Pesticidally active fused bicyclic heteroaromatic compounds

Abstract

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. # imgabs0 #

Description

[0001] The present invention relates to pesticidally active, in particular insecticidal, quinazoline compounds, to a process for their preparation, to compositions comprising those compounds, and to their use for controlling animal pests, including arthropods and in particular insects or representatives of the order Acarina.

[0002] WO 2021 / 083936, WO 2021 / 148639 and WO 2021 / 177160 describe certain quinazoline, quinazolinone and quinoline compounds.

[0003] Additional novel pesticidally active quinazoline compounds have now been discovered.

[0004] Therefore, the present invention relates in a first aspect to compounds of formula (I)

[0005]

[0006] in:

[0007] A 1 、A 2 and A 3 N or CR independently of each other Y ;or

[0008] A 1 =A 2 -A 3 Together they are NR-C(=O)-N;

[0009] A 4 and A 5 N or CR independently of each other YY ;

[0010] Q is wherein the staggered lines represent the connection of Q to the remainder of the compound of formula (I);

[0011] R is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy;

[0012] R 1is hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonyl C1-C6 alkyl, hydroxycarbonyl C1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilyl C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkyl C1-C6 -C2 alkyl-, C3-C4 cycloalkyl C1-C2 alkyl-, oxetan-3-yl-CH2-, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, benzyl or benzyl substituted by 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy and C1-C6 haloalkyl;

[0013] R 2a and R 2b each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, NO2, SF5, CN, C(O)NH2, C(O)OH, C(S)NH2, C3-C6 cycloalkyl, substituted by one to three independently selected R x C3-C6 cycloalkyl, C3-C6 cycloalkylcarbonyl, phenyl, substituted by one to three independently selected R x substituted phenyl, heteroaryl, substituted by one to three independently selected R x Substituents substituted heteroaryl; OR 6 , piperidin-2-one-1-yl, one to two independently selected from R x Substituents substituted piperidin-2-one-1-yl, pyridin-2-one-1-yl, substituted by one to two independently selected from R x substituted pyridin-2-one-1-yl, azetidin-1-yl, substituted by one to two independently selected from R x substituted azetidin-1-yl, pyrrolidin-1-yl, substituted by one to two independently selected from R x substituted pyrrolidin-1-yl, C3-C6 cycloalkyl C1-C4 alkyl, substituted by one to two independently selected R Z C3-C6 cycloalkyl C1-C4 alkyl substituted by a substituent; C3-C6 cycloalkyl C1-C3 alkoxy, substituted by one to two independently selected R x C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C5 cyanoalkyl, C1-C5 cyanoalkoxy, C1-C4 alkylsulfanyl, substituted by one to three independently selected R xC1-C4 alkylsulfanyl, C1-C4 alkylsulfonyl, substituted by one to three independently selected R x C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, and substituted by one to three independently selected R x C1-C4 alkylsulfinyl substituted with a substituent;

[0014] R 3 is C1-C3 alkyl or C1-C3 haloalkyl;

[0015] R 4 and R 4a is independently pyrimidinyl, pyrazinyl, pyridazinyl or thiazolyl, each of which is independently substituted by a single -C(O)NR 10 R 11 replace; or

[0016] R 4a is an N-attached pyrazolyl or N-attached triazolyl, each of which is independently substituted by a single -C(O)NR 10 R 11 replace; or

[0017] R 4 and R 4a is 4-cyano-pyrimidin-6-yl;

[0018] R 10 is hydrogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, cyanoC3-C4 cycloalkyl, C3-C4 cycloalkylC1-C3 cyanoalkyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl, or 3-methyl-1,1-dioxothietane-3-yl; and

[0019] R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or

[0020] R 10 and R 11 together with the nitrogen to which they are attached, form a pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl group;

[0021] R 5is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 alkoxyC(O)-, (C1-C3 alkoxy)2CH-, halogen, CN, NH2C(O), amino (i.e., NH2), (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, hydroxy, C3-C4 halocycloalkyl, C3-C4 cyanocycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C3 Alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)sulfonylamino, (C1-C3 alkyl)sulfonyl(C1-C3 alkyl)amino, (C1-C3 alkyl)NHC(O), (C1-C3 alkyl)2NC(O), (C1-C3 cycloalkyl)NHC(O), (C1-C3 cycloalkyl)(C1-C3 alkyl)NC(O), (C1-C3 alkyl)C(O)(C1-C3 alkyl)N, (C1-C3 alkyl)C(O)NH, (C1-C3 alkyl)C(O), (C1-C3 alkoxy)C(O), HC(O), benzophenone imine, C1-C3 haloalkoxy, phenyl, or a 5-membered heteroaromatic ring; or

[0022] R 5 is phenyl substituted with one to three substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, CN, and hydroxy; or

[0023] R 5 is a 5-membered heteroaromatic ring substituted with one to three substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, CN, and hydroxy;

[0024] R 5a and R 5b are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy;

[0025] R 6 is phenyl, benzyl, heteroaryl, or C3-C6 cycloalkyl; or

[0026] R 6 is phenyl, benzyl, heteroaryl, or C3-C6 cycloalkyl, each of which is independently substituted by one to three independently selected Rx Substituents substituted;

[0027] R x independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, NO2, SF5, CN, C(O)NH2, C(S)NH2, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl and C1-C4 alkylsulfonyl;

[0028] R Y is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl;

[0029] R YY is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl; and

[0030] R Z is selected from the group consisting of oxo, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and CN;

[0031] and agrochemically acceptable salts, stereoisomers, enantiomers, tautomers and N-oxides of the compound of formula (I).

[0032] Compounds of formula (I) with at least one basic center can form acid addition salts, for example, with strong inorganic acids (such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid or hydrohalic acids), strong organic carboxylic acids (such as unsubstituted or, for example, halogen-substituted C1-C4-alkanecarboxylic acids, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid), or organic sulfonic acids (such as unsubstituted or, for example, halogen-substituted C1-C4-alkanesulfonic acids or arylsulfonic acids, for example methanesulfonic acid or p-toluenesulfonic acid). Compounds of formula (I) having at least one acidic group can, for example, form salts with bases, for example mineral salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts; or with ammonia or organic amines such as morpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines, for example ethylamine, diethylamine, triethylamine or dimethylpropylamine, or mono-, di- or trihydroxy-lower alkylamines, for example monoethanolamine, diethanolamine or triethanolamine.

[0033] In each case, the compounds of formula (I) according to the invention are in free form, in an oxidized form (such as an N-oxide) or in the form of a salt (for example an agronomically usable salt).

[0034] N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen-containing heteroaromatic compounds. They are described, for example, in the book "Heterocyclic N-oxides" by A. Albini and S. Pietra, CRC Press, Boca Raton, 1991.

[0035] The compounds of formula (I) according to the invention also include hydrates which may be formed during salt formation.

[0036] As used herein, the term "C1-C n “Alkyl” refers to a saturated straight or branched chain hydrocarbon radical having 1 to n carbon atoms, attached via any carbon atom, such as any of the following: methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0037] As used herein, the term "C1-C n“Haloalkyl” refers to straight-chain or branched saturated alkyl groups (as mentioned above) having 1 to n carbon atoms, attached via any carbon atom, wherein some or all of the hydrogen atoms in these groups may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., for example, any of the following: chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl The term "Ci-C2 fluoroalkyl" shall mean a C1-C2 alkyl group having 1, 2, 3, 4 or 5 fluorine atoms, for example, any of the following groups: difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.

[0038] As used herein, the term "C1-C n "Alkoxy" refers to a straight-chain or branched saturated alkyl group (as mentioned above) having 1 to n carbon atoms, which is attached via an oxygen atom, i.e., for example, any of the following groups: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. As used herein, the term "halogenated C1-C n "Alkoxy" refers to C1-C n Alkoxy groups wherein one or more hydrogen atoms on the alkyl group are replaced by the same or different halogen atoms - examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.

[0039] As used herein, the term "C1-C n "Cyanoalkyl" refers to a straight or branched chain saturated C1-C n Alkyl groups (as mentioned above), wherein one of the hydrogen atoms in these groups is replaced by a cyano group: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, etc.

[0040] As used herein, the term "C3-C n The term "cycloalkyl" refers to a 3- to n-membered cycloalkyl group such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0041] As used herein, the term "cyano C3-C4 cycloalkyl" refers to a cyclopropane or cyclobutane group monosubstituted with a cyano group.

[0042] As used herein, the term "C3-C n "Cycloalkylcarbonyl" refers to a 3-n membered cycloalkyl group attached to a carbonyl (C=O) group, which is linked to the remainder of the molecule. Similarly, as used herein, the term "C1-C n Alkylcarbonyl", "C1-C n "Alkoxycarbonyl," "phenyloxycarbonyl," and "benzyloxycarbonyl" refer to alkyl, alkoxy, phenyloxy, and benzyloxy groups attached to a carbonyl (C=O) group that is attached to the remainder of the molecule.

[0043] As used herein, the term "C3-C4 cycloalkyl-C1-C2 alkyl" refers to a 3- or 4-membered cycloalkyl group with a methylene or ethylene group attached to the remainder of the molecule. In this case, the C3-C4 cycloalkyl-C1-C2 alkyl group is substituted, and one or more substituents may be on the cycloalkyl group and / or the alkyl group.

[0044] As used herein, the term "C3-C6 cycloalkyl C1-C4 haloalkoxy" refers to a 3- to 6-membered cycloalkyl group attached to a 1- to 4-membered haloalkoxy group, which is attached to the remainder of the molecule.

[0045] As used herein, the term "aminocarbonyl C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a CONH2 group.

[0046] As used herein, the term "hydroxycarbonyl C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a COOH group.

[0047] As used herein, the term "C1-C n "Alkylsulfanyl" refers to a C1-C n Similarly, as used herein, the term "C1-C n "Haloalkylthio" or "C1-C n "Haloalkylsulfanyl" refers to a C1-C n Similarly, the term "C3-C n"Cycloalkylsulfanyl" refers to a 3-n membered cycloalkyl moiety attached through a sulfur atom.

[0048] As used herein, the term "C1-C n "Alkylsulfinyl" refers to a C1-C2-alkyl group attached through the sulfur atom of an S(=O) group. n Similarly, as used herein, the term "C1-C n "Haloalkylsulfinyl" or "C1-C n "Haloalkylsulfinyl" refers to a C1-C2- n Similarly, the term "C3-C n "Cycloalkylsulfinyl" refers to a 3-n-membered cycloalkyl moiety attached through the sulfur atom of an S(=O) group.

[0049] As used herein, the term "C1-C n "Alkylsulfonyl" refers to a C1-C2 group attached through the sulfur atom of a S(=O)2 group. n Similarly, as used herein, the term "C1-C n "Haloalkylsulfonyl" or "C1-C n "Haloalkylsulfonyl" refers to a C1-C2 group attached through the sulfur atom of a S(=O)2 group. n Similarly, the term "C3-C n "Cycloalkylsulfonyl" refers to a 3-n-membered cycloalkyl moiety attached through the sulfur atom of a S(=O)2 group.

[0050] As used herein, the term "trimethylsilane C1-C n "Alkyl" refers to an alkyl group in which one of the hydrogen atoms in the group is replaced by a -Si(CH3)3 group.

[0051] As used herein, the term "C2-C n "Alkenyl" refers to a straight or branched alkenyl chain having from two to n carbon atoms and one or two double bonds, for example vinyl, prop-1-enyl, but-2-enyl.

[0052] As used herein, the term "C2-C n "Haloalkenyl" refers to a C2-C4 group substituted by one or more halogen atoms which may be the same or different. n Alkenyl moiety.

[0053] As used herein, the term "C2-C n "Alkynyl" 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.

[0054] As used herein, the term "C2-Cn "Haloalkynyl" refers to a C2-C6 substituted by one or more halogen atoms which may be the same or different. n Alkynyl moiety.

[0055] Halogen or "halo" is typically fluorine, chlorine, bromine or iodine. This also applies correspondingly to halogen in combination with other meanings, such as haloalkyl.

[0056] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring having 1 to 3 heteroatoms independently selected from N, O, and S. Examples are heteroaryl groups J-1 to J-41 shown below in Scheme A. Preferred heteroaryl groups are pyridinyl, pyrimidinyl, and pyrazolyl.

[0057] Scheme A: Heteroaryl groups J-1 to J-41:

[0058]

[0059]

[0060] R 4 and R 4a The pyridine, pyrimidine, pyrazine and pyridazine groups (unsubstituted or substituted) are each attached to the remainder of the compound through a carbon atom in the corresponding ring.

[0061] As used herein, the term "control" refers to reducing the number of pests, eliminating pests, and / or preventing further pest damage, such that damage to plants or to plant-derived products is reduced.

[0062] As in this article, for example, in Q a -1 and Q b The staggered lines used in -1 represent the point of connection / attachment to the rest of the compound.

[0063] As used herein, the term "pest" refers to insects and molluscs present in agriculture, horticulture, forestry, storage of products of plant origin (such as fruits, grains and wood); and those pests associated with damage to man-made structures. The term pest covers all stages of the life cycle of the pest.

[0064] As used herein, the term "effective amount" refers to an amount of a compound or a salt thereof that provides the desired effect upon single or multiple administrations.

[0065] An effective amount is readily determined by one skilled in the art by using known techniques and by observing results obtained under similar circumstances. In determining an effective amount, many factors are considered, including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled and its life cycle; the specific compound being applied; the type of application; and other relevant circumstances.

[0066] As will be understood by one of ordinary skill in the art, compounds of formula (I) contain stereocenters, which are indicated by asterisks in the following structures:

[0067]

[0068] where R 1 、R 2a 、R 2b 、R 3 , Q, A 1 、A 2 、A 3 、A 4 , and A 5 As defined in the first aspect.

[0069] The present invention contemplates both racemates and individual enantiomers. Compounds with preferred stereochemistry are listed below. Particularly preferred compounds of the present invention are compounds of formula (I'a):

[0070]

[0071] where R 1 、R 2a 、R 2b 、R 3 , Q, A 1 、A 2 、A 3 、A 4 , and A 5 As defined in the first aspect, and stereoisomers, enantiomers, tautomers and N-oxides of compounds of formula (I'a), and agrochemically acceptable salts thereof.

[0072] As used herein, the term "optionally substituted" means that the referenced group is unsubstituted or substituted with the specified substituent, for example, "C3-C4 cycloalkyl optionally substituted by 1 or 2 halo atoms" means C3-C4 cycloalkyl, C3-C4 cycloalkyl substituted by 1 halo atom, and C3-C4 cycloalkyl substituted by 2 halo atoms.

[0073] Examples according to the present invention are provided as listed below.

[0074] In an embodiment of each aspect of the invention, R is not hydrogen.

[0075] In an embodiment of each aspect of the present invention,

[0076] AA 1 、A 2 and A 3N or CR independently of each other Y , provided that no more than two of the three are N; or

[0077] BA 1 and A 3 It is N and A 2 It's CR Y ;or

[0078] CA 1 、A 2 and A 3 are independently N or CH; or

[0079] DA 1 、A 2 and A 3 are independently N or CH, provided that no more than two of the three are N; or

[0080] EA 1 is N, and A 2 and A 3 is CH; or

[0081] FA 1 and A 2 CH, and A 3 is N; or

[0082] GA 1 and A 3 is N, and A 2 is CH; or

[0083] HA 1 =A 2 -A 3 together are NR-C(=O)-N; or

[0084] IA 1 =A 2 -A 3 together is NH—C(═O)—N; or

[0085] In an embodiment of each aspect of the present invention,

[0086] AA 4 It's CR YY , and A 5 is N; or

[0087] BA 4 It's CR YY , and A 5 is CH; or

[0088] CA 4 is CH, and A 5 is N; or

[0089] DA 4 is N, and A 5 is CH; or

[0090] EA 4 and A 5 All are CH.

[0091] In an embodiment of each aspect of the present invention,

[0092] AA 1 It's N, A 2 and A 3 is CH, and A 4 and A 5 All CH; or

[0093] BA 1 and A 2 It is CH, A 3 is N, and A 4 and A 5 All are CH.

[0094] CA 1 and A 3 It's N, A 2 is CH, and A 4 It's CR Y And A 5 is CH; or

[0095] DA 1 and A 3 It's N, A 2 is CH, and A 4 is CH and A 5 is N; or

[0096] EA 1 and A 3 It's N, A 2 is CH, and A 4 It is N and A 5 is CH; or

[0097] FA 1 and A 3 It's N, A 2 is CH, and A 4 is N or CH and A 5 is CH; or

[0098] GA 1 and A 3 It's N, A 2 is CH, and A 4 is CH and A 5 is N or CH; or

[0099] HA 1 and A 3 It's N, A 2 is CH, and A 4 and A 5 All N; or

[0100] IA 1 and A 3 It's N, A 2 is CH, and A 4 and A 5 All CH; or

[0101] JA 1 =A 2 -A 3 Together they are NH-C(=O)-N and A 4 and A 5 All are CH.

[0102] In an embodiment of each aspect of the invention, wherein A 1 =A 2 -A 3 Together they are NR-C(=O)-N, R is

[0103] A. hydrogen, methyl, ethyl, difluoroethyl or trifluoroethyl; or

[0104] B. hydrogen; methyl, ethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl, or

[0105] C. Hydrogen; or

[0106] D. methyl or 2,2,2-trifluoroethyl; or

[0107] E. methyl; or

[0108] F. Hydrogen or methyl.

[0109] In a preferred embodiment of each aspect of the present invention, A 1 and A 3 It is nitrogen, A 2 、A 4 and A 5 It is CH.

[0110] In an embodiment of each aspect of the invention, R 1 yes

[0111] A. hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonylC1-C6 alkyl, hydroxycarbonylC1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilylC1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, C3-C4 cycloalkylC1-C2 alkyl- wherein the C3-C4 cycloalkyl group is substituted by 1 or 2 halogen atoms, oxetan-3-yl-CH2-, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, or benzyl; or

[0112] B. hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonyl C1-C6 alkyl, hydroxycarbonyl C1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilyl C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkyl C1-C2 alkyl-, benzyloxycarbonyl, or benzyl; or

[0113] C. hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonylC1-C6 alkyl, hydroxycarbonylC1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, benzyloxycarbonyl, or benzyl; or

[0114] D. hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, benzyloxycarbonyl, or benzyl; or

[0115] E. hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, benzyloxycarbonyl, or benzyl; or

[0116] F. hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C3-C4 cycloalkylC1-C2 alkyl-, benzyloxycarbonyl, or benzyl; or

[0117] G. hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl; or

[0118] H. hydrogen, methyl, ethyl, allyl, propargyl or cyclopropyl-methyl; or

[0119] I. hydrogen, methyl, propargyl or cyclopropyl-methyl; or

[0120] J. hydrogen, methyl, or cyclopropyl-methyl; or

[0121] K. hydrogen or methyl; or

[0122] L. Hydrogen.

[0123] In a preferred embodiment of each aspect of the present invention, R 1 is hydrogen, methyl or cyclopropyl-methyl, preferably, R 1 is hydrogen or methyl; more preferably, R 1 It's hydrogen.

[0124] In an embodiment of each aspect of the invention, R 2a yes

[0125] A. hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C4 cycloalkyl, C3-C6 cycloalkylcarbonyl, phenyl, heteroaryl selected from J-1 and J-41, each of C3-C4 cycloalkyl, phenyl or heteroaryl being independently substituted by one to three substituents R x substituted; OR6, piperidin-2-one-1-yl, pyridin-2-one-1-yl, optionally R x Substituted azetidin-1-yl, pyrrolidin-1-yl, substituted by one or two substituents R Z Substituted C3-C6 cycloalkyl C1-C4 alkyl, optionally substituted by R x Substituted C3-C6 cycloalkyl C1-C3 alkoxy, C1-C5 cyanoalkyl, C1-C5 cyanoalkoxy, optionally substituted by one to three substituents R x Substituted C1-C4 alkylsulfanyl, optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfonyl, or optionally substituted by one to three substituents R xsubstituted C1-C4 alkylsulfinyl; or

[0126] B. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C4 cycloalkyl, C3-C6 cycloalkylcarbonyl, phenyl, pyrazolyl (each of C3-C4 cycloalkyl, phenyl, pyrazolyl is independently substituted by one to three substituents R x substituted); OR6, piperidin-2-one-1-yl, pyridin-2-one-1-yl, optionally substituted by R x Substituted azetidin-1-yl, pyrrolidin-1-yl, optionally substituted by one or two substituents R Z Substituted C3-C6 cycloalkyl C1-C4 alkyl, optionally R x Substituted C3-C6 cycloalkyl C1-C3 alkoxy, C1-C5 cyanoalkyl, C1-C5 cyanoalkoxy, optionally substituted by one to three substituents R x Substituted C1-C4 alkylsulfanyl, optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfonyl, or optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfinyl; or

[0127] C. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C4 cycloalkyl, C3-C6 cycloalkylcarbonyl, phenyl or pyrazolyl (each of C3-C4 cycloalkyl, phenyl and pyrazolyl is independently substituted by one to two substituents R x Replace), OR 6 , optionally by R x Substituted azetidin-1-yl, optionally substituted by one or two substituents R Z Substituted C3-C6 cycloalkyl C1-C4 alkyl, optionally substituted by R x Substituted C3-C6 cycloalkyl C1-C3 alkoxy, optionally substituted by one to three substituents R x Substituted C1-C4 alkylsulfanyl, optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfonyl, or optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfinyl; or

[0128] D. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C4 cycloalkyl, substituted with one or two R x Substituted C3-C4 cycloalkyl; C3-C6 cycloalkylcarbonyl, OR 6, C3-C6 cycloalkyl C1-C4 alkyl, substituted by one or two R Z Substituted C3-C6 cycloalkyl C1-C4 alkyl, C1-C4 alkylsulfanyl, substituted by one to three R x Substituted C1-C4 alkylsulfanyl, C1-C4 alkylsulfonyl, substituted by one to three R x Substituted C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, or substituted by one to three R x substituted C1-C4 alkylsulfinyl; or

[0129] E. hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C4 cycloalkyl, C3-C4 cycloalkyl substituted by one to two substituents independently selected from halogen, C1-C3 alkyl and C1-C3 haloalkyl, C3-C4 cycloalkylcarbonyl, C3-C4 cycloalkylmethyl, C3-C4 cycloalkylmethyl substituted by one to two substituents independently selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C2 alkylsulfanyl substituted by one to three halogen, or C1-C2 alkylsulfonyl substituted by one to three halogen; or

[0130] F. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl, or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; or

[0131] G. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by one to three substituents independently selected from C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen, cyclopropylcarbonyl, C3-C6 cycloalkyl C1-C4 alkyl, substituted by one to five substituents independently selected from C3-C6 cycloalkyl, C1-C4 alkyl, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C3-C6 cycloalkylsulfanyl, C3-C6 cycloalkylsulfinyl, or C3-C6 cycloalkylsulfonyl substituted with a substituent selected from the group consisting of oxo, C1-C3 alkyl, C1-C3 haloalkyl, cyano, and halogen; or

[0132] H. Hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 alkoxy, C1-C3 haloalkoxy, CN, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by one or two substituents independently selected from C1-C3 haloalkyl, cyano, and halogen, C3-C4 cycloalkylcarbonyl, C3-C6 cycloalkylC1-C4 alkyl, substituted by one to three C3-C6 cycloalkyl, C1-C4 alkyl, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C3-C6 cycloalkylsulfanyl, C3-C6 cycloalkylsulfinyl, or C3-C6 cycloalkylsulfonyl substituted with a substituent independently selected from oxo, C1-C3 haloalkyl, cyano, and halogen; or

[0133] I. hydrogen, halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by one or two substituents independently selected from C1-C3 haloalkyl, cyano, and halogen, C3-C4 cycloalkylcarbonyl, C3-C6 cycloalkylC1-C4 alkyl, C3-C6 cycloalkylC1-C4 alkyl substituted by one to three substituents independently selected from oxo, C1-C3 haloalkyl, cyano, and halogen, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C3-C6 cycloalkylsulfanyl, C3-C6 cycloalkylsulfinyl, or C3-C6 cycloalkylsulfonyl; or

[0134] J. hydrogen, halogen, C3-C4 cycloalkyl, C3-C4 cycloalkylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted with one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; or

[0135] K. halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, or C1-C3 haloalkoxy; or

[0136] L. halogen, C1-C2 haloalkyl, C1-C2 haloalkylsulfanyl, C1-C2 haloalkylsulfonyl, or C1-C2 haloalkoxy; or

[0137] M. chloro, fluoro, bromo, iodo, difluoromethyl, trifluoromethyl, trifluoromethylsulfanyl or trifluoromethylsulfonyl; or

[0138] N. fluorine, chlorine, bromine, iodine, trifluoromethylsulfanyl, trifluoromethylsulfonyl or trifluoromethyl; or

[0139] O. chloro, bromo, iodo, trifluoromethylsulfonyl or trifluoromethyl; or

[0140] P. chlorine, bromine, iodine, methyl, trifluoromethylsulfonyl or trifluoromethyl; or

[0141] Q. chlorine, bromine, iodine, methyl or trifluoromethyl; or

[0142] R. Chloro, bromo, iodo, or trifluoromethyl.

[0143] In a preferred embodiment of each aspect of the present invention, R 2a is chloro, bromo, iodo or trifluoromethyl; preferably R 2a It is chloro or trifluoromethyl.

[0144] In an embodiment of each aspect of the invention, R 2b yes

[0145] A. hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, cyclopropylcarbonyl, optionally substituted by one or two R Z Substituted C3-C6 cycloalkyl, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN, optionally substituted by one to three substituents R x Substituted C1-C4 alkylsulfanyl, optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfonyl, or optionally substituted by one to three substituents R x substituted C1-C4 alkylsulfinyl; or

[0146] B. hydrogen, halogen, C3-C4-cycloalkyl, cyclopropylcarbonyl, C3-C4-cycloalkyl-C1-C2-alkyl optionally substituted with one to two substituents selected from oxo, halogen, C1-C3-alkyl and C1-C3-haloalkyl, C1-C3-haloalkylsulfanyl, C1-C3-haloalkylsulfonyl, C1-C3-alkoxy, C1-C3-haloalkoxy, or CN; or

[0147] C. halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, or C1-C3 haloalkoxy; or

[0148] D. halogen, C1-C2 haloalkyl, C1-C2 haloalkylsulfanyl, C1-C2 haloalkylsulfonyl, or C1-C2 haloalkoxy; or

[0149] E. fluorine, chlorine, bromine, iodine, difluoromethyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethylsulfonyl; or

[0150] F. fluorine, chlorine, bromine, iodine, trifluoromethylsulfanyl, trifluoromethylsulfonyl or trifluoromethyl; or

[0151] G. chlorine, bromine, iodine, trifluoromethylsulfonyl or trifluoromethyl; or

[0152] H. chlorine, bromine, iodine, or trifluoromethyl; or

[0153] I. chloro or trifluoromethyl; or

[0154] J. chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; or

[0155] K. a difluoromethylsulfonyl group or a trifluoromethylsulfonyl group.

[0156] In a preferred embodiment of each aspect of the present invention, R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; preferably R 2b is chloro, bromo, iodo or trifluoromethyl. In embodiments of each aspect of the invention, R 2b It is a difluoromethylsulfonyl group or a trifluoromethylsulfonyl group.

[0157] In an embodiment of each aspect of the present invention,

[0158] AR 2a and R 2b independently selected from halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl or C1-C3 haloalkoxy; or

[0159] BR 2a and R 2b independently selected from fluorine, chlorine, bromine, iodine, trifluoromethylsulfanyl, trifluoromethylsulfonyl or trifluoromethyl; or

[0160] CR 2a and R 2b independently selected from chloro, bromo, iodo, trifluoromethylsulfonyl or trifluoromethyl; or

[0161] DR 2a is chloro, bromo, iodo, methyl, trifluoromethylsulfonyl or trifluoromethyl; and R 2b is chloro, bromo, iodo, trifluoromethylsulfonyl or trifluoromethyl; or

[0162] ER 2a is chloro, bromo, iodo, methyl or trifluoromethyl; and R 2b is chloro, bromo, iodo or trifluoromethyl; or

[0163] FR 2a and R 2b variously selected from chloro, bromo, iodo, trifluoromethylsulfonyl or trifluoromethyl; or

[0164] GR 2a and R 2b variously selected from chloro, bromo, iodo or trifluoromethyl; or

[0165] HR 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; or

[0166] IR 2a is chloro or trifluoromethyl, and R 2b is chlorine, bromine, iodine or trifluoromethyl.

[0167] In a preferred embodiment of each aspect of the present invention, R 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; preferably R 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chlorine, bromine, iodine or trifluoromethyl, or R 2a is chloro or trifluoromethyl, and R 2b More preferably, R 2a is chloro or trifluoromethyl, and R 2b is chlorine, bromine, iodine or trifluoromethyl.

[0168] In an embodiment of each aspect of the invention, R 3 yes

[0169] A. C1-C3 alkyl or C1-C3 haloalkyl; or

[0170] B. methyl or trifluoromethyl; or

[0171] C. Methyl.

[0172] In a preferred embodiment of each aspect of the present invention, R 3 It's methyl.

[0173] In an embodiment of each aspect of the invention, Q is

[0174] AQ a ;or

[0175] BQ b .

[0176] In an embodiment of each aspect of the invention, Q a yes

[0177] A.Selected from Q a -1 to Q a -16; or

[0178] B.Selected from Q a -1, Q a -6, Q a -7, Q a -10, and Q a -15; or

[0179] CQ a -1 or Q a -15;

[0180] DQ a -1.

[0181]

[0182] In an embodiment of each aspect of the invention, Q b yes

[0183] A.Selected from Q b -1 to Q b -13; or

[0184] BQ b -1.

[0185]

[0186] In a preferred embodiment of each aspect of the invention, Q is Q a , and more preferably, Q is Q a -1. In another preferred embodiment of each aspect of the present invention, Q is Q b , and more preferably, Q is Q b -1. In a preferred embodiment of the present invention, Q is Q a -1 or Q b -1. More preferably, Q is Q a -1.

[0187] In an embodiment of each aspect of the invention, R 4 yes:

[0188] A. pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substituted, where R 10is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or

[0189] B. pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 substituted; wherein R 10 is hydrogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, cyanoC3-C4 cycloalkyl, C3-C4 cycloalkylC1-C3 cyanoalkyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl, or 3-methyl-1,1-dioxothietane-3-yl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or R 10 and R 11 together with the nitrogen to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl group; or

[0190] C.Selected from Q c -1 to Q c -6 and Q c -10:

[0191]

[0192] D.Selected from Q c -1 to Q c -6; or

[0193] EQ c -1, Q c -3, Q c -4;Q c -6, or Q c -10; or

[0194] FQ c -1, or Q c -6; or

[0195] GQ c -1; or

[0196] HQ c -6; or

[0197] IQ c-10; or

[0198] JQ c -2; or

[0199] KQ c -3.

[0200] And R 10 and R 11 is as defined herein.

[0201] In an embodiment of each aspect of the invention, R 4a yes:

[0202] A. pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, thiazol-2-yl, N-linked pyrazol-1-yl or triazol-1-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substitution; wherein R 10 is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or

[0203] B. pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substitution; wherein R 10 is hydrogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, cyanoC3-C4 cycloalkyl, C3-C4 cycloalkylC1-C3 cyanoalkyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl, or 3-methyl-1,1-dioxothietane-3-yl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or R 10 and R 11 together with the nitrogen to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl group; or

[0204] C. pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substitution; wherein R 10is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or

[0205] DN-linked pyrazol-1-yl or triazol-1-yl, each of which is independently substituted by a single C(O)NR 10 R 11 Substitution; wherein R 10 is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or

[0206] E. Selected from Q c -1 to Q c -8 and Q c -10:

[0207]

[0208] F.Selected from Q c -1 to Q c -6 and Q c -10; or

[0209] G. Selected from Q c -1 to Q c -6; or

[0210] HQ c -1, Q c -3, Q c -4;Q c -6, Q c -7, Q c -8, or Q c -10; or

[0211] IQ c -1, Q c -3, Q c -4;Q c -6, or Q c -10; or

[0212] JQ c -1, Q c -6, Q c -7, Q c -8 or Q c -10; or

[0213] KQc -1, Q c -6, Q c -7 or Q c -8; or

[0214] LQ c -7, Q c -8 or Q c -10; or

[0215] MQ c -1, or Q c -6; or

[0216] NQ c -7 or Q c -8; or

[0217] OQ c -1; or

[0218] PQ c -6; or

[0219] QQ c -7; or

[0220] RQ c -8; or

[0221] LQ c -10; or

[0222] MQ c -2; or

[0223] SQ c -3.

[0224] And R 10 and R 11 is as defined herein.

[0225] In an embodiment of each aspect of the invention, R 4 and R 4a is 4-cyano-pyrimidin-6-yl, which is described below as Qc-10:

[0226]

[0227] In an embodiment of each aspect of the invention, 4 and R 4a Related, R 10 yes

[0228] A. hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; or

[0229] B. hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, or cyano C3-C4 cycloalkyl; or

[0230] C. hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; or

[0231] D. hydrogen, methyl, ethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; or

[0232] E. hydrogen, methyl, ethyl, cyclopropyl or 1-cyanocyclopropyl; or

[0233] F. hydrogen, methyl, ethyl or cyclopropyl; or

[0234] G. hydrogen, methyl, or ethyl; or

[0235] H. hydrogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, cyanoC3-C4 cycloalkyl, C3-C4 cycloalkylC1-C3 cyanoalkyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl or 3-methyl-1,1-dioxothietane-3-yl; or

[0236] I. hydrogen, hydroxy, methyl, ethyl, trifluoromethyl, cyanoethyl, methoxy, ethoxy, cyclopropyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl or 3-methyl-1,1-dioxothietane-3-yl; or

[0237] J. hydrogen, hydroxy, methyl, ethyl, trifluoromethyl, cyanoethyl, methoxy, cyclopropyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl or 1,1-dioxothietane-3-yl; or

[0238] K. hydrogen, hydroxy, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methyl-ethyl, methoxy, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl or 1,1-dioxothietane-3-yl.

[0239] In an embodiment of each aspect of the invention, 4 and R 4a Related, R11 yes

[0240] A. hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl; or

[0241] B. hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl; or

[0242] C. hydrogen, methyl or trifluoromethyl; or

[0243] D. hydrogen, methyl, or ethyl; or

[0244] E. Hydrogen or methyl.

[0245] In an embodiment of each aspect of the invention, 4 and R 4a Related, R 10 and R 11 Together with the nitrogen to which they are attached they form a pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl, for example a 4-morpholinyl group.

[0246] Preferably, in the embodiments of each aspect of the present invention, R 4 and R 4a Independently Q c -1 or Q c -6; R 10 is hydrogen, methyl, ethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11 More preferably, in embodiments of each aspect of the present invention, R 4 and R 4a Independently Q c -1 or Q c -6; R 10 is hydrogen, methyl, ethyl or cyclopropyl; and R 11 is hydrogen, methyl or ethyl. Most preferably, in embodiments of each aspect of the invention, R 4 and R 4a Independently Q c -1; R 10 is hydrogen, methyl, or ethyl; and R 11 is hydrogen or methyl.

[0247] In an embodiment of each aspect of the invention, Q is Q a -1, R 4 It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, Q c -6 or Q c -10, such as Q c-1 or Q c -6, or as Q c -1, Q c -3, Q c -4, Q c -6 or Q c -10. Preferably, R 4 It's Q c -1, Q c -2 or Q c -3. Most preferably, R 4 It's Q c -1. In a preferred embodiment, R 10 is hydrogen, hydroxy, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methyl-ethyl, methoxy, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl or 1,1-dioxothietane-3-yl, and R 11 is hydrogen, methyl or ethyl, preferably R 11 In other preferred embodiments, R 10 is hydrogen, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methyl-ethyl, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl or 1-cyano-1-cyclopropyl-ethyl, and R 11 is hydrogen, methyl or ethyl; preferably, R 11 In other preferred embodiments, R 10 is hydrogen, methyl, ethyl; and R 11 is hydrogen or methyl.

[0248] In an embodiment of each aspect of the invention, Q is Q b -1, R 4a It's Q c -1, and R 10 and R 11 All are hydrogen.

[0249] In an embodiment of each aspect of the invention, R 5 yes

[0250] A. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, halogen, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)C(O), (C1-C3 alkoxy)C(O), HC(O), C1-C3 haloalkoxy, or a 5-membered heteroaromatic ring which may be optionally substituted with one to three substituents selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, CN, or hydroxy; or

[0251] B. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, halogen, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)C(O), (C1-C3 alkoxy)C(O), HC(O) or C1-C3 haloalkoxy; or

[0252] C. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, halogen, Cl, Br, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)C(O), (C1-C3 alkoxy)C(O), or C1-C2 haloalkoxy; or

[0253] D. hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 haloalkoxy, halogen, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)C(O), HC(O), or (C1-C3 alkoxy)C(O); or

[0254] E. hydrogen, C1-C2 alkyl, C1-C2 alkoxy, C3-C4 cycloalkyl, C1-C2 haloalkoxy, halogen, C1-C2 alkoxy-C1-C2 alkyl, C1-C2 alkoxy-C1-C2 alkoxy-C1-C2 alkyl, (C1-C2 alkyl)C(O), HC(O), or (C1-C2 alkoxy)C(O); or

[0255] F. hydrogen, methyl, trifluoromethoxy, methoxy, cyclopropyl, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2,2,2-trifluoroethyl, chlorine, bromine, methoxyethoxy, methylcarbonyl, or methoxycarbonyl; or

[0256] G. Hydrogen.

[0257] In a preferred embodiment of each aspect of the present invention, R 5 It's hydrogen.

[0258] In an embodiment of each aspect of the invention, R 5a yes

[0259] A. hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; or

[0260] B. hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl or C1-C3 alkoxy; or

[0261] C. hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy; or

[0262] D. hydrogen, halogen, CN, C1-C3 alkyl or C1-C3 alkoxy; or

[0263] E. hydrogen or halogen; or

[0264] F. Hydrogen.

[0265] In an embodiment of each aspect of the invention, R 5b yes

[0266] A. hydrogen, halogen, CN, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy; or

[0267] B. hydrogen, halogen or C1-C3 alkoxy; or

[0268] C. Hydrogen.

[0269] In a preferred embodiment of each aspect of the present invention, R 5a and R 5b It's hydrogen.

[0270] In an embodiment of each aspect of the invention, R 6 yes

[0271] A. phenyl, benzyl, heteroaryl, or C3-C6 cycloalkyl, each of which is independently optionally substituted by a x or

[0272] B. phenyl, benzyl, cyclopropyl or a group selected from R x The substituent is a cyclopropyl group substituted with.

[0273] In an embodiment of each aspect of the invention, R x Independently selected from

[0274] A. halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or CN; or

[0275] BF, Cl, Br, OCF2H, OCH3 or CN.

[0276] In an embodiment of each aspect of the invention, R Z Independently selected from

[0277] A. oxo, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or CN; or

[0278] B. Oxo, F, Cl, Br, OCF2H, OCH3 or CN.

[0279] In an embodiment of each aspect of the invention, R Y Independently selected from

[0280] A. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl; or

[0281] B. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, and cyclopropyl; or

[0282] C. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; or

[0283] D. hydrogen, methyl, trifluoromethyl, and methoxy; or

[0284] E. Hydrogen.

[0285] In an embodiment of each aspect of the invention, R YY Independently selected from

[0286] A. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl; or

[0287] B. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, and cyclopropyl; or

[0288] C. hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; or

[0289] D. hydrogen, methyl, trifluoromethyl, and methoxy; or

[0290] E. Hydrogen.

[0291] The present invention thus makes available compounds having substituents R, R 1 、R 2a 、R 2b 、R 3 , Q, A 1 、A 2 、A 3 、A 4 and A 5 Thus, for example, it is possible to obtain a compound of formula (I) wherein A 1 、A 2 , and A 3 It belongs to the first aspect (ie A 1 、A 2 and A 3 N or CR independently of each other Y ; and where R Y Belong to Example D (ie, R Y are independently selected from hydrogen, methyl, trifluoromethyl, and methoxy); A 4 and A 5 Belong to embodiment B (ie A 4 It's CR YY , and A 5 is CH, where R YY Belong to Example B (ie R Y hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, or cyclopropyl); R 1 is Embodiment B (i.e., hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonyl C1-C6 alkyl, hydroxycarbonyl C1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilane C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkyl C1-C2 alkyl-, benzyloxycarbonyl, or benzyl); R 2a is Example L (i.e., halogen, C1-C2 haloalkyl, C1-C2 haloalkylsulfanyl, C1-C2 haloalkylsulfonyl, or C1-C2 haloalkoxy); R 2b is Embodiment B (i.e., halogen, C1-C3 haloalkyl, or C1-C3 haloalkoxy); R 3is Example B (i.e., hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted with one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy or CN); Q is Example A (i.e., Q is Q a ), where Q a It can be Example B (ie Q a Selected from Q a -1, Q a -6, Q a -7, Q a -10, and Q a -15); and R 4 Example D (ie Q c -1, Q c -2, Q c -3, Q c -4, Q c -5 or Q c -6; where R 10 can be Example F [i.e., hydrogen, methyl, ethyl, or cyclopropyl]; and R 11 It can be Example D [ie, hydrogen, methyl or ethyl]).

[0292] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 、A 2 and A 3 N or CR independently of each other Y (where R Y is hydrogen, methyl, trifluoromethyl, and methoxy); A having 4 is N or CH, and has an A 5 is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2bis hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and Q having is selected from Q a -1 to Q a -16 and Q b -1 to Q b -13; with R 4 (For Q a -1 to Q a -16) is pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substitution; wherein R 10 is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or R 4a (For Q b -1 to Q b -13) is pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substitution; wherein R 10 is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0293] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 =A 2 -A 3 Together they are NR-C(=O)-N, R is hydrogen, methyl or 2,2,2-trifluoroethyl; A having 4 is N or CH, and has an A 5 is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2ais hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and Q having is selected from Q a -1 to Q a -16 and Q b -1 to Q b -13; with R 4 (For Q a -1 to Q a -16):

[0294]

[0295] , or with R 4a (For Q b -1 to Q b -13) Yes

[0296]

[0297]

[0298] where R 10 is hydrogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, or cyano C3-C4 cycloalkyl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0299] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 =A 2 -A 3 Together is NR-C(=O)-N, wherein R is methyl or 2,2,2-trifluoroethyl; having A 4 is N or CH, and has an A 5is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and Q having is selected from Q a -1 to Q a -16 and Q b -1 to Q b -13; with R 4 (For Q a -1 to Q a -16) is pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl or thiazol-2-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 Substituted, where R 10 is hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11 is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl; or having R 4a (For Q b -1 to Q b -13) is pyrimidin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, thiazol-2-yl, N-linked pyrazol-1-yl or triazol-1-yl, each of which is independently substituted by a single -C(O)NR 10 R 11 substituted; wherein R 10 is hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11 is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

[0300] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 、A 2 and A 3 N or CR independently of each other Y (where R Y is hydrogen, methyl, trifluoromethyl, and methoxy); A having 4 is N or CH, and has an A 5 is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and having Q selected from Q a -1 and Q b -1, and has an R 4 It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, or Q c -6, or with R 4a It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, Q c -6, Q c -7 or Q c -8; where R 10 is hydrogen, methyl, ethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl; or has Q as Q-1 to Q-18 as shown in Table Z below.

[0301] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 、A 2 and A 3 are independently N or CH; A having 4 and A 5 Each is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and having Q selected from Q a -1 and Q b -1; and has R 4 It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, or Q c -6; or with R 4a It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, Q c -6, Q c -7, or Q c -8; where R 10 is hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11is hydrogen, methyl or ethyl; or has Q as Q-1 to Q-18 as shown in Table Z below.

[0302] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 、A 2 and A 3 are independently N or CH; A having 4 and A 5 Each is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 haloalkyl, cyclopropyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 haloalkoxy, cyclopropyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to three halogens 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted with one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; having R 3 is methyl; having Q selected from Q a -1 and Q b -1, and has an R 4 It's Q c -1 or Q c -6; or with R 4a It's Q c -1, Q c -6, Q c -7 or Q c -8; where R 10 is hydrogen, methyl, ethyl or cyclopropyl; and R 11 is hydrogen, or methyl; or has Q as Q-1 to Q-18 as shown in Table Z below.

[0303] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 =A 2 -A 3 Together is NR-C(=O)-N, wherein R is methyl or 2,2,2-trifluoroethyl; having A 4 is N or CH, and has an A 5is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, cyclopropyl, cyclopropyl substituted by one to two substituents independently selected from halogen, methyl, and trifluoromethyl, cyclopropylcarbonyl, cyclopropylmethyl substituted by one to two substituents independently selected from oxo, halogen, and trifluoromethyl, or C1-C3 substituted by one to three halogens. 1- C2 alkylsulfanyl or C2 alkylsulfanyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is hydrogen, halogen, C3-C4 cycloalkyl, cyclopropylcarbonyl, C3-C4 cycloalkyl-C1-C2 alkyl optionally substituted by one to two substituents selected from oxo, halogen, C1-C3 alkyl and C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN; R having 3 is methyl; and has Q selected and has Q selected from Q a -1 and Q b -1, and has an R 4 or R 4a It's Q c -1 or Q c -6, where R 10 is hydrogen, methyl or ethyl; and R 11 is hydrogen, or methyl; or has Q as Q-1 to Q-18 as shown in Table Z below.

[0304] In an embodiment of each aspect of the invention, the compound of formula (I) has A 1 、A 2 and A 3 are independently N or CH; A having 4 and A 5 Each is CH; with R 1 is hydrogen, methyl, propargyl or cyclopropyl-methyl; having R 2a is halogen, C1-C3 haloalkyl or C1-C3 haloalkyl substituted by one to three halogens 1- C2 alkylsulfonyl; having R 2b is halogen or C1-C3 haloalkyl; having R 3 is methyl; and having Q selected from Q a -1 and Q b -1, and has an R 4 or R 4a It's Q c -1, where R10 is hydrogen, methyl or ethyl; and R 11 It is hydrogen or methyl.

[0305] In an embodiment of each aspect of the present invention, the compound of formula (I) wherein A 1 and A 3 It is N; A 2 It is CH; with A 4 and A 5 Each is CH; R 1 is hydrogen or methyl; R 2a is chlorine, bromine, iodine, methyl or trifluoromethyl; R 2b is chlorine, bromine, iodine or trifluoromethyl; R 3 is methyl; Q is Q a -1 or Q b -1; R 4 It's Q c -1, Q c -3, Q c -4;Q c -6, or Q c -10; R 4a It's Q c -1, Q c -3, Q c -4;Q c -6, Q c -7, Q c -8, or Q c -10; R 10 is hydrogen, hydroxy, methyl, ethyl, trifluoromethyl, cyanoethyl, methoxy, cyclopropyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 1,1-dioxothietane-3-yl; and R 11 is hydrogen, or methyl; or R 10 and R 11 Together with the nitrogen to which they are attached are pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl.

[0306] In a preferred embodiment of the present invention, A 1 and A 3 It is nitrogen, A 2 、A 4 and A 5 It is CH; R 1 is hydrogen, methyl or cyclopropyl-methyl; R 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; R 3 is methyl; Q is Q a -1 or Qb -1, preferably, Q is Q a -1.

[0307] In a preferred embodiment of the present invention, A 1 and A 3 It is nitrogen, A 2 、A 4 and A 5 It is CH; R 1 is hydrogen, methyl or cyclopropyl-methyl; R 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; R 3 is methyl; Q is Q a -1; R 4 It's Q c -1, Q c -2, Q c -3, Q c -4, Q c -5, Q c -6 or Q c -10, such as Q c -1 or Q c -6, or for example Q c -1, Q c -3, Q c -4, Q c -6, or Q c -10; R 10 is hydrogen, hydroxy, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methyl-ethyl, methoxy, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, or 1,1-dioxothietane-3-yl, and R 11 is hydrogen, methyl or ethyl, preferably R 11 is hydrogen or methyl. Preferably, R 4 It's Q c -1, Q c -2 or Q c -3; most preferably, R 4 It's Q c -1.

[0308] In other preferred embodiments of the present invention, A 1 and A 3 It is nitrogen, A 2 、A 4 and A 5 It is CH; R 1 is hydrogen, methyl or cyclopropyl-methyl; R2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chloro, bromo, iodo, trifluoromethyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; R 3 is methyl; Q is Q b -1, R 4a It's Q c -1, and R 10 and R 11 Preferably, R 1 is hydrogen or methyl; more preferably, R 1 is hydrogen. Preferably, R 2a is chlorine, bromine, iodine or trifluoromethyl, and R 2b is chlorine, bromine, iodine or trifluoromethyl, or R 2a is chloro or trifluoromethyl, and R 2b More preferably, R 2a is chloro or trifluoromethyl, and R 2b is chloro, bromo, iodo or trifluoromethyl. Preferably, Q is Q a -1, R 10 is hydrogen, methyl, ethyl, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methyl-ethyl, cyclopropyl, cyclopropylmethyl, 1-cyanocyclopropyl or 1-cyano-1-cyclopropyl-ethyl, and R 11 is hydrogen, methyl or ethyl; preferably, R 11 In other preferred embodiments, R 10 is hydrogen, methyl, ethyl; and R 11 is hydrogen or methyl.

[0309] In embodiments, the compound of formula (I) is Formula Iaa, Iab, Iac, Iad, or Iae (asterisk indicates stereocenter), wherein R 1 、R 2a 、R 2b and R 3 is as defined in the first aspect, and Q1 corresponds to Q as defined in the first aspect, each having corresponding embodiments as described above.

[0310]

[0311] In embodiments, compounds of Formula Iaa, Iab, and Iac will also be preferred as having the preferred stereochemistry shown in Formula (I'a). In preferred embodiments, compounds of Formula I'ab and I'ae having the following stereochemistry are preferred:

[0312]

[0313] where R1 、R 2a 、R 2b 、R 3 , Q1 (corresponding to Q in formula I) is as defined in the first aspect and R is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy, as well as stereoisomers, enantiomers, tautomers and N-oxides of compounds of formula (I'ab) and agrochemically acceptable salts thereof.

[0314] In a second aspect, the present invention makes available a composition comprising a compound of formula (I) as defined in the first aspect, one or more adjuvants and diluents, and optionally one or more other active ingredients.

[0315] In a third aspect, the present invention makes available a method for combating and controlling insects, acarids, nematodes or molluscs, which method comprises applying to the pest, the locus of the pest, or a plant susceptible to attack by the pest an insecticidally, acaridically, nematicidally or molluscicidally effective amount of a compound as defined in the first aspect or a composition as defined in the second aspect.

[0316] In a fourth aspect, the present invention makes available a method for protecting plant propagation material from attack by insects, mites, nematodes or molluscs, which method comprises treating the propagation material or the site in which 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.

[0317] In a fifth aspect, the present invention makes it possible to obtain a plant propagation material, such as a seed, which comprises a compound of formula (I) as defined in the first aspect or a composition as defined in the second aspect, or is treated with said compound or said composition, or has said compound or said composition attached thereto.

[0318] In a further aspect, the present invention provides a method for controlling parasites in or on an animal in need thereof, the method comprising administering an effective amount of a compound of the first aspect. The present invention further provides a method for controlling parasites on the body of an animal in need thereof, the method 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 a disease transmitted by parasites on the body, the method comprising administering an effective amount of a compound of formula (I) as defined in the first aspect to an animal in need thereof.

[0319] Compounds of formula (I) can be prepared by those skilled in the art according to known methods. More specifically, compounds of formula I and I'a and intermediates thereof can be prepared as described below in the schemes and examples. For the sake of clarity, certain stereocenters are not specified and are not intended to limit the teachings of these schemes in any way.

[0320] The process according to the invention for preparing the compounds of formula (I) is carried out by methods known to those skilled in the art.

[0321] Compounds of formula (I) can be prepared, for example, as shown in Scheme 1.

[0322] Option 1:

[0323]

[0324] A compound of formula II (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b Yes

[0325] As defined above for compounds of formula (I), and wherein X 1 is a leaving group, such as a halogen or sulfonate, such as chloride) and a compound of formula III or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or hydrobromide salt, or a trifluoroacetate salt, or any other equivalent salt) (wherein Q, R 1 and R 3 have the same meanings as given above for compounds of formula (I)) are reacted to give compounds of formula (I) (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a 、R 2b 、R 3and Q have the same meanings as given above for the compound of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N-dimethylformamide, in the presence or absence of a catalyst, for example a metal catalyst such as a palladium complex, and with or without addition of a base, such as an inorganic base, for example sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine.

[0326] A compound of formula II (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b are as defined above for compounds of formula (I)) are known or can be prepared in analogy to the 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.

[0327] Option 2:

[0328]

[0329] A compound of formula III or a salt thereof (Q, R 1 and R 3 has the same meanings as given above for compounds of formula (I)) can be prepared, for example, as shown in Scheme 2. A compound of formula V (wherein R 3 and Q have the same meanings as given above for the compound of formula (I) and wherein X 2 is a leaving group such as a halogen or sulfonate, for example bromide) with an amine of formula XIX or a salt thereof (wherein R 1 have the same meanings as given above for compounds of formula (I)) to give compounds of formula III or salts thereof (wherein Q, R 1 and R 3 has the same meanings as given above for the compound of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, at a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C, with or without addition of a base, such as an inorganic base (for example sodium carbonate, potassium carbonate or cesium carbonate) or an organic base (such as, for example, triethylamine, diisopropylethylamine or pyridine).

[0330] Alternatively, a compound of formula VII (wherein R 3 and Q have the same meanings as given above for the compound of formula (I)) with an amine of formula XIX or a salt thereof (wherein R 1 have the same meanings as given above for compounds of formula (I)) to give compounds of formula III or salts thereof (wherein Q, R 1 and R 3 has the same meaning as given above for the compound of formula (I). This reaction is carried out 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, in the presence or absence of an acid such as acetic acid or a Lewis acid such as zinc bromide or titanium(IV) isopropoxide, in a solvent such as, for example, methanol or in the absence of a solvent. The reaction can be carried out at a temperature ranging from -100°C to +300°C, preferably between ambient temperature and 200°C. Such methods for the alkylation and reductive alkylation of amines and the range of conditions under which these methods are carried out (for example in the presence of NaBH(OAc)3 or NaBH3CN, in a suitable solvent, preferably in acetic acid, at room temperature, analogously to WO 2002 / 088073; or alternatively, by using a combination of Ti(i-OiPr)4 and NaBH4, as described in Synthesis 2003(14), 2206) are well known to those skilled in the art. An amine having formula XIX or a salt thereof (wherein R 1 have the same meanings as given above for the compounds of formula (I)) are known or they can be prepared by methods known to a person skilled in the art.

[0331] Option 3:

[0332]

[0333] Alternatively, compounds of formula (I) can be prepared, for example, as shown in Scheme 3. An amine of formula IV is reacted with a compound of formula V (wherein X 2 is a leaving group such as a halogen or sulfonate, for example bromide) to give a compound of formula (I) (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a 、R 2b 、R 3and Q have the same meanings as given above for the compound of formula (I). The reaction can be carried out neat or in a solvent, preferably an organic solvent such as acetonitrile, at a temperature ranging from -100° C. to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base (e.g. potassium carbonate) or an organic base (e.g. triethylamine). Such methods for the alkylation of amines and the range of conditions under which they are carried out are well known to those skilled in the art.

[0334] Alternatively, an amine of formula IVa is reacted with a compound of formula VII to give a compound of formula (I) wherein R 1 is H and where A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b 、R 3 and Q have the same meanings as given above for compounds of formula (I). The reaction is carried out 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 an acid such as acetic acid or a Lewis acid such as zinc bromide, in a solvent such as, for example, methanol or without a solvent. The reaction can be carried out at a temperature ranging from -100°C to +300°C, preferably between ambient temperature and 200°C.

[0335] Such methods for the reductive alkylation of amines and the range of conditions under which they are carried out are well known to those skilled in the art.

[0336] Option 4:

[0337]

[0338] Compounds of formula V can be prepared, for example, as shown in Scheme 4. Compounds of formula VIII are treated with a halogenating agent, such as chlorine or bromine or N-bromosuccinimide, to give compounds of formula V, wherein the leaving group Q is a halogen, such as chloride or bromide. The reaction is carried out with or without a solvent, preferably in a solvent, with or without additives, such as free radical initiators, such as benzoyl peroxide or azoisobutyronitrile. The reaction can be carried out with or without exposure to visible light or UV light, and can be carried out at a temperature ranging from -100°C to +300°C, preferably between ambient temperature and 200°C.

[0339] Alternatively, a compound of formula VII can be treated with a reducing agent and then reacted with sulfonyl chloride, for example, methanesulfonyl chloride, to give a compound of formula V, wherein the leaving group Q is a sulfonate radical, for example, methanesulfonate radical. The reaction can be carried out in a solvent or in the absence of a solvent, in the presence of a base (such as an inorganic base such as potassium carbonate, or an organic base such as an amine base such as trimethylamine) or in the absence of a base, and it can be carried out in a temperature range of -100 ° C to +300 ° C, preferably between ambient temperature and 200 ° C. Suitable reducing agents can be, for example, hydrogen or a hydride (such as sodium borohydride), with or without a catalyst (such as a hydrogenation catalyst such as palladium carbon), with or without an acid (such as acetic acid or Lewis acid such as zinc bromide) in the presence of a solvent (such as methanol) or in the absence of a solvent. The reaction can be carried out in a temperature range of -100 ° C to +300 ° C, preferably between ambient temperature and 200 ° C.

[0340] Methods for such halogenations, reductions of carbonyl compounds and sulfonylations of alcohols and the range of conditions under which they are carried out are well known to those skilled in the art. Amines of formula VII and compounds of formula VIII are known or can be prepared by methods known to those skilled in the art.

[0341] Option 5:

[0342]

[0343] Alternatively, a compound of formula (I) wherein R 1 Other than hydrogen) can be prepared, for example, as shown in Scheme 5. Compounds of formula Ia (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b 、R 3 and Q have the same meanings as given above for compounds of formula (I)) can be combined with compounds of formula VI (wherein R 1 have the same meanings as given above for the compounds of formula (I), except that R 1 Different from hydrogen, and where X 3 is a leaving group, such as a halogen or sulfonate, such as chloride, bromide, iodide or mesylate) to give a compound of formula (I) wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a 、R2b 、R 3 and Q have the same meanings as given above for compounds of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent such as acetonitrile, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) or a mixture thereof, at a temperature range of -100 ° C to +300 ° C, preferably between ambient temperature and 200 ° C, with or without the addition of a base such as an inorganic base (e.g. sodium carbonate, potassium carbonate or cesium carbonate) or an organic base (e.g. triethylamine, diisopropylethylamine or pyridine). Such methods for the alkylation of amines and the range of conditions under which they are carried out are well known to those skilled in the art and are described, for example, in WO 2021 / 083936.

[0344] The compound of formula (VI) (wherein R 1 has the same meanings as given above for the compounds of formula (I), except that R 1 is not hydrogen, and where X 3 The leaving groups, such as halogen or sulfonate, for example chloride, bromide, iodide or mesylate, are known or they can be prepared by methods known to those skilled in the art.

[0345] Option 6:

[0346]

[0347] Compounds of formula Ib can be prepared, for example, as shown in Scheme 6. Compounds of formula II (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b has the same meaning as given above for the compound of formula (I), and wherein X 1 is a leaving group, such as a halogen or sulfonate, such as chloride) and a compound having IX or a salt thereof (wherein R 3 has the same meanings as given above for compounds of formula (I)) are reacted to give compounds of formula X (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b and R 3has the same meanings as given above for the compound of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N-dimethylformamide, at a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C, in the presence or absence of a catalyst, for example a metal catalyst such as a palladium complex, and with or without addition of a base, such as an inorganic base, for example sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine.

[0348] Compound X (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b and R 3 has the same meaning as given above for the compound of formula (I)) is treated with the known compound XIII (N,N-dimethylformamide dimethyl acetal, DMF-DMA) to give a compound of formula XI (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b and R 3 has the same meanings as given above for the compound of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent, such as an organic solvent, for example dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, in the absence of a base or in the presence of a base, such as an inorganic base, for example sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine, in a temperature range of -100°C to +300°C, preferably between ambient temperature and 100°C, or between ambient temperature and 50°C.

[0349] Compound XI (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b and R 3 has the same meaning as given above for the compound of formula (I)) and a hydrazine compound of formula XII or a tautomer thereof or a salt thereof (wherein R 4has the same meanings as given above for compounds of formula (I)) are further reacted to give compounds of formula Ib (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b 、R 3 and R 4 (Has the same meaning as given above for the compound of formula (I)). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example 1,4-dioxane or acetic acid or a mixture of 1,4-dioxane and acetic acid, in a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C or between ambient temperature and 80°C. Within this transformation sequence, the intermediate compounds of formula X and formula XI can be used as crude products in the subsequent steps, or they can be purified, for example by chromatography, and used in purified form in the next transformation.

[0350] A compound of formula IX or a salt thereof (wherein R 3 have the same meanings as given above for the compounds of formula (I)) are known or they can be prepared by methods known to those skilled in the art. Hydrazine compounds of formula XII or tautomers thereof or salts thereof (wherein R 4 have the same meanings as given above for the compounds of formula (I)) are known or they can be prepared by methods known to a person skilled in the art.

[0351] Compounds of Formula Ik

[0352]

[0353] It can be prepared by the following reaction: Amine or its salt having formula IIIf

[0354]

[0355] (where R 1 、R 3 、R 4 and R 5 is as described in formula (I)) and a compound having formula (II)

[0356]

[0357] (where A 1 、A 2 、A 3 、A 4 、A 5 、R 2aand R 2b is as described in formula (I) and X 1 is a leaving group such as a halogen or sulfonate, for example chloride) under the conditions already described in Scheme 1.

[0358] Option 7:

[0359]

[0360] Compounds of formula Ic can be prepared, for example, as shown in Scheme 7. Compounds of formula XVII (wherein X 05 A leaving group such as chloro, bromo, iodo, arylsulfonate, alkylsulfonate or trifluoromethanesulfonate) is reacted with an amine of formula XIX to yield a compound of formula XVI. The reaction is carried out 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 such as palladium on carbon, with or without an acid such as acetic acid or a Lewis acid such as zinc bromide, in a solvent such as, for example, methanol, or in the absence of a solvent. The reaction can be carried out at a temperature ranging from -100°C to +300°C, preferably between ambient temperature and 200°C. Such methods for the reductive alkylation of amines and the range of conditions under which they may be carried out are well known to those skilled in the art.

[0361] The subsequent reaction of the intermediate of formula XVI with a compound of formula II gives a compound of formula XIV. The reaction can be carried out neat or in a solvent, preferably an organic solvent such as acetonitrile, at a temperature ranging from -100°C to +300°C, preferably between ambient temperature and 200°C, in the presence or absence of a catalyst, for example a metal catalyst such as a palladium complex, and with or without the addition of a base, for example an inorganic base such as potassium carbonate or an organic base such as triethylamine.

[0362] Subsequently, the intermediate of formula XIV is reacted with a compound of formula XV to give a compound of formula Ic, wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b 、R 1 、R 3 and R 4a has the same meaning as given above for the compound of formula (I), and R 4a -M1 in which M1 is a metal, such as lithium, or -MgCl, or -ZnBr, or -B(OH)2; or R 4a-M1 represents a boric acid ester, such as the pinacol ester of boric acid, or a stannane such as R 4a -Sn(n-Bu) 3. Such conversions are known to those skilled in the art and are respectively Suzuki-, Kumada-, Negishi- or Stille-coupling reactions. Such reactions are carried out at temperatures between -100°C and +300°C, preferably in the temperature range between ambient temperature and 200°C, in the presence of a catalyst (such as a metal catalyst, such as a palladium catalyst) and a ligand (such as a phosphine ligand or an N-heterocyclic carbene (NHC) ligand or a phosphite ligand). The reaction can be carried out in the presence or absence of another metal catalyst, such as a copper salt (such as CuI). The reaction is carried out 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, such as triethylamine. The reaction is carried out with or without a solvent, preferably in a solvent. In the case of heating the reaction mixture, the reaction can be carried out under microwave irradiation or with conventional heating, such as heating the reaction vessel in an oil bath.

[0363] By an alternative route, compound XVII can be reacted with a compound of formula XV to give intermediate XVIII. This reaction is carried out under essentially the same range of conditions as described for the conversion of intermediate XIV to a compound of formula Ic.

[0364] Intermediate XVIII is then reacted with an amine IVa to give a compound of formula Ic, wherein R 1 is hydrogen and A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b 、R 3 and R 4a has the same meanings as given above for the compound of formula (I).The reaction is carried out in the presence of a reducing agent under essentially the same conditions as described above for the conversion of compound XVII to intermediate XVI.

[0365] By yet another alternative approach, an intermediate compound of formula XVIII can be reacted with an amine of formula XIX to give an intermediate of formula IIIa. This reaction is carried out in the presence of a reducing agent under essentially the same conditions as described above for converting compound XVII to intermediate XVI.

[0366] Subsequently, the intermediate of formula IIIa is reacted with a compound of formula II to give a compound of formula Ic, wherein A 1 、A 2 、A3 、A 4 、A 5 、R 2a 、R 2b 、R 1 、R 3 and R 4a has the same meanings as given above for the compound of formula (I).The reaction is carried out essentially under the same conditions as described above for the conversion of intermediate XVI to intermediate XIV.

[0367] In these various multi-step sequences, the intermediate compounds of formula XIV, XVI, XVIII and IIIa can be used as the crude products of the corresponding subsequent steps, or they can be purified, for example by chromatography, and used in the next transformation in purified form. Compounds of formula XVII are known or can be prepared by methods known to those of ordinary skill in the art.

[0368] Compounds of formula Id

[0369]

[0370] It can be prepared by reacting an amine of formula IIIb or a salt thereof

[0371]

[0372] (where R 1 、R 3 、R 4a 、R 5a and R 5b is as described in formula (I)) and a compound having formula II

[0373]

[0374] (where A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as described in formula (I) and X 1 is a leaving group such as a halogen or sulfonate, for example chloride).

[0375] This chemistry is described in more detail in Scheme 8.

[0376] Option 8:

[0377]

[0378] Compounds of Formula II (wherein X1 is a leaving group such as a halogen or sulfonate, for example chloride) with a compound of formula IIIb to give a compound of formula Id, wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a 、R 2b 、R 3 、R 4a 、R 5a and R 5b has the same meanings as given above for compounds of formula (I). The reaction can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, at a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C, in the presence or absence of a catalyst, for example a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for example potassium carbonate, or an organic base, such as, for example, triethylamine.

[0379] The formation of compounds having Formula IIIb is outlined in Scheme 9.

[0380] Option 9:

[0381]

[0382] Compounds of formula IIIb can be prepared, for example, by reacting a compound of formula XX (wherein R 1 is as defined in formula (I)) treating a compound of formula IIIc (wherein R 3 、R 4a 、R 5a and R 5b is as described in formula (I). Alternatively, another reagent system for reductive amination uses a combination of Ti(i-OiPr)4 and NaBH4 (see Synthesis 2003(14), 2206).

[0383] Amines of formula IIIc can be obtained by biocatalytic deracemization of amines of formula IIId. This can be done, for example, using a final immobilized form (e.g. 435), such as Candida antarctica lipase B or Pseudomonas fluorescens lipase, in the presence of an acyl donor (e.g. ethyl methoxyacetate or vinyl acetate), in a suitable solvent (e.g. acetonitrile or methyl tert-butyl ether) at a temperature between 20° C. and 100° C. Such methods are described, for example, in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical consequences of such enzymatic deracemization are known to those skilled in the art and are documented in the literature, for example, in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

[0384] In an alternative approach, a compound of formula IIIc or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or hydrobromide salt, or a trifluoroacetate salt, or any other equivalent salt) can be prepared from a compound of formula XXII (wherein R 3 、R 4a 、R 5a , and R 5b is as described in formula (I)) following the synthesis described in Scheme 10.

[0385] Option 10:

[0386]

[0387] Amines of formula IIIc or their salts can be prepared from intermediates of formula XXII (wherein R 3 、R 4a 、R 5a and R 5bis as described in formula (I) and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butoxycarbonyl) group)) are typically obtained by treatment with hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcoholic solvent such as ethanol or isopropanol (Z3 is -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 (Z3 is -NBoc2) under deprotection conditions known to those skilled in the art and described in the literature, such as, for example, those described 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.

[0388] Such intermediates have the formula XXII (wherein R 3 、R 4a 、R 5a and R 5b is as described in formula (I) and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis (tert-butyloxycarbonyl) group)) can be formed by an alcohol having formula XXI (wherein R 3 、R 4a 、R 5a and R 5b As described in formula (I)) is obtained by the Mitsunobu reaction (which involves treating an alcohol of formula XXI with an azodicarboxylate (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate) in the presence of a phosphine (e.g., triphenylphosphine or tributylphosphine) and an amine (e.g., phthalimide (HNPhth) or bis(tert-butoxycarbonyl)amine (HNBoc2)). The Mitsunobu reaction is known to those skilled in the art for inversion of stereocenters, as described, for example, in Chem. Rev. 2009, 109, 2551-2651.

[0389] Alternatively, the amine of formula IIIc can be reduced to the azide of formula XXIII (wherein R 3 、R 4a 、R5a and R 5b The azide of formula XXIII can be obtained by treating an alcohol of formula XXI (wherein R 3 、R 4a 、R 5a and R 5b is as described in formula (I)). Such methods are known to those skilled in the art for inversion of stereocenters and are described in the literature, for example in Adv. Synth. Catal. [Advanced Synthesis and Catalysis] 2018, 360, 2157-2165.

[0390] The alcohol of formula XXI can be converted to a ketone of formula XXIV (wherein R 3 、R 4a 、R 5a and R 5b (as described in formula (I)) by enantioselective reduction. Such reduction can be carried out in the presence of a hydrogen donor system (such as, for example, HCOOH / Et3N or HCO2NH4) using a catalyst (e.g., a ruthenium or rhodium catalyst with a chiral ligand, such as RuCl[(R,R)-TsDPEN] (mesitylene) or RuBF4[(R,R)-TsDPEN] (p-cymene)). Such methods are described in the literature, for example, in J. Org. Chem. 2017, 82, 5607.

[0391] Alternatively, compounds of formula IIIc can also be prepared as outlined in Scheme 11.

[0392] Option 11:

[0393]

[0394] An amine of formula IIIc or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or hydrobromide salt, or a trifluoroacetate salt, or any other equivalent salt) can be prepared by reacting an amine of formula XXV (wherein R 3 、R 4a 、R 5a and R 5b is as described in formula (I)), for example, by deprotection using an acid such as trifluoroacetic acid or hydrochloric acid, optionally in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane.

[0395] The amine of formula XXV can be prepared by reacting a diketone of formula XXVI (wherein R 3 and R 4ais as described in formula (I)) condensed with a diamine of formula XXVII (wherein R 5a and R 5b This condensation can be carried out in the presence of an oxidizing agent (such as air or DDQ) in the presence of a suitable solvent (such as ethanol or isopropanol).

[0396] The diketone of formula XXVI can be prepared by oxidizing the hydroxyketone of formula XXVII (wherein R 3 and R 4a is as described in formula (I)). The oxidation may involve, for example, SO 3 -pyridine in the presence of a solvent (such as dichloromethane or dimethyl sulfoxide DMSO, or a mixture thereof) and a base (such as triethylamine), or alternatively sodium hypochlorite in the presence of a catalyst (such as TEMPO / Bu 4 NHSO 4). Examples of such oxidations can be found in the literature, for example, in Synlett [Synthesis Express], 2014, 25, 596 or J. Am. Chem. Soc. [Journal of the American Chemical Society] 1990, 112, 5290-5313.

[0397] The hydroxyketone of formula XXVII can be prepared by reacting the aldehyde of formula XXIX (wherein R 4a is as described in formula (I)) with an aldehyde of formula XXVIII (wherein R 3 It is synthesized by cross-benzoin condensation between the two compounds as described in formula (I).

[0398] Aldehydes of formula XXVIII are commercially available in chiral form, such as, for example, Boc-L-alaninaldehyde (CAS 79069-50-4) or tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (CAS 881902-36-9). The cross-benzoin condensation is carried out in the usual manner by using an organic catalyst (such as a triazolium salt or a thiazolium salt) in the presence of a base (such as potassium tert-butoxide or N,N-isopropylethylamine) 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 example in J. Am. Chem. Soc. 2014, 136, 7539-7542 or Org. Lett. 2016, 18, 4518-4521.

[0399] Option 12:

[0400]

[0401] As shown in Scheme 12, compounds of formula Id can alternatively be prepared by reacting a compound of formula XXX (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a 、R 2b 、R 3 、R 5a , and R 5b is as defined in formula (I), and X 07 is a leaving group, such as, for example, chlorine, bromine, iodine) with a compound of formula XXXI (Stieler reaction; R in XXXI 4a is as defined in formula I) or a compound of formula XXXII (Suzuki-Miyaura reaction; R in XXXII 4a is as defined in formula (I) and W is a boronic acid B(OH)2 group, or a corresponding boronic acid ester, such as the pinacol ester of said boronic acid) in the presence of a palladium catalyst as detailed in Scheme 7.

[0402] The compound of formula XXX can be prepared by reacting an amine of formula XXXIII with a compound of formula II (wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 2a 、R 2b and X 1 is as described in Scheme 1) under the conditions described in detail in Scheme 1. Under the same conditions, if R 1 =H, then the compound of formula XXX can be directly obtained from the compound of formula XXXIV.

[0403] Compounds of formula XXXIII can be prepared by treating a compound of formula XXXIV with a compound of formula XXXV (wherein R is as defined in formula I), for example in the presence of NaBH(OAc) or NaBHCN in a suitable solvent, preferably acetic acid, at room temperature, analogously to WO 2002 / 088073, page 35. Alternatively, another reagent system for reductive amination uses a combination of Ti(i-OiPr) and NaBH (see Synthesis 2003 (14), 2206).

[0404] Amines of formula XXXIV can be prepared by deracemization procedures involving, for example, the selective acylation of one enantiomer. Such an example is described in more detail in Scheme 13.

[0405] Option 13:

[0406]

[0407] Amines of formula XXXIV can be biocatalytically deracemized to amines of formula XXXIVa (wherein R 3 、R 5a , and R 5b is as described in formula (I) and X 07 is a leaving group such as bromine, chloride or iodine). This can be achieved, for example, using a final immobilized form (e.g. 435), such as Candida antarctica lipase B or Pseudomonas fluorescens lipase, in the presence of an acyl donor (e.g. ethyl methoxyacetate or vinyl acetate), in a suitable solvent (e.g. acetonitrile or methyl tert-butyl ether) at a temperature between 20° C. and 100° C. Such methods are described, for example, in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical consequences of such enzymatic deracemization are known to those skilled in the art and are documented in the literature, for example, in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.

[0408] Alternatively, resolution of amines of formula XXXIVa to give amines of formula XXXIV can be achieved using a chiral auxiliary as described in Scheme 14.

[0409] Option 14:

[0410]

[0411] Amines of formula XXXIV can be prepared from intermediates of formula XXXVII (wherein R 3 、R 5a , and R 5b is such that in the compound of formula (I), X 07 is a leaving group such as bromine, chloride or iodine, and X 12* is a chiral auxiliary). The chiral auxiliary of Formula XXXVI is, for example, mandelic acid or (1R)-methylchloroformate. Intermediates of Formula XXXVII can be formed by coupling a chiral auxiliary of Formula XXXVI (wherein X is a leaving group, such as chlorine) with an amine of Formula XXXIVa according to the conditions detailed in Scheme 1. Examples of such deracemization methods are reported in the literature, for example, in J. Org. Chem. 2007, 72, 485-493.

[0412] Alternatively, an amine of formula XXXIV or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or hydrobromide salt, or a trifluoroacetate salt, or any other equivalent salt) can be formed as described in Scheme 15.

[0413] Option 15:

[0414]

[0415] Amines of formula XXXIV or salts thereof can be prepared from intermediates of formula XXIIa (wherein R 3 、R 5a and R 5b As described in formula (I), X 07 is a leaving group, such as a halogen or a sulfonate, such as bromide, and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butyloxycarbonyl) group)) is typically obtained by treatment with hydrazine, preferably hydrazine hydrate or hydrazine monohydrate, in an alcoholic solvent such as ethanol or isopropanol (Z3 is -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 (Z3 is -NBoc2) under deprotection conditions known to the person skilled in the art and described in the literature, such as, for example, those described 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.

[0416] Such intermediates have the formula XXIIa (wherein R 3 、R 5a and R 5bAs described in formula (I), X 07 is a leaving group such as a halogen or sulfonate, for example bromide, and Z3 is -NPhth (N-phthalimide group) or -NBoc2 (N-bis(tert-butyloxycarbonyl) group)) can be obtained from an alcohol having formula XXIa (wherein R 3 、R 5a , and R 5b is as described in formula (I) and X 07 is a leaving group) is obtained by the Mitsunobu reaction (which involves treating an alcohol of formula XXIa with an azodicarboxylate (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate) in the presence of a phosphine (e.g., triphenylphosphine or tributylphosphine) and an amine (e.g., phthalimide (HNPhth) or bis(tert-butoxycarbonyl)amine (HNBoc2)). The Mitsunobu reaction is known to those skilled in the art for inversion of stereocenters, as described, for example, in Chem. Rev. 2009, 109, 2551-2651.

[0417] Alternatively, the amine of formula XXXIV can be reduced to the azide of formula XXIIIa (where R 3 、R 5a , and R 5b is as described in formula (I) and X 07 is a leaving group, such as a halogen or sulfonate, such as bromide). Azides of formula XXIIIa can be obtained by treating an alcohol of formula XXIa with an azidating agent (such as diphenylphosphoryl azide) in a solvent (such as toluene or THF) in the presence of a base (such as DBU). Such methods are known to those skilled in the art for inversion of stereocenters and are described in the literature, for example, in Adv. Synth. Catal. [Advanced Synthesis and Catalysis] 2018, 360, 2157-2165.

[0418] The alcohol of formula XXIa can be prepared by reacting a ketone of formula XXIVa (wherein R 3 、R 5a , and R 5b is as described in formula (I) and X 07This can be obtained by enantioselective reduction of a hydroxyl group (e.g., a leaving group such as a halogen or sulfonate) in the presence of a hydrogen donor system (e.g., HCOOH / Et3N or HCO2NH4) using a catalyst (e.g., a ruthenium or rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN] (mesitylene) or RuBF4[(R,R)-TsDPEN] (p-cymene)). Such methods are described in the literature, for example, in J. Org. Chem. 2017, 82, 5607.

[0419] Compounds of formula II

[0420]

[0421] where X 1 is a leaving group, such as a halide or sulfonate, such as chloride, and can be prepared, for example, as shown in Schemes 16-18.

[0422] Option 16:

[0423]

[0424] Compounds of Formula IIa can be prepared according to Scheme 16, wherein R 2a 、R 2b 、A 4 and A 5 Is as described in formula (I). Compounds of formula XLII are known or can be prepared by methods known to those of ordinary skill in the art. For example, as described in J.Org.Chem. [Journal of Organic Chemistry] 2018, 83, 930, compounds of formula XL are reacted with an electrophilic iodination reagent (e.g., N-iodosuccinimide) in a solvent (e.g., hexafluoroisopropanol) to obtain compounds of formula XLI. The compound of formula XLI is cyanided with copper (I) cyanide in a solvent such as DMF at a temperature such as 100°C to provide a compound of formula XLII (a process similar to WO2005 / 100298, page 44). The compound of formula XLII is treated with formic acid and sulfuric acid at a temperature between 80°C and 100°C to provide a compound of formula XLIII (a method similar to WO2018 / 206539, page 80). Subsequent conversion of the compound of formula XLIII to the compound of formula IIa is accomplished by methods known to those skilled in the art, for example using thionyl chloride in the presence of catalytic N,N-dimethylformamide at reflux, analogously to WO 2015 / 54572, page 263.

[0425] The compound of formula XLIII (wherein R 2a 、A 4 and A5 is as described above in formula (I), and wherein R 2b is one to three independently selected from R x (where R x C1-C4 alkylsulfonyl (more particularly methylsulfonyl) substituted with a substituent (more particularly two to three substituents) which is halogen (more particularly fluorine) can be obtained by a compound of formula XLIIIa (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl).

[0426] Option 16a:

[0427]

[0428] Such sulfone compounds of formula XLIIIa can be obtained by the following manner (Scheme 16a): oxidation reaction of the corresponding sulfide compounds of formula XLIIIb or sulfoxide compounds of formula XLIIIb-1, involving reagents such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, potassium peroxymonosulfate Sodium periodate, sodium hypochlorite or tert-butyl hypochlorite and other oxidants, and optionally in the presence of a catalyst (such as ruthenium chloride, sodium tungstate or iron-based catalysts, manganese-based catalysts, cobalt-based catalysts and vanadium-based catalysts). The oxidation reaction is generally carried out in the presence of a solvent (such as, for example, an aliphatic halogenated hydrocarbon (such as dichloromethane, chloroform or carbon tetrachloride), an ester (such as ethyl acetate), an alcohol (such as methanol or ethanol), acetonitrile, acetic acid or water; or a mixture thereof). Similarly, the sulfoxide compound of formula XLIIIb-1 can be obtained by oxidation of the sulfur compound of formula XLIIIb. The amount of the oxidant to be used in the reaction is generally 1 to 3 moles, preferably 1 to 1.2 moles (relative to 1 mole of sulfur compound XLIIIb for producing sulfoxide compound XLIIIb-1), and preferably 2 to 2.2 moles of oxidant (relative to 1 mole of sulfur compound XLIIIb for producing sulfone compound XLIIIa).

[0429] The compound of formula XLIIIb (wherein R 2a 、A 4 and A 5 is as described above in formula (I), and wherein Gr is trifluoromethyl) can be prepared by: reacting a compound of formula XLIIIc (wherein R 2a 、A 4 and A 5 is as described above for formula (I), and wherein R 2bis iodine or bromine) with a trifluoromethylthiolating agent "CuS-Gr" (e.g. copper(I)trifluoromethylthiol) (CAS 3872-23-9) or copper(2,2-bipyridyl)trifluoromethylthiol (also known as (bpy)Cu(SCF3), CAS 1413732-47-4)) in a solvent (e.g. acetonitrile, dioxane, N,N-dimethylformamide or N,N-dimethylacetamide) at a temperature between 0°C and 180°C (preferably between room temperature and 150°C). Such conditions are described in the literature, for example in J. Org. Chem. 1976, 41, 1644 or Synthesis 1975, 721 (CAS 3872-23-9) and in Angew. Chem. Int. Ed. 2013, 52, 1548 or Tetrahedron, 2013, 69, 6046 (CAS 1413732-47-4).

[0430] The compound of formula XLIIIb (wherein R 2a 、A 4 and A 5 is as described above in formula (I), and wherein Gr is difluoromethyl) can be obtained by: reacting a compound of formula XLIIId (wherein R 2a 、A 4 and A 5 is as described above in formula (I)) with a CF2 carbene (e.g. formed from a difluoroacetate XcCF2COONa or a difluoromethyl (phosphonate) XcCF2P(O)(OEt)2, wherein Xc can be chlorine or bromine) in the presence of a base (e.g. sodium carbonate or potassium carbonate) in a suitable solvent (e.g. acetonitrile, N,N-dimethylformamide or N-methyl-2-pyrrolidone (NMP)) at a temperature between room temperature and the boiling point of the reaction mixture. Such methods have been described in the literature, for example, Org. Lett. 15(19), 5036-5039; 2013, Tet. 65(27), 5278-5283; 2009 or Chem. Commun. 53, 5706; 2017.

[0431] Alternatively, compounds of formula XLIIIb can be obtained by treating compounds of formula XLIIId with a difluoromethanesulfinate reagent in the presence of an oxidizing agent such as described in J. Fluor. Chem., 193, 113-117; 2017.

[0432] The compound of formula XLIIId (wherein R 2a 、A 4 and A5 is as described above in formula (I)) can be obtained by hydrolyzing a compound of formula XLIIIe (wherein R 2a 、A 4 and A 5 is as described above in formula (I).

[0433] Compounds of Formula XLIIIe (wherein R 2a 、A 4 and A 5 is as described above in formula (I)) can be obtained by: reacting a compound having formula XLIIIc (wherein R 2a 、A 4 and A 5 is as described in formula (I), wherein R 2b is iodine or bromine) is treated with potassium thioacetate (KSAc) or sodium thioacetate under Ullmann-type cross-coupling copper-mediated reaction conditions as described, for example, in J. Org. Chem. 21, 11464; 2017.

[0434] Alternatively, a compound of formula XLIIId (wherein R 2a 、A 4 and A 5 is as described above in formula (I)) can be obtained by: reacting a compound of formula XLIIIc (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein R 2b is iodine or bromine) is treated with sodium sulfide or potassium sulfide (alternatively sodium hydrosulfide or potassium hydrosulfide, optionally as a hydrated salt) in a suitable solvent (such as, for example, N,N-dimethylformamide, N-methyl-2-pyrrolidone (NMP) or ethanol) at a temperature between room temperature and the boiling point of the solvent, as described, for example, in Bioorg. Med. Chem. Lett. [Bioorg. Med. Chem. Lett.] 23(13), 3947-3953; 2013 or WO12 / 088190.

[0435] The chemistry shown above for the conversion of XLIIIc to XLIIId to XLIIIb (Scheme 16a) can be carried out via a few additional protection / deprotection steps as shown in Scheme 16b.

[0436] Option 16b:

[0437]

[0438] The chemistry and conditions for the conversion of XLIIIf to XLIIIg to XLIIIh (Scheme 16b) are similar to those described above for the conversion of XLIIIc to XLIIId to XLIIIb, where the substituents Gr, R 2a 、R 2b 、A 4 and A 5 The definition of is still as described in detail in scheme 16a, and wherein PG is a protecting group, for example tetrahydropyranyl (THP) or tert-butyloxycarbonyl (Boc) group. Protection conditions (conversion of XLIIIc to XLIIIf), corresponding deprotection conditions (conversion of XLIIIh to XLIIIb) are well known to those skilled in the art and are described in the following literature, for example: Protective Groups in Organic Synthesis [protecting groups in organic synthesis], 3rd edition, Theodora W.Green (The Rowland Institute for Science [Rowland Institute for Science]) and Peter G.M. Wuts (Pharmacia and Upjohn Company [Pharmacia and Upjohn Company]), John Wiley & Sons, Inc. [John Wiley and Sons], New York, NY 1999, ISBN 0-471-16019-9. For example, THP protection of XLIIIc to generate XLIIIf (wherein PG1 is tetrahydropyranyl (THP)) can be achieved by treatment with 3,4-dihydro-2H-pyran in the presence of a Lewis acid (e.g., trifluoroacetic acid) under an inert gas (e.g., dimethyl sulfoxide, toluene, or dioxane) at a temperature between room temperature and the boiling point of the reaction mixture. Deprotection of XLIIIh (wherein PG1 is tetrahydropyranyl (THP)) can be achieved by treatment with, for example, p-methoxybenzenesulfonic acid or p-toluenesulfonic acid (PTSA) (optionally as a hydrate salt) in an alcoholic solvent (e.g., methanol or ethanol), optionally in the presence of a cosolvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane) at a temperature between 0°C and 80°C (preferably around room temperature).

[0439] Alternatively, a compound of Formula XLIIIa (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl),

[0440] Plan 16c:

[0441]

[0442] can be obtained by (Scheme 16c): a compound of formula XLIIIi (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl and PG is a protecting group, such as tetrahydropyranyl (THP) or tert-butoxycarbonyl (Boc) group) is deprotected under the conditions already detailed in Scheme 16b (Conversion of XLIIIh to XLIIIb).

[0443] Similarly, compounds of formula XLIIIb-1 (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl) can be obtained by: a compound having formula XLIIIi-1 (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl and PG1 is a protecting group, such as tetrahydropyranyl (THP) or tert-butyloxycarbonyl (Boc) group).

[0444] Compounds of Formula XLIIIi (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl, and PG1 is a protecting group, such as tetrahydropyranyl (THP) or tert-butyloxycarbonyl (Boc) group) can be obtained by the following manner: the corresponding sulfur compound of formula XLIIIh or the sulfoxide compound of formula XLIIIi-1 (wherein R 2a 、A 4 and A 5 is as described in formula (I), and wherein Gr is difluoromethyl or trifluoromethyl and PG is a protecting group, such as, for example, tetrahydropyranyl (THP) or tert-butyloxycarbonyl (Boc) group) is oxidized under the conditions detailed in Scheme 16a (conversion of XLIIIb to XLIIIa, XLIIIb-1 to XLIIIa, respectively). Similarly, sulfoxide compounds of formula XLIIIi-1 can be obtained by oxidation of sulfide compounds of formula XLIIIh (conversion of XLIIIb to XLIIIb-1 in Scheme 16a).

[0445] Option 17:

[0446]

[0447] Compounds of Formula IIb can be prepared according to Scheme 17, wherein R 2a 、R 2b 、A 4 and A 5 Is as described in formula (I). The compound with formula XLII prepared as in Scheme 16 is reacted with chlorosulfonyl isocyanate and then further reacted with water under reflux, as described in Synth. Commun. [Synthesis Communication] 1988, 18, 525, to provide an intermediate with formula XLIV. Subsequently, a chlorination reagent such as POCl3 is used, optionally in the presence of a base such as N, N-diisopropylethylamine, to convert the intermediate with formula XLIV into a compound with formula IIb. These chlorination methods are well known to those skilled in the art and are described, for example, in WO 2021 / 148639.

[0448] Plan 18:

[0449]

[0450] Compounds of Formula IIc, wherein R 2a 、R 2b 、A 4 and A 5 The compound of formula (I) is similar to the procedure described in ChemCatChem [Chemical Catalysis] 2017, 10, 965. Meldrum's acid is converted to compound XLV by refluxing in trimethyl orthoformate and further converted to compound XLVI in the same vessel by adding aniline of formula XL. Compound XLVI is refluxed in diphenyl ether to obtain 4-hydroxyquinoline of formula XLVII. Compound XLVII is then chlorinated using a chlorinating agent well known to those skilled in the art, such as POCl3, to obtain compound IIc.

[0451] For example, a compound having formula IVc

[0452]

[0453] It can be prepared as shown in Scheme 19.

[0454] Scheme 19:

[0455]

[0456] Compounds of formula IVc, wherein Z is H, C1-C3 alkyl, cyclopropyl, CF3, and wherein R 2a 、R2b 、A 4 and A 5 Is as described in formula (I). The compound of formula XLII prepared as in Scheme 16 is reacted in the presence of a compound of formula XLVIII at elevated temperature, for example, 180° C., as described, for example, in Eur. J. Med. Chem. [European Journal of Medicinal Chemistry] 2017, 141, 446, to provide an amine of formula IVc.

[0457] Alternatively, compounds of Formula Iab can be prepared, for example, as shown in Scheme 20.

[0458] Option 20:

[0459]

[0460] Compounds of formula Ij, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5、 Q is as described in formula (I), analogous to the procedure in WO2010 / 093419, page 225. The compound of formula XLII prepared according to Scheme 16 is treated with N,N-dimethylformamide dimethyl acetal at elevated temperature, preferably 90°C, to provide the formamidine product of formula XLVIII. Reaction with an amine of formula III in a suitable solvent, preferably acetic acid, at elevated temperature, preferably 120°C, provides a compound of formula Iab.

[0461] For example, a compound having the formula If

[0462]

[0463] It can be prepared as shown in Scheme 21.

[0464] Option 21:

[0465]

[0466] Compounds of formula If, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5 , Q is as described in formula (I). The compound of formula IIb prepared in Scheme 17 (wherein R 2a 、R 2b 、A 4and A 5 is as described in formula (I)) with an amine of formula III or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or hydrobromide salt, or a trifluoroacetate or any other equivalent salt thereof) (wherein R 1 、R 3 and Q is as described in formula (I)) using the procedure shown in Scheme 1 to provide a compound of formula Ie. As described in Heterocycles 1996, 43, 2607, treatment of the compound of formula Ie under acidic conditions, preferably with acetic acid, at elevated temperature, preferably between 70° C. and 80° C., provides an intermediate of formula LI. As is well known to those skilled in the art, the compound of formula LI can be methylated using an electrophilic methyl source, such as dimethyl sulfate or methyl iodide, in the presence of a base, such as potassium carbonate or sodium hydride, to obtain a compound of formula If.

[0467] For example, a compound having formula Ig

[0468]

[0469] It can be prepared as shown in Scheme 22.

[0470] Option 22:

[0471]

[0472] Compounds of formula Ig can be prepared according to Scheme 22, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5, Q is as described in formula (I). As described in J. Org. Chem. 1990, 55, 2543, the compound of formula XLII prepared in Scheme 16 is treated with a diazotizing agent, preferably isoamyl nitrite, in diiodomethane at elevated temperature, preferably 80°C, to provide an intermediate of formula LX. Reduction of the compound of formula LX in the presence of a selective reducing agent, such as diisobutylaluminum hydride (DIBALH), in a solvent such as toluene at low temperature, preferably -78°C, provides a compound of formula LXI. Subsequent Sonogashira coupling with trimethylsilylacetylene in the presence of a suitable palladium and copper catalyst, preferably bis(triphenylphosphine)palladium chloride and copper(I) iodide, in a solvent such as triethylamine, provides a compound of formula LXII. Cyclization with ammonia in methanol provides a compound of formula LXIII. The procedures are similar to those described in Eur. J. Med. Chem. 2016, 118, 170. Compounds of formula LXIII are treated with an oxidizing agent such as 3-chloro-benzenecarboperoxy acid or hydrogen peroxide in a solvent (preferably dichloromethane) to give N-oxides of formula LXIV. Such oxidations are well known to those skilled in the art. Compounds of formula LXIV are oxidized in the presence of a suitable activating agent (e.g., bromotripyrrolidinophosphonium hexafluorophosphate). ), possibly in the presence of a base (eg N,N-diisopropylethylamine) with an amine of formula III, analogously to the method described in WO 2016 / 123627, page 87, gives a compound of formula Ig.

[0473] Compounds of formula IId

[0474]

[0475] (where X 1 is a leaving group such as a halide or sulfonate, eg chloride) can be prepared as shown in Scheme 23.

[0476] Option 23:

[0477]

[0478] Compounds of formula IId can be prepared according to Scheme 23, wherein R 2a 、R 2b 、A 4 、A 5is as described in formula (I). As described in EP1782811, page 57, the compound of formula XLI prepared in Scheme 16 is treated with a palladium catalyst, preferably Pd(PPh3)4, and tributyl(1-ethoxyvinyl)tin at elevated temperature, preferably at 105°C, to provide an intermediate of formula LXV. Similarly to Bioorg.Med.Chem.Lett. [Bioorganic and Medicinal Chemistry Letters], 25, 919, the compound of formula LXV is treated with an aqueous sodium nitrite solution in the presence of an acid such as hydrochloric acid or a sulfuric acid / acetic acid mixture at low temperature, preferably at a temperature between 0°C and 5°C, to give a compound of formula LXVI. The compound of formula IId is then obtained by chlorinating the compound of formula LXVI using a chlorinating agent well known to those skilled in the art, such as POCl3, optionally in the presence of an amine base well known to those skilled in the art, such as N,N-diisopropylethylamine.

[0479] Compounds of formula IIe

[0480]

[0481] (where X 1 is a leaving group such as a halide or sulfonate, eg, chloride) can be prepared as shown in Scheme 24.

[0482] Option 24:

[0483]

[0484] Compounds of Formula IIe can be prepared according to Scheme 24, wherein R 2a 、R 2b 、A 4 、A 5 As described in Tetrahedron Letters, 2015, 56, 5112, a compound of formula XL is heated with ethyl 2-cyano-3-ethoxyacrylate at an elevated temperature, preferably 140° C., to provide an intermediate of formula LXVII. At an elevated temperature, preferably between 260° C., in a solvent, preferably diphenyl ether or a diphenyl ether-biphenyl eutectic mixture (Dowtherm ) to give a compound of formula LXVIII. This is then converted to a compound of formula IIe using thionyl chloride according to methods known to those skilled in the art, for example in the presence of catalytic N,N-dimethylformamide at reflux, similar to US 2003 / 212276, page 15.

[0485] For example, a compound having formula Ih

[0486]

[0487] It can be prepared as shown in Scheme 25.

[0488] Option 25:

[0489]

[0490] Compounds of formula Ih can be prepared according to Scheme 25, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5 , Q is as described in formula (I). In a methanol-water solvent, in the presence of a base (preferably potassium carbonate), analogously to WO 2011 / 4276, page 132, a compound of formula XLII as prepared in Scheme 16 is treated with hydrogen peroxide (in the form of an aqueous solution or a urea adduct) to provide an intermediate of formula LXX. Analogously to US 2014 / 0275072, paragraph 133, a compound of formula LXX is treated with an aqueous solution of sodium nitrite in the presence of an acid (e.g., hydrochloric acid or a sulfuric acid / acetic acid mixture) at low temperature, preferably at a temperature between 0°C and 5°C, to give a compound of formula LXXI. The compound of formula LXXI is activated in the presence of a suitable activator (e.g., (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate). ), coupled with an amine of formula III in the presence of a base (eg N,N-diisopropylethylamine), analogously to the method described in WO 2014 / 085528, page 55, gives a compound of formula Ih.

[0491] For example, a compound having formula Ii

[0492]

[0493] It can be prepared as shown in Scheme 26.

[0494] Scheme 26:

[0495]

[0496] Compounds of formula Ii, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5, Q is as described in formula (I). A compound of formula Iaa as prepared in Scheme 1, 5 or 6 is treated with a fluorinating agent, preferably 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) in a solvent, preferably acetonitrile, similar to WO 2018 / 34917, page 91, to provide a compound of formula Ii.

[0497] For example, a compound having formula Ij

[0498]

[0499] It can be prepared as shown in Scheme 27.

[0500] Option 27:

[0501]

[0502] Compounds of formula Ij, wherein R 1 、R 2a 、R 2b 、R 3 、A 4 、A 5 , Q is as described in formula (I). A compound of formula Iaa prepared as in Scheme 1, 5 or 6 is treated with a chlorinating agent (preferably N-chlorosuccinimide) in the presence of catalytic dimethyl sulfoxide (DMSO) in a solvent (preferably dichloromethane) similar to Nature Catalysis, 2020, 3, 107 to provide a compound of formula Ij.

[0503] Certain compounds of formula III or salts thereof (e.g., hydrohalide salts, preferably hydrochloride or hydrobromide, or any other equivalent salts) (wherein R 1 、R 3 and Q have the same meanings as given above for the compounds of formula (I)) are known in the literature.

[0504] For example, as defined above, compounds of formula IIIa and IIIb or salts thereof (wherein R 1 、R 3 、R 4a 、R 5a and R 5b are as described in formula (I), in particular those compounds of formula IIIa and IIIb as defined above, or salts thereof (wherein R 3 and R 4a is as described in formula (I), and wherein R 1 、R 5a and R5b is hydrogen) can be prepared in analogy to the description found in WO 2021 / 069575.

[0505]

[0506] Similarly, compounds of formula IIIe and IIIf as defined above, or salts thereof (wherein R 1 、R 3 、R 4 and R 5 are as described in formula (I), in particular those compounds of formula IIIe and IIIf as defined above, or salts thereof (wherein R 3 and R 4 is as described in formula (I), wherein R 1 is hydrogen and R 5 is hydrogen, methyl or cyclopropyl) can be prepared analogously to the description found in, for example, WO 2021 / 099303, WO 2021 / 105091, WO 2021 / 165195 and WO 2021 / 224323.

[0507] Scheme 28:

[0508]

[0509] Compounds of formula (IIIf-TH-1) (a subset of compounds of formula (IIIf) wherein R 1 and R 5 is hydrogen, R 3 is as defined for compounds of formula (I), and wherein R 4 Is a single -C(O)NR 10 R 11 Substituted thiazolyl, wherein R 10 and R 11 is as defined for compounds of formula (I)) can be prepared (Scheme 28) by: from a compound of formula (IIIf-TH-2) wherein R 3 、R 10 and R 11 is as defined for the compound of formula (I), and X - is an anion) by treatment with a base (e.g. a hydroxide base or a carbonate base, such as sodium hydroxide or potassium carbonate, or an ion exchange resin). Such procedures are well known to those skilled in the art and are known from the literature and textbooks. Anion X -It is the conjugate base of an acid, such as an inorganic acid, for example hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, etc., or an organic acid, such as a carboxylic acid or a sulfonic acid, for example trifluoroacetic acid, or methanesulfonic acid or p-toluenesulfonic acid. Many such acids are known to those skilled in the art.

[0510] A compound having the formula (IIIf-TH-2) (wherein R 3 、R 10 and R 11 is as defined for the compound of formula (I), and X - is an anion) can be prepared from a compound having the formula (XXXVIIIa) wherein R 3 、R 10 and R 11 is as defined for compounds of formula (I) by treatment with an acid, such as those listed above. The reaction can be carried out neat or in a solvent, such as an organic solvent (e.g., methanol, tetrahydrofuran, dichloromethane or dioxane) or an inorganic solvent (e.g., water), or a mixture of such solvents. The reaction can be carried out at a temperature between -100°C and 200°C, more typically between 0°C and 150°C, such as, for example, at ambient temperature.

[0511] The compound of formula (XXXVIIIa) (wherein R 3 、R 10 and R 11 is as defined for the compound of formula (I)) can be prepared by: from a compound of formula (XXXVIIIb) wherein R 3 is as defined for the compound of formula (I)) by reacting a compound of formula HNR 10 R 11 An amine compound or a salt thereof (wherein R 10 and R 11The acid compound of formula (XXXVIIIb) is treated under standard amide bond forming conditions known to those skilled in the art. Typically, the acid compound of formula (XXXVIIIb) is activated to its corresponding acid chloride with oxalyl chloride or thionyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in an inert solvent such as, for example, dichloromethane (DCM) or tetrahydrofuran (THF) at a temperature between 0°C and 100°C (preferably about 25°C). Such methods are known to those skilled in the art and are described, for example, in Tetrahedron 2005, 61(46), 10827-10852. Alternatively, it may be advantageous to carry out the reaction in the presence of a dehydrating agent, for example a peptide coupling reagent such as carbodiimide, HATU (1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as azabenzotriazole tetramethyluronium hexafluorophosphate) or propanephosphonic acid cyclic anhydride Such amidation reactions can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N-dimethylformamide, at a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C, in the presence or absence of a catalyst, for example an acylation catalyst such as 4-dimethylaminopyridine (DMAP), and with or without the addition of a base, such as an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate or an organic base such as triethylamine, diisopropylethylamine or pyridine. 10 R 11 Amine compounds (wherein R 10 =R 11 =Hydrogen (i.e. HNR 10 R 11 In certain amidation reactions characterized by the presence of ammonia), it may be advantageous to use an ammonia alternative, such as an ammonium salt (e.g., ammonium hydroxide or ammonium chloride) or a silica-supported ammonium salt (e.g., silica-supported ammonium chloride NH4Cl / SiO2, as described in Tetrahedron Letters [Tetrahedron Letters] 2005, 46, 6879-6882).

[0512] A compound of formula (XXXVIIIb) (wherein R 3 is as defined for compounds of formula (I)) can be prepared by: a compound of formula (XXXVIIIc) wherein R 3is as defined for compounds of formula (I), and wherein R a is C 1 -C 6 alkyl) is saponified under conditions known to those skilled in the art (using, for example, aqueous sodium hydroxide, potassium hydroxide or lithium hydroxide in methanol, ethanol, tetrahydrofuran or dioxane at room temperature, or up to reflux conditions).

[0513] Alternatively, a compound of formula (XXXVIIIa) wherein R 3 、R 10 and R 11 is as defined for compounds of formula (I)) can be prepared directly from compounds of formula (XXXVIIIc) wherein R 3 is as defined for a compound of formula (I), and wherein R is C1-C6 alkyl) by reacting a compound of formula HNR 40 with a methyl group having the formula HNR 40 in the presence of a base (e.g. an inorganic base, for example sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as for example triethylamine, diisopropylethylamine or pyridine) in a solvent (e.g. an organic solvent, for example methanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide) at a temperature in the range of -100°C to +300°C (preferably between ambient temperature and 100°C), optionally in a microwave. 10 R 11 An amine compound or a salt thereof (wherein R 10 and R 11 The reaction is as defined for compounds of formula (I).

[0514] A compound of formula (XXXVIIIc) wherein R 3 is as defined for the compound of formula (I), and wherein R a is C1-C6 alkyl) can be obtained by reacting a compound of formula (XXXVIIIe) or a tautomer thereof or a salt thereof, wherein R a is C1-C6 alkyl, with a compound of formula (XXXVIIId) wherein R 3 The reaction is carried out neat or in a solvent (e.g. an organic solvent) or in a mixture of solvents (e.g. dioxane and acetic acid as solvents). The reaction can be carried out in the presence or absence of a desiccant, such as, for example, in the presence of molecular sieves, at a temperature between -100°C and 200°C, more typically between 0°C and 150°C, such as, for example, at 80°C.

[0515] A compound of formula (XXXVIIId) wherein R 3are as defined for compounds of formula (I) are known, for example, from WO2021 / 083936 or WO2021 / 165195, or they can be prepared analogously to the descriptions found therein. Compounds of formula (XXXVIIIe) or tautomers thereof or salts thereof, in which R is C1-C6-alkyl, are known or even commercially available, or they can be prepared by known methods.

[0516] Scheme 29:

[0517]

[0518] Similarly, compounds of formula (IIIf-PYM-1) (a subset of compounds of formula (IIIf) wherein R 1 and R 5 is hydrogen, R 3 is as defined for compounds of formula (I), and wherein R 4 Is a single -C(O)NR 10 R 11 Substituted pyrimidinyl, wherein R 10 and R 11 is as defined for the compound of formula (I)) or a salt thereof (IIIf-PYM-2) (wherein X - is an anion as defined above in Scheme 28) can be prepared from a compound of formula (XXXIXe) or a tautomer thereof or a salt thereof, wherein R a is C1-C6 alkyl and a compound of formula (XXXVIIId) wherein R 3 is as defined for compounds of formula (I)) following the chemistry and conditions described above in Scheme 28 (Scheme 29).

[0519] Compounds of formula (XXXIXe) or tautomers thereof or salts thereof, wherein Ra is C1-C6 alkyl, are known or even commercially available, or they can be prepared by known methods.

[0520] Option 29a:

[0521]

[0522] Similarly, compounds of formula (IIIf-PYM-1-1) (a subset of compounds of formula (IIIf) wherein R 5 is hydrogen, R 1 and R 3 is as defined for compounds of formula (I), and wherein R 4 Is a single -C(O)NR 10 R 11Substituted pyrimidinyl, wherein R 10 and R 11 is as defined for the compound of formula (I)) or a salt thereof (IIIf-PYM-2-1) (wherein X - is an anion as defined above in Scheme 28) can be prepared from a compound of formula (XXXIXe) or a tautomer thereof or a salt thereof (wherein Ra is C1-C6 alkyl) and a compound of formula (XXXVIIId-1) (wherein R 1 and R 3 is as defined for compounds of formula (I)) following the chemistry and conditions described above in Schemes 28 and 29 (Scheme 29a).

[0523] The compound of formula (XXXVIIId-1) (wherein R 1 and R 3 are as defined for compounds of formula (I)) are known or they can be prepared analogously to the description found, for example, in WO 2021 / 083936 or WO 2021 / 165195.

[0524] Option 30:

[0525]

[0526] Compounds of formula (Im) (a subset of compounds of formula (I) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 、A 5 、R 10 and R 11 is as defined for compounds of formula (I)) can be prepared (Scheme 30) by: from a compound of formula (XL-a) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for the compound of formula (I)) by reacting a compound of formula HNR 10 R 11 Amine compound or salt (wherein R 10 and R 11The acid compound of formula (XL-a) is treated under standard amide bond forming conditions known to those skilled in the art. Typically, the acid compound of formula (XL-a) is activated to its corresponding acid chloride with oxalyl chloride or thionyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in an inert solvent such as, for example, dichloromethane (DCM) or tetrahydrofuran (THF) at a temperature between 0° C. and 100° C. (preferably about 25° C.). Such methods are known to those skilled in the art and are described, for example, in Tetrahedron 2005, 61(46), 10827-10852. Alternatively, it may be advantageous to carry out the reaction in the presence of a dehydrating agent, for example a peptide coupling reagent such as carbodiimide, HATU (1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, also known as azabenzotriazole tetramethyluronium hexafluorophosphate) or propanephosphonic acid cyclic anhydride Such amidation reactions can be carried out neat or in a solvent, preferably in a solvent such as an organic solvent, for example acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide or N,N-dimethylformamide, at a temperature range of -100°C to +300°C, preferably between ambient temperature and 200°C, in the presence or absence of a catalyst, for example an acylation catalyst such as 4-dimethylaminopyridine (DMAP), and with or without the addition of a base, such as an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate or an organic base such as triethylamine, diisopropylethylamine or pyridine. 10 R 11 Amine compounds (wherein R 10 =R 11 =Hydrogen (i.e. HNR 10 R 11 In certain amidation reactions characterized by the presence of ammonia), it may be advantageous to use an ammonia alternative, such as an ammonium salt (e.g., ammonium hydroxide or ammonium chloride) or a silica-supported ammonium salt (e.g., silica-supported ammonium chloride NH4Cl / SiO2, as described in Tetrahedron Letters [Tetrahedron Letters] 2005, 46, 6879-6882).

[0527] A compound having the formula (XL-a) (wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5is as defined for compounds of formula (I)) can be prepared by: a compound of formula (XL-b) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for the compound of formula (I), and wherein R a is C 1 -C 6 alkyl or benzyl) is saponified under conditions known to those skilled in the art (using, for example, aqueous sodium hydroxide, potassium hydroxide or lithium hydroxide in methanol, ethanol, tetrahydrofuran or dioxane at room temperature, or up to reflux conditions).

[0528] Alternatively, a compound of formula (Im) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 、A 5 、R 10 and R 11 is as defined for compounds of formula (I)) can be prepared directly from compounds of formula (XL-b) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for a compound of formula (I), and wherein R is C1-C6 alkyl or benzyl) by reacting a methyl group with a methyl group having the formula HNR in the presence of a base (e.g. an inorganic base, for example sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as for example triethylamine, diisopropylethylamine or pyridine) in a solvent (e.g. an organic solvent, for example methanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide) at a temperature in the range of -100°C to +300°C (preferably between ambient temperature and 100°C), optionally in a microwave. 10 R 11 An amine compound or a salt thereof (wherein R 10 and R 11 The reaction is as defined for compounds of formula (I).

[0529] The compound of formula (XL-b) (wherein R 2a 、R2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for the compound of formula (I), and wherein Ra is C1-C6 alkyl or benzyl) can be prepared by reacting a compound of formula (XL-c) (wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein Xa is a halogen, preferably Br, Cl or I (even more preferably Cl). In such carbonylation reactions, typically, compounds of formula (XL-c) are reacted with carbon monoxide, CO, in the presence of a metal catalyst, such as a palladium catalyst (e.g. palladium(II) acetate, or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dppf)), optionally in the presence of a phosphine ligand, preferably in the presence of a base (e.g. triethylamine, diisopropylethylamine or pyridine), in an alcoholic RaOH solvent (optionally in the presence of an organic co-solvent), and at a temperature ranging between 0°C and 250°C (preferably between room temperature and 200°C), typically under pressure, for example in the range of 5 to 200 bar.

[0530] A compound of formula (XL-c) (wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) can be prepared by: compounds of formula II (wherein R 2a 、R 2b 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein X 1is a leaving group, such as a halogen or sulfonate, such as chloride) and a compound of formula (XL-d) or its free base (wherein R 3 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl) and X - is an anion as defined in Scheme 28) under similar conditions to those already described in Scheme 1 above.

[0531] A compound of formula (XL-d) or a free base thereof (wherein R 3 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl) and X - is an anion as defined in Scheme 28) can be prepared by: from a compound of formula (XL-e) wherein R 3 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) by treatment with acid under similar conditions to those already described in Scheme 28 above (conversion of XXXVIIIa to IIIf-TH-2).

[0532] Certain compounds of formula (XL-e) (wherein R 3 are as defined for compounds of formula (I) and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) are known, for example, from WO 2021 / 224323 or WO 2021 / 165195, or they can be prepared by known methods.

[0533] Option 30a:

[0534]

[0535] Similarly, compounds of formula (Im-1) (a subset of compounds of formula (I) wherein R 1 、R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 、A 5 、R 10 and R 11 is as defined for the compound of formula (I)) can be obtained from a compound of formula (XL-c-1) wherein R 1 、R 2a 、R 2b 、R 3、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I) and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) is prepared following the chemistry and conditions described in Scheme 30 above (Scheme 30a).

[0536] A compound having the formula (XL-c-1) (wherein R 1 、R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) can be prepared by: compounds of formula (XL-c) wherein R 2a 、R 2b 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein Xa is halogen, preferably Br, Cl or I (even more preferably Cl)) and has formula R 1 -X 3 (VI) compound (wherein R 1 have the same meanings as given above for the compounds of formula (I), except that R 1 Different from hydrogen, and where X 3 is a leaving group, such as a halogen or a sulfonate, for example chloride, bromide, iodide or mesylate) under the conditions already described in Scheme 5 above.

[0537] Option 31:

[0538]

[0539] Compounds of formula (IIIf-PYR-1) (a subset of compounds of formula (IIIf) wherein R 5 is hydrogen, R 1 and R 3 is as defined for compounds of formula (I), and wherein R 4 Is a single -C(O)NR 10R 11 Substituted pyrazinyl, wherein R 10 and R 11 is as defined for the compound of formula (I)) or a salt thereof (IIIf-PYR-2) (wherein X - is an anion as defined above in Scheme 28) can be obtained from a compound having formula (XLI-c) wherein R 1 and R 3 is as defined for compounds of formula (I), and wherein Ra is C1-C6 alkyl or benzyl) are prepared following the chemistry and conditions as described above in Schemes 28, 29 and 29a (Scheme 31).

[0540] A compound of formula (XLI-c) (wherein R 1 and R 3 is as defined for the compound of formula (I), and wherein Ra is C1-C6 alkyl or benzyl) can be prepared by reacting a compound of formula (XLI-d) (wherein R 1 and R 3 is a carbonylation reaction as defined for compounds of formula (I), and wherein Xb is a halogen, preferably Br, Cl or I (even more preferably Br or Cl). In such carbonylation reactions, typically, a compound of formula (XLI-d) is reacted with carbon monoxide, CO, in the presence of a metal catalyst, such as a palladium catalyst (e.g. palladium(II) acetate, or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dppf)), optionally in the presence of a phosphine ligand, preferably in the presence of a base (e.g. triethylamine, diisopropylethylamine or pyridine), in an alcoholic RaOH solvent (optionally in the presence of an organic co-solvent), and at a temperature ranging between 0°C and 250°C (preferably between room temperature and 200°C), typically under pressure, for example in the range of 5 bar to 200 bar.

[0541] Option 32:

[0542]

[0543] A compound having the formula (XLI-d) (wherein R 1 and R 3is as defined for the compound of formula (I), and wherein Xb is halogen, preferably Br, Cl or I (even more preferably Br or Cl)) can be prepared by (Scheme 32): a compound of formula (XLI-e) or a tautomer thereof or a salt thereof, wherein Xb is halogen, preferably Br, Cl or I (even more preferably Br or Cl)) and a compound of formula (XXXVIIId-1) wherein R 1 and R 3 The reaction is carried out neat or in a solvent (e.g. an organic solvent such as dioxane or acetic acid, or a mixture thereof). The reaction may be carried out in the presence or absence of a desiccant, such as, for example, in the presence of molecular sieves, at a temperature between -100°C and 200°C, more typically between 0°C and 150°C, such as, for example, at 80°C.

[0544] Compounds of formula (XLI-e) or tautomers thereof or salts thereof, wherein Xb is halogen, preferably Br, Cl or I (even more preferably Br or Cl) are known or even commercially available, or they can be prepared by known methods.

[0545] Option 33:

[0546]

[0547] Compounds of formula (In) (a subset of compounds of formula (I) wherein R 2a 、R 2b 、R 1 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I)) can be prepared as follows (Scheme 33): a compound of formula (XLII-a) wherein R 2a 、R 2b 、R 1 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5is as defined for compounds of formula (I), and wherein PG is a benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl group). Such deprotection reactions are known to those skilled in the art and are described in the literature, such as described 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. Benzyl deprotection can be achieved by catalytic hydrogenolysis, treatment with an acid (e.g., trifluoroacetic acid), or under oxidizing conditions by treatment with ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In particular, reaction of a compound of formula (XLII-a) wherein PG is a methoxybenzyl group with aqueous ceric ammonium nitrate in a solvent such as acetonitrile and at a temperature between 0°C and 100°C (preferably around room temperature) can produce a compound of formula (In).

[0548] The compound of formula (XLII-a) (wherein R 2a 、R 2b 、R 1 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for the compound of formula (I), and wherein PG is a benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl group) can be prepared by: a compound of formula (XLII-b) wherein R 2a 、R 2b 、R 1 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5is as defined for the compound of formula (I), and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br)) in the presence of benzylamine, p-methoxybenzylamine, 3,4-dimethoxybenzylamine or 2,4-dimethoxybenzylamine. Typically in such an aminocarbonylation reaction, a compound of formula (XLII-b) is reacted with carbon monoxide CO in the presence of a metal catalyst, for example a palladium catalyst (for example palladium(II) acetate, bis(benzonitrile)palladium(II) chloride or [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride PdCl2(dppf)), optionally in the presence of a phosphine ligand (for example Xantphos), in the presence of the above-mentioned benzylamine, preferably in the presence of a base (for example triethylamine, diisopropylethylamine or pyridine), in an inert solvent (for example toluene) at a temperature in the range of between 0°C and 250°C (preferably between room temperature and 200°C) (usually under pressure, for example in the range of 5 bar to 200 bar).

[0549] A compound of formula (XLII-b) (wherein R 2a 、R 2b 、R 1 、R 3 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br)) can be prepared by: compounds of formula II (wherein R 2a 、R 2b 、A 1 、A 2 、A 3 、A 4 and A 5 is as defined for compounds of formula (I), and wherein X 1 is a leaving group, such as a halogen or sulfonate, such as chloride) and a compound of formula (XLII-c) or its free base (wherein R 1 and R 3 is as defined for compounds of formula (I), and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br) and X - is an anion as defined in Scheme 28) under similar conditions to those already described in Scheme 1 above.

[0550] A compound of formula (XLII-c) or a free base thereof (wherein R 1 and R 3is as defined for compounds of formula (I), and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br) and X - is an anion as defined in Scheme 28) can be prepared by: from a compound of formula (XLII-d) wherein R 1 and R 3 is as defined for compounds of formula (I), and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br)) by treatment with acid under similar conditions to those already described in Scheme 28 above (conversion of XXXVIIIa to IIIf-TH-2).

[0551] A compound of formula (XLII-d) (wherein R 1 and R 3 is as defined for compounds of formula (I) and wherein Xd is halogen, preferably Br, Cl or I (even more preferably Br)) can be prepared as described above in Scheme 32 or in analogy to conditions found in, for example, WO 21 / 083936.

[0552] Depending on the procedure or reaction conditions, the reactants can be reacted in the presence of a base. Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxide and carbocyclic amines. Examples that may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0553] These reactants can react with each other as is, i.e. without adding solvents or diluents. However, in most cases, it is advantageous to add inert solvents or diluents or mixtures of these. If the reaction is carried out in the presence of a base, the base used in excess (e.g., triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline) can also serve as a solvent or diluent.

[0554] These reactions are advantageously carried out in a temperature range of from about -80°C to about +140°C, preferably from about -30°C to about +100°C, in many cases in a range between ambient temperature and about +80°C.

[0555] Depending on the reaction conditions and starting materials chosen as appropriate in the respective case, it is possible, for example, to replace only one substituent with another substituent according to the invention in one reaction step or to replace several substituents with other substituents according to the invention in one and the same reaction step.

[0556] 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 exchange reagent, and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchange reagent.

[0557] Salts of compounds of formula (I) can be converted in a customary manner into the free compounds I, acid addition salts (for example by treatment with suitable basic compounds or with suitable ion exchange reagents) and base salts (for example by treatment with suitable acids or with suitable ion exchange reagents).

[0558] Salts of compounds of formula (I) can be converted in a manner known per se into other salts, acid addition salts of compounds of formula (I), for example into other acid addition salts, for example by treating salts of inorganic acids (such as hydrochlorides) with suitable metal salts of the acid (such as sodium salts, barium salts or silver salts, for example with silver acetate) in a suitable solvent in which the inorganic salt formed (such as silver chloride) is insoluble and therefore precipitates from the reaction mixture.

[0559] Depending on the procedure or reaction conditions, compounds of formula (I) having salt-forming properties can be obtained in free form or in the form of salts.

[0560] Depending on the number of asymmetric carbon atoms present in the molecule, the absolute and relative configuration and / or the configuration of non-aromatic double bonds present in the molecule, the compounds of the formula (I) and, where appropriate, their tautomers, in each case in free form or in salt form, may be present in the form of one of the possible isomers or as a mixture thereof, for example in the form of pure isomers, such as enantiomers and / or diastereomers, or as isomer mixtures, such as enantiomeric mixtures, for example racemates, diastereomeric mixtures or racemic mixtures; the present invention relates both to the pure isomers and also to all possible isomer mixtures, and the above and below are to be understood as such in each case, even if stereochemical details are not explicitly mentioned in each case.

[0561] Diastereomeric mixtures or racemic mixtures of compounds of formula (I) in free form or in salt form, the acquisition of which may depend on the starting materials and procedures chosen, can be separated in a known manner into the pure diastereomers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and / or chromatography.

[0562] Enantiomeric mixtures obtainable in an analogous manner (e.g., racemates) can be resolved into the optical antipodes by known methods, for example, by recrystallization from optically active solvents; by chromatography on chiral adsorbents, for example, high performance liquid chromatography (HPLC) on acetylcellulose; by cleavage with specific immobilized enzymes with the aid of suitable microorganisms; by forming inclusion compounds, for example, using chiral crown ethers, in which only one enantiomer is complexed; or by conversion into diastereomeric salts, for example, by reacting the basic end product racemate with an optically active acid (e.g., a carboxylic acid, for example, camphoric acid, tartaric acid or malic acid, or a sulfonic acid, for example, camphorsulfonic acid) and separating the diastereomeric mixtures obtainable in this way, for example, by fractional crystallization on the basis of their different solubilities, thereby obtaining the diastereomers from which the desired enantiomer can be freed by the action of suitable reagents, for example, basic reagents.

[0563] Pure diastereomers or enantiomers can be obtained according to the invention not only by separation of the appropriate isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the method according to the invention with starting materials having the appropriate stereochemistry.

[0564] N-oxides can be prepared by reacting a compound of formula (I) with a suitable oxidizing agent (e.g. H O / urea adduct) in the presence of an anhydride (e.g. trifluoroacetic anhydride). Such oxidations are known from the literature, for example from J. Med. Chem., 32 (12), 2561-73, 1989 or WO 2000 / 15615.

[0565] If the individual components have different biological activities, it is advantageous to isolate or synthesize the biologically more effective isomers, such as enantiomers or diastereomers or isomer mixtures, such as enantiomeric mixtures or diastereomeric mixtures, in each case.

[0566] The compounds of formula (I) and, where appropriate, their tautomers (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, such as those which can be used for crystallization of compounds present in solid form.

[0567] The compounds of formula (I) according to the following tables A-1 to A-71 can be prepared according to the methods described above. The following examples are intended to illustrate the invention and show preferred compounds of formula (I) (in the form of compounds of formula IA).

[0568]

[0569] Table A-1 38 compounds A-1.001 to A-1.038 of formula IA are provided, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is CF3, R 2b is CF3 and Q is as defined in Table Z. For example, compound A-13.003 is

[0570]

[0571] Table A-2 Provided are 38 compounds A-2.001 to A-2.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is CF3, R 2b is Cl and Q is as defined in Table Z.

[0572] Table A-3 Provided are 38 compounds A-3.001 to A-3.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is CF3, R 2b is Br and Q is as defined in Table Z.

[0573] Table A-4 Provided are 38 compounds A-4.001 to A-4.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is CF3 and Q is as defined in Table Z.

[0574] Table A-5Provided are 38 compounds A-5.001 to A-5.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is Cl and Q is as defined in Table Z.

[0575] Table A-6 Provided are 38 compounds A-6.001 to A-6.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is Br and Q is as defined in Table Z.

[0576] Table A-7 Provided are 38 compounds A-7.001 to A-7.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is CF3 and Q is as defined in Table Z.

[0577] Table A-8 Provided are 38 compounds A-8.001 to A-8.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is Cl and Q is as defined in Table Z.

[0578] Table A-9 Provided are 38 compounds A-9.001 to A-9.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is Br and Q is as defined in Table Z.

[0579] Table A-10 Provided are 38 compounds A-10.001 to A-10.038 of formula IA, wherein A 1 It's N, A2 It is CH, A 3 It's N, R 1 It's H, R 2a It is SO2-CF3, R 2b is CF3 and Q is as defined in Table Z.

[0580] Table A-11 Provided are 38 compounds A-11.001 to A-11.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is SO2-CF3, R 2b is Cl and Q is as defined in Table Z.

[0581] Table A-12 Provided are 38 compounds A-12.001 to A-12.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is SO2-CF3, R 2b is Br and Q is as defined in Table Z.

[0582] Table A-13 Provided are 38 compounds A-13.001 to A-13.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is CF3, R 2b is CF3 and Q is as defined in Table Z.

[0583] Table A-14 Provided are 38 compounds A-14.001 to A-14.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is CF3, R 2b is Cl and Q is as defined in Table Z.

[0584] Table A-15 Provided are 38 compounds A-15.001 to A-15.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3It's N, R 1 It is CH3, R 2a It is CF3, R 2b is Br and Q is as defined in Table Z.

[0585] Table A-16 Provided are 38 compounds A-16.001 to A-16.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is CF3 and Q is as defined in Table Z.

[0586] Table A-17 Provided are 38 compounds A-17.001 to A-17.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is Cl and Q is as defined in Table Z.

[0587] Table A-18 Provided are 38 compounds A-18.001 to A-18.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is Br and Q is as defined in Table Z.

[0588] Table A-19 Provided are 38 compounds A-19.001 to A-19.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Br, R 2b is CF3 and Q is as defined in Table Z.

[0589] Table A-20 Provided are 38 compounds A-20.001 to A-20.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2aIt is Br, R 2b is Cl and Q is as defined in Table Z.

[0590] Table A-21 Provided are 38 compounds A-21.001 to A-21.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Br, R 2b is Br and Q is as defined in Table Z.

[0591] Table A-22 Provided are 38 compounds A-22.001 to A-22.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is SO2-CF3, R 2b is CF3 and Q is as defined in Table Z.

[0592] Table A-23 Provided are 38 compounds A-23.001 to A-23.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is SO2-CF3, R 2b is Cl and Q is as defined in Table Z.

[0593] Table A-24 Provided are 38 compounds A-24.001 to A-24.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is SO2-CF3, R 2b is Br and Q is as defined in Table Z.

[0594] Table A-25 Provided are 38 compounds A-25.001 to A-25.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is CF3, R 2bis CF3 and Q is as defined in Table Z.

[0595] Table A-26 Provided are 38 compounds A-26.001 to A-26.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is CF3, R 2b is Cl and Q is as defined in Table Z.

[0596] Table A-27 Provided are 38 compounds A-27.001 to A-27.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is CF3, R 2b is Br and Q is as defined in Table Z.

[0597] Table A-28 Provided are 38 compounds A-28.001 to A-28.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Cl, R 2b is CF3 and Q is as defined in Table Z.

[0598] Table A-29 Provided are 38 compounds A-29.001 to A-29.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Cl, R 2b is Cl and Q is as defined in Table Z.

[0599] Table A-30 Provided are 38 compounds A-30.001 to A-30.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Cl, R 2b is Br and Q is as defined in Table Z.

[0600] Table A-31 Provided are 38 compounds A-31.001 to A-31.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Br, R 2b is CF3 and Q is as defined in Table Z.

[0601] Table A-32 Provided are 38 compounds A-32.001 to A-32.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Br, R 2b is Cl and Q is as defined in Table Z.

[0602] Table A-33 Provided are 38 compounds A-33.001 to A-33.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Br, R 2b is Br and Q is as defined in Table Z.

[0603] Table A-34 Provided are 38 compounds A-34.001 to A-34.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is SO2-CF3, R 2b is CF3 and Q is as defined in Table Z.

[0604] Table A-35 Provided are 38 compounds A-35.001 to A-35.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is SO2-CF3, R 2b is Cl and Q is as defined in Table Z.

[0605] Table A-36 Provided are 38 compounds A-36.001 to A-36.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is SO2-CF3, R 2b is Br and Q is as defined in Table Z.

[0606] Table A-37 Provided are 38 compounds A-37.001 to A-37.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is CF3, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0607] Table A-38 Provided are 38 compounds A-38.001 to A-38.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0608] Table A-39 Provided are 38 compounds A-39.001 to A-39.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0609] Table A-40 Provided are 38 compounds A-40.001 to A-40.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is I and Q is as defined in Table Z.

[0610] Table A-41Provided are 38 compounds A-41.001 to A-41.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is I, R 2b is Cl and Q is as defined in Table Z.

[0611] Table A-42 Provided are 38 compounds A-42.001 to A-42.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is I and Q is as defined in Table Z.

[0612] Table A-43 Provided are 38 compounds A-43.001 to A-43.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is I, R 2b is Br and Q is as defined in Table Z.

[0613] Table A-44 Provided are 38 compounds A-44.001 to A-44.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is CF3, R 2b is I and Q is as defined in Table Z.

[0614] Table A-45 Provided are 38 compounds A-45.001 to A-45.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is I, R 2b is CF3 and Q is as defined in Table Z.

[0615] Table A-46 Provided are 38 compounds A-46.001 to A-46.038 of formula IA, wherein A 1 It's N, A2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is CF3, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0616] Table A-47 Provided are 38 compounds A-47.001 to A-47.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0617] Table A-48 Provided are 38 compounds A-48.001 to A-48.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Br, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0618] Table A-49 Provided are 38 compounds A-49.001 to A-49.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is I and Q is as defined in Table Z.

[0619] Table A-50 Provided are 38 compounds A-50.001 to A-50.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is I, R 2b is Cl and Q is as defined in Table Z.

[0620] Table A-51 Provided are 38 compounds A-51.001 to A-51.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3It's N, R 1 It is CH3, R 2a It is Br, R 2b is I and Q is as defined in Table Z.

[0621] Table A-52 Provided are 38 compounds A-52.001 to A-52.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is I, R 2b is Br and Q is as defined in Table Z.

[0622] Table A-53 Provided are 38 compounds A-53.001 to A-53.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is CF3, R 2b is I and Q is as defined in Table Z.

[0623] Table A-54 Provided are 38 compounds A-54.001 to A-54.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is I, R 2b is CF3 and Q is as defined in Table Z.

[0624] Table A-55 Provided are 38 compounds A-55.001 to A-55.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is CF3, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0625] Table A-56 Provided are 38 compounds A-56.001 to A-56.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R2a It is Cl, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0626] Table A-57 Provided are 38 compounds A-57.001 to A-57.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Br, R 2b is SO2-CF3 and Q is as defined in Table Z.

[0627] Table A-58 Provided are 38 compounds A-58.001 to A-58.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Cl, R 2b is I and Q is as defined in Table Z.

[0628] Table A-59 Provided are 38 compounds A-59.001 to A-59.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is I, R 2b is Cl and Q is as defined in Table Z.

[0629] Table A-60 Provided are 38 compounds A-60.001 to A-60.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is Br, R 2b is I and Q is as defined in Table Z.

[0630] Table A-61 Provided are 38 compounds A-61.001 to A-61.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2aIt is I, R 2b is Br and Q is as defined in Table Z.

[0631] Table A-62 Provided are 38 compounds A-62.001 to A-62.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is CF3, R 2b is I and Q is as defined in Table Z.

[0632] Table A-63 Provided are 38 compounds A-63.001 to A-63.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 is CH2-cyclopropyl, R 2a It is I, R 2b is CF3 and Q is as defined in Table Z.

[0633] Table A-64 Provided are 38 compounds A-64.001 to A-64.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a is SO2-CHF2, R 2b is Cl and Q is as defined in Table Z.

[0634] Table A-65 Provided are 38 compounds A-65.001 to A-65.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a is SO2-CHF2, R 2b is Br and Q is as defined in Table Z.

[0635] Table A-66 Provided are 38 compounds A-66.001 to A-66.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a is SO2-CHF2, R 2bis Cl and Q is as defined in Table Z.

[0636] Table A-67 Provided are 38 compounds A-67.001 to A-67.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a is SO2-CHF2, R 2b is Br and Q is as defined in Table Z.

[0637] Table A-68 Provided are 38 compounds A-68.001 to A-68.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Cl, R 2b is SO2-CHF2 and Q is as defined in Table Z.

[0638] Table A-69 Provided are 38 compounds A-69.001 to A-69.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It's H, R 2a It is Br, R 2b is SO2-CHF2 and Q is as defined in Table Z.

[0639] Table A-70 Provided are 38 compounds A-70.001 to A-70.038 having formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Cl, R 2b is SO2-CHF2 and Q is as defined in Table Z.

[0640] Table A-71 Provided are 38 compounds A-71.001 to A-71.038 of formula IA, wherein A 1 It's N, A 2 It is CH, A 3 It's N, R 1 It is CH3, R 2a It is Br, R 2b is SO2-CHF2 and Q is as defined in Table Z.

[0641] Table Z : Definition of substituents of Q

[0642]

[0643]

[0644]

[0645]

[0646] It also provides access to certain intermediate compounds of formula II(i), III(i), IV(i), V(i), VII(i), XI(i) and XIV(i), or other intermediate compounds shown in Schemes 1 to 33, some of which are novel. For example:

[0647] - a compound of formula II(i), wherein (i) X 1 is Cl and A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71; or wherein (ii) X 1 is Br and A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71.

[0648]

[0649] - a compound of formula III(i), wherein (i) R 1 is H and Q is as defined in Table Z; or wherein (ii) R 1 It is CH 3 and Q is as defined in Table Z; or wherein (iii) R 1 It is CH 2 -cyclopropyl and Q is as defined in Table Z.

[0650]

[0651] - a compound of formula IV(i), wherein A 1 、A 2 、A3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71.

[0652]

[0653] - a compound of formula V(i), wherein (i) X 2 is Cl and Q is as defined in Table Z; or wherein (ii) X 2 is Br and Q is as defined in Table Z; or wherein (iii) X 2 is I and Q is as defined in Table Z.

[0654]

[0655] - a compound of formula VII(i), wherein Q is as defined in Table Z.

[0656]

[0657] - a compound of formula XI(i), wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71.

[0658]

[0659] - a compound of formula XIV(i), wherein A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71.

[0660]

[0661] -With XL-Q ac -a, XL-Q ac -b or XL-Q ac -c compounds:

[0662]

[0663] In each case, where applicable, A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71, R 1 is hydrogen or methyl, R 3 is methyl, Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl, and wherein Q c -COOH, Q c -COORa and Q c - Xa is as defined in Table Z1:

[0664] Table Z1: Q c -a, Q c -b and Q c Definition of substituents of -c

[0665]

[0666]

[0667] Particularly contemplated are compounds having the formula

[0668] -XL-Q ac1 -a, XL-Q ac1 -b and XL-Q ac1 -c:

[0669]

[0670] -XL-Q ac2 -a, XL-Q ac2 -b and XL-Q ac2 -c:

[0671]

[0672] -XL-Q ac3 -a, XL-Q ac3 -b and XL-Q ac3 -c:

[0673]

[0674] -XL-Q ac6 -a, XL-Q ac6 -b and XL-Q ac6 -c:

[0675]

[0676] In each case, where applicable, A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71, R 1 is hydrogen or methyl, R 3 is methyl, Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl.

[0677] -With XL-Q bc -a, XL-Q bc -b or XL-Q bc -c compounds:

[0678]

[0679] In each case, where applicable, A 1 、A 2 、A 3 、A 4 、A 5 、R 2a and R 2b is as defined in any one of Tables A-1 to A-71, R 1 is hydrogen or methyl, R 3 is methyl, Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl, and wherein Q c -COOH, Q c -COORa and Q c -Xa are Q as defined in Table Z1 above respectively c1 -a, Q c1 -b and Q c1 -c.

[0680] - Compounds of formula XLIIIa(i), XLIIIb(i), XLIIIb-1(i), XLIIId(i) or XLIIIe(i):

[0681]

[0682] Among them A 4 、A 5 and R 2ais as defined in any one of Tables A-1 to A-71, and wherein Gr is difluoromethyl or trifluoromethyl.

[0683] In a further aspect, the present invention accordingly provides compounds of formula II(i), III(i), IV(i), V(i), VII(i), XI(i), and XIV(i), wherein in each case, where applicable, A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a and R 2b and Q are as defined for formula (I) in the first aspect; and for formula II(i), X 1 is halogen, preferably chlorine or bromine.In addition, the corresponding embodiment shown in formula (I) also applies to the compound with formula II (i), III (i), IV (i), V (i), VII (i), XI (i) and XIV (i).

[0684] In a further aspect, the present invention accordingly provides a compound having the formula XL-Q ac -a, XL-Q ac -b, XL-Q ac -c, XL-Q bc -a, XL-Q bc -b and XL-Q bc -c compounds, wherein in each case, where applicable, A 1 、A 2 、A 3 、A 4 、A 5 、R 1 、R 2a and R 2b and Q are as defined for formula (I) in the first aspect; and then have the formula XL-Q ac -b, XL-Q ac -c, XL-Q bc -b and XL-Q bc -c, Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl. In addition, the corresponding embodiments shown in formula (I) are also applicable to compounds having formula XL-Q ac -a, XL-Q ac -b, XL-Q ac -c, XL-Q bc -a, XL-Q bc -b and XL-Q bc-c compound.

[0685] In a further aspect, the present invention accordingly provides compounds of formula XLIIIa(i), XLIIIb(i), XLIIIb-1(i), XLIIId(i) or XLIIIe(i), wherein in each case, where applicable, A 4 、A 5 and R 2a is as defined for formula (I) in the first aspect; Gr is difluoromethyl or trifluoromethyl. In addition, the corresponding embodiments shown for formula (I) also apply to compounds having formula XLIIIa (i), XLIIIb (i), XLIIIb-1 (i), XLIIId (i) or XLIIIe (i).

[0686] The compounds of formula (I) according to the invention are active ingredients of preventive and / or therapeutic value in the field of pest control. Even at low application rates, they have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish, and plants. These active ingredients according to the invention act on all or individual developmental stages of normally sensitive as well as 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., by destroying the pests immediately or only after a certain period of time (e.g., during molting), or indirectly, for example, by reducing egg laying and / or hatching rates.

[0687] Examples of the animal pests mentioned above are:

[0688] From the order Acarina, e.g.

[0689] Acalitus spp., Aculus spp., Acaricalus spp., Aceria spp., Acarus siro, Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia spp., Calipitrimerus spp., Chorioptes spp., Dermanyssus gallinae, Dermatophagoides spp., Eotetranychus spp., Eriophyes spp.), Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Olygonychus spp., Ornithodoros spp., Polyphagotarsone latus, Panonychus spp., Phyllocoptruta oleivora, Phytonemus spp., Polyphagotarsonemus spp., Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp.), Steneotarsonemus spp., Tarsonemus spp., and Tetranychus spp.;

[0690] From the order Phthirus, e.g.

[0691] Haematopinus spp., Linognathus spp., Pediculus spp., Pemphigus spp., and Phylloxera spp.;

[0692] From the order Coleoptera, e.g.

[0693] Agriotes spp., Amphimallon majale, Anomala orientalis, Anthonomus spp., Aphodius spp., Astylus atromaculatus, Ataenius spp., Atomaria linearis, Chaetocnema tibialis, Cerotomas spp., Conoderus spp., Cosmopolites spp., Cotinis nitida, Curculio spp., Cyclocephalas spp., Dermestes spp., Diabrotica spp.), Diloboderus abderus, Epilachna spp., Eremnus spp., Heteronychus arator, Hypothenemus hampei, Lagria vilosa, Leptinotarsa ​​decemlineata, Lissorhoptrus spp., Liogenys spp., Maecolaspis spp., Maladera castanea, Megascelis spp., Melighetes aeneus, Melolontha spp., Myochrousarmatus, Orycaephilus spp.), Otiorhynchus spp., Phyllophaga spp., Phlyctinus spp., Popillia spp., Psylliodes spp., Rhyssomatus aubtilis, Rhizopertha spp.), Scarabeidae, Sitophilus spp., Sitotroga spp., Somaticus spp., Sternechus subsignatus, Tenebrio spp., Tribolium spp., and Trogoderma spp.;

[0694] From the order Diptera, e.g.

[0695] Aedes spp., Anopheles spp., Antherigonas occata., Bactrocea oleae, Bibio hortulanus, Bradysia spp., Calliphora erythrocephala, Ceratitis spp., Chrysomyia spp., Culex spp., Cuterebra spp., Dacus spp., Delia spp., Drosophila melanogaster, Fannia spp., Gastrophilus spp., Geomyza tripunctata), Glossina spp., Hypoderma spp., Hyppobosca spp., Liriomyza spp., Lucilia spp., Melanagromyza spp., Musca spp., Oestrus spp., Orseolia spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Rhagoletis spp., Riveria quadrifasciata, Scatella spp., Sciara spp., Stomoxys spp.), Tabanus spp., Tannia spp., and Tipula spp.;

[0696] From the order Hemiptera, e.g.

[0697] Acanthocoris scabrator, Acrosternum spp., Adelphocoris lineolatus, Aleurodes spp., Amblypelta nitida, Bathycoelia thalassina, Acanthocoris spp., Clavigrallatomentosicollis, Creontiades spp., Dichelops furcatus, Edessa spp., Euchistus spp., Eurydema pulchrum, Acrosternum spp., Brown-winged stink bug, Horcias nobilellus), rice stink bug species, grass stink bug species, tropical scale bug species, cabbage stink bug (Murgantia histrionic), new long-margin stink bug species, tobacco blind bug (Nesidiocoris tenuis), green stink bug species, Nysius simulans, island stink bug, skin stink bug species, wall stink bug species, red assassin bug species, cocoa stink bug, chestnut stink bug (Scaptocoris castanea), black stink bug species (Scotinophara spp.), Thyanta species, trypanosoma species, cassava web stink bug (Vatiga illudens);

[0698] Acyrthosium pisum, Adalges species, Agalliano ensigera, Targuiron vein psyllid, Aleurodicus species, Aleurocanthus species, sugarcane hole whitefly, Aleurothrixus floccosus, Aleyrodes brassicae, Amarasca biguttula, lemon leafhopper, Nephrodisiac species, Aphididae, Aphid species, Aspidiotus species, eggplant groove aphid, Bactericera cockerelli, Aleurodicus species, Brachycaudus species, cabbage aphid, Cavariella species, Cavariella aegopodii Scop.), wax scale species, black-brown round shield scale, orange-brown round shield scale, leafhopper species, large white leafhopper (Cofana spectra), Cryptophyllum species, leafhopper species, brown soft scale, corn yellow-winged leafhopper, naked whitefly species, citrus psyllid, wheat aphid, western round tail aphid species, small green leafhopper species, apple aphid, grape leafhopper species, Gascardia species, red eucalyptus psyllid (Glycaspis brimblecombei), cabbage constrictor aphid (Hyadaphis pseudobrassicae), large tail aphid species (Hyalopterus spp.), Hyperomyzus pallidus, lemon green leafhopper (Idioscopus clypealis), African leafhopper, Laodelphax striatellus species, water-hard scale, oyster shield scale species, radish aphid (Lopaphis erysimi), Lyogenys maidis, Aphid species, Cicada species, Metcalfa pruinosa, Aphid, Cicada, Aphid species, Neotoxoptera sp, Blacktail leafhopper species, Nilaparvata spp.), pear green aphid, Odonaspis ruthae, sugarcane cotton aphid, bayberry whitefly, Caulis psyllid, Shield scale species, Gall aphid species, Corn waxhopper, Flat-horned planthopper species, Hob wart aphid, Phylloxera species, Mosella species, Mulberry white scale species, Mealybug species, Cotton blind bug (Pseudatomoscelis seriatus), Psyllid species, Cotton scale (Pulvinaria aethiopica), Toothed scale species, Quesada gigas, Electric leafhopper (Recilia dorsalis), Constrictor aphid species, Black helmet scale species, Banded leafhopper species, Aphid species, Sitobion spp., White-backed planthopper, Spissistilus triangularis festinus), Tarophagus Proserpina, aphid species, whitefly species, Tridiscus sporoboli, Trionymus spp., African psyllids, scaly scale, flame leafhopper, and Zyginidia scutellaris.

[0699] From the order Hymenoptera, e.g.

[0700] Acromyrmex, Arge spp., Atta spp., Cephus spp., Diprion spp., Diprionidae, Gilpinia polytoma, Hoplocampa spp., Lasius spp., Monomorium pharaonis, Neodiprions spp., Pogonomyrmex spp., imported fire ants, Solenopsis spp., and Vespa spp.

[0701] From the order Isoptera, e.g.

[0702] Coptotermes spp., Corniternes cumulans, Incisitermes spp., Macrotermes spp., Mastotermes spp., Microtermes spp., Reticulitermes spp.; Tropical fire ants (Solenopsis geminate)

[0703] From the order Lepidoptera, for example,

[0704] Species of the genus Long-winged Roller Moth, species of the genus Brown-banded Roller Moth, species of the genus Clearwing Moth, species of the genus Noctua, cotton leafworm, species of the genus Amylois, species of the genus Mucuna, species of the genus Yellow Roller Moth, species of the genus Argyresthia, species of the genus Banded Roller Moth, species of the genus Spodoptera, species of cotton miner, corn armyworm, powdery moth, peach fruit moth, species of the genus Graminus, species of the genus Color Roller Moth, Chrysoteuchia topiaria, grape fruit moth, species of the genus Leaf Roller, species of the genus Cloud Roller, species of the genus Striped Roller Moth, species of the genus Sheath Moth, Colias lesbia, Cosmophila flava), grass borer species, cabbage borer, apple fritter moth, boxwood moth, fritter moth species, boxwood silk borer, stem borer species, Sudan cotton bollworm, Spodoptera species, South American corn seedling borer (Elasmopalpus lignosellus), sweet potato stem borer, mealybug species, leaf fritter moth species (Epinotia spp.), salt marsh moth (Etiella acrea), bean pod borer (Etiella zinckinella), flower fritter moth species, ring needle fritter moth, yellow tussock moth species, root cutter species, Feltia jaculiferia, small borer species (Grapholita spp.), clouded broad-winged fritter moth, Heliothis species, cabbage borer, leaf cutter species (Herpetogramma spp.), American white moth, tomato codling moth, Lasmopalpus lignosellus, spiral leafminer, leafminer species, grape flower moth, Loxostege bifidalis, tussock moth species, miner species, Malacosoma spp., cabbage armyworm, tobacco hornworm, Mythimna spp., noctuid species, fall moth species, Orniodes indica, European corn borer, super-small tortoise species, brown tortoise species, small-eyed moth, stem borer, red bell moth, coffee leafminer, one-star armyworm, potato moth, cabbage butterfly, Pieris species, diamondback moth, white nest moth species, leaf moth species, mint ash moth (Rachiplusia nu), western bean groundworm (Richia albicosta), Scirpophaga spp., Spodoptera spp., Cyprinodon spp., Spodoptera spp., Cotton Leaffolder, Cnaphalocrocis spp., Heteroptera spp., Cyprinodon spp., Trichoplusia spp., Tomato Leafminer, and Lycosa spp.;

[0705] From the order Mallophaga, for example,

[0706] Damalina spp. and Trichodectes spp.;

[0707] From the order Orthoptera, for example,

[0708] Blatta spp., Blattella spp., Gryllotalpa spp., Leucophaea maderae, Locusta spp., Neocurtilla hexadactyla, Periplaneta spp., Scapteriscus spp., and Schistocerca spp.;

[0709] From the order Psocoptera, for example,

[0710] Liposcelis spp.;

[0711] From the order Siphonaptera, for example,

[0712] Ceratophyllus spp., Ctenocephalides spp., and Xenopsylla cheopis;

[0713] From the order Thysanoptera, for example,

[0714] Calliothrips phaseoli, Frankliniella spp., Heliothrips spp., Hercinothrips spp., Parthenothrips spp., Scirtothrips aurantii, Sericothrips variabilis, Taeniothrips spp., Thrips spp.

[0715] From the order of the Thysanura, for example, Lepisma saccharina.

[0716] In a further aspect, the present invention may also relate to a method of controlling damage to plants and parts thereof by plant-parasitic nematodes (endoparasitic nematodes, semi-endoparasitic nematodes and ectoparasitic nematodes), in particular the following plant-parasitic nematodes, such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other species of Meloidogyne; cyst-forming nematodes, Globodera rostochiensis and other species of Globodera; cereal cyst nematodes, soybean cyst nematodes, Heterodera avenae, soybean cyst nematodes, Heterodera schachtii and Heterodera exigua. schachtii), Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Belonolaimus longicaudatus, and other Belonolaimus species; Pine nematodes, Bursaphelenchus xylophilus, and other Bursaphelenchus species; Ring nematodes, nematodes), Criconema species, Criconemella species, Criconemoides species, Mesocriconema species; Stemand bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci, and other Ditylenchus species; Awl nematodes, Dolichodorus species;Spiral nematodes, Heliocotylenchus multicinctus, and other species of the genus Helicotylenchus; Sheath and sheathoid nematodes, species of the genera Hemicycliophora, and species of the genera Hemicriconemoides; Hirshmanniella species; Lancenematodes, species of the genus Hoploaimus; False rootknot nematodes, species of the genus Nacobbus; Needle nematodes, Longidoruse longatus, and other species of the genus Longidorus; Pin nematodes, species of the genus Pratylenchus; Lesion nematodes. nematodes), Pratylenchus negletus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi, and other Pratylenchus species; Burrowing nematodes, Radopholus similis, and other Radopholus species; Reniform nematodes, Rotylenchus robustus, Rotylenchus reniformis, and other Rotylenchus species; Scutellonema species; Stubby root nematodes, Trichodorus primitivus) and other Trichodorus species, Paratrichodorus species; Stunt nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius, and other Tylenchorhynchus species;Citrus nematodes, Tylenchulus species; Dagger nematodes, Xiphinema species; and other plant-parasitic nematode species, such as Subanguina spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp., and Quinisulcius spp.

[0717] The compounds of the present invention may also have activity against mollusks. Examples include, for example, the Pomacea family; the Arion family (A. ater, A. circumscriptus, A. hortensis, A. rufus); the Bradybaenidae family (Bradybaenidae); fruticum); Cepaea (Cepaea hortensis, C. nemoralis); Ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (Galba trunculata); Helicelia (H. itala, H. obvia); Helicigona (Helicidae). arbustorum); Helicodiscus; Helix (H. aperta); Limax (L. cinereoniger, L. flavus, L. marginatus, L. maximus, L. tenellus); Lymnaea; Milax (Slugidae) (M. gagates, M. marginatus, M. sowerbyi); Opeas; Pomacea (P. canaticulata); Vallonia and Zanitoides.

[0718] The active ingredients according to the invention can be used for controlling (i.e. suppressing or destroying) pests of the above-mentioned type, which occur in particular on plants, especially on useful and ornamental plants in agriculture, in horticulture and in forestry, or on organs of these plants, such as fruits, flowers, leaves, stems, tubers or roots, and in some cases even plant organs formed at a later point in time still remain protected against these pests.

[0719] In particular, suitable target crops are cereals, such as wheat, barley, rye, oats, rice, corn or sorghum; beets, such as sugar beets or fodder beets; fruits, such as pome, stone or soft fruit, such as apples, pears, plums, peaches, apricots, cherries or berries, such as strawberries, raspberries or blackberries; leguminous crops, such as beans, lentils, peas or soybeans; oilseed crops, such as rapeseed, mustard, poppy, olives, sunflower, coconut, castor, cocoa beans, or peanuts; cucurbits such as pumpkin, cucumber, or melon; fiber plants such as cotton, flax, hemp, or jute; citrus fruits such as oranges, lemons, grapefruits, or tangerines; vegetables such as spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, or bell peppers; lauraceae such as avocado, cinnamon, or camphor; and also tobacco, nuts, coffee, eggplant, sugarcane, tea, pepper, grapevines, hops, plantago, and latex plants.

[0720] The compositions and / or methods of the present invention may also be used on any ornamental and / or vegetable crop, including flowers, shrubs, broadleaf trees, and evergreen plants.

[0721] For example, the present invention can be used with any of the following ornamental plant species: Ageratum species, Alonsoa species, Anemone species, Anisodontea capsenisis, Anthemis species, Antirrhinum species, Aster species, Begonia species (e.g., Rieger Begonia, Begonia sempervirens, Begonia tubéreux), Bougainvillea species, Brachycome species, Brassica species (ornamentals), Calceolaria species, Capsicum, Catharanthus roseus, Canna species, Centaurea species, Chrysanthemum species, Cineraria species (C. maritime), Coreopsis species, Crassula coccinea, Cupheaignea, Dahlia species, Delphinium species, Dicentra species, Dorotheantus species. spp.), Lisianthus, Forsythia species, Fuchsia species, Geranium gnaphalium, Gerbera species, Globe amaranth, Heliotrope species, Sunflower species, Hibiscus species, Hydrangea species, Hydrangea species, Rhododendron, Impatiens species (African balsam), Amaranth species (Iresines spp.), Kalanchoe species, Lantana, March flower, Lion's ear, Lilium species, Mesembryanthemum species, Physalis species, Monarda species, Dracaena species, Marigold species, Dianthus species (carnation), Canna species, Oxalis species, Daisy species, Pelargonium species (Shieldleaf Pelargonium, Horseshoe Pelargonium), Viola species (Viola tricolor), Petunia species, Phlox species, Plecthranthus species spp.), poinsettia species, creeper species (five-leaf creeper, Parthenocissus quinquefolia), primula species, ranunculus species, azalea species, Rosa species (roses), rudbeckia species, African violet species, salvia species, Scaevola aemola, Schizanthus wisetonensis, sedum species, Solanum species, Surfinia petunia species (Surfinia spp.), marigold species, Nicotiana species, verbena species, zinnia species, and other bedding plants.

[0722] For example, the present invention can be used with any of the following vegetable species: Allium species (garlic, onion, shallot (A. oschaninii), leek, shallot, scallion), beaked parsley, celery, asparagus, beets, Brassica species (cabbage, Chinese cabbage, turnip), peppers, chickpeas, endive, chicory species (radicchio, endive), watermelon, Cucurbita species (cucumber, cantaloupe), Cucurbita species (zucchini, Indian pumpkin), Cynara species (artichoke, cardoon), carrot, fennel, Hypericum species, lettuce, Lycopersicon species (tomato, cherry tomato), mint species, basil, parsley, Phaseolus species (bean, pea), pea, radish, edible rhubarb, Rosemary species, sage species, black salsify, eggplant, spinach, Valerian species (V. eriocarpa), and broad beans.

[0723] Preferred ornamental plant species include African violet, begonia, dahlia, gerbera, hydrangea, verbena, rose, kalanchoe, poinsettia, aster, cornflower, coreopsis, delphinium, monarda, phlox, rudbeckia, sedum, petunia, violet, impatiens, geranium, chrysanthemum, ranunculus, fuchsia, salvia, hydrangea, rosemary, sage, St. John's wort, mint, sweet pepper, tomato, and cucumber.

[0724] The active ingredients according to the invention are particularly suitable for controlling the bean aphid, cucumber leaf beetle, tobacco budworm, peach aphid, diamondback moth and sea moth on cotton, vegetables, corn, rice and soybean crops. The active ingredients according to the invention are also particularly suitable for controlling the cabbage looper (preferably on vegetables), the codling moth (preferably on apples), the green leafhopper (preferably on vegetables, in vineyards), the potato beetle (preferably on potatoes) and the striped stem borer (preferably on rice).

[0725] Compounds of formula (I) are particularly suitable for controlling:

[0726] pests of the order Hemiptera, for example one or more of the following species: Bemisia tabaci, Bean aphid, Green peach aphid, Rhopalosiphum padi, Brown rice hopper (Nilaparvata lugens), and Euschistus heros (preferably on vegetables, soybeans, and sugarcane);

[0727] Pests of the order Lepidoptera, for example one or more of the following species: Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Codling moth, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includesns, and Tomato leafminer (preferably on vegetables and corn);

[0728] pests of the order Thysanoptera, such as the family Thripidae, for example one or more of Thrips tabaci and Thrips occidentalis (preferably on vegetables); and

[0729] • Soil pests (e.g. of the order Coleoptera), for example species of Diabrotica spp., species of the genus Leptinotarsa ​​and potato beetles (preferably on vegetables and maize).

[0730] The term "crops" is to be understood as also including crop plants which have been transformed by the use of recombinant DNA techniques such that they are able to synthesize one or more selectively acting toxins, such as are known, for example, from toxigenic bacteria, in particular those of the genus Bacillus.

[0731] Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, for example, insecticidal proteins from Bacillus cereus or Bacillus japonicus; or insecticidal proteins from Bacillus thuringiensis, such as delta-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1, or Cry9C, or vegetative insecticidal proteins (Vips), for example Vip1, Vip2, Vip3, or Vip3A; or insecticidal proteins of nematode-parasitic bacteria, for example, Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophila, or Xenorhabdus spp. nematophilus); toxins produced by animals, such as scorpion toxins, spider toxins, bee toxins and other insect-specific neurotoxins; toxins produced by fungi, such as streptomycin, plant lectins, such as pea lectin, barley lectin or snowdrop lectin; agglutinin; protease inhibitors, such as trypsin inhibitors, serine protease inhibitors, potato glycoproteins, cysteine ​​protease inhibitors, papain inhibitors; ribosome inactivating proteins (RIPs), such as ricin, maize-RIP, abrin, luffain, saporin or bryophyllin; steroid metabolizing enzymes, such as 3-hydroxysteroid oxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidase, ecdysteroid inhibitors, HMG-COA-reductase, ion channel blockers, such as sodium channel or calcium channel blockers, juvenile hormone esterase, diuretic hormone receptor, stilbene synthase, bibenzyl synthase, chitinase and glucanase.

[0732] In the context of the present invention, δ-endotoxins, such as Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vips), such as Vip1, Vip2, Vip3 or Vip3A, should be understood to include, but are not limited to, mixed toxins, truncated toxins and modified toxins. Mixed toxins are recombinantly produced by combining the different domains of those proteins (see, for example, WO 02 / 15701). Truncated toxins, such as truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of a naturally occurring toxin are replaced. In such amino acid replacements, it is preferred that a non-naturally occurring protease recognition sequence be inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G recognition sequence is inserted into the Cry3A toxin (see WO 03 / 018810).

[0733] Examples of such toxins or transgenic plants capable of synthesizing such toxins are disclosed in, for example, EP-A-0 374 753, WO 93 / 07278, WO 95 / 34656, EP-A-0 427 529, EP-A-451 878 and WO 03 / 052073.

[0734] Methods for preparing such transgenic plants are generally known to those skilled in the art and are described, for example, in the publications mentioned above. CryI-type deoxyribonucleic acids and their preparation are known, for example, from WO 95 / 34656, EP-A-0 367474, EP-A-0 401 979 and WO 90 / 13651.

[0735] The toxins included in the transgenic plants render the plants tolerant to harmful insects. Such insects can be found in any insect taxonomic group, but are particularly common among beetles (Coleoptera), two-winged insects (Diptera), and moths (Lepidoptera).

[0736] Transgenic plants comprising one or more genes encoding insecticide resistance and expressing one or more toxins are known and some of them are commercially available. Examples of such plants are: (corn variety expressing Cry1Ab toxin); YieldGard (corn variety expressing Cry3Bb1 toxin); YieldGard (corn varieties expressing Cry1Ab and Cry3Bb1 toxins); (corn variety expressing Cry9C toxin); Herculex (a maize variety expressing the Cry1Fa2 toxin and the enzyme phosphinothricin N-acetyltransferase (PAT) that confers tolerance to the herbicide glufosinate ammonium); NuCOTN (cotton variety expressing Cry1Ac toxin); Bollgard (cotton variety expressing Cry1Ac toxin); Bollgard (cotton varieties expressing Cry1Ac and Cry2Ab toxins); (cotton variety expressing Vip3A and Cry1Ab toxins); (potato variety expressing Cry3A toxin); GT Advantage (GA21 glyphosate tolerance trait), CB Advantage (Bt11 corn borer (CB) trait) and

[0737] Further examples of such genetically modified crops are:

[0738] 1. Bt11 corn, from Syngenta Seeds SAS, Chemin de Hobit 27, F-31 790 St. Sauveur, France, registration number C / FR / 96 / 05 / 10. This genetically modified maize plant is resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia inermis) by transgenic expression of a truncated Cry1Ab toxin. Bt11 corn also transgenicly expresses the PAT enzyme to confer tolerance to the herbicide glufosinate ammonium.

[0739] 2. Bt176 maize, from Syngenta Seeds, 27 Rue de Hobbitt, F-31 790 Saint-Sauveur, France, registration number C / FR / 96 / 05 / 10. This genetically modified maize strain is resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia inermis) by transgenic expression of the toxin Cry1Ab. Bt176 maize also transgenicly expresses the enzyme PAT to confer tolerance to the herbicide glufosinate ammonium.

[0740] 3. MIR604 maize, from Syngenta Seeds, 27 Rue de Hobbit, F-31 790 Saint-Sauveur, France, registration number C / FR / 96 / 05 / 10. This maize plant is rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a cathepsin G protease recognition sequence. The preparation of this transgenic maize plant is described in WO 03 / 018810.

[0741] 4. MON 863 maize, from Monsanto Europe SA, 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C / DE / 02 / 9. MON 863 expresses the Cry3Bb1 toxin and confers resistance to certain coleopteran insects.

[0742] 5. IPC 531 cotton, from Monsanto Europe SA, 270-272 Avenue Tervuren, B-1150 Brussels, Belgium, registration number C / ES / 96 / 02.

[0743] 6.1507 maize, from Pioneer Overseas Corporation, Avenue Tedesco, 7B-1160 Brussels, Belgium, registration number C / NL / 00 / 10. Genetically modified maize expressing the protein Cry1F for resistance to certain lepidopteran insects and the protein PAT for tolerance to the herbicide glufosinate-ammonium.

[0744] 7. NK603×MON 810 corn, from Monsanto Europe, 270-272 Boulevard Tervuren, B-1150 Brussels, Belgium, registration number C / GB / 02 / M3 / 03. This corn is a conventionally bred hybrid corn variety, produced by crossing the genetically modified varieties NK603 and MON 810. NK603×MON 810 corn transgenically expresses the protein CP4 EPSPS obtained from the Agrobacterium strain CP4, rendering it herbicide tolerant. (contains glyphosate), and also Cry1Ab toxin from Bacillus thuringiensis subsp. kurstakia, which confers resistance to certain lepidopteran insects, including the European corn borer.

[0745] Transgenic crops of insect-resistant plants are also described in the BATS (Zentrum für Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) report 2003 ( http: / / bats.ch ).

[0746] The term "crop" should be understood to also include crop plants that have been transformed using recombinant DNA technology to enable them to synthesize selectively acting antipathogenic substances, such as, for example, so-called "pathogenesis-related proteins" (PRPs, see, for example, EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesizing such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95 / 33818, and EP-A-0 353 191. Methods for producing such transgenic plants are generally known to those skilled in the art and are described, for example, in the publications mentioned above.

[0747] Crops can also be modified to increase resistance to fungal (eg, Fusarium, Anthracnose, or Phytophthora), bacterial (eg, Pseudomonas), or viral (eg, Potato Leaf Roll Virus, Tomato Spotted Wilt Virus, Cucumber Mosaic Virus) pathogens.

[0748] Crops also include those with increased resistance to nematodes, such as Heterodera glycines.

[0749] Crops with tolerance to abiotic stress include those with increased tolerance to drought, high salinity, high temperature, cold, frost or light radiation, for example, through expression of NF-YB or other proteins known in the art.

[0750] Antipathogenic substances that can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers of sodium channels and calcium channels, for example viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; so-called "pathogenesis-related proteins" (PRPs; see, for example, EP-A-0 392 225); antipathogenic substances produced by microorganisms, such as peptide antibiotics or heterocyclic antibiotics (see, for example, WO 95 / 33818) or proteins or polypeptide factors which are involved in plant pathogen defense (so-called "plant disease resistance genes", as described in WO 03 / 000906).

[0751] Other areas of use of the compositions according to the invention are the protection of stored goods and storage rooms and the protection of raw materials such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, in particular the protection of humans, domestic animals and productive livestock from pests of the types mentioned.

[0752] 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 parasites on the body of an animal. The present invention further provides a compound of the first aspect for use in preventing and / or treating a disease transmitted by parasites on the body.

[0753] The present invention provides the use of the compound of the first aspect for the manufacture of a medicament for controlling parasites in or on the body of an animal. The present invention further provides the use of the compound of the first aspect for the manufacture of a medicament for controlling parasites on the body of an animal. The present invention further provides the use of the compound of the first aspect for the manufacture of a medicament for preventing and / or treating diseases transmitted by parasites on the body.

[0754] The present invention provides a use of the compound of the first aspect in controlling parasites in or on the body of an animal. The present invention further provides a use of the compound of the first aspect in controlling parasites on the body of an animal.

[0755] When used in the context of parasites in or on animals, the term "control" means reducing the number of pests or parasites, eliminating pests or parasites and / or preventing further infestation by pests or parasites.

[0756] When used in the context of parasites in or on animals, the term "treat" means to inhibit, slow, halt or reverse the progression or severity of existing symptoms or disease.

[0757] The term "prevent" when used in the context of parasites in or on animals means avoiding the development of symptoms or disease in the animal.

[0758] When used in the context of parasites in or on animals, the term "animal" may refer to both mammals and non-mammals, such as birds or fish. In the case of a mammal, it can be a human or a non-human mammal. Non-human mammals include, but are not limited to, livestock animals and pets. Livestock animals include, but are not limited to, cattle, camels, pigs, sheep, goats, and horses. Pets include, but are not limited to, dogs, cats, and rabbits.

[0759] A "parasite" is a harmful organism that lives in or on a host animal and benefits by obtaining nutrients at the host animal's expense. An "endoparasite" is a parasite that lives inside the host animal. An "ectoparasite" is a parasite that lives on the host animal's surface. ectoparasites include, but are not limited to, ticks, insects, and crustaceans (e.g., sea lice). The subclass Ixodida (or Acarina) includes ticks and mites. Ticks include, but are not limited to, members of the genera Rhipicaphalus, such as Rhipicaphalus microplus (Boophilus microplus) and Rhipicephalus sanguineus; Amblyomrna; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros. Mites include, but are not limited to, members of the genera: Dermestes, such as P. calves; P. spp., such as P. goat; Cheyletus; Dermatophagida; such as Dermatophagida gallinae; Ortnithonyssus; Demodex, such as Demodex canis; Sarcoptes, such as Sarcoptes hominis; and Psoralea. Insects include, but are not limited to, members of the orders: Siphonaptera, Diptera, Trichoderma, Lepidoptera, Coleoptera, and Homoptera. Members of Siphonaptera include, but are not limited to, Ctenocephatides cati and Ctenocephatides canis. Members of Diptera include, but are not limited to, species of the genus Musca; skin flies, such as horse flies and sheep flies; biting flies; gadflies, such as species of the genus Tabunus and species of the genus Tabunus; black horn flies, such as blood flies; biting flies; green flies; midges; and mosquitoes. Members of the order Trichoderma include, but are not limited to, blood-sucking lice and chewing lice, such as the wool louse (Bovicola Ovis) and the bovine feather louse.

[0760] The term "effective amount," when used in the context of parasites in or on an animal, refers to the amount or dosage of a compound of the invention, or a salt thereof, which, when administered to an animal in a single dose or multiple doses, provides the desired effect in or on the animal. An effective amount can be readily determined by the attending diagnostician (being one skilled in the art) by using known techniques and by observing results obtained in similar situations. In determining an effective amount, the attending diagnostician considers a number of factors, including, but not limited to: the species of mammal; its size, age, and general health; the parasite to be controlled and the degree of infestation; the specific disease or condition involved; the extent or severity of the disease or condition; the individual's response; the specific compound to be administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; the use of concomitant medications; and other relevant circumstances.

[0761] The compounds of the present invention can be applied to animals by any route with the desired effect, including but not limited to topical, oral, parenteral and subcutaneous. Topical application is preferred. Preparations suitable for topical application include, for example, solutions, emulsions and suspensions, and can be poured, dotted, sprayed, sprayed, or immersed in the form of a spray race. In an alternative, the compounds of the present invention can be applied by ear tags or collars.

[0762] The salt forms of the compounds of the present invention include both pharmaceutically acceptable salts and veterinarily acceptable salts, which may be different from agrochemically acceptable salts. Pharmaceutically and veterinarily acceptable salts and common methods for preparing them are well known in the art. See, for example, Gould, PL, "Salt selection for basic drugs", International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities", Organic Process Research and Development, 4:427-435 (2000); and Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 66:1-19, (1977). Those skilled in the art of synthesis will appreciate that, using technology and conditions well-known to those of ordinary skill in the art, compound of the present invention easily changes into salt, and can be used as salt (such as hydrochloride) and separate.In addition, those skilled in the art of synthesis will appreciate that, compound of the present invention easily changes into corresponding free alkali, and can be used as corresponding free alkali and separate from corresponding salt.

[0763] The present invention also provides methods for controlling pests (such as mosquitoes and other disease vectors; see also http: / / www.who.int / malaria / vector_control / irs / en / ). In one embodiment, the method for controlling pests comprises applying the composition of the present invention to the target pests, their locus, or a surface or substrate by painting, rolling, spraying, coating, or dipping. By way of example, IRS (indoor residual spraying) application to surfaces (such as walls, ceilings, or floor surfaces) is contemplated by the methods of the present invention. In another embodiment, application of such compositions to substrates such as nonwoven or fabric materials in the form of (or for use in the manufacture of) netting, coverings, bedding, curtains, and tents is contemplated.

[0764] In one embodiment, the method for controlling this type of harmful organism comprises applying the composition of the present invention of pest-killing effective dose to target harmful organism, their place or surface or substrate, so that on this surface or substrate, effective pest-killing activity of retention is provided.Such application can be carried out by brushing, rolling, spraying, coating or dipping pest-killing composition of the present invention.By way of example, the IRS application of surface (such as wall, ceiling or floor surface) has been considered by method of the present invention, so that effective pest-killing activity of retention is provided on this surface.In another embodiment, it has been considered to use this type of composition for the residual control of the harmful organism on substrate, and this substrate is the fabric material of the form (or can be used in the manufacture of these articles) such as being in netting, covering, bedding, curtain and tent.

[0765] The substrate to be treated (including nonwovens, fabrics or nettings) can be made of natural fibers such as cotton, raffia, jute, flax, sisal, burlap or wool, or synthetic fibers such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. Polyester is particularly suitable. Methods for textile treatment are known, for example WO 2008 / 151984, WO 2003 / 034823, US 5631072, WO 2005 / 64072, WO 2006 / 128870, EP 1724392, WO 2005113886 or WO 2007 / 090739.

[0766] A further area of ​​use of the compositions according to the invention is in the field of tree injection / trunk treatment of all ornamental trees as well as all kinds of fruit and nut trees.

[0767] In the field of tree injection / trunk treatment, the compounds according to the invention are particularly suitable for combating wood-boring insects from the orders Lepidoptera and from the orders Coleoptera mentioned above, in particular against the wood-boring insects listed in the following Tables A and B:

[0768] Table A. Examples of economically important exotic wood-boring insects.

[0769]

[0770] Table B. Examples of economically important native wood-boring insects.

[0771]

[0772]

[0773]

[0774] The present invention can also be used to control any insect pest that may be present in turfgrass, including, for example, beetles, caterpillars, fire ants, ground pearls, millipedes, woodlice, mites, mole crickets, scale insects, mealybugs, ticks, cicadas, southern wheat stink bugs, and white grubs. The present invention can be used to control insect pests at all stages of their life cycle, including eggs, larvae, nymphs, and adults.

[0775] In particular, the present invention can be used to control insect pests that feed on the roots of turfgrasses, including grubs (such as Cyclocephala spp. (e.g., the marked beetle, C. lurida), Rhizotrogus spp. (e.g., the European beetle, R. majalis), Cotinus spp. (e.g., the Green June beetle, C. nitida), Popillia spp. (e.g., the Japanese beetle, P. japonica), Phyllophaga spp. (e.g., the May / June beetle), Ataenius spp. (e.g., the Black turfgrass ataenius, A. spretulus), Maladera spp. (e.g., the Asiatic garden beetle, A. beetle, M. castanea, and Tomarus genera), ground pearls (Margarodes spp.), mole crickets (tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana), and leatherjackets (European crane fly, Tipula spp.).

[0776] The present invention can also be used to control insect pests of turfgrass in thatched homes, including armyworms (such as the fall armyworm Spodoptera frugiperda, and the common armyworm Pseudaletia unipuncta), cutworms, weevils (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and grass borers (such as Crambus spp. and the tropical grass borer, Herpetogramma phaeopteralis).

[0777] The present invention can also be used to control insect pests in turfgrasses that live above ground and feed on turfgrass leaves, including wheat stink bugs (such as the southern wheat stink bug, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), Grass mealybug (Antonina graminis), Propsapia bicincta, leafhoppers, cutworms (Noctuidae), and Schizaphis graminis.

[0778] The present invention can also be used to control other pests in turfgrass, such as introduced fire ants (Solenopsis invicta) that create nests in lawns.

[0779] In the hygiene sector, the compositions according to the invention are effective against epiparasites such as hard ticks, soft ticks, scabies, autumn mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.

[0780] Examples of such parasites are:

[0781] From the order of the Pediculus: Haemaphysalis spp., Linognathus spp., Pediculus hominis spp., and Phtirus spp., Phitirus spp.

[0782] From the order Trichophagus: Felicola species, Felicola species, Felicola species, Felicola species, Werneckiella spp., Lepikentron spp., Felicola species, Felicola species, and Felicola species.

[0783] Of the order Diptera and the suborders Nematocerina and Brachycerina, for example, Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp. spp.), Braula spp., Musca spp., Hydrotaea spp., Biting flies, Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp.) and Melophagus spp.

[0784] From the order of the Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllum spp.

[0785] From the order of the Heteropterida, for example, Cimex spp., Triatominae spp., Panstrongylus spp.

[0786] From the order of the Blattarida, for example, Blatta orientalis, Periplaneta americana, Blattelagermanica and Supella spp.

[0787] Subclass Acaria (family Acarida) and orders Meta-stigmata and Meso-stigmata, for example, Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyommas spp., Boophilus spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Rhipicephalus spp., Dermanyssus spp., Raillietia spp., Pneumonyssus spp. spp.), Sternostoma spp., and Varroa spp.

[0788] From the orders Actinedida (Prostigmata) and Acaridida (Astigmata), for example, Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp. spp.), Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcooptes spp., Notoedress spp., Knemidocoptes spp., Cytodites spp., and Laminosioptes spp.

[0789] The compositions according to the invention are also suitable for protecting materials in the case of, for example, wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and construction from infestation by insects.

[0790] The compositions according to the invention can be used, for example, to combat the following pests: beetles, such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale), Minthes rugicollis, Xyleborus spec., Tryptodendron spec., Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec., and Dinoderus minutus, as well as Hymenoptera, such as Sirex juvencus, Urocerus gigas, Urocerus gigas taignus, and Urocerus augu, and termites, such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes spp. indicola), Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis, and Coptotermes formosanus, as well as borers such as Silverfish (Lepisma saccharina).

[0791] The compounds of formula I and I'a or their salts are particularly suitable for controlling one or more pests selected from the following families: Noctuidae, Diamondback Moths, Chrysomelidae, Thripidae, Pentatomidae, Tomentosaidae, Delphacidae, Aphididae, Noctuidae, Pyralidae, Meloidogyneidae and Heteroderae. In a preferred embodiment of each aspect, compound TX (wherein the abbreviation "TX" refers to a compound selected from the compounds defined in Tables A-1 to A-71 and compounds P1 to P85 of Table P (i.e., compounds P1 to P5, P6 to P17, P18 to P41 and P42 to P85)) controls one or more pests selected from the following families: Noctuidae, Diamondback Moths, Chrysomelidae, Thripidae, Pentatomidae, Tomentosaidae, Delphacidae, Aphididae, Noctuidae, Pyralidae, Meloidogyneidae and Heteroderae.

[0792] The compounds of formula I and I'a or their salts are particularly suitable for controlling one or more pests selected from the group consisting of Spodoptera spp, Plutella spp, Frankliniella spp, Thrips spp, Euschistus spp, Cydia spp, Nilaparvata spp, Myzus spp, Aphis spp, Diabrotica spp, Rhopalosiphum spp, Pseudoplusia spp and Chilo spp. In a preferred embodiment of each aspect, compound TX (wherein the abbreviation "TX" refers to "a compound selected from the compounds defined in Tables A-1 to A-71 and compounds P1 to P85 of Table P (i.e., compounds P1 to P5, P6 to P17, P18 to P41 and P42 to P85)) controls one or more pests selected from the following genera: Spodoptera species, Diamondback moth species, Flower Thrips species, Thrips species, American stink bug species, Codling moth species, Nilaparvata species, Tufts aphid species, Aphis species, Rootworm species, Aphis species, Spodoptera species, Geometridae species, and Graminaria species.

[0793] The compounds of formula I and I'a or their salts are particularly useful for controlling one or more of the following: Spodoptera littoralis, Plutella xylostella, Western flower thrips, Thrips tabaci, American stink bug, codling moth, brown rice hopper, peach aphid, soybean looper, bean aphid, cucumber leaf beetle, cereal aphid, and striped stem borer.

[0794] In a preferred embodiment of each aspect, compound TX (wherein the abbreviation "TX" refers to "a compound selected from the group consisting of the compounds defined in Tables A-1 to A-71 and compounds P1 to P85 of Table P (i.e., compounds P1 to P5, P6 to P17, P18 to P41, and P42 to P85)) controls one or more of the following: Spodoptera littoralis, diamondback moth, western flower thrips, tabaci thrips, hero stink bug, codling moth, brown rice hopper, peach aphid, soybean looper, bean aphid, cucumber leaf beetle, cereal aphid, and striped stem borer, such as Spodoptera littoralis+TX, diamondback moth+TX, western flower thrips+TX, tabaci thrips+TX, hero stink bug+TX, codling moth+TX, brown rice hopper+TX, peach aphid+TX, soybean looper+TX, bean aphid+TX, cucumber leaf beetle+TX, cereal aphid+TX, and striped stem borer+TX.

[0795] In an embodiment of each aspect, one compound from Tables A-1 to A-71 and Table P (i.e., compounds P1 to P5, P6 to P17, P18 to P41, and P42 to P85) is suitable for controlling Spodoptera littoralis, Plutella xylostella, Western flower thrips, Thrips tabaci, American stink bug, Codling moth, Brown rice hopper, Green peach aphid, Soybean looper, Bean aphid, Cucumber leaf beetle, Grain aphid, and Chilo suppressalis on cotton, vegetables, corn, corn, rice, and soybean crops.

[0796] In the embodiments, one compound from Tables A-1 to A-71 and Table P, compounds P1 to P85 (i.e. compounds P1 to P5, P6 to P17, P18 to P41 and P42 to P85) is suitable for controlling Mamestra (preferably on vegetables), Codling moth (preferably on apples), Empoasca (preferably on vegetables, vineyards), Leptinotarsa ​​(preferably on potatoes) and Chilo suppressalis (preferably on rice).

[0797] The compounds according to the present invention may have any number of benefits, including, among others, favorable levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (e.g., higher biological activity, favorable activity spectrum, increased safety (against non-target organisms above and below ground, such as fish, birds, and bees), improved physico-chemical properties, or increased biodegradability). In particular, it has been unexpectedly discovered that certain compounds of formula (I) can exhibit favorable safety profiles relative to non-target arthropods, particularly pollinators such as honey bees, solitary bees, and bumblebees. Most particularly, relative to the Italian honey bee (Apis mellifera).

[0798] The compounds according to the invention can be used as pesticides in unmodified form, but they are usually formulated into compositions in various ways using formulation adjuvants such as carriers, solvents and surfactants. These formulations can be in different physical forms, for example, in the form of dusts, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent compressed tablets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, mobile oils, aqueous dispersions, oily dispersions, suspoemulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as a carrier), impregnated polymer films or in other known forms, for example, from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, 1st edition, second revision (2010). Such formulations can be used directly or diluted before use. Dilution can be performed with, for example, water, liquid fertilizers, micronutrients, biological organisms, oils or solvents.

[0799] These formulations can be prepared, for example, by mixing the active ingredient with a formulation adjuvant to obtain a composition in the form of a finely divided solid, granules, solution, dispersion or emulsion. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of plant or animal origin, modified oils of plant or animal origin, organic solvents, water, surface-active substances or combinations thereof.

[0800] These active ingredients can also be contained in very fine microcapsules. Microcapsules contain active ingredients in porous carriers. This allows the active ingredients to be released (e.g., slowly released) into the environment in controlled amounts. Microcapsules typically have a diameter of from 0.1 to 500 microns. The amount of active ingredient they contain is approximately from 25% to 95% of the capsule weight by weight. These active ingredients can be in the form of a holistic solid, in the form of fine particles in a solid or liquid dispersion, or in the form of a suitable solution. The encapsulated membrane can include, for example, natural or synthetic rubber, cellulose, styrene / butadiene copolymer, polyacrylonitrile, polyacrylate, polyester, polyamide, polyurea, polyurethane, or chemically modified polymers and starch xanthate, or other polymers known to those skilled in the art. Alternatively, very fine microcapsules can be formed, in which the active ingredient is contained in the form of finely dispersed particles in a solid matrix of a base material, but these microcapsules themselves are not wrapped.

[0801] Formulation adjuvants suitable for preparing the compositions according to the invention are known per se. As liquid carriers, water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol rosinate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethyl Formamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, dipropylene glycol, alkyl pyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, α-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, γ-butyrolactone, glycerol, acetic acid glyceryl, diacetic acid glyceryl, triacetic acid glyceryl, decaglycerol Hexadecane, Hexanediol, Isoamyl Acetate, Isobornyl Acetate, Isooctane, Isophorone, Cumene, Isopropyl Myristate, Lactic Acid, Lauramine, Mesityl Oxide, Methoxypropanol, Methyl Isoamyl Ketone, Methyl Isobutyl Ketone, Methyl Laurate, Methyl Caprylate, Methyl Oleate, Methylene Chloride, m-Xylene, n-Hexane, n-Octylamine, Octadecanoic Acid, Octylamine Acetate, Oleic Acid, Oleylamine, o-Xylene, Phenol, Polyethylene Glycol, Propionic Acid, Propyl Lactate , propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol and higher molecular weight alcohols such as amyl alcohol, tetrahydrofuranol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, etc.

[0802] Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, diatomaceous earth, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed hulls, wheat flour, soy flour, pumice, wood flour, ground walnut shells, lignin, and similar substances.

[0803] Many surface-active substances can be used advantageously in both solid and liquid formulations, especially those which can be diluted with a carrier before use. Surface-active substances can be anionic, cationic, nonionic or polymeric and they can act as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol / alkylene oxide addition products, such as ethoxylated nonylphenol; alcohol / alkylene oxide addition products, such as ethoxylated tridecanol; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; salts of dialkylsulfosuccinates, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary ammoniums, such as dodecyltrimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and dialkyl phosphates; as well as other substances, such as described in: McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Company (MC Publishing Company). Corp., Ridgewood New Jersey (1981).

[0804] Additional adjuvants that can be used in pesticidal formulations include crystallization inhibitors, viscosity regulators, suspending agents, dyes, antioxidants, foaming agents, light absorbers, mixing aids, defoamers, complexing agents, substances and buffers that neutralize or vary the pH, corrosion inhibitors, fragrances, wetting agents, absorption enhancers, micronutrients, plasticizers, glidants, lubricants, dispersants, thickeners, antifreeze agents, microbicides, and liquid and solid fertilizers.

[0805] The composition according to the invention may comprise an additive comprising an oil of plant or animal origin, a mineral oil, an alkyl ester of such an oil or a mixture of such an oil and an oil derivative. The amount of the 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 may be added to the spray tank in the desired concentration after the spray mixture has been prepared. Preferred oil additives include mineral oil or an oil of plant origin, such as rapeseed oil, olive oil or sunflower oil; emulsified vegetable oils; alkyl esters of oils of plant origin, such as methyl derivatives; or oils of animal origin, such as fish oil or tallow. Preferred oil additives include C8-C 22 Alkyl esters of fatty acids, especially C 12 -C 18Methyl derivatives of fatty acids, such as the methyl esters of lauric acid, palmitic acid, and oleic acid (methyl laurate, methyl palmitate, and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th edition, Southern Illinois University, 2010.

[0806] These compositions according to the invention generally comprise from 0.1% to 99% by weight, in particular from 0.1% to 95% by weight, of a compound according to the invention and from 1% to 99.9% by weight of formulation adjuvants, preferably including from 0 to 25% by weight of surface-active substances. While commercial products may preferably be formulated as concentrates, the end user will generally use dilute formulations.

[0807] The application rate varies within wide limits and depends on the nature of the soil, the application method, the crop plants, the harmful organisms to be controlled, the prevailing climatic conditions, and other factors dictated by the application method, the time of application, and the target crop. In general, the compound can be applied at a rate of from 1 l / ha to 2000 l / ha, in particular from 10 l / ha to 1000 l / ha.

[0808] A preferred formulation may have the following composition (wt %):

[0809] Emulsifiable concentrates :

[0810] Active ingredient: 1% to 95%, preferably 60% to 90%

[0811] Surfactant: 1% to 30%, preferably 5% to 20%

[0812] Liquid carrier: 1% to 80%, preferably 1% to 35%

[0813] Dust agent :

[0814] Active ingredient: 0.1% to 10%, preferably 0.1% to 5%

[0815] Solid carrier: 99.9% to 90%, preferably 99.9% to 99%

[0816] Suspension concentrate:

[0817] Active ingredient: 5% to 75%, preferably 10% to 50%

[0818] Water: 94% to 24%, preferably 88% to 30%

[0819] Surfactant: 1% to 40%, preferably 2% to 30%

[0820] wettable powder :

[0821] Active ingredient: 0.5% to 90%, preferably 1% to 80%

[0822] Surfactant: 0.5% to 20%, preferably 1% to 15%

[0823] Solid carrier: 5% to 95%, preferably 15% to 90%

[0824] Granules:

[0825] Active ingredient: 0.1% to 30%, preferably 0.1% to 15%

[0826] Solid carrier: 99.5% to 70%, preferably 97% to 85%

[0827] The following examples further illustrate (but do not limit) the present invention.

[0828] <![CDATA[ wettable powder ]]> a) b) c) Active ingredient 25％ 50％ 75％ Sodium lignin sulfonate 5％ 5％ - Sodium lauryl sulfate 3％ - 5％ Sodium diisobutylnaphthalenesulfonate - 6％ 10％ Phenol polyglycol ether (7-8 mol of ethylene oxide) - 2％ - Highly dispersed silicic acid 5％ 10％ 10％ Kaolin 62％ 27％ -

[0829] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable grinder to obtain a wettable powder which can be diluted with water to give a suspension of the desired concentration.

[0830] <![CDATA[ Powder for dry seed treatment ]]> a) b) c) Active ingredient 25％ 50％ 75％ Light mineral oil 5％ 5％ 5％ Highly dispersed silicic acid 5％ 5％ - Kaolin 65％ 40％ - talc - 20％

[0831] The combination is thoroughly mixed with adjuvants and the mixture is thoroughly ground in a suitable grinder to obtain a dust that can be used directly for seed treatment.

[0832] <![CDATA[ Emulsifiable concentrates ]]> Active ingredient 10％ Octylphenol polyglycol ether (4-5 mol of ethylene oxide) 3％ Calcium dodecylbenzenesulfonate 3％ Castor oil polyglycol ether (35 mol of ethylene oxide) 4％ Cyclohexanone 30％ Xylene mixture 50％

[0833] Emulsions of any desired dilution which can be used in plant protection can be obtained from these concentrates by dilution with water.

[0834] <![CDATA[ Dust agent ]]> a) b) c) Active ingredient 5％ 6％ 4％ talc 95％ - - Kaolin - 94％ - Mineral fillers - - 96％

[0835] Ready-to-use dusts are obtained by mixing the combination with a carrier and grinding the mixture in a suitable grinder. Such dusts can also be used for dry seed dressing of seeds.

[0836] <![CDATA[ Extruder pellets ]]> Active ingredient 15％ Sodium lignin sulfonate 2％ Carboxymethyl cellulose 1％ Kaolin 82％

[0837] The combination is mixed and ground with the adjuvants, and the mixture is moistened with water.

[0838] The mixture is extruded and then dried in a stream of air.

[0839] <![CDATA[ Coated granules ]]> Active ingredient 8％ Polyethylene glycol (molecular weight 200) 3％ Kaolin 89％

[0840] This finely ground combination is applied uniformly in a mixer to the kaolin moistened with polyethylene glycol. In this way, dust-free coated granules are obtained.

[0841] Suspension concentrates

[0842] Active ingredient 40％ Propylene glycol 10％ Nonylphenol polyglycol ether (15 mol of ethylene oxide) 6％ Sodium lignin sulfonate 10％ Carboxymethyl cellulose 1％ Silicone oil (in the form of a 75% emulsion in water) 1％ water 32％

[0843] The finely ground combination is intimately mixed with adjuvants to give 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 materials can be treated and protected against microbial infestation by spraying, pouring or immersion.

[0844] Flowable concentrate for seed treatment

[0845] Active ingredient 40％ Propylene glycol 5％ Copolymer butanol PO / EO 2％ Tristyrylphenol with 10-20 moles of EO 2％ 1,2-Benzisothiazolin-3-one (in the form of a 20% solution in water) 0.5％ Monoazo-pigment calcium salt 5％ Silicone oil (in the form of a 75% emulsion in water) 0.2％ water 45.3％

[0846] The finely ground combination is intimately mixed with adjuvants to give 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 materials can be treated and protected against microbial infestation by spraying, pouring or immersion.

[0847] Extended-release capsule suspension

[0848] 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of a toluene diisocyanate / polymethylene-polyphenyl isocyanate mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinyl alcohol, 0.05 parts of a defoamer, and 51.6 parts of water until the desired particle size is reached. To this emulsion, 2.8 parts of a mixture of 1,6-hexanediamine in 5.3 parts of water are added. The mixture is stirred until the polymerization reaction is complete. The resulting capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersant. The capsule suspension formulation contains 28% active ingredient. The diameter of the medium capsules is 8-15 microns. The resulting formulation is applied to the seeds as an aqueous suspension in a device suitable for this purpose.

[0849] Formulation types include emulsion concentrates (EC), suspension concentrates (SC), suspoemulsions (SE), capsule suspensions (CS), water-dispersible granules (WG), emulsifiable granules (EG), emulsions, water-in-oil emulsions (EO), oil-in-water emulsions (EW), microemulsions (ME), oil dispersions (OD), oil suspensions (OF), oil-soluble concentrates (OL), soluble concentrates (SL), ultra-low volume suspensions (SU), ultra-low volume concentrates (UL), finished products (TK), dispersible concentrates (DC), wettable powders (WP), soluble granules (SG), or any technically feasible formulation in combination with agriculturally acceptable adjuvants.

[0850] By adding other insecticidal, acaricidal and / or fungicidal active ingredients, the activity of the compositions according to the invention can be significantly broadened and adapted to prevailing conditions. Mixtures of compounds of formula (I) with other insecticidal, acaricidal and / or fungicidal active ingredients can also have further surprising advantages, which can also be described in a broader sense as synergistic activities. For example, better tolerance of plants, reduced phytotoxicity, insects can be controlled at different stages of their development, or better behavior during their production (e.g., during grinding or mixing, during their storage or during their use).

[0851] Suitable active ingredients for addition here are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.

[0852] Preparation example:

[0853] "Mp" means melting point in ° C. Free radical refers to methyl group. Recorded on a Brucker 400 MHz spectrometer 1 H NMR measurements, chemical shifts are given in ppm relative to a TMS standard. Spectra were measured in deuterated solvents as specified. The compounds were characterized using any of the following LCMS methods. Characteristic LCMS values ​​obtained for each compound are the retention time ("Rt", reported in minutes) and the measured molecular ion (M+H). + or (MH) - .

[0854] Method 1:

[0855] Spectra were recorded on a mass spectrometer from Waters Corporation (SQD, SQDII or QDA single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive and negative ions), capillary voltage: 0.8-3.00 kV, cone: 5-30 V, source temperature: 120-150°C, desolvation temperature: 350-600°C, cone gas flow: 50-150 l / h, desolvation gas flow: 650-1000 l / h, mass range: 100 to 900 Da and Acquity UPLC from Waters Corporation: binary pump, heated column compartment, diode array detector and ELSD. Column: Waters UPLC HSST3, 1.8 μm, 30 x 2.1 mm, temperature: 60°C, DAD wavelength range (nm): 210 to 400, run time: 1.5 min; solvent: A = water + 5% MeOH + 0.05% HCOOH, B = acetonitrile + 0.05% HCOOH; flow rate (ml / min) 0.85, gradient: 10% B isocratic for 0.2 min, then 10%-100% B in 1.0 min, 100% B isocratic for 0.2 min, 100%-10% B in 0.05 min, 10% B isocratic for 0.05 min.

[0856] Method 2:

[0857] Spectra were recorded on a mass spectrometer from Waters (SQD, SQDII single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive and negative, capillary: 3.00 kV, cone range: 41 V, extractor: 2.00 V, source temperature: 150°C, desolvation temperature: 5000°C, cone gas flow: 50 l / h, desolvation gas flow: 1000 l / h, mass range: 110 to 800 Da) and an Acquity UPLC from Waters: binary pump, heated column compartment, diode array detector and ELSD detector. Column: Waters UPLC HSS T3 C18, 1.8 μm, 30 x 2.1 mm, temperature: 40° C., PDA wavelength range (nm): 200 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.05% HCOOH; gradient: 10%-100% B in 1.3 min; flow rate (ml / min) 0.6.

[0858] Method 3:

[0859] Spectra were recorded on a mass spectrometer from Waters (SQD2 or QDA single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive and negative switching, capillary: 0.8-3.00 kV, cone range: 25 ° C, source temperature: 120 ° C -150 ° C, desolvation temperature: 500 ° C -600 ° C, cone gas flow: 50 L / h, desolvation gas flow: 1000 L / h, mass range: 110 to 850 Da) and Acquity UPLC from Waters: quaternary solvent manager, heated column compartment, diode array detector. Column: Acquity UPLC HSS T3 C18, 1.8 μm, 30 x 2.1 mm, temperature: 40°C, DAD wavelength range (nm): 200 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.05% HCOOH: Gradient: 0 min 10% B; 0.min-0.2 min 10%-50% B; 0.2 min-0.6 min 50%-100% B; 0.6-1.3 min 100% B; 1.3 min-1.4 min 100%-10% B; 1.4 min-1.6 min 10% B; flow rate (mL / min) 0.6.

[0860] Method 4:

[0861] Spectra were recorded on a mass spectrometer from Waters (SQD2 or QDA single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive and negative switching, capillary: 0.8-3.00 kV, cone range: 25 ° C, source temperature: 120 ° C -150 ° C, desolvation temperature: 500 ° C -600 ° C, cone gas flow: 50 L / h, desolvation gas flow: 1000 L / h, mass range: 110 to 850 Da) and Acquity UPLC from Waters: quaternary solvent manager, heated column compartment, diode array detector. Column: Acquity UPLC HSS T3 C18, 1.8 μm, 30 x 2.1 mm, temperature: 40°C, DAD wavelength range (nm): 200 to 400, solvent gradient: A = water + 5% acetonitrile + 0.1% HCOOH, B = acetonitrile + 0.05% HCOOH: gradient: 0 min 10% B; 0.0-0.5 min 10% B; 0.5-2 min 100% B; 2-3 min 100% B; 3-3.5 min 10% B; 3.5-4 min 10% B; flow rate (mL / min) 0.6.

[0862] Method 5:

[0863] Spectra were recorded on an ACQUITY mass spectrometer from Waters (QDa or SQDII single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative, capillary: 3.0 kV, cone: 30 V, extractor: 3.00 V, source temperature: 150°C, desolvation temperature: 400°C, cone gas flow: 60 L / hr, desolvation gas flow: 700 L / hr, mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters with a solvent degasser, binary pump, heated column compartment, and diode array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 x 2.1 mm, temperature: 60° C., DAD wavelength range (nm): 210 to 400, solvent gradient: A = water / methanol 9:1 + 0.1% formic acid, B = acetonitrile + 0.1% formic acid, gradient: 0% -100% B in 3.0 min; flow rate (ml / min) 0.75.

[0864] Example E1: 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-ethyl-N-methyl-thiazole-5-carboxamide (Compound P6)

[0865]

[0866] Step 1: Preparation of methyl 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylate (I-1)

[0867]

[0868] To a solution of tert-butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]carbamate (CAS2641011-39-2, prepared as described in, for example, WO21 / 083936) (5.2 g, 21 mmol) in 1,4-dioxane (31 mL) and acetic acid (31 mL) was added methyl 2-hydrazinothiazole-5-carboxylate (CAS2648006-04-4) (3.7 g, 21 mmol). The reaction mixture was heated at 50 ° C for 16 hours, then cooled to room temperature and diluted with EtOAc and water. The phases were separated, the aqueous layer was extracted with EtOAc, the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (gradient ethyl acetate in cyclohexane) to give methyl 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylate.

[0869] LCMS (method 2): retention time 1.11 min, m / z 298 [M+H-tBu] + .

[0870] Step 2: Preparation of 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid (I-2)

[0871]

[0872] A mixture of methyl 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylate (I-1) (3.7 g, 10 mmol) and lithium hydroxide (0.78 g, 31 mmol) in tetrahydrofuran (37 mL) and water (3.7 mL) was stirred at room temperature for 16 hours and then diluted with EtOAc, water and 5% aqueous sodium dihydrogen phosphate solution (NaH2PO4). The phases were separated and the aqueous layer was washed with EtOAc, cooled by adding crushed ice, and then acidified with 10% aqueous HCl solution. The formed precipitate was filtered, the solid was washed with water and dried. The solid was further washed with pentane and dried in vacuo to give 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid as an off-white solid. This material was used in the next step without further purification.

[0873] LCMS (Method 2): Retention time 1.03 min, m / z 284 [M+H-tBu] + .

[0874] Step 3: Preparation of tert-butyl N-[(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]carbamate (I-3)

[0875]

[0876] To a suspension of 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid (I-2) (0.5 g, 1.43 mmol) in EtOAc (11.8 mL) were added ethylmethylamine (0.19 mL, 2.21 mmol), N,N-diisopropylethylamine (0.76 mL, 4.42 mmol), followed by propanephosphonic acid cyclic anhydride ( 50wt.%, in ethyl acetate, 2.63mL, 4.42mmol). The reaction mixture was stirred at room temperature overnight. After dilution with water, the product was extracted with EtOAc (3x), the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (gradient ethyl acetate in cyclohexane) to give tert-butyl N-[(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]carbamate. LCMS (method 2): retention time 1.09min, m / z 381[M+H] + .

[0877] Step 4: Preparation of [(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-4)

[0878]

[0879] To a solution of tert-butyl N-[(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]carbamate (I-3) (0.43g, 1.13mmol) in 1,4-dioxane (3mL), hydrochloric acid (4.0M in 1,4-dioxane, 3mL, 12mmol) is added. The reaction mixture is stirred at room temperature for 5 hours, then concentrated to dryness in a vacuum. The residue is ground together with TBME, the formed solid is filtered and dried to give [(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]ammonium chloride as a white solid.

[0880] LCMS (Method 2): Retention time of the corresponding free base 0.17 min, m / z 281 [M+H] + .

[0881] Step 5: Preparation of 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-ethyl-N-methyl-thiazole-5-carboxamide (Compound P6)

[0882]

[0883] A stirred solution of 4,6-dichloro-8-(trifluoromethyl)quinazoline (prepared as described in WO 2021 / 083936) (155 mg, 90%, 0.52 mmol), [(1S)-1-[2-[5-[ethyl(methyl)carbamoyl]thiazol-2-yl]-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-4) (150 mg, 0.47 mmol) and triethylamine (241 mg, 2.37 mmol) in tetrahydrofuran (3 mL) was heated in a microwave at 100 °C for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was purified by combiflash (gradient ethyl acetate in cyclohexane) to give 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-ethyl-N-methyl-thiazole-5-carboxamide (Compound P6) as a white solid.

[0884] LCMS (Method 3): retention time 1.09 min, m / z 511 / 513 [M+H] + .

[0885] Example E2: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]pyrimidine-4-carboxamide (Compound P5)

[0886]

[0887] A solution of 4,6-dichloro-8-(trifluoromethyl)quinazoline (prepared as described in WO 2021 / 083936) (150 mg, 0.562 mmol), 6-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide hydrochloride (prepared as described in WO 2021 / 165195) (181.8 mg, 0.674 mmol) and cesium carbonate (549.1 mg, 1.685 mmol) in acetonitrile (3 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and the precipitate formed was filtered, washed with water, then with pentane, and dried. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (Compound P5) (85 mg) as an off-white solid.

[0888] LCMS (method 2): retention time 1.07 min, m / z 464 / 466 [M+H] + . 1HNMR(400MHz,DMSO-d6)δppm 9.30(s,1H),9.14(br d,1H),8.97(d,1H),8.46(br s,1H),8.40(s,2H),8.20-8.30(m,2H),8.13(br s,1H),6.56(m,1H),1.76(d,3H).

[0889] Example E3: 6-[5-[(1S)-1-[(6,8-Dibromoquinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol- Preparation of [oxazol-1-yl]-N-methyl-pyrimidine-4-carboxamide (Compound P11)

[0890]

[0891] To a stirred solution of 6-[5-[(1S)-1-[(6,8-dibromoquinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]-N-methyl-pyrimidine-4-carboxamide (Compound P12) (0.14 g, 0.262 mmol) in acetonitrile (2.8 mL) was added cesium carbonate (0.27 g, 0.787 mmol) and the mixture was heated to 90° C. Iodomethane (0.392 g, 2.62 mmol) was added at 90° C. and the reaction mixture was stirred at this temperature for 1 hour. After cooling to room temperature, water was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-[5-[(1S)-1-[(6,8-dibromoquinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]-N-methyl-pyrimidine-4-carboxamide (P11) as a solid.

[0892] LCMS (Method 3): retention time 1.00 min, m / z 546 / 548 / 550 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 9.06(q,1H),8.57(d,1H),8.53(s,1H),8.40(s,1H),8.37(d,1H),8.34( d,1H),7.99(d,1H),6.79(q,1H),3.23(s,3H),2.84(d,3H),1.83(d,3H).

[0893] Example E4: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-(1-cyanocyclopropyl)pyrimidine-4-carboxamide (Compound P22)

[0894]

[0895] Step 1:Preparation of [(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-17)

[0896]

[0897] To a solution of tert-butyl N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (CAS 2694010-23-4, prepared as described, for example, in WO 21 / 165195) (20.0 g, 61.58 mmol) in 1,4-dioxane (200 mL) was added a solution of hydrochloric acid (4 M in dioxane) (77.0 mL, 308 mmol) at room temperature. The reaction mixture was stirred at room temperature for 25 hours, the formed precipitate was isolated by filtration, and the solid was dried under vacuum to give [(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-17) as a white solid.

[0898] LCMS (Method 3): Retention time of the corresponding free base 0.20 min, m / z 225 / 227 [M+H] + .

[0899] Step 2: Preparation of 6-chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-8-(trifluoromethyl)quinazolin-4-amine (I-18)

[0900]

[0901] To a mixture of 4,6-dichloro-8-(trifluoromethyl)quinazoline (prepared as described in WO 21 / 083936) (9.0 g, 33.70 mmol) and [(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-17) (9.24 g, 35.39 mmol) in tetrahydrofuran (90 mL) was added triethylamine (10.34 g, 14.2 mL, 101.11 mmol) at room temperature. The reaction mixture was stirred at 70 ° C for 1 hour and then diluted with water (1000 mL). The precipitate formed was isolated by filtration, and the solid was washed with water and dried in vacuo to give 6-chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-8-(trifluoromethyl)quinazolin-4-amine (I-18) as a light yellow solid.

[0902] LCMS (Method 3): retention time 1.33 min, m / z 455 / 457 [M+H]+ .

[0903] Step 3: Preparation of methyl 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate (I-19)

[0904]

[0905] 6-Chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-8-(trifluoromethyl)quinazolin-4-amine (I-18) (3.8 g, 5.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf), 0.487 g, 0.584 mmol), triethylamine (0.597 g, 0.823 mL, 5.84 mmol) and methanol (76 mL) were placed in a pressure vessel. The vessel was flushed with nitrogen and then with carbon monoxide. The reaction mixture was heated to 80°C under 15 bar carbon monoxide pressure for 6 hours. After cooling to room temperature, the pressure was carefully released and the vessel was flushed with nitrogen. The mixture was filtered through a bed of celite, the filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue is purified by combiflash (ethyl acetate in cyclohexane) to give methyl 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate (I-19) as a white solid.

[0906] LCMS (Method 3): retention time 1.17 min, m / z 479 / 481 [M+H] + .

[0907] Similarly, methyl 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate (I-22) can be obtained from intermediate (I-21) using the above protocol. LCMS (Method 3): retention time 1.21 min, m / z 493 / 495 [M+H] + .

[0908] Step 4: Preparation of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20)

[0909]

[0910] To a solution of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid methyl ester (I-19) (2.2 g, 4.60 mmol) in methanol (44 mL) and water (44 mL) was added sodium hydroxide (0.2205 g, 5.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours, diluted with water (20 mL) and extracted once with TBME (50 mL). The aqueous layer was acidified with citric acid, stirred for 10 minutes, and the precipitate formed was isolated by filtration. The solid was washed with water and dried in vacuo to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) as a white solid. LCMS (Method 3): retention time 1.06 min, m / z 465 / 467 [M+H] + .

[0911] Similarly, 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-23) can be obtained from intermediate (I-22) using the above protocol. LCMS (Method 3): retention time 1.12 min, m / z 479 / 481 [M+H] + .

[0912] Step 5: Preparation of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(1-cyanocyclopropyl)pyrimidine-4-carboxamide (Compound P22)

[0913]

[0914] To a solution of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (0.15 g, 0.323 mmol) and (1-cyanocyclopropyl)ammonium chloride (0.153 g, 1.291 mmol) in acetonitrile (3 mL) at room temperature was added 1-propanephosphonic acid cyclic anhydride (50% by mass in EtOAc, 0.5763 mL, 0.968 mmol) followed by triethylamine (0.164 g, 0.226 mL, 1.614 mmol). The reaction mixture was stirred at room temperature for 25 hours, then diluted with saturated aqueous NaHCO solution, and the product was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(1-cyanocyclopropyl)pyrimidine-4-carboxamide (Compound P22) as a white solid.

[0915] LCMS (Method 3): retention time 1.22 min, m / z 529 / 531 [M+H] + . 1 HNMR(400MHz, CDCl3)δppm:9.26(d,1H),8.84(d,1H),8.59(s,1H),8.44(s,1H),8.15(s,1H),8.0 1(d,1H),7.86-7.94(m,2H),6.70(quint,1H),1.84(d,3H),1.71-1.78(m,2H),1.39-1.44(m,2H).

[0916] Example E5: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-(thietan-3-yl)pyrimidine-4-carboxamide (Compound P25)

[0917]

[0918] Following Procedural Example E4, Step 5, similarly obtained from 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (0.30 g, 0.645 mmol), thietan-3-ylammonium chloride (0.162 g, 1.290 mmol), 1-propanephosphonic acid cyclic anhydride (50% by mass in EtOAc, 0.5763 mL, 0.968 mmol) and triethylamine (0.144 g, 0.199 mL, 1.420 mmol) in acetonitrile (6 mL). After stirring at room temperature for 25 hours, the reaction mixture was diluted with aqueous NaHCO3 solution and stirring was continued for 20 minutes. The precipitate formed was isolated by filtration, the solid was washed with water and dried in vacuo to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(thietan-3-yl)pyrimidine-4-carboxamide (Compound P25) as a white solid.

[0919] LCMS (Method 3): retention time 1.28 min, m / z 536 / 538 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm:9.83(d,1H),9.33(s,1H),9.16(d,1H),8.96(d,1H),8.40(s,1H),8.38(d,1H), 8.28(s,1H),8.23(d,1H),6.55(quint,1H),5.23-5.36(m,1H),3.71(m,2H),3.15-3.28(m,2H),1.76(d,3H).

[0920] Similarly, when cyclopropylamine was used instead of thietan-3-ylammonium chloride, the above protocol could be used to obtain 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-cyclopropyl-pyrimidine-4-carboxamide (Compound P23).

[0921] LCMS (Method 3): retention time 1.24 min, m / z 504 / 506 [M+H] + .

[0922] Example E6: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-(1,1-dioxothietane-3-yl)pyrimidine-4-carboxamide (Compound P24)

[0923]

[0924] To a solution of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(thietan-3-yl)pyrimidine-4-carboxamide (Compound P25) (0.140 g, 0.261 mmol) in a mixture of acetonitrile (1.4 mL), carbon tetrachloride (1.4 mL) and water (2.8 mL) was added ruthenium (III) chloride (5.42 mg, 0.026 mmol) followed by sodium periodate (0.118 g, 0.549 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then quenched with a saturated aqueous solution of Na2S2O5, and the product was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(1,1-dioxothietane-3-yl)pyrimidine-4-carboxamide (Compound P24) as a white solid.

[0925] LCMS (Method 3): retention time 1.20 min, m / z 568 / 570 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δppm:9.90(d,1H),9.36(d,1H),9.16(d,1H),8.97(d,1H),8.37- 8.41(m,2H),8.28(s,1H),8.24(d,1H),6.56(quint,1H),4.47-4.71(m,5H),1.76(d,3H).

[0926] Example E7: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-methoxy-pyrimidine-4-carboxamide (Compound P28)

[0927]

[0928] Obtained analogously following Procedural Example E4, Step 5, from 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (0.15 g, 0.323 mmol), methoxyammonium chloride (0.135 g, 1.614 mmol), 1-propanephosphonic acid cyclic anhydride (50% by mass in EtOAc, 0.2882 mL, 0.484 mmol) and triethylamine (0.197 g, 0.271 mL, 1.936 mmol) in acetonitrile (3 mL). After stirring at room temperature for 25 hours, the reaction mixture was diluted with aqueous NaHCO3 solution and stirring was continued for 20 minutes. The precipitate formed was isolated by filtration, the solid was washed with water and dried in vacuo to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-methoxy-pyrimidine-4-carboxamide (Compound P28) as a white solid.

[0929] LCMS (Method 3): retention time 1.16 min, m / z 494 / 496 [M+H] + . 1 HNMR(DMSO-d6)δppm:12.53(s,1H),9.28(s,1H),9.16(d,1H),8.97(d,1H),8.40(s,1H ),8.37(s,1H),8.28(s,1H),8.24(d,1H),6.55(quint,1H),3.75(s,3H),1.76(d,3H).

[0930] Example E8: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-ethyl-N-methyl-pyrimidine-4-carboxamide (Compound P31)

[0931]

[0932] According to Procedural Example E4, step 5 (wherein triethylamine was omitted here), was similarly obtained from 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (0.15 g, 0.323 mmol), N-methylethylamine (0.095 g, 1.614 mmol) and 1-propanephosphonic acid cyclic anhydride (50% by mass in EtOAc, 0.5763 mL, 0.968 mmol) in acetonitrile (3 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with water and stirred for another 20 minutes. The formed precipitate was isolated by filtration, the solid was washed with water and dried in vacuo to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-ethyl-N-methyl-pyrimidine-4-carboxamide (Compound P31) as a white solid. LCMS (Method 3): retention time 1.23 min, m / z 506 / 508 [M+H] + .

[0933] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 9.24 (dd, 2H), 9.16 (br d, 2H), 8.98 (s, 2H), 8.40 (s, 2H), 8.26 (s, 2H), 8.24 (d, 2H), 8.04 (d, 2H), 6.52 (quint, 2H), 3.52 (q, 2H), 3.28 (q, 2H), 3.02 (s, 3H), 2.94 (s, 3H), 1.78 (d, 6H), 1.18 (t, 3H), 1.14 (t, 3H) as a mixture of two rotamers.

[0934] Similarly, when morpholine is used instead of N-methylethylamine, [6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidin-4-yl]-morpholino-methanone (Compound P32) can be obtained using the above protocol. The crude product obtained after aqueous workup was purified by reverse phase column chromatography (C18 column, HO:ACN eluent).

[0935] LCMS (Method 3): retention time 1.20 min, m / z 534 / 536 [M+H] + .

[0936] Example E9: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-(cyanomethyl)pyrimidine-4-carboxamide (Compound P38)

[0937]

[0938] Obtained analogously following Procedural Example E4, Step 5, from 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (0.15 g, 0.323 mmol), cyanomethylammonium chloride (0.119 g, 1.291 mmol), 1-propanephosphonic acid cyclic anhydride (50% by mass in EtOAc, 0.5763 mL, 0.968 mmol) and triethylamine (0.164 g, 0.226 mL, 1.614 mmol) in acetonitrile (3 mL). Purification by combiflash gave 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-(cyanomethyl)pyrimidine-4-carboxamide (Compound P38) as a white solid.

[0939] LCMS (Method 3): retention time 1.18 min, m / z 503 / 505 [M+H] + . 1 HNMR(400MHz, CDCl3)δppm:9.31(s,1H),8.90(s,1H),8.77(br d,1H),8.40-8.52(m,2H),8.24(s,1H),7.94(s,1H),7.72(s,1H),6.67(quint,1H),4.38-4.60(m,2H),1.89(d,3H).

[0940] Example E10: 6-[5-[(1S)-1-[(8-Chloro-6-iodo-quinazolin-4-yl)amino]ethyl]-1,2,4-triazole-1- Preparation of [4-[[(4-(2-methyl-1-pyrimidine-4-carbonitrile)]]]

[0941]

[0942] A solution of 4,8-dichloro-6-iodo-quinazoline (CAS 100948-96-7, prepared similarly to the description found, for example, in WO 2021 / 083936) (100 mg, 0.277 mmol, 90% by mass), [(1S)-1-[2-(6-cyanopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]2,2,2-trifluoroacetate ammonium (I-13, CAS 2694010-00-7, prepared as described in WO 2021 / 165195) (101.3 mg, 0.277 mmol, 90% by mass) and triethylamine (0.194 mL, 0.141 g, 1.385 mmol) in tetrahydrofuran (2 mL) was heated in a microwave at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane), and the resulting product was washed with TBME, filtered and dried under high vacuum to give 6-[5-[(1S)-1-[(8-chloro-6-iodo-quinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile (Compound P18) as a white solid. LCMS (Method 3): retention time 1.13 min, m / z 504 / 506 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm: 1.73(d,3H),6.47(quint,1H),8.27(d,1H),8.30(s,1H),8.36(s,1H),8.61(d,1H),8.90(d,1H),9.05(d,1H),9.36(d,1H).

[0943] Example E11: 6-[5-[(1S)-1-[(6-Chloro-8-iodo-quinazolin-4-yl)-methyl-amino]ethyl]-1,2,4- Preparation of triazol-1-yl]pyrimidine-4-carboxamide (Compound P47)

[0944]

[0945] To a mixture of 4,6-dichloro-8-iodoquinazoline (CAS 100949-33-5) (0.1 g, 0.307 mmol) and [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-methyl-ammonium chloride (I-29) (0.096 g, 0.338 mmol) in ACN (2 mL) was added triethylamine (0.156 g, 1.53 mmol) and the mixture was heated to 90 ° C. for 1 hour. After cooling to room temperature, ice-cold water was added and the product was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in cyclohexane) to give 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (P47) as a solid. LCMS (Method 3): retention time 1.11 min, m / z 536 / 538 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 8.55(s,1H),8.49(s,1H),8.35-8.44(m,4H),8.08(br s,1H),7.89(d,1H),6.79(q,1H),3.23(s,3H),1.83(d,3H).

[0946] Example E12: 5-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]pyrazine-2-carboxamide (Compound P21)

[0947]

[0948] To a mixture of 4,6-dichloro-8-(trifluoromethyl)quinazoline (prepared as described in WO 21 / 083936) (100 mg, 0.374 mmol) and [(1S)-1-[2-(5-carbamoylpyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-16) (0.411 mmol) was added ACN (2 mL) and triethylamine (1.87 mmol). The reaction mixture was stirred at 80 ° C for 1 hour and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate in cyclohexane) to give 5-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrazine-2-carboxamide (P21) as a light yellow solid. LCMS (Method 4): retention time 1.74 min, m / z 464 / 466 [M+H] + .

[0949] Example E13: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (Compound P63)

[0950]

[0951] To a mixture of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylic acid (I-20) (200 mg, 0.43 mmol) and cyclopropyl(methyl)ammonium chloride (4.3 mmol) in acetonitrile (4 mL) was added HATU (0.245 mmol) at room temperature, followed by triethylamine (1.29 mmol) at 0-5° C. The reaction mixture was stirred at room temperature for 14 hours and further stirred at 80° C. for 11 hours, then diluted with water and saturated aqueous sodium bicarbonate solution. The product was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase combiflash (acetonitrile in water) using a C18 column to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoro-methyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-cyclopropyl-N-methyl-pyrimidine-4-carboxamide (P63) as a white solid. LCMS (Method 3): retention time 1.11 min, m / z 518 / 520 [M+H] + .

[0952] 1 H NMR(DMSO-d6)δppm:9.22(s,1H),9.15(br d,1H),8.95(m,1H),8.39(s,1H),8.25(s,1H),8.22(m,1H),8.10(s,1H),6.50(quint,1H),3.04(s,3H),2.80-2.97(m,1H),1.78(br d,3H),0.40-0.59(m,4H).

[0953] Example E14: 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-yl]amino]ethyl]- Preparation of 1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (Compound P59)

[0954]

[0955] Step 1: Preparation of 6-chloro-8-(trifluoromethylsulfanyl)quinazolin-4-ol

[0956]

[0957] To a solution of 6-chloro-8-iodo-quinazolin-4-ol (CAS101581-08-2) (4 g, 13.05 mmol) in degassed N, N-dimethylacetamide (40 mL) was added trifluoromethanethiol copper (I) (4.94 g, 30.02 mmol) at room temperature. The reaction mixture was heated at 90 ° C for 48 hours. After cooling, the mixture was diluted with 2N HCl aqueous solution (100 mL) and water (300 mL). The precipitated solid was filtered, the solid was redissolved in ethyl acetate, and the solution was passed through a celite bed. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-chloro-8-(trifluoromethylsulfanyl)quinazolin-4-ol as a light brown solid. LCMS (method 3): retention time 1.11 min, m / z 279 / 281 [MH] - .

[0958] 1 H NMR(DMSO-d6)δ:12.79(br s,1H),8.31(s,1H),8.20(s,1H),8.13(s,1H).

[0959] Step 2: Preparation of 6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-ol (I-45)

[0960]

[0961] To a solution of 6-chloro-8-(trifluoromethylsulfanyl)quinazolin-4-ol (prepared as described above) (0.65 g, 2.32 mmol) in acetonitrile (6.5 mL), carbon tetrachloride (6.5 mL) and water (13 mL) was added ruthenium (III) chloride (0.048 g, 0.23 mmol) at room temperature followed by sodium periodate (1.05 g, 4.86 mmol). After addition, the reaction mixture was stirred at room temperature for 2 hours, then diluted with an aqueous sodium metabisulfite solution, and the product was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-ol as a white solid. LCMS (method 3): retention time 1.08 min, m / z 313 / 315 [M+H] + . 1 H NMR(DMSO-d6)δ:13.05(br s,1H),8.60(d,1H),8.53(d,1H),8.43(s,1H).

[0962] Step 3: Preparation of 4,6-dichloro-8-(trifluoromethylsulfonyl)quinazoline

[0963]

[0964] A mixture of 6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-ol (I-45, prepared as described above) (0.43 g, 1.37 mmol), thionyl chloride (117.9 mmol) and N,N-dimethylformamide (0.068 mmol) was heated to 100 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure to give crude 4,6-dichloro-8-(trifluoromethylsulfonyl)quinazoline (460 mg) as a pale yellow solid, which was used immediately in the next reaction. 1 H NMR (CDCl3) δ: 9.30 (s, 1H), 8.81 (d, 1H), 8.72 (d, 1H).

[0965] Similarly, 4,6-dichloro-8-(difluoromethylsulfonyl)quinazoline can be obtained from 6-chloro-8-(difluoromethylsulfonyl)quinazolin-4-ol (I-44) using the above protocol.

[0966] 1 H NMR (400MHz, DMSO-d6) δppm 8.58 (s, 1H), 8.07 (d, 1H), 7.96 (d, 1H), 7.89 (t, 1H).

[0967] Step 4: Preparation of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (Compound P59)

[0968]

[0969] To a mixture of 4,6-dichloro-8-(trifluoromethylsulfonyl)quinazoline (prepared as described above) (0.07 g, 0.21 mmol) and [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-12) (0.085 g, 0.32 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.63 mmol) at room temperature. The reaction mixture was heated at 70°C for 1 hour, cooled to room temperature and diluted with water (20 mL). The precipitated solid was isolated by filtration and washed with water, then dried in vacuo. The crude material was purified by reverse phase column chromatography using a C18 (40-60 μm) column (acetonitrile in water) to give 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethylsulfonyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (P59) as a white solid.

[0970] LCMS (Method 3): retention time 1.11 min, m / z 528 / 530 [M+H] + . 1 HNMR(acetonitrile-d3)δ:9.12(s,1H),8.55(s,1H),8.53(s,1H),8.36(s,2H),8.01(s,1H),7.98(br d,1H),7.74(br s,1H),6.59(quint,1H),6.47(br s,1H),1.76(d,3H).

[0971] Similarly, 6-[5-[(1S)-1-[[6-chloro-8-(difluoromethylsulfonyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide (Compound P84) can be obtained from 4,6-dichloro-8-(difluoromethylsulfonyl)quinazoline (1.0 equiv) and [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-12, 1.2 equiv) in acetonitrile in the presence of potassium carbonate (3.0 equiv). The mixture is stirred at 0°C to room temperature for 2 hours. After standard workup, the crude material is purified by combiflash (ethyl acetate in cyclohexane) and then by reverse phase column chromatography (acetonitrile in water) to give the desired compound P84.

[0972] 1H NMR(400MHz,DMSO-d6)δppm 9.40(d,1H),9.29(s,1H),9.14(d,1H),8.46(br s,1H),8.42(m,2H),8.40(s,1H),8.28(s,1H),8.13(br s,1H),7.67(t,1H),6.57(quint,1H),1.77(d,3H).

[0973] Example E15: 6-[3-[1-[(6-Chloro-8-iodo-quinazolin-4-yl)amino]ethyl]pyrazin-2-yl]pyrimidine-4-carboxylate Preparation of amide (Compound P58)

[0974]

[0975] Step 1: Preparation of 2-(1-methylprop-2-ynyl)isoindoline-1,3-dione

[0976]

[0977] To a mixture of triphenylphosphine (37.4 g, 135.6 mmol) and phthalimide (18 g, 116.250 mmol) in anhydrous THF (100 mL) was added 3-butyn-2-ol (7 g, 96.8 mmol). The reaction mixture was cooled to 0 ° C and diisopropyl azodicarboxylate (116.2 mmol) was slowly added at 0-5 ° C. After stirring at room temperature for 16 hours, the reaction mixture was quenched with an aqueous ammonium chloride solution, the product was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to obtain 2- (1-methylprop-2-ynyl) isoindoline-1,3-dione as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm7.84-7.92(m,4H),5.11(dd,1H),3.33-3.37(m,1H),1.62(d,3H).

[0978] Step 2: Preparation of 6-[3-(1,3-dioxoisoindolin-2-yl)but-1-ynyl]pyrimidine-4-carboxamide

[0979]

[0980] A mixture of 6-chloropyrimidine-4-carboxamide (4.95 g, 31.4 mmol), cesium carbonate (18.2 g, 94.3 mmol) and XPhos (3.77 mmol) in ACN (49.5 mL) was flushed with nitrogen for 15 minutes. 2- (1-methylprop-2-ynyl) isoindoline-1,3-dione (prepared as described above) (8.14 g, 40.8 mmol), bis (acetonitrile) palladium (II) dichloride (1.57 mmol) and copper (I) iodide (3.14 mmol) were then added and the reaction mixture was stirred at 100 ° C for 2 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (ethyl acetate in cyclohexane) to obtain 6- [3- (1,3-dioxoisoindoline-2-yl) but-1-ynyl] pyrimidine-4-carboxamide as a solid. LCMS (Method 3): retention time 1.01 min, m / z 321 [M+H] + .

[0981] Step 3: Preparation of 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyl]pyrimidine-4-carboxamide

[0982]

[0983] To 6-[3-(1,3-dioxoisoindolin-2-yl)but-1-ynyl]pyrimidine-4-carboxamide (prepared as described above) (300 mg, 0.936 mmol) was slowly added sulfuric acid (3 mL) at 0-5°C. The reaction mixture was stirred at room temperature for 6 hours and then carefully poured into cold water. The precipitated solid was isolated by filtration and dried in vacuo to give 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyl]pyrimidine-4-carboxamide. LCMS (Method 3): retention time 1.00 min, m / z 339 [M+H] + .

[0984] Step 4: Preparation of 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyryl]pyrimidine-4-carboxamide

[0985]

[0986] To 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyl]pyrimidine-4-carboxamide (prepared as described above) (1.6 g, 4.7 mmol) in tetrahydrofuran (32 mL) was added selenium dioxide (1.1 g, 9.5 mmol) at room temperature. The reaction mixture was stirred at 65 ° C for 16 hours, cooled to room temperature and filtered through celite. The filter cake was washed with EtOAc and the filtrate was concentrated in vacuo to give the crude product 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyryl]pyrimidine-4-carboxamide, which was used directly in the next step.

[0987] Step 5: Preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]pyrimidine-4-carboxamide

[0988]

[0989] To a 0°C mixture of 6-[3-(1,3-dioxoisoindolin-2-yl)-2-oxo-butyryl]pyrimidine-4-carboxamide (prepared as described above) (1.7 g) in ethanol (17 mL) was added dropwise a 0°C solution of ethane-1,2-diamine (2.9 g, 48 mmol, 3.3 mL) in ethanol (17 mL). After addition, the reaction mixture was stirred at room temperature for 24 hours, then diluted with water and the product was extracted with 30% ACN in ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude 6-[3-(1-aminoethyl)pyrazin-2-yl]pyrimidine-4-carboxamide, which was used directly in the next step.

[0990] LCMS (Method 3): retention time 0.17 min, m / z 245 [M+H] + .

[0991] Step 6: Preparation of 6-[3-[1-[(6-chloro-8-iodo-quinazolin-4-yl)amino]ethyl]pyrazin-2-yl]pyrimidine-4-carboxamide (Compound P58)

[0992]

[0993] To a mixture of 4,6-dichloro-8-iodoquinazoline (CAS100949-33-5) (0.088 g, 0.27 mmol) and crude 6-[3-(1-aminoethyl)pyrazine-2-yl]pyrimidine-4-carboxamide (prepared as described above) (0.07 g, 0.286 mmol) in ACN (1.4 mL) was added triethylamine (0.573 mmol). The reaction mixture was heated at 90 ° C for 1 hour, cooled to room temperature and quenched with ice-cold water. The product was extracted several times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 6-[3-[1-[(6-chloro-8-iodo-quinazoline-4-yl)amino]ethyl]pyrazine-2-yl]pyrimidine-4-carboxamide (P58) as a solid. LCMS (Method 3): retention time 1.09 min, m / z 533 / 535 [M+H] + .

[0994] 1 H NMR(400MHz,DMSO-d6)δppm 9.46(s,1H),8.88(br d,1H),8.77(d,1H),8.72(d,1H),8.64(d,1H),8.57(s,1H),8.46(s,1H),8.35(d,1H),8.02-8.11(m,2H),6.15(quint,1H),1.77(d,3H).

[0995] Example E16: 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4- Preparation of triazol-1-yl]pyrimidine-5-carboxamide (Compound P68)

[0996]

[0997] Step 1: Preparation of N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]-6-chloro-8-(trifluoromethyl)quinazolin-4-amine

[0998]

[0999] To a mixture of 4,6-dichloro-8-(trifluoromethyl)quinazoline (prepared as described in WO 21 / 083936) (4.04 g, 15.1 mmol) and [(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (prepared similarly according to the procedure found, for example, in WO 21 / 083936) (5.09 g, 16.6 mmol) in ACN (80.8 mL) was added triethylamine (4.62 g, 45.4 mmol, 5.32 mL) at room temperature. The reaction mixture was stirred at 90 ° C for 1 hour, cooled to room temperature, then diluted with ice-cold water (50 mL), and the product was extracted with EtOAc (5 x 60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]-6-chloro-8-(trifluoromethyl)quinazolin-4-amine as a solid.

[1000] LCMS (Method 3): retention time 1.14 min, m / z 499 / 501 / 503 [M+H] + .

[1001] Step 2: Preparation of 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-[(4-methoxyphenyl)methyl]pyrimidine-5-carboxamide

[1002]

[1003] A reaction vessel was charged with N-[(1S)-1-[2-(5-bromopyrimidin-2-yl)-1,2,4-triazol-3-yl]ethyl]-6-chloro-8-(trifluoromethyl)quinazolin-4-amine (prepared as described above) (700 mg, 1.41 mmol), 4-methoxybenzylamine (0.211 g, 1.54 mmol), bis(benzonitrile)palladium(II) chloride (0.1 equiv, 0.141 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.141 mmol), toluene (7 mL) and triethylamine (2.1 mmol). The vessel was flushed with nitrogen and then with carbon monoxide. The reaction mixture was heated to 80° C. under 8 bar carbon monoxide pressure for 3 hours. After cooling to room temperature, the pressure was carefully released and the vessel was flushed with nitrogen. The mixture was filtered through a bed of celite, the filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate in cyclohexane) to give 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-[(4-methoxyphenyl)methyl]-pyrimidine-5-carboxamide as a solid. LCMS (Method 3): retention time 1.10 min, m / z 584 / 586 [M+H] + .

[1004] 1 H NMR(400MHz,DMSO-d6)δppm 9.41(t,1H),9.33(s,2H),9.11(d,1H),8.91(d,1H),8.28(s,1H),8.20(d,1H),8.18(s, 1H),7.31(d,2H),6.92(d,2H),6.32(quint,1H),4.47(d,2H),3.74(s,3H),1.77(d,3H).

[1005] Step 3: Preparation of 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-5-carboxamide (Compound P68)

[1006]

[1007] To a solution of 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-N-[(4-methoxyphenyl)methyl]pyrimidine-5-carboxamide (prepared as described above) (0.15 g, 0.256 mmol) in acetonitrile (3.75 mL) was added a solution of cerium (IV) ammonium nitrate (0.283 g, 0.513 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 16 hours and then diluted with saturated aqueous sodium bicarbonate solution. The product was extracted several times with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to give 2-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]pyrimidine-5-carboxamide (P68) as a solid. LCMS (Method 3): retention time 0.99 min, m / z 464 / 466 [M+H] + .

[1008] Example E17: 6-[5-[(1S)-1-[[6-Chloro-8-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]- Preparation of 1,2,4-triazol-1-yl]-N-(2-cyanoethyl)pyrimidine-4-carboxamide (Compound P53)

[1009]

[1010] By 6- [5- [(1S) -1- [[6- chloro- 8- (trifluoromethyl) quinazoline -4- base] -methyl -amino] ethyl] -1,2,4- triazol -1- base] pyrimidine -4- carboxylic acid methyl ester (I-22) (0.15g, 0.304mmol) and 3- aminopropionitrile (0.913mmol) in methanol (1.5mL) at room temperature stirred 18 hours. The reaction mixture is diluted with water (15mL) and the solid formed is separated by filtration. The crude solid material is purified by combiflash (ethyl acetate in cyclohexane) to obtain 6- [5- [(1S) -1- [[6- chloro- 8- (trifluoromethyl) quinazoline -4- base] -methyl -amino] ethyl] -1,2,4- triazol -1- base] -N- (2- cyanoethyl) pyrimidine -4- carboxamide (P53) as a white solid. LCMS (Method 3): retention time 1.13 min, m / z 531 / 533 [M+H] + .

[1011] 1H NMR(CDCl3)δ: 8.71(d,1H),8.64(d,1H),8.52(s,1H),8.35(br t,1H),8.07(s,1H),8.04(s,2H),6.91(quint,1H),3.81(m,2H),3.45(s,3H),2.79(t,2H),1.96(d,3H).

[1012] Table P : Examples of compounds having formula (I)

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034] pass 1 Compounds P84 and P85 characterized by H NMR measurements:

[1035] P84： 1 H NMR(400MHz,DMSO-d6)δppm 9.40(d,1H),9.29(s,1H),9.14(d,1H),8.46(br s,1H),8.42(m,2H),8.40(s,1H),8.28(s,1H),8.13(br s,1H),7.67(t,1H),6.57(quint,1H),1.77(d,3H).

[1036] P85： 1 H NMR(400MHz,DMSO-d6)δppm 9.40(d,1H),9.15(d,1H),8.47(s,1H),8.44(d,1H),8.28(s,1H),8.26(br s,1H),8.22(s,1H),7.79(br s,1H),7.68(t,1H),6.33(quint,1H),1.74(d,3H).

[1037] Preparation of intermediates

[1038] Example PI-1 :Preparation of tert-butyl N-[(1S)-1-[2-(5-carbamoylthiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7)

[1039]

[1040] Step 1: Preparation of Silica Gel Supported Ammonium Chloride (NH4Cl / SiO2)

[1041] According to Tetrahedron Letters 2005, 46, 6879-6882: Silica gel (5.0 g, Merck Kieselgel 60, particle size 0.063-0.200 mm, 70-230 mesh) was mixed with a solution of ammonium chloride (20 mmol) in water (5.0 mL). The water was evaporated in vacuo to give a white powder, which was further dried under reduced pressure. This material was used as an ammonia source in the next step.

[1042] Step 2:Preparation of tert-butyl N-[(1S)-1-[2-(5-carbamoylthiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7)

[1043]

[1044] To a mixture of 2-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]thiazole-5-carboxylic acid (I-2) (400 mg, 1.18 mmol), silica gel-supported ammonium chloride (NH4Cl / SiO2, prepared as described above, 700 mg) and tosyl chloride (227 mg, 1.18 mmol) was added triethylamine (479 mg, 4.71 mmol). The reaction mixture was thoroughly mixed with a spatula. After 2 min, the mixture was directly purified by column chromatography without any post-treatment (50% EtOAc in cyclohexane) to give tert-butyl N-[(1S)-1-[2-(5-carbamoylthiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7) as a white solid.

[1045] LCMS (Method 3): Retention time 0.44 min, m / z 283 [M+H-tBu] + . 1 HNMR (400MHz, MeOH-d4) δppm 8.21 (s, 1H), 8.05 (s, 1H), 5.77 (m, 1H), 1.54 (d, 1H), 1.40 (br s, 9H).

[1046] Example PI-2 : Preparation of 6-chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-8-(trifluoromethyl)quinazolin-4-amine (I-21)

[1047]

[1048] To a solution of 6-chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-8-(trifluoromethyl)quinazolin-4-amine (I-18) (4 g, 8.79 mmol) in acetonitrile (40 mL) was added iodomethane (5.50 mL, 87.87 mmol) and cesium carbonate (5.73 g, 17.57 mmol) at room temperature. The reaction mixture was stirred at 80 ° C for 6 h. The mixture was cooled to room temperature, diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by combiflash using ethyl acetate and cyclohexane as eluents to give 6-chloro-N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-8-(trifluoromethyl)quinazolin-4-amine (1.7 g) as a light yellow solid.

[1049] LCMS (Method 3): retention time 1.26 min, m / z 469 / 471 [M+H] + . 1 HNMR (CDCl3) δ: 8.49-8.55 (m, 2H), 8.01-8.07 (m, 4H), 6.88 (q, 1H), 3.50 (s, 3H), 1.94 (d, 3H).

[1050] Similarly, 6-chloro-N-[(1S)-1-[2-(6-iodopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-8-(trifluoromethyl)quinazolin-4-amine (Compound I-39) can be obtained from 6-chloro-N-[(1S)-1-[2-(6-iodopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-8-(trifluoromethyl)quinazolin-4-amine (I-38) using the above protocol. LCMS (Method 4): Retention time 2.32 min, m / z 561 / 563 [M+H] + .

[1051] Example PI-3 : Preparation of [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-methyl-ammonium chloride (I-29)

[1052]

[1053] Step 1: Preparation of N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-carbamic acid tert-butyl ester (I-28)

[1054]

[1055] To a solution of N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (CAS 344609-43-4) (0.454 g, 2.24 mmol) in 2-methyltetrahydrofuran (4.5 mL) was added N,N-dimethylformamide dimethyl acetal (2.69 mmol) at room temperature. The resulting reaction mixture was stirred at 40°C for 1 hour and then concentrated in vacuo to give the crude intermediate N-[(1S)-2-[1-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (LCMS (Method 3): retention time 0.96 min, m / z 202 [M+H-tBu] + ).

[1056] 1,4-Dioxane (2.724 mL), acetic acid (2.724 mL) and 6-hydrazinopyrimidine-4-carboxamide (CAS 2283190-21-4) (0.34 g, 2.22 mmol) were added to the intermediate and the mixture was stirred at 80 ° C for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (acetonitrile in water) to give N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-carbamic acid tert-butyl ester (I-28).

[1057] LCMS (Method 3): Retention time 1.01 min, m / z 292 [M+H-tBu] + .

[1058] Step 2: Preparation of [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-methyl-ammonium chloride (I-29)

[1059]

[1060] To a solution of tert-butyl N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-N-methyl-carbamate (I-28) (0.3 g, 0.86 mmol) in 1,4-dioxane (4.3 mL) was added a 4M hydrochloric acid solution (2.3 mL) in 1,4-dioxane at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated to dryness in vacuo. The residue was triturated with TBME, and the resulting solid was filtered and dried in vacuo to give [(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]-methyl-ammonium chloride (I-29) as a solid.

[1061] LCMS (Method 3): Retention time of the corresponding free base 0.16 min, m / z 248 [M+H] + .

[1062] Example PI-4 :Preparation of [(1S)-1-[2-(5-carbamoylpyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]ammonium chloride (I-16)

[1063]

[1064] Step 1: Preparation of tert-butyl N-[(1S)-1-[2-(5-bromopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate...

Claims

1. A compound having formula (I) in: A 1 , A 2 and A 3 N or CR independently of each other Y ;or A 1 =A 2 -A 3 Together they are NR-C(=O)-N; A 4 and A 5 N or CR independently of each other YY ; Q is wherein the staggered lines represent the connection of Q to the remainder of the compound of formula (I); R is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy; R 1 is hydrogen, C1-C6 alkyl, C1-C6 cyanoalkyl, aminocarbonyl C1-C6 alkyl, hydroxycarbonyl C1-C6 alkyl, C1-C6 nitroalkyl, trimethylsilane C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C4 cycloalkyl C1-C6 -C2 alkyl-, C3-C4 cycloalkyl C1-C2 alkyl-, oxetan-3-yl-CH2-, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, benzyl or benzyl substituted by 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy and C1-C6 haloalkyl; R 2a and R 2b each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, NO2, SF5, CN, C(O)NH2, C(O)OH, C(S)NH2, C3-C6 cycloalkyl, one to three independently selected from R x C3-C6 cycloalkyl, C3-C6 cycloalkylcarbonyl, phenyl, substituted by one to three independently selected from R x substituted phenyl, heteroaryl, substituted by one to three independently selected from R x Substituents substituted heteroaryl; OR 6 , piperidin-2-one-1-yl, one to two independently selected from R x Substituents substituted with piperidin-2-one-1-yl, pyridin-2-one-1-yl, substituted with one or two independently selected from R x substituted pyridin-2-one-1-yl, azetidin-1-yl, substituted by one to two independently selected from R x substituted azetidin-1-yl, pyrrolidin-1-yl, substituted by one or two independently selected from R x substituted pyrrolidin-1-yl, C3-C6 cycloalkyl, C1-C4 alkyl, substituted by one or two independently selected from R Z C3-C6 cycloalkyl C1-C4 alkyl substituted with a substituent; C3-C6 cycloalkyl C1-C3 alkoxy, substituted with one or two independently selected from R x C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C5 cyanoalkyl, C1-C5 cyanoalkoxy, C1-C4 alkylsulfanyl, substituted by one to three independently selected from R x C1-C4 alkylsulfanyl, C1-C4 alkylsulfonyl, substituted by one to three independently selected from R x C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, and substituted by one to three independently selected from R x C1-C4 alkylsulfinyl substituted with a substituent; R 3 is C1-C3 alkyl or C1-C3 haloalkyl; R 4 and R 4a is independently pyrimidinyl, pyrazinyl, pyridazinyl or thiazolyl, each of which is independently substituted by a single -C(O)NR 10 R 11 replace; or R 4a is an N-attached pyrazolyl or N-attached triazolyl, each of which is independently substituted by a single -C(O)NR 10 R 11 replace; or R 4 and R 4a is 4-cyano-pyrimidin-6-yl; R 10 is hydrogen, hydroxy, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, cyanoC3-C4 cycloalkyl, C3-C4 cycloalkylC1-C3 cyanoalkyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl, or 3-methyl-1,1-dioxothietane-3-yl; and R 11 is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or R 10 and R 11 together with the nitrogen to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or 4-morpholinyl group; R 5 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, C3-C4 alkoxy C(O)-, (C1-C3 alkoxy)2CH-, halogen, CN, NH2C(O), amino (i.e., NH2), (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, hydroxy, C3-C4 halocycloalkyl, C3-C4 cyanocycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C3 Alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkoxy-C1-C3 alkyl, (C1-C3 alkyl)sulfonylamino, (C1-C3 alkyl)sulfonyl(C1-C3 alkyl)amino, (C1-C3 alkyl)NHC(O), (C1-C3 alkyl)2NC(O), (C1-C3 cycloalkyl)NHC(O), (C1-C3 cycloalkyl)(C1-C3 alkyl)NC(O), (C1-C3 alkyl)C(O)(C1-C3 alkyl)N, (C1-C3 alkyl)C(O)NH, (C1-C3 alkyl)C(O), (C1-C3 alkoxy)C(O), HC(O), benzophenone imine, C1-C3 haloalkoxy, phenyl, or a 5-membered heteroaromatic ring; or R 5 is phenyl substituted by one to three substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, CN and hydroxy; or R 5 is a 5-membered heteroaromatic ring substituted with one to three substituents selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, CN and hydroxy; R 5a and R 5b are independently selected from hydrogen, halogen, CN, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy; R 6 is phenyl, benzyl, heteroaryl, or C3-C6 cycloalkyl; or R 6 is phenyl, benzyl, heteroaryl, or C3-C6 cycloalkyl, each of which is independently selected from one to three R x Substituents are substituted; R x independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, NO2, SF5, CN, C(O)NH2, C(S)NH2, C1-C4 haloalkylsulfanyl, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfanyl, C1-C4 alkylsulfinyl and C1-C4 alkylsulfonyl; R Y is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl; R YY is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, CN and cyclopropyl; and R Z is selected from the group consisting of oxo, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and CN; or an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer or N-oxide of the compound of formula (I).

2. The compound of claim 1, wherein A 1 and A 3 is N, and A 2 is CH, and A 4 Yes CR Y And A 5 is CH; and R Y is selected from the group consisting of hydrogen, methyl, trifluoromethyl and methoxy.

3. The compound of claim 1 or claim 2, wherein R 1 is hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl.

4. The compound according to any one of claims 1 to 3, wherein R 2a is halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by one or two substituents independently selected from C1-C3 haloalkyl, cyano, and halogen, C3-C6 cycloalkylC1-C4 alkyl, C3-C6 cycloalkylC1-C4 alkyl substituted by one to three substituents independently selected from C1-C3 haloalkyl, cyano, and halogen, C1-C5 cyanoalkyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylsulfinyl, C1-C4 haloalkylsulfinyl, C3-C6 cycloalkylsulfanyl, C3-C6 cycloalkylsulfinyl, or C3-C6 cycloalkylsulfonyl.

5. The compound according to any one of claims 1 to 4, wherein R 2b It is halogen, C1-C3 haloalkyl, C1-C3 haloalkylsulfanyl, C1-C3 haloalkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or CN.

6. The compound according to any one of claims 1 to 5, wherein R 3 It is a C1-C3 alkyl group or a C1-C3 haloalkyl group.

7. The compound of any one of claims 1 to 6, wherein Q is selected from Q a -1 to Q a -16 and R 4 is 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 is independently unsubstituted or substituted with one to two substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halo, hydroxy, CN, ... C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, C1-C3 alkyl, C1-C3 C6 haloalkoxy, C2-C6 haloalkenyloxy, C2-C6 haloalkynyloxy, C3-C4 halocycloalkoxy, NH2C(O)-, NH2C(S)-, (OH)N=C(NH2)- and a 5-membered heteroaryl ring optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.

8. A compound as claimed in any one of claims 1 to 6, wherein Q is selected from Q b -1 to Q b -13 and R 4a is 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 is independently unsubstituted or substituted with one to two substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, halogen, hydroxy, cyano, and C1-C3 haloalkoxy.

9. The compound of any one of claims 1 to 8, wherein R 4 Selected from Q c -1.Q c -2.Q c -3.Q c -4.Q c -5.Q c -6 and Q c -10; or R 4a Selected from Q c -1.Q c -2.Q c -3.Q c -4.Q c -5.Q c -6.Q c -7.Q c -8 and Q c -10: Where R 10 is hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; or Where R 10 is hydrogen, hydroxy, methyl, ethyl, trifluoromethyl, cyanoethyl, methoxy, ethoxy, cyclopropyl, 1-cyanocyclopropyl, 1-cyano-1-cyclopropyl-ethyl, oxetan-3-yl, thietan-3-yl, 3-methylthietan-3-yl, 1,1-dioxothietane-3-yl or 3-methyl-1,1-dioxothietane-3-yl; And R 11 is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

10. The compound of claim 1, wherein the formula (I) is represented by formula Iaa, Iab, Iac, Iad or Iae, wherein the asterisk represents a stereocenter: Among them, R 1 , R 2a , R 2b and R 3 is as defined in any one of claims 1, 3, 4, 5 or 6, and Q1 corresponds to Q as defined in any one of claims 1, 7, 8 or 9.

11. The compound of claim 10, wherein Q1 is selected from Q a -1 and Q b -1: And where R 4 and R 4a Independently selected from Where R 10 is hydrogen, methyl, ethyl, cyanomethyl, difluoromethyl, trifluoromethyl, cyclopropyl or 1-cyanocyclopropyl; and R 11 is hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

12. The compound of claim 10, wherein Q1 is selected from Q a -1 and Q b -1: And where R 4 and R 4a It's Q c -10.

13. A composition comprising a compound as claimed in any one of claims 1 to 12, one or more adjuvants and diluents and optionally one or more other active ingredients.

14. A method, which is (i) a method for combating and controlling insects, mites, nematodes or molluscs, the method comprising applying an insecticidal, acaricidal, nematicidal or molluscicidal effective amount of the compound according to any one of claims 1 to 12 or the composition according to claim 13 to the pest, the location of the pest, or a plant susceptible to attack by the pest; or (ii) a method for protecting plant propagation material from attack by insects, mites, nematodes or molluscs, which method comprises treating the propagation material or the site where the propagation material is planted with an effective amount of a compound as claimed in any one of claims 1 to 12 or a composition as claimed in claim 13; or (iii) A method for controlling parasites in or on an animal in need thereof, the method comprising administering an effective amount of the compound according to any one of claims 1 to 12 or the composition according to claim 13.

15. A plant propagation material, such as a seed, comprising a compound according to any one of claims 1 to 12 or a composition according to claim 13, or treated with or having attached thereto said compound or said composition.

16. A method having the formula XL-Q ac -a, XL-Q ac -b or XL-Q ac -c compounds: Where in each case, where applicable: A 1 , A 2 , A 3 , A 4 , A 5 , R 2a and R 2b is as defined in any one of claims 1 to 6, R 1 is hydrogen or methyl, R 3 It is methyl, Q c -COOH, Q c -COORa and Q c -Xa is: Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl.

17. A method having the formula XL-Q bc -a, XL-Q bc -b or XL-Q bc -c compounds: Where applicable: A 1 , A 2 , A 3 , A 4 , A 5 , R 2a and R 2b is as defined in any one of claims 1 to 6, R 1 is hydrogen or methyl, R 3 It is methyl, Q c -COOH, Q c -COORa and Q c -Xa are respectively Q as defined in claim 16 c1 -a, Q c1 -b and Q c1 -c, Ra is benzyl or C1-C6 alkyl, preferably Ra is methyl, and Xa is halogen, such as Br, Cl or I, preferably Cl.

18. A compound of formula XLIIIa(i), XLIIIb(i), XLIIIb-1(i), XLIIId(i) or XLIIIe(i): Among them A 4 , A 5 and R 2a is as defined in 1, 2 and 4, and wherein Gr is difluoromethyl or trifluoromethyl.

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