilomyces fumosoroseus (alternative name) (613) + TX, Phytoseiulus persimilis (alternative name) (644) + TX, Spodoptera exigua multicapsid nuclear polyhedrosis virus (scientific name) (741) + TX, Steinernema bibionis (alternative name) (742) + TX, Steinernema carpocapsae (alternative name) (742) + TX, Steinernema feltiae (alternative name) (742) + TX, Steinernema glaseri (alternative name) (742) + TX, Steinernema riobrave (alternative name) (742) + TX, Steinernema riobravis (alternative name) (742) + TX, Steinernema scapterisci (alternative name) (742) + TX, Steinernema spp. (alternative name) (742) + TX, Trichogramma spp. (alternative name) (826) + TX, Typhlodromus occidentalis (alternative name) (844) and Verticillium lecanii (alternative name) (848) + TX, a soil sterilizer selected from the group of substances consisting of iodomethane (IUPAC name) (542 ) and methyl bromide (537) + TX, a chemosterilant selected from the group of substances consisting of afolate [CCN] + TX, bisazir (alternative name) [CCN] + TX, busulfan (alternative name) [CCN] + TX, diflubenzuron (250 ) + TX, dimatipha (alternative name) [CCN] + TX, hemel [CCN] + TX, hemp [CCN] + TX, metep [CCN] + TX, methiotepa [CCN] + TX, methylafolate [CCN] + TX, morzide [CCN] + TX, penfluron (alternative name) [CCN] + TX, tepa [CCN] + TX, thiochempa (alternative name) [CCN] + TX, thiotepa (alternative name) [CCN] + TX, tretamine (alternative name) name) [CCN] and uredeps (alternative name) [CCN] + TX, an insect pheromone selected from the group of substances consisting of (E)dec-5-ene-1-yl acetate with (E)-dec-5-ene- 1-olom (IUPAC name) (222) + TX, (E)-tridec-4-en-1-yl acetate (IUPAC name) (829) + TX, (E)-6-methylhept-2-ene-4- ola (IUPAC name) (541) + TX, (E,Z)-tetradeca-4,10-dien-1-ylacetate (IUPAC name) (779) + TX, (Z)-dodec-7ene-1- yl acetate (IUPAC name) (285) + TX, (Z)-hexadec-11-enal (IUPAC name) (436) + TX, (Z)-hexadec-11-en-1-ylacetate (IUPAC name) (437) + TX, (Z)-hexadec-13-en11-yne-1-yl acetate (IUPAC name) (438) + TX, (Z)-eicos-13-en-10-one (IUPAC name) (448) + TX, (Z)-tetradec-7-en-1-ala (IUPAC name) (782) + TX, (Z)-tetradec-9-en-1ol (IUPAC name) (783) + TX, (Z)-tetradec-9-en-1-yl acetate (IUPAC name) (784) + TX, (7E,9Z)-dodeca-7,9-dien-1-ylacetate (IUPAC name) (283 ) + TX, (9Z,11E)- 93 045353 tetradeca-9,11-dien-1-ylacetate (IUPAC name) (780) + TX, (9Z,12E)-tetradeca-9,12-dien-1ylacetate ( IUPAC name) (781) + TX, 14-methyloctadec-1-ene (IUPAC name) (545) + TX, 4-methylnonan-5-ol with 4-methylnonan-5-one (IUPAC name) (544 ) + TX, alphamultistriatin (alternate name) [CCN] + TX, brevicomin (alternate name) [CCN] + TX, codelur (alternate name) [CCN] + TX, codlemon (alternate name) (167) + TX, quelur ( alternative name) (179) + TX, disparlura (277) + TX, dodec-8-en-1-yl acetate (IUPAC name) (286) + TX, dodec-9-en-1-yl acetate (IUPAC name) (287) + TX, dodeca-8 + TX, 10-dien-1-yl acetate (IUPAC name) (284) + TX, dominicalur (alternate name) [CCN] + TX, ethyl 4-methyloctanoate (IUPAC name) ) (317) + TX, eugenol (alternate name) [CCN] + TX, frontalina (alternate name) [CCN] + TX, gossyplura (alternate name) (420) + TX, grandlura (421) + TX, grandlura I ( alternative name) (421) + TX, grandlura II (alternative name) (421) + TX, grandlura III (alternative name) (421) + TX, grandlura IV (alternative name) (421) + TX, hexalura [CCN] + TX, ipsdienol (alternate name) [CCN] + TX, ipsenol (alternate name) [CCN] + TX, japonilura (alternate name) (481) + TX, lineatin (alternate name) [CCN] + TX, litlura (alternative name ) [CCN] + TX, luplura (alternative name) [CCN] + TX, medlura [CCN] + TX, megatomoic acid (alternative name) [CCN] + TX, methyleugenol (alternative name) (540) + TX, muscalura ( 563) + TX, octadeca-2,13-dien-1-ylacetate (IUPAC name) (588) + TX, octadeca-3,13-dien-1-ylacetate (IUPAC name) (589) + TX, orphralur (alternative name) [CCN] + TX, oryctalura (alternative name) (317) + TX, ostramon (alternative name) [CCN] + TX, siglura [CCN] + TX, sordidina (alternative name) (736) + TX, sulcatol (alternative name) [CCN] + TX, tetradec-11-en-1-ylacetate (IUPAC name) (785) + TX, trimedlura (839) + TX, trimedlura A (alternative name) (839) + TX, trimedlura B1 (alternative name) (839) + TX, trimedlura B ₂ (alternative name) (839) + TX, trimedlura C (alternative name) (839) and Trank-Cola (alternative name) [CCN] + TX, an agent for insect repellent, selected from the group of substances 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, diethyltoluamide [CCN] + TX, dimethyl carbate [CCN] + TX, dimethyl phthalate [CCN] + TX, ethylhexanediol (1137) + TC, hexamide [CCN] + TC, methoquin-butyl (1276) + TC, methylneodecanamide [CCN] + TC, oxamate [CCN] and picaridin [CCN] + TC, a molluscicide selected from the group of substances consisting of bis( tributyltin) (IUPAC name) (913) + TC, bromoacetamide [CCN] + TC, calcium arsenate [CCN] + TC, cloetocarb (999) + TC, copper acetoarsenite [CCN] + TC, copper sulfate (172) + TC , fentin (347) + TC, iron phosphate (IUPAC name) (352) + TC, metaldehyde (518) + TC, methiocarb (530) + TC, niclosamide (576) + TC, niclosamide-olamine (576 ) + TQ, pentachlorophenol (623) + TQ, sodium pentachlorophenoxide (623) + TQ, tazimcarb (1412) + TQ, thiodicarb (799) + TQ, tributyltin oxide (913) + TQ, triphenmorph (1454) + TQ, trimetacarb ( 840) + TC, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347) + TC, pyriprole [394730-71-3] + TC, nematicide selected from the group of substances consisting of AKD -3088 (compound code) + TX, 1,2-dibromo-3-chloropropane (IUPAC/Chemical Abstract Service name) (1045) + TX, 1,2-dichloropropane (IUPAC/Chemical Abstract Service name) (1062) + TX, 1,2-dichloropropane with 1,3-dichloropropene (IUPAC name) (1063) + TX, 1,3-dichloropropene (233) + TX, 3,4-dichlorotetrahydrothiophene 1,1 dioxide (IUPAC/Chemical name abstract service) (1065) + TX, 3-(4-chlorophenyl)-5methylrhodanine (IUPAC name) (980) + TX, 5-methyl-6-thioxo-1,3,5-thiadiazinan-3ylacetic acid (name according to IUPAC) (1286) + TX, 6-isopentenylaminopurine (alternate name) (210) + TX, abamectin (1) + TX, acetoprol [CCN] + TX, alanicarb (15)+ TX, aldicarb (16) + TX, aldoxycarb (863) + TX, AZ 60541 (compound code) + TX, benclothiase [CCN] + TX, benomyl (62) + TX, butylpyridabene (alternate name) + TX, cadusafos (109) + TX, carbofuran (118) + TX , carbon disulfide (945) + TC, carbosulfan (119) + TC, chloropicrin (141) + TC, chlorpyrifos (145) + TC, cloetocarb (999) + TC, cyclobutrifluram + TC, cytokinins (alternative name) (210) + TX, dazomet (216) + TX, DBCP (1045) + TX, DCIP (218) + TX, diamidaphos (1044) + TX, dichlorofenthione (1051) + TX, diclifos (alternative name) + TX, dimethoate (262) + TX, doramectin (alternate name) [CCN] + TX, emamectin (291) + TX, emamectin benzoate (291) + TX, eprinomectin (alternative name) [CCN] + TX, ethoprophos (312) + TX, ethylene dibromide (316) + TX, fenamiphos (326) + TX, fenpyrad (alternative name) + TX, fensulfothione (1158) + TX, fosthiazate (408) + TX, fostietane (1196) + TX, furfural (alternative name) [CCN] + TX, GY-81 (development code) (423) + TX, heterophos [CCN] + TX, iodomethane (IUPAC name) (542) + TX, isamidophos (1230) + TX, isazophos (1231) + TX, ivermectin (alternative name ) [CCN] + TX, kinetin (alternative name) (210) + TX, mecarphone (1258) + TX, metam (519) + TX, metam-potassium (alternative name) (519) + TX, metam-sodium (519) ) + TC, methyl bromide (537) + TC, methyl isothiocyanate (543) + TC, milbemycin oxime (alternate name) [CCN] + TX, moxidec

- 94 045353 tina (alternative name) [CCN] + TX, compositions based on Myrothecium verrucaria (alternative name) (565) + TX, NC-184 (compound code) + TX, oxamyl (602) + TX, phorate (636) + TX, phosphamidone (639) + TX, phosphocarb [CCN] + TX, sebuphos (alternative name) + TX, selamectin (alternative name) [CCN] + TX, spinosad (737) + TX, terbam (alternative name) + TX , terbufos (773) + TX, tetrachlorothiophene (IUPAC/Chemical Abstract Service name) (1422) + TX, thiaphenox (alternate name) + TX, thionazine (1434) + TX, triazophos (820) + TX, triazuron (alternate name ) + TX, xylenols [CCN] + TX, YI-5302 (compound code) and zeatin (alternate name) (210) + TX, fluensulfone [318290-98-1] + TX, fluopyram + TX, nitrification inhibitor selected from a group of substances consisting of potassium ethyl xanthate [CCN] and nitrapyrine (580) + TX; plant growth activator selected from the group of substances consisting of acibenzolar (6) + TX, acibenzolar-S-methyl (6) + TX, probenazole (658) and Reynoutria sachalinensis extract (alternative name) (720) + TX, rodenticide selected from the group of substances consisting of 2isovalerylindane-1,3-dione (IUPAC name) (1246) + TX, 4-(quinoxalin-2ylamino)benzenesulfonamide (IUPAC name) (748) + TX, alpha-chlorohydrin [CCN] + TX, aluminum phosphide (640) + TX, ANTU (880) + TX, arsenic oxide (882) + TX, barium carbonate (891) + TX, bisthiosemium (912) + TX, brodifacoum (89) + TX, bromadiolone (91 ) + TC, bromethalin (92) + TC, calcium cyanide (444) + TC, chloralose (127) + TC, chlorophacinone (140) + TC, cholecalciferol (alternative name) (850) + TC, coumachlor (1004) + TC , coumafuryl (1005) + TX, coumatetral (175) + TX, crimidine (1009) + TX, difenacoum (246) + TX, difethialone (249) + TX, diphacinone (273) + TX, ergocalciferol (301) + TX, flocumafen (357) + TX, fluoroacetamide (379) + TX, flupropadine (1183) + TX, flupropadine hydrochloride (1183) + TX, gamma-HCN (430) + TX, NCH (430) + TX, hydrogen cyanide (444) + TC, iodomethane (IUPAC name) (542) + TC, lindane (430) + TC, magnesium phosphide (IUPAC name) (640) + TC, methyl bromide (537) + TC, norbormide (1318) + TC, fosacetim ( 1336) + TX, phosphine (IUPAC name) (640) + TX, phosphorus [CCN] + TX, pindone (1341) + TX, potassium arsenite [CCN] + TX, pyrinuron (1371) + TX, scylliroside (1390) + TQ, sodium arsenite [CCN] + TQ, sodium cyanide (444) + TQ, sodium fluoroacetate (735) + TQ, strychnine (745) + TQ, thallium sulfate [CCN] + TQ, warfarin (851) and zinc phosphide ( 640) + TX, a synergist selected from the group of substances consisting of 2-(2-butoxyethoxy)ethyl piperonylate (IUPAC name) (934) + TX, 5-(1,3benzodioxol-5-yl)-3-hexylcyclohex-2 -enone (IUPAC name) (903) + TX, farnesol with nerolidol (alternative name) (324) + TX, MB-599 (development code) (498) + TX, MGK 264 (development code) (296) + TX , piperonyl butoxide (649) + TX, piprotal (1343) + TX, propyl isomer (1358) + TX, S421 (development code) (724) + TX, sesamex (1393) + TX, sesasmolin (1394) and sulfoxide (1406) + TC, animal repellent selected from the group of substances consisting of anthraquinone (32) + TC, chloralose (127) + TC, copper naphthenate [CCN] + TC, copper oxychloride (171) + TC, diazinon (227) + TC, dicyclopentadiene (chemical name) (1069) + TC, guazatine (422) + TC, guazatine acetates (422) + TC, methiocarb (530) + TC, pyridin-4-amine (IUPAC name) (23) + TX , tirama (804) + TX, trimetacarb (840) + TX, zinc naphthenate [CCN] and ziram (856) + TX, a virucide selected from the group of substances consisting of imanin (alternative name) [CCN] and ribavirin (alternative name ) [CCN] + TC, a wound protectant selected from the group of substances consisting of mercuric oxide (512) + TC, octylinone (590) and thiophanate-methyl (802) + TC, a biologically active substance selected from 1,1 -bis(4-chlorophenyl)-2-ethoxyethanol + TX, 2,4-dichlorophenylbenzenesulfonate + TX, 2-fluoro-N-methyl-N-1-naphtylacetamide + TX, 4-chlorophenylphenylsulfone + TX, acetoprol + TX, aldoxycarb + TX, amidithione + TX, amidothioate + TX, amitone + TX, amitone hydroxalate + TX, amitraz + TX, aramite + TX, arsenic oxide + TX, azobenzene + TX, azotoate + TX, benomyl + TX, benoxaphos + TX, benzyl benzoate + TX, bixafen + TX, brofenvalerate + TX, bromocyclene + TX, bromophos + TX, bromopropylate + TX, buprofezin + TX, butocarboxim + TX, butoxycarboxim + TX, butylpyridabene + TX, calcium polysulfide + TX, camphechlor + TX, carbanolate + TX , carbophenothione + TX, cimiazole + TX, quinomethionate + TX, chlorobenzide + TX, chlordimeform + TX, chlordimeform hydrochloride + TX, chlorphenetol + TX, chlorphenson + TX, chlorphensulfide + TX, chlorobenzilate + TX, chloromebuform + TX, chloromethiuron + TX, chloropropylate + TX, chlorothiophos + TX, cinerin I + TX, cinerin II + TX, cinerin + TX, closantel + TX, coumaphos + TX, crotamiton + TX, crotoxiphos + TX, kufraneb + TX, cyanoate + TX, DCPM + TX, DDT + TX, demefion + TX, demefion-O + TX, demefion-S + TX, demeton-methyl + TX, demeton-O + TX, demeton-O-methyl + TX, demeton-S + TX, demeton-S-methyl + TX, demetonS-methylsulfone + TX, dichlorofluanide + TX, dichlorvos + TX, diclifos + TX, dienochlor + TX, dimefox + TX, dinex + TX, dinexdiclexin + TX, dinocapa-4 + TX, dinocapa-6 + TX, dinoctone + TX, dinopentone + TX, dinosulfone + TX, dinoterbone + TX, dioxathion + TX, diphenylsulfone + TX, disulfiram + TX, DNOC + TX, dofenapine + TX, doramectin + TX, endothione + TX, eprinomectin + TX, methyl ethoate + TX, etrimphos + TX, phenazaflor + TX, fenbutatin oxide + TX, phenothiocarb + TX, fenpyrad + TX, fenpyroximate + TX, fenpyrazamine + TX, fenzone + TX, fentrifanil + TX, flubenzimine + TX, flucycloxuron + TX, fluenethyl + TX , fluorbenzide + TX, FMC 1137 + TX, formethanate + TX, formatenate hydrochloride + TX, formparanate + TX, gamma-NSN + TX, gliodin + TX, galfenprox + TX, hexadecylcyclopropanecarboxylate + TX, isocarbophos + TX, jasmoline I +

- 95 045353

TX, jasmoline II + TX, iodofenphos + TX, lindane + TX, malonobene + TX, mecarbate + TX, mephospholane + TX, mesulfene + TX, metacryphos + TX, methyl bromide + TX, metolcarb + TX, mexacarbate + TX, milbemycin oxime + TX, mipafox + TX, monocrotophos + TX, morphothione + TX, moxidectin + TX, naleda + TX, 4-chloro-2-(2-chloro-2-methylpropyl)-5-[(6-iodo-3-pyridyl) methoxy]pyridazin-3-one + TX, nifluridide + TX, nikkomycin + TX, nitrilecarb + TX, complex of nitrilecarb and zinc chloride 1:1+ TX, omethoate + TX, oxideprofos + TX, oxydisulfoton + TX, pp'-DDT + TX, parathion + TX, permethrin + TX, phencapton + TX, fozalone + TX, phospholan + TX, phosphamidon + TX, polychlorterpenes + TX, polynactins + TX, proclonol + TX, promacil + TX, propoxur + TX, protidation + TX, protoate + TX, pyrethrin I + TX, pyrethrin II + TX, pyrethrins + TX, pyridafenthione + TX, pyrimitate + TX, quinalphos + TX, quinthiophos + TX, R-1492 + TX, phosglycine + TX, rotenone + TX, shradan + TX, sebuphos + TX, selamectin + TX, sofamide + TX, SSI-121 + TX, sulfiram + TX, sulfluramide + TX, sulfotepa + TX, sulfur + TX, diflovidazine + TX, tau-fluvalinate + TX, TERP + TX, terbam + TX, tetradiphon + TX, tetrasula + TX, thiaphenoxa + TX, thiocarboxim + TX, thiophanox + TX, thiometon + TX, thioquinoxa + TX, thuringiensin + TX, triamiphos + TX, triarathene + TX, triazophos + TX, triazuron + TX, triphenofos + TX, trinactin + TX, vamidothione + TX, vaniliprol + TX, betoxazin + TX, copper dioctanoate + TX, copper sulfate + TX, cibutrin + TX, dichlorophen + TX, endothal + TX, fentin + TC, slaked lime + TC, nabama + TC, quinoclamine + TC, quinonamide + TC, simazine + TC, triphenyltin acetate + TC, triphenyltin hydroxide + TC, crufomate + TC, piperazine + TC, thiophanate + TC, chloralose + TC, fenthion + TX, pyridin-4-amine + TX, strychnine + TX, 1-hydroxy-1H-pyridine-2-thione + TX, 4-(quinoxalin-2ylamino)benzenesulfonamide + TX, 8-hydroxyquinoline sulfate + TX, bronopol + TX , copper hydroxide + TX, cresol + TX, dipyrithione + TX, dodicine + TX, fenaminosulfate + TX, formaldehyde + TX, hydrargafen + TX, kasugamycin + TX, kasugamycin hydrochloride hydrate + TX, nickel bis(dimethyldithiocarbamate) + TX, nitrapyrine + TX, octilinone + TX, oxolinic acid + TX, oxytetracycline + TX, potassium hydroxyquinoline sulfate + TX, probenazole + TX, streptomycin + TX, streptomycin sesquisulfate + TX, teclophthalam + TX, thiomersal + TX, Adoxophyes orana GV + TX, Agrobacterium radiobacter + TX, Amblyseius spp. + TX, Anagrapha falcifera NPV + TX, Anagrus atomus + TX, Aphelinus abdominalis + TX, Aphidius colemani + TX, Aphidoletes aphidimyza + TX, Autographa californica NPV + TX, Bacillus sphaericus Neide + TX, Beauveria brongniartii + TX, Chrysoperla carnea + TX , Cryptolaemus montrouzieri + TX, Cydia pomonella GV + TX, Dacnusa sibirica + TX, Diglyphus isaea + TX, Encarsia formosa + TX, Eretmocerus eremicus + TX, Heterorhabditis bacteriophora and H. megidis + TX, Hippodamia convergens + TX, Leptomastix dactylopii + TX , Macrolophus caliginosus + TX, Mamestra brassicae NPV + TX, Metaphycus helvolus + TX, Metarhizium anisopliae var. acridum + TX, Metarhizium anisopliae var. anisopliae + TX, Neodiprion sertifer NPV and N. lecontei NPV + TX, Orius spp. + TX, Paecilomyces fumosoroseus + TX, Phytoseiulus persimilis + TX, Steinernema bibionis + TX, Steinernema carpocapsae + TX, Steinernema feltiae + TX, Steinernema glaseri + TX, Steinernema riobrave + TX, Steinernema riobravis + TX, Steinernema scapterisci + TX, Steinernema spp . + TX, Trichogramma spp. + TX, Typhlodromus occidentalis + TX, Verticillium lecanii + TX, afolate + TX, bisasira + TX, busulfan + TX, dimatifa + TX, hemela + TX, hemps + TX, meteps + TX, methiotheps + TX, methylafolate + TX, morzida + TX, penfluron + TX, tepa + TX, thiochempa + TX, thiotepa + TX, tretamine + TX, uredep + TX, (E)-dec-5-ene-1-yl acetate and (E)-dec5-ene-1 -ol + TX, (E)-tridec-4-en-1-yl acetate + TX, (E)-6-methylhept-2-en-4-ol + TX, (E,Z)-tetradeca4,10-diene -1-ylacetate + TX, (Z)-dodec-7-en-1-yl acetate + TX, (Z)-hexadec-11-enal + TX, (Z)-hexadec11-en-1-yl acetate + TX, ( Z)-hexadec-13-en-11-yn-1-yl acetate + TX, (Z)-icos-13-en-10-one + TX, (Z)tetradec-7-en-1-ala + TX, (Z)-tetradec-9-en-1-ol + TX, (Z)-tetradec-9-en-1-yl acetate + TX, (7E,9Z)dodeca-7,9-dien-1-yl acetate + TX , (9Z,11E)-tetradeca-9,11-dien-1-ylacetate + TX, (9Z,12E)-tetradeca9,12-dien-1-yl acetate + TX, 14-methyloctadec-1-ene + TX, 4 -methylnonan-5-ol and 4-methylnonan-5-one + TX, alpha-multistriatin + TX, brevicomin + TX, codelur + TX, codelemon + TX, quelur + TX, disparlura + TX, dodec-8-en-1 -yl acetate + TX, dodec-9-en-1-yl acetate + TX, dodec-8 + TX, 10-dien-1yl acetate + TX, dominicalur + TX, ethyl-4-methyloctanoate + TX, eugenol + TX, frontalin + TX , grandlura + TX, grandlura I + TX, grandlura II + TX, grandlura III + TX, grandlura IV + TX, hexalura + TX, ipsdienol + TX, ipsenol + TX, japonilura + TX, lineatina + TX, litlura + TX, luplura + TC, medlura + TC, megatomoic acid + TC, methyl eugenol + TC, muscalure + TC, octadeca-2,13-dien-1-yl acetate + TC, octadeca-3,13-dien-1-yl acetate + TC, orphralur + TC, oryctalura + TX, ostramona + TX, siglura + TX, sordidina + TX, sulcatol + TX, tetradec-11-en-1-yl acetate + TX, trimedlura + TX, trimedlura A + TX, trimedlura B1 + TX, trimedlura B ₂ + TX, trimedlura C + TX, trunk-colla + TX, 2(octylthio)-ethanol + TX, butopyronoxyl + TX, butoxy(polypropylene glycol) + TX, dibutyl adipate + TX, dibutyl phthalate + TX, dibutyl succinate + TX, diethyltoluamide + TX, dimethyl carbate + TC, dimethyl phthalate + TC, ethylhexanediol + TC, hexamide + TC, methoquin-butyl + TC, methylneodecanamide + TC, oxamate + TC, ricaridin + TC, 1-dichloro-1-nitroethane + TC, 1,1-dichloro-2 ,2-bis(4-ethylphenyl)ethane + TX, 1,2-dichloropropane and 1,3-dichloropropene + TX, 1-bromo-2-chloroethane + TX, 2,2,2-trichloro-1(3,4 -dichlorophenyl)ethyl acetate + TX, 2,2-dichlorovinyl 2-ethylsulfinylethyl methylphosphate + TX, 2-(1,3dithiolan-2-yl)phenyldimethylcarbamate + TX, 2-(2-butoxyethoxy)ethyl thiocyanate + TX, 2-(4,5 -dimethyl

- 96 045353

1,3-dioxolan-2-yl)phenylmethylcarbamate + TX, 2-(4-chloro-3,5-xylyloxy)ethanol + TX, 2-chlorovinyl diethyl phosphate + TX, 2-imidazolidone + TX, 2-isovalerylindane-1,3-dione + TX, 2methyl(prop-2-ynyl)aminophenylmethylcarbamate + TX, 2-thiocyanatoethyl laurate + TX, 3-bromo-1chloroprop-1-ene + TX, 3-methyl-1-phenylpyrazol-5-yldimethylcarbamate + TX, 4-methyl (prop-2inyl)amino-3,5-xylylmethylcarbamate + TX, 5,5-dimethyl-3-oxocyclohex-1-enyldimethylcarbamate + TX, acethione + TX, acrylonitrile + TX, aldrin + TX, allosamidine + TX, allixicarb + TX , alphaecdysone + TX, aluminum phosphide + TX, aminocarb + TX, anabasine + TX, atidation + TX, azametifos + TX, Bacillus thuringiensis delta-endotoxins + TX, barium hexafluorosilicate + TX, barium polysulfide + TX, bartrin + TX, Bayer 22 /190 + TX, Bayer 22408 + TX, beta-cyfluthrin + TX, betacypermethrin + TX, bioethanomethrin + TX, biopermethrin + TX, bis(2-chloroethyl) ether + TX, borax + TX, bromfenvinphos + TX, bromine-DDT + TC, bufencarb + TC, butacarb + TC, butathiophos + TC, butonate + TC, calcium arsenate + TC, calcium cyanide + TC, carbon disulfide + TC, carbon tetrachloride + TC, cartap hydrochloride + TC, cevadin + TC, chlorobicyclene + TC, chlordane + TC, chlordecone + TC, chloroform + TC, chloropicrin + TC, chlorphoxime + TC, chlorprazophos + TC, cis-resmethrin + TC, cismethrin + TC, clocitrin + TC, copper acetoarsenite + TC, copper arsenate + TC, copper oleate + TX, cumitoate + TX, cryolite + TX, CS 708 + TX, cyanophenphos + TX, cyanophos + TX, cycletrin + TX, cythioate + TX, d-tetramethrin + TX, DAEP + TX, dazomet + TX, decarbofuran + TX, diamidaphos + TX, dicaptone + TX, dichlorofenthione + TX, dicresyl + TX, dicyclanil + TX, dieldrin + TX, diethyl-5-methylpyrazol-3-ylphosphate + TX, dilor + TX, dimefluthrin + TX, dimethane + TX, dimethrin + TX , dimethylvinphos + TX, dimethylane + TX, dinoprop + TX, dinosam + TX, dinoseb + TX, diophenolan + TX, dioxabenzophos + TX, diticrophos + TX, DSP + TX, ecdysterone + TX, EI 1642 + TX, EMPC + TX, ERBP + TX, ethaphos + TX, etiophencarb + TX, ethyl formate + TX, ethylene dibromide + TX, ethylene dichloride + TX, ethylene oxide + TX, EXD + TX, fenchlorvos + TX, fenetacarb + TX, fenitrothion + TX, fenoxacrim + TX, fenpyritrin + TC, fensulfothione + TC, fenthion-ethyl + TC, flucofuron + TC, fosmethylane + TC, fospirate + TC, fostiethane + TC, furathiocarb + TC, furethrin + TC, guazatin + TC, guazatin acetates + TC, sodium tetrathiocarbonate + TC , galfenprox + TX, NCH + TX, HEOD + TX, heptachlor + TX, heterophos + TX, HHDN + TX, hydrocyanic acid + TX, hiquincarb + TX, IPSP + TX, isazophos + TX, isobenzan + TX, isodrine + TX, isofenphos + TX, isolane + TX, isoprothiolane + TX, isoxathione + TX, juvenile hormone I + TX, juvenile hormone II + TX, juvenile hormone III + TX, kelevan + TX, kinoprene + TX, lead arsenate + TX, leptophos + TX , lyrimphos + TX, litidathione + TX, m-cumenylmethylcarbamate + TX, magnesium phosphide + TX, mazidox + TX, mecarfone + TX, menasone + TX, mercuric chloride + TX, mesulfenphos + TX, metam + TX, metampotassium + TX, metam -sodium + TX, methanesulfonyl fluoride + TX, metocrotophos + TX, methoprene + TX, methotrin + TX, methoxychlor + TX, methyl isothiocyanate + TX, methyl chloroform + TX, methylene chloride + TX, methoxadiazone + TX, mirex + TX, naphthalophos + TX, naphthalene + TX, NC-170 + TX, nicotine + TX, nicotine sulfate + TX, nithiazine + TX, nornicotine + TX, O-5-dichloro-4-iodophenyl-Oethylethylphosphonothioate + TX, O,O-diethyl-O-4 -methyl-2-oxo-2H-chromen-7-ylphosphorothioate + TX, O,Odiethyl-O-6-methyl-2-propylpyrimidin-4-ylphosphorothioate + TX, Ο,Ο,Ο',Ο'-tetrapropyldithiopyrophosphate + TX , oleic acid + TX, para-dichlorobenzene + TX, parathion-methyl + TX, pentachlorophenol + TX, pentachlorophenyl laurate + TX, pH 60-38 + TX, phencaptone + TX, phosnichlor + TX, phosphine + TX, phoxim-methyl + TX , pyrimetafos + TX, isomers of polychlorodicyclopentadiene + TX, potassium arsenite + TX, potassium thiocyanate + TX, precocene I + TX, precocene II + TX, precocene III + TX, primidophos + TX, profluthrin + TX, promecarb + TX, prothiophos + TX , pyrazophos + TX, pyresmethrin + TX, quassia + TX, quinalphos-methyl + TX, quinothione + TX, rafoxanide + TX, resmethrin + TX, rotenone + TX, cadetrin + TX, ryanium + TX, ryanodine + TX, sabadilla) + TX, shradana + TX, sebuphos + TX, SI0009 + TX, tiapronil + TX, sodium arsenite + TX, sodium cyanide + TX, sodium fluoride + TX, sodium hexafluorosilicate + TX, sodium pentachlorophenoxide + TX, sodium selenate + TX, sodium thiocyanate + TX, sulcofuron + TX, sulcofuron-sodium + TX, sulfuryl fluoride + TX, sulprophos + TX, tar oils + TX, tazimkarb + TX, TDE + TX, tebupirimphos + TX, temephos + TX, terallethrin + TX, tetrachloroethane + TX, ticrophos + TX, thiocyclam + TX, thiocyclam hydroxalate + TX, thionazine + TX, thiosultap + TX, thiosultap-sodium + TX, tralomethrin + TX, transpermethrin + TX, triazamate + TX, trichlorometaphos-3 + TX, trichloronate + TX, trimetacarb + TC, tolprocarb + TC, trichloropyricarb + TC, triprene + TC, veratridine + TC, veratrin + TC, CMS + TC, zetamethrin + TC, zinc phosphide + TC, zolaprofos + TC, and meperfluthrin + TC, tetramethylfluthrin + TC, oxide bis(tributyltin) + TX, bromoacetamide + TX, iron phosphate + TX, niclosamide-olamine + TX, tributyltin oxide + TX, pyrimorph + TX, triphenmorph + TX, 1,2-dibromo-3-chloropropane + TX, 1,3dichloropropene + TC, 3,4-dichlorotetrahydrothiophene-1,1-dioxide + TC, 3-(4-chlorophenyl)-5methylrhodanine + TC, 5-methyl-6-thioxo-1,3,5-thiadiazinan-3-ylacetic acid + TX, 6-isopentenylaminopurine + TX, 2-fluoro-N-(3-methoxyphenyl)-9H-purine-6-amine + TX, benclothiase + TX, cytokinins + TX, DCIP + TX, furfural + TX, isamidophos + TX, kinetin + TX, compositions based on Myrothecium verrucaria + TX, tetrachlorothiophene + TX, xylenols + TX, zeatin + TX, potassium ethyl xanthate + TX, acibenzolar + TX, acibenzolar-S-methyl + TX, Reynoutria sachalinensis extract + TX,

- 97 045353 alpha-chlorohydrin + TX, antu + TX, barium carbonate + TX, bisthiosemium + TX, brodifacoum + TX, bromadiolone + TX, bromethalin + TX, chlorophacinone + TX, cholecalciferol + TX, coumachlor + TX, coumafuryl + TX, coumatetralyl + TX, crimidine + TX, difenacoum + TX, difethialone + TX, diphacinone + TX, ergocalciferol + TX, flocumafen + TX, fluoroacetamide + TX, flupropadine + TX, flupropadine hydrochloride + TX, norbormide + TX, fosacetim + TX, phosphorus + TX, pindone + TX, pyrinuron + TX, skilliroside + TX, -sodium fluoroacetate + TX, thallium sulfate + TX, warfarin + TX, -2-(2-butoxyethoxy)ethylpiperonylate + TX, 5-(1,3-benzodioxol) -5-yl)-3-hexylcyclohex-2-enone + TX, farnesol with nerolidol + TX, verbutin + TX, MGK 264 + TX, piperonyl butoxide + TX, piprotal + TX, propyl isomer + TX, S421 + TX, sesamex + TC, sesasmoline + TC, sulfoxide + TC, anthraquinone + TC, copper naphthenate + TC, copper oxychloride + TC, dicyclopentadiene + TC, thiram + TC, zinc naphthenate + TC, ziram + TC, imanin + TC, ribavirin + TC, oxide mercury + tx, thiophanatmethyla + tx, azaconazola + cracker, bitethanol + cracked, bromaconazola + tx, ziprookonazole + crackeler, diphenoconazole + tx, dinoconazole - + tx, epoxiconazole + tx, fenbuconazole + tx, fluvinconazole + tx, flusylazole + tx, flusylazole, flusylazola, flusylazola, flusylazole, flusylazole + tx Flutriafol + TX, furamethpyra + TX, hexaconazole + TX, imazalil + TX, imibenconazole + TX, ipconazole + TX, metconazole + TX, myclobutanil + TX, paclobutrazol + TX, pefurazoate + TX, penconazole + TX, prothioconazole + TX, pyrifenox + TX , prochloraz + TX, propiconazole + TX, pyrizoxazole + TX, -simeconazole + TX, tebucon-azole + TX, tetraconazole + TX, triadimefon + TX, triadimenol + TX, triflumizole + TX, triticonazole + TX, ancymidol + TX, fenarimol + TX, nuarimol + TX, bupirimate + TX, dimethirimol + TX, ethirimol + TX, dodemorph + TX, fenpropidine + TX, fenpropimorph + TX, spiroxamine + TX, tridemorph + TX, cyprodinil + TX, mepanipyrim + TX, pyrimethanil + TX, fenpiclonil + TX, fludioxonil + TX, benalaxyl + TX, furalaxyl + TX, -metalaxyl - + TX, R metalaxyl + TX, ofuras + TX, oxadixil + TX, carbendazim + TX, debacarb + TX, fuberidazole -+ TX, thiabendazole + TX, chlozolinate + TX, dichlozolin + TX, myclozolin- + TX, procymidone + TX, vinclozolin + TX, boscalid + TX, carboxin + TX, fenfuram + TX, flutolanil + TX, mepronil + TX, oxycarboxin + TX, pentiopyrad + TX , tifluzamide + TX, dodine + TX, iminoctadine + TX, azoxystrobin + TX, dimoxystrobin + TX, enestroburin + TX, phenaminestrobin + TX, flufenoxystrobin + TX, fluoxastrobin + TX, kresoximmethyl + TX, metominostrobin + TX, trifloxystrobin + TX, orisa strobe + TX, picoxystrobin + TX, pyraclostrobin + TX, pyramethostrobin + TX, pyraoxystrobin + TX, ferbam + TX, mancozeb + TX, maneba + TX, metiram + TX, propineba + TX, cineba + TX, captafol + TX, captan + TX , fluoroimide + TX, folpet + TX, tolylfluanid + TX, Bordeaux mixture + TX, copper oxide + TX, mancopper + TX, oxine copper + TX, nitrotal isopropyl + TX, edifenphos + TX, iprobenphos + TX, phosdifene + TX, tolclofos-methyl + TX, anilazine + TX, benthiavalicarb + TX, blasticidin-S + TX, chloroneba -+ TX, chlorothalonil + TX, cyflufenamide + TX, cymoxanil + TX, cyclobutrifluram + TX, diclocimet + TX, diclomesine -+ TX, dicloran + TX, diethofencarb + TX, dimethomorpha -+ TX, flumorpha + TX, dithianone + TX, ethaboxam + TX, etridiazole + TX, famoxadone + TX, fenamidone + TX, fenoxanil + TX, ferimzone + TX, fluazinam + TX, fluopicolide + TX, flusulfamide + TX, fluxapyroxad + TX, -fenhexamide + TX, fosetyl-aluminum -+ TX, chemexazole + TX, iprovalicarb + TX, cyazofamide + TX, metasulfocarb + TX, metrafenone + TX, pencycuron + TX, phthalide + TX , polyoxins + TX, propamocarb + TX, pyribencarb + TX, proquinazide + TX, pyroquilone + TX, pyriophenone + TX, quinoxifene + TX, quintozene + TX, tiadinil + TX, triazoxide + TX, tricyclazole + TX, triforin + TX, validamycin + TX, valifenalate + TX, zoxamide + TX, mandipropamide + TX, flubeneteram + TX, isopyrazam + TX, sedaxane + TX, benzovindiflupyr + TX, pidiflumetofen + TX, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acids (3',4',5'-trifluorobiphenyl-2-yl)amide + TX, isoflucipram + TX, isothianyl + TX, dipimethytrone + TX, 6-ethyl-5,7dioxopyrrolo[4,5][1, 4]dithiino[1,2-c]isothiazol-3-carbonitrile + TX, 2-(difluoromethyl)-C-[3-ethyl-1,1dimethylindan-4-yl]pyridin-3-carboxamide + TX, 4-( 2,6-difluorophenyl)-6-methyl-5-phenylpyridazin-3carbonitrile + TX, (R)-3-(difluoromethyl)-1-methyl-N-[1,1,3-trimethylindan-4-yl]pyrazol- 4-carboxamide + TX, 4-(2-bromo-4-fluorophenyl)-C-(2-chloro-6-fluorophenyl)-2,5-dimethylpyrazol-3-amine + TX, 4-(2-bromo-4fluorophenyl) )-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine + TX, fluindapyr + TX, coumethoxysrobin (jiaxiangjunzhi) + TX, lvbenmixianan + TX, dichlorobenthiazox + TX, mandestrobin + TX, 3-(4,4-difluoro-3,4-dihydro-3,3-dimethylisoquinolin-1-yl)quinolone + TX, 2-[2-fluoro-6-[(8-fluoro-2methyl-3 -quinolyl)oxy]phenyl]propan-2-ol + TX, oxathiapiproline + TX, tert-butyl-K-[6-[[[(1methyltetrazol-5-yl)-phenylmethylene]amino]oxymethyl]-2-pyridyl] carbamate + TX, pyraziflumide + TX, inpirfluxam + TX, trolprocarb + TX, mefentrifluconazole + TX, ipfentrifluconazole + TX, 2(difluoromethyl)-N-[(3R)-3-ethyl-1,1-dimethylindan-4-yl] pyridine-3-carboxamide + TX, N'-(2,5-dimethyl-4phenoxyphenyl)-K-ethyl-K-methylformamidine + TX, K'-[4-(4,5-dichlorothiazol-2-yl)oxy- 2,5dimethylphenyl]-C-ethyl-C-methylformamidine + TX, [2-[3-[2-[1-[2-[3,5-bis(difluoromethyl)pyrazol-1yl]acetyl]-4-piperidyl] thiazol-4-yl]-4,5-dihydroisoxazol-5-yl]-3-chlorophenyl]methanesulfonate + TX, but-3-ynyl-N-[6-[[(Z)-[(1-methyltetrazol-5 -yl)-phenylmethylene]amino]oxymethyl]-2-pyridyl]carbamate + TC, methyl-K-[[5-[4-(2,4-dimethylphenyl)triazol-2-yl]-2-methylphenyl]methyl] carbamate + TX, 3-chloro-6methyl-5-phenyl-4-(2,4,6-trifluorophenyl)pyridazine + TX, pyridachloromethyl + TX, 3-(difluoromethyl)-1

- 98 045353 methyl-N-[1,1,3-trimethylindan-4-yl]pyrazol-4-carboxamide + TX, 1-[2-[[1-(4-chlorophenyl)pyrazol-3yl]oxymethyl]-3 -methylphenyl]-4-methyltetrazol-5-one + TX, 1-methyl-4-[3-methyl-2-[[2-methyl-4-(3,4,5trimethylpyrazol-1-yl)phenoxy]methyl] phenyl]tetrazol-5-one + TX, aminopyrifene + TX, amethoctradine + TX, amisulbrom + TX, penflufen + TX, (Z,2E)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy- 2methoxyimino-N,3-dimethylpent-3-enamide + TX, florylpicoxamide + TX, fenpicoxamide + TX, tebufloquin + TX, ipflufenoquin + TX, quinofumeline + TX, isofetamide + TX, N-[2-[2,4dichlorophenoxy]phenyl] -3-(difluoromethyl)-1-methylpyrazole-4-carboxamide + TX, Ν-[2-[2-χλορ-4(trifluoromethyl)phenoxy]phenyl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide + TX, benzothiostrobin + TX, fenamacryl + TX, zinc salt of 5-amino-1,3,4-thiadiazol-2-thiol (2:1) + TX, fluopyram + TX, flutianil + TX, fluopimomide + TX, pyrapropoin + TX , picarbutrazox + TX, 2-(difluoromethyl)N-(3-ethyl-1,1-dimethylindan-4-yl)pyridin-3-carboxamide + TX, 2-(difluoromethyl)-N-((3R)-1, 1,3trimethylindan-4-yl)pyridin-3-carboxamide + TX, 4-[[6-[2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy3-(1,2,4- triazol-1-yl)propyl]-3-pyridyl]oxy]benzonitrile + TX, methyltetraprole + TX, 2(difluoromethyl)-N-((3R)-1,1,3-trimethylindan-4-yl)pyridin-3 -carboxamide + TX, α-(1,1-dimethylethyl)a-[4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]-5-pyrimidinemethanol + TX, fluoxapiproline + TX, enoxastrobin + TX , 4-[[6-[2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1,2,4-triazol-1 -yl)propyl]-3pyridyl]oxy] benzonitrile + TX, 4-[[6-[2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(5-sulfanyl1,2,4-triazol-1-yl)propyl] -3-pyridyl]oxy]benzonitrile + TX, 4-[[6-[2-(2,4-difluorophenyl)-1,1-difluoro2-hydroxy-3-(5-thioxo-4H-1,2,4 -triazol-1-yl)propyl]-3-pyridyl]oxy] enzonitrile + TX, trinexapac + TX, cumoxystrobin + TX, zhongshenmicin + TX, copper thiodiazole + TX, zinc thiazole + TX, amectotractin + TX, iprodione + TX; N'-[5-bromo-2-methyl-6-[(1S)-1-methyl-2-propoxyethoxy]-3-pyridyl]-Nethyl-N-methylformamidine + TX, N'-[5-bromo-2 -methyl-6-[(1 R)-1 -methyl-2-propoxyethoxy]-3-pyridyl]-N ethyl-N-methylformamidine + TX, N-[5-bromo-2-methyl-6-(1- methyl-2-propoxyethoxy)-3-pyridyl]-N-ethylN-methylformamidine + TX, N-[5-chloro-2-methyl-6-(1-methyl-2-propoxyethoxy)-3-pyridyl]-N- ethyl-Nmethylformamidine + TX, N'-[5-bromo-2-methyl-6-(1-methyl-2-propoxyethoxy)-3-pyridyl]-N-isopropyl-Nmethylformamidine + TX (these compounds can be prepared according to methods described in WO 2015/155075); N'-[5-bromo-2-methyl-6-(2-propoxypropoxy)-3-pyridyl]-N-ethyl-N-methylformamidine + TX (this compound can be prepared according to the methods described in IPCOM000249876D); Nisopropyl-N'-[5-methoxy-2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)phenyl]-N-methylformamidine + TX, N'-[4-(1 -cyclopropyl-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-2-methylphenyl]-N-isopropylN-methylformamidine + TX (these compounds can be prepared according to the methods described in WO 2018/228896); N-ethyl-N'-[5-methoxy-2-methyl-4-[2-trifluoromethyl)oxetan-2-yl]phenyl]-Nmethylformamidine + TX, N-ethyl-N'-[5-methoxy-2- methyl 4-[2-trifluoromethyl)tetrahydrofuran-2yl]phenyl]-N-methylformamidine + TX (these compounds can be prepared according to the methods described in WO 2019/110427); N-[(1R)-1-benzyl-3-chloro-1-methylbut-3-enyl]-8-fluoroquinoline-3carboxamide + TX, N-[(1S)-1-benzyl-3,3,3-trifluoro -1-methylpropyl]-8-fluoroquinoline-3-carboxamide + TX, N-[(1S)-1-benzyl-1,3-dimethylbutyl]-7,8-difluoroquinoline-3-carboxamide + TX, 8-fluoro- N[1-[(3fluorophenyl)methyl]-1,3-dimethylbutyl]quinoline-3-carboxamide + TX, N-(1-benzyl-1,3-dimethylbutyl)-8fluoroquinoline-3-carboxamide + TX, N-[ (1R)-1-benzyl-1,3-dimethylbutyl]-8-fluoroquinoline-3-carboxamide + TX, N-[(1S)-1-benzyl-1,3-dimethylbutyl]-8-fluoroquinoline-3-carboxamide + TX, N-(1-benzyl-3-chloro-1methylbut-3-enyl)-8-fluoroquinoline-3-carboxamide + TX (these compounds can be prepared according to the methods described in WO 2017/153380); 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5trifluoro-3,3-dimethylisoquinoline + TQ, 1-(6,7-dimethylpyrazolo[1,5-a ]pyridin-3-yl)-4,4,6-trifluoro-3,3dimethylisoquinoline + TX, 4,4-difluoro-3,3-dimethyl-1-(6-methylpyrazolo[1,5-a]pyridin-3yl )isoquinoline + TX, 4,4-difluoro-3,3-dimethyl-1-(7-methylpyrazolo[1,5-a]pyridin-3-yl)isoquinoline + TX, 1-(6-chloro-7-methylpyrazolo [1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethylisoquinoline + TX (these compounds can be prepared according to the methods described in WO 2017/025510); 1-(4,5dimethylbenzimidazol-1-yl)-4,4,5-trifluoro-3,3-dimethylisoquinoline + TQ, 1-(4,5-dimethylbenzimidazol1-yl)-4,4-difluoro-3,3- dimethylisoquinoline + TX, 6-chloro-4,4-difluoro-3,3-dimethyl-1-(4-methylbenzimidazol-1-yl)isoquinoline + TX, 4,4-difluoro-1-(5-fluoro-4- methylbenzimidazol-1-yl)-3,3-dimethylisoquinoline + TX, 3-(4,4-difluoro-3,3-dimethyl-1-isoquinolyl)-7,8-dihydro-6H-cyclopenta[e]benzimidazole + TX (these compounds can be prepared according to the methods described in WO 2016/156085); Nmethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide + TX, N,2-dimethoxy-N-[[4-[5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide + TX, N-ethyl2-methyl-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl]phenyl]methyl]propanamide + TC, 1-methoxy-3methyl-1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]urea + TX, 1,3-dimethoxy-1-[[4[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]urea + TX, 3-ethyl-1-methoxy-1- [[4-[5(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]urea + TC, N-[[4-[5-(trifluoromethyl)-1,2,4oxadiazol-3 -yl]phenyl]methyl]propanamide + TX, 4,4-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol3-yl]phenyl]methyl]isoxazolidin-3-one + TX, 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3yl]phenyl]methyl]isoxazolidin-3-one + TX, ethyl-1-[[4 -[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phe

- 99 045353 nil]methyl]pyrazol-4-carboxylate + TC, N,N-dimethyl-1-[[4-[5-(trifluoromethyl)-1,2,4-oxaduazol-3yl]phenyl]methyl]-1 ,2,4-triazol-3-amine + TX. The compounds in this paragraph can be prepared according to the methods described in WO 2017/055473, WO 2017/055469, WO 2017/093348 and WO 2017/118689; 2-[6(4-chlorophenoxy)-2-(trifluoromethyl)-3-pyridyl]-1-(1,2,4-triazol-1-yl)propan-2-ol + TX (this compound can be prepared according to methods described in WO 2017/029179); 2-[6-(4-bromophenoxy)-2(trifluoromethyl)-3-pyridyl]-1-(1,2,4-triazol-1-yl)propan-2-ol + TX (this compound can be prepared according to methods described in WO 2017/029179); 3-[2-(1-chlorocyclopropyl)-3-(2fluorophenyl)-2-hydroxypropyl]imidazole-4-carbonitrile + TX (this compound can be prepared according to the methods described in WO 2016/156290); 3-[2-(1-chlorocyclopropyl)-3-(3-chloro-2fluorophenyl)-2-hydroxypropyl]imidazole-4-carbonitrile + TX (this compound can be prepared according to the methods described in WO 2016/156290); (4-phenoxyphenyl)methyl-2-amino-6-methylpyridine-3-carboxylate + TX (this compound can be prepared according to the methods described in WO 2014/006945); 2,6-dimethyl-1H,5H-[1,4]dutuino[2,3-с:5,6-с']dunurrol-1,3,5,7(2H,6H)-tetrona + TC (this the compound can be prepared according to the methods described in WO 2011/138281); N-methyl4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide + TX; N-methyl-4-[5-(trifluoromethyl)1,2,4-oxadiazol-3-yl]benzamide + TX; (Z,2E)-5-[1-(2,4-dichlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethylpent-3-enamide + TX (this compound can be prepared according to methods described in WO 2018/153707); N'-(2-chloro-5-methyl-4-phenoxyphenyl)-N-ethyl-N-methylformamidine + TX; N'-[2-chloro-4-(2-fluorophenoxy)-5-methylphenyl]-N-ethyl-N-methylformamidine + TX (this compound can be prepared according to the methods described in WO 2016/202742); 2-(difluoromethyl)-N[(3S)-3-ethyl-1,1-dimethylindan-4-yl]pyridin-3-carboxamide + TX (this compound can be prepared according to the methods described in WO 2014/095675); (5-methyl-2-pyridyl)-[4-[5-(trifluoromethyl)1,2,4-oxadiazol-3-yl]phenyl]methanone + TX, (3-methylisoxazol-5-yl)-[4- [5-(trifluoromethyl)-1,2,4oxadiazol-3-yl]phenyl]methanone + TX (these compounds can be prepared according to the methods described in WO 2017/220485); 2-oxo-N-propyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3yl]phenyl]acetamide + TX (this compound can be prepared according to the methods described in WO 2018/065414 ); ethyl 1-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-thienyl]methyl]pyrazole-4carboxylate + TX (this compound can be prepared according to the methods described in WO 2018/158365) ; 2,2-difluoro-N-methyl-2-[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]acetamide + TX, N-[(E)-methoxyiminomethyl]- 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide + TX, N-[(Z)methoxyiminomethyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazole -3-yl]benzamide + TX, N-[N-methoxy-Smethylcarbonimidoyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide + TX (these compounds can be prepared according to methods described in WO 2018/202428); microorganisms, including Acinetobacter lwoffii + TX, Acremonium alternatum + TX + TX, Acremonium cephalosporium + TX + TX, Acremonium diospyri + TX, Acremonium obclavatum + TX, Adoxophyes orana granulovirus (AdoxGV) (Capex®) + TX, Agrobacterium radiobacter, strain K84 (Galltrol-A®) + TX, Alternaria alternate + TX, Alternaria cassia + TX, Alternaria destruens (Smolder®) + TX, Ampelomyces quisqualis (AQ10®) + TX, Aspergillus flavus AF36 (AF36®) + TX, Aspergillus flavus NRRL 21882 (Aflaguard®) + TX, Aspergillus spp. + TX, Aureobasidium pullulans + TX, Azospirillum + TX, (MicroAZ® + TX, TAZO B®) + TX, Azotobacter + TX, Azotobacter chroocuccum (Azotomeal®) + TX, Azotobacter cysts (Bionatural Blooming Blossoms®) + TX, Bacillus amyloliquefaciens + TX, Bacillus cereus + TX, Bacillus chitinosporus, strain CM-1 + TX, Bacillus chitinosporus, strain AQ746 + TX, Bacillus licheniformis, strain HB-2 (Biostart™ Rhizoboost®) + TX, Bacillus licheniformis, strain 3086 (EcoGuard ® + TX, Green Releaf®) + TX, Bacillus circulans + TX, Bacillus firmus (BioSafe® + TX, BioNem-WP® + TX, VOTiVO®) + TX, Bacillus firmus, strain I-1582 + TX, Bacillus macerans + TX, Bacillus marismortui + TX, Bacillus megaterium + TX, Bacillus mycoides, strain AQ726 + TX, Bacillus papillae (Milky Spore Powder®) + TX, Bacillus pumilus spp. + TX, Bacillus pumilus, strain GB34 (Yield Shield®) + TX, Bacillus pumilus, strain AQ717 + TX, Bacillus pumilus, strain QST 2808 (Sonata® + TX, Ballad Plus®) + TX, Bacillus spahericus (VectoLex®) + TX, Bacillus spp. + TX, Bacillus spp., strain AQ175 + TX, Bacillus spp., strain AQ177 + TX, Bacillus spp., strain AQ178 + TX, Bacillus subtilis, strain QST 713 (CEASE® + TX, Serenade® + TX, Rhapsody®) + TX, Bacillus subtilis, strain QST 714 (JAZZ®) + TX, Bacillus subtilis, strain AQ153 + TX, Bacillus subtilis, strain AQ743 + TX, Bacillus subtilis, strain QST3002 + TX, Bacillus subtilis, strain QST3004 + TX, Bacillus subtilis variety amyloliquefaciens, strain FZB24 (Taegro® + TX, Rhizopro®) + TX, Cry2Ae Bacillus thuringiensis + TX, Cry1Ab Bacillus thuringiensis + TX, Bacillus thuringiensis aizawai GC 91 (Agree®) + TX, Bacillus thuringiensis israelensis (BMP123® + TX, Aquabac® + TX, VectoBac®) + TX, Bacillus thuringiensis kurstaki (Javelin® + TX, Deliver® + TX, CryMax® + TX, Bonide® + TX, Scutella WP® + TX, Turilav WP ® + TX, Astuto® + TX, Dipel WP® + TX, Biobit® + TX, Foray®) + TX, Bacillus thuringiensis kurstaki BMP 123 (Baritone®) + TX, Bacillus thuringiensis kurstaki HD-1 (Bioprotec-CAF/3P®) + TX, Bacillus thuringiensis , strain BD No. 32 + TX, Bacillus thuringiensis strain AQ52 + TX, Bacillus thuringiensis variety aizawai (XenTari® + TX, DiPel®) + TX, bacterial species (GROWMEND® + TX, GROWSWEET® + TX, Shootup®) +

- 100 045353

TX, bacteriophage Clavipacter michiganensis (AgriPhage®) + TX, Bakflor® + TX, Beauveria bassiana (Beaugenic® + TX, Brocaril WP®) + TX, Beauveria bassiana GHA (Mycotrol ES® + TX, Mycotrol O® + TX, BotaniGuard® ) + TX, Beauveria brongniartii (Engerlingspilz® + TX, Schweizer Beauveria® + TX, Melocont®) + TX, Beauveria spp. + TX, Botrytis cineria + TX, Bradyrhizobium japonicum (TerraMax®) + TX, Brevibacillus brevis + TX, Bacillus thuringiensis tenebrionis (Novodor®) + TX, BtBooster + TX, Burkholderia cepacia (Deny® + TX, Intercept® + TX, Blue Circle®) + TX, Burkholderia gladii + TX, Burkholderia gladioli + TX, Burkholderia spp. + TX, field thistle fungus (SVN Canadian Bioherbicide®) + TX, Candida butyri + TX, Candida famata + TX, Candida fructus + TX, Candida glabrata + TX, Candida guilliermondii + TX, Candida melibiosica + TX, Candida oleophila, strain O + TX, Candida parapsilosis + TX, Candida pelliculosa + TX, Candida pulcherrima + TX, Candida reukaufii + TX, Candida saitoana (Bio-Coat® + TX, Biocure®) + TX, Candida sake + TX, Candida spp. + TX, Candida tenius + TX, Cedecea dravisae + TX, Cellulomonas flavigena + TX, Chaetomium cochliodes (Nova-Cide®) + TX, Chaetomium globosum (Nova-Cide®) + TX, Chromobacterium subtsugae, strain PRAA4-1T (Grandevo® ) + TX, Cladosporium cladosporioides + TX, Cladosporium oxysporum + TX, Cladosporium chlorocephalum + TX, Cladosporium spp. + TX, Cladosporium tenuissimum + TX, Clonostachys rosea (EndoFine®) + TX, Colletotrichum acutatum + TX, Coniothyrium minitans (Cotans WG®) + TX, Coniothyrium spp. + TX, Cryptococcus albidus (YIELDPLUS®) + TX, Cryptococcus humicola + TX, Cryptococcus infirmo-miniatus + TX, Cryptococcus laurentii + TX, Cryptophlebia leucotreta granulovirus (Cryptex®) + TX, Cupriavidus campinensis + TX, Cydia pomonella granulovirus (CYD- X®) + TX, Cydia pomonella granulovirus (Madex® + TX, Madex Plus® + TX, Madex Max/Carpovirusine®) + TX, Cylindrobasidium laeve (Stumpout®) + TX, Cylindrocladium + TX, Debaryomyces hansenii + TX, Drechslera hawaiinensis + TX, Enterobacter cloacae + TX, Enterobacteriaceae + TX, Entomophtora virulenta (Vektor®) + TX, Epicoccum nigrum + TX, Epicoccum purpurascens + TX, Epicoccum spp. + TX, Filobasidium floriforme + TX, Fusarium acuminatum + TX, Fusarium chlamydosporum + TX, Fusarium oxysporum (Fusaclean®/Biofox C®) + TX, Fusarium proliferatum + TX, Fusarium spp. + TX, Galactomyces geotrichum + TX, Gliocladium catenulatum (Primastop® + TX, Prestop®) + TX, Gliocladium roseum + TX, Gliocladium spp. (SoilGard®) + TX, Gliocladium virens (Soilgard®) + TX, Granulovirus (Granupom®) + TX, Halobacillus halophilus + TX, Halobacillus litoralis + TX, Halobacillus trueperi + TX, Halomonas spp. + TX, Halomonas subglaciescola + TX, Halovibrio variabilis + TX, Hanseniaspora uvarum + TX, Helicoverpa armigera nuclear polyhedrosis virus (Helicovex®) + TX, Helicoverpa zea nuclear polyhedrosis virus (Gemstar®) + TX, isoflavone - formononetin (Myconate®) + TX, Kloeckera apiculata + TX, Kloeckera spp. + TX, Lagenidium giganteum (Laginex®) + TX, Lecanicillium longisporum (Vertiblast®) + TX, Lecanicillium muscarium (Vertikil®) + TX, Lymantria Dispar nuclear polyhedrosis virus (Disparvirus®) + TX, Marinococcus halophilus + TX, Meira geulakonigii + TX, Metarhizium anisopliae (Met52®) + TX, Metarhizium anisopliae (Destruxin WP®) + TX, Metschnikowia fruticola (Shemer®) + TX, Metschnikowia pulcherrima + TX, Microdochium dimerum (Antibot®) + TX, Micromonospora coerulea + TX, Microsphaeropsis ochracea + TX, Muscodor albus 620 (Muscudor®) + TX, Muscodor roseus strain A3-5 + TX, Mycorrhizae spp. (AMykor® + TX, Root Maximizer®) + TX, Myrothecium verrucaria, strain AARC-0255 (DiTera®) + TX, BROS PLUS® + TX, Ophiostoma piliferum, strain D97 (Sylvanex®) + TX, Paecilomyces farinosus + TX, Paecilomyces fumosoroseus (PFR-97® + TX, PreFeRal®) + TX, Paecilomyces linacinus (Biostat WP®) + TX, Paecilomyces lilacinus strain 251 (MeloCon WG®) + TX, Paenibacillus polymyxa + TX, Pantoea agglomerans (BlightBan C9- 1®) + TX, Pantoea spp. + TX, Pasteuria spp. (Econem®) + TX, Pasteuria nishizawae + TX, Penicillium aurantiogriseum + TX, Penicillium billai (Jumpstart® + TX, TagTeam®) + TX, Penicillium brevicompactum + TX, Penicillium frequentans + TX, Penicillium griseofulvum + TX, Penicillium purpurogenum + TX , Penicillium spp. + TX, Penicillium viridicatum + TX, Phlebiopsis gigantean (Rotstop®) + TX, phosphate solubilizing bacteria (Phosphomeal®) + TX, Phytophthora cryptogea + TX, Phytophthora palmivora (Devine®) + TX, Pichia anomala + TX, Pichia guilermondii + TX , Pichia membranaefaciens + TX, Pichia onychis + TX, Pichia stipites + TX, Pseudomonas aeruginosa + TX, Pseudomonas aureofasciens (Spot-Less Biofungicide®) + TX, Pseudomonas cepacia + TX, Pseudomonas chlororaphis (AtEze®) + TX, Pseudomonas cor rugate + TX, Pseudomonas fluorescens, strain A506 (BlightBan A506®) + TX, Pseudomonas putida + TX, Pseudomonas reactans + TX, Pseudomonas spp. + TX, Pseudomonas syringae (Bio-Save®) + TX, Pseudomonas viridiflava + TX, Pseudomons fluorescens (Zequanox®) + TX, Pseudozymaflocculosa, strain PF-A22 UL (Sporodex L®) + TX, Puccinia canaliculata + TX, Puccinia thlaspeos (Wood Warrior®) + TX, Pythium paroecandrum + TX, Pythium oligandrum (Polygandron® + TX, Polyversum®) + TX, Pythium periplocum + TX, Rhanella aquatilis + TX, Rhanella spp. + TX, Rhizobia (Dormal® + TX, Vault®) + TX, Rhizoctonia + TX, Rhodococcus globerulus, strain AQ719 + TX, Rhodosporidium diobovatum + TX, Rhodosporidium toruloides + TX, Rhodotorula spp. + TX, Rhodotorula glutinis + TX, Rhodotorula graminis + TX, Rhodotorula mucilagnosa + TX, Rhodotorula rubra + TX, Saccharomyces cerevisiae + TX, Salinococcus roseus + TX, Sclerotinia minor + TX, Sclerotinia minor (SARRITOR®) + TX, Scytalidium spp. + TX, Scytalidium uredinicola + TX, nuclear polyhedrosis virus Spodoptera exigua (Spod-X® + TX, Spexit®) + TX, Serratia marcescens + TX, Serratia plymuthica + TX, Serratia spp. + TX, Sordaria fimicola

- 101 045353 + TX, nuclear polyhedrosis virus Spodoptera littoralis (Littovir®) + TX, Sporobolomyces roseus + TX, Stenotrophomonas maltophilia + TX, Streptomyces ahygroscopicus + TX, Streptomyces albaduncus + TX, Streptomyces exfoliates + TX, Streptomyces galbus + TX , Streptomyces griseoplanus + TX, Streptomyces griseoviridis (Mycostop®) + TX, Streptomyces lydicus (Actinovate®) + TX, Streptomyces lydicus WYEC-108 (ActinoGrow®) + TX, Streptomyces violaceus + TX, Tilletiopsis minor + TX, Tilletiopsis spp. + TX, Trichoderma asperellum (T34 Biocontrol®) + TX, Trichoderma gamsii (Tenet®) + TX, Trichoderma atroviride (Plantmate®) + TX, Trichoderma hamatum TH 382 + TX, Trichoderma harzianum rifai (Mycostar®) + TX, Trichoderma harzianum T-22 (Trianum-P® + TX, PlantShield HC® + TX, RootShield® + TX, Trianum-G®) + TX, Trichoderma harzianum T-39 (Trichodex®) + TX, Trichoderma inhamatum + TX, Trichoderma koningii + TX, Trichoderma spp. LC 52 (Sentinel®) + TX, Trichoderma lignorum + TX, Trichoderma longibrachiatum + TX, Trichoderma polysporum (Binab T®) + TX, Trichoderma taxi + TX, Trichoderma virens + TX, Trichoderma virens (formerly Gliocladium virens GL-21) ( SoilGuard®) + TX, Trichoderma viride + TX, Trichoderma viride strain ICC 080 (Remedier®) + TX, Trichosporon pullulans + TX, Trichosporon spp. + TX, Trichothecium spp. + TX, Trichothecium roseum + TX, Typhula phacorrhiza strain 94670 + TX, Typhula phacorrhiza strain 94671 + TX, Ulocladium atrum + TX, Ulocladium oudemansii (Botry-Zen®) + TX, Ustilago maydis + TX, various bacteria and additional trace elements (Natural II®) + TX, various fungi (Millennium Microbes®) + TX, Verticillium chlamydosporium + TX, Verticillium lecanii (Mycotal® + TX, Vertalec®) + TX, Vip3Aa20 (VIPtera®) + TX, Virgibaclillus marismortui + TX, Xanthomonas campestris pv. Poae (Camperico®) + TX, Xenorhabdus bovienii + TX, Xenorhabdus nematophilus; plant extracts, including pine oil (Retenol®) + TX, azadirachtin (Plasma Neem Oil® + TX, AzaGuard® + TX, MeemAzal® + TX, Molt-X® + TX, Botanical IGR (Neemazad® + TX, Neemix ®) + TX, canola oil (Lilly Miller Vegol®) + TX, Chenopodium ambrosioides near ambrosioides (Requiem®) + TX, Chrysanthemum extract (Crisant®) + TX, Margosa oil extract (Trilogy®) + TX, Labiatae essential oils ( Botania®) + TX, extracts of clove oil, rosemary, peppermint and thyme (Garden insect killer®) + TX, glycine betaine (Greenstim®) + TX, garlic + TX, lemongrass oil (GreenMatch®) + TX, margosa oil + TX , Nepeta cataria (catnip oil) + TX, Nepeta catarina + TX, nicotine + TX, oil of oregano (MossBuster®) + TX, Pedaliaceae oil (Nematon®) + TX, feverfew + TX, Quillaja saponaria (NemaQ®) + TX , Reynoutria sachalinensis (Regalia® + TX, Sakalia®) + TX, rotenone (Eco Roten®) + TX, plant extract from the family Rutaceae (Soleo®) + TX, soybean oil (Ortho ecosense®) + TX, tea tree oil ( Timorex Gold®) + TX, thyme oil + TX, AGNIQUE® MMF + TX, BugOil® + TX, a mixture of rosemary, sesame, peppermint, thyme and cinnamon extracts (EF 300®) + TX, a mixture of clove, rosemary and pepper extracts mint (EF 400®) + TX, a mixture of cloves, peppermint, garlic oil and mint (Soil Shot®) + TX, kaolin (Screen®) + TX, a glucan stored by brown algae (Laminarin®); pheromones, including blackheaded fireworm pheromone (3M Sprayable Blackheaded Fireworm Pheromone®) + TX, codling moth pheromone (Paramount dispenser-(CM)/ Isomate C-Plus®) + TX, grape leafroller pheromone (3M MEC-GBM Sprayable Pheromone® ) + TX, leafroller pheromone (3M MEC - LR Sprayable Pheromone®) + TX, muscamon (Snip7 Fly Bait® + TX, Starbar Premium Fly Bait®) + TX, eastern peach leafroller pheromone (3M oriental fruit moth sprayable pheromone®) + TX, peach glassworm pheromone (Isomate-P®) + TX, tomato pinworm pheromone (3M Sprayable pheromone®) + TX, Entostat powder (palm tree extract) (Exosex CM®) + TX, (E + TX,Z + TX,Z)-3 + TX,8 + TX,11 tetradecatrienylacetate + TX, (Z + TX,Z + TX,E)-7 + TX,11 + TX,13-hexadecatrienal + TX, (E + TX,Z )7 + TX,9-dodecadien-1-yl acetate + TX, 2-methyl-1-butanol + TX, calcium acetate + TX, Scenturion® + TX, Biolure® + TX, Check-Mate® + TX, lavandulyl senate; macroorganisms, including Aphelinus abdominalis + TX, Aphidius ervi (Aphelinus-System®) + TX, Acerophagus papaya + TX, Adalia bipunctata (Adalia-System®) + TX, Adalia bipunctata (Adaline®) + TX, Adalia bipunctata (Aphidalia ®) + TX, Ageniaspis citricola + TX, Ageniaspis fuscicollis + TX, Amblyseius andersoni (Anderline® + TX, Andersoni-System®) + TX, Amblyseius californicus (Amblyline® + TX, Spical®) + TX, Amblyseius cucumeris (Thripex® + TX, Bugline cucumeris®) + TX, Amblyseius fallacis (Fallacis®) + TX, Amblyseius swirskii (Bugline swirskii® + TX, Swirskii-Mite®) + TX, Amblyseius womersleyi (WomerMite®) + TX, Amitus hesperidum + TX, Anagrus atomus + TX, Anagyrus fusciventris + TX, Anagyrus kamali + TX, Anagyrus loecki + TX, Anagyrus pseudococci (Citripar®) + TX, Anicetus benefices + TX, Anisopteromalus calandrae + TX, Anthocoris nemoralis (Anthocoris-System®) + TX, Aphelinus abdominalis (Apheline® + TX, Aphiline®) + TX, Aphelinus asychis + TX, Aphidius colemani (Aphipar®) + TX, Aphidius ervi (Ervipar®) + TX, Aphidius gifuensis + TX, Aphidius matricariae (Aphipar-M®) + TX, Aphidoletes aphidimyza (Aphidend®) + TX, Aphidoletes aphidimyza (Aphidoline®) + TX, Aphytis lingnanensis + TX, Aphytis melinus + TX, Aprostocetus hagenowii + TX, Atheta coriaria (Staphyline®) + TX, Bombus spp. + TX, Bombus terrestris (Natupol Beehive®) + TX, Bombus terrestris (Beeline® + TX, Tripol®) + TX, Cephalonomia stephanoderis + TX, Chilocorus nigritus + TX, Chrysoperla carnea (Chrysoline®) + TX, Chrysoperla carnea (Chrysopa ®) + TX, Chrysoperla rufilabris + TX, Cir

- 102 045353 rospilus ingenuus + TX, Cirrospilus quadristriatus + TX, Citrostichus phyllocnistoides + TX, Closterocerus chamaeleon + TX, Closterocerus spp. + TX, Coccidoxenoides perminutus (Planopar®) + TX, Coccophagus cowperi + TX, Coccophagus lycimnia + TX, Cotesia flavipes + TX, Cotesia plutellae + TX, Cryptolaemus montrouzieri (Cryptobug® + TX, Cryptoline®) + TX, Cybocephalus nipponicus + TX , Dacnusa sibirica + TX, Dacnusa sibirica (Minusa®) + TX, Diglyphus isaea (Diminex®) + TX, Delphastus catalinae (Delphastus®) + TX, Delphastus pusillus + TX, Diachasmimorpha krausii + TX, Diachasmimorpha longicaudata + TX, Diaparsis jucunda + TX, Diaphorencyrtus aligarhensis + TX, Diglyphus isaea + TX, Diglyphus isaea (Miglyphus® + TX, Digline®) + TX, Dacnusa sibirica (DacDigline® + TX, Minex®) + TX, Diversinervus spp. + TX, Encarsia citrina + TX, Encarsia formosa (Encarsia max® + TX, Encarline® + TX, En-Strip®) + TX, Eretmocerus eremicus (Enermix®) + TX, Encarsia guadeloupae + TX, Encarsia haitiensis + TX, Episyrphus balteatus (Syrphidend®) + TX, Eretmoceris siphonini + TX, Eretmocerus californicus + TX, Eretmocerus eremicus (Ercal® + TX, Eretline e®) + TX, Eretmocerus eremicus (Bemimix®) + TX, Eretmocerus hayati + TX, Eretmocerus mundus ( Bemipar® + TX, Eretline m®) + TX, Eretmocerus siphonini + TX, Exochomus quadripustulatus + TX, Feltiella acarisuga (Spidend®) + TX, Feltiella acarisuga (Feltiline®) + TX, Fopius arisanus + TX, Fopius ceratitivorus + TX, formononetin (Wirless Beehome®) + TX, Franklinothrips vespiformis (Vespop®) + TX, Galendromus occidentalis + TX, Goniozus legneri + TX, Habrobracon hebetor + TX, Harmonia axyridis (HarmoBeetle®) + TX, Heterorhabditis spp. (Lawn Patrol®) + TX, Heterorhabditis bacteriophora (NemaShield HB® + TX, Nemaseek® + TX, Terranem-Nam® + TX, Terranem® + TX, Larvanem® + TX, B-Green® + TX, NemAttack ® + TX , Nematop®) + TX, Heterorhabditis megidis (Nemasys H® + TX, BioNem H® + TX, Exhibitline hm® + TX, Larvanem-M®) + TX, Hippodamia convergens + TX, Hypoaspis aculeifer (Aculeifer-System® + TX , Entomite-A®) + TX, Hypoaspis miles (Hypoline m® + TX, Entomite-M®) + TX, Lbalia leucospoides + TX, Lecanoideus floccissimus + TX, Lemophagus errabundus + TX, Leptomastidea abnormis + TX, Leptomastix dactylopii (Leptopar ®) + TX, Leptomastix epona + TX, Lindorus lophanthae + TX, Lipolexis oregmae + TX, Lucilia caesar (Natufly®) + TX, Lysiphlebus testaceipes + TX, Macrolophus caliginosus (Mirical-N® + TX, Macroline c® + TX, Mirical®) + TX, Mesoseiulus longipes + TX, Metaphycus flavus + TX, Metaphycus lounsburyi + TX, Micromus angulatus (Milacewing®) + TX, Microterys flavus + TX, Muscidifurax raptorellus and Spalangia cameroni (Biopar®) + TX, Neodryinus typhlocybae + TX, Neoseiulus californicus + TX, Neoseiulus cucumeris (THRYPEX®) + TX, Neoseiulus fallacis + TX, Nesideocoris tenuis (NesidioBug® + TX, Nesibug®) + TX, Ophyra aenescens (Biofly®) + TX, Orius insidiosus (Thripor-I ® + TX, Oriline i®) + TX, Orius laevigatus (Thripor-L® + TX, Online l®) + TX, Orius majusculus (Oriline m®) + TX, Orius strigicollis (Thripor-S®) + TX, Pauesia juniperorum + TX, Pediobius foveolatus + TX, Phasmarhabditis hermaphrodita (Nemaslug®) + TX, Phymastichus coffea + TX, Phytoseiulus macropilus + TX, Phytoseiulus persimilis (Spidex® + TX, Phytoline p®) + TX, Podisus maculiventris (Podisus®) + TX, Pseudacteon curvatus + TX, Pseudacteon obtusus + TX, Pseudacteon tricuspis + TX, Pseudaphycus maculipennis + TX, Pseudleptomastix mexicana + TX, Psyllaephagus pilosus + TX, Psyttalia concolor (species complex) + TX, Quadrastichus spp. + TX, Rhyzobius lophanthae + TX, Rodolia cardinalis + TX, Rumina decollate + TX, Semielacher petiolatus + TX, Sitobion avenae (Ervibank®) + TX, Steinernema carpocapsae (Nematac C® + TX, Millenium® + TX, BioNem C® + TX, NemAttack® + TX, Nemastar® + TX, Capsanem®) + TX, Steinernema feltiae (NemaShield® + TX, Nemasys F® + TX, BioNem F® + TX, Steinemema-System® + TX, NemAttack® + TX, Nemaplus® + TX, Exhibitline sf® + TX, Scia-rid® + TX, Entonem®) + TX, Steinernema kraussei (Nemasys L® + TX, BioNem L® + TX, Exhibitline srb®) + TX, Steinernema riobrave (BioVector ® + TX, BioVektor®) + TX, Steinernema scapterisci (Nematac S®) + TX, Steinernema spp. + TX, Steinernematid spp. (Guardian Nematodes®) + TX, Stethorus punctillum (Stethorus®) + TX, Tamarixia radiate + TX, Tetrastichus setifer + TX, Thripobius semiluteus + TX, Torymus sinensis + TX, Trichogramma brassicae (Tricholine b®) + TX, Trichogramma brassicae ( TrichoStrip®) + TX, Trichogramma evanescens + TX, Trichogramma minutum + TX, Trichogramma ostriniae + TX, Trichogramma plaineri + TX, Trichogramma pretiosum + TX, Xanthopimpla stemmator; and other biologicals, including abscisic acid + TX, bioSea® + TX, Chondrostereum purpureum (Chontrol Paste®) + TX, Colletotrichum gloeosporioides (Collego®) + TX, copper octanoate (Cueva®) + TX, delta traps (Trapline d®) + TX, Erwinia amylovora (harpin) (ProAct® + TX, Ni-HIBIT Gold CST®) + TX, ferrophosphate (Ferramol®) + TX, funnel traps (Trapline u®) + TX, Gallex® + TX, Grower's Secret® + TX, Homobrassinolide + TX, Ferric Phosphate (Lilly Miller Worry Free Ferramol Slug & Snail Bait®) + TX, MCPhail (Trapline f®) + TX, Microctonus hyperodae + TX, Mycoleptodiscus terrestris (Des-X®) + TX, BioGain® + TX, Aminomite® + TX, Zenox® + TX, pheromone trap (Thripline ams®) + TX, potassium bicarbonate (MilStop®) + TX, potassium salts of fatty acids (Sanova®) + TX, silicate solution potassium (Sil-Matrix®) + TX, potassium iodide + potassium thiocyanate (Enzicur®) + TX, SuffOil-X® + TX, spider venom + TX, Nosema locustae (Semaspore Organic Grasshopper Control®) + TX, sticky traps (Trapline YF® + TX, Rebell Amarillo®) + TX and traps (Takitrapline y + b®) + TX.

References in square brackets after active ingredients, for example [3878-19-1], refer to Chemical Abstracts Service number 103 045353. The above-described mixing ingredients are known. If the active ingredients are included in The Pesticide Manual [The Pesticide Manual - A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; British Crop Protection Council], they are described therein under the entry number given in this document above in parentheses for the specific compound; for example, the compound abamectin is described under registration number (1). If [CCN] is appended to a particular compound above in this document, then the compound in question is included in the Compendium of Pesticide Common Names, which is available online [A. Wood; Compendium of Pesticide Common Names, Copyright © 1995-2004]; for example, the compound acetoprole is described at the Internet address http://www.alanwood.net/pesticides/acetoprole.html.

Most of the active ingredients described above are listed above under the so-called common name, corresponding to the ISO common name or other common name used in individual cases. If the designation is not a common name, for a particular compound the nature of the designation used instead is given in parentheses; in this case, use the IUPAC name, the IUPAC/Chemical Abstract Service name, the chemical name, the traditional name, the compound name, or the development code, or, if neither of these names nor the common name is used, then the alternative name is used.

CAS Registration No. means the registration number according to the Chemical Abstract Service.

A mixture of active ingredients of compounds of formula I selected from the compounds defined in table. A-1 - A-27, B-1 - B-27, C-1 - C-27, D-1 - D-27 and E-1 - E-27, and with the active ingredients described above, contains the compound , selected from one compound defined in table. A-1 - A-27, B-1 - B-27, C-1 - C-27, D-1 - D-27 and E-1 - E-27, and the active ingredient described above, preferably in the ratio components in a mixture of from 100:1 to 1:6000, in particular from 50:1 to 1:50, more preferably at a ratio of from 20:1 to 1:20, even more preferably from 10:1 to 1:10, extremely preferably 5:1 to 1:5, with particular preference being given to a ratio of 2:1 to 1:2, while a ratio of 4:1 to 2:1 is also preferred, especially for a ratio of 1:1 or 5 :1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1 :5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1 :600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1 :3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. These mixture ratios are given by weight.

The above-described mixtures can be used in a pest control method that involves applying a composition containing the above-described mixture to pests or their habitat, excluding the method of treating a human or animal body by surgery or therapy and diagnostic methods used in practice on the body person or animal.

Mixtures containing a compound of formula I selected from the compounds defined in table. A-1A-27, B-1-B-27, C-1-C-27, D-1-D-27 and E-1-E-27, and one or more of the active ingredients described above may be used , for example, in the form of a separate ready-mix, in a combined spray mixture consisting of separate formulations of individual components representing the active ingredients, such as a tank mixture, and in the combined use of individual active ingredients, in the case of their application in a sequential manner, i.e. . one after the other within an acceptable short period such as a few hours or days.

The order of use of the compounds of formula I and the active ingredients described above is not necessary for the practice of the present invention.

The compositions of the present invention may also contain additional solid or liquid auxiliaries such as stabilizers, for example non-epoxidized or epoxidized vegetable oils (for example, epoxidized coconut oil, rapeseed oil or soybean oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients to provide specific effects, for example bactericides, fungicides, nematicides, plant growth promoters, molluscicides or herbicides.

The compositions according to the present invention are prepared in a manner known per se, in the absence of auxiliary agents, for example by grinding, sieving and/or pressing the solid active ingredient, and in the presence of at least one auxiliary agent, for example by thoroughly mixing and/or grinding the active ingredient with excipient(s). Such methods for preparing compositions and the use of compounds I to obtain such compositions are also the object of the present invention.

Methods of application of the compositions, that is, methods of controlling pests of the above type, such as spraying, sprinkling, dusting, brushing, pelleting, scattering or pouring, which will be selected to meet the intended purposes taking into account the given circumstances, and the use of compositions for controlling pests of the above type are others

- 104 045353 objects of the present invention. Typical concentration levels of the active ingredient are from 0.1 to 1000 ppm, preferably from 0.1 to 500 ppm. The application rate per hectare is generally from 1 to 2000 g of active ingredient per hectare, in particular from 10 to 1000 g/ha, preferably from 10 to 600 g/ha.

The preferred method of application in the field of crop protection is foliar application (foliar application), and the frequency and rate of application can be selected according to the risk of infestation by the pest in question. Alternatively, the active ingredient may reach the plants through the root system (systemic action) by irrigating the plant site with a liquid composition or by incorporating the active ingredient in solid form into the plant site, for example into the soil, for example in the form of granules (applied to soil). In the case of the paddy crop, such granules can be dosed in a certain quantity into a flooded paddy field.

The compounds of formula I of the present invention and compositions based thereon are also suitable for protecting plant propagation material, for example seeds such as fruit, tubers or grains, or seedlings from pests of the type mentioned above. Propagation material can be treated with a compound before planting, for example seed can be treated before sowing. Alternatively, the compound can be applied to seed pits (coating), either by soaking the pits in a liquid composition or by applying a layer of a solid composition. The compositions can also be used when planting propagation material at the site of application, for example, when applied to a seed furrow during row sowing. These methods for treating plant propagation material and the plant propagation material thus treated are further objects of the present invention. Typical application rates will depend on the plant and the pest/fungi being controlled and will typically range from 1 to 200 g per 100 kg seed, preferably from 5 to 150 g per 100 kg seed, such as 10 to 100 g per 100 kg of seeds.

The term seed includes seeds and vegetative parts of plants of all kinds, including, without limitation, true seeds, seed pieces, root shoots, cereal grains, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots, etc., and according to in a preferred embodiment means true seeds.

The present invention also provides seeds coated or treated with or containing a compound of formula I. The term coated or treated and/or containing generally means that the active ingredient is present on most of the surface of the seed at the time of application, although more or less of the ingredient may penetrate into the seed depending on the method of application. If said seed product is (re)planted, it can absorb the active ingredient. In one embodiment, the present invention provides a plant propagation material having a compound of Formula I attached thereto. Also provided herein is a composition comprising a plant propagation material treated with a compound of Formula I.

Seed treatment includes all suitable seed treatment techniques known in the art, such as seed pelleting, seed coating, seed dusting, seed soaking and seed pelleting. The use of a compound of formula I in seed treatment can be carried out using any known methods, such as spraying on the seeds or dusting the seeds, before sowing or during sowing/planting of the seeds.

In each aspect and embodiment of the present invention, the expression comprising essentially and its modified forms are a preferred embodiment of the expression consisting of and its modified forms, and the expression consisting of and its modified forms are a preferred embodiment of the expression essentially consisting of and its modified forms.

The disclosure of this application represents each and every combination of embodiments disclosed herein.

It should be noted that the disclosure herein regarding a compound of formula I is equally applicable to a compound of each of formulas I*, I'a, I-A, I'-A, and Table. A-1 - A27, B-1 - B-27, C-1 - C-27, D-1 - D-27 and E-1 - E-27. In addition, the preferred enantiomer of formula I'a is also applicable to the compounds in table. A-1 - A-27, B-1 - B-27, C-1 - C-27, D-1 D-27 and E-1 - E-27.

The compounds of the present invention may differ from other similar compounds due to higher effectiveness at low application rates and/or control of different pest species, which can be verified by one skilled in the art using experimental techniques, using lower concentrations if necessary, for example, 10 ppm , 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, for example, 300 mg a.i., 200 mg a.i. or 100 mg a.i. per m ² . Greater effectiveness may be observed through a more favorable safety profile (against non-target organisms living on and in soil (such as fish,

- 105 045353 birds and bees), improved physico-chemical properties or increased biodegradability).

Biological examples

The following examples serve to illustrate the present invention. Certain compounds of the present invention may differ from known compounds by being more effective at low application rates, as can be verified by one skilled in the art using the experimental procedures set forth in the Examples, using lower application rates if necessary, e.g. 50 ppm, 24 ppm , 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.

Example B1. Diabrotica balteata (corn beetle).

Maize seedlings plated on an agar layer in 24-well microtiter plates were treated with aqueous solutions of the test compound prepared from DMSO stock solutions containing 10,000 ppm by nebulization. After drying, the plates were inoculated with L2 larvae (6-10 per well). Samples were assessed for mortality and growth inhibition compared to untreated samples 4 days postinfection.

The following compounds provided an effect representing at least 80% control, in at least one of two categories (mortality or growth inhibition), at an application rate of 200 ppm: P1, P2, P3, P4, P6, P7, P8, P9 , R13, R16, R19, R22, R23, R24, R25, R27, R28, R29, R32, R33, R34, R36, R37, R38, R40, R41, R42, R43, R44, R46, R47, R48, R49 , P50.

Example B2. Euschistus heros (Neotropical brown stink bug)

Soybean leaves on agar in 24-well microtiter plates were sprayed with aqueous solutions of the test compound prepared from stock solutions in DMSO containing 10,000 ppm. After drying, the leaves were infested with N2 nymphs.

Samples were assessed for mortality and growth inhibition compared to untreated samples 5 days postinfection.

The following compounds provided an effect representing at least 80% control in at least one of two categories (mortality or growth inhibition) at a dose rate of 200 ppm: P2, P28, P29, P32, P34, P36, P40, P47, P48, P49.

Example B3. Frankliniella occidentalis (Western flower thrips): Feeding/contact effects.

Sunflower leaf disks were placed on agar in 24-well microtiter plates and sprayed with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, leaf discs were infected with Frankliniella populations of different ages. At 7 days postinfection, samples were assessed for mortality.

The following compounds resulted in at least 80% mortality at 200 ppm: P44, P48.

Example B4. Chilo suppressalis (yellow rice moth)

24-well microtiter plates containing artificial culture media were pipetted with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, the plates were inoculated with L2 larvae (6-8 per well). Samples were assessed for mortality, counterfeeding, and growth inhibition compared to untreated samples 6 days postinfection. Control of Chilo suppressalis by a sample of the test compound was present if at least one of the categories representing mortality, antifeeding and growth inhibition was higher than that of the untreated sample. The following compounds provided at least 80% control in at least one of three categories (mortality, nutritional interference, or growth inhibition) at the 200 ppm application rate: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P22, P23, P24, P25, P26, P27, P28, P29, P32, P33, P34, P35, P36, P37, P38, P39, P40, P41, P42, P43, P44, P45, P46, P47, P48, P49, P50.

Example B5. Plutella xylostella (cabbage moth)

24-well microtiter plates containing artificial culture media were pipetted with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, Plutella eggs were pipetted through a plastic stencil onto gel blotting paper and covered the plate. Samples were assessed for mortality and growth inhibition compared to untreated samples 8 days postinfection.

The following compounds provided an effect representing at least 80% control in at least one of two categories (mortality or growth inhibition) at a dose rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P22, P23, P24, P25, P26, P27, P28, P29, P30, P32, P33, P34, P35, P36, P37, P38, P39, P40, P41, P42, P43, P44, P45, P46, P47, P48, P49, P50.

- 106 045353

Example B6. Myzus persicae (green peach aphid)

Feeding/contact action

Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, the leaf discs were infested with populations of aphids of different ages. Samples were assessed for mortality 6 days postinfection.

The following compounds resulted in at least 80% mortality at 200 ppm: 49.

Example B7. Myzuspersicae (green peach aphid)

System activity

Roots of pea seedlings infested with aphid populations of different ages were placed directly into aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. Samples were assessed for mortality 6 days after seedlings were placed in solutions of test compounds.

Example B8. Myzus persicae (green peach aphid) Intrinsic activity Test compounds prepared from stock solutions in DMSO containing 10,000 ppm were pipetted into 24-well microtiter plates and mixed with sucrose solution. The plates were covered with stretchable Parafilm film. A 24-hole plastic stencil was placed on the plate and infected pea seedlings were placed directly onto the Parafilm film. Plates containing infected plants were covered with gel blotting paper and another plastic stencil and then turned upside down. Samples were assessed for mortality 5 days postinfection.

The following compounds resulted in at least 80% mortality at the test compound rate of 12 ppm: P2, P9, P32, P34, P37, P40, P44, P47, P48, P49.

Example B9. Spodoptera littoralis (Egyptian cotton bollworm)

Cotton leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, leaf discs were infested with five L1 larvae. Samples were assessed for mortality, counterfeeding, and growth inhibition compared to untreated samples 3 days postinfection. Control of Spodoptera littoralis by test samples was present if at least one of the categories of mortality, antifeedant effect and growth inhibition was higher than for the untreated sample.

The following compounds provided at least 80% control in at least one of three categories (mortality, nutritional interference, or growth inhibition) at the 200 ppm application rate: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P22, P23, P24, P25, P26, P28, P29, P32, P33, P34, P35, P36, P37, P38, P39, P40, P41, P42, P43, P44, P46, P47, P48, P49, P50.

Example B10. Spodoptera littoralis (Egyptian cotton bollworm)

Test compounds were pipetted using 10,000 ppm DMSO stock solutions into 24-well plates and mixed with agar. Lettuce seeds were placed on agar and the multiwell plate was covered with another plate that also contained agar. After 7 days, the compound was absorbed by the roots and the lettuce sprouted into the plate placed on top. Then lettuce leaves were cut into a tablet placed on top. Spodoptera eggs were pipetted through a plastic stencil onto moistened gel blotting paper and covered the plate. Samples were assessed for mortality, counterfeeding, and growth inhibition compared to untreated samples 6 days postinfection.

The following compounds provided an effect representing at least 80% control in at least one of three categories (mortality, nutritional interference, or growth inhibition) at the 12.5 ppm test compound rate: P32, P34, P36, P40.

Example B11. Tetranychus urticae (two-spotted spider mite)

Bean leaf disks in 24-well agar microtiter plates were sprayed with aqueous solutions of test compounds prepared from stock solutions in DMSO containing 10,000 ppm. After drying, the leaf discs were infested with a population of mites of different ages. Samples were assessed for mixed population mortality (mobile stages) 8 days postinfection.

The following compounds resulted in at least 80% mortality at 200 ppm: P22.

Example B12. Myzus persicae (green peach aphid)

Test compounds prepared from stock solutions in DMSO containing 10,000 ppm were added using an automated liquid handler into 96-well microtiter plates and mixed with sucrose solution. Parafilm was stretched over a 96-well microtiter plate and a 96-hole plastic stencil was placed on the plate. Aphids were sifted into wells directly onto Parafilm. The infected plates were covered with a gel blotting card and a second plastic stencil and then turned upside down. Samples of assessment - 107 -

Claims (17)

nivali in terms of mortality 5 days after infection. The following compounds resulted in at least 80% mortality at 50 ppm: P25, P32, P34, P36, P40. Example B13. Plutella xylostella (cabbage moth) 96-well microtiter plates containing artificial culture medium were treated with aqueous solutions of test compound prepared from 10,000 ppm DMSO stock solutions using an automated liquid handling device. After drying, infection was carried out by placing eggs (-30 per well) on a mesh lid, which was suspended above the nutrient medium. The eggs hatched into L1 larvae, which moved down to the nutrient medium. Samples were assessed for mortality 9 days postinfection. The following compounds provided an effect representing at least 80% mortality at a dose rate of 500 ppm: P19, P20, P22, P23, P24, P25, P26, P27, P28, P29, P31, P32, P33, P34, P36, P37, P38, P39, P40, P41. CLAIM 1. Compound of formula I R ₂ b R§a I where R1 is hydrogen, methyl or cyclopropylmethyl; A1 represents N or CH; R _2a is cyclopropyl, 1-methoxycyclopropyl, 2-(trifluoromethyl)cyclopropyl, 1-cyanocyclopropyl, cyclopropyl(difluoro)methyl, 1-cyano-1-methylethyl or trifluoromethylsulfonyl; R _2b is trifluoromethyl, difluoromethoxy or trifluoromethoxy; R ₃ represents methyl; A2 represents CH or N; R4 _a is cyano, difluoromethoxy, 2,2,2-trifluoromethoxy or 2,2-difluoroethoxy; R _5a and R _5b are hydrogen; or agrochemically acceptable salts and stereoisomers of compounds of formula I. 2. The compound according to claim 1, where A1 represents N. 3. The compound according to claim 1, where A1 represents CH. 4. A compound according to any one of claims 1 to 3, where R1 represents hydrogen. 5. A compound according to any one of claims 1 to 4, wherein R _2a represents 1-cyanocyclopropyl. 6. A compound according to any one of claims 1 to 5, wherein R _2b represents trifluoromethyl. 7. A compound according to any one of claims 1 to 6, where R4 _a represents cyano. 8. A compound according to any one of claims 1 to 7, where A ₂ represents N. 9. A compound according to any one of claims 1 to 7, where A ₂ represents CH. 10. A compound according to any one of claims 1 to 9, wherein said compound is an enantiomer. 11. A pesticide composition comprising a compound according to any one of claims 1 to 10, one or more auxiliary agents and a diluent, and optionally another additional active ingredient. 12. A method of combating and controlling insects, mites, nematodes or mollusks, which includes applying an insecticidal, acaricidal, nematocidal or molluscicidal effective amount of a compound according to any one of claims to a pest, to a pest habitat or to a plant susceptible to attack by a pest. 1-10 or compositions according to claim 11. 13. A method of protecting plant propagation material from attack by insects, mites, nematodes or molluscs, which includes treating the propagation material or the area where the propagation material is planted with an effective amount of a compound according to any one of claims 1 to 10 or a composition according to claim .eleven. 14. A method of controlling parasites in or on an animal in need thereof, comprising administering an effective amount of a compound according to any one of claims 1 to 10 or a composition according to claim 11. 15. A plant propagation material containing, treated with, or attached to a compound according to any one of claims 1 to 10 or a composition according to claim 11. 16. The plant propagation material according to claim 15, wherein the plant propagation material is a seed. 17. Compound of formulas IIaa - 108 045353 where Ri is as defined in claim 1 or 4, and R4 is a cyclic group containing A ₂ and the substituent R4 _a in formula I, where A ₂ and R4 _a are as defined in any of claim 1, 7, 8 and 9. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 109-