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

The present invention relates to pesticidally active, in particular insecticidally active, cyclic sulfonimidamide and sulfoximine compounds, e.g. as active ingredients, which have pesticidal activity. The invention also relates to preparation of these cyclic sulfonimidamide and sulfoximine compounds, to intermediates useful in the preparation of these cyclic sulfonimidamide and sulfoximine compounds, to the preparation of these intermediates, to agrochemical compositions which comprise at least one of these cyclic sulfonimidamide and sulfoximine compounds, to preparation of these compositions and to the use of these cyclic sulfonimidamide and sulfoximine compounds or compositions in agriculture or horticulture for controlling animal pests, including arthropods and in particular insects or representatives of the order Acarina.

There have now been found further novel pesticidally active bicyclic sulfonimidamide and sulfoximine compounds.

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

Compounds of formula I which have at least one basic centre 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, a phosphorus acid or a hydrohalic acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example by 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 C1-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Compounds of formula I which have 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 mono-, di- or tri-lower-alkylamine, for example ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower-alkylamine, for example mono-, di- or triethanolamine.

In each case, the compounds of formula I according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.

N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Hieterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.

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

The term “C1-Cnalkoxy” as used herein refers to a straight-chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. The term “C1-Cnhaloalkoxy” as used herein refers to a C1-Cnalkoxy radical where one or more hydrogen atoms on the alkyl radical is replaced by the same or different halo atom(s)—examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.

The term “C1-CnalkoxyC1-Cmalkyl” as used herein refers to an alkoxy radical having 1 to n carbon atoms (as mentioned above) which is attached via the oxygen atom to an alkyl radical having 1 to m carbon atoms (as mentioned above), which alkyl radical is connected to the rest of the molecule.

The term “C1-Cncyanoalkyl” as used herein refers to a straight chain or branched saturated C1-Cnalkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in these radicals is replaced by a cyano group —CN: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, and the like.

The term “C1-Cnnitroalkyl” as used herein refers to a straight chain or branched saturated C1-Cnalkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in these radicals is replaced by a nitro group —NO2: for example, nitromethyl, 2-nitroethyl, 2-nitropropyl, 3-nitropropyl, 1-(nitromethyl)-2-ethyl, 1-(methyl)-2-nitroethyl, 4-nitrobutyl, and the like.

The term “C3-Cncycloalkyl” as used herein refers to 3-n membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term “C3-Cncycloalkylcarbonyl” as used herein refers to a 3-n membered cycloalkyl group attached to a carbonyl (C═O) group, which carbonyl group is connected to the rest of the molecule. Similarly the terms “C1-Cnalkylcarbonyl”, “C1-Cnalkoxycarbonyl”, “phenyloxycarbonyl” and “benzyloxycarbonyl” as used herein refers to an alkyl, alkoxy, phenyloxy and benzyloxy group attached to a carbonyl (C═O) group, which carbonyl group is connected to the rest of the molecule.

The term “C3-C4cycloalkylC1-C2alkyl” as used herein refers to 3 or 4 membered cycloalkyl group with either a methylene or ethylene group, which methylene or ethylene group is connected to the rest of the molecule. In the instance the C3-C4cycloalkyl-C1-C2alkyl group is substituted, the substituent(s) can be on the cycloalkyl group and/or on the alkyl group.

The term “C3-C6cycloalkylC1-C4haloalkoxy” as used herein refers to a 3 to 6 membered cycloalkyl group connected to a 1 to 4 membered haloalkoxy group, which haloalkoxy group is connected to the rest of the molecule.

The term “aminocarbonylC1-Cnalkyl” as used herein refers to an alkyl radical where one of the hydrogen atoms in the radical is replaced by CONH2 group.

The term “hydroxycarbonylC1-Cnalkyl” as used herein refers to an alkyl radical where one of the hydrogen atoms in the radical is replaced by COOH group.

The term “C1-Cnalkylsulfanyl” as used herein refers to a C1-Cnalkyl moiety linked through a sulfur atom. Similarly, the term “C1-Cnhaloalkylthio” or “C1-Cnhaloalkylsulfanyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through a sulfur atom. Similarly, the term “C3-Cncycloalkylsulfanyl” refers to 3-n membered cycloalkyl moiety linked through a sulfur atom.

The term “C1-Cnalkylsulfinyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O) group. Similarly, the term “C1-Cnhaloalkylsulfinyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O) group. Similarly, the term “C3-Cncycloalkylsulfinyl” refers to 3-n membered cycloalkyl moiety linked through the sulfur atom of the S(═O) group.

The term “C1-Cnalkylsulfonyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O)2group. Similarly, the term “C1-Cnhaloalkylsulfonyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O)2group. Similarly, the term “C3-Cncycloalkylsulfonyl” refers to 3-n membered cycloalkyl moiety linked through the sulfur atom of the S(═O)2group

The term “trimethylsilaneC1-Cnalkyl” as used herein refers to an alkyl radical where one of the hydrogen atoms in the radical is replaced by a —Si(CH3)3group.

The term “C2-Cnalkenyl” as used herein 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.

The term “C2-Cnhaloalkenyl” as used herein refers to a C2-Cnalkenyl moiety substituted with one or more halo atoms which may be the same or different.

The term “C2-Cnalkynyl” as used herein refers to a straight or branched alkynyl chain having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl.

The term “C2-Cnhaloalkynyl” as used herein refers to a C2-Cnalkynyl moiety substituted with one or more halo atoms which may be the same or different.

Halogen or “halo” is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl.

The term “heteroaryl” as used herein refers to a 5- or 6-membered aromatic monocyclic ring having 1 to 3 heteroatoms independently selected from N, O and S. Examples are heteroaryls J-1 to J-41 shown in Scheme A below. Preferred heteroaryl is pyridyl, pyrimidyl, and pyrazolyl.

The pyridine, pyrimidine, pyrazine and pyridazine groups (unsubstituted or substituted) for R4and R4aare each connected via a carbon atom on the respective ring to the rest of the compound.

As used herein, the term “controlling” refers to reducing the number of pests, eliminating pests and/or preventing further pest damage such that damage to a plant or to a plant derived product is reduced.

The staggered line as used herein, for example, in Qa-1 and Qb-1, represent the point of connection/attachment to the rest of the compound.

As used herein, the term “pest” refers to insects, and molluscs that are found in agriculture, horticulture, forestry, the storage of products of vegetable origin (such as fruit, grain and timber); and those pests associated with the damage of man-made structures. The term pest encompasses all stages in the life cycle of the pest.

As used herein, the term “effective amount” refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect. An effective amount is readily determined by the skilled person in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled & its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.

As one of ordinary skill in the art will appreciate, compounds of formula I contain a stereogenic centre which is indicated with an asterisk in the formula I* below:

where A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and Q are as defined in the first aspect. As one of ordinary skill in the art will appreciate, the sulfur atom in compounds of formula I is also a stereogenic centre. Hence, as one of ordinary skill in the art will appreciate, compounds of formula I* may have up to four stereoisomers.

The present invention contemplates both racemates and individual enantiomers, as well as pure diastereomers or diastereomer mixtures. Compounds having preferred stereochemistry are set out below.

Particularly preferred compounds of the present invention are compounds of formula I′ a where A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and Q are as defined in the first aspect, and stereoisomers, enantiomers, tautomers and N-oxides of the compounds of formula (I′a), and agrochemically acceptable salts thereof.

As one of ordinary skill in the art will appreciate, compounds of formula I′a exist in two diastereomers, as shown with compounds of formula I″a and I″b:

The term “optionally substituted” as used herein means that the group referenced is either unsubstituted or is substituted by a designated substituent, for example, “C3-C4cycloalkyl is optionally substituted with 1 or 2 halo atoms” means C3-C4cycloalkyl, C3-C4cycloalkyl substituted with 1 halo atom and C3-C4cycloalkyl substituted with 2 halo atoms.

Embodiments according to the invention are provided as set out below.

In an embodiment of each aspect of the invention,A. A1and A2, independently from each other, are N or CRY, with the proviso that at least one out of two is N; orB. A1and A2, independently from each other, are N or CH, with the proviso that at least one out of two is N; orC. A1is N and A2is N; orD. A1is CR and A2is N; orE. A1is N and A2is CRY; orF. A1is CH and A2is N; orG. A1is N and A2is CH; orH. A1is N and A2is N or CH.

In an embodiment of each aspect of the invention,A. A3and A4, independently from each other, are N or CRY, with the proviso that at least one out of two is CRY; orB. A3and A4, independently from each other, are N or CRY, with the proviso that at least one out of two is CH; orC. A3and A4are, independently from each other, are N or CH, with the proviso that at least one out of two is CH; orD. A3is CR and A4is N; orE. A3is CR and A4is CH; orF. A3is CH and A4is N; orG. A3is N and A4is CH; orH. A3and A4are both CH.

In an embodiment of each aspect of the invention, R3isA. C1-C3alkyl or C1-C3haloalkyl; orB. methyl or trifluoromethyl; orC. methyl.

In an embodiment of each aspect of the invention, Q isA. Qa; orB. Qb.

In an embodiment of each aspect of the invention, QaisA. selected from Qa-1 to Qa-16; orB. selected from Qa-1, Qa-6, Qa-7, Qa-10, and Qa-15; orC. Qa-1 or Qa-15; orD. Qa-1.

In an embodiment of each aspect of the invention, QbisA. selected from Qb-1 to Qb-13; orB. Qb-1.

In an embodiment of each aspect of the invention, Q is Qa-1 or Qb-1.

In an embodiment of each aspect of the invention, R4aisA. pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine, independent of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, C3-C4cycloalkyl, halogen, cyano, C1-C3haloakoxy and selected from Y-1 to Y-4; orB. pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine, independent of each other, is optionally substituted with one substituent selected from F, C1, Br, CN, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy and selected from Y-1 to Y-4; orC. pyridine or, pyrimidine, wherein the pyridine or pyrimidine is optionally substituted with one substituent selected from C1-C3haloalkyl, C3-C4cycloalkyl, halogen, cyano, C1-C3haloakoxy and selected from Y-1 to Y-4; orD. pyridine or, pyrimidine, wherein the pyridine or pyrimidine is optionally substituted with one substituent selected from cyclopropyl, F, C, Br, CN, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy and selected from Y-1 to Y-4; orE. 5-cylopropylpyridine, 5-fluoropyridine, 5-chloropyridine, 5-bromopyridine, 5-difluoromethoxypyridine, 5-trifluoromethoxypyridine, 5-cyanopyridine, 5-(2,2-difluoroethoxy)-pyridine, 5-(2,2,2-trifluoroethoxy)-pyridine, pyridine, 5-cylopropylpyrimidine, 5-fluoropyrimidine, 5-chloropyrimidine, 5-bromopyrimidine, 5-difluoromethoxypyrimidine, 5-trifluoromethoxypyrimidine, 5-cyanopyrimidine, 5-(2,2-difluoroethoxy)-pyrimidine, 5-(2,2,2-trifluoroethoxy)-pyrimidine, pyrimidine, or 1,2,3-triazole; orF. 5-cylopropylpyridin-2-yl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 5-bromopyridin-2-yl, 5-difluoromethoxypyridin-2-yl, 5-trifluoromethoxypyridin-2-yl, 5-cyanopyridin-2-yl, 5-(2,2-difluoroethoxy)-pyridin-2-yl, 5-(2,2,2-trifluoroethoxy)-pyridin-2-yl, pyridin-2-yl, 5-cylopropylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-bromopyrimidin-2-yl, 5-difluoromethoxypyrimidin-2-yl, 5-trifluoromethoxypyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-(2,2-difluoroethoxy)-pyrimidin-2-yl, 5-(2,2,2-trifluoroethoxy)-pyrimidin-2-yl, pyrimidin-2-yl, or 1,2,3-triazol-2-yl (or Y2); orG. 1,2,3-triazol-2-yl (or Y2), pyrimidin-2-yl, or 5-cyanopyridin-2-yl; orH. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halogen, hydroxyl, cyano, and C1-C3haloakoxy; orI. 1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halogen, hydroxyl, cyano, and C1-C3haloakoxy; orJ. thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halogen, hydroxyl, cyano, and C1-C3haloakoxy; orK. thiazol-2-yl or thiazol-4-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halogen, hydroxyl, cyano, and C1-C3haloakoxy; orL. thiazol-2-yl, which is optionally substituted with one to two substituents independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halogen, hydroxyl, cyano, and C1-C3haloakoxy; orM. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orN. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orO. 1,2,4-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orP. thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orQ. thiazol-2-yl or thiazol-4-yl, each of which, independently of each other, is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orR. thiazol-2-yl, which is optionally substituted with one to two substituents independently selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C3haloalkoxy; orS. thiazol-2-yl, which is substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C6haloalkoxy; orT. pyrimidin-2-yl, 5-cyanopyridin-2-yl, or 3-pyrazin-2-yl.

In an embodiment of each aspect of the invention, R6isA. phenyl, benzyl, heteroaryl, or C3-C6cycloalkyl, each of which, independent of each other, is optionally substituted with one substituent selected from Rx; orB. phenyl, benzyl, cyclopropyl or cyclopropyl substituted with one substituent selected from Rx.

In an embodiment, the compound of formula I is formula Iaa, Iab, Iac, Iad, Iae or Iaf (with asterisk indicating a stereogenic centre), wherein R1, R2a, R2b, R2c, R3and Q are as defined in the first aspect, each with the corresponding embodiments as described above. In preferred embodiments, the compound of formula I is a compound of formula Iaa, Iab, Iad, or Iae (with asterisk indicating a stereogenic centre), wherein R1, R2a, R2b, R2c, R3and Q are as defined in the first aspect, each with the corresponding embodiments as described above. In most preferred embodiments, the compound of formula I is a compound of formula Iaa, or Iab (with asterisk indicating a stereogenic centre), wherein R1, R2a, R2b, R2c, R3and Q are as defined in the first aspect, each with the corresponding embodiments as described above.

In an embodiment, compounds having preferred stereochemistry depicted in formula I′a would also be preferred for compounds of formulae Iaa, Iab, Iac, Iad, Iae and Iaf. In a preferred embodiment, a compound of formula I′aa and I′ab with the following stereochemistry is preferred:

wherein R1, R2a, R2b, R3and Q are as defined in the first aspect, and stereoisomers, enantiomers, tautomers and N-oxides of the compounds of formula I′aa and I′ab, and agrochemically acceptable salts thereof.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen, methyl, cyclopropyl-methyl or propargyl; as R2ahydrogen, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, cyclopropyl, cyclopropyl substituted with one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted with one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C2alkylsulfanyl substituted with one to three halogens or C1-C2alkylsulfonyl substituted with one to three halogens; as R2bhydrogen, halogen, C3-C4cycloalkyl, cyclopropylcarbonyl, C3-C4cycloalkyl-C1-C2alkyl optionally substituted with one to two substituents selected from oxo, halogen, C1-C3alkyl and C1-C3haloalkyl, C1-C3haloalkyl, C1-C3haloalkysulfanyl, C1-C3haloalkysulfonyl, C1-C3alkoxy, C1-C3haloalkoxy, or CN; as R2c(for formulae lad, Iae and Iaf) methyl, ethyl, n-propyl, isopropyl, cyclopropyl, vinyl, allyl or propargyl; as R3methyl; as Q Qa-1 to Qa-16 or Qb-1 to Qb-13; as R4(for Qa-1 to Qa-16) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halo, hydroxyl, CN, C1-C6haloalkoxy, C2-C6haloalkenyloxy, C2-C6haloalkynyloxy, C3-C4halocycloalkoxy, C3-C6cycloalkylC1-C4haloalkoxy, NH2C(O)—, NH2C(S)—, (OH)N═C(NH2)—, J-13 optionally substituted by C1-C3haloalkyl, J-20 optionally substituted by C1-C3haloalkyl and 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C6haloalkoxy; and as R4a(for Qb-1 to Qb-13) pyridine or, pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, C3-C4cycloalkyl, halogen, cyano, C1-C3haloakoxy and selected from Y-1 to Y-4 (where R′4a, R′4b, and R′4c, independently of each other and independently of Y-1 to Y-4, are selected from hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, and C1-C3haloalkoxy), thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C6haloalkoxy.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen, methyl or cyclopropyl-methyl; as R2ahalogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, cyclopropyl, cyclopropyl substituted with one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylmethyl substituted with one to two substituents independently selected from halogen and trifluoromethyl, or C1-C2alkylsulfanyl substituted with one to three halogens or C1-C2alkylsulfonyl substituted with one to three halogens; as R2bhalogen, C3-C4cycloalkyl, C3-C4cycloalkyl-C1-C2alkyl optionally substituted with one to two substituents selected from halogen, C1-C3alkyl and C1-C3haloalkyl, C1-C3haloalkyl, C1-C3haloalkysulfanyl, C1-C3haloalkysulfonyl, C1-C3alkoxy, C1-C3haloalkoxy; as R2c(for formulae Iad, Iae and Iaf) methyl, ethyl or cyclopropyl; as R3methyl; as Q Qa-1 to Qa-16 or Qb-1 to Qb-13; as R4(for Qa-1 to Qa-16) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halo, hydroxyl, CN, C1-C6haloalkoxy, C2-C6haloalkenyloxy, C2-C6haloalkynyloxy, NH2C(O)—, NH2C(S)—, (OH)N═C(NH2)—, J-13 optionally substituted by C1-C3haloalkyl, J-20 optionally substituted by C1-C3haloalkyl and 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo, CN and C1-C6haloalkoxy; and as R4a(for Qb-1 to Qb-13) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, C3-C4cycloalkyl, halogen, cyano, C1-C3haloakoxy and selected from Y-1 to Y-4 (where R′4a, R′4b, and R′4c, independently of each other and independently of Y-1 to Y-4, are selected from hydrogen, halogen, C1-C2alkyl, C1-C2haloalkyl), thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C2haloalkyl, chloro, bromo and CN.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen or methyl; as R2ahalogen, C1-C3alkyl, C1-C3haloalkyl, cyclopropyl substituted with one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylmethyl substituted with one to two substituents independently selected from halogen and trifluoromethyl; as R2bhalogen, C3-C4cycloalkyl, C3-C4cycloalkyl-C1-C2alkyl optionally substituted with one to two substituents selected from halogen, C1-C3alkyl and C1-C3haloalkyl, or C1-C3haloalkyl; as R2c(for formulae Iad, Iae and Iaf) methyl or ethyl; as R3methyl; as Q Qa-1, Qa-4, Qa-5 Qa-7 Qa-15, Qa-16 or Qb-1 Qb-2, Qb-3 Qb-6; as R4(for Qa-1 to Qa-16) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3alkyl, C1-C3haloalkyl, halo, CN, J-13 optionally substituted by C1-C3haloalkyl, J-20 optionally substituted by C1-C3haloalkyl and 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo and CN; and as R4a(for Qb-1 to Qb-13) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, halogen, and cyano, and selected from Y-1 to Y-4 (where R′4a, R′4b, and R′4c, independently of each other and independently of Y-1 to Y-4, are selected from hydrogen, halogen, C1-C2alkyl), thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C2chloroalkyl, chloro, bromo and CN.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen or methyl; as R2achloro, bromo, C1-C3haloalkyl or trifluoromethyl; as R2bchloro, bromo, C1-C3haloalkyl or trifluoromethyl; as R2c(for formulae Iad, Iae and Iaf) methyl or ethyl; as R3methyl; as Q Qa-1 or Qb-1; as R4(for Qa-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3alkyl, C1-C3haloalkyl, halo, CN, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, chloro, bromo and CN; and as R4a(for Qb-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, halogen, and cyano, and selected from Y-1 to Y-4 (where R′4a, R′4b, and R′4c, independently of each other and independently of Y-1 to Y-4, are selected from hydrogen, halogen, C1-C2alkyl), thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with one substituent selected from C1-C2chloroalkyl, chloro, bromo and CN.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen or methyl; as R2achloro, bromo, or trifluoromethyl; as R2bchloro, bromo, or trifluoromethyl; as R2c(for formulae Iad, Iae and Iaf) methyl; as R3methyl; as Q Qa-1 or Qb-1; as R4(for Qa-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with CN, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted with CN; and as R4a(for Qb-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with cyano, and selected from Y-1 to Y-4 (where R′4a, R′4b, and R′4c, independently of each other and independently of Y-1 to Y-4, are selected from hydrogen), thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, each of which, independently of each other, is optionally substituted CN.

In an embodiment of each aspect of the invention, the compound of formula I has N or CH as A1and A2, with the proviso that at least one out of two is N, has N or CH as A3and A4, with the proviso that at least one out of two is CH, or the compound of formula I is represented by formula Iaa, Iab, Iac, Iad, Iae or Iaf; and the compound of formula I has as R1hydrogen; as R2abromo or trifluoromethyl; as R2bbromo or trifluoromethyl; as R2c(for formulae Iad, Iae and Iaf) methyl; as R3methyl; as Q Qa-1 or Qb-1; as R4(for Qa-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with CN; and as R4a(for Qb-1) pyridine or pyrimidine, wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with cyano.

In an embodiment of each aspect of the invention, the compound of formula I has formula Iaa or Iab, such as I′aa, or I′ab; R2ais trifluoromethyl, bromine, or chlorine; R2bis hydrogen, trifluoromethyl, bromine or chlorine; R2cis methyl; R1is hydrogen or methyl, preferably hydrogen; R3is methyl; Q is Q is QaaQab, QahQba, Qbb, or Qbg; preferably Qaa, Qab, Qah, and Qbg.

For example, embodiment 1 provides compounds of formula (I), or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer and N-oxide of the compound of formula (I), as defined above.

Embodiment 2 provides compounds as defined for embodiment 1, or each aspects of the invention, wherein A1is N, A2is N or CH, A3is CH, and A4is CH.

Embodiment 3 provides compounds as defined for embodiment 2, or each aspects of the invention, wherein A2is N.

Embodiment 4 provides compounds as defined for any one of embodiments 1, 2 or 3, or each aspects of the invention, wherein R1is hydrogen, methyl, or cyclopropylmethyl.

Embodiment 5 provides compounds as defined for any one of embodiments 1, 2, 3 or 4, or each aspects of the invention, wherein R1is hydrogen, or methyl.

Embodiment 6 provides compounds as defined for any one of embodiments 1, 2, 3, 4, or 5, or each aspects of the invention, wherein R1is hydrogen.

Embodiment 7 provides compounds as defined for any one of embodiments 1, 2, 3, 4, 5, or 6, or each aspects of the invention, wherein R3is methyl.

Embodiment 9 provides compounds as defined for any one of embodiments 1, 2, 3, 4, 5, 6, 7, or 8, or each aspects of the invention, wherein R2ais chlorine, bromine, trifluoromethyl, or trifluoromethylsulfonyl.

Embodiment 10 provides compounds as defined for any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, or 9, or each aspects of the invention, wherein R2ais bromine, chlorine, or trifluoromethyl.

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

In a third aspect, the present invention makes available a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound as defined in the first aspect or a composition as defined in the second aspect.

In a fourth aspect, the present invention makes available a method for the protection of plant propagation material from the attack by insects, acarines, nematodes or molluscs, which comprises treating the propagation material or the site, where the propagation material is planted, with an effective amount of a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.

In a fifth aspect, the present invention makes available a plant propagation material, such as a seed, comprising, or treated with or adhered thereto, a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.

The present invention in a further aspect provides 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 for 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.

Compounds of formula I can be prepared by those skilled in the art following known methods. More specifically compounds of formulae I, and I′a, and intermediates therefor can be prepared as described below in the schemes and examples. Certain stereogenic centers have been left unspecified for the clarity and are not intended to limit the teaching of the schemes in any way.

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

Compounds of formula I can be made, for example, as shown in scheme 1.

Reaction of a compound of the formula II, wherein X1 is a leaving group, such as a halogen or sulfonate, for instance chloride, with a compound of formula III, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), gives a compound of the formula I, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and Q have the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, tetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N-dimethylformamide, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine. Compounds of the formula II are either known, or can be prepared in analogy to descriptions found for example in WO 2021/083936 and WO 2021/177160, or they can be prepared by methods known to a person skilled in the art.

Compounds of formula III, or a salt thereof, can be made, for example, as shown in scheme 2. Treatment of a compound of the formula V, wherein X2is a leaving group, such as a halogen or sulfonate, for instance bromide, with an amine of the formula XIX, or a salt thereof, gives compounds of the formula III, wherein R1and R3have the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.

Alternatively, treatment of a compound of the formula VII with an amine of the formula XIX, or a salt thereof, gives compounds of the formula III, wherein R1and R3have the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C.

Such methods, and the range of conditions to perform them, for the alkylation of amines and for the reductive alkylation of amines are well known to a person skilled in the art. The amines of formula XIX, or a salt thereof, are either known, or they can be prepared by methods known to a person skilled in the art.

Alternatively, compounds of formula I can be made, for example, as shown in scheme 3. Reaction of an amine of the formula IV with a compound of the formula V, wherein X2is a leaving group, such as a halogen or sulfonate, for instance bromide, gives a compound of formula I, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and Q have the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Such methods for the alkylation of amines, and the range of conditions to perform them, are well known to a person skilled in the art.

Alternatively, reaction of an amine of the formula IVa with a compound of the formula VII gives a compound of the formula I wherein R1is H and A1, A2, A3, A4, R2a, R2b, R2c, R3and Q have the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods for the reductive alkylation of amines, and the range of conditions to perform them, are well known to a person skilled in the art.

Compounds of formula V can be made, for example, as shown in scheme 4. Treatment of a compound of the formula VIII with a halogenating agent, such as chlorine or bromine or N-bromosuccinimide, for example, gives compound of the formula V, wherein the leaving group X2is a halogen, for instance chloride or bromide and wherein R3and Q have the same meaning as given above for compounds of the formula I. This reaction is done with or without a solvent, preferably in a solvent, with or without an additive, such as a radical starter, such as, for example, benzoyl peroxide or azoisobutyronirile. The reaction can be done with or without exposure to visible light, or to UV light, and it can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C.

Alternatively, a compound of the formula VII can be treated with a reducing agent, followed by reaction with a sulfonyl chloride, for instance methanesulfonyl chloride, to give a compound of the formula V, wherein the leaving group X2is a sulfonate, for instance a mesylate and wherein R3and Q have the same meaning as given above for compounds of the formula I. This reaction can be done in a solvent, or without a solvent, in the presence of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as an amine base, for instance trimethylamine, or without a base, and it can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. A suitable reducing agent could be, for example, hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C.

Such methods for the halogenation, the reduction of carbonyl compounds and the sulfonylation of alcohols, and the range of conditions to perform them, are well known to a person skilled in the art. The compounds of formula VII and the compounds of formula VIII are either known, or they can be prepared by methods known to a person skilled in the art.

Alternatively, compounds of formula I wherein R1is different from H can be made, for example, as shown in scheme 5. A compound of the formula Ia can be reacted with a compound of the formula VI wherein X3is a leaving group, such as a halogen or sulfonate, for instance a chloride, bromide, iodide or mesylate, to give a compound of formula I, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and Q have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), or mixtures thereof, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine. Such methods for the alkylation of amines, and the range of conditions to perform them, are well known to a person skilled in the art, and can be applied in analogy to descriptions found for example in WO 2021/083936.

Compounds of formula Ib can be made, for example, as shown in scheme 6. Reaction of a compound of the formula II, wherein X1is a leaving group, such as a halogen or sulfonate, for instance chloride, with a compound of formula IX gives a compound of the formula X, wherein A1, A2, A3, A4, R1, R2a, R2b, R2cand R3have the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile or N,N-dimethylformamide, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.

Subsequent treatment of compound X with the known compound XIII gives a compound of the formula XI, wherein A1, A2, A3, A4, R1, R2a, R2b, R2cand R3have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 100° C., or between ambient temperature and 50° C., without a base or in the presence of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.

Further reaction of compound XI with hydrazine XII gives the compound of formula Ib, wherein A1, A2, A3, A4, R2a, R2b, R2c, R3and R4have the same meaning as given above for compounds of the formula I.

This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance 1,4-dioxane, or acetic acid, or a mixture of 1,4-dioxane and acetic acid, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., or between ambient temperature and 80° C. Within this sequence of transformations, the intermediate compounds of formula X and of formula XI can be used as crude products for the subsequent step, or they can be purified, for instance by chromatography, and used in purified form for the next transformation.

Compounds of formula Ic can be made, for example, as shown in scheme 7. Reaction of a compound of the formula XVII (wherein X05is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate) with an amine of the formula XIX, or a salt thereof, gives compounds of the formula XVI, wherein R1and R3have the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide or titanium(IV) isopropoxide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods, and the range of conditions to perform them, for the reductive alkylation of amines are well known to a person skilled in the art.

Subsequent reaction of the intermediate of the formula XVI, or a salt thereof, with a compound of the formula II gives a compound of the formula XIV, wherein A1, A2, A3, A4, R1, R2a, R2b, R2cand R3have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.

Subsequently, the intermediate of the formula XIV is reacted with a compound of the formula XV to give the compound of formula Ic, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and R4ahave the same meaning as given above for compounds of the formula I, and M1in R4a-M1is a metal, such as for instance lithium, or —MgCl, or —ZnBr, or —B(OH)2; or R4a-M1represents a boronate, such as a pinacol ester of a boronic acid, or a stannane such as R4a—Sn(n-Bu)3. Such transformations are known to a person skilled in the art as Suzuki-, Kumada-, Negishi- or Stille-coupling reactions, respectively. Such reactions are carried out in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., in the presence of a catalyst, such as a metal catalyst, for instance a palladium catalyst, and a ligand, such as for example a phosphine ligand, or an N-heterocyclic carbene (NHC) ligand, or a phosphite ligand.

The reaction can be done in the presence or absence of an additional metal catalyst, such as, for example, a copper salt, for instance Cul. The reaction is done with or without a base, which can be an inorganic base, such as potassium carbonate, or sodium hydroxide, or cesium carbonate, or an organic base, such as an amine base, for instance triethyl amine. This reaction is done with or without a solvent, preferentially in a solvent. Where the reaction mixture is heated, the reaction can be conducted under microwave irradiation or with conventional heating, such as heating the reaction vessel in an oil bath.

By an alternative route, compound XVII can be reacted with a compound of the formula XV to give intermediate XVIII, wherein R3and R4ahave the same meaning as given above for compounds of the formula I. This reaction is done essentially under in the same range of conditions as described for the transformation of intermediate XIV to the compound of formula Ic. Subsequently, the intermediate XVIII is reacted with amine IVa to give a compound of the formula Ic, wherein R1is hydrogen and A1, A2, A3, A4, A5, R2a, R2b, R2c, R3and R4ahave the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, essentially under the same conditions as described above for the transformation of compound XVII to intermediate XVI.

By yet another alternative route, the intermediate compound of the formula XVIII can be reacted with an amine of the formula XIX, or a salt thereof, to give the intermediate of the formula IIIIa, or a salt thereof.

This reaction is done in the presence of a reducing agent, essentially under the same conditions as described above for the transformation of compound XVII to intermediate XVI. Subsequently, the intermediate of the formula IIIIa, or a salt thereof, is reacted with a compound of the formula I to give the compound of the formula Ic, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3and R4ahave the same meaning as given above for compounds of the formula I. This reaction is done essentially under the same conditions as described above for the transformation of intermediate XVI to intermediate XIV. Within these different multistep sequences, the intermediate compounds of formulas XIV, XVI, XVIII and IIIIa can be used as crude products for the respective subsequent step, or they can be purified, for instance by chromatography, and used in purified form for the next transformation. Compounds of the formula XVII are known, or they can be prepared by methods known to a person skilled in the art.

Compounds of the formula Id

can be prepared by the reaction of an amine of the formula IIIIb

wherein R1, R3, R4a, R5aand R5bare as described in formula I with a compound of the formula II

wherein A1, A2, A3, A4, R2a, R2band R2care as described in formula I and X1is a leaving group, such as a halogen or a sulfonate, for instance chloride.

The chemistry is described in more detail in Scheme 8.

Reaction of a compound of the formula II, wherein X1is a leaving group, such as a halogen or sulfonate, for instance chloride, with a compound of formula IIIb, or a salt thereof, gives a compound of the formula Id, wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3, R4a, R5aand R5bhave the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine.

The formation of compounds of formula IIIb is outlined in Scheme 9.

Compounds of formula IIIb can be prepared by treatment of compounds of formula IIIc, wherein R3, R4a, R5a, and R5bare as described in formula I, with compounds of formula XX wherein R1is as defined in formula I, e.g. in the presence of NaBH(OAc)3or NaBH3CN, in a suitable solvent, preferably in acetic acid at room temperature analog to WO2002/088073, page 35. Alternatively, another reagent system for the reductive amination uses a combination of Ti(i-OiPr)4and NaBH4(see Synthesis 2003 (14), 2206).

Amines of formula IIIc may be obtained by biocatalyzed deracemization of amines of formula IIId. This may be done for instance using a lipase, e.g.Candida Antarcticalipase B orPseudomonas fluorescenslipase, eventually in immobilized form (e.g. Novozym® 435) in presence of an acyl donor, e.g. ethyl methoxyacetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at temperatures between 20° C. to 100° C. Such processes are described for instance inJ. Org. Chem.2007, 72, 6918-6923 orAdv. Synth. Catal.2007, 349, 1481-1488. The expected stereochemical outcome of such enzymatic deracemization are known of those skilled in the art and are documented in the literature, for instance inJ. Org. Chem.1991, 56, 2656-2665 orJ. Am. Chem. Soc.2015, 137, 3996-4009.

In an alternative process, compounds of formula IIIc, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be obtained from compounds of the formula XXII wherein R3, R4a, R5a, and R5bare as described in formula I, following the synthesis described in Scheme 10:

Amines of formula IIIc, or a salt thereof, may be obtained from intermediates of formula XXII, wherein R3, R4a, R5a, and R5bare as described in formula I and Z3is -NPhth (N-phthalimide group) or -NBoc2(N-bis(tert-butyloxycarbonyl) group), typically by treatment with either hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcohol solvent such as ethanol or isopropanol (Z3is -NPhth), or with an acid such as trifluoroacetic acid or hydrochloric acid in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane (Z3is -NBoc2), under deprotection conditions known to a person skilled in the art, and described in the literature, such as for example in: Protective Groups in Organic Synthesis, 3rd Edition Theodora W. Green (The Rowland Institute for Science) and Peter G. M. Wuts (Pharmacia and Upjohn Company), John Wiley & Sons, Inc., New York, NY. 1999, ISBN 0-471-16019-9.

Such intermediates of formula XXII, wherein R3, R4a, R5a, and R5bare as described in formula I and Z3is —NPhth (N-phthalimide group) or —NBoc2(N-bis(tert-butyloxycarbonyl) group), can be obtained from alcohols of formula XXI, wherein R3, R4a, R5a, and R5bare as described in formula I, by a Mitsunobu reaction, which involves treating alcohols of formula XXI with an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine or tributylphosphine, and of an amine such as phthalimide (HNPhth) or bis(tert-butoxycarbonyl)amine (HNBoc2). Mitsunobu reactions are known by those skilled in the art to proceed with inversion of the stereocenter, as described for instance inChem. Rev.2009, 109, 2551-2651.

Alternatively, amines of formula IIIc may be obtained by reduction of azides of formula XXIII, wherein R3, R4a, R5a, and R5bare 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 XXIII may be obtained by treatment of alcohols of formula XXI, wherein R3, R4a, R5a, and R5bare as described in formula I, with an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THE in presence of a base such as DBU. Such processes are known by those skilled in the art to proceed with inversion of the stereocenter and are described in the literature for instance inAdv. Synth. Catal.2018, 360, 2157-2165.

Alcohols of formula XXI may be obtained by enantioselective reduction of ketones of formula XXIV, wherein R3, R4a, R5a, and R5bare as described in formula I. Such reductions can be done using a catalyst, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4. Such processes are described in the literature for instance inJ. Org. Chem.2017, 82, 5607.

Alternatively, compounds of formula IIIc may also be prepared as outlined in Scheme 11.

Amines of formula IIIc, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be prepared by deprotection of amines of formula XXV, wherein R3, R4a, R5a, and R5bare as described in formula I, for instance using an acid such as trifluoroacetic acid or hydrochloric acid, optionally in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane.

Amines of formula XXV can be obtained by condensation of diamines of formula XXVII, wherein R5a, and R5bare as described in formula I, on diketones of formula XXVI, wherein R3, and R4aare as described in formula I. This condensation can take place in the presence of a suitable solvent such as ethanol or isopropanol in presence of an oxidant such as air or DDQ.

Diketones of formula XXVI may be formed by oxidation of hydroxyketones of formula XXVII wherein R3, and R4aare as described in formula I. This oxidation can involve for instance SO3-pyridine in presence of solvents such as dichloromethane or dimethyl sulfoxide DMSO, or mixtures thereof, and a base for instance triethylamine or N,N-diisopropylethylamine or alternatively sodium hypochlorite in presence of a catalyst such as TEMPO/Bu4NHSO4. Examples of such oxidations can be found in the literature, for instance inSynlett,2014, 25, 596 orJ. Am. Chem. Soc.1990, 112, 5290-5313.

Hydroxyketones of formula XXVII may be synthesized by cross-benzoin condensation between aldehydes of formula XXIX, wherein R4ais as described in formula I, and aldehydes of formula XXVIII, wherein R3is as described in formula I.

Aldehydes of formula XXVIII are commercially available in chiral form, like for instance Boc-L-alaninal (CAS 79069-50-4) or tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (CAS 881902-36-9). Cross-benzoin condensations are done in the usual way by employing an organocatalyst such as a triazolium salt or a 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 between −20° C. and the boiling point of the solvent. Examples of catalysts for such transformations have been described in the literature for instance in J. Am. Chem. Soc. 2014, 136, 7539-7542 or in Org. Lett. 2016, 18, 4518-4521.

As shown in Scheme 12, compounds of formula Id can be alternatively prepared by reaction of compounds of formula XXX wherein A1, A2, A3, A4, R1, R2a, R2b, R2c, R3, R5aand R5bare as defined in formula I and X07is a leaving group like, for example, chlorine, bromine, iodine) with compounds of formula XXXI (Stille reaction; R4ain XXXI is as defined in formula I) or compounds of formula XXXII wherein W is boronate, for example pinacol boronate or B(OH)2(Suzuki-Miyaura reaction; R4ain XXXII is as defined in formula I) in the presence of a palladium catalyst as described in detail in Scheme 7.

Compounds of formula XXX can be prepared by coupling of amines of formula XXXIII and compounds of formula II, wherein A1, A2, A3, A4, R2a, R2b, R2eand X1are as described in Scheme 1, under the conditions described in detail in Scheme 1. Under the same conditions, if R1═H, compounds of formula XXX may be obtained directly from compounds of formula XXXIV, wherein A1, A2, A3, A4, R2a, R2b, R2c, R3, R5aand R5bare as defined in formula I and X07is as defined above.

Compounds of formula XXXIII can be prepared by treatment of compounds of formula XXXIV, with compounds of formula XXXV (wherein R1is as defined in formula I), e.g. in the presence of NaBH(OAc)3or NaBH3CN, in a suitable solvent, preferably in acetic acid at room temperature analog to WO2002/088073, page 35. Alternatively, another reagent system for the reductive amination uses a combination of Ti(i-OiPr)4and NaBH4(see Synthesis 2003 (14), 2206).

Amines of formula XXXIV can be prepared by deracemization procedure method, which involves for example, a selective acylation of one enantiomer. Such an example is described more in details in Scheme 13.

Amines of formula XXXIV may be obtained by biocatalyzed deracemization of amines of formula XXXIVa, wherein R3, R5a, and R5bare as defined in formula I and X07is a leaving group such as bromine, chlorine or iodine. This may be done for instance using a lipase, e.g.Candida Antarcticalipase B orPseudomonas fluorescenslipase, eventually in immobilized form (e.g. Novozym® 435) in presence of an acyl donor, e.g. ethyl methoxyacetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at temperatures between 20° C. to 100° C. Such processes are described for instance inJ. Org. Chem.2007, 72, 6918-6923 orAdv. Synth. Catal.2007, 349, 1481-1488. The expected stereochemical outcome of such enzymatic deracemization are known of those skilled in the art and are documented in the literature, for instance inJ. Org. Chem.1991, 56, 2656-2665 orJ. Am. Chem. Soc.2015, 137, 3996-4009.

Alternatively, resolution of amines of formula XXXIVa to give amines of formula XXXIV may be achieved using a chiral auxiliary, as described in Scheme 14.

Amines of formula XXXIV can be prepared from intermediates of formula XXXVII, wherein R3, R5a, and R5bare as in compounds of the formula I, X07is a leaving group such as bromine, chlorine or iodine, and X12* is a chiral auxiliary, by treatment with acids such as HCl or bases such as NaOH. Chiral auxiliaries of formula LII are for instance mandelic acid or (1R)-menthylchloroformate. Intermediates of formula XXXVII can be formed by coupling of a chiral auxiliary of formula XXXVI, wherein X0is a leaving group, such as chlorine, with amines of the formula XXXIVa following the conditions detailed in Scheme 1. Examples of such deracemization processes are reported in the literature, for instance inJ. Org. Chem.2007, 72, 485-493.

Alternatively, amines of formula XXXIV, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be formed as described in Scheme 15.

Alternatively, amines of formula XXXIV, or a salt thereof, may be obtained from intermediates of formula XXIIa, wherein R3, R5a, and R5bare as described in formula I, X07is a leaving group such as a halogen or sulfonate, for instance bromide, and Z3is —NPhth (N-phthalimide group) or —NBoc2(N-bis(tert-butyloxycarbonyl) group), typically by treatment with either hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcohol solvent such as ethanol or isopropanol (Z3is -NPhth), or with an acid such as trifluoroacetic acid or hydrochloric acid in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane (Z3is —NBoc2), under deprotection conditions known to a person skilled in the art, and described in the literature, such as for example in: Protective Groups in Organic Synthesis, 3rd Edition Theodora W. Green (The Rowland Institute for Science) and Peter G. M. Wuts (Pharmacia and Upjohn Company), John Wiley & Sons, Inc., New York, NY. 1999, ISBN 0-471-16019-9.

Such intermediates of formula XXIIa, wherein R3, R5a, and R5bare as described in formula I, X07is a leaving group such as a halogen or sulfonate, for instance bromide, and Z3is —NPhth (N-phthalimide group) or —NBoc2(N-bis(tert-butyloxycarbonyl) group), can be obtained from alcohols of formula XXIa, wherein R3, R5a, and R5bare as described in formula I and X07is a leaving group, by a Mitsunobu reaction, which involves treating alcohols of formula XXIa with an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine or tributylphosphine and of an amine such as phthalimide (HNPhth) or bis(tert-butoxycarbonyl)amine(HNBoc2). Mitsunobu reactions are known by those skilled in the art to proceed with inversion of the stereocenter, as described for instance inChem. Rev.2009, 109, 2551-2651.

Alternatively, amines of formula XXXIV may be obtained by reduction of azides of formula XXIIIa, wherein R3, R5a, and R5bare as described in formula I and X07is a leaving group such as a halogen or sulfonate, for instance bromide, 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 XXIIIa may be obtained by treatment of alcohols of formula XXIa with an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THF in presence of a base such as DBU. Such processes are known by those skilled in the art to proceed with inversion of the stereocenter and are described in the literature for instance inAdv. Synth. Catal.2018, 360, 2157-2165.

Alcohols of formula XXIa may be obtained by enantioselective reduction of ketones of formula XXIVa, wherein R3, R5a, and R5bare as described in formula I and X07is a leaving group such as a halogen or sulfonate, for instance bromide. Such reductions can be done using catalysts, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4. Such processes are described in the literature for instance inJ. Org. Chem.2017, 82, 5607.

Compounds of formula IIb (a subset of compounds of formula II), wherein A1and A2are both N, and wherein A3, A4, R2a, R2band R2chave the same meaning as defined for compounds of formula I, and wherein X1is a leaving group, such as a halogen or sulfonate, for instance chloride, can be made, for example, as shown in Scheme 16:

Treatment of a compound of formula XXXVIII, or a tautomer thereof, wherein A1and A2are both N, and wherein A3, A4, R2a, R2band R2chave the same meaning as defined for compounds of formula I, with a desoxychlorination agent, such as for instance phosphoryl chloride, optionally in the presence of base, such as triethylamine, N,N-diisopropylethylamine or pyridine, gives a compound of the formula IIb, wherein X1is chlorine. Such a reaction is performed in a solvent (such as for example toluene, xylene or chlorobenzene), or without a solvent, at a temperature between 0° C. and 200° C., such as for example at 60° C. or at 100° C.

A compound of formula XXXVIII, or a tautomer thereof, can be made, for example, from a compound of formula XXXIX, wherein A1and A2are both N, and wherein A3, A4, R2a, R2band R2chave the same meaning as defined for compounds of formula I, by removal of a protecting group PG, such as for instance removal of a benzyl group, or of a para-methoxybenzyl group, or of a 3,4-dimethoxybenzyl group. Such deprotection reactions are known to a person skilled in the art. This reaction is done, for instance, by treatment with an acid, such as for example trifluoroacetic, in a solvent, such as for instance toluene, xylene or chlorobenzene, at a temperature between 0° C. and 200° C., such as for example at ambient temperature.

A compound of formula XXXIX can be made, for example, from a compound of formula XL, or a tautomer thereof, wherein A1and A2are both N, and wherein A3, A4, R2a, R2band R2chave the same meaning as defined for compounds of formula I, and in which PG is for instance a benzyl, a para-methoxybenzyl or a 3,4-dimethoxybenzyl group, by a cyclisation reaction. This reaction can be done in the presence of a dehydrating agent, such as for example propanephosphonic acid anhydride (T3P), without a solvent or in the presence of a solvent, such as, for example, ethyl acetate or acetonitrile, in the absence or in the presence of a base, such as, for example, triethylamine, diisopropylethylamine or pyridine, and at temperatures between 0° C. to approximately 80° C., such as for example at ambient temperature. Such cyclization reactions, or cyclo-condensation reactions, are well known to a person skilled in the art.

A compound of formula XL, or a tautomer thereof, can be made, for example, from a compound of the formula XLII, or a tautomer thereof, wherein A1and A2are both N, and wherein R2chas the same meaning as defined for compounds of formula I, and in which PG is for instance a benzyl, a para-methoxybenzyl or a 3,4-dimethoxybenzyl group, by treatment with a compound of the formula XLI, wherein A3, A4, R2aand R2bhave the same meaning as defined for compounds of formula I, and wherein X4is a leaving group, such as a halogen, for instance iodine, without solvent or in the presence of a solvent, for instance N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-pyrrolidone. The reaction can be carried out in the presence of a catalyst, such as a metal catalyst, for example a copper halide, for instance copper (1) iodide, at a temperature between 0° C. and 200° C., such as for example at 50° C., in the absence or in the presence of a base, such as for example sodium, potassium or cesium carbonate.

Compounds of the formula XLI are known or can be made by known methods, for example by reacting compounds of formula XLI-1, wherein A3, A4, R2aand R2bhave the same meaning as defined for compounds of formula I, with a nitrite, such as tert-butyl nitrite t-BuONO or isoamyl nitrite (examples of non-aqueous conditions), or sodium nitrite in the presence of a hydrohalic acid (for example HX4, or for instance hydrochloric acid) in water (aqueous conditions), and a copper salt Cu(I)X4, or a related salt such as for instance a potassium salt KX4, wherein X4is a leaving group, such as a halogen, for instance iodine, under Sandmeyer-type reaction conditions. This transformation is preferably performed in an inert solvent, such as acetonitrile or a halogenated solvent like 1,2-dichloroethane or 1,2-dibromoethane (non-aqueous conditions), or water (optionally in the presence of a co-solvent, such as for instance acetonitrile) at temperatures between 0-150° C., preferably at temperatures ranging from room temperature to the boiling point of the reaction mixture.

Compounds of the formula XLI-1 are known or can be made by known methods

A compound of formula XLII, or a tautomer thereof, can be made, for example, from a compound of the formula XLIII, or a tautomer thereof, wherein A1and A2are both N, and wherein R2chas the same meaning as defined for compounds of formula I, and in which PG is for instance a benzyl, a para-methoxybenzyl or a 3,4-dimethoxybenzyl group, and in which SPG is a protecting group, such as for instance a silyl protecting group, for example a t-butyldimethylsilyl group, by a deprotection reaction.

Such reactions are known to a person skilled in the art, for instance the reaction can be done by treatment with acid or fluoride, such as tetra-n-butylammonium fluoride, without a solvent or in the presence of a solvent, for instance in tetrahydrofuran as a solvent, at a temperature between 0° C. and 200° C., such as for example at ambient temperature.

A compound of formula XLIII, or a tautomer thereof, can be made, for example, from a compound of the formula XLV, wherein A1is N, and wherein R2chas the same meaning as defined for compounds of formula I, and in which SPG is a protecting group, such as for instance a silyl protecting group, for example a t-butyldimethylsilyl group, by treatment with a compound of the formula XLIV, wherein A2is N, and in which PG is for instance a benzyl, a para-methoxybenzyl or a 3,4-dimethoxybenzyl group, which said compound od formula XLIV is known (e.g. 3,4-dimethoxybenzyl amine) or can be made by known methods. The reaction is performed, for instance, in the presence of a desoxychlorination reagent, such as, for example, dichloro(triphenyl)-λ5-phosphane, without a solvent or in the presence of a solvent, such as for example chloroform, in the absence or in the presence of a base, such as, for example, triethylamine, at a temperature between 0° C. and 200° C., such as for example at 0° C., or at ambient temperature.

A compound of the formula XLV can be made, for example, from a sulfonamide of formula XLV-1, wherein A1is N, and wherein R2chas the same meaning as defined for compounds of formula I, such as from methylsulfonamide, in which case R2cis methyl. Such sulfonamides are known or can be made by known methods. The sulfonamide of formula XLV-1is reacted with a silyating agent of the formula SPG-CI, in which SPG is a protecting group, such as for instance a silyl protecting group, such as, for example, tert-butyl-chloro-dimethyl-silane, in the absence or in the presence of a base, such as for instance triethylamine, without a solvent or in a solvent, for instance in toluene as a solvent, at a temperature between 0° C. and 200° C., such as for example at ambient temperature.

Alternatively, a compound of formula XLII, or a tautomer thereof, can be made, for example, from a compound of the formula XLII-1, wherein A1is N and Tr is the trityl group (i.e. XLII-1 is N-sulfinyltriphenylmethylamine, CAS 503596-47-2; also called N-sulfinyltritylamine) by treatment with a compound of the formula XLII-2, wherein R2chas the same meaning as defined for compounds of formula I and in which X7is a halogen, such as for example, chlorine or bromine (typically such a compound of the formula XLII-2 is a Grignard reagent, for example methylmagnesium bromide), and with tert-butyl hypochlorite of formula XLII-3, or any equivalent source of “Cl+”, and with a compound of the formula XLIV, wherein A2is N, and in which PG is for instance a benzyl, a para-methoxybenzyl or a 3,4-dimethoxybenzyl group, under conditions described in, for example, Angew.Chem. Int.Ed. 2017, 56, 14937-14941 (and supporting information found under https://doi.org/10.1002/anie.201708590).

Compounds of formula XXXVIII-3 (a subset of compounds of formula XXXVIII), or a tautomer thereof, wherein A1and A2are both N, and wherein R2aand R2bare, independently of each other, either chlorine, bromine or iodine, preferably bromine or iodine, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, can be made, for example, as shown in Scheme 16a.

Compounds of formula XXXVIII-2, or a tautomer thereof, wherein A1and A2are both N, and wherein R2ais either chlorine, bromine or iodine, preferably bromine or iodine, and in which R2bis hydrogen, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, can be prepared by a halogenation reaction, which involves for example, reacting compounds of formula XXXVIII-1, wherein A1and A2are both N, and in which R2aand R2bare both hydrogen, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, with halogenating reagents, such as N-chlorosuccinimide (NCS), N-bromo-succinimide (NBS) or N-iodosuccinimide (NIS), or alternatively chlorine, bromine or iodine, optionally in the presence of an activating agent. Such halogenation reactions are carried out in an inert solvent, such as chloroform, carbon tetrachloride, 1,2-dichloroethane, acetic acid, ethers, acetonitrile or N,N-dimethylformamide, at temperatures between 20-200° C., preferably room temperature to 80° C. Preferably approximately 1 equivalent of halogenating reagent is used per equivalent of compound of formula XXXVIII-1 involved.

Similarly, compounds of formula XXXVIII-3, or a tautomer thereof, wherein A1and A2are both N, and wherein R2aand R2bare, independently of each other, either chlorine, bromine or iodine, preferably bromine or iodine, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, can be prepared by a halogenation reaction, which involves for example, reacting compounds of formula XXVIII-2, or a tautomer thereof, wherein A1and A2are both N, and wherein R2ais either chlorine, bromine or iodine, preferably bromine or iodine, and in which R2bis hydrogen, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, with halogenating reagents, such as N-chlorosuccinimide (NCS), N-bromo-succinimide (NBS) or N-iodosuccinimide (NIS), or alternatively chlorine, bromine or iodine, optionally in the presence of an activating agent. Such halogenation reactions are carried out in an inert solvent, such as chloroform, carbon tetrachloride, 1,2-dichloroethane, acetic acid, ethers, acetonitrile or N,N-dimethylformamide, at temperatures between 20-200° C., preferably room temperature to 80° C. Preferably approximately 1 equivalent of halogenating reagent is used per equivalent of compound of formula XXXVIII-2 involved.

In the particular situation wherein R2aand R2bare equivalent (and defined as being, independently of each other, either chlorine, bromine or iodine, preferably bromine or iodine), then the compounds of formula XXXVIII-3 can be prepared directly from compounds of formula XXXVIII-1 under halogenating conditions described above in scheme 16a, preferably using approximately 2 equivalents (or more) of the halogenating reagent per equivalent of compound of formula XXXVIII-1 involved.

Compounds of formula XXXVIII-1, wherein A1and A2are both N, and in which R2aand R2bare both hydrogen, and wherein A3, A4and R2chave the same meaning as defined for compounds of formula I, represent a particular subset of compounds of formula XXXVIII, and can be prepared following scheme 16.

Compounds of formula IVa′, wherein A1is N, A2is CRY, and wherein A3, A4, R2a, R2band R2chave the same meaning as defined for compounds of formula I, can be made, for example, as shown in Scheme 17.

Treatment of a compound of formula XLVI with a base, for instance with an organolithium compound, such as n-butyllithium, in a solvent, for instance in tetrahydrofuran, gives a compound of formula IVa′. The reaction can be carried out in the absence or in the presence of additives that improve the solubility of the organolithium compound, such as, for example, tetramethyl-ethylenediamine, at a temperature between −100° C. and 100° C., such as for example at 0° C.

A compound of formula XLVI can be made, for example, from a compound of formula XLVII, wherein X5 is a leaving group, such as for instance triflate or a halogen, for example iodine, by a coupling reaction with a sulfoximine compound of the formula L, which is known or can be prepared by known methods. This coupling reaction is familiar to a person skilled in the art, and are described in the literature, for example in WO2017146186, WO2013128028, or Advanced Synthesis & Catalysis (2008), 350(3), 391-394. It can be performed in the presence of a catalyst, for instance a metal catalyst, such as a copper-, an iron-, or a palladium-catalyst, for example tris(dibenzylideneacetone) dipalladium(0), in the absence or in the presence of a base, such as for example cesium carbonate, without a solvent or in a solvent, such as for example in 1,4-dioxane as a solvent, at a temperature between 0° C. and 200° C., such as for example at 100° C.

Compounds of formula XLVII are known, or they can be made, for example, from a compound of formula XLVIII by known methods, for instance by the Sandmeyer reaction, which is described in the literature, for example in Chemical Reviews. 40 (2): 251-277, doi:10.1021/cr60126a003.

Compounds of formula XLVIII are known, or they can be made by known methods, for instance from compounds of formula XLIX, wherein X6is a leaving group, such as a halogen, for instance iodine, by a cyanation reaction. Such cyanation reactions of aromatic halogen compounds are known to a person skilled in the art, and described in the literature, for example in Journal of Organic Chemistry (1998), 63(23), 8224-8228, or in Journal of Organometallic Chemistry (2012), 696(26), 4173-4178, or in Journal of Chemical Research (2007), (8), 484-485.

Compounds of formula IV can be made, for example, as shown in Scheme 18. Reaction of an amine of the formula IVa with a compound of the formula III, wherein X3is a leaving group, such as a halogen or sulfonate, for instance bromide, gives a compound of formula IV, wherein A1, A2, A3, A4, R1, R2a, R2band R2chave the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Such methods for the alkylation of amines, and the range of conditions to perform them, are well known to a person skilled in the art.

Compounds of formula III, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or any other equivalent salt), wherein R1, R3and Q have the same meaning as given above for compounds of the formula I, are known in the literature or can be synthesized in analogy to literature precedent.

For example, compounds of the formula IIIa and IIIb, or a salt thereof as defined above, wherein R1, R3, R4a, R5aand R5bare as described in formula I, particularly those compounds of the formula IIIa and IIIb, or a salt thereof as defined above, wherein R3and R4aare as described in formula I and in which R1, R5aand R5bare hydrogen, can be prepared in analogy to descriptions found in WO 2020/201079 and WO 2020/201398.

Similarly, compounds of the formula IIIe and IIIf, or a salt thereof as defined above, wherein R1, R3, R4and R5are as described in formula I, particularly those compounds of the formula IIIe and IIIf, or a salt thereof as defined above, wherein R3and R4are as described in formula I and in which R1is hydrogen and R5is hydrogen, methyl or cyclopropyl, can be prepared in analogy to descriptions found for example in WO 2017/192385, WO 2020/002563, WO 2020/083936, WO 2021/110891 and WO 2021/165195.

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

The reactants can be reacted with each other as such, i.e. without adding a solvent or diluent. In most cases, however, it is advantageous to add an inert solvent or diluent or a mixture of these. If the reaction is carried out in the presence of a base, bases which are employed in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline, may also act as solvents or diluents.

The reactions are advantageously carried out in a temperature range from approximately −80° C. to approximately +140° C., preferably from approximately −30° C. to approximately +100° C., in many cases in the range between ambient temperature and approximately +80° C.

Depending on the choice of the reaction conditions and starting materials which are suitable in each case, it is possible, for example, in one reaction step only to replace one substituent by another substituent according to the invention, or a plurality of substituents can be replaced by other substituents according to the invention in the same reaction step.

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

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

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

Depending on the procedure or the reaction conditions, the 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, the tautomers thereof, in each case in free form or in salt form, can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the configuration of non-aromatic double bonds which occur in the molecule; the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.

Diastereomer mixtures or racemate mixtures of 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 the pure diastereomers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and/or chromatography.

Enantiomer mixtures, such as racemates, which can be obtained in a similar manner can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example high-performance liquid chromatography (HPLC) on acetyl cellulose, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphor, tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separating the diastereomer mixture which can be obtained in this manner, for example by fractional crystallization based on their differing solubilities, to give the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents, for example basic agents.

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

N-oxides can be prepared by reacting a compound of the formula I with a suitable oxidizing agent, for example the H2O2/urea adduct in the presence of an acid anhydride, e.g. trifluoroacetic anhydride. Such oxidations are known from the literature, for example fromJ. Med. Chem.,32 (12), 2561-73, 1989 or WO 2000/15615.

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

The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.

The compounds of formula I according to the following Tables A-1 to A-72 can be prepared according to the methods described above. The examples which follow are intended to illustrate the invention and show preferred compounds of formula I, in the form of a compound of formula I-A.

TABLE ZSubstituent definitions of Q:IndexQ12345678

A compound of formula II(i), (a) wherein X1is halogen and A1, A2, A3, A4, R23, R2band R2care as defined in any one Tables A-1 to A-72; or (b) wherein X1is Cl and A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72; or (c) wherein X1is sulfonate and A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

A compound of formula III(i), wherein R1and R3are as defined in any one Tables A-1 to A-72, and Q is as defined in table Z:

A compound of formula IV(i), wherein A1, A2, A3, A4, R1, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

A compound of formula V(i), (a) wherein X2is halogen, R3is as defined in any one Tables A-1 to A-72, and Q is as defined in table Z; or (b) wherein X2is Cl, R3is as defined in any one Tables A-1 to A-72, and Q is as defined in table Z; or (c) X2is Br, R3is as defined in any one Tables A-1 to A-72, and Q is as defined in table Z; or (d) X2is sulfonate, R3is as defined in any one Tables A-1 to A-72, and Q is as defined in table Z:

A compound of formula VII(i), wherein R3is as defined in any one Tables A-1 to A-72 and Q is as defined in table Z:

A compound of formula X(i), wherein A1, A2, A3, A4, R2a, R2b, R2cand R3are as defined in any one Tables A-1 to A-72:

A compound of formula XI(i), wherein A1, A2, A3, A4, R2a, R2b, R2cand R3are as defined in any one Tables A-1 to A-72:

A compound of formula XXXVIII(i), wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

A compound of formula XXXIX(i), (a) wherein PG is benzyl, and wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72; (b) wherein PG is 3,4-dimethoxybenzyl, and wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

A compound of formula XL(i), (a) wherein PG is benzyl, and wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72; (b) wherein PG is 3,4-dimethoxybenzyl, and wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

A compound of formula XLII(i), (a) wherein PG is benzyl, and wherein A1, A2, and R2care as defined in any one Tables A-1 to A-72; (b) wherein PG is 3,4-dimethoxybenzyl, and wherein A1, A2, and R2care as defined in any one Tables A-1 to A-72:

A compound of formula XLIII(i), (a) wherein PG is benzyl, SPG is t-butyldimethylsilyl, and wherein A1, A2, and R2care as defined in any one Tables A-1 to A-72; (b) wherein PG is 3,4-dimethoxybenzyl, SPG is t-butyldimethylsilyl, and wherein A1, A2, and R2care as defined in any one Tables A-1 to A-72:

A compound of formula XLVI(i), wherein A1, A2, A3, A4, R2a, R2band R2care as defined in any one Tables A-1 to A-72:

In further aspect, the present invention accordingly makes available compounds of formulae II(i), III(i), IV(i), V(i), VII(i), X(i), XI(i), XXXVIII(i), XXXIX(i), XL(i), XLII(i), XLIII(i) and XLVI(i) wherein in each case, as applicable, A1, A2, A3, A4, R2a, R2b, R2cand R3and Q are as defined for formula I in the first aspect; in respect of formula II(i), X1is a halogen, preferably chloro or bromo; in respect of formula V(i), X2is a halogen, preferably chloro, bromo or iodo; in respect of formulae XXXIX(i), XL(i), XLII(i) and XLIII(i), PG is a protecting group, preferably benzyl or 3,4-dimethoxybenzyl; and in respect of formula XLIII(i), SPG is a silyl protecting group, preferably t-butyldimethylsilyl. Furthermore, the corresponding embodiments illustrated for formula I also apply to the compounds of formulae II(i), III(i), IV(i), V(i), VII(i), X(i), XI(i), XXXVIII(i), XXXIX(i), XL(i), XLII(i), XLIII(i) and XLVI(i).

The compounds of formula I according to the invention are preventively and/or curatively valuable active ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the invention act against all or individual developmental stages of normally sensitive, but also resistant, animal pests, such as insects or representatives of the order Acarina. The insecticidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i.e. in destruction of the pests, which takes place either immediately or only after some time has elapsed, for example during ecdysis, or indirectly, for example in a reduced oviposition and/or hatching rate.

The active ingredients according to the invention can be used for controlling, i.e. containing or destroying, pests of the abovementioned type which occur in particular on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time remain protected against these pests.

The compositions and/or methods of the present invention may be also used on any ornamental and/or vegetable crops, including flowers, shrubs, broad-leaved trees and evergreens.

The active ingredients according to the invention are especially suitable for controllingAphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostellaandSpodoptera littoralisin cotton, vegetable, maize, rice and soya crops. The active ingredients according to the invention are further especially suitable for controllingMamestra(preferably in vegetables),Cydia pomonella(preferably in apples),Empoasca(preferably in vegetables, vineyards),Leptinotarsa(preferably in potatos) andChilosupressalis (preferably in rice).

The compounds of formula I are particularly suitable for control ofa pest of the order Hemiptera, for example, one or more of the speciesBemisia tabaci, Aphis craccivora, Myzus persicae, Rhopalosiphum padi, Nilaparvata lugens, andEuschistus heros(preferably in vegetables, soybeans, and sugarcane);a pest of the order Lepidoptera, for example, one or more of the speciesSpodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, andTuta absoluta(preferably in vegetables and corn);a pest of the order Thysanoptera, such as the family Thripidae, for example, one or more ofThrips tabaciandFrankliniella occidentalis(preferably in vegetables); andsoil pests (such as of the order Coleoptera), for example, the speciesDiabroticabalteata,Agriotesspp. andLeptinotarsa decemlineata(preferably in vegetables and corn).

The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesizing one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genusBacillus.

In the context of the present invention there are to be understood by d-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a 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-0 374 753, WO 93/07278, WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.

The processes for the preparation of such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above. Cry1-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.

The toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects. Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).

Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a Cry1Ac toxin); Bollgard 1® (cotton variety that expresses a Cry1Ac toxin); Bollgard 11@(cotton variety that expresses a Cry1Ac and a Cry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and a Cry1Ab toxin); NewLeaf® (potato variety that expresses a Cry3A toxin); NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.

Further examples of such transgenic crops are:1. Bt11 Maize from Syngenta Seeds SAS, Chernin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modifiedZea mayswhich has been rendered resistant to attack by the European corn borer (Ostrinia nubilalisandSesamia nonagrioides) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate arnmonium.2. Bt176 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modifiedZea mayswhich has been rendered resistant to attack by the European corn borer (Ostrinia nubilalisandSesamia nonagrioides) by transgenic expression of a Cry1Ab toxin. Bt176 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.3. MIR604 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Maize which has been rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a cathepsin-G-protease recognition sequence. The preparation of such transgenic maize plants is described in WO 03/018810.4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.5. IPC 531 Cotton from Monsanto Europe S.A.: 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/ES/96/02.6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-1160 Brussels, Belgium, registration number C/NL/00/10. Genetically modified maize for the expression of the protein Cry1F for achieving resistance to certain Lepidoptera insects and of the PAT protein for achieving tolerance to the herbicide glufosinate ammonium.7. NK603×MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of conventionally bred hybrid maize varieties by crossing the genetically modified varieties NK603 and MON 810. NK603×MON 810 Maize transgenically expresses the protein CP4 EPSPS, obtained fromAgrobacteriumsp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a Cry1Ab toxin obtained fromBacillus thuringiensissubsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.

The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818 and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.

Crops may also be modified for enhanced resistance to fungal (for exampleFusarium, Anthracnose, orPhytophthora), bacterial (for examplePseudomonas) or viral (for example potato leafroll virus, tomato spotted wilt virus, cucumber mosaic virus) pathogens.

Crops also include those that have enhanced resistance to nematodes, such as the soybean cyst nematode.

Crops that are tolerance to abiotic stress include those that have enhanced tolerance to drought, high salt, high temperature, chill, frost, or light radiation, for example through expression of NF-YB or other proteins known in the art.

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

Further areas of use of the compositions according to the invention are the protection of stored goods and store rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, especially the protection of humans, domestic animals and productive livestock against 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 controlling parasites in or on an animal.

The present invention further provides a compound of the first aspect, for use in controlling ectoparasites on an animal. The present invention further provides a compound of the first aspect, for use in preventing and/or treating diseases transmitted by ectoparasites.

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

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

The term “controlling” when used in context of parasites in or on an animal refers to reducing the number of pests or parasites, eliminating pests or parasites and/or preventing further pest or parasite infestation.

The term “treating” when used in context of parasites in or on an animal refers to restraining, slowing, stopping or reversing the progression or severity of an existing symptom or disease.

The term “preventing” when used in context of parasites in or on an animal refers to the avoidance of a symptom or disease developing in the animal.

The term “animal” when used in context of parasites in or on an animal may refer to a mammal and a non-mammal, such as a bird or fish. In the case of a mammal, it may be a human or non-human mammal. Non-human mammals include, but are not limited to, livestock animals and companion animals. Livestock animals include, but are not limited to, cattle, camelids, pigs, sheep, goats and horses. Companion animals include, but are not limited to, dogs, cats and rabbits.

A “parasite” is a pest which lives in or on the host animal and benefits by deriving nutrients at the host animal's expense. An “endoparasite” is a parasite which lives in the host animal. An “ectoparasite” is a parasite which lives on the host animal. Ectoparasites include, but are not limited to, acari, insects and crustaceans (e.g. sea lice). The Acari (or Acarina) sub-class comprises ticks and mites. Ticks include, but are not limited to, members of the following genera: Rhipicaphalus, for example, Rhipicaphalus (Boophilus)microplusandRhipicephalus sanguineus; Amblyomrna;Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus;Argas; Otobius; andOrnithodoros. Mites include, but are not limited to, members of the following genera:Chorioptes, for exampleChorioptes bovis; Psoroptes, for examplePsoroptes ovis; Cheyletiella; Dermanyssus; for exampleDermanyssus gallinae; Ortnithonyssus;Demodex, for exampleDemodex canis; Sarcoptes, for exampleSarcoptes scabiei; and Psorergates. Insects include, but are not limited to, members of the orders: Siphonaptera, Diptera, Phthiraptera, Lepidoptera, Coleoptera and Homoptera. Members of the Siphonaptera order include, but are not limited to,Ctenocephalides felisand Ctenocephatidescanis. Members of the Diptera order include, but are not limited to,Muscaspp.; bot fly, for example Gasterophilus intestinalis andOestrus ovis; biting flies; horse flies, for example Haematopota spp. and Tabunus spp.;haematobia, for examplehaematobia irritans; Stomoxys; Lucilia; midges; and mosquitoes. Members of the Phthiraptera class include, but are not limited to, blood sucking lice and chewing lice, for exampleBovicola OvisandBovicola Bovis.

The term “effective amount” when used in context of parasites in or on an animal refers to the amount or dose of the compound of the invention, or a salt thereof, which, upon single or multiple dose administration to the animal, provides the desired effect in or on the animal. The effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the parasite to be controlled and the degree of infestation; the specific disease or disorder involved; the degree of involvement or the severity of the disease or disorder; the response of the individual; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

The compounds of the invention may be administered to the animal by any route which has the desired effect including, but not limited to topically, orally, parenterally and subcutaneously. Topical administration is preferred. Formulations suitable for topical administration include, for example, solutions, emulsions and suspensions and may take the form of a pour-on, spot-on, spray-on, spray race or dip. In the alternative, the compounds of the invention may be administered by means of an ear tag or collar.

Salt forms of the compounds of the invention include both pharmaceutically acceptable salts and veterinary acceptable salts, which can be different to agrochemically acceptable salts.

Pharmaceutically and veterinary acceptable salts and common methodology for preparing them 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 invention are readily converted to and may 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 invention are readily converted to and may be isolated as the corresponding 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, the method for controlling pests comprises applying the compositions of the invention to the target pests, to their locus or to a surface or substrate by brushing, rolling, spraying, spreading or dipping. By way of example, an IRS (indoor residual spraying) application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention. In another embodiment, it is contemplated to apply such compositions to a substrate such as non-woven or a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.

In one embodiment, the method for controlling such pests comprises applying a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, or to a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate. Such application may be made by brushing, rolling, spraying, spreading or dipping the pesticidal composition of the invention. By way of example, an IRS application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention so as to provide effective residual pesticidal activity on the surface. In another embodiment, it is contemplated to apply such compositions for residual control of pests on a substrate such as a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.

Substrates including non-woven, fabrics or netting to be treated may be made of natural fibres such as cotton, raffia, jute, flax, sisal, hessian, or wool, or synthetic fibres such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. The polyesters are particularly suitable. The methods of textile treatment are known, e.g. WO 2008/151984, WO 2003/034823, U.S. Pat. No. 5,631,072, WO 2005/64072, WO2006/128870, EP 1724392, WO 2005113886 or WO 2007/090739.

Further areas of use of the compositions according to the invention are the field of tree injection/trunk treatment for all ornamental trees as well all sort of fruit and nut trees.

In the field of tree injection/trunk treatment, the compounds according to the present invention are especially suitable against wood-boring insects from the order Lepidoptera as mentioned above and from the order Coleoptera, especially against woodborers listed in the following tables A and B:

The present invention may also be used to control insect pests of turfgrass that are thatch dwelling, including armyworms (such as fall armywormSpodoptera frugiperda, and common armywormPseudaletia unipuncta), cutworms, billbugs (Sphenophorusspp., such as S. venatus verstitus andS. parvulus), and sod webworms (such asCrambusspp. and the tropical sod webworm,Herpetogrammaphaeopteralis).

The present invention may also be used to control insect pests of turfgrass that live above the ground and feed on the turfgrass leaves, including chinch bugs (such as southern chinch bugs,Blissus insularis), Bermudagrass mite (Eriophyescynodoniensis), rhodesgrass mealybug (Antoninagraminis), two-lined spittlebug (Propsapia bicincta), leafhoppers, cutworms (Noctuidae family), and greenbugs.

The present invention may also be used to control other pests of turfgrass such as red imported fire ants (Solenopsis invicta) that create ant mounds in turf.

In the hygiene sector, the compositions according to the invention are active against ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.

Examples of such parasites are: Of the order Anoplurida:Haematopinusspp.,Linognathusspp.,Pediculusspp. and Phtirus spp.,Solenopotesspp..

Of the order Siphonapterida, for examplePulexspp.,Ctenocephalidesspp.,Xenopsyllaspp.,Ceratophyllusspp..

Of the order Heteropterida, for exampleCimexspp.,Triatomaspp.,Rhodniusspp., Panstrongylus spp..

The compositions according to the invention are also suitable for protecting against insect infestation in the case of materials such as wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and buildings.

The compounds of formulae I, and I′a, or salts thereof, are especially suitable for controlling 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, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-72, and Table P”) controls one or more of pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae, and Heteroderidae.

The compounds of formulae I, and I′a, or salts thereof, are especially suitable for controlling one or more of pests selected from the genus:Spodopteraspp,Plutellaspp,Frankliniellaspp,Thripsspp,Euschistusspp,Cydiaspp,Nilaparvataspp,Myzusspp,Aphisspp,Diabroticaspp,Rhopalosiphumspp,Pseudoplusiaspp andChilospp.. In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-72, and Table P”) controls one or more of pests selected from the genus:Spodopteraspp,Plutellaspp,Frankliniellaspp,Thripsspp,Euschistusspp,Cydiaspp,Nilaparvataspp,Myzusspp,Aphisspp,Diabroticaspp,Rhopalosiphumspp,Pseudoplusiaspp andChilospp.

In an embodiment, one compound from Tables A-1 to A-72, and Table P is suitable for controllingMamestra(preferably in vegetables),Cydia pomonella(preferably in apples),Empoasca(preferably in vegetables, vineyards),Leptinotarsa(preferably in potatos) andChilosupressalis (preferably in rice). Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability). In particular, it has been surprisingly found that certain compounds of formula I may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees. Most particularly,Apis mellifera.

The compounds according to the invention can be used as pesticidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, micro-emulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. 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 used directly or diluted prior to use.

The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.

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

The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or 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 the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.

A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).

The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a 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 invention is generally from 0.01 to 10%, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8-C22fatty acids, especially the methyl derivatives of C12-C18fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively).

Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10thEdition, Southern Illinois University, 2010.

The inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance.

Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.

The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 I/ha, especially from 10 to 1000 I/ha.

Preferred formulations can have the following compositions (weight %):

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

Wettable powdersa)b)c)active ingredients25%50%75%sodium lignosulfonate5%5%—sodium lauryl sulfate3%—5%sodium—6%10%diisobutylnaphthalenesulfonatephenol polyethylene glycol—2%—ether (7-8 mol of ethylene oxide)highly dispersed silicic acid5%10%10%Kaolin62%27%—
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

Powders for dry seed treatmenta)b)c)active ingredients25%50%75%light mineral oil5%5%5%highly dispersed silicic acid5%5%—Kaolin65%40%—Talcum—20%
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

Emulsifiable concentrateactive ingredients10%octylphenol polyethylene glycol3%ether (4-5 mol of ethylene oxide)calcium dodecylbenzenesulfonate3%castor oil polyglycol ether4%(35 mol of ethylene oxide)Cyclohexanone30%xylene mixture50%
Emulsions of any require dilution, which can be use in plant protection, can be obtained from this concentrate by dilution with water.

Dustsa)b)c)Active ingredients5%6%4%Talcum95%——Kaolin—94%—mineral filler——96%
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

Extruder granulesActive ingredients15%sodium lignosulfonate2%carboxymethylcellulose1%Kaolin82%
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

Coated granulesActive ingredients8%polyethylene glycol3%(mol. wt. 200)Kaolin89%
The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

Suspension Concentrate

active ingredients40%propylene glycol10%nonylphenol polyethylene glycol6%ether (15 mol of ethylene oxide)Sodium lignosulfonate10%carboxymethylcellulose1%silicone oil (in the form of a1%75% emulsion in water)Water32%
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

Flowable Concentrate for Seed Treatment

The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

Slow Release Capsule Suspension

28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

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

Either one of the LCMS or GCMS methods below was used to characterize the compounds. The characteristic LCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and the measured molecular ion (M+H)+or (M−H)−.

Step A: Preparation of N-[tert-butyl(dimethyl)silyl]methanesulfonamide

To a solution of methane sulfonamide (9.0 g, 94.62 mmol, 1.00 equiv.) in tetrahydrofuran (142 mL) was added triethylamine (26.4 mL, 189.2 mmol, 2.00 equiv.). Then, a solution of tert-butyl-chloro-dimethyl-silane (15.69 g, 104.1 mmol, 1.10 equiv.) in toluene (56.8 mL) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for 48 hours. Then, the cloudy solution was filtered, and filtrate was concentrated under reduced pressure to afford the desired compound, N-[tert-butyl(dimethyl)silyl]methanesulfonamide, as a beige solid.

Step B: Preparation of N-[N-[tert-butyl(dimethyl)silyl]-S-methyl-sulfonimidoyl]-1-(3,4-dimethoxyphenyl)methanamine

Under nitrogen atmosphere, to a suspension of dichloro(triphenyl)-λ5-phosphane (3.50 g, 10.51 mmol, 1.1 equiv.) in chloroform (23.88 mL) was added triethylamine (2.01 mL, 14.33 mmol, 1.50 equiv.). The suspension was stirred at room temperature for 10 minutes. Then, the reaction mixture was cooled to 0° C. and a solution of N-[tert-butyl(dimethyl)silyl]methanesulfonamide (2.00 g, 9.55 mmol, 1.00 equiv.) in chloroform (11.94 mL) was added. The resulting clear solution was stirred at 0° C. for 20 minutes. Then, a solution of 3,4-dimethoxybenzylamine (4.50 mL, 28.65 mmol, 3.00 equiv.) in chloroform (6.37 mL) was added in one portion to the reaction mixture. The resulting suspension was stirred at 0° C. for 1 hour, then it was allowed to reach room temperature overnight. Acetonitrile (20 mL) was added to the reaction mass and the suspension was filtered through celite pad. The filtrate was concentrated under reduced pressure then purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, N-[N-[tert-butyl(dimethyl)silyl]-S-methyl-sulfonimidoyl]-1-(3,4-dimethoxyphenyl)methanamine, as a pale yellow oil.

Step C: Preparation of 1-(3,4-dimethoxyphenyl)-N-(methylsulfonimidoyl)methanamine

Under argon atmosphere, to a solution of N-[N-[tert-butyl(dimethyl)silyl]-S-methyl-sulfonimidoyl]-1-(3,4-dimethoxyphenyl)methanamine (5.50 g, 15.0 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) cooled at 0° C., was added tetra-n-butylammonium fluoride (31 mL, 31.0 mmol, 2.00 equiv.). The reaction mixture was stirred at room temperature for 6 hours, concentrated under reduced pressure and purified by flash chromatography (methanol: ethyl acetate (1:9) in cyclohexane), to afford the desired compound 1-(3,4-dimethoxyphenyl)-N-(methylsulfonimidoyl)methanamine, as a colorless oil.

Step D: Preparation of 2-[[[(3,4-dimethoxyphenyl)methylamino]-methyl-oxo-λ6-sulfanylidene]amino]benzoic acid

To a solution of 1-(3,4-dimethoxyphenyl)-N-(methylsulfonimidoyl)methanamine (3.4 g, 14.0 mmol, 1.00 equiv.) and 2-iodobenzoic acid (3.5 g, 14.0 mmol, 1.00 equiv.) in dimethylformamide (20 mL) was added potassium carbonate (4.8 g, 35.0 mmol, 2.50 equiv.), and copper (1) iodide (0.53 g, 2.8 mmol, 0.20 equiv.). The reaction was stirred at room temperature for 2 hours, then at 50° C. for 1 hour. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate. The aqueous layer was acidified using HCl solution (2N, 10 mL), extracted three times with ethyl acetate (3*25 mL). The combined organic layers were dried over sodium sulfate, filtrated, and concentrated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 2-[[[(3,4-dimethoxyphenyl)methylamino]-methyl-oxo-λ6-sulfanylidene]amino]benzoic acid.

Step E: Preparation of 4-[(3,4-dimethoxyphenyl)methyl]-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one

To a solution of 2-[[[(3,4-dimethoxyphenyl)methylamino]-methyl-oxo-λ6-sulfanylidene]amino]benzoic acid (1.02 g, 2.80 mmol, 1.00 equiv.) in acetonitrile (14 mL) was added triethylamine (1.18 mL, 4.20 mmol, 1.50 equiv.) and propanephosphonic acid anhydride (2.50 mL, 4.20 mmol, 1.50 equiv.). The reaction mixture was stirred at room temperature for 20 minutes. The reaction was diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Charcoal was added and the solution was filtered through celite to afford the desired crude product, 4-[(3,4-dimethoxyphenyl)methyl]-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one, as a brown oil, which was used in next step without further purification.

Step F: Preparation of 3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one

To a solution of 4-[(3,4-dimethoxyphenyl)methyl]-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one (1.45 g, 4.19 mmol, 1.00 equiv.) in toluene (20.9 mL) was added trifluoroacetic acid (8.37 mL, 109 mmol, 26.10 equiv.). The reaction mixture was stirred at room temperature for 1 hour, the concentrated under reduced pressure. The residue was crystalized in pentane and few drops of ethyl acetate. The crystals were filtered and dried under reduced pressure to afford the desired product, 3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one as a light brown solid.

Step G: Preparation of 8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one

To a solution of 3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one (0.250 g, 1.274 mmol, 1.00 equiv.) in acetonitrile (1.27 mL) was added N-bromosuccinimide (0.525 g, 2.803 mmol, 2.20 equiv.). The reaction mixture was stirred at room temperature for 20 minutes. Then, water was added. A precipitation was observed. The mixture was filtered, and precipitate was washed with water. The crystals were triturated in methanol to afford the desired compound, 8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one as a light yellow solid.

Then, filtrate was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate, then with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was crystalized in pentane and crystals were isolated after filtration to afford the desired product, 8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one, as a yellow solid.

8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one (0.125 g, 0.353 mmol, 1.00 equiv.) was placed in a vial under argon atmosphere. Phosphoryl chloride (0.263 mL, 2.825 mmol, 8.00 equiv.) was added. The mixture was stirred at 60° C. for 1 hour. Then it was heated at 100° C. for 1 hour. The reaction mixture was evaporated under reduced pressure and the crude oil was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 8,10-dibromo-5-chloro-3-methyl-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaene 3-oxide, as a bright yellow oil.

To a solution of 8,10-dibromo-5-chloro-3-methyl-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaene 3-oxide (0.100 g, 0.268 mmol, 1.00 equiv.) in tetrahydrofuran (1.34 mL) was added [(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]ammonium;2,2,2-trifluoroacetate (0.090 g, 0.295 mmol, 1.10 equiv.). To this mixture was added triethylamine (0.05 g, 0.49 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 20 minutes, then it was evaporated under reduced pressure. The residue was solubilized with ethyl acetate. Precipitation occurred, the mixture was filtered and the filtrate was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 8,10-dibromo-3-methyl-3-oxo-N-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine, as a yellow foam.

The NMR shows the presence of two diastereoisomers:

Step A: Preparation of 2-iodo-4,6-bis(trifluoromethyl)aniline

To a solution of 2,4-bis(trifluoromethyl)aniline (8.00 g, 33.2 mmol, 1.00 equiv.) in acetic acid (109 mL) was added N-iodosuccinimide (7.86 g, 33.2 mmol, 1.00 equiv.) portion-wise at room temperature. The reaction mixture was stirred at room temperature overnight. Then, the mixture was poured in ethyl acetate, water was added. The organic layer was washed with sodium bicarbonate (sat. aqueous solution), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 2-iodo-4,6-bis(trifluoromethyl)aniline, as a solid.

Step B: Preparation of 2-amino-3,5-bis(trifluoromethyl)benzonitrile

To a solution of 2-iodo-4,6-bis(trifluoromethyl)aniline (10.3 g, 29.0 mmol, 1.00 equiv.) in acetonitrile (116 mL) was added dicyanozinc (3.41 g, 29.0 mmol, 1.00 equiv.). The mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium(0) (1.68 g, 1.45 mmol, 0.05 equiv.) was added and the mixture was stirred overnight at 80° C. The mixture was cooled down, filtered over celite pad, and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 2-amino-3,5-bis(trifluoromethyl)benzonitrile, as a solid.

Step C: Preparation of 2-iodo-3,5-bis(trifluoromethyl)benzonitrile

Under argon atmosphere, to a solution of 2-amino-3,5-bis(trifluoromethyl)benzonitrile (7.0 g, 27.54 mmol, 1.0 equiv.) in acetonitrile (44 mL) were added diiodomethane (2.22 mL, 27.54 mmol, 1.0 equiv.) and isopentyl nitrite (7.0 mL, 52.33 mmol, 1.9 equiv.). The reaction mixture was stirred at room temperature for 10 minutes, then at 50° C. for 1 hour, then at 80° C. for 1 hour. The solution was cooled down and evaporated under reduced pressure. The crude material was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 2-iodo-3,5-bis(trifluoromethyl)benzonitrile, as a solid.

Step D: Preparation of 2-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3,5-bis(trifluoromethyl)benzonitrile

Step E: Preparation of 3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine

Step F: Preparation of ethyl 2-[[3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]propanoate

To a solution of 3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine (3.80 g, 12 mmol, 1.00 equiv.) in acetonitrile (120 mL) were added ethyl 2-bromopropanoate (2.2 mL, 17 mmol, 1.5 equiv.) and cesium carbonate (11 g, 35 mmol, 3.00 equiv.). The reaction mixture was stirred at 60° C. for 45 min, then cooled down to room temperature. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane).

Step G: Preparation of 2-[[3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]propanamide

Ethyl 2-[[3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]propanoate (0.660 g, 1.533 mmol, 1.00 equiv.) was dissolved in ammonia (7M in methanol, 3.07 mL, 21.47 mmol, 14.0 equiv.). The solution was stirred at 50° C. overnight. Then, the mixture was evaporated and the crude was washed with ether to afford the desired product 2-[[3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]propenamide as a solid.

To a solution of 2-[[3-methyl-3-oxo-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]propenamide (0.375 g, 0.935 mmol, 1.00 equiv.) in dichloromethane (9.35 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (0.372 mL, 2.803 mmol, 3.00 equiv.). The reaction mixture was stirred at 50° C. for 1 hour. The solution was evaporated, then dissolved in 1,4-dioxane (4.15 mL). To this solution was added pyrimidin-2-ylhydrazine (0.229 g, 2.077 mmol, 2.00 equiv.) followed by acetic acid (2.60 mL, 1.039 mmol, 1.00 equiv.). The reaction mixture was stirred at 80° C. for 1 hour, cooled down to room temperature. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane), to afford the desired compound 3-methyl-3-oxo-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-8,10-bis(trifluoromethyl)-3λ6-thia-2-azabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine, as a solid.

The NMR shows the presence of two diastereoisomers:

Example 3: Preparation of 6-[5-[(1S)-1-[[(3S)-8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyridine-3-carbonitrile and 6-[5-[(1S)-1-[[(3R)-8,10-dibromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyridine-3-carbonitrile by separation of diastereomers

The separation of the diastereomers resulted in two fractions eluting respectively at −13.3 and −17.7 min, which were each concentrated to giveCompound P6 (first eluting diastereomer-1) as a solid, mp 220-223° C.,

Yield: 49 mg eluting at −13.3 min in the preparative SFC.

Yield: 42 mg eluting at −17.7 min in the preparative SFC.

To a solution of 8-chloro-3-methyl-3-oxo-N-[(1S)-1-(2-pyrazin-2-yl-1,2,4-triazol-3-yl)ethyl]-10-(trifluoromethyl)-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine (compound P17) (0.058 g, 0.123 mmol) in acetonitrile (0.5 mL) were added cesium carbonate (0.120 g, 0.369 mmol), followed by iodomethane (0.0155 mL, 0.246 mmol) and the reaction mixture was stirred at room temperature for 17 hours. Another portion of iodomethane (2 equiv.) was further added and stirring continued for 6 hours before dilution with water. The product was extracted with ethyl acetate (2×), the combined organic layers washed with brine, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 8-chloro-N,3-dimethyl-3-oxo-N-[(18)-1-(2-pyrazin-2-yl-1,2,4-triazol-3-yl)ethyl]-10-(trifluoromethyl)-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-amine.

Example E1: Alternative preparation of 1-(3,4-dimethoxyphenyl)-N-(methylsulfonimidoyl)methanamine

To a solution at 0° C. of N-sulfinyltriphenylmethylamine (CAS 503596-47-2) (5 g, 16.37 mmol) dissolved in 2-methyltetrahydrofuran (115 mL) was added a 3M methylmagnesium bromide solution in diethyl ether (5.5 mL, 16.5 mmol) dropwise. The reaction mixture was stirred for 30 minutes, then another portion of 3M methylmagnesium bromide solution (0.15 equiv.) was added and stirring continued at 0° C. for 2 hours. Tert-butyl hypochlorite (2.05 mL, 17.19 mmol) was added at 0° C. in a darkened fume hood and the mixture stirred for 20 minutes. Another portion of tert-butyl hypochlorite was added (0.14 equiv.) and stirring continued at 0° C. for 30 minutes. Triethylamine (1 equiv., 16.37 mmol) and (3,4-dimethoxyphenyl)methanamine (1 equiv., 16.37 mmol) were then added and the mixture was stirred at room temperature for 18 hours. Methanesulfonic acid (5 equiv., 81.86 mmol) was added and the mixture stirred vigorously at room temperature for 50 minutes. Another portion of methanesulfonic acid (5 equiv.) was further added and stirring continued for 2 hours before dilution with dichloromethane. The solution was washed with a saturated aqueous sodium bicarbonate solution, then the layers were separated and the aqueous phase was extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silicagel, gradient 15% to 100% ethyl acetate in cyclohexane) to afford 1-(3,4-dimethoxyphenyl)-N-(methylsulfonimidoyl)methanamine as an oil.

Example E2: Preparation of 5-chloro-2-iodo-3-(trifluoromethyl)benzoic acid (1-10)

To a mixture of 2-amino-5-chloro-3-(trifluoromethyl)benzoic acid (CAS 58026-23-6) (3.0 g, 12.52 mmol) in4N aqueous hydrochloric acid (15 mL) and acetonitrile (30 mL) cooled to 0° C. was added slowly a solution of sodium nitrite (0.9503 g, 13.77 mmol) in water (30 mL) dropwise over 30 minutes. Following further dilution with acetonitrile (15 mL), a solution of potassium iodide (10.39 g, 62.59 mmol) in water (30 mL) was added dropwise at 0° C. The reaction mixture was then stirred at room temperature overnight, and stopped by adding 10 ml of an aqueous saturated sodium thiosulfate solution. The volatiles were removed under reduced pressure and the product extracted twice with ethyl acetate from the aqueous layer. The combined organic phases were washed with aqueous saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound 5-chloro-2-iodo-3-(trifluoromethyl)benzoic acid (1-10) as solid (3.04 g).

Example E3: Preparation of [(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]ammonium-2,2,2-trifluoroacetate

A 25 ml round bottom flask was charged with tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (0.725 g), 3-benzyl-5-(3-hydroxyethyl)-4-methylthiazol-3-ium bromide (0.210 g), pyrazine-2-carbaldehyde (1.13 g) and dichloromethane (12 ml). Then N,N-diisopropylethylamine (1.46 ml) was added, and the mixture was stirred for 2 h at ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by preparative HPLC on a reversed phase C18 column, using water and acetonitrile as eluent. Thus, tert-butyl N-[(1S)-2-hydroxy-1-methyl-3-oxo-3-pyrazin-2-yl-propyl]carbamate was obtained as a mixture of diastereoisomers in the approximate ratio of 3:1. The diastereoisomeric mixture was used for the next step without further separation.

tert-butyl N-[(1S)-2-hydroxy-1-methyl-3-oxo-3-pyrazin-2-yl-propyl]carbamate (0.590 g) was dissolved in a mixture of dichloromethane (7 ml), dimethyl sulfoxide (1 ml) and N,N-diisopropylethylamine (1.08 ml). The mixture was cooled to 0° C. and then sulfur trioxide pyridine complex (688 mg) was added in a single portion to the orange solution. After 30 minutes at 0° C., the reaction was quenched with water, and diluted with dichloromethane and aqueous HCl (1N). The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, and concentrated under reduced pressure to give crude tert-butyl N-[(1S)-1-methyl-2,3-dioxo-3-pyrazin-2-yl-propyl]carbamate as a brown oil. The crude product was used for the next step without further purification.

To a solution of crude tert-butyl N-[(1S)-1-methyl-2,3-dioxo-3-pyrazin-2-yl-propyl]carbamate (570 mg) in ethanol (8 ml) was added ethane-1,2-diamine (1.39 ml). The resulting brown solution was stirred at ambient temperature open to air. After 48 hours, the orange solution was concentrated under vacuum and the residue purified by chromatography on silica gel, using cyclohexane and ethyl acetate as eluent. Thus, tert-butyl N-[(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]carbamate was obtained as a yellow gum.

Step 4: Preparation of [(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]ammonium-2,2,2-trifluoroacetate

A solution of tert-butyl N-[(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]carbamate (282 mg) in dichloromethane (7 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at ambient temperature for 20 hours. All volatiles were then removed under reduced pressure to give crude [(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]ammonium-2,2,2-trifluoroacetate as a thick oil.

To a solution of 3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one (50 mg, 0.255 mmol, 1 equiv.) in acetonitrile (30 mL/mmol) was added a solution of N-bromosuccinimide (48 mg, 0.255 mmol, 1 equiv.) in acetonitrile (3 mL) dropwise over 3 minutes. The reaction mixture was stirred at room temperature for 10 minutes, before addition of water. The formed precipitation was removed by filtration. Three drops of an aqueous 1M hydrochloric acid solution were added to the filtrate and the product extracted from the aqueous phase using ethyl acetate (3×). The combined organic phases were washed with brine, dried and the solvent removed under reduced pressure to afford the desired compound 8-bromo-3-methyl-3-oxo-3λ6-thia-2,4-diazabicyclo[4.4.0]deca-1(6),2,7,9-tetraen-5-one (1-11) as a solid.

Abbreviations Used in Synthesis Schemes and Preparatory Examples

The activity of the compositions according to the invention can be broadened considerably, and adapted to prevailing circumstances, by adding other insecticidally, acaricidally and/or fungicidally active ingredients. The mixtures of the compounds of formula I with other insecticidally, acaricidally and/or fungicidally active ingredients may also have further surprising advantages which can also be described, in a wider sense, as synergistic activity. For example, better tolerance by plants, reduced phytotoxicity, insects can be controlled in their different development stages or better behavior during their production, for example during grinding or mixing, during their storage or during their use.

The references in brackets behind the active ingredients, e.g. [3878-19-1]refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual—A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood;Compendium of Pesticide Common Names, Copyright © 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.

Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “development code” is used or, if neither one of those designations nor a “common name” is used, an “alternative name” is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.

The active ingredient mixture of the compounds of formula I selected from the compounds defined in the Tables A-1 to A-72, and Table P with active ingredients described above comprises a compound selected from one compound defined in the Tables A-1 to A-72, and Table P and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 to 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in 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. Those mixing ratios are by weight. The compounds and mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a compound or mixture respectively as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practiced on the human or animal body.

The mixtures comprising a compound of formula I selected from the compounds defined in the Tables A-1 to A-72, and Table P and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I and the active ingredients as described above is not essential for working the present invention.

The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.

The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.

The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.

A preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question. Alternatively, the active ingredient can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application). In the case of paddy rice crops, such granules can be metered into the flooded paddy-field.

The compounds of formula I of the invention and compositions thereof are also suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type. The propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing. Alternatively, the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling. These treatment methods for plant propagation material and the plant propagation material thus treated are further subjects of the invention. Typical treatment rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.

The term seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means in a preferred embodiment true seeds.

The present invention also comprises seeds coated or treated with or containing a compound of formula I. The term “coated or treated with and/or containing” generally signifies that the active ingredient is for the most part on the surface of the seed at the time of application, although a greater or lesser part of the ingredient may penetrate into the seed material, depending on the method of application. When the said seed product is (re)planted, it may absorb the active ingredient. In an embodiment, the present invention makes available a plant propagation material adhered thereto with a compound of formula I. Further, it is hereby made available, a composition comprising a plant propagation material treated with a compound of formula I.

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

The compounds of the invention can be distinguished from other similar compounds by virtue of greater efficacy at low application rates and/or different pest control, which can be verified by the person skilled in the art using the experimental procedures, using lower concentrations if necessary, for example 10 ppm, 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, such as 300, 200 or 100, mg of A1 per m2. The greater efficacy can be observed by an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).

In each aspect and embodiment of the invention, “consisting essentially” and inflections thereof are a preferred embodiment of “comprising” and its inflections, and “consisting of” and inflections thereof are a preferred embodiment of “consisting essentially of” and its inflections.

The disclosure in the present application makes available each and every combination of embodiments disclosed herein.

It should be noted that the disclosure herein in respect of a compound of formula I applies equally in respect of a compound of each of formulae I*, I′a, Iaa, Iab, Iac, Iad, Iae, Iaf, I′aa, I′ab, I′ac, I′ad, ′Iae, I′af and Tables A-1 to A-72, and Table P.

The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 24 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.

24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (6-8 per well). The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 6 days after infestation. Control ofChilo suppressalisby a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.

Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation.

The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P4, P5, P6, P7, P9, P10, P11, P12, P13, P15, P16, P17, P18, P19, P20.

24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions by pipetting. After drying,Plutellaeggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 8 days after infestation.

The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20.

Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control ofSpodoptera littoralisby a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.

Sunflower leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10'000 DMSO stock solutions. After drying the leaf discs were infested with aFrankliniellapopulation of mixed ages. The samples were assessed for mortality 7 days after infestation.

The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P10, P13.

Sunflower leaf discs were placed onto agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation.

The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P10, P14.

Test compounds prepared from 10'000 ppm DMSO stock solutions were applied by pipette into 24-well microtiter plates and mixed with sucrose solution. The plates were closed with a stretched Parafilm. A plastic stencil with 24 holes was placed onto the plate and infested pea seedlings were placed directly on the Parafilm. The infested plate was closed with a gel blotting paper and another plastic stencil and then turned upside down. The samples were assessed for mortality 5 days after infestation.

The following compounds resulted in at least 80% mortality at a test rate of 12 ppm: P1, P10, P13, P16, P18.

Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10'000 ppm DMSO stock solutions. After drying the leaf discs were infested with a mite population of mixed ages. The samples were assessed for mortality on mixed population (mobile stages) 8 days after infestation.

The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P14.