Patent Application
20230064576
The present invention relates to heterocyclyl pyridazine compounds and the uses thereof for controlling phytopathogenic microorganisms such as phytopathogenic fungi. It also relates to processes and intermediates for preparing these compounds.
Numerous crop protection agents to combat or prevent microorganisms' infestations have been developed until now. However, the need remains for the development of new compounds as such, so as to provide compounds being effective against a broad spectrum of phytopathogenic microorganisms, such as fungi, having low toxicity, high selectivity or that can be used at low application rate whilst still allowing effective pest control. It may also be desired to have new compounds to prevent the emergence of resistances.
The present invention provides new compounds for controlling phytopathogenic microorganisms such as fungi which have advantages over known compounds and compositions in at least some of these aspects.
The present invention relates compounds of the formula (I):
Wherein A, T, m, R3, R4, R5, R6, R7 R8, L and Q are as recited herein as well as their salts, N-oxides and solvates.
The present invention relates to a composition comprising at least one compound of formula (I) as defined herein and at least one agriculturally suitable auxiliary.
The present invention also relates to the use of a compound of formula (I) as defined herein or a composition as defined herein for controlling phytopathogenic fungi.
The present invention relates to a method for controlling phytopathogenic fungi which comprises the step of applying at least one compound of formula (I) as defined herein or a composition as defined herein to the plants, plant parts, seeds, fruits or to the soil in which the plants grow.
The present invention also relates to processes and intermediates for preparing compounds of formula (I) as disclosed herein.
The term “halogen” as used herein refers to fluorine, chlorine, bromine or iodine atom.
The term “methylidene” as used herein refers to a CH2 group connected to a carbon atom via a double bond.
The term “halomethylidene” as used herein refers to a CX2 group connected to a carbon atom via a double bond, wherein X is halogen.
The term “oxo” as used herein refers to an oxygen atom which is bound to a carbon atom or sulfur atom via a double bound.
The term “formyl” as used herein refers to —CH(═O).
The term “C1-C6-alkyl” as used herein refers to a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of C1-C6-alkyl include but are not limited to methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Particularly, said hydrocarbon chain has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl or tert-butyl.
The term “C1-C6-alkylene” as used herein refers to a divalent C1-C6-alkyl group as defined herein. Examples of C1-C6-alkylene include but are not limited to —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —CH2—C(CH3)—CH2—, —CH2—CH2—CH2—CH2—, —CH2—C(CH3)—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—CH2—CH2—.
The term “C2-C6-alkenyl” or “alkanediyl” as used herein refers to an unsaturated, branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and comprising at least one double bond.
Examples of C2-C6-alkenyl include but are not limited to ethenyl (or “vinyl”), prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl, 3-methylbut-1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3-enyl, 1-methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1-methylpent-2-enyl, 4-methyl-pent-1-enyl, 3-methylpent-1-enyl, 2-methylpent-1-enyl, 1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethyl-but-3-enyl, 1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1-ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethylbut-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, 2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl, 1-isopropyl-prop-1-enyl, 3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl or methylhexadienyl group.
The term “C2-C6-alkenylene” as used herein refers to a divalent C2-C6-alkenyl group as defined herein. Examples of C2-C6-alkenylene include but are not limited to ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, undecenylene, dodecenylene, and the like.
The term “C2-C6-alkynyl” as used herein refers to a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and comprising at least one triple bond. Examples of C2-C6-alkynyl include but are not limited to ethynyl, prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methyl-but-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methyl-pent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methyl-pent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl group.
The term “C2-C6-alkynylene” as used herein refers to a divalent C2-C6-alkynyl group as defined herein.
The term “C1-C6-haloalkyl” as used herein refers to a C1-C6-alkyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C2-C6-haloalkenyl” as used herein refers to a C2-C6-alkenyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C2-C6-haloalkynyl” as used herein refers to a C2-C6-alkynyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-alkoxy” as used herein refers to a group of formula (C1-C6-alkyl)-O—, in which the term “C1-C6-alkyl” is as defined herein. Examples of C1-C6-alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.
The term “C1-C6-haloalkoxy” as used herein refers to a C1-C6-alkoxy group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different. Examples of C1-C6-haloalkoxy include but are not limited to chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoro-methoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy.
The term “C1-C6-haloalkoxy” as used herein refers to a C1-C6-alkoxy group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-hydroxyalkyl” as used herein refers to a C1-C6-alkyl group as defined above in which at least one hydrogen atom is replaced with a hydroxyl group. Examples of C1-C6-hydroxyalkyl include but are not limited to hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1,2-dihydroxyethyl, 3-hydroxy-propyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2, 3-dihydroxy-propyl and 1,3-dihydroxypropan-2-yl.
The term “C1-C6-alkylsulfanyl” as used herein refers to a saturated, linear or branched group of formula (C1-C6-alkyl)-S—, in which the term “C1-C6-alkyl” is as defined herein. Examples of C1-C6-alkylsulfanyl include but are not limited to methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropyl-sulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentyl-sulfanyl, hexylsulfanyl group.
The term “C1-C6-haloalkylsulfanyl” as used herein refers to a C1-C6-alkylsulfanyl as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-alkylsulfinyl” s used herein refers to a saturated, linear or branched group of formula (C1-C6-alkyl)-S(═O)—, in which the term “C1-C6-alkyl” is as defined herein. Examples of C1-C6-alkylsulfinyl include but are not limited to saturated, straight-chain or branched alkylsulfinyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) C1-C6-alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butyl-sulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethyl-propylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1-ethyl-2-methylpropylsulfinyl.
The term “C1-C6-haloalkylsulfinyl” as used herein refers to a C1-C6-alkylsulfinyl as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-alkylsulfonyl” s used herein refers to a saturated, linear or branched group of formula (C1-C6-alkyl)-S(═O)2—, in which the term “C1-C6-alkyl” is as defined herein. Examples of C1-C6-alkylsulfonyl include but are not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methyl-ethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1-ethyl-2-methylpropylsulfonyl.
The term “C1-C6-haloalkylsulfonyl” as used herein refers to a C1-C6-alkylsulfonyl as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-alkylcarbonyl” as used herein refers to a saturated, linear or branched group of formula (C1-C6-alkyl)-C(═O)—, in which the term “C1-C6-alkyl” is as defined herein.
The term “C1-C6-haloalkylcarbonyl” as used herein refers to a C1-C6-alkylcarbonyl as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-alkoxycarbonyl” as used herein refers to a saturated, linear or branched group of formula (C1-C6-alkoxy)-C(═O)—, in which the term “C1-C6-alkoxy” is as defined herein.
The term “C1-C6-haloalkoxycarbonyl” as used herein refers to a C1-C6-alkoxycarbonyl as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms that may be the same or different.
The term “C1-C6-dialkylamino” as used herein refers to an amino radical having two independently selected C1-C6-alkyl groups as defined herein. Examples of C1-C6-dialkylamino include but are not limited to N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.
The term “non-aromatic C3-C12-carbocycle” as used herein refers to a non-aromatic, saturated or unsaturated, hydrocarbon ring system in which all of the ring members, which vary from 3 to 12, are carbon atoms. The ring system may be monocyclic or polycyclic (fused, spiro or bridged). Non-aromatic C3-C12-carbocycles include but are not limited to C3-C12-cycloalkyl (mono or bicyclic), C3-C12-cycloalkenyl (mono or bicyclic), bicylic system comprising an aryl (e.g. phenyl) fused to a monocyclic C3-C8-cycloalkyl (e.g. tetrahydronaphthalenyl, indanyl), bicylic system comprising an aryl (e.g. phenyl) fused to a monocyclic C3-C8-cycloalkenyl (e.g. indenyl, dihydronaphthalenyl) and tricyclic system comprising a cyclopropyl connected through one carbon atom to a bicylic system comprising an aryl (e.g. phenyl) fused to a monocyclic C3-C8-cycloalkyl or to a monocyclic C3-C8-cycloalkenyl. The non-aromatic C3-C12-carbocycle can be attached to the parent molecular moiety through any carbon atom.
The term “C3-C12-cycloalkyl” as used herein refers to a saturated, monovalent, mono- or bicylic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Examples of monocyclic C3-C8-cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Examples of bicyclic C6-C12-cycloalkyls include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.0]octyl, octahydropentalenyl and bicyclo[4.2.1]nonane.
The term “C3-C12-cycloalkylene” as used herein refers to a divalent C3-C12-cycloalkyl group as defined herein, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and bicyclo[2.2.1]hept-2-ylene.
The term “C3-C12-cycloalkenyl” as used herein refers to an unsaturated, monovalent, mono- or bicylic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Examples of monocyclic C3-C8-cycloalkenyl group include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl group. Examples of bicyclic C6-C12-cycloalkenyl group include but are not limited to bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.
The term “C3-C12-cycloalkenylene” as used herein refers to a divalent C3-C12-cycloalkenyl as disclosed herein.
The term “aromatic C6-C14-carbocycle” or “aryl” as used herein refers to an aromatic hydrocarbon ring system in which all of the ring members, which vary from 6 to 14, preferably from 6 to 10, are carbon atoms. The ring system may be monocyclic or fused polycyclic (e.g. bicyclic or tricyclic). Examples of aryl include but are not limited to phenyl, azulenyl and naphthyl. The aryl can be attached to the parent molecular moiety through any carbon atom. It is further understood that when said aryl group is substituted with one or more substituents, said substituent(s) may be at any positions on said aryl ring(s). Particularly, in the case of aryl being a phenyl group, said substituent(s) may occupy one or both ortho positions, one or both meta positions, or the para position, or any combination of these positions.
The term “non-aromatic 3- to 14-membered heterocycle” as used herein refers to a saturated or unsaturated non-aromatic ring system comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. If the ring system contains more than one oxygen atoms, they are not directly adjacent. Non aromatic heterocycles include but are not limited to 3- to 7-membered monocyclic non-aromatic heterocycles and 6- to 14-membered polycyclic (e.g. bicyclic or tricyclic) non-aromatic heterocycles. The non-aromatic 3- to 14-membered heterocycle can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained within the heterocycle.
The term “non-aromatic 3- to 7-membered monocyclic heterocycle” as used herein refers to a 3-, 4-, 5-, 6- or 7-membered monocyclic ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur where the ring system is saturated or unsaturated but not aromatic. For instance, the heterocycle may comprise one to three nitrogen atoms, or one or two oxygen atoms, or one or two sulfur atoms, or one to three nitrogen atoms and one oxygen atom, or one to three nitrogen atoms and a sulfur atom or one sulfur atom and one oxygen atom. Examples of saturated non-aromatic heterocycles include but are not limited to 3-membered ring such as oxiranyl, aziridinyl, 4-membered ring such as azetidinyl, oxetanyl, thietanyl, 5-membered ring such as tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl, isoxazolidinyl, oxazolidinyl, oxadiazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, 6-membered ring such as piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, triazinanyl, hexahydrotriazinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl, dithianyl, morpholinyl, 1,2-oxazinanyl, oxathianyl, thiomorpholinyl or 7-membered ring such as oxepanyl, azepanyl, 1,4-diazepanyl and 1,4-oxazepanyl. Examples of unsaturated non-aromatic hererocyles include but are not limited to 5-membered ring such as dihydrofuranyl, 1,3-dioxolyl, dihydrothienyl, pyrrolinyl, dihydroimidazolyl, dihydropyrazolyl, isoxazolinyl, dihydrooxazolyl, dihydrothiazolyl or 6-membered ring such as pyranyl, thiopyranyl, thiazinyl and thiadiazinyl.
The term “non-aromatic 6- to 14-membered polycyclic heterocycle” as used herein refers to a 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered polycyclic (e.g. bicyclic or tricyclic) ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur where the ring system is saturated or unsaturated but not aromatic. Non-aromatic bicyclic heterocycles may consist of a monocyclic heteroaryl as defined herein fused to a monocyclic C3-C8-cycloalkyl, a monocyclic C3-C8-cycloalkenyl or a monocyclic non-aromatic heterocycle or may consist of a monocyclic non-aromatic heterocycle fused either to an aryl (e.g. phenyl), a monocyclic C3-C8-cycloalkyl, a monocyclic C3-C8-cycloalkenyl or a monocyclic non-aromatic heterocycle. When two monocyclic heterocycles (aromatic or non-aromatic) comprising nitrogen atoms are fused, nitrogen atom may be at the bridgehead (e.g. 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl). Non-aromatic tricyclic heterocycles may consist of a monocyclic cycloalkyl connected through one common atom to a non-aromatic bicyclic heterocycle.
The term “non-aromatic 3- to 7-membered monocyclic heterocyclylene” as used herein refers to a divalent non-aromatic 3- to 7-membered monocyclic heterocycle as disclosed herein.
The term “aromatic 5- to 14-membered heterocycle” or “heteroaryl” as used herein refers to an aromatic ring system comprising 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. If the ring system contains more than one oxygen atom, they are not directly adjacent. Aromatic heterocycles include aromatic 5- or 6-membered monocyclic heterocycles and 6- to 14-membered polycyclic (e.g. bicyclic or tricyclic) aromatic heterocycles. The 5- to 14-membered aromatic heterocycle can be connected to the parent molecular moiety through any carbon atom or nitrogen atom contained within the heterocycle.
The term “aromatic 5- or 6-membered monocyclic heterocycle” or “monocyclic heteroaryl” as used herein refers to a 5- or 6-membered monocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Examples of 5-membered monocyclic heteroaryl include but are not limited to furyl (furanyl), thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isothiazolyl, thiazolyl, thiadiazolyl and thiatriazolyl. Examples of 6-membered monocyclic heteroaryl include but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl.
The term “6- to 14-membered polycyclic aromatic heterocycle” or “polycyclic heteroaryl” as used herein refers to a 6-, 7-, 8-, 9-, 10-, 11-,12-, 13- or 14-membered polycyclic (e.g. bicyclic or tricyclic) ring system containing 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Aromatic bicyclic heterocycles may consist of a monocyclic heteroaryl as defined herein fused to an aryl (e.g. phenyl) or to a monocyclic heteroaryl. Examples of bicyclic aromatic heterocycle include but are not limited to 9-membered ring such as indolyl, indolizinyl, isoindolyl, benzimadozolyl, imidazopyridinyl, indazolyl, benzotriazolyl, purinyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl and benzisoxazolyl or 10-membered ring such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinal and benzodioxinyl. In 9- or 10-membered aromatic bicyclic heterocycles comprising two fused 5- or 6-membered monocyclic aromatic heterocycles, nitrogen atom may be at the bridgehead (e.g. imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]oxazolyl, furo[2,3-d]isoxazolyl). Examples of tricyclic aromatic heterocyle include but are not limited to carbazolyl, acridinyl and phenazinyl.
The terms “non-aromatic C3-C12-carbocyclyloxy”, “C3-C8-cycloalkyloxy”, “aromatic C6-C14-carbocyclyloxy”, “aromatic 5- to 14-membered heterocyclyloxy”, “non-aromatic 5- to 14-membered heterocyclyloxy” as used herein designate a group of formula —O—R wherein R is respectively a non-aromatic C3-C12-carbocyclyl, a C3-C8-cycloalkyl, an aromatic C6-C14-carbocyclyl, an aromatic 5- to 14-membered heterocyclyl or a non-aromatic 5- to 14-membered heterocyclyl group as defined herein.
As used herein, when a group is said to be “substituted”, the group may be substituted with one or more substituents. The expression “one or more substituents” refers to a number of substituents that ranges from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the conditions of stability and chemical feasibility are met.
The term “leaving group” as used herein is to be understood as meaning a group which is displaced from a compound in a substitution or an elimination reaction, for example a halogen atom, a trifluoromethanesulphonate (“triflate”) group, alkoxy, methanesulphonate, p-toluenesulphonate, etc.
The terms “as described herein” when referring to a variable A, Q, L, m, T, R1, R2, R3, R4, R5, R6, R7, R8 incorporates by reference the broad definition of the variable as well as preferred, more preferred and even more preferred definitions, if any.
The present invention relates to compounds of the formula (I)
wherein
The embodiment disclosed above is referred herein as “embodiment 1”.
Not encompassed herein are compounds resulting from combinations which are against natural laws and which the person skilled in the art would therefore exclude based on his/her expert knowledge. For instance, ring structures having three or more adjacent oxygen atoms are excluded.
The compound of formula (I) can suitably be in its free form, salt form, N-oxides form or solvate form (e.g. hydrate).
Depending on the nature of the substituents, the compound of formula (I) may be present in the form of different stereoisomers. These stereoisomers are, for example, enantiomers, diastereomers, atropisomers or geometric isomers. Accordingly, the invention encompasses both pure stereoisomers and any mixture of these isomers. Where a compound can be present in two or more tautomer forms in equilibrium, reference to the compound by means of one tautomeric description is to be considered to include all tautomer forms.
Any of the compounds of the present invention can also exist in one or more geometric isomer forms depending on the number of double bonds in the compound. Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (═Z-) or trans (=E-) form. The invention thus relates equally to all geometric isomers and to all possible mixtures, in all proportions.
Depending on the nature of the substituents, the compound of formula (I) may be present in the form of the free compound and/or a salt thereof, such as an agrochemically active salt.
Agrochemically active salts include acid addition salts of inorganic and organic acids well as salts of customary bases. Examples of inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulfuric acid, phosphoric acid and nitric acid, and acidic salts, such as sodium bisulfate and potassium bisulfate. Useful organic acids include, for example, formic acid, carbonic acid and alkanoic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, saturated or mono- or diunsaturated fatty acids having 6 to 20 carbon atoms, alkylsulphuric monoesters, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals having 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which bear one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals having 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which bear one or two phosphonic acid radicals), where the alkyl and aryl radicals may bear further substituents, for example p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.
Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
The compounds of the invention may exist in multiple crystalline and/or amorphous forms. Crystalline forms include unsolvated crystalline forms, solvates and hydrates.
Aliphatic R1 and R2 substituents as used herein in the expression “aliphatic R1, R2, R3, R4 and R5 substituents may be substituted with one or more substituents” designates C1-C6-alkyl.
Aliphatic R3 and R4 substituents as used herein in the expression “aliphatic R1, R2, R3, R4 and R5 substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl and the C1-C6-alkyl moiety of —Si(C1-C6-alkyl)3.
Aliphatic R5 substituents as used herein in the expression “aliphatic R1, R2, R3, R4 and R5 substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl and the C1-C6-alkyl moiety of —O—Si(C1-C6-alkyl)3.
Aliphatic L substituents as used herein in the expression “aliphatic L substituents may be substituted with one or more LSa substituents” designates C1-C6-alkylene, C2-C6-alkenylene, C2-C6-alkynylene and the C1-C6-alkylene moiety of C1-C6-alkylene-C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene, C1-C6-alkylene-C3-C8-cycloalkylene-C1-C6-alkylene, C1-C6-alkylene-(C═O)—, C1-C6-alkylene-C3-C8-cycloalkenylene, C3-C8-cycloalkenylene-C1-C6-alkylene, C1-C6-alkylene-C3-C8-cycloalkenylene-C1-C6-alkylene.
Aliphatic R6S substituents as used herein in the expression “aliphatic R6S, Rc and Rd substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl and the C1-C6-alkyl moiety of —Si(C1-C6-alkyl)3 and —O—Si(C1-C6-alkyl)3.
Aliphatic Rc substituents as used herein in the expression “aliphatic R6S, Rc and Rd substituents may be substituted with one or more substituents” designates C1-C6-alkyl.
Aliphatic Rd substituents as used herein in the expression “aliphatic R6S, Rc and Rd substituents may be substituted with one or more substituents” designates C1-C6-alkyl and C1-C6-haloalkyl.
Aliphatic R7 substituents as used herein in the expression “aliphatic R7, Re, Rf and Rg substituents may be substituted with one or more R7Sa substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C2-C6-alkynyloxy, C2-C6-haloalkynyloxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl and the C1-C6-alkyl moiety of —Si(C1-C6-alkyl)3 and —O—Si(C1-C6-alkyl)3.
Aliphatic Re substituents as used herein in the expression “aliphatic R7, Re, Rf and Rg substituents may be substituted with one or more R7Sa substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl and C2-C6-haloalkynyl.
Aliphatic Rf substituents as used herein in the expression “aliphatic R7, Re, Rf and Rg substituents may be substituted with one or more R7Sa substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and the C1-C6-alkyl moiety of C1-C6-alkylamino and di(C1-C6-alkyl)amino.
Aliphatic Rg substituents as used herein in the expression “aliphatic R7, Re, Rf and Rg substituents may be substituted with one or more R7Sa substituents” designates C1-C6-alkyl and C1-C6-haloalkyl.
Aliphatic R8 substituents as used herein in the expression “aliphatic R8, Rh and Ri substituents may be substituted with one or more R8Sa substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C2-C6-alkynyloxy, C2-C6-haloalkynyloxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl and the C1-C6-alkyl moiety of —Si(C1-C6-alkyl)3 and —O—Si(C1-C6-alkyl)3.
Aliphatic Rh substituents as used herein in the expression “aliphatic R8, Rh and Rk substituents may be substituted with one or more R8a substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl and C2-C6-haloalkynyl.
Aliphatic Rj substituents as used herein in the expression “aliphatic R8, Rh and Ri substituents may be substituted with one or more R8Sa substituents” designates C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl and C2-C6-haloalkynyl.
Aliphatic QS substituents as used herein in the expression “aliphatic QS, Rj and Ri substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl and the C1-C6-alkyl moiety of —Si(C1-C6-alkyl)3 and —O—Si(C1-C6-alkyl)3.
Aliphatic Rj substituents as used herein in the expression “aliphatic QS, Rj and Rk substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy.
Aliphatic Rk substituents as used herein in the expression “aliphatic QS, Rj and Rk substituents may be substituted with one or more substituents” designates C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl and C2-C6-haloalkenyl.
Cyclic R1, R2 and R5 substituents as used herein in the expression “cyclic R1, R2, R3, R4 and R5 substituents may be substituted with one or more substituents” designates C3-C8-cycloalkyl.
Cyclic R3 and R4 substituents as used herein in the expression “cyclic R1, R2, R3, R4 and R5 substituents may be substituted with one or more substituents” designates C3-C8-cycloalkyl, aromatic C6-C14-carbocycle, non-aromatic 3- to 14-membered heterocycle and aromatic 5- to 14-membered heterocycle.
Cyclic L substituents as used herein in the expression “cyclic or cyclic moiety of L substituents may be substituted with one or more LSc substituents” designates C3-C8-cycloalkylene, C3-C8-cycloalkenylene and non-aromatic 3- to 7-membered monocyclic heterocyclylene.
Cyclic L substituents as used herein in the expression “cyclic or cyclic moiety of L substituents may be substituted with one or more LSc substituents” designates C3-C8-cycloalkylene moiety of C1-C6-alkylene-C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene, C1-C6-alkylene-C3-C8-cyclo-alkylene-C1-C6-alkylene and the C3-C8-cycloalkenylene moiety of C1-C6-alkylene-C3-C8-cycloalkenylene, C3-C8-cycloalkenylene-C1-C6-alkylene and C1-C6-alkylene-C3-C8-cycloalkenylene-C1-C6-alkylene.
Cyclic R6 substituents as used herein in the expression “cyclic, or cyclic moiety of, R6 substituents may be substituted with one or more R6S substituents” designate non-aromatic C3-C12-carbocycle, aromatic C6-C14-carbocycle, non-aromatic 3- to 14-membered heterocycle and aromatic 5- to 14-membered heterocycle.
Cyclic moiety of R6 substituents as used herein in the expression “cyclic, or cyclic moiety of, R6 substituents may be substituted with one or more R6S substituents” designate the non-aromatic C3-C12-carbocycle of non-aromatic C3-C12-carbocyclyloxy, the aromatic C6-C14-carbocyclyle of aromatic C6-C14-carbocyclyloxy, the aromatic 5- to 14-membered heterocycle of aromatic 5- to 14-membered heterocyclyloxy, the non-aromatic 5- to 14-membered heterocycle of non-aromatic 5- to 14-membered heterocyclyloxy, the non-aromatic C3-C12-carbocycle of C1-C3-alkoxy substituted by a non-aromatic C3-C12-carbocycle, the aromatic C6-C14-carbocycle of C1-C3-alkoxy substituted by an aromatic C6-C14-carbocycle, the non-aromatic 3- to 14-membered heterocycle of C1-C3-alkoxy substituted by a non-aromatic 3- to 14-membered heterocycle, the aromatic 5- to 14-membered heterocycle of C1-C3-alkoxy substituted by an aromatic 5- to 14-membered heterocycle, the non-aromatic C3-C12-carbocycle of C1-C3-haloalkoxy substituted by a non-aromatic C3-C12-carbocycle, the aromatic C6-C14-carbocycle of C1-C3-haloalkoxy substituted by an aromatic C6-C14-carbocycle, the non-aromatic 3- to 14-membered heterocycle of C1-C3-haloalkoxy substituted by a non-aromatic 3- to 14-membered heterocycle and the aromatic 5- to 14-membered heterocycle of C1-C3-haloalkoxy substituted by an aromatic 5- to 14-membered heterocycle.
Cyclic R6S substituents as used herein in the expression “cyclic R6S and Rc substituents may be substituted with one or more substituents” designates C3-C8-cycloalkyl, C3-C8-cycloalkenyl, aromatic C6-C14-carbocycle, aromatic 5- or 6-membered monocyclic heterocycle and non-aromatic 3- to 7-membered monocyclic heterocycle.
Cyclic moiety of R6S substituents as used herein in the expression “cyclic or cyclic moiety of R6S and cyclic Rc substituents may be substituted with one or more substituents” designates the C3-C8-cycloalkyl of C3-C8-cycloalkyloxy.
Cyclic Rc substituents as used herein in the expression “cyclic or cyclic moiety of R6S and cyclic Rc substituents may be substituted with one or more substituents” designates C3-C8-cycloalkyl.
Cyclic R7 substituents as used herein in the expression “cyclic R7, Re and Rg substituents may be substituted with one or more R7Sc substituents” designates C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aromatic C6-C14-carbocycle, aromatic 5- or 6-membered monocyclic heterocycle and non-aromatic 3- to 7-membered monocyclic heterocycle.
Cyclic moiety of R7 substituents as used herein in the expression “cyclic or cyclic moiety of R7, cyclic Re and cyclic Rg substituents may be substituted with one or more R7Sc substituents” designates the C3-C8-cycloalkyl of C3-C8-cycloalkyloxy, the aromatic C6-C14-carbocycle of aromatic C6-C14-carbocyclyloxy, the aromatic 5- or 6-membered monocyclic heterocycle of aromatic 5- or 6-membered monocyclic heterocyclyloxy and the non-aromatic 3- to 7-membered monocyclic heterocycle of non-aromatic 3- to 7-membered monocyclic heterocyclyloxy.
Cyclic Re substituents as used herein in the expression “cyclic R7, Re and Rg substituents may be substituted with one or more R7Sc substituents” designates C3-C8-cycloalkyl, C3-C8-halocycloalkyl, aromatic C6-C14-carbocycle, aromatic 5- or 6-membered monocyclic heterocycle and non-aromatic 3- to 7-membered monocyclic heterocycle.
Cyclic Rg substituents” as used herein in the expression “cyclic R7, Re and Rg substituents may be substituted with one or more R7Sc substituents” designates C3-C8-cycloalkyl.
Cyclic R8 substituents as used herein in the expression “wherein cyclic R8, Rh and Ri substituents may be substituted with one or more R7Sc substituents” designates C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aromatic C6-C14-carbocycle, non-aromatic 3- to 14-membered heterocycle and aromatic 5- to 14-membered heterocycle.
Cyclic moiety of R8 substituents as used herein in the expression “wherein cyclic or cyclic moiety of R8, cyclic Rh and cyclic Ri substituents may be substituted with one or more R8Sc substituents” designates the C3-C8-cycloalkyl of C3-C8-cycloalkyloxy, the aromatic C6-C14-carbocycle of aromatic C6-C14-carbocyclyloxy, the non-aromatic 3- to 14-membered heterocycle of non-aromatic 3- to 14-membered heterocyclyloxy and the aromatic 5- to 14-membered heterocycle of aromatic 5- to 14-membered heterocyclyloxy.
Cyclic Rh substituents as used herein in the expression “wherein cyclic or cyclic moiety of R8, cyclic Rh and cyclic Ri substituents may be substituted with one or more R8Sc substituents” designates C3-C8-cycloalkyl, C3-C8-halocycloalkyl, aromatic C6-C14-carbocycle, aromatic 5- to 14-membered heterocycle and non-aromatic 3- to 7-membered monocyclic heterocycle.
Cyclic Ri substituents as used herein in the expression “wherein cyclic R8, Rh and Ri substituents may be substituted with one or more R8Sc substituents” designates C3-C8-cycloalkyl, C3-C8-halocycloalkyl, aromatic C6-C14-carbocycle, aromatic 5- to 14-membered heterocycle and non-aromatic 3- to 7-membered monocyclic heterocycle.
Cyclic QS substituents as used herein in the expression “cyclic or cyclic moiety of QS and cyclic Rk substituents may be substituted with one or more RQs substituents” designates C3-C8-cycloalkyl, C3-C6-cycloalkenyl, non-aromatic 3- to 7-membered monocyclic heterocycle and aromatic 5- to 14-membered heterocycle.
Cyclic moiety of QS substituents as used herein in the expression “cyclic or cyclic moiety of QS and cyclic Rk substituents may be substituted with one or more RQs substituents” designates the C3-C8-cycloalkyl of C3-C8-cycloalkyloxy.
Cyclic Rk substituents as used herein in the expression “cyclic QS and Rk substituents may be substituted with one or more RQs substituents” designates C3-C8-cycloalkyl.
In the above formula (I), A is preferably selected from the group consisting of O, C(═O), S(═O)2, NR1 and CR1R2 with R1 and R2 being as described herein above, preferably with R1 being hydrogen or C1-C4-alkyl (e.g. methyl, ethyl) and R2 being a hydrogen atom.
In the above formula (I), A is more preferably selected from the group consisting of O, C(═O), NR1 and CR1R2 with R1 and R2 being hydrogen.
In the above formula (I), A is even more preferably selected from the group consisting of O, C(═O), NR1 and CR1R2 with R1 and R2 being hydrogen.
In some embodiments, when m is 0, A is preferably CR1R2 with R1 and R2 being as described herein above, preferably with R1 and R2 being a hydrogen atom, or A is 0.
In some embodiments, when m is 0, A is more preferably CR1R2 with R1 and R2 being hydrogen.
In some embodiments, when m is 1, A is preferably O, C(═O), S(═O)2, NR1 and CR1R2 with R1 and R2 being as described herein above, preferably with R1 and R2 being a hydrogen atom.
In some embodiments, when m is 2, A is preferably O, C(═O) and CR1R2 with R1 and R2 being as described herein above, preferably with R1 being hydrogen or C1-C6-alkyl (e.g. methyl, ethyl) and R2 being a hydrogen atom.
In a more preferred embodiment, T is selected from the group consisting of hydrogen and C1-C4-alkyl,
R3 and R4 are independently selected from the group consisting of hydrogen, fluorine, chlorine, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C3-C6-cycloalkyl,
and
R5 is selected from the group consisting of hydrogen, hydroxyl, C1-C4-alkyl and C1-C4-alkoxy.
In the above formula (I), m is more preferably is 1.
In the above formula (I), T is preferably hydrogen or —C(═O)(ORa1) with Ra1 being as described herein above, more preferably Ra1 is C1-C6-alkyl, even more preferably T is hydrogen.
In the above formula (I), R3 and R4, when present, are preferably selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C3-C8-cycloalkyl and aromatic C6-C14-carbocycle (e.g. phenyl), or R3 and R4 form together with the carbon atom to which they are attached to a C3-C8-cycloalkyl (e.g. cyclopropyl), more preferably R3 and R4 are hydrogen, fluorine, methyl or ethyl, even more preferably R3 and R4 are hydrogen and fluorine.
In the above formula (I), R5 is preferably selected from the group consisting of hydrogen, hydroxyl and C1-C6-alkoxy, more preferably R5 is hydrogen.
In the above formula (I), when L is a C1-C6-alkylene substituted on a same carbon atom by two substituents, forming together with the carbon atom to which they are attached to, a C3-C8-cycloalkyl, L is preferably:
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In the above formula (I), when L is a C1-C6-alkylene substituted on a same carbon atom by two substituents, forming together with the carbon atom to which they are attached to, a non-aromatic 3- to 7-membered monocyclic heterocycle, L is preferably:
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In the above formula (I), when L is a C3-C8-cycloalkylene or comprises a C3-C8-cycloalkylene (C1-C6-alkylene-C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene and C1-C6-alkylene-C3-C8-cyclo-alkylene-C1-C6-alkylene), L is more preferably C3-C8-cycloalkylene (x=0, y=0, C3-cycloalkylene.
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In the above formula (I), when L is a C3-C8-cycloalkenylene or comprises a C3-C8-cycloalkenylene (C1-C6-alkylene-C3-C8-cycloalkenylene, C3-C8-cycloalkenylene-C1-C6-alkylene and C1-C6-alkylene-C3-C8-cycloalkenylene-C1-C6-alkylene), L is preferably:
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In a preferred embodiment L represents a direct bond or L is selected from the group consisting of C1-C6-alkylene, C1-C6-alkylene substituted on a same carbon atom by two substituents forming together with the carbon atom to which they are attached to a C3-C6-cycloalkyl, C1-C6-alkylene substituted on a same carbon atom by two substituents forming together with the carbon atom to which they are attached to a non-aromatic 3- to 7-membered monocyclic heterocycle,
wherein aliphatic L substituents may be substituted with one to three LSa substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-cycloalkyl and C3-C6-halocycloalkyl,
wherein cyclic or cyclic moiety of L substituents may be substituted with one to three LSc substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, oxo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C3-C6-cycloalkyl and C3-C6-halocycloalkyl.
In a more preferred embodiment L represents a direct bond or L is selected from the group consisting of C1-C6-alkylene,
wherein aliphatic L substituents may be substituted with one to three LSa substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C3-C6-cycloalkyl,
wherein cyclic or cyclic moiety of L substituents may be substituted with one to three LSc substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, oxo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C3-C6-cycloalkyl.
In the above formula (I), L is preferably a direct bond or a C1-C6-alkylene that may be substituted as described herein, even more preferably L is a direct bond, —CH2— or —CF2-.
When L is a “direct bond”, it means that the R6 group is directly attached to the carbon atom to which the R5 group is attached, thus forming a “—CR5R6-” moiety.
In the above formula (I), R6 is preferably selected from the group consisting of non-aromatic C3-C12-carbocycle, aromatic C6-C14-carbocycle, non-aromatic 3- to 14-membered heterocycle, aromatic 5- to 14-membered heterocycle, aromatic C6-C14-carbocyclyloxy, C1-C3-alkoxy substituted by an aromatic C6-C14-carbocycle and aromatic C6-C14-carbocyclylsulfanyl.
In some embodiments, R6 is selected from the group consisting of indanyl, 1,2,3,4-tetrahydronaphthalenyl, spiro[cyclopropane-1,2′-indane]-1-yl, phenyl, naphthyl, 2,3-dihydrobenzofuranyl, indolinyl, 1,3-benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, 2,3-dihydro-1,4-benzodioxinyl, 5,6,7,8-tetrahydroquinolinyl, 4,5,6,7-tetrahydrobenzothiophenyl, furanyl, thienyl, pyridinyl, pyrimidinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[2,3-b]pyridin-3-yl, phenoxy, benzyloxy and phenylsulfanyl.
In the above formula (I), R6 is more preferably selected from the group consisting of non-aromatic C3-C12-carbocycle (e.g. indan-5-yl) aromatic C6-C14-carbocycle (e.g. phenyl or 2-naphthyl) and aromatic 5- to 14-membered heterocycle (e.g. 2-furyl, 2-thienyl, indol-3-yl).
In some embodiments, R6 is selected from the group consisting of indanyl, phenyl, naphthyl, furanyl, thienyl and indolyl.
Preferably R6 is selected from the group consisting of non-aromatic C5-C10-carbocycle, phenyl, naphthyl, non-aromatic 5- to 10-membered heterocycle, aromatic 5- to 10-membered heterocycle, non-aromatic C5-C10-carbocyclyloxy, phenoxy, naphthyloxy, aromatic 5- to 10-membered heterocyclyloxy, non-aromatic 5- to 10-membered heterocyclyloxy and phenylsulfanyl.
More preferably R6 is selected from the group consisting of indanyl, phenyl, naphthyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, furanyl, thienyl, pyridinyl, indolyl, benzofuranyl, benzothiophenyl, pyrrolo[2,3-b]pyridin-3-yl, phenoxy, benzyloxy and phenylsulfanyl.
Even more preferably R6 is selected from the group consisting of indanyl, 1,2,3,4-tetrahydronaphthalenyl, phenyl, naphthyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-1,4-benzodioxinyl, thienyl, pyridinyl, indolyl, benzofuranyl, benzothiophenyl and phenoxy,
In some embodiments, R6 is
wherein
R6s1 is hydrogen or R6s,
R6s2 is hydrogen or R6s,
R6s being as described herein (above or below), preferably at least one of R6s1 and R6s2 is different from hydrogen.
R6 groups as disclosed herein may be substituted with one or more R6S substituents as disclosed herein above or as disclosed herein below.
R6 groups as disclosed herein may be substituted preferably with one to three R6S substituents as disclosed herein above or as disclosed herein below that may be the same or different.
R6 groups as disclosed herein may be substituted more preferably with one to three R6S substituents as disclosed herein above or as disclosed herein below that may be the same or different.
R6 groups as disclosed herein may be substituted even more preferably with one or two R6S substituents as disclosed herein above or as disclosed herein below that may be the same or different.
In some embodiments, R6 is substituted with one or more R6S substituents as disclosed herein above or as disclosed herein below that may be the same or different.
R6S substituents are preferably selected from the group consisting of halogen, nitro, cyano, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-haloalkylsulfanyl, C3-C8-cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aromatic C6-C14-carbocycle (e.g. phenyl), aromatic 5- or 6-membered monocyclic heterocycle (e.g. pyridinyl, pyrimidinyl, thienyl, furanyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, thiazolyl, preferably pyridinyl, pyrazolyl, imidazolyl, triazolyl) and non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (oxanyl), pyrrolidinyl, azetidinyl, morpholinyl, preferably oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (oxanyl)), wherein cyclic R6S substituents may be substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxycarbonyl.
R6S substituents are more preferably selected from the group consisting of halogen (e.g. chlorine, bromine, fluorine), nitro, hydroxyl, C1-C6-alkyl (e.g. methyl, isopropyl), C1-C6-haloalkyl (e.g. CF3, CHF2), C1-C6-alkoxy (e.g. methoxy), C1-C6-haloalkoxy (e.g. difluoromethoxy, trifluoromethoxy), C2-C6-alkenyl (e.g. prop-1-en-2-yl), C2-C6-alkynyl (e.g. ethynyl), C1-C6-haloalkylsulfanyl (e.g.—SCF3), cyclopropyl, cyclobutyl, cyclopentyl, pyridin-3-yl, oxetan-3-yl, and tetrahydrofuran-3-yl, wherein cyclic R6S substituents may be substituted with one or more substituents independently selected from the group consisting of halogen (e.g. chlorine), C1-C6-alkyl (e.g. methyl), C1-C6-haloalkyl (e.g. CF3) and C1-C6-alkoxycarbonyl (e.g. methoxycarbonyl).
R6S substituents are likewise more preferably selected from the group consisting of halogen, nitro, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkylsulfanyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, oxetanyl and tetrahydrofuranyl, wherein cyclic R6S substituents may be substituted with one or two substituents independently selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl and C1-C4-alkoxycarbonyl. R6S substituents are even more preferably selected from the group consisting of chlorine, bromine, nitro, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, difluoromethoxy, trifluoromethoxy, C2-C4-alkenyl, C2-C4-alkynyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, cyclopropyl, cyclobutyl, cyclopentyl, pyridinyl, oxetanyl and tetrahydrofuranyl.
Non-limiting examples of suitable -L-R6 groups include any of the -L-R6 groups disclosed in column “-L-R6” of Table 1.
In the above formula (I), when L represents a direct bond, R6 is preferably selected from the group consisting of non-aromatic C3-C12-carbocycle, aromatic C6-C14-carbocycle and aromatic 5- to 14-membered heterocycle, more preferably R6 is selected from the group consisting of indanyl, phenyl, naphtyl, furanyl, thienyl, pyridyl, dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, chromanyl, isochromanyl, quinolinyl, isoquinolinyl and indolyl.
In the above formula (I), when L represents a direct bond, R6 is even more preferably selected from the group consisting of indan-5-yl, phenyl, naphtyl, furan-2-yl, furan-3-yl, pyridin-2-yl, thien-2-yl, thien-3-yl, benzofuran-2-yl, benzothiophen-3-yl, and indol-3-yl.
In the above formula (I), when L represents a C1-C6-alkylene, R6 is preferably selected from the group consisting of an aromatic C6-C14-carbocycle (e.g. phenyl) and aromatic 5- to 14-membered heterocycle (pyridine, thienyl).
In the above formula (I), when L represents a C1-C4-alkylene, R6 is more preferably selected from the consisting of phenyl, thienyl, furanyl, pyrazolyl, pyridinyl and pyrimidinyl.
In the above formula (I), R7 is preferably selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-hydroxyalkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfonyl, C3-C8-cycloalkyl, aromatic 5- or 6-membered monocyclic heterocycle, non-aromatic 3- to 7-membered monocyclic heterocycle, —N(Re)2, —C(═NRf)Rf and —C(═O)N(Rg)2,
More preferred aliphatic R7, Re and Rg substituents as disclosed herein may be substituted with one to three R7Sa substituents independently selected from the group consisting of hydroxyl, C1-C4-alkoxy and C3-C6-cycloalkyl.
More preferred cyclic R7, Re and Rg substituents as disclosed herein may be substituted with one to three R7Sc substituents independently selected from the group consisting of halogen, hydroxyl, C1-C4-alkyl and C1-C4-alkoxy.
R7 is even more preferably selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxy, C3-C6-cycloalkyl, pyridinyl, imidazolyl, pyrazolyl and thiazolyl,
Even more preferred aliphatic R7 substituents as disclosed herein may be substituted with one or two R7Sa substituents independently selected from the group consisting of cyano, C1-C4-alkoxy, C3-C6-cycloalkyl and —Si(C1-C6-alkyl)3.
More preferred cyclic R7 substituents as disclosed herein may be substituted with one or two R7Sc substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, C1-C4-alkyl and C1-C4-alkoxy.
Preferred aliphatic R7, Re substituents as disclosed herein may be substituted with one or more R7Sa substituents that may be the same or different as disclosed herein above or as disclosed herein below. R7Sa substituents are preferably selected from the group consisting of hydroxyl, C1-C6-alkoxy (e.g. methoxy, ethoxy), C3-C8-cycloalkyl (e.g. cyclobutyl), C1-C6-alkoxycarbonyl (e.g. ethoxycarbonyl) and aromatic C6-C14-carbocycle (e.g. phenyl), more preferably C1-C6-alkoxy.
Most preferably R7Sa substituents are C1-C4-alkoxy.
In some embodiments, R7 is an unsubstituted C1-C6-alkenyl or a C1-C6-alkenyl substituted by a C1-C6-alkoxy.
Preferred cyclic R7 and Re substituents as disclosed herein may be substituted with one or more R7Sc substituents that may be the same or different as disclosed herein above or as disclosed herein below. Preferred cyclic R7 and Re substituents as disclosed herein may be substituted with one or more R7Sc substituents that may be the same or different as disclosed herein above or as disclosed herein below. R7Sc substituents are preferably selected from the group consisting of halogen (e.g. fluorine, chlorine), hydroxyl, C1-C6-alkyl (e.g. methyl) and C1-C6-alkoxy (e.g. methoxy), more preferably chlorine.
In some embodiments, R7 is an unsubstituted pyridinyl (e.g. pyridin-4-yl) or a pyridinyl substituted by a halogen atom (e.g. chlorine).
Non-limiting examples of suitable R7 include any of the R7 groups listed in column “R7” of Table 1.
In the above formula (I), R8 is preferably selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C3-C8-cycloalkyl, aromatic C6-C14-carbocycle, non-aromatic 3- to 14-membered heterocycle, aromatic 5- to 14-membered heterocycle, C3-C8-cycloalkyloxy, non-aromatic 3- to 14-membered heterocyclyloxy and —N(Rh)2,
Preferred aliphatic R8 and Rh substituents as disclosed herein may be substituted with one to three R8Sa substituents preferably independently selected from the group consisting of hydroxyl, carboxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C3-C6-cycloalkyl, C1-C4-alkylsulfanyl and non-aromatic 3- to 7-membered monocyclic heterocycle.
Preferred cyclic R8 and Rh substituents may be substituted with one to three R8Sc substituents preferably independently selected from the group consisting of oxo, halogen, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C3-C6-cycloalkyl and non-aromatic 3- to 7-membered monocyclic heterocycle or two R8Sc substituents form together with the carbon atom to which they are attached to a non-aromatic 3- to 7-membered monocyclic heterocycle.
In the above formula (I), R8 is more preferably selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C2-C4-alkenyl, C1-C4-alkylsulfanyl, C1-C4-haloalkylsulfanyl, C1-C4-alkylsulfinyl, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, phenyl, naphthyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, C3-C6-cycloalkyloxy and —N(Rh)2,
More preferred aliphatic R8 and Rh substituents as disclosed herein may be substituted with one or two R8 substituents independently selected from the group consisting of hydroxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C3-C6-cycloalkyl, C1-C4-alkylsulfanyl oxetanyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl.
More preferred cyclic R8 and Rh substituents may be substituted with one or two R8Sc substituents independently selected from the group consisting of oxo, fluorine, chlorine, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C3-C6-cycloalkyl, oxetanyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl In the above formula (I), R8 is even more preferably selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylsulfanyl, C3-C6-cycloalkyl, oxetanyl, azetidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, pyridinyl and —N(Rh)2, with Rh being independently selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, oxetanyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl
In the above formula (I), R8 is most preferably selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C3-C6-cycloalkyloxy and —N(Rh)2,
Most preferred aliphatic R8 and Rh substituents may be substituted with one or two R8Sa substituents independently selected from the group consisting of hydroxyl, methoxy and ethoxy.
Most preferred cyclic or cyclic moiety of R8 and cyclic Rh substituents may be substituted with one or two R8Sc substituents independently selected from the group consisting of fluorine, methyl, ethyl and cyclopropyl.
In some embodiments, R8 is selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl, cyclopropyloxy, oxetanyloxy, azetidinyloxy and —N(Rh)2 with Rh being preferably independently selected from the group consisting of hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C3-C8-cycloalkyl (e.g. cyclopropyl, cyclohexyl), aromatic C6-C14-carbocycle (e.g. phenyl) and non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxetanyl),
In the above formula (I), R8 is more preferably selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-alkoxy and —N(Rh)2 with Rh being independently selected from the group consisting of hydrogen, C1-C6-alkyl and C3-C8-cycloalkyl.
Preferred aliphatic R8 and Rh substituents as disclosed herein may be substituted with one or more R8Sa substituents as disclosed herein above or as disclosed herein below.
R8Sa substituents are preferably selected from the group consisting of hydroxyl, carboxyl, C1-C6-alkoxy (e.g. methoxy), C1-C6-alkoxycarbonyl (e.g. methoxycarbonyl), C3-C8-cycloalkyl (e.g. cyclopropyl), C1-C6-alkylsulfanyl (e.g. methylsulfanyl, non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. 1,3-dioxolanyl)
Preferred cyclic R8 and Rh substituents may be substituted with one or more R8Sc substituents that may be the same or different as disclosed herein above or below.
R8Sc substituents are preferably selected from the group consisting of oxo, halogen (e.g. chlorine), cyano, hydroxyl, C1-C6-alkyl (e.g. methyl), C1-C6-haloalkyl (e.g. difluoromethyl), C1-C6-alkoxy (e.g. methoxy), C1-C6-alkoxycarbonyl (e.g. ethoxycarbonyl, propyloxycarbonyl), C3-C8-cycloalkyl (e.g. cyclopropyl) and non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxolanyl, oxetanyl, tetrahydrofuranyl) or two R8Sc substituents form together with the carbon atom to which they are attached to a non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxetanyl).
R8Sc substituents are more preferably selected from the group consisting of oxo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C3-C6-cycloalkyl and non-aromatic 4- to 7-membered monocyclic heterocycle or two R8Sc substituents form together with the carbon atom to which they are attached to a non-aromatic 4- to 7-membered monocyclic heterocycle.
Non-limiting examples of suitable R8 include any of the R8 groups listed in column “R8” of Table 1.
In the above formula (I), when Q is an aromatic C6-C14-carbocycle, Q is preferably phenyl or naphthyl, more preferably phenyl.
In the above formula (I), when Q is a non-aromatic C3-C12-carbocycle, Q is preferably a C7-C12 bicyclic system comprising an aryl fused to a C3-C8-cycloalkyl or a C7-C12 bicyclic system comprising an aryl fused to a C3-C8-cycloalkenyl.
When Q is a non-aromatic C3-C12-carbocycle, Q is more preferably a C7-C12 bicyclic system comprising an aryl (e.g. phenyl) fused to a C3-C8-cycloalkyl, even more preferably a bicyclo[4.2.0]octa-1,3,5-trienyl, more specifically 3-bicyclo[4.2.0]octa-1,3,5-trienyl, indan-4-yl and indan-5-yl.
In the above formula (I), when Q is a non-aromatic 3- to 14-membered heterocycle, Q is typically a non-aromatic 6- to 14-membered bicyclic heterocycle, preferably Q is a non-aromatic bicyclic heterocycle comprising a 4- to 6-membered monocyclic non-aromatic hererocycle fused to an aryl or a non-aromatic bicyclic heterocycle comprising a 5- or 6-membered monocyclic heteroaryl fused to a monocyclic C3-C8-cycloalkyl.
When Q is a non-aromatic 3- to 14-membered heterocycle, Q is more preferably a non-aromatic bicyclic heterocycle comprising a 4- to 6-membered monocyclic non-aromatic hererocycle fused to an aryl, even more preferably Q is 1,3-benzodioxolyl or 2,3-dihydrobenzofuranyl, more specifically Q is 1,3-benzodioxol-5-yl or 2,3-dihydrobenzofuran-5-yl.
In the above formula (I), when Q is an aromatic 5- to 14-membered heterocycle, Q is preferably an aromatic 5- or 6-membered monocyclic heterocycle, an aromatic 9- or 10-membered bicyclic heterocycle comprising an aromatic 5- or 6-membered monocyclic heterocycle fused to an aryl (phenyl) or a 9- or 10-membered aromatic bicyclic heterocycle comprising two fused aromatic 5- or 6-membered monocyclic heterocycles.
When Q is an aromatic 5- to 14-membered heterocycle, Q is more preferably an aromatic 5- or 6-membered monocyclic heterocycle quinolinyl, benzothiophenyl or indolyl), even more preferably Q is pyrazolyl, thiazolyl, thienyl, pyridinyl or indolyl, more specifically Q is pyrazol-4-yl, thiazol-4-yl, pyridin-2-yl, pyridin-3-yl, thien-3-yl or indol-5-yl.
Preferably, Q is selected from the group consisting of phenyl, naphthyl, bicyclo[4.2.0]octa-1,3,5-trienyl, benzodioxolyl, 2,3-dihydrobenzofuranyl, indolinyl, benzofuranyl, benzothienyl, quinolinyl, pyridinyl, pyrazolyl, thiazolyl, thienyl and indolyl.
Preferred Q groups may be substituted with one to three QS substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkylsulfanyl, C1-C4-haloalkylsulfanyl, C1-C4-alkylsulfonyl, C3-C6-cycloalkyl, non-aromatic 3- to 7-membered monocyclic heterocycle, phenyl, aromatic 5- or 6-membered heterocycle and —N(Rk)2 with Rk being independently selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-haloalkyl and C3-C6-cycloalkyl.
Said preferred aliphatic QS substituents may be substituted with one or two substituents independently selected from the group consisting of hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl and C3-C6-cycloalkyl.
More preferably Q is selected from the group consisting of phenyl, 1,3-benzodioxol-5-yl, 2,3-dihydrobenzofuranyl, pyridinyl, thienyl and indol-5-yl.
More preferred Q groups may be substituted with one or two QS substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkylsulfanyl, C3-C6-cycloalkyl and non-aromatic 3- to 7-membered monocyclic heterocycle.
Said more preferred aliphatic QS substituents may be substituted with one or two substituents independently selected from the group consisting of hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl and C3-C6-cycloalkyl.
Even more preferably Q is selected from the group consisting of phenyl, pyridinyl and thien-yl.
Even more preferred Q groups may be substituted with one or two QS substituents independently selected from the group consisting of halogen, cyano, nitro, formyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkylsulfanyl, C3-C8-cycloalkyl, oxiranyl and oxetanyl.
Said even more preferred aliphatic QS substituents may be substituted with one or two substituents independently selected from the group consisting of hydroxyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
Q groups as disclosed herein may be substituted with one or more QS substituents that may be the same or different as disclosed herein above or as disclosed herein below.
In some embodiments, Q is substituted with one or more QS substituents as disclosed herein above or as disclosed herein below that may be the same or different.
QS substituents are preferably selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, nitro, formyl, C1-C6-alkyl (e.g. methyl, ethyl, propyl, isopropyl), C1-C6-haloalkyl (e.g. trifluoromethyl, difluoromethyl), C1-C6-alkylcarbonyl (e.g. methylcarbonyl), C1-C6-alkoxycarbonyl (e.g. methoxycarbonyl), C1-C6-alkoxy (e.g. methoxy, ethoxy), C1-C6-haloalkoxy (e.g. difluoromethoxy, trifluoromethoxy), C2-C6-alkenyl (e.g. vinyl), C2-C6-alkynyl (e.g. ethynyl), C1-C6-alkylsulfanyl (e.g. methylsulfanyl), C1-C6-haloalkylsulfanyl (e.g. trifluoromethylsulfanyl), C1-C6-alkylsulfonyl (e.g. methylsulfonyl), C3-C8-cycloalkyl (e.g. cyclopropyl, cyclobutyl), non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxiranyl, oxetanyl), aromatic C6-C14-carbocycle (e.g. phenyl), aromatic 5- to 14-membered heterocycle (e.g. pyrazole) and —N(Rk)2 with Rk being methyl.
Said aliphatic QS substituents may be substituted with one or two substituents independently selected from the group consisting of hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl and C3-C6-cycloalkyl.
Said cyclic QS substituents may be substituted as disclosed herein or preferably with one or more halogen atom (e.g. fluorine).
QS substituents are more preferably selected from the group consisting of halogen (e.g. chlorine, bromine, iodine, fluorine), C1-C4-alkyl (e.g. methyl, ethyl), C1-C4-haloalkyl (e.g. trifluoromethyl, difluoro-methyl), C1-C4-alkoxy (e.g. methoxy, ethoxy), C1-C4-haloalkoxy (e.g. difluoromethoxy, trifluoromethoxy), C2-C4-alkenyl (e.g. vinyl), C2-C4-alkynyl (e.g. ethynyl), C1-C4-alkylsulfanyl (e.g. methylsulfanyl) and C3-C6-cycloalkyl (e.g. cyclopropyl).
Said aliphatic QS substituents may be substituted with one or two substituents independently selected from the group consisting of hydroxyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
Said cyclic QS substituents may be substituted as disclosed herein or preferably with one or more halogen atoms (e.g. fluorine).
Non-limiting examples of suitable Q include any of the Q groups listed in column “Q” of Table 1.
In some embodiments, Q is an unsubstituted phenyl or a phenyl substituted by one or more QS substituents as described herein.
In some embodiments, Q is
wherein
Qs1 is hydrogen or halogen (preferably fluorine).
Qs2 is hydrogen or QS, wherein QS is as described herein above, preferably Qs2 is selected from the group consisting of hydrogen, halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, nitro, hydroxyl, amino, C1-C6-alkyl (e.g. methyl, ethyl), C1-C6-haloalkyl (e.g. trifluoromethyl, difluoromethyl), C1-C6-alkylcarbonyl (e.g. methoxycarbonyl), C1-C6-alkoxy (e.g. methoxy), C1-C6-haloalkoxy (e.g. trifluoromethoxy), C2-C6-alkenyl (e.g. vinyl), C2-C6-alkynyl (e.g. ethynyl), C1-C6-alkylsulfanyl (e.g. methylsulfanyl), C1-C6-haloalkylsulfanyl (e.g. trifluoromethylsulfanyl), C3-C8-cycloalkyl (e.g. cyclopropyl, cyclobutyl) that may be substituted with one or more halogen atoms and non-aromatic 3- to 7-membered monocyclic heterocycle (e.g. oxetanyl) that may be substituted with one or more halogen atoms, more preferably Qs2 is selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, vinyl, ethynyl, methylsulfanyl, trifluoromethylsulfanyl, cyclopropyl that may be substituted with one or more halogen atoms and oxetanyl that may be substituted with one or more halogen atoms, preferably at least one of Qs1 and Qs2 is different from hydrogen.
The above specified definitions of R1, R2, R3, R4, R5, R6, R7, R8, L, m and Q (broad definition as well as preferred, more preferred, even more preferred definitions) can be combined in various manners.
These combinations of definitions thus provide sub-classes of compounds according to the invention, such as for instance the ones disclosed below.
Preferably the present invention relates to compounds of the formula (I),
wherein
More preferably the present invention relates to compounds of the formula (I),
wherein
Most preferably the present invention relates to compounds of the formula (1), wherein
A is selected from the group consisting of O, NR1 and CR1R2, with R1 and R2 being independently selected from the group consisting of hydrogen, methyl or ethyl,
In some embodiments (referred herein as embodiment 2), compounds according to the present invention are compounds of the formula (I):
wherein
In some embodiments (referred herein as embodiment 3), compounds according to the present invention are compounds of the formula (I):
wherein
In some embodiments (referred herein as embodiment 4), compounds according to the present invention are compounds of the formula (I):
wherein
wherein
In some embodiments (referred herein as embodiment 5), compounds according to the present invention are compounds of the formula (I):
wherein
wherein
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein m is 0 and A is CR1R2 with R1 and R2 being as described herein above, preferably with R1 and R2 being a hydrogen atom, or A is O.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein m is 1 and A is O, C(═O) or CR1R2 with R1 and R2 being as described herein above, preferably with R1 and R2 being a hydrogen atom.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein m is 2 and A is O, C(═O) or CR1R2 with R1 and R2 being as described herein above, preferably with R1 and R2 being a hydrogen atom.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L is a direct bond or C1-C6-alkylene (e.g. —CH2-).
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L is
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L is
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L is
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L is
with x is 0 or 1 and y is 0 or 1, preferably x and y are 0.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L represents a direct bond and R6 is selected from the group consisting of non-aromatic C3-C12-carbocycle, aromatic C6-C14-carbocycle and aromatic 5- to 14-membered heterocycle, preferably R6 is selected from the group consisting of indan-5-yl, phenyl, naphtyl, furan-2-yl and indol-3-yl.
In some embodiments, compounds according to the invention are compounds of formula (I) in accordance with embodiments 1, 2, 3, 4 or 5 wherein L represents a C1-C6-alkylene and R6 is an aromatic C6-C14-carbocycle (e.g. phenyl).
In a more preferred embodiment, L represents a direct bond or L is selected from the group consisting of C1-C6-alkylene,
wherein aliphatic L substituents may be substituted with one to three LSa substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C3-C6-cycloalkyl,
wherein cyclic or cyclic moiety of L substituents may be substituted with one to three LSc substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, oxo, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C3-C6-cycloalkyl.
The present invention also relates to any compounds of formula (I) disclosed in Table 1.
The compounds of formula (I) may be used as fungicides (for controlling phytopathogenic fungi), in particular in methods for controlling phytopathogenic fungi which comprises the step of applying one or more compounds of formula (I) to the plants, plant parts, seeds, fruits or to the soil in which the plants grow.
The present invention relates to processes for the preparation of compounds of formula (I) and their intermediates. Unless indicated otherwise, the radicals A, Q, T, L, R1, R2, R3, R4, R5, R6, R7, R8, m have the meanings given above for the compounds of formula (I). These definitions apply not only to the end products of formula (I) but also to all intermediates.
Compounds of formula (I-a)-(I-f) are various subsets of formula (I). Compounds of formula (I-a-1)-(I-a-7) are various subsets of formula (I-a). All substituents for formula (I-a)-(I-f) and (I-a-1)-(I-a-7) are as defined above for formula (I) unless otherwise noted.
The compounds of formula (I) can be prepared by various routes in analogy to known processes (see e.g. and references therein). Non-limiting examples of suitable processes are herein described.
A compound of formula (I) may be directly obtained by performing process A to I or may be obtained by conversion or derivatization of another compound of formula (I) prepared in accordance with the processes described herein. For instance, a compound of formula (I) can be converted into another compound of formula (I) by replacing one or more substituents of the starting compound of formula (I) by other substituents. Non-limiting examples of such conversion or derivatization are described below (processes J to L).
The processes described herein may be suitably performed using one or more inert organic solvents which is/are customary for the considered reaction. Suitable inert organic solvents can be chosen from the following: aliphatic, alicyclic or aromatic hydrocarbons (e.g. petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, ligroin, benzene, toluene, xylene or decalin), halogenated aliphatic, alicyclic or aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane or trichloroethane), ethers (e.g. diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole), ketones (e.g. acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone), esters (e.g. methyl acetate, ethyl acetate or butyl acetate), alcohols (e.g. methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol), nitriles (e.g. acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile), amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethyl-phosphoric triamide), sulfoxides (e.g. dimethyl sulfoxide) or sulfones (e.g. sulfolane), ureas (e.g. 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) or any mixture thereof.
Some processes described herein may require or be optionally performed using one or more inorganic or organic bases which are customary for such reactions. Examples of suitable inorganic and organic bases include, but are not limited to, alkaline earth metal or alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate), alkali metal hydrides (e.g. sodium hydride), alkaline earth metal or alkali metal hydroxides (e.g. sodium hydroxide, calcium hydroxide, potassium hydroxide or other ammonium hydroxide derivatives), alkaline earth metal, alkali metal or ammonium fluorides (e.g. potassium fluoride, cesium fluoride or tetrabutylammonium fluoride), alkali metal or alkaline earth metal acetates (e.g. sodium acetate, lithium acetate, potassium acetate or calcium acetate), alkali metal alcoholates (e.g. potassium tert-butoxide or sodium tert-butoxide), alkali metal phosphates (e.g. tri-potassium phosphate), tertiary amines (e.g. trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, N,N-dicyclohexylmethyl-amine, N,N-diisopropylethylamine, N-methylpiperidine, N,N-dimethylaminopyridine, diazabicyclo-octane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), quinuclidine, 3-acetoxy-quinuclidine, guanidines or aromatic bases (e.g. pyridines, picolines, lutidines or collidines).
Some of the processes described herein may be optionally performed in the presence of a transition metal catalyst, such as a metal (e.g. copper or palladium) salt or complex, if appropriate in the presence of a ligand.
Suitable copper salts or complexes and their hydrates include, but are not limited to, copper metal, copper(I) iodide, copper(I) chloride, copper(I) bromide, copper(II) chloride, copper(II) bromide, copper(II) oxide, copper(I) oxide, copper(II) acetate, copper(I) acetate, copper(I) thiophene-2-carboxylate, copper(I) cyanide, copper(II) sulfate, copper(II) bis(2,2,6,6-tetramethyl-3,5-heptane-dionate), copper(II) trifluoromethanesulfonate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, tetrakis(acetonitrile)-copper(I) tetrafluoroborate.
It is also possible to generate in situ a suitable copper complex in the reaction mixture by separate addition to the reaction of a copper salt and a ligand or salt, such as ethylenediamine, N,N-dimethylethylenediamine, N,N′-dimethylethylenediamine, rac-trans-1,2-diaminocyclohexane, rac-trans-N,N′-dimethylcyclohexane-1,2-diamine, 1,1′-binaphthyl-2,2′-diamine, N,N,N′,N′-tetramethylethylenediamine, proline, N,N-dimethylglycine, quinolin-8-ol, pyridine, 2-aminopyridine, 4-(dimethyl-amino)pyridine, 2,2′-bipyridyl, 2,6-di(2-pyridyl)pyridine, 2-picolinic acid, 2-(dimethylaminomethyl)-3-hydroxypyridine, 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, N,N′-bis[(E)-pyridin-2-ylmethylidene]cyclohexane-1,2-diamine, N-[(E)-phenylmethylidene], N-[(E)-phenylmethylidene]-cyclohexanamine, 1,1,1-tris(hydroxymethyl)ethane, n-butylimidazol, ethylene glycol, 2,2,6,6-tetramethylheptane-3,5-dione, 2-(2,2-dimethylpropanoyl)cyclohexanone, acetylacetone, dibenzoylmethane, 2-(2-methyl-propanoyl)cyclohexanone, biphenyl-2-yl(di-tert-butyl)phosphane, ethylenebis-(diphenylphosphine), N,N-diethylsalicylamide, 2-hydroxybenzaldehyde oxime, oxo[(2,4,6-trimethylphenyl)amino]acetic acid or 1H-pyrrole-2-carboxylic acid.
Suitable palladium salts or complexes include, but are not limited to, palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(cinnamyl)dichlorodipalladium(II), bis(allyl)-dichlorodipalladium(II) or [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).
It is also possible to generate a palladium complex in the reaction mixture by separate addition to the reaction of a palladium salt and a ligand or salt, such as triethylphosphine, tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, tricyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl, 2-(tert-butylphosphino)-2′-(N,N-dimethylamino)biphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, triphenyl-phosphine, tris-(o-tolyl)phosphine, sodium 3-(diphenylphosphino)benzenesulfonate, tris-(2-methoxy-phenyl)phosphine, 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl, 1,4-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino) ethane, 1,4-bis(dicyclohexylphosphino)butane, 1,2-bis(dicyclohexylphosphino)-ethane, 2-(dicyclohexyl-phosphino)-2′-(N,N-dimethylamino)-biphenyl, 1,1′-bis(diphenylphosphino)-ferrocene, (R)-(−)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, tris-(2,4-tert-butyl-phenyl)phosphite, di(1-adamantyl)-2-morpholinophenylphosphine or 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride.
The appropriate catalyst and/or ligand may be chosen from commercial catalogues such as “Metal Catalysts for Organic Synthesis” by Strem Chemicals or from reviews (Chemical Society Reviews (2014), 43, 3525, Coordination Chemistry Reviews (2004), 248, 2337 and references therein).
Some of the processes described herein may be performed by metallo-photoredox catalysis according to methods reported in the literature (Nature chemistry review, (2017) 0052 and references therein; Science (2016) 352, 6291, 1304; Org. Lett. 2016, 18, 4012, J. Org. Chem 2016, 81, 6898; J. Am. Chem. Soc. 2016, 138, 12715, J. Am. Chem. Soc. 2016, 138, 13862; J. Am. Chem. Soc. 2016, 138, 8034; J. Org. Chem. 2016, 81, 12525, J. Org. Chem. 2015, 80, 7642). The process is then performed in the presence a photosensitizer, such as Ir and Ru complexes or organic dyes, and a metal catalyst such as Ni complexes. The reaction can be performed in the presence of a ligand and if appropriate in the presence of a base under irradiation with blue or white light.
Suitable photosensitizers include, but are not limited to, Ir(III) photocatalyst such as [Ir(dFCF3ppy)2(bpy)]PF6 (dFCF3ppy=2-(2,4-difluorophenyl)-5-trifluoromethylpyridine, bpy=2,2′-bipyridine), [Ir(dFCF3ppy)2(dtbbpy)]PF6 (dtbbpy=4,4′-di-tert-butyl-2,2′-bipyridine), Ir(ppy)2(dtbbpy)PF6 (ppy=2-phenylpyridine), Ir(ppy)2(bpy)PF6, Ir(dFppy)3PF6 (dFCF3ppy=2-(2,4-difluorophenyl)pyridine), fac-Ir(ppy)3, (Ir[diF(5-Me)ppy]2(tetraMePhen)PF6 (diF(5-Me)ppy=2-(2,4-difluorophenyl)-5-methy-pyridine, tetraMePhen=3,4,7,8-tetramethyl-1,10-phenanthroline), Ru(II) photocatalyst such as Ru(bpy)3C12 or Ru(bpy)3(PF6)2 or organic dyes like 9-mesityl-10-acridinium perchlorate or tetrafluoroborate, or 2,4,5,6-tetra-9H-carbazol-9-yl-1,3-benzenedicarbonitrile, 9-fluorenone and 9,10-phenanthrenequinone.
Suitable nickel catalysts include, but are not limited to, bis(1,5-cyclooctadiene)nickel (0), nickel(II) choride, nickel(II) bromide, nickel(II) iodide under their anhydrous or hydrate forms or as dimethoxyethane complexes, nickel(II) acetylacetonate, nickel(II) nitrate hexahydrate. These nickel catalysts can be used in combination with bipyridine ligand such as 2,2′-bipyridine, 4,4′-di-tert-butyl-2,2′-bipyridine, 4,4′-dimethoxy-2,2′-bipyridine, 4,4′-dimethyl-2,2′-bipyridine or phenantroline such as 1,10-phenanthroline, 4,7-dimethyl-1,10-phenantroline, 4,7-dimethoxy-1,10-phenantroline or diamines such as N,N,N′,N′-tetramethylethylenediamine or dione such as tetramethylheptanedione.
The processes described herein may be performed at temperature ranging from −105° C. to 250° C., preferably from −78° C. to 185° C.
The reaction time varies as a function of the scale of the reaction and of the reaction temperature, but is generally between a few minutes and 48 hours.
The processes described herein are generally performed under standard pressure. However, it is also possible to work under elevated or reduced pressure.
The processes described herein may optionally be performed under microwave irradiation under standard or elevated pressure.
In the processes described herein, the starting materials are generally used in approximately equimolar amounts. However, it is also possible to use one of the starting materials in a relatively large excess.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) can be prepared by a process, as shown in scheme 1, comprising the steps of:
The compound of formula (I-a-1) can be obtained by treating a compound of formula (4) with a dehydrating agent such as POCl3, P2O5 or triflic anhydride, optionally in the presence of a base. Such methods to form oxadiazine rings are known and have been described in the literature (J. Med. Chem. 2017, 60, 2383-2400). The reaction may be performed in any customary inert organic solvents. Preference is given to using optionally halogenated aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichlorethane or trichlorethane; ethers, such as diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; alcohols, such as ethanol or isopropanol.
When W represents an amino protecting group, step 3 is followed by an additional deprotection step using reaction conditions described in the literature (Greene's Protective Groups in organic Synthesis; Peter G. M. Wuts; Wiley; Fifth Edition; 2014; 895-1194). For example a tert-butoxycarbonyl group can be removed in acidic medium such as hydrochloric acid or trifluoroacetic acid.
Compound of formula (4) can be obtained by:
Compounds of formula (1) can be prepared by one or more processes described herein (see processes N, O and P)
Amines of formula (2) can be prepared by process S described herein.
Compounds of formula (1) wherein U1 is a hydroxyl group can be reacted with an amine of formula (2) in the presence of a condensing reagent by means of methods described in the literature (e.g. Tetrahedron 2005, 61, 10827-10852). Examples of suitable condensing reagents include, but are not limited to, halogenating reagents (e.g. phosgene, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide, oxalyl chloride or thionyl chloride), dehydrating reagents (e.g. ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate or methanesulfonyl chloride), carbodiimides (e.g. N,N′-dicyclohexylcarbodiimide (DCC)) or other customary condensing (or peptide coupling) reagents (e.g. phosphorous pentoxide, polyphosphoric acid, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N′-carbonyl-diimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloro-methane, 4-(4,6-dimethoxy[1.3.5]-triazin-2-yl)-4-methylmorpholinium chloride hydrate, bromo-tripyrrolidinophos-phoniumhexafluorophosphate or propanephosphonic anhydride (T3P).
Compounds of formula (1) wherein U1 is a halogen atom can be reacted with an amine of formula (2) in the presence of an acid scavenger by means of well-known methods. Suitable acid scavengers include any inorganic and organic bases, as described herein, which are customary for such reactions. Preference is given to alkali metal carbonates, alkaline earth metal acetates, tertiary amines or aromatic bases.
Compounds of formula (1) wherein U1 is a C1-C6-alkoxy group can be reacted with an excess of amine of formula (2), optionally in the presence of a Lewis acid such as trimethylaluminium.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) can be prepared by a process comprising the steps of reacting a compound of formula (7) with a compound of formula (8) in the presence of a base (e.g. organic or inorganic base) and optionally in the presence of a suitable copper salt or complex as shown in scheme 2.
Compounds of formula (7) can be prepared by:
The reaction of compound of formula (7) with a compound of formula (8) may be performed in the presence of a transition metal catalyst such as a copper salt or complex, and if appropriate in the presence of a ligand as described herein.
Compounds of formula (5) are commercially available or may be prepared by process Q described herein.
Compounds of formula (8) are commercially available or may be obtained by conversion or derivatization of another compound of formula (8) in accordance to well-known methods.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) can be prepared by a process, as shown in scheme 3, comprising the step of adding a reducing agent to the compound of formula (12) under acidic conditions to provide a compound of formula (I-a-1).
Compound of formula (12) can be cyclized under acidic conditions in the presence of a reducing agent such as sodium cyanoborohydride to provide a compound of formula (I-a-1). Reaction conditions to form oxadiazine rings with this methodology are known and have been described in the literature (Heterocycles 2016, 92, 2166-2200).
Compound of formula (12) can be obtained by reacting a compound of formula (10) with a compound of formula (11) in the presence of a base. Suitable bases can be alkali metal hydrides such as sodium hydride, alkali metal carbonates such as potassium carbonate, alkali metal hydroxides such as potassium hydroxide, or phosphazene bases such as BEMP as described in the literature (Heterocycles 2016, 92, 2166-2200).
Compound of formula (10) can be obtained by reacting a compound of formula (9) with hydroxylamine or one of its salt. Reaction conditions to perform such transformations are known and have been reported in the literature (WO2010138600).
Compounds of formula (9) may be prepared by process R described herein.
Compounds of formula (11) are either commercially available or can be prepared by processes described in the literature (Eur. J. Med. Chem. 2014, 84, 302, Eur. J. Med. Chem. 2015, 100, 18-23, WO2017031325).
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen, L is a direct bond and m is 1 or 2) can be prepared by a process comprising the steps of:
The compound of formula (14) can be reacted with an aromatic C6-C14-carbocycle, a non-aromatic C7-C14-carbocycle, a non-aromatic 7- to 14-membered heterocycle, or an aromatic 5- to 14-membered heterocycle (R6—H) under acidic conditions to provide a compound of formula (I-a-1). Reaction conditions to form oxadiazine rings with this methodology are known and have been described in the literature (WO2017031325).
Compounds of formula (14) can be obtained from a compound of formula (13) under oxidative conditions, for example in the presence of osmium trioxide and sodium periodate.
Compounds of formula (13) may be prepared by process R described herein.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) can be prepared by a process comprising the steps of:
Aminoalcohols of formula (19-a, E1=hydroxyl) are commercially available or may be producible by methods described in the literature (Molecules, 9 (6), 405-426; 2004; WO2017203474). Compounds of formula (19-b, E1=halogen) or one of its salts can be obtained from the corresponding aminoalcohol by well-known methods.
When E1 is hydroxyl, the compound of formula (20) can be converted by Step 4 of the process into a compound of formula (I-a-1) using classical Mitsunobu reaction conditions known by the skilled person of the art (Strategic Applications of Named Reactions in Organic Synthesis; Laszlo Kürti, Barbara Czako; Elsevier; 2005; 294-295 and reference herein).
When E1 is halogen, the compound of formula (20) can be converted by Step 4 of the process into a compound of formula (I-a-1) in the presence of a base as referred herein.
When W represents an amino protecting group, Step 4 is followed by an additional deprotection step using reaction conditions described in the literature (Greene's Protective Groups in organic Synthesis; Peter G. M. Wuts; Wiley; Fifth Edition; 2014; 895-1194) to provide a compound of formula (I-a-1). Compound of formula (18) can be treated with a compound of formula (19) or one of its salt in the presence of a base such as triethylamine to form a compound of formula (20).
Compound of formula (18) can be obtained by Step 2 of the process by treating an oxime of formula (17) with a halogenating reagent such as NCS. Reaction conditions to perform such transformations have been reported in the literature (WO2013173672; RSC Advances 2015, 5, 58587-58594).
An oxime of formula (17) can be obtained by Step 1 from an aldehyde of formula (16) in the presence of hydroxylamine or one of its salt, optionally in the presence of a base. Such transformations are known and have been reported in the literature (Tetrahedron 2000, 56, 1057-1064; ChemMedChem 2013, 8, 1210-1223).
Aldehydes of formula (16) can be prepared according to well-known methods for the one skilled in the art; for example either by treating the weinreb amide precursor with DIBAL-H (WO2016045591) or by converting the ester precursor into the primary alcohol followed by oxidation of the alcohol into the corresponding aldehyde (WO199850031). The ester precursors to access such aldehydes can be prepared according to Process N, O, P described herein.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) or (I-a-2) (i.e. compound of formula (I) wherein A is NH, T is hydrogen and m is 1 or 2) can be prepared by a process comprising the steps of:
Step 2 and step 3 of process F can be performed using similar reaction conditions as described in process E.
Aminoalcohols of formula (19-a, E1=hydroxyl) are commercially available or may be producible by methods described in the literature (Molecules, 9 (6), 405-426; 2004; WO2017203474). Compounds of formula (19-b, E1=halogen) or one of its salt can be obtained from the corresponding aminoalcohol by well-known methods.
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2) or (I-a-2) (i.e. compound of formula (I) wherein A is NH, T is hydrogen and m is 1 or 2) can be prepared by a process comprising the steps of:
A compound of formula (I-a-1) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 1 or 2), (I-a-3) (i.e. compound of formula (I) wherein A is CR1R2, T is hydrogen and m is 1 or 2), (I-a-4) (i.e. compound of formula (I) wherein A is C(═O), T is hydrogen and m is 1 or 2) or (I-a-5) (i.e. compound of formula (I) wherein A is S(═O)2, T is hydrogen and m is 1 or 2) can be prepared by a process comprising the steps of:
Alternatively, a compound of formula (I-a-5) may be prepared by treating a pyridazine 4-carboxamidine compound with a trans-styrylsulfonyl chloride in analogy to methods described in the literature (J. Org. Chem. 1974, 39, 3080)
The compound of formula (25) can be obtained by treating a compound of formula (9) with an alkoxide such as sodium methanolate or sodium ethanolate according to methods described in the literature (Heterocycles, 34, 1992, 929-935).
The compound of formula (25) is treated with a compound of formula (26-a-1), (26-a-2), (26-a-3) or (26-a-4) and cyclized under acidic conditions to form respectively a compound of formula (I-a-1), (I-a-3), (I-a-4) or (I-a-5). Reaction conditions to perform such transformations based on this methodology have been described in the literature (Heterocycles 2016, 92, 2166-2200).
Amines of formula (26-a-1), (26-a-2), (26-a-3) or (26-a-4) are either commercially available, or may be prepared by methods described in the literature (Molecules, 9 (6), 405-426; 2004, WO2017203474; J.
Med. Chem 1985, 28, 694-698; J. Med. Chem 2006, 49, 4333-4343) and by Process S of this invention.
A compound of formula (I-a-6) (i.e. compound of formula (I) wherein A is 0, T is hydrogen and m is 2), can be prepared by a process comprising the steps of:
Reagents of formula (27) are either commercially available or producible by processes described in the literature (WO2010099279).
Reagents of formula (29) are commercially available or can be prepared by known processes.
A compound of formula (I-a-7) (i.e. compound of formula (I) wherein A is CR1R2, T is hydrogen and m is 0) can be prepared by a process comprising the step of reacting a compound of formula (1) with a diamine of formula (31) as shown in scheme 10.
Process J can be performed in the presence of a dehydrating agent such as POCl3.
Diamines of formula (31) are commercially available or can be prepared by methods described in the literature (Eur. J. Med. Chem 1990, 25(1), 35-44; J. Org. Chem 2012, 77(9), 4375-4384; WO2009003867).
A compound of formula (I-a) can be converted by means of methods described in the literature to the corresponding compounds (I-b) or (I-c) in one or more steps as shown in scheme 11.
In scheme 11, Re, Rf, Rg are as disclosed herein and the aliphatic and cyclic substituents R7b, R7, Re, Rf, Rg may be substituted as disclosed herein.
Non-limiting examples of conversions performed in accordance with scheme 11 are provided below.
A compound of formula (I-a) wherein R7a is a chlorine atom can be converted into a compound of formula (I-b) wherein R7b is a bromine or an iodine atom by means of methods described in the literature (e.g. WO2016185342, WO2007022937).
A compound of formula (I-a) wherein R7a is a halogen atom can be converted into a compound of formula (I-b) wherein R7b is a hydrogen atom in the presence of a palladium catalyst as reported in the literature (Journal of Molecular Catalysis A: Chemical, 2014, 393, 191-209).
A compound of formula (I-a) wherein R7a is a hydrogen atom or a halogen atom can be converted into a compound of formula (I-b) wherein R7b is cyano, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aromatic C6-C14-carbocycle, aromatic 5- or 6-membered monocyclic heterocycle, non-aromatic 3- to 7-membered monocyclic heterocycle, —N(Re)2 or —C(═O)(ORg) by transition metal catalyzed or metallo-photoredox catalyzed processes as described herein.
A compound of formula (I-b) wherein R7b is a C2-C6-alkenyl group substituted by a C1-C3-alkoxy can be converted into a compound of formula (I-c) wherein R7c is a C1-C6-alkylcarbonyl group by means of methods described in the literature (e.g. J. Org. Chem. 1993, 55, 3114).
The compound of formula (I-c) wherein R7c is a C1-C6-alkylcarbonyl group can be further converted in a compound of formula (I-c) wherein R7c is —C(═NRf)—C1-C6-alkyl group by methods described in the literature (e.g. Greene's Protective Groups in organic Synthesis; Peter G. M. Wuts; Wiley; Fifth Edition; 2014; 655, 661, 667).
A compound of formula (I-c) wherein R7c is a C1-C6-alkylcarbonyl group can be further converted in a compound of formula (I-c) wherein R7c is C1-C6-hydroxyalkyl group by classical functional group interconversion such as reductions of ketones to alcohols in the presence of NaBH4 in MeOH.
A compound of formula (I-c) wherein R7c is C1-C6-hydroxyalkyl group can be further converted into a compound (I-c) wherein R7c is C1-C6-fluoroalkyl in the presence of a fluorinating agent. Non-limitative examples of fluorinating agents include sulfur fluorides such as sulfur tetrafluoride, diethylaminosulfurtrifluoride, morpholinosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, 2,2-difluoro-1,3-dimethylimidazolidine or 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride.
A compound of formula (I-a) can be prepared by one or more of the processes herein described.
A compound of formula (I-a) can be converted by means of methods described in the literature to the corresponding compound of formula (I-d) or compound of formula (I-e) in one or more steps as shown in scheme 12.
Non-limiting examples of conversions performed in accordance with scheme 12 are provided below.
A compound of formula (I-a) can be converted into a compound of formula (I-d) wherein R8a is a halogen atom in the presence of a base and an electrophile such as NCS, NBS, NIS, hexachloroethane, bromine or iodine by means of methods described in the literature (e.g. Org. Lett. 2009, 11, 1837). Suitable bases for carrying out the process can be selected from lithium-diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, n-butyl lithium, methyl lithium, TMPZnCl.LiCl, TMP2Zn-2MgCl2-2LiCl (see e.g. Dissertation Albrecht Metzer 2010, University Munich).
A compound of formula (I-a) can be converted into a compound of formula (I-d) wherein R8a is a C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-hydroxyalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C6-cycloalkenyl, aromatic C6-C14-carbocycle, 5- to 14-membered aromatic heterocycle or a 3- to 14-membered non-aromatic heterocycle, optionally in the presence of a base, and when appropriate in the presence of a transition metal catalyst such as a metal salt or complex and a ligand as described herein or by methods described in the literature (Heterocycles 1976, 4(8), 1331).
A compound of formula (I-d) wherein R8a is a halogen atom can be converted in a compound of formula (I-e) wherein R8b represents cyano, nitro, amino, mercapto, hydroxyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aromatic 5- to 14-membered heterocycle, C3-C8-cycloalkyloxy, aromatic C6-C14-carbocyclyloxy, non-aromatic 3- to 14-membered heterocyclyloxy, aromatic 5- to 14-membered heterocyclyloxy, —N(Rb)2 or —SRi in the presence of a base and optionally in the presence of a transition metal catalyst such as a metal salt or complex, and if appropriate in the presence of a ligand.
A compound of formula (I-e) wherein R8b is a C2-C6-alkenyl group can be further converted in a compound of formula (I-e) wherein R8b is C1-C6-alkyl substituted by C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, non-aromatic 3- to 7-membered monocyclic heterocycle and —N(Ra′)2 with Ra′ being independently selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C3-C8-cycloalkyl, by treating the reacting compound of formula (I-e) with an oxygen, a sulfur or an amino based nucleophile.
A compound of formula (I-e) wherein R8b is a SRi group can be further converted in a compound of formula (I-a-8) wherein R8b is a —S(═O)Ri or a —S(═O)2Ri group by reacting the starting compound of formula (I-a-8) with an oxidant such as hydrogen peroxide.
A compound of formula (I-a) can be prepared by one or more of the processes herein described.
A compound of formula (I-f) (i.e. formula (I) wherein T is —C(═O)Ra1, —C(═O)(ORa1), —C(═O)N(Ra2)2, —S(═O)Ra1, —S(═O)2Ra1 and —S(═O)2N(Ra2)2 with Ra1 and Ra2 being as described herein) can be prepared by a process comprising the step of reacting a compound of formula (I-a) formula with a compound of formula (32) as shown in scheme 13.
Process M can be performed by means of methods described in the literature (e.g. Tetrahedron Lett. 1995, 36, 8949; Greene's Protective Groups in organic Synthesis; Peter G. M. Wuts; Wiley; Fifth Edition; 2014; 1174-1175).
Compounds of formula (32) are commercially available.
Compounds of formula (I-a) can be prepared by one or more of the processes herein described.
A compound of formula (1) as described herein may be directly obtained by performing process N described below or may be obtained by conversion or derivatization of another compound of formula (1) prepared in accordance with the processes described herein. Compounds of formula (1-a)-(1-e) are various subsets of formula (1).
A compound of formula (1-a) (i.e. formula (1) wherein R7 and R8 are as defined in scheme 14) can be prepared by a process comprising the step of reacting a compound of formula (5) with a reagent of formula (8) as shown in scheme 14 in the presence of a base.
In scheme 14, Re is as disclosed herein and R7, R8 and Re may be substituted as disclosed herein.
Process N may be performed in the presence of suitable transition metal catalyst salts or complexes, if appropriate in the presence of a ligand.
The obtained compound of formula (1-a) can then be converted into a compound of formula (1-b) in one or more steps.
Non-limiting examples of such conversion are described below.
Compounds of formula (1-a) wherein U1 is a C1-C6-alkoxy can be converted to compounds of formula (1-b) wherein U2 is a hydroxyl group by well-known functional group interconversion methods, for example by hydrolysis of an ester group with LiOH in THE/water.
Compounds of formula (1-b) wherein U2 is a hydroxyl can be converted to compounds of formula (1-b) wherein U2 is a halogen in the presence of halogenating agents by well-known methods. Suitable halogenating reagents include, but are not limited to, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide, oxalyl chloride or thionyl chloride.
Compounds of formula (1-b) wherein U2 is a hydroxyl or halogen can be converted to compounds of formula (1-b) wherein U2 is —N(CH3)OCH3 by well-known methods.
Compounds of formula (5) are commercially available or may be prepared by process Q described herein.
Compounds of formula (8) are commercially available or may be obtained by conversion or derivatization of another compound of formula (8) in accordance to well-known methods.
A compound of formula (1-c) (i.e. formula (1) wherein R7 is R7a as defined in scheme 15) can be converted by means of known methods to the corresponding compounds of formula (1-d) (i.e. formula (1) wherein R7 is R7b as defined in scheme 15) or (1-e) (i.e. formula (1) wherein R7 is R7c as defined in scheme 15) in one or more steps as shown in scheme 15.
In scheme 15, Re, Rf, Rg are as disclosed herein and the aliphatic and cyclic substituents R7b, R7c, Re, Rf, Rg may be substituted as disclosed herein.
Non-limiting examples of conversion may be performed in accordance to the description provided in process K.
The obtained compound of formula (1-d) and (1-e) can then be converted into compound of formula (1-d) and (1-e) wherein Uf (C1-C6-alkoxy) is replaced with hydroxyl or halogen.
Examples of such conversion are described below.
Compounds of formula (1-c), (1-d), (1-e) wherein Uf is a C1-C6-alkoxy can be converted to compounds of formula (1-b), (1-c), (1-d) wherein Uf is replaced with a hydroxyl group by well-known functional group interconversion methods, for example by hydrolysis of an ester group with LiOH in THE/water.
Compounds of formula (1-c), (1-d), (1-e) wherein U1 has been replaced with a hydroxyl can then be further converted to compounds of formula (1-b), (1-c), (1-d) wherein the hydroxyl is replaced with a halogen in the presence of halogenating agents by well-known methods. Suitable halogenating reagents include, but are not limited to, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide, oxalyl chloride or thionyl chloride.
Compounds of formula (1-c), (1-d), (1-e) wherein U1 is a hydroxyl or halogen can be converted to compounds of formula (1-c), (1-d), (1-e) wherein U1 is —N(CH3)OCH3 by well-known methods.
Compounds of formula (1-c) can be prepared by one or more of the processes described herein.
A compound of formula (1-f) (i.e. formula (1) wherein R8 is H) can be converted by means of methods described in the literature to the corresponding compound of formula (1-g) (i.e. formula (1) wherein R8 is R8a as defined in scheme 16) or compound of formula (1-h) (i.e. formula (1) wherein R8 is R8b as defined in scheme 16) in one or more steps as shown in scheme 16.
In scheme 16, Rh and Ri are as disclosed herein and the aliphatic and cyclic substituents R8a and R8b may be substituted as disclosed herein.
Non-limiting examples of conversion may be performed in accordance to the description provided in process L.
The obtained compound of formula (1-f) and (1-g) can then be converted into compound of formula (1-f) and (1-g) wherein U1 (C1-C6-alkoxy) is replaced with hydroxyl or halogen.
Compounds of formula (1-f), (1-g), (1-h) wherein U1 is a C1-C6-alkoxy can be converted to compounds of formula (1-f), (1-g), (1-h) wherein U1 is replaced with a hydroxyl group by well-known functional group interconversion methods, for example by hydrolysis of an ester group with LiOH in THE/water.
Compounds of formula (1-f), (1-g), (1-h) wherein U1 has been replaced with a hydroxyl can then be further converted to compounds of formula (1-f), (1-g), (1-h) wherein the hydroxyl is replaced with a halogen in the presence of halogenating agents by well-known methods. Suitable halogenating reagents include, but are not limited to, phosphorous tribromide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide, oxalyl chloride or thionyl chloride.
Compounds of formula (1-f), (1-g), (1-h) wherein U1 is a hydroxyl or halogen can be converted to compounds of formula (1-f), (1-g), (1-h) wherein U1 is —N(CH3)OCH3 by well-known methods.
Compounds (1-f) can be prepared by one or more of the processes described herein.
A compound of formula (5) as described herein may be commercially available or directly obtained by performing process Q described below. Compounds of formula (5-a) and (5-b) are various subsets of formula (5).
A compound of formula (5-a) (i.e. compound of formula 5 wherein R7 is halogen) can be converted by means of known methods (WO2000044755) into a compound of formula (5-b) (i.e. compound of formula 5 wherein R7 is as shown in scheme 17) in the presence of either an oxygen (ethanol), a sulfur (thioethyl) or an amino (methylamine) based nucleophile, optionally in the presence of base as shown in scheme 17.
The compounds of formula (5-a) and (5-b) can be converted into compound of formula (5-a) and (5-b) wherein U1 (C1-C6-alkoxy) is replaced with hydroxyl or halogen using the same conditions as described in process N.
Starting materials of formula (5-a) are commercially available.
A compound of formula (9) may be obtained by performing process R described below or may be obtained by conversion or derivatization of another compound of formula (9-a) prepared in accordance with the processes described herein. Compounds of formula (9-a) and (9-b) are various subsets of formula (9).
A compound of formula (9-a) can be converted by means of methods described in the literature to the corresponding compounds (13) in one or more steps as shown in scheme 18.
Compounds of formula (33) are commercially available or producible by processes described in the literature (Chemical & Pharmaceutical Bulletin 1977, 25(8), 1856-61).
A compound of formula (33) can be converted according to Step 1 of Process R into a compound of formula (9-a) in the presence of a reagent of formula (8) and a base (e.g organic or inorganic base) as described herein.
Non-limiting examples of conversion of (9-a) to (9-b) may be performed in accordance to scheme 18.
For example, a compound of formula (9-a) can be further converted in a compound of formula (9-b) wherein R7 is hydroxyl, mercapto, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyloxy, C2-C6-haloalkenyloxy, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C3-C8-cycloalkyloxy, aromatic C6-C14-carbocyclyloxy, aromatic 5- or 6-membered monocyclic heterocyclyloxy, non-aromatic 3- to 7-membered monocyclic heterocyclyloxy, —N(Re)2 by treating the reacting compound of formula (9-a) with an oxygen, a sulfur or an amino based nucleophile.
A compound of formula (9-a) can be converted into a compound of formula (9-b) wherein R7 is cyano, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C6-cycloalkenyl, aromatic C6-C14-carbocycle, aromatic 5- or 6-membered monocyclic heterocycle, non-aromatic 3- to 7-membered monocyclic heterocycle by transition metal catalyzed or metallo-photoredox catalyzed processes as described herein.
An intermediate of formula (13) can be obtained according to Step 3 of Process R by treating a compound of formula (9) with a compound of formula (34) optionally in the presence of a base using well-known methods.
Compounds of formula (8) are commercially available or may be obtained by conversion or derivatization of another compound of formula (8) in accordance to well-known methods.
Process for the Preparation of Compounds of Formula (2), (19), (26-a-1)
A compound of formula (35) can be converted by means of methods described in the literature to the corresponding compounds (2), (19-a), (19-b) and (26-a-1) in one or more steps as shown in scheme 19.
Aminoalcohols of formula (35) are commercially available or may be producible by methods described in the literature (Molecules, 9 (6), 405-426; 2004, WO2017203474).
The amino function of compound 35 is protected in accordance with known methods to provide compound of formula (19-a).
Subsequently, the compound of formula (19-a) can be converted by Step 2 of Process S into a compound of formula (2) using classical Mitsunobu reaction conditions known by the skilled person of the art (Strategic Applications of Named Reactions in Organic Synthesis; Laszlo Kürti, Barbara Czako; Elsevier; 2005; 294-295 and reference herein).
Compounds of formula (2) can be converted into compounds of formula (26-a-1) by well-known methods.
The present invention also relates to intermediates for the preparation of compounds of formula (I).
Thus, the present invention relates to compounds of formula (1):
wherein
Q, R7 and R8 are as described herein,
U1 is hydroxyl, halogen, C1-C6-alkoxy or —N(CH3)OCH3,
R7, R8 are as described herein and do not represent simultaneously hydrogen and methyl, provided that the compound of formula (1) is not:
The present invention also relates to compounds of formula (2):
wherein
L, R5, R6 are as defined herein,
R3, R4 represents hydrogen, halogen, or C1-C6-alkyl or R3 and R4 form, together with the carbon atom to which they are attached to a C3-C8-cycloalkyl,
m is 1
and
W represents hydrogen, tert-butoxycarbonyl, benzyl, allyl or (4-methoxyphenyl)methyl, provided that the compound of formula (2) is not:
The present invention also relates to compounds of formula (3):
wherein
Q, L, R3, R4, R5, R6, R7 and R8 are defined as herein,
m is 1 or 2,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl, allyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (4):
wherein
Q, L, R3, R4, R5, R6, R7 and R8 are defined as herein,
m is 1 or 2,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl, allyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (6a) and (6b):
wherein
Q, L, R3, R4, R5, R6, R7 and R8 are defined as herein,
m is 1 or 2,
W represents hydrogen, tert-butoxycarbonyl, benzyl, allyl or (4-methoxyphenyl)methyl, and
X represents halogen.
The present invention also relates to compounds of formula (7):
wherein
Q, L, R3, R4, R5, R6, R7 and R8 are defined as herein,
m is 1 or 2,
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl, and
X represents halogen.
The present invention also relates to compounds of formula (9):
wherein
Q, R7 and R8 are as described herein,
provided that R7 and R8 are not both simultaneously hydrogen, methyl or ethyl and the compound of formula (9) is not:
The present invention also relates to compounds of formula (10):
wherein
Q, R7 and R8 are as described herein,
provided that R7 and R8 are not both simultaneously hydrogen or methyl and that the compound of formula (10) is not:
The present invention also relates to compounds of formula (12):
wherein Q, L, R3, R4, R6, R7 and R8 are defined as herein
and
m is 1 or 2.
The present invention also relates to compounds of formula (13):
wherein Q, R3, R4, R5, R7 and R8 are defined as herein
and
m is 1 or 2.
The present invention also relates to compounds of formula (14):
wherein Q, R3, R4, R5, R7, R8 are defined as herein
and
m is 1 or 2.
The present invention also relates to compounds of formula (16):
wherein Q, R7 and R8 are defined as herein.
The present invention also relates to compounds of formula (11):
wherein Q, R7 and R8 are defined as herein.
The present invention also relates to compounds of formula (18):
wherein Q, R7 and R8 are defined as herein.
The present invention also relates to compounds of formula (19)
wherein
m is 1,
L represents —CH2— or —CF2—,
R3 and R4 represent hydrogen,
E1 represents chlorine, bromine or iodine,
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl and salts, solvates or salts of the solvates thereof.
The present invention also relates to compounds of formula (20):
wherein
Q, L, R3, R4, R5, R6, R7 and R8 are defined as herein,
m is 1 or 2,
E1 represents hydroxyl or halogen,
E2 represents hydroxyl or amino,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (21):
wherein
Q, L, R3, R4, R5, R6, R7, R8 and m are defined as herein,
E1 represents hydroxyl or halogen,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (21):
wherein
Q, R6, R7, R8 and m are defined as herein,
m is 1,
L is CH2, CHF or CF2,
R3, R4 and R5 represent hydrogen,
E1 represents hydroxyl or halogen,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (22):
wherein
L, R3, R4, R5, R6, R7, R8 are defined as herein,
m is 1 or 2,
X represents halogen,
E1 represents hydroxyl or halogen,
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl,
provided the compound of formula (22) is not:
The present invention also relates to compounds of formula (23):
wherein
L, R3, R4, R5, R6, R7, R8 are defined as herein,
m is 1 or 2,
X represents halogen,
E1 represents hydroxyl or halogen,
E2 represents hydroxyl or amino,
and
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (24):
wherein
L, R3, R4, R5, R6, R7, R8 are defined as herein,
m is 1 or 2,
X represents halogen,
W represents hydrogen, tert-butoxycarbonyl, benzyl or (4-methoxyphenyl)methyl.
The present invention also relates to compounds of formula (25):
wherein Q, Y, R7 and R8 are defined as herein.
The present invention also relates to compounds of formula (28):
wherein Q, R3, R4, R5, R7 and R8 are defined as herein.
The present invention also relates to compounds of formula (30):
wherein Q, R3, R4, R5, R6, R7 and R8 are defined as herein.
The present invention also relates to intermediates of formula (8):
Q-OH (8)
wherein Q is
wherein
QS is selected from the group consisting of C3-C4-cycloalkyl, C3-C8-halocycloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl and C2-C6-alkynyl,
provided that the compound of formula (8) does not represent:
The present invention further relates to a composition, in particular a composition for controlling unwanted phytopathogenic microorganisms. The compositions may be applied to the microorganisms and/or in their habitat.
The composition typically comprises at least one compound of formula (I) and at least one agriculturally suitable auxiliary, e.g. carrier(s) and/or surfactant(s).
A carrier is a solid or liquid, natural or synthetic, organic or inorganic substance that is generally inert. The carrier generally improves the application of the compounds, for instance, to plants, plants parts or seeds. Examples of suitable solid carriers include, but are not limited to, ammonium salts, natural rock flours, such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite and diatomaceous earth, and synthetic rock flours, such as finely divided silica, alumina and silicates. Examples of typically useful solid carriers for preparing granules include, but are not limited to crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, synthetic granules of inorganic and organic flours and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks. Examples of suitable liquid carriers include, but are not limited to, water, organic solvents and combinations thereof. Examples of suitable solvents include polar and nonpolar organic chemical liquids, for example from the classes of aromatic and nonaromatic hydrocarbons (such as cyclohexane, paraffins, alkylbenzenes, xylene, toluene alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride), alcohols and polyols (which may optionally also be substituted, etherified and/or esterified, such as butanol or glycol), ketones (such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone), esters (including fats and oils) and (poly)ethers, unsubstituted and substituted amines, amides (such as dimethylformamide), lactams (such as N-alkylpyrrolidones) and lactones, sulfones and sulfoxides (such as dimethyl sulfoxide). The carrier may also be a liquefied gaseous extender, i.e. liquid which is gaseous at standard temperature and under standard pressure, for example aerosol propellants such as halohydrocarbons, butane, propane, nitrogen and carbon dioxide. The amount of carrier typically ranges from 1 to 99.99%, preferably from 5 to 99.9%, more preferably from 10 to 99.5%, and most preferably from 20 to 99% by weight of the composition.
The surfactant can be an ionic (cationic or anionic) or non-ionic surfactant, such as ionic or non-ionic emulsifier(s), foam former(s), dispersant(s), wetting agent(s) and any mixtures thereof. Examples of suitable surfactants include, but are not limited to, salts of polyacrylic acid, salts of lignosulfonic acid, salts of phenolsulfonic acid or naphthalenesulfonic acid, polycondensates of ethylene and/or propylene oxide with fatty alcohols, fatty acids or fatty amines (polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers), substituted phenols (preferably alkylphenols or arylphenols), salts of sulfosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols and derivatives of compounds containing sulfates, sulfonates, phosphates (for example, alkylsulfonates, alkyl sulfates, arylsulfonates) and protein hydrolysates, lignosulfite waste liquors and methylcellulose. A surfactant is typically used when the compound of formula (I) and/or the carrier is insoluble in water and the application is made with water. Then, the amount of surfactants typically ranges from 5 to 40% by weight of the composition.
Further examples of suitable auxiliaries include water repellents, siccatives, binders (adhesive, tackifier, fixing agent, such as carboxymethylcellulose, natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, natural phospholipids such as cephalins and lecithins and synthetic phospholipids, polyvinylpyrrolidone and tylose), thickeners, stabilizers (e.g. cold stabilizers, preservatives, antioxidants, light stabilizers, or other agents which improve chemical and/or physical stability), dyes or pigments (such as inorganic pigments, e.g. iron oxide, titanium oxide and Prussian Blue, organic dyes, e.g. alizarin, azo and metal phthalocyanine dyes), antifoams (e.g. silicone antifoams and magnesium stearate), preservatives (e.g. dichlorophene and benzyl alcohol hemiformal), secondary thickeners (cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica), stickers, gibberellins and processing auxiliaries, mineral and vegetable oils, perfumes, waxes, nutrients (including trace nutrients, such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc), protective colloids, thixotropic substances, penetrants, sequestering agents and complex formers.
The choice of the auxiliaries is related to the intended mode of application of the compound of formula (I) and/or on the physical properties. Furthermore, the auxiliaries may be chosen to impart particular properties (technical, physical and/or biological properties) to the compositions or use forms prepared therefrom. The choice of auxiliaries may allow customizing the compositions to specific needs.
The composition may be in any customary form, such as solutions (e.g aqueous solutions), emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural or synthetic products impregnated with the compound of formula (I), fertilizers and also microencapsulations in polymeric substances. The compound of formula (I) may be present in a suspended, emulsified or dissolved form.
The composition may be provided to the end user as ready-for-use formulation, i.e. the compositions may be directly applied to the plants or seeds by a suitable device, such as a spraying or dusting device.
Alternatively, the compositions may be provided to the end user in the form of concentrates which have to be diluted, preferably with water, prior to use.
The composition can be prepared in conventional manners, for example by mixing the compound of formula (I) with one or more suitable auxiliaries, such as disclosed herein above.
The composition contains generally from 0.01 to 99% by weight, from 0.05 to 98% by weight, preferably from 0.1 to 95% by weight, more preferably from 0.5 to 90% by weight, most preferably from 1 to 80% by weight of the compound of formula (I). It is possible that a composition comprises two or more compounds formula (I). In such case the outlined ranges refer to the total amount of compounds of the present invention.
The compound of formula (I) and composition comprising thereof can be mixed with other active ingredients like fungicides, bactericides, acaricides, nematicides, insecticides, herbicides, fertilizers, growth regulators, safeners or semiochemicals. This may allow to broaden the activity spectrum or to prevent development of resistance. Examples of known fungicides, insecticides, acaricides, nematicides and bactericides are disclosed in the Pesticide Manual, 17th Edition.
Examples of especially preferred fungicides which could be mixed with the compound of formula (I) and the composition are:
1) Inhibitors of the ergosterol biosynthesis, for example (1.001) cyproconazole, (1.002) difenoconazole, (1.003) epoxiconazole, (1.004) fenhexamid, (1.005) fenpropidin, (1.006) fenpropimorph, (1.007) fenpyrazamine, (1.008) fluquinconazole, (1.009) flutriafol, (1.010) imazalil, (1.011) imazalil sulfate, (1.012) ipconazole, (1.013) metconazole, (1.014) myclobutanil, (1.015) paclobutrazol, (1.016) prochloraz, (1.017) propiconazole, (1.018) prothioconazole, (1.019) Pyrisoxazole, (1.020) spiroxamine, (1.021) tebuconazole, (1.022) tetraconazole, (1.023) triadimenol, (1.024) tridemorph, (1.025) triticonazole, (1.026) (1R,2S,5S)-5-(4-chlorobenzyl)-2-(chloromethyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, (1.027) (1S,2R,5R)-5-(4-chlorobenzyl)-2-(chloromethyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, (1.028) (2R)-2-(1-chlorocyclopropyl)-4-[(1R)-2,2-dichlorocyclopropyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.029) (2R)-2-(1-chlorocyclopropyl)-4-[(1S)-2,2-dichlorocyclopropyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.030) (2R)-2-[4-(4-chlorophenoxy)-2-(trifluoro-methyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, (1.031) (2S)-2-(1-chlorocyclopropyl)-4-[(1R)-2,2-dichlorocyclopropyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.032) (2S)-2-(1-chlorocyclopropyl)-4-[(1S)-2,2-dichlorocyclopropyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.033) (2S)-2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, (1.034) (R)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)-1,2-oxazol-4-yl](pyridin-3-yl)methanol, (1.035) (S)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)-1,2-oxazol-4-yl](pyridin-3-yl)methanol, (1.036) [3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)-1,2-oxazol-4-yl](pyridin-3-yl)methanol, (1.037) 1-({(2R,4S)-2-[2-chloro-4-(4-chloro-phenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl}methyl)-1H-1,2,4-triazole, (1.038) 1-({(2S,4S)-2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl}methyl)-1H-1,2,4-triazole, (1.039) 1-{[3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazol-5-yl thiocyanate, (1.040) 1-{[rel(2R,3R)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazol-5-yl thiocyanate, (1.041) 1-{[rel(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazol-5-yl thiocyanate, (1.042) 2-[(2R,4R,5R)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.043) 2-[(2R,4R,5S)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.044) 2-[(2R,4S,5R)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.045) 2-[(2R,4S,5S)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.046) 2-[(2S,4R,5R)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.047) 2-[(2S,4R,5S)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.048) 2-[(2S,4S,5R)-1-(2,4-dichloro-phenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.049) 2-[(2S,4S,5S)-1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.050) 2-[1-(2,4-dichlorophenyl)-5-hydroxy-2,6,6-trimethylheptan-4-yl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.051) 2-[2-chloro-4-(2,4-dichlorophenoxy)phenyl]-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, (1.052) 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.053) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (1.054) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)pentan-2-ol, (1.055) Mefentrifluconazole, (1.056) 2-{[3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.057) 2-{[rel(2R,3R)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.058) 2-{[rel(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione, (1.059) 5-(4-chlorobenzyl)-2-(chloromethyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, (1.060) 5-(allylsulfanyl)-1-{[3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole, (1.061) 5-(allylsulfanyl)-1-{[rel(2R,3R)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole, (1.062) 5-(allylsulfanyl)-1-{[rel(2R,3S)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole, (1.063) N′-(2,5-dimethyl-4-{[3-(1,1,2,2-tetrafluoroethoxy)phenyl]sulfanyl}phenyl)-N-ethyl-N-methylimidoformamide, (1.064) N′-(2,5-dimethyl-4-{[3-(2,2,2-trifluoroethoxy)phenyl]sulfanyl}phenyl)-N-ethyl-N-methylimidoformamide, (1.065) N′-(2,5-dimethyl-4-{[3-(2,2,3,3-tetrafluoro-propoxy)phenyl]sulfanyl}phenyl)-N-ethyl-N-methylimidoformamide, (1.066) N′-(2,5-dimethyl-4-{[3-(pentafluoroethoxy)phenyl]sulfanyl}phenyl)-N-ethyl-N-methylimidoformamide, (1.067) N′-(2,5-dimethyl-4-{3-[(1,1,2,2-tetrafluoroethyl)sulfanyl]phenoxy}phenyl)-N-ethyl-N-methylimidoformamide, (1.068) N′-(2,5-dimethyl-4-{3-[(2,2,2-trifluoroethyl)sulfanyl]phenoxy}phenyl)-N-ethyl-N-methylimidoformamide, (1.069) N′-(2,5-dimethyl-4-{3-[(2,2,3,3-tetrafluoropropyl)sulfanyl]phenoxy}phenyl)-N-ethyl-N-methylimidoformamide, (1.070) N′-(2,5-dimethyl-4-{3-[(pentafluoroethyl)sulfanyl]phenoxy}phenyl)-N-ethyl-N-methylimidoformamide, (1.071) N′-(2,5-dimethyl-4-phenoxyphenyl)-N-ethyl-N-methylimidoformamide, (1.072) N′-(4-{[3-(difluoromethoxy)phenyl]sulfanyl}-2,5-dimethylphenyl)-N-ethyl-N-methylimidoformamide, (1.073) N′-(4-{3-[(difluoromethyl)sulfanyl]phenoxy}-2,5-dimethylphenyl)-N-ethyl-N-methylimidoformamide, (1.074) N′-[5-bromo-6-(2,3-dihydro-1H-inden-2-yloxy)-2-methylpyridin-3-yl]-N-ethyl-N-methylimidoformamide, (1.075) N′-{4-[(4,5-dichloro-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide, (1.076) N′-{5-bromo-6-[(1R)-1-(3,5-difluorophenyl)ethoxy]-2-methylpyridin-3-yl}-N-ethyl-N-methylimidoformamide, (1.077) N′-{5-bromo-6-[(1S)-1-(3,5-difluorophenyl)ethoxy]-2-methylpyridin-3-yl}-N-ethyl-N-methylimidoformamide, (1.078) N′-{5-bromo-6-[(cis-4-isopropylcyclohexyl)oxy]-2-methylpyridin-3-yl}-N-ethyl-N-methylimidoformamide, (1.079) N′-{5-bromo-6-[(trans-4-isopropylcyclohexyl)oxy]-2-methylpyridin-3-yl}-N-ethyl-N-methylimidoformamide, (1.080) N′-{5-bromo-6-[1-(3,5-difluorophenyl)ethoxy]-2-methylpyridin-3-yl}-N-ethyl-N-methylimidoformamide, (1.081) Ipfentrifluconazole.
2) Inhibitors of the respiratory chain at complex I or II, for example (2.001) benzovindiflupyr, (2.002) bixafen, (2.003) boscalid, (2.004) carboxin, (2.005) fluopyram, (2.006) flutolanil, (2.007) fluxapyroxad, (2.008) furametpyr, (2.009) Isofetamid, (2.010) isopyrazam (anti-epimeric enantiomer 1R,4S,9S), (2.011) isopyrazam (anti-epimeric enantiomer 1S,4R,9R), (2.012) isopyrazam (anti-epimeric racemate 1RS,4SR,9SR), (2.013) isopyrazam (mixture of syn-epimeric racemate 1RS,4SR,9RS and anti-epimeric racemate 1RS,4SR,9SR), (2.014) isopyrazam (syn-epimeric enantiomer 1R,4S,9R), (2.015) isopyrazam (syn-epimeric enantiomer 1S,4R,9S), (2.016) isopyrazam (syn-epimeric racemate 1 RS,4SR,9RS), (2.017) penflufen, (2.018) penthiopyrad, (2.019) pydiflumetofen, (2.020) Pyraziflumid, (2.021) sedaxane, (2.022) 1,3-dimethyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, (2.023) 1,3-dimethyl-N-[(3R)-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1H-pyrazole-4-carboxamide, (2.024) 1,3-dimethyl-N-[(3S)-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1H-pyrazole-4-carboxamide, (2.025) 1-methyl-3-(trifluoromethyl)-N-[2′-(trifluoromethyl)biphenyl-2-yl]-1H-pyrazole-4-carboxamide, (2.026) 2-fluoro-6-(trifluoromethyl)-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)benzamide, (2.027) 3-(difluoromethyl)-1-methyl-N-(1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)-1H-pyrazole-4-carboxamide, (2.028) 3-(difluoromethyl)-1-methyl-N-[(3R)-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1H-pyrazole-4-carboxamide, (2.029) 3-(difluoromethyl)-1-methyl-N-[(3S)-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1H-pyrazole-4-carboxamide, (2.030) Fluindapyr, (2.031) 3-(difluoromethyl)-N-[(3R)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1-methyl-1H-pyrazole-4-carboxamide, (2.032) 3-(difluoromethyl)-N-[(3S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl]-1-methyl-1H-pyrazole-4-carboxamide, (2.033) 5,8-difluoro-N-[2-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]oxy}-phenyl)ethyl]quinazolin-4-amine, (2.034)N-(2-cyclopentyl-5-fluorobenzyl)-N-cyclopropyl-3-(difluoro-methyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.035)N-(2-tert-butyl-5-methylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.036)N-(2-tert-butylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.037) N-(5-chloro-2-ethylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.038) isoflucypram, (2.039)N-[(1R,4S)-9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.040)N-[(1S,4R)-9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.041)N-[1-(2,4-dichlorophenyl)-1-methoxypropan-2-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.042)N-[2-chloro-6-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.043)N-[3-chloro-2-fluoro-6-(trifluoro-methyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.044) N-[5-chloro-2-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.045)N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[5-methyl-2-(trifluoro-methyl)benzyl]-1H-pyrazole-4-carboxamide, (2.046)N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-fluoro-6-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.047)N-cyclopropyl-3-(difluoro-methyl)-5-fluoro-N-(2-isopropyl-5-methylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.048)N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carbothioamide, (2.049)N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.050)N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(5-fluoro-2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide, (2.051)N-cyclopropyl-3-(difluoromethyl)-N-(2-ethyl-4,5-dimethyl-benzyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.052)N-cyclopropyl-3-(difluoromethyl)-N-(2-ethyl-5-fluorobenzyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.053)N-cyclopropyl-3-(difluoro-methyl)-N-(2-ethyl-5-methylbenzyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.054)N-cyclo-propyl-N-(2-cyclopropyl-5-fluorobenzyl)-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.055)N-cyclopropyl-N-(2-cyclopropyl-5-methylbenzyl)-3-(difluoromethyl)-5-fluoro-1-methyl-1 H-pyrazole-4-carboxamide, (2.056)N-cyclopropyl-N-(2-cyclopropylbenzyl)-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, (2.057) pyrapropoyne.
3) Inhibitors of the respiratory chain at complex III, for example (3.001) ametoctradin, (3.002) amisulbrom, (3.003) azoxystrobin, (3.004) coumethoxystrobin, (3.005) coumoxystrobin, (3.006) cyazofamid, (3.007) dimoxystrobin, (3.008) enoxastrobin, (3.009) famoxadone, (3.010) fenamidone, (3.011) flufenoxystrobin, (3.012) fluoxastrobin, (3.013) kresoxim-methyl, (3.014) metominostrobin, (3.015) orysastrobin, (3.016) picoxystrobin, (3.017) pyraclostrobin, (3.018) pyrametostrobin, (3.019) pyraoxystrobin, (3.020) trifloxystrobin, (3.021) (2E)-2-{2-[({[(1E)-1-(3-{[(E)-1-fluoro-2-phenyl-vinyl]oxy}phenyl)ethylidene]amino}oxy)methyl]phenyl}-2-(methoxyimino)-N-methylacetamide, (3.022) (2E,3Z)-5-{[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy}-2-(methoxyimino)-N,3-dimethylpent-3-enamide, (3.023) (2R)-2-{2-[(2,5-dimethylphenoxy)methyl]phenyl}-2-methoxy-N-methylacetamide, (3.024) (2S)-2-{2-[(2,5-dimethylphenoxy)methyl]phenyl}-2-methoxy-N-methylacetamide, (3.025) (3S,6S,7R,8R)-8-benzyl-3-[({3-[(isobutyryloxy)methoxy]-4-methoxypyridin-2-yl}carbonyl)amino]-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl 2-methylpropanoate, (3.026) mandestrobin, (3.027)N-(3-ethyl-3,5,5-trimethylcyclohexyl)-3-formamido-2-hydroxybenzamide, (3.028) (2E,3Z)-5-{[1-(4-chloro-2-fluoro-phenyl)-1H-pyrazol-3-yl]oxy}-2-(methoxyimino)-N,3-dimethylpent-3-enamide, (3.029) methyl {5-[3-(2,4-dimethylphenyl)-1H-pyrazol-1-yl]-2-methylbenzyl}carbamate, (3.030) metyltetraprole, (3.031) florylpicoxamid.
4) Inhibitors of the mitosis and cell division, for example (4.001) carbendazim, (4.002) diethofencarb, (4.003) ethaboxam, (4.004) fluopicolide, (4.005) pencycuron, (4.006) thiabendazole, (4.007) thiophanate-methyl, (4.008) zoxamide, (4.009) 3-chloro-4-(2,6-difluorophenyl)-6-methyl-5-phenylpyridazine, (4.010) 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methylpyridazine, (4.011) 3-chloro-5-(6-chloropyridin-3-yl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine, (4.012) 4-(2-bromo-4-fluorophenyl)-N-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.013) 4-(2-bromo-4-fluorophenyl)-N-(2-bromo-6-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.014) 4-(2-bromo-4-fluorophenyl)-N-(2-bromophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.015) 4-(2-bromo-4-fluoro-phenyl)-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.016) 4-(2-bromo-4-fluoro-phenyl)-N-(2-chlorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.017) 4-(2-bromo-4-fluorophenyl)-N-(2-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.018) 4-(2-chloro-4-fluorophenyl)-N-(2,6-difluoro-phenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.019) 4-(2-chloro-4-fluorophenyl)-N-(2-chloro-6-fluoro-phenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.020) 4-(2-chloro-4-fluorophenyl)-N-(2-chlorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.021) 4-(2-chloro-4-fluorophenyl)-N-(2-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.022) 4-(4-chlorophenyl)-5-(2,6-difluorophenyl)-3,6-dimethylpyridazine, (4.023)N-(2-bromo-6-fluorophenyl)-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.024)N-(2-bromophenyl)-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine, (4.025)N-(4-chloro-2,6-difluorophenyl)-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine.
5) Compounds capable to have a multisite action, for example (5.001) bordeaux mixture, (5.002) captafol, (5.003) captan, (5.004) chlorothalonil, (5.005) copper hydroxide, (5.006) copper naphthenate, (5.007) copper oxide, (5.008) copper oxychloride, (5.009) copper(2+) sulfate, (5.010) dithianon, (5.011) dodine, (5.012) folpet, (5.013) mancozeb, (5.014) maneb, (5.015) metiram, (5.016) metiram zinc, (5.017) oxine-copper, (5.018) propineb, (5.019) sulfur and sulfur preparations including calcium polysulfide, (5.020) thiram, (5.021) zineb, (5.022) ziram, (5.023) 6-ethyl-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3′,4′:5,6][1,4]dithiino[2,3-c][1,2]thiazole-3-carbonitrile.
6) Compounds capable to induce a host defence, for example (6.001) acibenzolar-S-methyl, (6.002) isotianil, (6.003) probenazole, (6.004) tiadinil.
7) Inhibitors of the amino acid and/or protein biosynthesis, for example (7.001) cyprodinil, (7.002) kasugamycin, (7.003) kasugamycin hydrochloride hydrate, (7.004) oxytetracycline, (7.005) pyrimethanil, (7.006) 3-(5-fluoro-3,3,4,4-tetramethyl-3,4-dihydroisoquinolin-1-yl)quinoline.
8) Inhibitors of the ATP production, for example (8.001) silthiofam.
9) Inhibitors of the cell wall synthesis, for example (9.001) benthiavalicarb, (9.002) dimethomorph, (9.003) flumorph, (9.004) iprovalicarb, (9.005) mandipropamid, (9.006) pyrimorph, (9.007) valifenalate, (9.008) (2E)-3-(4-tert-butylphenyl)-3-(2-chloropyridin-4-yl)-1-(morpholin-4-yl)prop-2-en-1-one, (9.009) (2Z)-3-(4-tert-butylphenyl)-3-(2-chloropyridin-4-yl)-1-(morpholin-4-yl)prop-2-en-1-one.
10) Inhibitors of the lipid and membrane synthesis, for example (10.001) propamocarb, (10.002) propamocarb hydrochloride, (10.003) tolclofos-methyl.
11) Inhibitors of the melanin biosynthesis, for example (11.001) tricyclazole, (11.002) 2,2,2-trifluoroethyl {3-methyl-1-[(4-methylbenzoyl)amino]butan-2-yl}carbamate.
12) Inhibitors of the nucleic acid synthesis, for example (12.001) benalaxyl, (12.002) benalaxyl-M (kiralaxyl), (12.003) metalaxyl, (12.004) metalaxyl-M (mefenoxam).
13) Inhibitors of the signal transduction, for example (13.001) fludioxonil, (13.002) iprodione, (13.003) procymidone, (13.004) proquinazid, (13.005) quinoxyfen, (13.006) vinclozolin.
14) Compounds capable to act as an uncoupler, for example (14.001) fluazinam, (14.002) meptyldinocap.
15) Further compounds, for example (15.001) Abscisic acid, (15.002) benthiazole, (15.003) bethoxazin, (15.004) capsimycin, (15.005) carvone, (15.006) chinomethionat, (15.007) cufraneb, (15.008) cyflufenamid, (15.009) cymoxanil, (15.010) cyprosulfamide, (15.011) flutianil, (15.012) fosetyl-aluminium, (15.013) fosetyl-calcium, (15.014) fosetyl-sodium, (15.015) methyl isothiocyanate, (15.016) metrafenone, (15.017) mildiomycin, (15.018) natamycin, (15.019) nickel dimethyldithio-carbamate, (15.020) nitrothal-isopropyl, (15.021) oxamocarb, (15.022) oxathiapiprolin, (15.023) oxyfenthiin, (15.024) pentachlorophenol and salts, (15.025) phosphorous acid and its salts, (15.026) propamocarb-fosetylate, (15.027) pyriofenone (chlazafenone), (15.028) tebufloquin, (15.029) tecloftalam, (15.030) tolnifanide, (15.031) 1-(4-{4-[(5R)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, (15.032) 1-(4-{4-[(5S)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, (15.033) 2-(6-benzylpyridin-2-yl)quinazoline, (15.034) dipymetitrone, (15.035) 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone, (15.036) 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone, (15.037) 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-fluoro-6-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone, (15.038) 2-[6-(3-fluoro-4-methoxyphenyl)-5-methylpyridin-2-yl]quinazoline, (15.039) 2-{(5R)-3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-chlorophenyl methanesulfonate, (15.040) 2-{(5S)-3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-chlorophenyl methanesulfonate, (15.041) Ipflufenoquin, (15.042) 2-{2-fluoro-6-[(8-fluoro-2-methylquinolin-3-yl)oxy]phenyl}propan-2-ol, (15.043) 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-chlorophenyl methanesulfonate, (15.044) 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}phenyl methanesulfonate, (15.045) 2-phenylphenol and salts, (15.046) 3-(4,4,5-trifluoro-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline, (15.047) quinofumelin, (15.048) 4-amino-5-fluoropyrimidin-2-ol (tautomeric form: 4-amino-5-fluoropyrimidin-2(1H)-one), (15.049) 4-oxo-4-[(2-phenylethyl)amino]butanoic acid, (15.050) 5-amino-1,3,4-thiadiazole-2-thiol, (15.051) 5-chloro-N′-phenyl-N′-(prop-2-yn-1-yl)thiophene-2-sulfonohydrazide, (15.052) 5-fluoro-2-[(4-fluoro-benzyl)oxy]pyrimidin-4-amine, (15.053) 5-fluoro-2-[(4-methylbenzyl)oxy]pyrimidin-4-amine, (15.054) 9-fluoro-2,2-dimethyl-5-(quinolin-3-yl)-2,3-dihydro-1,4-benzoxazepine, (15.055) but-3-yn-1-yl {6-[({[(Z)-(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate, (15.056) ethyl (2Z)-3-amino-2-cyano-3-phenylacrylate, (15.057) phenazine-1-carboxylic acid, (15.058) propyl 3,4,5-trihydroxybenzoate, (15.059) quinolin-8-ol, (15.060) quinolin-8-ol sulfate (2:1), (15.061) tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate, (15.062) 5-fluoro-4-imino-3-methyl-1-[(4-methylphenyl)sulfonyl]-3,4-dihydropyrimidin-2(1H)-one, (15.063) amino-pyrifen.
All named mixing partners of the classes (1) to (15) as described here above can be present in the form of the free compound and/or, if their functional groups enable this, an agriculturally acceptable salt thereof.
The compound of formula (I) and the composition may also be combined with one or more biological control agents.
Examples of biological control agents which may be combined with the compound of formula (I) and composition comprising thereof are:
(A) Antibacterial agents selected from the group of:
(A1) bacteria, such as (A1.1) Bacillus subtilis, in particular strain QST713/AQ713 (available as SERENADE OPTI or SERENADE ASO from Bayer CropScience LP, US, having NRRL Accession No. B21661 and described in U.S. Pat. No. 6,060,051); (A1.2) Bacillus amyloliquefaciens, in particular strain D747 (available as Double Nickel™ from Certis, US, having accession number FERM BP-8234 and disclosed in U.S. Pat. No. 7,094,592); (A1.3) Bacillus pumilus, in particular strain BU F-33 (having NRRL Accession No. 50185); (A1.4) Bacillus subtilis var. amyloliquefaciens strain FZB24 (available as Taegro® from Novozymes, US); (A1.5) a Paenibacillus sp. strain having Accession No. NRRL B-50972 or Accession No. NRRL B-67129 and described in International Patent Publication No. WO 2016/154297; and
(A2) fungi, such as (A2.1) Aureobasidium pullulans, in particular blastospores of strain DSM14940; (A2.2) Aureobasidium pullulans blastospores of strain DSM 14941; (A2.3) Aureobasidium pullulans, in particular mixtures of blastospores of strains DSM14940 and DSM14941;
(B) Fungicides selected from the group of:
(B1) bacteria, for example (B1.1) Bacillus subtilis, in particular strain QST713/AQ713 (available as SERENADE OPTI or SERENADE ASO from Bayer CropScience LP, US, having NRRL Accession No. B21661 and described in U.S. Pat. No. 6,060,051); (B1.2) Bacillus pumilus, in particular strain QST2808 (available as SONATA® from Bayer CropScience LP, US, having Accession No. NRRL B-30087 and described in U.S. Pat. No. 6,245,551); (B1.3) Bacillus pumilus, in particular strain GB34 (available as Yield Shield® from Bayer AG, DE); (B11.4) Bacillus pumilus, in particular strain BU F-33 (having NRRL Accession No. 50185); (B11.5) Bacillus amyloliquefaciens, in particular strain D747 (available as Double Nickel™ from Certis, US, having accession number FERM BP-8234 and disclosed in U.S. Pat. No. 7,094,592); (B11.6) Bacillus subtilis Y1336 (available as BIOBAC® WP from Bion-Tech, Taiwan, registered as a biological fungicide in Taiwan under Registration Nos. 4764, 5454, 5096 and 5277); (B11.7) Bacillus amyloliquefaciens strain MBI 600 (available as SUBTILEX from BASF SE); (B11.8) Bacillus subtilis strain GB03 (available as Kodiak® from Bayer AG, DE); (B11.9) Bacillus subtilis var. amyloliquefaciens strain FZB24 (available from Novozymes Biologicals Inc., Salem, Va. or Syngenta Crop Protection, LLC, Greensboro, N.C. as the fungicide TAEGRO® or TAEGRO® ECO (EPA Registration No. 70127-5); (B1.10) Bacillus mycoides, isolate J (available as BmJ TGAI or WG from Certis USA); (B11.11) Bacillus licheniformis, in particular strain SB3086 (available as EcoGuard™ Biofungicide and Green Releaf from Novozymes); (B1.12) a Paenibacillus sp. strain having Accession No. NRRL B-50972 or Accession No. NRRL B-67129 and described in International Patent Publication No. WO 2016/154297.
In some embodiments, the biological control agent is a Bacillus subtilis or Bacillus amyloliquefaciens strain that produces a fengycin or plipastatin-type compound, an iturin-type compound, and/or a surfactin-type compound. For background, see the following review article: Ongena, M., et al., “Bacillus Lipopeptides: Versatile Weapons for Plant Disease Biocontrol,” Trends in Microbiology, Vol 16, No. 3, March 2008, pp. 115-125. Bacillus strains capable of producing lipopeptides include Bacillus subtilis QST713 (available as SERENADE OPTI or SERENADE ASO from Bayer CropScience LP, US, having NRRL Accession No. B21661 and described in U.S. Pat. No. 6,060,051), Bacillus amyloliquefaciens strain D747 (available as Double Nickel™ from Certis, US, having accession number FERM BP-8234 and disclosed in U.S. Pat. No. 7,094,592); Bacillus subtilis MB1600 (available as SUBTILEX® from Becker Underwood, US EPA Reg. No. 71840-8); Bacillus subtilis Y1336 (available as BIOBAC® WP from Bion-Tech, Taiwan, registered as a biological fungicide in Taiwan under Registration Nos. 4764, 5454, 5096 and 5277); Bacillus amyloliquefaciens, in particular strain FZB42 (available as RHIZOVITAL® from ABiTEP, DE); and Bacillus subtilis var. amyloliquefaciens FZB24 (available from Novozymes Biologicals Inc., Salem, Va. or Syngenta Crop Protection, LLC, Greensboro, N.C. as the fungicide TAEGRO® or TAEGRO® ECO (EPA Registration No. 70127-5); and
(B2) fungi, for example: (B2.1) Coniothyrium minitans, in particular strain CON/M/91-8 (Accession No. DSM-9660; e.g. Contans® from Bayer); (B2.2) Metschnikowia fructicola, in particular strain NRRL Y-30752 (e.g. Shemer®); (B2.3) Microsphaeropsis ochracea (e.g. Microx® from Prophyta); (B2.5) Trichoderma spp., including Trichoderma atroviride, strain SC1 described in International Application No. PCT/IT2008/000196); (B2.6) Trichoderma harzianum rifai strain KRL-AG2 (also known as strain T-22, /ATCC 208479, e.g. PLANTSHIELD T-22G, Rootshield®, and TurfShield from BioWorks, US); (B2.14) Gliocladium roseum, strain 321U from W.F. Stoneman Company LLC; (B2.35) Talaromyces flavus, strain V117b; (B2.36) Trichoderma asperellum, strain ICC 012 from Isagro; (B2.37) Trichoderma asperellum, strain SKT-1 (e.g. ECO-HOPE® from Kumiai Chemical Industry); (B2.38) Trichoderma atroviride, strain CNCM I-1237 (e.g. Esquive® WP from Agrauxine, FR); (B2.39) Trichoderma atroviride, strain no. V08/002387; (B2.40) Trichoderma atroviride, strain NMI no. V08/002388; (B2.41) Trichoderma atroviride, strain NMI no. V08/002389; (B2.42) Trichoderma atroviride, strain NMI no. V08/002390; (B2.43) Trichoderma atroviride, strain LC52 (e.g. Tenet by Agrimm Technologies Limited); (B2.44) Trichoderma atroviride, strain ATCC 20476 (IMI 206040); (B2.45) Trichoderma atroviride, strain T11 (IM1352941/CECT20498); (B2.46) Trichoderma harmatum; (B2.47) Trichoderma harzianum; (B2.48) Trichoderma harzianum rifai T39 (e.g. Trichodex® from Makhteshim, US); (B2.49) Trichoderma harzianum, in particular, strain KD (e.g. Trichoplus from Biological Control Products, SA (acquired by Becker Underwood)); (B2.50) Trichoderma harzianum, strain ITEM 908 (e.g. Trianum-P from Koppert); (B2.51) Trichoderma harzianum, strain TH35 (e.g. Root-Pro by Mycontrol); (B2.52) Trichoderma virens (also known as Gliocladium virens), in particular strain GL-21 (e.g. SoilGard 12G by Certis, US); (B2.53) Trichoderma viride, strain TV1 (e.g. Trianum-P by Koppert); (B2.54) Ampelomyces quisqualis, in particular strain AQ 10 (e.g. AQ 10® by IntrachemBio Italia); (B2.56) Aureobasidium pullulans, in particular blastospores of strain DSM14940; (B2.57) Aureobasidium pullulans, in particular blastospores of strain DSM 14941; (B2.58) Aureobasidium pullulans, in particular mixtures of blastospores of strains DSM14940 and DSM 14941 (e.g. Botector® by bio-ferm, CH); (B2.64) Cladosporium cladosporioides, strain H39 (by Stichting Dienst Landbouwkundig Onderzoek); (B2.69) Gliocladium catenulatum (Synonym: Clonostachys rosea f. catenulate) strain J1446 (e.g. Prestop® by AgBio Inc. and also e.g. Primastop® by Kemira Agro Oy); (B2.70) Lecanicillium lecanii (formerly known as Verticillium lecanii) conidia of strain KV01 (e.g. Vertalec® by Koppert/Arysta); (B2.71) Penicillium vermiculatum; (B2.72) Pichia anomala, strain WRL-076 (NRRL Y-30842); (B2.75) Trichoderma atroviride, strain SKT-1 (FERM P-16510); (B2.76) Trichoderma atroviride, strain SKT-2 (FERM P-16511); (B2.77) Trichoderma atroviride, strain SKT-3 (FERM P-17021); (B2.78) Trichoderma gamsii (formerly T. viride), strain ICC080 (IMI CC 392151 CABI, e.g. BioDerma by AGROBIOSOL DE MEXICO, S.A. DE C.V.); (B2.79) Trichoderma harzianum, strain DB 103 (e.g., T-Gro 7456 by Dagutat Biolab); (B2.80) Trichoderma polysporum, strain IMI 206039 (e.g. Binab TF WP by BINAB Bio-Innovation AB, Sweden); (B2.81) Trichoderma stromaticum (e.g. Tricovab by Ceplac, Brazil); (B2.83) Ulocladium oudemansii, in particular strain HRU3 (e.g. Botry-Zen® by Botry-Zen Ltd, NZ); (B2.84) Verticillium albo-atrum (formerly V. dahliae), strain WCS850 (CBS 276.92; e.g. Dutch Trig by Tree Care Innovations); (B2.86) Verticillium chlamydosporium; (B2.87) mixtures of Trichoderma asperellum strain ICC 012 and Trichoderma gamsii strain ICC 080 (product known as e.g. BIO-TAM™ from Bayer CropScience LP, US).
Further examples of biological control agents which may be combined with the compound of formula (I) and composition comprising thereof are:
bacteria selected from the group consisting of Bacillus cereus, in particular B. cereus strain CNCM I-1562 and Bacillus firmus, strain I-1582 (Accession number CNCM I-1582), Bacillus subtilis strain OST 30002 (Accession No. NRRL B-50421), Bacillus thuringiensis, in particular B. thuringiensis subspecies israelensis (serotype H-14), strain AM65-52 (Accession No. ATCC 1276), B. thuringiensis subsp. aizawai, in particular strain ABTS-1857 (SD-1372), B. thuringiensis subsp. kurstaki strain HD-1, B. thuringiensis subsp. tenebrionis strain NB 176 (SD-5428), Pasteuria penetrans, Pasteuria spp. (Rotylenchulus reniformis nematode)-PR3 (Accession Number ATCC SD-5834), Streptomyces microflavus strain AQ6121 (=QRD 31.013, NRRL B-50550), and Streptomyces galbus strain AQ 6047 (Acession Number NRRL 30232);
fungi and yeasts selected from the group consisting of Beauveria bassiana, in particular strain ATCC 74040, Lecanicillium spp., in particular strain HRO LEC 12, Metarhizium anisopliae, in particular strain F52 (DSM3884 or ATCC 90448), Paecilomyces fumosoroseus (now: Isaria fumosorosea), in particular strain IFPC 200613, or strain Apopka 97 (Accession No. ATCC 20874), and Paecilomyces lilacinus, in particular P. lilacinus strain 251 (AGAL 89/030550);
viruses selected from the group consisting of Adoxophyes orana (summer fruit tortrix) granulosis virus (GV), Cydia pomonella (codling moth) granulosis virus (GV), Helicoverpa armigera (cotton bollworm) nuclear polyhedrosis virus (NPV), Spodoptera exigua (beet armyworm) mNPV, Spodoptera frugiperda (fall armyworm) mNPV, and Spodoptera littoralis (African cotton leafworm) NPV.
bacteria and fungi which can be added as ‘inoculant’ to plants or plant parts or plant organs and which, by virtue of their particular properties, promote plant growth and plant health. Examples are: Agrobacterium spp., Azorhizobium caulinodans, Azospirillum spp., Azotobacter spp., Bradyrhizobium spp., Burkholderia spp., in particular Burkholderia cepacia (formerly known as Pseudomonas cepacia), Gigaspora spp., or Gigaspora monosporum, Glomus spp., Laccaria spp., Lactobacillus buchneri, Paraglomus spp., Pisolithus tinctorus, Pseudomonas spp., Rhizobium spp., in particular Rhizobium trifolii, Rhizopogon spp., Scleroderma spp., Suillus spp., and Streptomyces spp.
plant extracts and products formed by microorganisms including proteins and secondary metabolites which can be used as biological control agents, such as Allium sativum, Artemisia absinthium, azadirachtin, Biokeeper WP, Cassia nigricans, Celastrus angulatus, Chenopodium anthelminticum, chitin, Armour-Zen, Dryopteris filix-mas, Equisetum arvense, Fortune Aza, Fungastop, Heads Up (Chenopodium quinoa saponin extract), Pyrethrum/Pyrethrins, Quassia amara, Quercus, Quillaja, Regalia, “Requiem™ Insecticide”, rotenone, ryania/ryanodine, Symphytum officinale, Tanacetum vulgare, thymol, Triact 70, TriCon, Tropaeulum majus, Urtica dioica, Veratrin, Viscum album, Brassicaceae extract, in particular oilseed rape powder or mustard powder.
Examples of insecticides, acaricides and nematicides, respectively, which could be mixed with the compound of formula (I) and composition comprising thereof are:
(1) Acetylcholinesterase (AChE) inhibitors, such as, for example, carbamates, for example alanycarb, aldicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, trimethacarb, XMC and xylylcarb; or organophosphates, for example acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, cadusafos, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenamiphos, fenitrothion, fenthion, fosthiazate, heptenophos, imicyafos, isofenphos, isopropyl O-(methoxyaminothiophosphoryl) salicylate, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, triclorfon and vamidothion.
(2) GABA-gated chloride channel blockers, such as, for example, cyclodiene-organochlorines, for example chlordane and endosulfan or phenylpyrazoles (fiproles), for example ethiprole and fipronil.
(3) Sodium channel modulators, such as, for example, pyrethroids, e.g. acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin s-cyclopentenyl isomer, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin [(1R)-trans-isomer], deltamethrin, empenthrin [(EZ)-(1R)-isomer], esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, kadethrin, momfluorothrin, permethrin, phenothrin [(1R)-trans-isomer], prallethrin, pyrethrins (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tetramethrin [(1R)-isomer)], tralomethrin and transfluthrin or DDT or methoxychlor.
(4) Nicotinic acetylcholine receptor (nAChR) competitive modulators, such as, for example, neonicotinoids, e.g. acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam or nicotine or sulfoxaflor or flupyradifurone.
(5) Nicotinic acetylcholine receptor (nAChR) allosteric modulators, such as, for example, spinosyns, e.g. spinetoram and spinosad.
(6) Glutamate-gated chloride channel (GluCl) allosteric modulators, such as, for example, avermectins/milbemycins, for example abamectin, emamectin benzoate, lepimectin and milbemectin.
(7) Juvenile hormone mimics, such as, for example, juvenile hormone analogues, e.g. hydroprene, kinoprene and methoprene or fenoxycarb or pyriproxyfen.
(8) Miscellaneous non-specific (multi-site) inhibitors, such as, for example, alkyl halides, e.g. methyl bromide and other alkyl halides; or chloropicrine or sulphuryl fluoride or borax or tartar emetic or methyl isocyanate generators, e.g. diazomet and metam.
(9) Modulators of Chordotonal Organs, such as, for example pymetrozine or flonicamid.
(10) Mite growth inhibitors, such as, for example clofentezine, hexythiazox and diflovidazin or etoxazole.
(11) Microbial disruptors of the insect gut membrane, such as, for example Bacillus thuringiensis subspecies israelensis, Bacillus sphaericus, Bacillus thuringiensis subspecies aizawai, Bacillus thuringiensis subspecies kurstaki, Bacillus thuringiensis subspecies tenebrionis, and B.t. plant proteins: Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/35Ab1.
(12) Inhibitors of mitochondrial ATP synthase, such as, ATP disruptors such as, for example, diafenthiuron or organotin compounds, for example azocyclotin, cyhexatin and fenbutatin oxide or propargite or tetradifon.
(13) Uncouplers of oxidative phosphorylation via disruption of the proton gradient, such as, for example, chlorfenapyr, DNOC and sulfluramid.
(14) Nicotinic acetylcholine receptor channel blockers, such as, for example, bensultap, cartap hydrochloride, thiocylam, and thiosultap-sodium.
(15) Inhibitors of chitin biosynthesis, type 0, such as, for example, bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron.
(16) Inhibitors of chitin biosynthesis, type 1, for example buprofezin.
(17) Moulting disruptor (in particular for Diptera, i.e. dipterans), such as, for example, cyromazine.
(18) Ecdysone receptor agonists, such as, for example, chromafenozide, halofenozide, methoxyfenozide and tebufenozide.
(19) Octopamine receptor agonists, such as, for example, amitraz.
(20) Mitochondrial complex III electron transport inhibitors, such as, for example, hydramethylnone or acequinocyl or fluacrypyrim.
(21) Mitochondrial complex I electron transport inhibitors, such as, for example from the group of the METI acaricides, e.g. fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad and tolfenpyrad or rotenone (Derris).
(22) Voltage-dependent sodium channel blockers, such as, for example indoxacarb or metaflumizone.
(23) Inhibitors of acetyl CoA carboxylase, such as, for example, tetronic and tetramic acid derivatives, e.g. spirodiclofen, spiromesifen and spirotetramat.
(24) Mitochondrial complex IV electron transport inhibitors, such as, for example, phosphines, e.g. aluminium phosphide, calcium phosphide, phosphine and zinc phosphide or cyanides, e.g. calcium cyanide, potassium cyanide and sodium cyanide.
(25) Mitochondrial complex II electron transport inhibitors, such as, for example, beta-ketonitrile derivatives, e.g. cyenopyrafen and cyflumetofen and carboxanilides, such as, for example, pyflubumide.
(28) Ryanodine receptor modulators, such as, for example, diamides, e.g. chlorantraniliprole, cyantraniliprole and flubendiamide,
further active compounds such as, for example, Afidopyropen, Afoxolaner, Azadirachtin, Benclothiaz, Benzoximate, Bifenazate, Broflanilide, Bromopropylate, Chinomethionat, Chloroprallethrin, Cryolite, Cyclaniliprole, Cycloxaprid, Cyhalodiamide, Dicloromezotiaz, Dicofol, epsilon-Metofluthrin, epsilon-Momfluthrin, Flometoquin, Fluazaindolizine, Fluensulfone, Flufenerim, Flufenoxystrobin, Flufiprole, Fluhexafon, Fluopyram, Fluralaner, Fluxametamide, Fufenozide, Guadipyr, Heptafluthrin, Imidaclothiz, Iprodione, kappa-Bifenthrin, kappa-Tefluthrin, Lotilaner, Meperfluthrin, Paichongding, Pyridalyl, Pyrifluquinazon, Pyriminostrobin, Spirobudiclofen, Tetramethylfluthrin, Tetraniliprole, Tetrachlorantraniliprole, Tigolaner, Tioxazafen, Thiofluoximate, Triflumezopyrim and iodomethane; furthermore preparations based on Bacillus firmus (1-1582, BioNeem, Votivo), and also the following compounds: 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulphinyl]phenyl}-3-(trifluoromethyl)-1H-1,2,4-triazole-5-amine (known from WO2006/043635) (CAS 885026-50-6), {1′-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]-5-fluorospiro[indol-3,4′-piperidin]-1(2H)-yl}(2-chloropyridin-4-yl)methanone (known from WO2003/106457) (CAS 637360-23-7), 2-chloro-N-[2-{1-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]piperidin-4-yl}-4-(trifluoromethyl)phenyl]isonicotinamide (known from WO2006/003494) (CAS 872999-66-1), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy-1,8-diazaspiro[4.5]dec-3-en-2-one (known from WO 2010052161) (CAS 1225292-17-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-2-oxo-1,8-diazaspiro[4.5]dec-3-en-4-yl ethyl carbonate (known from EP2647626) (CAS 1440516-42-6), 4-(but-2-yn-1-yloxy)-6-(3,5-dimethylpiperidin-1-yl)-5-fluoropyrimidine (known from WO2004/099160) (CAS 792914-58-0), PF1364 (known from JP2010/018586) (CAS 1204776-60-2), N-[(2E)-1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (known from WO2012/029672) (CAS 1363400-41-2), (3E)-3-[1-[(6-chloro-3-pyridyl)methyl]-2-pyridylidene]-1,1,1-trifluoro-propan-2-one (known from WO2013/144213) (CAS 1461743-15-6), N-[3-(benzylcarbamoyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (known from WO2010/051926) (CAS 1226889-14-0), 5-bromo-4-chloro-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxamide (known from CN103232431) (CAS 1449220-44-3), 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)-benzamide, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(trans-1-oxido-3-thietanyl)-benzamide and 4-[(5S)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)benzamide (known from WO 2013/050317 A1) (CAS 1332628-83-7), N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3, 3,3-trifluoropropyl)sulfinyl]-propanamide, (+)-N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3, 3,3-trifluoropropyl)sulfinyl]-propanamide and (−)-N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propanamide (known from WO 2013/162715 A2, WO 2013/162716 A2, US 2014/0213448 A1) (CAS 1477923-37-7), 5-[[(2E)-3-chloro-2-propen-1-yl]amino]-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile (known from CN 101337937 A) (CAS 1105672-77-2), 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)thioxomethyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, (Liudaibenjiaxuanan, known from CN 103109816 A) (CAS 1232543-85-9); N-[4-chloro-2-[[(1,1-dimethylethyl)amino]carbonyl]-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-3-(fluoromethoxy)-1H-Pyrazole-5-carboxamide (known from WO 2012/034403 A1) (CAS 1268277-22-0), N-[2-(5-amino-1,3,4-thiadiazol-2-yl)-4-chloro-6-methylphenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known from WO 2011/085575 A1) (CAS 1233882-22-8), 4-[3-[2,6-dichloro-4-[(3,3-dichloro-2-propen-1-yl)oxy]phenoxy]propoxy]-2-methoxy-6-(trifluoromethyl)-pyrimidine (known from CN 101337940 A) (CAS 1108184-52-6); (2E)- and 2(Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(difluoromethoxy)phenyl]-hydrazinecarboxamide (known from CN 101715774 A) (CAS 1232543-85-9); 3-(2,2-dichloroethenyl)-2,2-dimethyl-4-(1H-benzimidazol-2-yl)phenyl-cyclopropanecarboxylic acid ester (known from CN 103524422 A) (CAS 1542271-46-4); (4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-[(trifluoromethyl)thio]phenyl]amino]carbonyl]-indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylic acid methyl ester (known from CN 102391261 A) (CAS 1370358-69-2); 6-deoxy-3-O-ethyl-2,4-di-O-methyl-, 1-[N-[4-[1-[4-(1,1,2,2,2-pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]carbamate]-α-L-mannopyranose (known from US 2014/0275503 A1) (CAS 1181213-14-8); 8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (CAS 1253850-56-4), (8-anti)-8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (CAS 933798-27-7), (8-syn)-8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (known from WO 2007040280 A1, WO 2007040282 A1) (CAS 934001-66-8), N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)thio]-propanamide (known from WO 2015/058021 A1, WO 2015/058028 A1) (CAS 1477919-27-9) and N-[4-(aminothioxomethyl)-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known from CN 103265527 A) (CAS 1452877-50-7), 5-(1,3-dioxan-2-yl)-4-[[4-(trifluoromethyl)phenyl]methoxy]-pyrimidine (known from WO 2013/115391 A1) (CAS 1449021-97-9), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diazaspiro[4.5]dec-3-en-2-one (known from WO 2010/066780 A1, WO 2011/151146 A1) (CAS 1229023-34-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1-methyl-1,8-diazaspiro[4.5]decane-2,4-dione (known from WO 2014/187846 A1) (CAS 1638765-58-8), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1-methyl-2-oxo-1, 8-diazaspiro[4.5]dec-3-en-4-yl-carbonic acid ethyl ester (known from WO 2010/066780 A1, WO 2011151146 A1) (CAS 1229023-00-0), N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylidene]-2,2,2-trifluoro-acetamide (known from DE 3639877 A1, WO 2012029672 A1) (CAS 1363400-41-2), [N(E)]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylidene]-2,2,2-trifluoro-acetamide, (known from WO 2016005276 A1) (CAS 1689566-03-7), [N(Z)]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylidene]-2,2,2-trifluoro-acetamide, (CAS 1702305-40-5), 3-endo-3-[2-propoxy-4-(trifluoromethyl)phenoxy]-9-[[5-(trifluoromethyl)-2-pyridinyl]oxy]-9-azabicyclo[3.3.1]nonane (known from WO 2011/105506 A1, WO 2016/133011 A1) (CAS 1332838-17-1).
Examples of safeners which could be mixed with the compound of formula (I) and composition comprising thereof are, for example, benoxacor, cloquintocet (-mexyl), cyometrinil, cyprosulfamide, dichlormid, fenchlorazole (-ethyl), fenclorim, flurazole, fluxofenim, furilazole, isoxadifen (-ethyl), mefenpyr (-diethyl), naphthalic anhydride, oxabetrinil, 2-methoxy-N-({4-[(methylcarbamoyl)amino]phenyl}-sulphonyl)benzamide (CAS 129531-12-0), 4-(dichloroacetyl)-1-oxa-4-azaspiro[4.5]decane (CAS 71526-07-3), 2,2,5-trimethyl-3-(dichloroacetyl)-1,3-oxazolidine (CAS 52836-31-4).
Examples of herbicides which could be mixed with the compound of formula (I) and composition comprising thereof are:
Acetochlor, acifluorfen, acifluorfen-sodium, aclonifen, alachlor, allidochlor, alloxydim, alloxydim-sodium, ametryn, amicarbazone, amidochlor, amidosulfuron, 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methylphenyl)-5-fluoropyridine-2-carboxylic acid, aminocyclopyrachlor, aminocyclopyrachlor-potassium, aminocyclopyrachlor-methyl, aminopyralid, amitrole, ammoniumsulfamate, anilofos, asulam, atrazine, azafenidin, azimsulfuron, beflubutamid, benazolin, benazolin-ethyl, benfluralin, benfuresate, bensulfuron, bensulfuron-methyl, bensulide, bentazone, benzobicyclon, benzofenap, bicyclopyron, bifenox, bilanafos, bilanafos-sodium, bispyribac, bispyribac-sodium, bromacil, bromobutide, bromofenoxim, bromoxynil, bromoxynil-butyrate, -potassium, -heptanoate, and -octanoate, busoxinone, butachlor, butafenacil, butamifos, butenachlor, butralin, butroxydim, butylate, cafenstrole, carbetamide, carfentrazone, carfentrazone-ethyl, chloramben, chlorbromuron, chlorfenac, chlorfenac-sodium, chlorfenprop, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlorophthalim, chlorotoluron, chlorthal-dimethyl, chlorsulfuron, cinidon, cinidon-ethyl, cinmethylin, cinosulfuron, clacyfos, clethodim, clodinafop, clodinafop-propargyl, clomazone, clomeprop, clopyralid, cloransulam, cloransulam-methyl, cumyluron, cyanamide, cyanazine, cycloate, cyclopyrimorate, cyclosulfamuron, cycloxydim, cyhalofop, cyhalofop-butyl, cyprazine, 2,4-D, 2,4-D-butotyl, -butyl, -dimethylammonium, -diolamin, -ethyl, -2-ethylhexyl, -isobutyl, -isooctyl, -isopropylammonium, -potassium, -triisopropanolammonium, and -trolamine, 2,4-DB, 2,4-DB-butyl, -dimethylammonium, -isooctyl, -potassium, and -sodium, daimuron (dymron), dalapon, dazomet, n-decanol, desmedipham, detosyl-pyrazolate (DTP), dicamba, dichlobenil, 2-(2,4-dichlorobenzyl)-4,4-dimethyl-1,2-oxazolidin-3-one, 2-(2,5-dichlorobenzyl)-4,4-dimethyl-1,2-oxazolidin-3-one, dichlorprop, dichlorprop-P, diclofop, diclofop-methyl, diclofop-P-methyl, diclosulam, difenzoquat, diflufenican, diflufenzopyr, diflufenzopyr-sodium, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimetrasulfuron, dinitramine, dinoterb, diphenamid, diquat, diquat-dibromid, dithiopyr, diuron, DNOC, endothal, EPTC, esprocarb, ethalfluralin, ethametsulfuron, etha-metsulfuron-methyl, ethiozin, ethofumesate, ethoxyfen, ethoxyfen-ethyl, ethoxysulfuron, etobenzanid, F-9600, F-5231, i.e. N-{2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl]phenyl}ethanesulfonamide, F-7967, i. e. 3-[7-chloro-5-fluoro-2-(trifluoromethyl)-1H-benzimidazol-4-yl]-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, fenoxaprop, fenoxaprop-P, fenoxaprop-ethyl, fenoxaprop-P-ethyl, fenoxasulfone, fenquinotrione, fentrazamide, flamprop, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, florasulam, fluazifop, fluazifop-P, fluazifop-butyl, fluazifop-P-butyl, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flufenacet, flufenpyr, flufenpyr-ethyl, flumetsulam, flumiclorac, flumiclorac-pentyl, flumioxazin, fluometuron, flurenol, flurenol-butyl, -dimethylammonium and -methyl, fluoroglycofen, fluoroglycofen-ethyl, flupropanate, flupyrsulfuron, flupyrsulfuron-methyl-sodium, fluridone, flurochloridone, fluroxypyr, fluroxypyr-meptyl, flurtamone, fluthiacet, fluthiacet-methyl, fomesafen, fomesafen-sodium, foramsulfuron, fosamine, glufosinate, glufosinate-ammonium, glufosinate-P-sodium, glufosinate-P-ammonium, glufosinate-P-sodium, glyphosate, glyphosate-ammonium, -isopropylammonium, -diammonium, -dimethylammonium, -potassium, -sodium, and -trimesium, H-9201, i.e. 0-(2,4-dimethyl-6-nitrophenyl) O-ethyl isopropylphosphoramidothioate, halauxifen, halauxifen-methyl, halosafen, halosulfuron, halosulfuron-methyl, haloxyfop, haloxyfop-P, haloxyfop-ethoxyethyl, haloxyfop-P-ethoxyethyl, haloxyfop-methyl, haloxyfop-P-methyl, hexazinone, HW-02, i.e. 1-(dimethoxyphosphoryl) ethyl-(2,4-dichlorophenoxy)acetate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazethapyr, imazethapyr-immonium, imazosulfuron, indanofan, indaziflam, iodosulfuron, iodosulfuron-methyl-sodium, ioxynil, ioxynil-octanoate, -potassium and -sodium, ipfencarbazone, isoproturon, isouron, isoxaben, isoxaflutole, karbutilate, KUH-043, i.e. 3-({[5-(difluoromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfonyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole, ketospiradox, lactofen, lenacil, linuron, MCPA, MCPA-butotyl, -dimethylammonium, -2-ethylhexyl, -isopropylammonium, -potassium, and -sodium, MCPB, MCPB-methyl, -ethy,l and -sodium, mecoprop, mecoprop-sodium, and -butotyl, mecoprop-P, mecoprop-P-butotyl, -dimethylammonium, -2-ethylhexyl, and -potassium, mefenacet, mefluidide, mesosulfuron, mesosulfuron-methyl, mesotrione, methabenzthiazuron, metam, metamifop, metamitron, metazachlor, metazosulfuron, methabenzthiazuron, methiopyrsulfuron, methiozolin, methyl isothiocyanate, metobromuron, metolachlor, S-metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, metsulfuron-methyl, molinat, mono-linuron, monosulfuron, monosulfuron-ester, MT-5950, i.e. N-(3-chloro-4-isopropylphenyl)-2-methyl-pentan amide, NGGC-011, napropamide, NC-310, i.e. [5-(benzyloxy)-1-methyl-1H-pyrazol-4-yl](2,4-dichlorophenyl)methanone, neburon, nicosulfuron, nonanoic acid (pelargonic acid), norflurazon, oleic acid (fatty acids), orbencarb, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxasulfuron, oxaziclo-mefon, oxyfluorfen, paraquat, paraquat dichloride, pebulate, pendimethalin, penoxsulam, pentachlor-phenol, pentoxazone, pethoxamid, petroleum oils, phenmedipham, picloram, picolinafen, pinoxaden, piperophos, pretilachlor, primisulfuron, primisulfuron-methyl, prodiamine, profoxydim, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham, propisochlor, propoxycarbazone, propoxycarbazone-sodium, propyrisulfuron, propyzamide, prosulfocarb, prosulfuron, pyraclonil, pyraflufen, pyraflufen-ethyl, pyrasulfotole, pyrazolynate (pyrazolate), pyrazosulfuron, pyrazosulfuron-ethyl, pyrazoxyfen, pyribambenz, pyribambenz-isopropyl, pyribambenz-propyl, pyribenzoxim, pyri-buticarb, pyridafol, pyridate, pyriftalid, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrithiobac, pyrithiobac-sodium, pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, rimsulfuron, saflufenacil, sethoxydim, siduron, simazine, simetryn, SL-261, sulcotrion, sulfentrazone, sulfometuron, sulfo-meturon-methyl, sulfosulfuron, SYN-523, SYP-249, i.e. 1-ethoxy-3-methyl-1-oxobut-3-en-2-yl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoate, SYP-300, i.e. 1-[7-fluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-3-propyl-2-thioxoimidazolidine-4,5-dione, 2,3,6-TBA, TCA (trichloroacetic acid), TCA-sodium, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbumeton, terbuthylazin, terbutryn, thenylchlor, thiazopyr, thiencarbazone, thien-carbazone-methyl, thifensulfuron, thifensulfuron-methyl, thiobencarb, tiafenacil, tolpyralate, topra-mezone, tralkoxydim, triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tribenuron-methyl, triclopyr, trietazine, trifloxysulfuron, trifloxysulfuron-sodium, trifludimoxazin, trifluralin, triflusulfuron, triflusulfuron-methyl, tritosulfuron, urea sulfate, vernolate, XDE-848, ZJ-0862, i.e. 3,4-dichloro-N-{2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzyl}aniline, and the following compounds:
Examples for plant growth regulators are:
Acibenzolar, acibenzolar-S-methyl, 5-aminolevulinic acid, ancymidol, 6-benzylaminopurine, Brassinolid, catechine, chlormequat chloride, cloprop, cyclanilide, 3-(cycloprop-1-enyl) propionic acid, daminozide, dazomet, n-decanol, dikegulac, dikegulac-sodium, endothal, endothal-dipotassium, -disodium, and -mono(N,N-dimethylalkylammonium), ethephon, flumetralin, flurenol, flurenol-butyl, flurprimidol, forchlorfenuron, gibberellic acid, inabenfide, indol-3-acetic acid (IAA), 4-indol-3-ylbutyric acid, isoprothiolane, probenazole, jasmonic acid, maleic hydrazide, mepiquat chloride, 1-methyl-cyclopropene, methyl jasmonate, 2-(1-naphthyl)acetamide, 1-naphthylacetic acid, 2-naphthyloxy-acetic acid, nitrophenolate-mixture, paclobutrazol, N-(2-phenylethyl)-beta-alanine, N-phenylphthalamic acid, prohexadione, prohexadione-calcium, prohydrojasmone, salicylic acid, strigolactone, tecnazene, thidiazuron, triacontanol, trinexapac, trinexapac-ethyl, tsitodef, uniconazole, uniconazole-P.
The compound of formula (I) and composition comprising thereof comprising thereof have potent microbicidal activity and/or plant defense modulating potential. They can be used for controlling unwanted microorganisms, such as unwanted fungi and bacteria. They can be particularly useful in crop protection (they control microorganisms that cause plants diseases) or for protecting materials (e.g. industrial materials, timber, storage goods) as described in more details herein below. More specifically, the compound of formula (I) and composition comprising thereof can be used to protect seeds, germinating seeds, emerged seedlings, plants, plant parts, fruits, harvest goods and/or the soil in which the plants grow from unwanted microorganisms.
Control or controlling as used herein encompasses protective, curative and eradicative treatment of unwanted microorganisms. Unwanted microorganisms may be pathogenic bacteria, pathogenic virus, pathogenic oomycetes or pathogenic fungi, more specifically phytopathogenic bacteria, phytopathogenic virus, phytopathogenic oomycetes or phytopathogenic fungi. As detailed herein below, these phytopathogenic microorganims are the causal agents of a broad spectrum of plants diseases.
More specifically, the compound of formula (I) and composition comprising thereof can be used as fungicides. For the purpose of the specification, the term “fungicide” refers to a compound or composition that can be used in crop protection for the control of unwanted fungi, such as Plasmodiophoromycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes and/or for the control of Oomycetes.
The compound of formula (I) and composition comprising thereof may also be used as antibacterial agent. In particular, they may be used in crop protection, for example for the control of unwanted bacteria, such as Pseudomonadaceae, Rhizobiaceae, Xanthomonadaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
The compound of formula (I) and composition comprising thereof may also be used as antiviral agent in crop protection. For example the compound of formula (I) and composition comprising thereof may have effects on diseases from plant viruses, such as the tobacco mosaic virus (TMV), tobacco rattle virus, tobacco stunt virus (TStuV), tobacco leaf curl virus (VLCV), tobacco nervilia mosaic virus (TVBMV), tobacco necrotic dwarf virus (TNDV), tobacco streak virus (TSV), potato virus X (PVX), potato viruses Y, S, M, and A, potato acuba mosaic virus (PAMV), potato mop-top virus (PMTV), potato leaf-roll virus (PLRV), alfalfa mosaic virus (AMV), cucumber mosaic virus (CMV), cucumber green mottlemosaic virus (CGMMV), cucumber yellows virus (CuYV), watermelon mosaic virus (WMV), tomato spotted wilt virus (TSWV), tomato ringspot virus (TomRSV), sugarcane mosaic virus (SCMV), rice drawf virus, rice stripe virus, rice black-streaked drawf virus, strawberry mottle virus (SMoV), strawberry vein banding virus (SVBV), strawberry mild yellow edge virus (SMYEV), strawberry crinkle virus (SCrV), broad beanwilt virus (BBWV), and melon necrotic spot virus (MNSV).
The present invention also relates to a method for controlling unwanted microorganisms, such as unwanted fungi, oomycetes and bacteria, comprising the step of applying at least one compound of formula (I) or at least one composition to the microorganisms and/or their habitat (to the plants, plant parts, seeds, fruits or to the soil in which the plants grow).
Typically, when the compound of formula (I) and composition comprising thereof are used in curative or protective methods for controlling phytopathogenic fungi and/or phytopathogenic oomycetes, an effective and plant-compatible amount thereof is applied to the plants, plant parts, fruits, seeds or to the soil or substrates in which the plants grow. Suitable substrates that may be used for cultivating plants include inorganic based substrates, such as mineral wool, in particular stone wool, perlite, sand or gravel; organic substrates, such as peat, pine bark or sawdust; and petroleum based substrates such as polymeric foams or plastic beads. Effective and plant-compatible amount means an amount that is sufficient to control or destroy the fungi present or liable to appear on the cropland and that does not entail any appreciable symptom of phytotoxicity for said crops. Such an amount can vary within a wide range depending on the fungus to be controlled, the type of crop, the crop growth stage, the climatic conditions and the respective compound of formula (I) or composition used. This amount can be determined by systematic field trials that are within the capabilities of a person skilled in the art.
The compound of formula (I) and composition comprising thereof may be applied to any plants or plant parts.
Plants mean all plants and plant populations, such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants may be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the genetically modified plants (GMO or transgenic plants) and the plant cultivars which are protectable and non-protectable by plant breeders' rights.
Genetically modified plants (GMO or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome. This gene gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example, antisense technology, cosuppression technology, RNA interference—RNAi—technology or microRNA—miRNA—technology). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Plant cultivars are understood to mean plants which have new properties (“traits”) and have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. They can be cultivars, varieties, bio- or genotypes.
Plant parts are understood to mean all parts and organs of plants above and below the ground, such as shoots, leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. The plant parts also include harvested material and vegetative and generative propagation material, for example cuttings, tubers, rhizomes, slips and seeds.
Plants which may be treated in accordance with the methods described herein include the following: cotton, flax, grapevine, fruit, vegetables, such as Rosaceae sp. (for example pome fruits such as apples and pears, but also stone fruits such as apricots, cherries, almonds and peaches, and soft fruits such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for example banana trees and plantations), Rubiaceae sp. (for example coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example lemons, oranges and grapefruit); Solanaceae sp. (for example tomatoes), Liliaceae sp., Asteraceae sp. (for example lettuce), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (for example cucumber), Alliaceae sp. (for example leek, onion), Papilionaceae sp. (for example peas); major crop plants, such as Gramineae sp. (for example maize, turf, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Asteraceae sp. (for example sunflower), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, radishes, and oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example bean, peanuts), Papilionaceae sp. (for example soya bean), Solanaceae sp. (for example potatoes), Chenopodiaceae sp. (for example sugar beet, fodder beet, swiss chard, beetroot); useful plants and ornamental plants for gardens and wooded areas; and genetically modified varieties of each of these plants.
Plants and plant cultivars which may be treated by the above disclosed methods include plants and plant cultivars which are resistant against one or more biotic stresses, i.e. said plants show a better defense against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids.
Plants and plant cultivars which may be treated by the above disclosed methods include those plants which are resistant to one or more abiotic stresses. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, flooding, increased soil salinity, increased mineral exposure, ozone exposure, high light exposure, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients, shade avoidance.
Plants and plant cultivars which may be treated by the above disclosed methods include those plants characterized by enhanced yield characteristics. Increased yield in said plants may be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield may furthermore be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to, early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance.
Further yield traits include seed composition, such as carbohydrate content and composition for example cotton or starch, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
Plants and plant cultivars which may be treated by the above disclosed methods include plants and plant cultivars which are hybrid plants that already express the characteristic of heterosis or hybrid vigor which results in generally higher yield, vigor, health and resistance towards biotic and abiotic stresses.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars which are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars which are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars which are disease-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars which are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars which show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered fiber characteristics.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered oil profile characteristics.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars, such as oilseed rape or related Brassica plants, with altered seed shattering characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered seed shattering characteristics and include plants such as oilseed rape plants with delayed or reduced seed shattering.
Plants and plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated by the above disclosed methods include plants and plant cultivars, such as Tobacco plants, with altered post-translational protein modification patterns.
Non-limiting examples of pathogens of fungal diseases which may be treated in accordance with the invention include:
diseases caused by powdery mildew pathogens, for example Blumeria species, for example Blumeria graminis; Podosphaera species, for example Podosphaera leucotricha; Sphaerotheca species, for example Sphaerotheca fuliginea; Uncinula species, for example Uncinula necator;
diseases caused by rust disease pathogens, for example Gymnosporangium species, for example Gymnosporangium sabinae; Hemileia species, for example Hemileia vastatrix; Phakopsora species, for example Phakopsora pachyrhizi or Phakopsora meibomiae; Puccinia species, for example Puccinia recondita, Puccinia graminis oder Puccinia striiformis; Uromyces species, for example Uromyces appendiculatus;
diseases caused by pathogens from the group of the Oomycetes, for example Albugo species, for example Albugo candida; Bremia species, for example Bremia lactucae; Peronospora species, for example Peronospora pisi or P. brassicae; Phytophthora species, for example Phytophthora infestans; Plasmopara species, for example Plasmopara viticola; Pseudoperonospora species, for example Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium species, for example Pythium ultimum;
leaf blotch diseases and leaf wilt diseases caused, for example, by Alternaria species, for example Alternaria solani; Cercospora species, for example Cercospora beticola; Cladiosporium species, for example Cladiosporium cucumerinum; Cochliobolus species, for example Cochliobolus sativus (conidial form: Drechslera, syn: Helminthosporium) or Cochliobolus miyabeanus; Colletotrichum species, for example Colletotrichum lindemuthanium; Corynespora species, for example Corynespora cassiicola; Cycloconium species, for example Cycloconium oleaginum; Diaporthe species, for example Diaporthe citri; Elsinoe species, for example Elsinoe fawcettii; Gloeosporium species, for example Gloeosporium laeticolor; Glomerella species, for example Glomerella cingulata; Guignardia species, for example Guignardia bidwelli; Leptosphaeria species, for example Leptosphaeria maculans; Magnaporthe species, for example Magnaporthe grisea; Microdochium species, for example Microdochium nivale; Mycosphaerella species, for example Mycosphaerella graminicola, Mycosphaerella arachidicola or Mycosphaerella fijiensis; Phaeosphaeria species, for example Phaeosphaeria nodorum; Pyrenophora species, for example Pyrenophora teres or Pyrenophora tritici repentis; Ramularia species, for example Ramularia collo-cygni or Ramularia areola; Rhynchosporium species, for example Rhynchosporium secalis; Septoria species, for example Septoria apii or Septoria lycopersici; Stagonospora species, for example Stagonospora nodorum; Typhula species, for example Typhula incarnata; Venturia species, for example Venturia inaequalis;
root and stem diseases caused, for example, by Corticium species, for example Corticium graminearum; Fusarium species, for example Fusarium oxysporum; Gaeumannomyces species, for example Gaeumannomyces graminis; Plasmodiophora species, for example Plasmodiophora brassicae; Rhizoctonia species, for example Rhizoctonia solani; Sarocladium species, for example Sarocladium oryzae; Sclerotium species, for example Sclerotium oryzae; Tapesia species, for example Tapesia acuformis; Thielaviopsis species, for example Thielaviopsis basicola;
ear and panicle diseases (including corn cobs) caused, for example, by Alternaria species, for example Alternaria spp.; Aspergillus species, for example Aspergillus flavus; Cladosporium species, for example Cladosporium cladosporioides; Claviceps species, for example Claviceps purpurea; Fusarium species, for example Fusarium culmorum; Gibberella species, for example Gibberella zeae; Monographella species, for example Monographella nivalis; Stagnospora species, for example Stagnospora nodorum;
diseases caused by smut fungi, for example Sphacelotheca species, for example Sphacelotheca reiliana; Tilletia species, for example Tilletia caries or Tilletia controversa; Urocystis species, for example Urocystis occulta; Ustilago species, for example Ustilago nuda;
fruit rot caused, for example, by Aspergillus species, for example Aspergillus flavus; Botrytis species, for example Botrytis cinerea; Monilinia species, for example Monilinia laxa; Penicillium species, for example Penicillium expansum or Penicillium purpurogenum; Rhizopus species, for example Rhizopus stolonifer; Sclerotinia species, for example Sclerotinia sclerotiorum; Verticilium species, for example Verticilium alboatrum;
seed- and soil-borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Alternaria species, for example Alternaria brassicicola; Aphanomyces species, for example Aphanomyces euteiches; Ascochyta species, for example Ascochyta lentis; Aspergillus species, for example Aspergillus flavus; Cladosporium species, for example Cladosporium herbarum; Cochliobolus species, for example Cochliobolus sativus (conidial form: Drechslera, Bipolaris Syn: Helminthosporium); Colletotrichum species, for example Colletotrichum coccodes; Fusarium species, for example Fusarium culmorum; Gibberella species, for example Gibberella zeae; Macrophomina species, for example Macrophomina phaseolina; Microdochium species, for example Microdochium nivale; Monographella species, for example Monographella nivalis; Penicillium species, for example Penicillium expansum; Phoma species, for example Phoma lingam; Phomopsis species, for example Phomopsis sojae; Phytophthora species, for example Phytophthora cactorum; Pyrenophora species, for example Pyrenophora graminea; Pyricularia species, for example Pyricularia oryzae; Pythium species, for example Pythium ultimum; Rhizoctonia species, for example Rhizoctonia solani; Rhizopus species, for example Rhizopus oryzae; Sclerotium species, for example Sclerotium rolfsii; Septoria species, for example Septoria nodorum; Typhula species, for example Typhula incarnata; Verticillium species, for example Verticillium dahliae;
cancers, galls and witches' broom caused, for example, by Nectria species, for example Nectria galligena;
wilt diseases caused, for example, by Verticillium species, for example Verticillium longisporum; Fusarium species, for example Fusarium oxysporum;
deformations of leaves, flowers and fruits caused, for example, by Exobasidium species, for example Exobasidium vexans; Taphrina species, for example Taphrina deformans;
degenerative diseases in woody plants, caused, for example, by Esca species, for example Phaeomoniella chlamydospora, Phaeoacremonium aleophilum or Fomitiporia mediterranea; Ganoderma species, for example Ganoderma boninense;
diseases of plant tubers caused, for example, by Rhizoctonia species, for example Rhizoctonia solani; Helminthosporium species, for example Helminthosporium solani;
diseases caused by bacterial pathogens, for example Xanthomonas species, for example Xanthomonas campestris pv. oryzae; Pseudomonas species, for example Pseudomonas syringae pv. lachrymans; Erwinia species, for example Erwinia amylovora; Liberibacter species, for example Liberibacter asiaticus; Xyella species, for example Xylella fastidiosa; Ralstonia species, for example Ralstonia solanacearum; Dickeya species, for example Dickeya solani; Clavibacter species, for example Clavibacter michiganensis; Streptomyces species, for example Streptomyces scabies.
diseases of soya beans:
Fungal diseases on leaves, stems, pods and seeds caused, for example, by Alternaria leaf spot (Alternaria spec. atrans tenuissima), Anthracnose (Colletotrichum gloeosporoides dematium var. truncatum), brown spot (Septoria glycines), cercospora leaf spot and blight (Cercospora kikuchii), choanephora leaf blight (Choanephora infundibulifera trispora (Syn.)), dactuliophora leaf spot (Dactuliophora glycines), downy mildew (Peronospora manshurica), drechslera blight (Drechslera glycini), frogeye leaf spot (Cercospora sojina), leptosphaerulina leaf spot (Leptosphaerulina trifolii), phyllostica leaf spot (Phyllosticta sojaecola), pod and stem blight (Phomopsis sojae), powdery mildew (Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta glycines), rhizoctonia aerial, foliage, and web blight (Rhizoctonia solani), rust (Phakopsora pachyrhizi, Phakopsora meibomiae), scab (Sphaceloma glycines), stemphylium leaf blight (Stemphylium botryosum), sudden death syndrome (Fusarium virguliforme), target spot (Corynespora cassiicola).
Fungal diseases on roots and the stem base caused, for example, by black root rot (Calonectria crotalariae), charcoal rot (Macrophomina phaseolina), fusarium blight or wilt, root rot, and pod and collar rot (Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthe phaseolorum), stem canker (Diaporthe phaseolorum var. caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
In addition, the compound of formula (I) and composition comprising thereof may reduce the mycotoxin content in the harvested material and the foods and feeds prepared therefrom. Mycotoxins include particularly, but not exclusively, the following: deoxynivalenol (DON), nivalenol, 15-Ac-DON, 3-Ac-DON, T2- and HT2-toxin, fumonisins, zearalenon, moniliformin, fusarin, diaceotoxyscirpenol (DAS), beauvericin, enniatin, fusaroproliferin, fusarenol, ochratoxins, patulin, ergot alkaloids and aflatoxins which can be produced, for example, by the following fungi: Fusarium spec., such as F. acuminatum, F. asiaticum, F. avenaceum, F. crookwellense, F. culmorum, F. graminearum (Gibberella zeae), F. equiseti, F. fujikoroi, F. musarum, F. oxysporum, F. proliferatum, F. poae, F. pseudograminearum, F. sambucinum, F. scirpi, F. semitectum, F. solani, F. sporotrichoides, F. langsethiae, F. subglutinans, F. tricinctum, F. verticillioides etc., and also by Aspergillus spec., such as A. flavus, A. parasiticus, A. nomius, A. ochraceus, A. clavatus, A. terreus, A. versicolor, Penicillium spec., such as P. verrucosum, P. viridicatum, P. citrinum, P. expansum, P. claviforme, P. roqueforti, Claviceps spec., such as C. purpurea, C. fusiformis, C. paspali, C. africana, Stachybotrys spec. and others.
The compound of formula (I) and composition comprising thereof may also be used in the protection of materials, especially for the protection of industrial materials against attack and destruction by phytopathogenic fungi.
In addition, the compound of formula (I) and composition comprising thereof may be used as antifouling compositions, alone or in combinations with other active ingredients.
Industrial materials in the present context are understood to mean inanimate materials which have been prepared for use in industry. For example, industrial materials which are to be protected from microbial alteration or destruction may be adhesives, glues, paper, wallpaper and board/cardboard, textiles, carpets, leather, wood, fibers and tissues, paints and plastic articles, cooling lubricants and other materials which can be infected with or destroyed by microorganisms. Parts of production plants and buildings, for example cooling-water circuits, cooling and heating systems and ventilation and air-conditioning units, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected. Industrial materials within the scope of the present invention preferably include adhesives, sizes, paper and card, leather, wood, paints, cooling lubricants and heat transfer fluids, more preferably wood.
The compound of formula (I) and composition comprising thereof may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
In the case of treatment of wood the compound of formula (I) and composition comprising thereof may also be used against fungal diseases liable to grow on or inside timber.
Timber means all types of species of wood, and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood, and plywood. In addition, the compound of formula (I) and composition comprising thereof may be used to protect objects which come into contact with saltwater or brackish water, especially hulls, screens, nets, buildings, moorings and signalling systems, from fouling.
The compound of formula (I) and composition comprising thereof may also be employed for protecting storage goods. Storage goods are understood to mean natural substances of vegetable or animal origin or processed products thereof which are of natural origin, and for which long-term protection is desired.
Storage goods of vegetable origin, for example plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, may be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting. Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture.
Storage goods of animal origin are, for example, hides, leather, furs and hairs. The compound of formula (I) and composition comprising thereof may prevent adverse effects, such as rotting, decay, discoloration, decoloration or formation of mould.
Microorganisms capable of degrading or altering industrial materials include, for example, bacteria, fungi, yeasts, algae and slime organisms. The compound of formula (I) and composition comprising thereof preferably act against fungi, especially moulds, wood-discoloring and wood-destroying fungi (Ascomycetes, Basidiomycetes, Deuteromycetes and Zygomycetes), and against slime organisms and algae. Examples include microorganisms of the following genera: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor; Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Ophiostoma spp., Ceratocystis spp., Humicola spp., Petriella spp., Trichurus spp., Coriolus spp., Gloeophyllum spp., Pleurotus spp., Poria spp., Serpula spp. and Tyromyces spp., Cladosporium spp., Paecilomyces spp. Mucor spp., Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus, Candida spp. and Saccharomyces spp., such as Saccharomyces cerevisae.
The compound of formula (I) and composition comprising thereof may also be used to protect seeds from unwanted microorganisms, such as phytopathogenic microorganisms, for instance phytopathogenic fungi or phytopathogenic oomycetes. The term seed(s) as used herein include dormant seeds, primed seeds, pregerminated seeds and seeds with emerged roots and leaves.
Thus, the present invention also relates to a method for protecting seeds from unwanted microorganisms which comprises the step of treating the seeds with the compound of formula (I) or the composition.
The treatment of seeds with the compound of formula (I) or the composition protects the seeds from phytopathogenic microorganisms, but also protects the germinating seeds, the emerging seedlings and the plants after emergence from the treated seeds. Therefore, the present invention also relates to a method for protecting seeds, germinating seeds and emerging seedlings.
The seeds treatment may be performed prior to sowing, at the time of sowing or shortly thereafter.
When the seeds treatment is performed prior to sowing (e.g. so-called on-seed applications), the seeds treatment may be performed as follows: the seeds may be placed into a mixer with a desired amount of the compound of formula (I) or the composition, the seeds and the compound of formula (I) or the composition are mixed until an homogeneous distribution on seeds is achieved. If appropriate, the seeds may then be dried.
The invention also relates to seeds coated with the compound of formula (I) or composition comprising thereof.
Preferably, the seeds are treated in a state in which it is sufficiently stable for no damage to occur in the course of treatment. In general, seeds can be treated at any time between harvest and shortly after sowing. It is customary to use seeds which have been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. For example, it is possible to use seeds which have been harvested, cleaned and dried down to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seeds which, after drying, for example, have been treated with water and then dried again, or seeds just after priming, or seeds stored in primed conditions or pre-germinated seeds, or seeds sown on nursery trays, tapes or paper.
The amount of the compound of formula (I) or composition comprising thereof applied to the seeds is typically such that the germination of the seed is not impaired, or that the resulting plant is not damaged. This must be ensured particularly in case the the compound of formula (I) would exhibit phytotoxic effects at certain application rates. The intrinsic phenotypes of transgenic plants should also be taken into consideration when determining the amount of the compound of formula (I) to be applied to the seed in order to achieve optimum seed and germinating plant protection with a minimum amount of compound being employed.
The compound of formula (I) can be applied as such, directly to the seeds, i.e. without the use of any other components and without having been diluted. Also the composition comprising thereof can be applied to the seeds.
The compound of formula (I) and composition comprising thereof are suitable for protecting seeds of any plant variety. Preferred seeds are that of cereals (such as wheat, barley, rye, millet, triticale, and oats), oilseed rape, maize, cotton, soybean, rice, potatoes, sunflower, beans, coffee, peas, beet (e.g. sugar beet and fodder beet), peanut, vegetables (such as tomato, cucumber, onions and lettuce), lawns and ornamental plants. More preferred are seeds of wheat, soybean, oilseed rape, maize and rice.
The compound of formula (I) and composition comprising thereof may be used for treating transgenic seeds, in particular seeds of plants capable of expressing a polypeptide or protein which acts against pests, herbicidal damage or abiotic stress, thereby increasing the protective effect. Seeds of plants capable of expressing a polypeptide or protein which acts against pests, herbicidal damage or abiotic stress may contain at least one heterologous gene which allows the expression of said polypeptide or protein. These heterologous genes in transgenic seeds may originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. These heterologous genes preferably originate from Bacillus sp., in which case the gene product is effective against the European corn borer and/or the Western corn rootworm. Particularly preferably, the heterologous genes originate from Bacillus thuringiensis.
The compound of formula (I) can be applied as such, or for example in the form of as ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural products impregnated with the compound of formula (I), synthetic substances impregnated with the compound of formula (I), fertilizers or microencapsulations in polymeric substances.
Application is accomplished in a customary manner, for example by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading-on and the like. It is also possible to deploy the compound of formula (I) by the ultra-low volume method, via a drip irrigation system or drench application, to apply it in-furrow or to inject it into the soil stem or trunk. It is further possible to apply the compound of formula (I) by means of a wound seal, paint or other wound dressing.
The effective and plant-compatible amount of the compound of formula (I) which is applied to the plants, plant parts, fruits, seeds or soil will depend on various factors, such as the compound/composition employed, the subject of the treatment (plant, plant part, fruit, seed or soil), the type of treatment (dusting, spraying, seed dressing), the purpose of the treatment (curative and protective), the type of microorganisms, the development stage of the microorganisms, the sensitivity of the microorganisms, the crop growth stage and the environmental conditions.
When the compound of formula (I) is used as a fungicide, the application rates can vary within a relatively wide range, depending on the kind of application. For the treatment of plant parts, such as leaves, the application rate may range from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, more preferably from 50 to 300 g/ha (in the case of application by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rockwool or perlite are used). For the treatment of seeds, the application rate may range from 0.1 to 200 g per 100 kg of seeds, preferably from 1 to 150 g per 100 kg of seeds, more preferably from 2.5 to 25 g per 100 kg of seeds, even more preferably from 2.5 to 12.5 g per 100 kg of seeds. For the treatment of soil, the application rate may range from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.
These application rates are merely examples and are not intended to limit the scope of the present invention.
Aspects of the present teaching may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teaching in any way.
Measurement of Log P values as provided herein was performed according to EEC directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on reversed phase columns with the following methods:
If more than one Log P value is available within the same method, all the values are given and separated by “+”.
Calibration was done with straight-chain alkan2-ones (with 3 to 16 carbon atoms) with known Log P values (measurement of Log P values using retention times with linear interpolation between successive alkanones). Lambda-max-values were determined using UV-spectra from 200 nm to 400 nm and the peak values of the chromatographic signals
1H-NMR data of selected examples as provided herein are written in form of 1H-NMR-peak lists. To each signal peak are listed the δ-value in ppm and the signal intensity in round brackets. Between the δ-value—signal intensity pairs are semicolons as delimiters.
The peak list of an example has therefore the form:
δ1 (intensity1); δ2 (intensity2); . . . ; δi (intensityi); . . . ; δn (intensityn)
Intensity of sharp signals correlates with the height of the signals in a printed example of a NMR spectrum in cm and shows the real relations of signal intensities. From broad signals several peaks or the middle of the signal and their relative intensity in comparison to the most intensive signal in the spectrum can be shown.
For calibrating chemical shift for 1H spectra, we use tetramethylsilane and/or the chemical shift of the solvent used, especially in the case of spectra measured in DMSO. Therefore in NMR peak lists, tetramethylsilane peak can occur but not necessarily.
The 1H-NMR peak lists are similar to classical 1H-NMR prints and contains therefore usually all peaks, which are listed at classical NMR-interpretation.
Additionally they can show like classical 1H-NMR prints signals of solvents, stereoisomers of the target compounds, which are also object of the invention, and/or peaks of impurities.
To show compound signals in the delta-range of solvents and/or water the usual peaks of solvents, for example peaks of DMSO in DMSO-D6 and the peak of water are shown in our 1H-NMR peak lists and have usually on average a high intensity.
The peaks of stereoisomers of the target compounds and/or peaks of impurities have usually on average a lower intensity than the peaks of target compounds (for example with a purity >90%).
Such stereoisomers and/or impurities can be typical for the specific preparation process. Therefore their peaks can help to recognize the reproduction of our preparation process via “side-products-fingerprints”.
An expert, who calculates the peaks of the target compounds with known methods (MestreC, ACD-simulation, but also with empirically evaluated expectation values) can isolate the peaks of the target compounds as needed optionally using additional intensity filters. This isolation would be similar to relevant peak picking at classical 1H-NMR interpretation.
Further details of NMR-data description with peak lists you find in the publication “Citation of NMR Peaklist Data within Patent Applications” of the Research Disclosure Database Number 564025.
Enantiomeric separations of racemates are performed by preparative supercritical fluid chromatography using supercritical carbon dioxide as mobile phase and lower alcohols as modifier, more preferably methanol, ethanol or isopropanol in a ratio comprised between 15 and 30% by volume. Total flow rates are in a range 70-100 ml/min and chromatographic separations are done at a temperature in a range of between 30° C. and 50° C. and a back pressure in a range of between 70 bar to 130 bar on one of the thermostated chiral stationary phases, commercially available and known as follows:
The separations on preparative scale were performed on apparatus SFC-PICLAB Hybrid 10-150 from Pic Solution with UV-detection in a range of between 210 nm and 280 nm, preferably 220 and 254 nm.
The following examples illustrate in a non-limiting manner the preparation and biological activity of the compounds of formula (I) according to the invention.
Under argon, sodium hydride (2.8 g, 70 mmol) was added to a solution of 3-(trifluoromethyl)phenol (9.7 g, 60 mmol) in DMF (30 mL). The reaction mixture was stirred 1 h at room temperature, then ethyl 3,6-dichloropyridazine-4-carboxylate (13.8 g, 50 mmol) was added portionwise to the solution. The reaction mixture was stirred for 18 h at room temperature, then diluted with water and extracted with ether (3×200 mL). The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 20 g (90% purity, 100% yield) of ethyl 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylate as an oil.
To a solution of ethyl 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylate (15 g, 35 mmol) in dioxane/water 2:1 (75 mL) was added lithium hydroxide (2.5 g, 105 mmol). The reaction was stirred for 4 h at room temperature then diluted with water. The aqueous phase was acidified with 1M aqueous HCl solution and extracted with ethyl acetate (3×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 9.7 g (98% purity, 85% yield) of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid as a solid.
Under argon, to a solution of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid (5.0 g, 15.7 mmol) and HATU (6.56 g, 17.26 mmol) in DMF (100 mL) were successively added at 0° C., 2-[rac-2-amino-3-(2,4-dimethylphenyl)propoxy]isoindoline-1,3-dione;2,2,2-trifluoroacetic acid (7.57 g, 17.26 mmol) and N,N-Diisopropylethylamine (8.2 mL, 47.07 mmol). After 15 min at 0° C., the reaction mixture was stirred for 3 h at room temperature. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 7.95 g (100% purity, 81% yield) of 6-chloro-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide as a white solid.
Under argon, hydrazine monohydrate (2.31 mL, 37.92 mmol) was added to a solution of 6-chloro-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamide (7.9 g, 12.64 mmol) in DCM/MeOH (110 mL, 1:1). The reaction mixture was stirred for 4 h at room temperature and concentrated. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 6.35 g (97% purity, 98% yield) of 6-chloro-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide as a yellow oil.
Under argon, POCl3 (3.56 mL, 38.19 mmol) was added at 80° C. to a solution 6-chloro-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide (6.3 g, 12.73 mmol) in AcCN (114 mL). The reaction mixture was stirred for 18 h at 80° C. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution, then extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 2.52 g (98% purity, 41% yield) of rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
To a solution of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) in dichloromethane (2 mL) was added at room temperature oxalyl chloride (119 mg, 0.94 mmol) and a drop of dimethylformamide. After 30 min, the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and added at 0° C. to a suspension of 1-chloro-3-(2,4-dimethylphenyl)propan-2-amine;hydrochloride (73 mg, 0.31 mmol) in dichloromethane (1 mL), followed by addition of N,N-diisopropylethylamine (0.16 mL, 0.94 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 142 mg (87% purity, 79% yield) of 6-chloro-N-[1-(chloromethyl)-2-(2,4-dimethylphenyl)ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide as a colourless oil.
To a solution of 6-chloro-N-[1-(chloromethyl)-2-(2,4-dimethylphenyl)ethyl]-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamide (130 mg, 0.23 mmol) in AcCN (2 mL) was added phosphorous pentachloride (205 mg, 0.99 mmol). The reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The residue was dissolved in AcCN (5 mL) and a solution of hydroxylamine in water (300 mg, 4.53 mmol, 50% in water) was added to the reaction mixture. After stirring at room temperature for 1 h the reaction mixture was diluted with water and toluene, and extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents, afforded 150 mg (65% purity, 83% yield) of 6-chloro-N-[1-(chloromethyl)-2-(2,4-dimethylphenyl)ethyl]-N′-hydroxy-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine as a yellow oil.
To a solution of 6-chloro-N-[1-(chloromethyl)-2-(2,4-dimethylphenyl)ethyl]-N′-hydroxy-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamidine (150 mg, 0.23 mmol) in AcCN (2 mL) was added potassium tert-butoxide (47.3 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 1 h30, then diluted with a saturated ammonium chloride solution and extracted with dichloromethane (2×50 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 56 mg (87% purity, 43% yield) of rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
Under argon, sodium hydride (1.30 g, 32 mmol) was added at 0° C. to a solution of 3-(trifluoro-methyl)phenol (4.6 g, 28 mmol) in THE (100 mL). After 30 min, 3,6-dichloropyridazine-4-carbonitrile (5.0 g, 28.7 mmol) was added portionwise to the solution. The reaction mixture was stirred for 3 h at room temperature, then diluted with saturated ammonium chloride solution and extracted with EtOAc (3×200 mL). The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 6.1 g (95% purity, 67% yield) of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile as an oil.
Under argon, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (12.57 g, 50.0 mmol) was added to a stirred solution of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile (3.0 g, 10.0 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (64 mg, 0.10 mmol) and cesium carbonate (4.89 g, 15.0 mmol) in dioxane (30 mL). The reaction mixture was stirred at 100° C. for 4 h, then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.82 g (100% purity, 65% yield) of 6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile as a solid.
To a solution of 6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile (1.82 g, 6.52 mmol) in EtOH (32 mL) was added hydroxylamine hydrochloride (1.13 g, 16.29 mmol) and potassium carbonate (2.25 g, 16.29 mmol). The reaction mixture was stirred at 60° C. for 2 h. The precipitate was filtered off. The filtrate was concentrated, diluted with water and extracted with EtOAc (2×100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.38 g (91% purity, 62% yield) of N′-hydroxy-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine as a yellow solid.
Under argon, 2-tert-butylimino-N,N-diethyl-1,3-dimethyl-1,3,2lambda5-diazaphosphinan-2-amine (BEMP) (210.9 mg, 0.77 mmol) was added at room temperature to a solution of N′-hydroxy-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine (200 mg, 0.64 mmol) in AcCN (2.7 mL). After 15 min, 2-bromo-1-(4-chlorophenyl)ethanone (224 mg, 0.96 mmol) was added, the reaction was stirred further for 3 h, then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 65.6 mg (91% purity, 20% yield) of N′-[2-(4-chlorophenyl)-2-oxo-ethoxy]-6-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamidine as an oil.
Under argon, N′-[2-(4-chlorophenyl)-2-oxo-ethoxy]-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine (69.2 mg, 0.13 mmol) was dissolved in MeOH (0.94 mL) and acetic acid (0.21 mL) and heated to 60° C. After 1 h, sodium cyanoborohydride (9.3 mg, 0.15 mmol) was added and the reaction was stirred further for 2 h. After cooling to room temperature, the mixture was poured into a 1 M NaOH solution and extracted with ethyl acetate (2×20 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 29 mg (100% purity, 47% yield) of rac-5-(4-chlorophenyl)-3-[6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as a solid.
Under argon, O-allylhydroxylamine hydrochloride (658 mg, 5.4 mmol) was added at room temperature to a stirred solution of 6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile (500 mg, 1.79 mol) and NaHCO3 (752.1 mg, 8.95 mmol) in MeOH. The resulting mixture was stirred at 60° C. for 36 h, cooled to room temperature and concentrated under vacuum. The resulting mixture was extracted with dichloromethane (3×200 mL). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient PE/EtOAc) afforded, after evaporation of the solvents, 400 mg (98% purity, 63% yield) of N′-allyloxy-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine as a brown oil.
In a 50 mL round bottom flask OSO4 (902 mg, 0.14 mmol, 4% wt in water) and NaIO4 (759 mg, 3.55 mmol) were added at room temperature to a solution of N′-allyloxy-6-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamidine (500 mg, 1.42 mmol) in THE (20 mL) and water (5 mL). The reaction mixture was stirred for 2 h at room temperature, then diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (2×100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 260 mg (100% purity, 51% yield) of rac-3-[6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazin-5-ol as a white solid.
In a 50 mL round bottom flask, 1-methylindole (37 mg, 0.28 mmol) was added to a solution of rac-3-[6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazin-5-ol (50 mg, 0.14 mmol) in formic acid (2 mL). The reaction mixture was stirred for 45 min at 50° C. then cooled to room temperature and stirred further for 3 h. The solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 59 mg (100% purity, 89% yield) of rac-5-(1-methylindol-3-yl)-3-[6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as a pink solid.
Under argon, sodium methanolate (32 mg, 0.59 mmol) was added at 0° C. to a solution of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile (160 mg, 0.33 mmol) in MeOH (1.5 mL). The reaction mixture was stirred at 0° C. for 30 min. The crude solution contained 53% of methyl 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboximidate and was used without further purification in the next step.
To the previous solution was added O-[rac-2-amino-3-(4-bromo-2-chloro-phenyl)propyl]hydroxylamine (157 mg, 0.51 mmol) dissolved in MeOH/acetic acid (1 mL, 1:1). The reaction mixture was stirred at room temperature for 3 h then heated at 100° C. for 7 h. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC afforded, after evaporation of the solvents, 5 mg (93% purity, 2% yield) of rac-5-[(4-bromo-2-chloro-phenyl)methyl]-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as an oil.
Under argon, to a solution of 3,6-dichloropyridazine-4-carboxylic acid (700 mg, 3.62 mmol) and HATU (1.52 g, 3.99 mmol) in DMF (25 mL) were successively added at 0° C., 2-[rac-2-amino-3-(2,4-dimethylphenyl)propoxy]isoindoline-1,3-dione;2,2,2-trifluoroacetic acid (1.75 g, 4.0 mmol) and N,N-Diisopropylethylamine (1.89 mL, 10.88 mmol). After 15 min at 0° C., the reaction mixture was stirred for 18 h at room temperature. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.15 g (87% purity, 55% yield) of 3,6-dichloro-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]pyridazine-4-carboxamide as a white solid.
Under argon, hydrazine monohydrate (0.42 mL, 6.91 mmol) was added to a solution of 3,6-dichloro-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]pyridazine-4-carboxamide (1.15 g, 2.3 mmol) in DCM/MeOH (15 mL, 1:1). The reaction mixture was stirred for 3 h at room temperature and concentrated. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 900 mg (74% purity, 78% yield) of 3,6-dichloro-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]pyridazine-4-carboxamide as a yellow solid.
Under argon, POCl3 (0.56 mL, 6.0 mmol) was added at 80° C. to a solution of 3,6-dichloro-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]pyridazine-4-carboxamide (738 mg, 2.0 mmol) in AcCN (15 mL). The reaction mixture was stirred for 18 h at 80° C. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution, then extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 90 mg (92% purity, 17% yield) of rac-3-(3,6-dichloropyridazin-4-yl)-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
To a solution of rac-3-(3,6-dichloropyridazin-4-yl)-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (60 mg, 0.17 mmol) in AcCN (1 mL) were added 2-fluoro-3-methoxy-phenol (27 mg, 0.19 mmol) and potassium carbonate (47 mg, 0.34 mmol). The reaction mixture was stirred at 50° C. for 5 h, then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 74 mg (97% purity, 90% yield) of rac-3-[6-chloro-3-(2-fluoro-3-methoxy-phenoxy)pyridazin-4-yl]-5-[(2,4-dimethyl-phenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow oil.
In a microwave vial, rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethyl-phenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (500 mg, 1.05 mmol), tributyl(1-ethoxyvinyl)stannane (473 mg, 1.31 mmol) and bis(triphenylphosphine)palladium dichloride (73 mg, 0.103 mmol) were dissolved under argon in DMF (0.5 mL). The tube was sealed and the reaction mixture was heated in the microwave at 120° C. for 20 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 435 mg (100% purity, 80% yield) of rac-5-[(2,4-dimethylphenyl)methyl]-3-[6-(1-ethoxyvinyl)-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as an oil.
To a solution of rac-5-[(2,4-dimethylphenyl)methyl]-3-[6-(1-ethoxyvinyl)-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine (100 mg, 0.19 mmol) in THE (1 mL) was added at room temperature a 2M aqueous HCl solution (0.15 mL, 0.30 mmol). The reaction was stirred for 30 min then diluted with water and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 35 mg (100% purity, 37% yield) of 1-[5-[rac-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazin-3-yl]-6-[3-(trifluoromethyl)phenoxy]pyridazin-3-yl]ethanone as a oil.
Under argon, a solution of TMPZnCl.LiCl (2.77 mmol, 5.1 mL, 17% in THF, CAS number 109-99-9) was added to rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethyl-phenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (600 mg, 1.26 mmol) in THE (60 mL). After stirring 1 h at room temperature, NIS (566 mg, 2.52 mmol) was added portionwise. The reaction mixture was stirred 2 h at room temperature, then it was diluted with a saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, and extracted with ethyl acetate (2×250 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 178 mg (70% purity, 16% yield) of rac-3-[6-chloro-5-iodo-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
Under argon, cyclopropylamine (6 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.10 mmol) were added at room temperature to a solution of rac-3-[6-chloro-5-iodo-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (50 mg, 0.08 mmol) in AcCN (0.7 mL). The reaction mixture was stirred at 50° C. for 18 h, then it was diluted with water and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvent afforded 42 mg (98% purity, 93% yield) of 3-chloro-N-cyclopropyl-5-[rac-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazin-3-yl]-6-[3-(trifluoromethyl)phenoxy]pyridazin-4-amine as an oil.
A solution of POCl3 (1.05 mL, 11.3 mmol) was added at room temperature to a mixture of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid (400 mg, 1.25 mmol) and 3-(2,4-dichlorophenyl)propane-1,2-diamine (550 mg, 2.51 mmol) in 1,4-dioxane (10 mL). The reaction was heated to reflux and stirred for 36 h. After cooling, the reaction mixture was poured into a saturated sodium bicarbonate solution at 0° C., then extracted with ethyl acetate (2×100 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 90 mg (98% purity, 14% yield) of 6-chloro-4-[rac-5-[(2,4-dichlorophenyl)methyl]-4,5-dihydro-1H-imidazol-2-yl]-3-[3-(trifluoromethyl)phenoxy]pyridazine as a yellow oil.
To a suspension of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid (5.0 g, 16.7 mmol) in dichloromethane (75 mL) was added oxalyl chloride (3.19 g, 25.14 mmol) followed by two drops of DMF. The reaction mixture was stirred at room temperature for 1 h. To the pre-formed acyl chloride was added N-methoxymethanamine;hydrochloride (2.12 g, 21.79 mmol) and triethylamine (8.17 mL, 58.68 mmol). The reaction mixture was stirred at room temperature for 2 h, then it was diluted with water and extracted with dichloromethane (2×200 mL). The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was diluted in dichloromethane and filtered over silica gel. Evaporation of the solvent afforded 3.38 g (95% purity, 56% yield) of 6-chloro-N-methoxy-N-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamide as a oil.
Under argon, a solution of DIBAL-H (0.88 mL, 0.88 mmol, 1M in hexan) was added at −50° C. to a solution of 6-chloro-N-methoxy-N-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide (100 mg, 0.29 mmol) in THE (1.8 mL). After 4 h at −30° C., the reaction was stopped by addition of saturated ammonium chloride solution then the mixture was extracted with ethyl acetate (2×50 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 43.6 mg (90% purity, 47% yield) of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbaldehyde as an oil.
Under argon, hydroxylamine;hydrochloride (156 mg, 2.24 mmol) and potassium acetate (415 mg, 4.23 mmol) were added to 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbaldehyde (400 mg, 1.32 mmol) in EtOH (40 mL). The reaction mixture was stirred at reflux for 2 h, diluted in water and extracted with ethyl acetate (2×50 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 215 mg (90% purity, 47% yield) of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbaldehyde oxime as a solid.
To a solution of 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbaldehyde oxime (10 mg, 0.031 mmol) in AcCN (0.2 mL) was added NCS (5.4 mg, 0.04 mmol) at room temperature. The reaction mixture was stirred for 1 h, then a solution of (2S)-1-bromo-3-phenyl-propan-2-amine;2,2,2-trifluoroacetic acid (15.4 mg, 0.047 mmol) in AcCN/water (0.3 mL, 2:1) was added. The reaction was stirred at room temperature for 5 h then 1,2-bis(dimethylamino)ethane (18.3 mg, 0.16 mmol) was added to the reaction mixture. After 30 min, a solution of sodium carbonate (34 mg, 0.31 mmol, 1 M in water) was added and the reaction was further stirred for 1 h at room temperature. The reaction mixture was diluted with water and dichloromethane and the aqueous phase was extracted with dichloromethane (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC afforded, after evaporation of the solvents, 10.9 mg (85% purity, 65% yield) of (5S)-5-benzyl-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
Under argon, 2-methoxyethanol (0.15 mL, 0.30 mmol) and sodium hydride (11 mg, 0.27 mmol) were added at room temperature to a solution of rac-3-[6-chloro-5-iodo-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (150 mg, 0.25 mmol) in AcCN (2 mL). The reaction mixture was stirred at room temperature for 1 h, then it was diluted with water and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 30 mg (90% purity, 19% yield) of rac-3-[6-chloro-5-(2-methoxyethoxy)-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a colorless oil.
Under argon, a solution of TMPZnCl.LiCl (0.22 mmol, 0.40 mL, 17% in THF, CAS number 109-99-9) was added to rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethyl-phenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (50 mg, 0.10 mmol) in THE (3 mL), followed by addition of 4-bromopyridine (20 mg, 0.12 mmol), Pd(dba)2 (18 mg, 0.031 mmol) and trifurylphosphine (15 m, 0.063 mmol). The reaction mixture was stirred 4 h at 60° C., then diluted with saturated ammonium chloride solution and saturated sodium bicarbonate solution, and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 32 mg (86% purity, 47% yield) of rac-3-[6-chloro-5-(4-pyridyl)-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as an oil.
Under argon, 2-methoxyethanethiol (20 mg, 0.22 mmol) and sodium hydride (8 mg, 0.22 mmol) were added at 0° C. to a solution of rac-3-[6-chloro-5-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine (100 mg, 0.20 mmol) in THE (2 mL). The reaction mixture was stirred at 0° C. for 2 h, then it was diluted with water and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 21 mg (96% purity, 18% yield) of rac-5-[(2,4-dimethylphenyl)methyl]-3-[6-(2-methoxyethylsulfanyl)-5-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as a colorless oil.
Under argon, sodium methanolate (43 mg, 0.81 mmol) was added at 0° C. to a solution of 6-chloro-3-(3-cyclopropylphenoxy)pyridazine-4-carbonitrile (200 mg, 0.74 mmol) in MeOH (2 mL). The reaction mixture was stirred at 0° C. for 30 min. The crude solution contained 48% of methyl 6-chloro-3-(3-cyclopropylphenoxy)pyridazine-4-carboximidate and was used without further purification in the next step.
To the previous solution was added rac-3-amino-4-(2,4-dimethylphenyl)butanamide (93 mg, 0.45 mmol) dissolved in MeOH (0.5 mL) and acetic acid (17 μL). The reaction mixture was stirred at room temperature for 15 min then heated at 60° C. for 18 h. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC afforded, after evaporation of the solvents, 40.7 mg (100% purity, 29% yield) of rac-2-[6-chloro-3-(3-cyclopropylphenoxy)pyridazin-4-yl]-6-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-1H-pyrimidin-4-one as an oil.
Under argon, diisopropyl azodicarboxylate (1.92 g, 9.51 mmol) was added to a solution of tert-butyl rac-4-(hydroxymethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (2.0 g, 8.64 mmol), 2,4-dimethylphenol (1.16 g, 9.51 mmol) and triphenylphosphine (2.49 g, 9.51 mmol) in 2-methyltetrahydrofuran (30 mL). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and extracted with ethyl acetate (2×200 mL). The organic layer was washed with 1 M aqueous NaOH solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.82 g (95% purity, 59% yield) of tert-butyl rac-4-[(2,4-dimethylphenoxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylate as a colorless oil.
A solution of tert-butyl rac-4-[(2,4-dimethylphenoxy)methyl]-2,2-dimethyl-oxazolidine-3-carboxylate (1.8 g, 5.37 mmol) was dissolved in MeOH (25 mL) and aqueous 1M HCl solution (15 mL). The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the solvents were evaporated and the residue was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 833 mg (87% purity, 69% yield) of rac-2-amino-3-(2,4-dimethylphenoxy)propan-1-ol as a yellow oil.
Di-tert-butyl dicarbonate (1.02 mL, 4.46 mmol) and N,N-Diisopropylethylamine (1.55 mL, 8.93 mmol) were successively added to a solution of rac-2-amino-3-(2,4-dimethylphenoxy)propan-1-ol (830 mg, 4.25 mmol) in 2-methyltetrahydrofuran (5.5 mL). The reaction mixture was stirred at room temperature for 1 h30, then it was diluted with brine and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 909 mg (97% purity, 70% yield) of tert-butyl N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-hydroxy-ethyl]carbamate as a colorless oil.
Under argon, diisopropyl azodicarboxylate (684 mg, 3.38 mmol) was added to a solution of tert-butyl N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-hydroxy-ethyl]carbamate (909 mg, 3.0 mmol), N-hydroxyphthalimide (552.2 mg, 3.38 mmol) and triphenylphosphine (888 mg, 3.38 mmol) in 2-methyltetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 2 h, then extracted with ethylacetate (2×200 mL). The organic layer was washed with 1M aqueous NaOH solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.16 g (92% purity, 79% yield) of tert-butyl N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]carbamate as a colorless oil.
To a solution of tert-butyl N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]carbamate (1.16 g, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added trifluoroacetic acid (1.014 mL, 13.17 mmol). The reaction mixture was stirred at room temperature for 4 h. Evaporation of the solvents afforded 1.4 g (79% purity, 93% yield) of 2-[rac-2-amino-3-(2,4-dimethyl-phenoxy)propoxy]isoindoline-1,3-dione;2,2,2-trifluoroacetic acid as a yellow oil.
Under argon, to a solution of 6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxylic acid (405 mg, 1.36 mmol) and HATU (542 mg, 1.42 mmol) in DMF (10 mL) were successively added 2-[rac-2-amino-3-(2,4-dimethylphenoxy)propoxy]isoindoline-1,3-dione;2,2,2-trifluoroacetic acid (647 mg, 1.42 mmol) and N,N-Diisopropylethylamine (0.71 mL, 4.07 mmol). The reaction mixture was stirred for 1 h at room temperature. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 550 mg (93% purity, 60% yield) of 6-methyl-N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide as a colorless oil.
Under argon, hydrazine monohydrate (0.16 mL, 2.66 mmol) was added to a solution of 6-methyl-N-[rac-1-[(2,4-dimethylphenoxy)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamide (550 mg, 0.89 mmol) in DCM/MeOH (16 mL, 1:1). The reaction mixture was stirred for 2 h at room temperature then concentrated. The residue was diluted with water and extracted with dichloromethane (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 490 mg (75% purity, 84% yield) of 6-methyl-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenoxy)ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide as a white oil.
Under argon, POCl3 (0.22 mL, 2.39 mmol) was added at 80° C. to a solution of 6-methyl-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenoxy)ethyl]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamide (490 mg, 0.80 mmol) in AcCN (10 mL). The reaction mixture was stirred for 4 h at 80° C. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution, then extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 89 mg (95% purity, 22% yield) of rac-5-[(2,4-dimethylphenoxy)methyl]-3-[6-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-5,6-dihydro-4H-1,2,4-oxadiazine as a brown oil.
In analogy to step 1 of example 4.
Under argon, a mixture of N′-allyloxy-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine (500 mg, 1.42 mmol), 5-bromo-1-methyl-indole (596 mg, 2.83 mmol), triethylamine (0.40 mL, 2.84 mmol), palladium(II) acetate (32 mg, 0.14 mmol) and tri-2tolylphosphine (86 mg, 0.28 mmol) in AcCN (5 mL) was stirred at reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (3×30 mL). Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 203 mg (93% purity, 27% yield) of 6-methyl-N′-[3-(1-methylindol-5-yl)allyloxy]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine as an oil.
A solution of iodine (13.2 mg, 0.052 mmol) and phenylsilane (11.2 mg, 0.104 mmol) in dichloromethane (5 mL) was stirred at room temperature for 30 min, then 6-methyl-N′-[3-(1-methylindol-5-yl)allyloxy]-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine (25.0 mg, 0.052 mmol) was added. The reaction mixture was stirred for 1 h, then diluted with a saturated sodium thiosulfate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 8 mg (88% purity, 28% yield) of rac-5-(1-methylindol-5-yl)-3-[6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-4,5,6,7-tetrahydro-1,2,4-oxadiazepine as an oil.
See step 1 of example 2.
To a solution of 6-chloro-N-[1-(chloromethyl)-2-(2,4-dimethylphenyl)ethyl]-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamide (339 mg, 0.68 mmol) in toluene (6 mL) was added phosphorous pentachloride (425 mg, 2.04 mmol). The reaction mixture was stirred at 75° C. for 1 h30, then concentrated under reduced pressure. The residue was dissolved in AcCN (4 mL) and a solution of hydrazine hydrate (170.27 mg, 3.40 mmol) was added at room temperature to the reaction mixture. After stirring at room temperature for 1 h the reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 197 mg (100% purity, 60% yield) of rac-3-[6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-1,4,5,6-tetrahydro-1,2,4-triazine.
Di-tert-butyl dicarbonate (2.13 g, 9.79 mmol) and triethylamine (2.73 mL, 19.6 mmol) were successively added at 0° C. to a suspension of rac-3-amino-4-(2,4-dimethylphenyl)butan-1-ol hydrochloride (1.5 g, 6.52 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 1.8 g (97% purity, 91% yield) of tert-butyl N-[rac-1-[(2,4-dimethylphenyl)methyl]-3-hydroxy-propyl]carbamate as a white solid.
Under argon, diethyl azodicarboxylate (6.87 g, 15.3 mmol) was added at 0° C. to a solution of tert-butyl N-[rac-1-[(2,4-dimethylphenyl)methyl]-3-hydroxy-propyl]carbamate (1.8 g, 6.13 mmol), phthalimide (5.41 g, 36.8 mmol) and triphenylphosphine (9.65 g, 36.8 mmol) in tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for 24 h, diluted with water and extracted with ethylacetate (3×200 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 2.0 g (84% purity, 60% yield) of tert-butyl N-[rac-1-[(2,4-dimethylphenyl)methyl]-3-(1,3-dioxoisoindolin-2-yl)propyl]carbamate as a colorless oil.
To a solution of tert-butyl N-[rac-1-[(2,4-dimethylphenyl)methyl]-3-(1,3-dioxoisoindolin-2-yl)propyl]carbamate (1.2 g, 2.84 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.65 mL, 8.52 mmol). The reaction mixture was stirred at room temperature for 3 days. Evaporation of the solvents afforded 1.2 g (54% purity, 52% yield) of 2-[rac-3-amino-4-(2,4-dimethylphenyl)butyl]iso-indoline-1,3-dione;2,2,2-trifluoroacetic acid as a solid.
Under argon, hydrazine monohydrate (3.73 mL, 41.24 mmol) was added to a solution of 2-[rac-3-amino-4-(2,4-dimethylphenyl)butyl]isoindoline-1,3-dione;2,2,2-trifluoroacetic acid (1.2 g, 2.75 mmol) in EtOH (5 mL). The reaction mixture was stirred for 3 days at room temperature then concentrated. It was then diluted with water and extracted with dichloromethane (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred in MTBE and the white solid that formed was filtered off. Concentration of the filtrate afforded 520 mg (95% purity, 93% yield) of rac-4-(2,4-dimethylphenyl)butane-1,3-diamine as a white solid.
See step 1 of example 5 starting from 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carbonitrile (100 mg, 0.33 mmol)
To the previous solution of methyl 6-chloro-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboximidate was added at 0° C. rac-4-(2,4-dimethylphenyl)butane-1,3-diamine (124 mg, 0.45 mmol) dissolved in MeOH (0.5 mL) and acetic acid (9 μL). The reaction mixture was stirred at room temperature for 5 h, then the mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 26 mg (90% purity, 16% yield) of 6-chloro-4-[rac-6-[(2,4-dimethylphenyl)methyl]-1,4,5,6-tetrahydropyrimidin-2-yl]-3-[3-(trifluoromethyl)phenoxy]pyridazine as a yellow oil.
See step 3 of example 3
Under argon, 2-tert-butylimino-N,N-diethyl-1,3-dimethyl-1,3,2lambda5-diazaphosphinan-2-amine (BEMP) (105 mg, 0.38 mmol) was added at room temperature to a solution of N′-hydroxy-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine (100 mg, 0.32 mmol) in AcCN (1.5 mL). After 15 min, 2-bromo-2,2-difluoro-1-(4-methoxyphenyl)ethanone (127 mg, 0.48 mmol) was added and the reaction was stirred further for 15 min. The reaction mixture was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (2×50 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 222 mg (27% purity, 80% yield) of N′-[1,1-difluoro-2-(4-methoxyphenyl)-2-oxo-ethoxy]-6-methyl-3-[3-(trifluoromethyl)phenoxy]pyridazine-4-carboxamidine as an oil.
Under argon, N′-[1,1-difluoro-2-(4-methoxyphenyl)-2-oxo-ethoxy]-6-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazine-4-carboxamidine (222 mg, 0.25 mmol) was dissolved in tert-butanol (6.4 mL) and acetic acid (1.6 mL) and heated to 80° C. After 30 min, sodium cyanoborohydride (21 mg, 0.34 mmol) was added and the reaction was stirred further for 2 h. After cooling to room temperature, the mixture was poured into a 1M aqueous NaOH solution and extracted with ethyl acetate (2×20 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by PREP-HPLC afforded, after evaporation of the solvents, 4 mg (96% purity, 3% yield) of rac-6,6-difluoro-5-(4-methoxyphenyl)-3-[6-methyl-3-[3-(trifluoro-methyl)phenoxy]pyridazin-4-yl]-4,5-dihydro-1,2,4-oxadiazine as a yellow solid.
To a solution of isopropyl 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)pyridazine-4-carboxylate (800 mg, 2.28 mmol) in dimethyl sulfoxide (2.5 mL) was added nitromethane (0.62 mL, 11.40 mmol). The reaction was stirred at room temperature for 30 min, then triethylamine (0.48 mL, 3.42 mmol) was added. The reaction was stirred at room temperature for 24 h, then it was diluted with water and extracted with ethyl acetate (2×100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 917 mg (76% purity, 84% yield) of isopropyl 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazine-4-carboxylate as an orange oil.
To a solution of isopropyl 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazine-4-carboxylate (927 mg, 2.5 mmol) in tetrahydrofuran (4 mL) was added a 2M aqueous solution of lithium hydroxide (182 mg, 7.62 mmol). The reaction was stirred for 4 days at room temperature then it was diluted with water. The aqueous phase was acidified with 1 M aqueous HCl solution and extracted with ethyl acetate (3×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 617 mg (81% purity, 60% yield) of 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazine-4-carboxylic acid as a solid.
Under argon, to a solution of 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazine-4-carboxylic acid (500 mg, 1.55 mmol) and HATU (648 mg, 1.70 mmol) in DMF (10 mL) were successively added at 0° C., 2-[rac-2-amino-3-(2,4-dimethylphenyl)propoxy]isoindoline-1,3-dione 2,2,2-trifluoroacetate (747 mg, 1.70 mmol) and N,N-Diisopropylethylamine (0.80 mL, 4.64 mmol). After 15 min at 0° C., the reaction mixture was stirred for 18 h at room temperature. It was then diluted with water and extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 639.5 g (100% purity, 65% yield) of 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]pyridazine-4-carboxamide as a solid.
Under argon, hydrazine monohydrate (0.18 mL, 3.0 mmol) was added to a solution of 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-N-[rac-1-[(2,4-dimethylphenyl)methyl]-2-(1,3-dioxoisoindolin-2-yl)oxy-ethyl]pyridazine-4-carboxamide (639 mg, 1.0 mmol) in DCM/MeOH (12 mL, 1:1). The reaction mixture was stirred for 18 h at room temperature and concentrated. It was then diluted with water and extracted with dichloromethane (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Evaporation of the solvents afforded 453 mg (100% purity, 89% yield) of 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]pyridazine-4-carboxamide as a white oil.
Under argon, POCl3 (0.25 mL, 2.72 mmol) was added at 80° C. to a solution 6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-N-[rac-1-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]pyridazine-4-carboxamide (453 mg, 0.90 mmol) in AcCN (5 mL). The reaction mixture was stirred for 18 h at 80° C. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate solution, then extracted with ethyl acetate (2×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient heptane/EtOAc) afforded, after evaporation of the solvents, 196 mg (100% purity, 44% yield) of rac-3-[6-chloro-3-(3-cyclopropyl-2-fluoro-phenoxy)-5-methyl-pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-1,2,4-oxadiazine as a yellow solid.
The compounds as shown in table 1 below were prepared in analogy with the examples provided above or following methods described herein. 1H-NMR data of these compounds is shown in table 2.
The compounds as shown in table 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 and 43 below were prepared in analogy with the examples provided above or following methods described herein. 1H-NMR data of these compounds is respectively shown in tables 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38 40, 42 and 44.
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of radish or cabbage were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween® 80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Alternaria brassicae spores. The contaminated radish or cabbage plants were incubated for 6 days at 20° C. and at 100% relative humidity.
The test was evaluated 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-180; I-184
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-031; I-074; I-182; I-235
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-007; I-008; I-009; I-010; I-011; I-012; I-013; I-014; I-015; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-029; I-030; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-040; I-041; I-042; I-043; I-044; I-045; I-046; I-047; I-048; I-049; I-050; I-051; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-060; I-061; I-062; I-063; I-064; I-065; I-066; I-067; I-068; I-069; I-070; I-071; I-072; I-073; I-075; I-076; I-077; I-078; I-079; I-080; I-081; I-082; I-083; I-084; I-085; I-086; I-087; I-088; I-089; I-090; I-091; I-092; I-093; I-094; I-095; I-096; I-097; I-098; I-099; I-100; I-103; I-104; I-105; I-106; I-107; I-108; I-109; I-110; I-111; I-112; I-113; I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-126; I-127; I-128; I-129; I-130; I-131; I-132; I-133; I-134; I-135; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-144; I-145; I-146; I-147; I-148; I-149; I-150; I-151; I-152; I-153; I-154; I-155; I-156; I-157; I-158; I-159; I-160; I-161; I-162; I-163; I-164; I-165; I-166; I-167; I-169; I-170; I-171; I-172; I-173; I-174; I-175; I-178; I-181; I-183; I-185; I-186; I-187; I-188; I-189; I-190; I-192; I-193; I-194; I-195; I-196; I-197; I-198; I-199; I-200; I-201; I-202; I-203; I-204; I-205; I-206; I-207; I-208; I-209; I-210; I-211; I-212; I-213; I-214; I-215; I-216; I-217; I-218; I-219; I-220; I-221; I-222; I-223; I-225; I-226; I-227; I-228; I-229; I-230; I-231; I-232; I-233; I-234; I-236; I-237; I-238; I-239; I-240; I-241; I-242; I-243; I-244; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-256; I-258; I-259; I-260; I-261; I-262; I-263; I-264; I-265; I-266; I-267; I-268; I-270; I-271; I-273; I-274; I-275; I-276; I-279; I-280; I-281; I-282; I-283; I-284; I-285; I-286; I-287; I-288; I-289; I-290; I-292; I-293; I-294; I-295; I-296; I-297; I-298; I-299; I-300; I-301; I-302; I-303; I-304; I-305; I-306; I-307; I-308; I-310; I-311; I-340
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of gherkin or cabbage were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween® 80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Botrytis cinerea spores. The contaminated gherkin plants were incubated for 4 to 5 days at 17° C. and at 90% relative humidity. The contaminated cabbage plants were incubated for 4 to 5 days at 20° C. and at 100% relative humidity.
The test was evaluated 4 to 5 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-182; I-235
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-106; I-115; I-176; I-181
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-007; I-008; I-009; I-010; I-011; I-012; I-014; I-015; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-029; I-030; I-031; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-040; I-041; I-042; I-043; I-044; I-045; I-046; I-047; I-048; I-049; I-050; I-051; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-060; I-061; I-062; I-063; I-066; I-067; I-068; I-069; I-070; I-071; I-072; I-073; I-074; I-075; I-076; I-077; I-078; I-079; I-080; I-081; I-082; I-083; I-084; I-085; I-086; I-087; I-088; I-089; I-090; I-091; I-092; I-093; I-094; I-095; I-096; I-097; I-098; I-099; I-100; I-103; I-104; I-105; I-107; I-108; I-109; I-110; I-111; I-112; I-113; I-114; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-127; I-128; I-129; I-130; I-131; I-133; I-134; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-144; I-145; 1-146; I-147; I-148; I-149; I-150; I-151; I-152; I-153; I-154; I-155; I-156; I-157; I-158; I-159; I-160; I-161; I-162; I-163; I-164; I-165; I-166; I-167; I-169; I-170; I-171; I-172; I-173; I-174; I-175; I-178; I-180; I-184; I-186; I-187; I-188; I-190; I-192; I-193; I-194; I-195; I-196; I-197; I-198; I-202; I-203; I-208; I-209; I-210; I-211; I-212; I-213; I-214; I-216; I-217; I-221; I-222; I-223; I-225; I-226; I-228; I-230; I-231; I-234; I-240; I-242; I-244; I-245; I-246; I-247; I-248; I-249; I-250; I-252; I-258; I-259; I-260; I-261; I-272; I-274; I-275; I-276; I-279; I-292; I-293; I-294; I-295; I-296; I-297; I-298; I-299; I-300; I-301; I-302; I-303; I-304; I-305; I-306; I-307; I-308; I-310; I-311
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of barley were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween®80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Pyrenophora teres spores. The contaminated barley plants were incubated for 48 hours at 20° C. and at 100% relative humidity and then for 8 days at 20° C. and at 70-80% relative humidity.
The test was evaluated 10 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-011; I-060; I-065; I-066; I-095; I-125; I-134; I-140; I-141; I-157; I-159; I-160; I-162; I-166; I-209; I-214; I-215; I-216; I-231; I-238; I-267; I-292; I-297; I-311
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-008; I-010; I-015; I-040; I-051; I-058; I-072; I-076; I-077; I-078; I-079; I-082; I-085; I-092; I-109; I-110; I-122; I-136; I-145; I-146; I-153; I-155; I-176; I-188; I-196; I-213; I-223; I-225; I-228; I-234; I-235; I-263; I-268; I-272; I-289; I-293; I-294; I-340
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-009; I-012; I-014; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-030; I-032; I-035; I-036; I-038; I-042; I-045; I-047; I-048; I-050; I-052; I-053; I-054; I-055; I-056; I-057; I-059; 1-070; I-075; I-084; I-086; I-087; I-088; I-089; I-090; I-091; I-094; I-097; I-111; I-123; I-124; I-127; I-129; I-130; I-137; I-138; I-142; I-143; I-147; I-152; I-154; I-161; I-163; I-165; I-170; I-171; I-172; I-173; I-174; I-186; I-189; I-190; I-197; I-199; I-200; I-201; I-203; I-204; I-205; I-206; I-207; I-208; I-210; I-211; I-212; I-217; I-218; I-219; I-220; I-221; I-222; I-226; I-227; I-229; I-230; I-232; I-233; I-236; I-237; I-239; I-240; I-241; I-242; I-243; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-256; I-258; I-259; I-260; I-261; I-262; I-264; I-265; I-266; I-270; I-271; I-273; I-280; I-281; I-283; I-284; I-285; I-286; I-287; I-288; I-290; I-295; I-296; I-298; I-299; I-300; I-301; I-302; I-303; I-305; I-306; I-307; I-308; I-310
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of wheat were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween®80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Septoria tritici spores. The contaminated wheat plants were incubated for 72 hours at 17° C. and at 100% relative humidity and then for 15 days at 20° C. and at 90% relative humidity.
The test was evaluated 19 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-003; I-013; I-032; I-088; I-091; I-123; I-129; I-130; I-146; I-161; I-189; I-196; I-197; I-198; I-233; I-241; I-252; I-272; I-282; I-286; I-287
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-001; I-004; I-008; I-012; I-035; I-052; I-053; I-057; I-075; I-082; I-087; I-089; I-090; I-131; I-136; I-140; I-153; I-159; I-170; I-186; I-188; I-239; I-261; I-265; I-266; I-271; I-283; I-284; I-288; I-289; I-292; I-294; I-299; I-304
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-002; I-005; I-006; I-009; I-016; I-017; I-019; I-020; I-021; I-022; I-023; I-025; I-026; I-027; I-028; I-030; I-036; I-038; I-042; I-054; I-056; I-059; I-072; I-076; I-084; I-085; I-086; I-097; I-128; I-138; I-147; I-152; I-163; I-165; I-176; I-247; I-250; I-259; I-260; I-264; I-267; I-270; I-273; I-280; I-281; I-285; I-290; I-298; I-300; I-302
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of gherkin were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween®80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Sphaerotheca fuliginea spores. The contaminated gherkin plants were incubated for 8 days at 20° C. and at 70-80% relative humidity.
The test was evaluated 8 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-144; I-206; I-217; I-221; I-242; I-243; I-280
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-040; I-078; I-107; I-119; I-120; I-150; I-151; I-167; I-230; I-286; I-340
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-008; I-009; I-010; I-011; I-012; I-013; I-014; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-030; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-041; I-042; I-043; I-044; I-045; I-047; I-048; I-049; I-050; I-051; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-060; I-062; I-063; I-064; I-066; I-067; I-068; I-069; I-070; I-072; I-074; I-075; I-076; I-079; I-082; I-084; I-085; I-087; I-088; I-089; I-090; I-091; I-092; I-094; I-097; I-098; I-099; I-103; I-106; I-109; I-110; I-111; I-112; I-113; I-115; I-121; I-122; I-123; I-124; I-125; I-127; I-128; I-129; I-130; I-131; I-132; I-133; I-136; I-137; I-138; I-139; I-141; I-142; I-143; I-145; I-146; I-147; I-148; I-149; I-152; I-153; I-154; I-155; I-157; I-159; I-160; I-161; I-162; I-163; I-164; I-165; I-166; I-169; I-170; I-171; I-172; I-173; I-174; I-176; I-180; I-181; I-183; I-186; I-187; I-188; I-189; I-190; I-192; I-193; I-194; I-196; I-197; I-198; I-199; I-200; I-201; I-203; I-204; I-205; I-207; I-208; I-209; I-210; I-211; I-212; I-214; I-216; I-218; I-220; I-222; I-223; I-225; I-226; I-227; I-228; I-229; I-232; I-233; I-234; I-235; I-236; I-237; I-238; I-239; I-240; I-241; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-256; I-258; I-259; I-260; I-261; I-262; I-263; I-264; I-265; I-266; I-267; I-268; I-270; I-272; I-273; I-275; I-276; I-279; I-281; I-282; I-283; I-284; I-285; I-287; I-288; I-289; I-290; I-292; I-293; I-294; I-295; I-296; I-297; I-298; I-299; I-300; I-301; I-302; I-303; I-305; I-306; I-307; I-308; I-310
The active ingredients were made soluble and homogenized in a mixture of Dimethyl sulfoxide/Acetone//Tween®80 and then diluted in water to the desired concentration.
The young plants of bean were treated by spraying the active ingredient prepared as described above. Control plants were treated only with an aqueous solution of Acetone/Dimethyl sulfoxide/Tween® 80.
After 24 hours, the plants were contaminated by spraying the leaves with an aqueous suspension of Colletotrichum lindemuthianum spores. The contaminated bean plants were incubated for 24 hours at 20° C. and at 100% relative humidity and then for 6 days at 20° C. and at 90% relative humidity.
The test was evaluated 7 days after the inoculation. 0% means an efficacy which corresponds to that of the control plants while an efficacy of 100% means that no disease was observed.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 500 ppm of active ingredient: I-080; I-100; I-132; I-148; I-151; I-183; I-288
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 500 ppm of active ingredient: I-011; I-051; I-079; I-096; I-098; I-113; I-158; I-160; I-169; I-194; I-208; I-210; I-213; I-219; I-222; I-228; I-233; I-293
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 500 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-008; I-009; I-010; I-012; I-013; I-014; I-015; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-030; I-031; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-040; I-042; I-043; I-044; I-045; I-047; I-048; I-049; I-050; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-061; I-062; I-065; I-066; I-067; I-068; I-069; I-070; I-072; I-075; I-076; I-077; I-078; I-082; I-083; I-084; I-085; I-086; I-087; I-088; I-089; I-090; I-091; I-092; I-093; I-094; I-095; I-097; I-099; I-103; I-104; I-105; I-106; I-107; I-109; I-110; I-111; I-112; I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-126; I-127; I-128; I-129; I-130; I-133; I-134; I-135; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-145; I-146; I-147; I-149; I-150; I-152; I-153; I-154; I-155; I-157; I-159; I-161; I-162; I-163; I-165; I-166; I-167; I-170; I-171; I-172; I-173; I-174; I-176; I-186; I-188; I-189; I-190; I-192; I-193; I-196; I-197; I-198; I-199; I-200; I-201; I-202; I-203; I-204; I-205; I-206; I-207; I-211; I-212; I-214; I-215; I-216; I-217; I-218; I-220; I-221; I-225; I-226; I-229; I-231; I-232; I-236; I-237; I-238; I-239; I-240; I-241; I-242; I-243; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-256; I-258; I-259; I-260; I-261; I-262; I-263; I-264; I-266; I-267; I-270; I-271; I-272; I-273; I-276; I-280; I-281; I-282; I-283; I-285; I-286; I-289; I-290; I-292; I-294; I-295; I-296; I-298; I-299; I-300; I-301; I-302; I-303; I-305; I-306; I-307; I-308; I-310
Fungicides were solubilized in DMSO and the solution used to prepare the required range of concentrations. The final concentration of DMSO used in the assay was ≤1%.
A spore suspension of A. alternata was prepared and diluted to the desired spore density.
Fungicides were evaluated for their ability to inhibit spore germination and mycelium growth in liquid culture assay. The compounds were added in the desired concentration to the culture medium with spores. After 5 days incubation, fungi-toxicity of compounds was determined by spectrometric measurement of mycelium growth. Inhibition of fungal growth was determined by comparing the absorbance values in wells containing the fungicides with the absorbance in control wells without fungicides.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 20 ppm of active ingredient: I-091; I-126; I-132; I-134; I-180; I-191; I-214; I-224; I-340
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 20 ppm of active ingredient: I-081; I-169; I-184; I-194; I-244; I-282
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 20 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-007; I-008; I-009; I-010; I-011; I-012; I-013; I-014; I-015; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-030; I-031; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-040; I-041; I-042; I-043; I-044; I-045; I-046; I-047; I-048; I-049; I-050; I-051; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-060; I-061; I-063; I-064; I-065; I-066; I-067; I-068; I-069; I-070; I-071; I-072; I-073; I-074; I-075; I-076; I-077; I-078; I-079; I-080; I-082; I-084; I-085; I-086; I-087; I-088; I-089; I-090; I-092; I-093; I-094; I-097; I-098; I-099; I-100; I-101; I-102; I-103; I-104; I-105; I-106; I-107; I-108; I-109; I-110; I-111; I-112; I-113; I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-127; I-128; I-129; I-130; I-133; I-135; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-144; I-145; I-146; I-147; I-148; I-149; I-150; I-151; I-152; I-153; I-154; I-155; I-156; I-157; I-158; I-159; I-160; I-161; I-162; I-163; I-164; I-165; I-166; I-167; I-168; I-170; I-171; I-172; I-173; I-174; I-175; I-176; I-177; I-179; I-181; I-182; I-183; I-185; I-186; I-187; I-188; I-189; I-190; I-192; I-193; I-195; I-196; I-197; I-198; I-199; I-200; I-201; I-202; I-203; I-204; I-205; I-207; I-208; I-210; I-211; I-212; I-213; I-216; I-217; I-218; I-219; I-220; I-221; I-222; I-223; I-225; I-226; I-227; I-229; I-230; I-232; I-233; I-234; I-236; I-237; I-239; I-240; I-241; I-242; I-243; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-254; I-255; I-256; I-257; I-258; I-259; I-260; I-261; I-262; I-263; I-264; I-265; I-266; I-267; I-268; I-269; I-270; I-271; I-272; I-273; I-274; I-275; I-276; I-277; I-278; I-279; I-280; I-281; I-283; I-284; I-285; I-286; I-287; I-288; I-289; I-290; I-291; I-292; I-293; I-294; I-295; I-296; I-297; I-298; I-299; I-300; I-301; I-302; I-303; I-304; I-305; I-306; I-307; I-308; I-309; I-310; I-311; I-312; I-313; I-315; I-316; I-317; I-318; I-319
Fungicides were solubilized in DMSO and the solution used to prepare the required range of concentrations. The final concentration of DMSO used in the assay was ≤1%.
A spore suspension of C. lindemuthianum was prepared and diluted to the desired spore density.
Fungicides were evaluated for their ability to inhibit spores germination and mycelium growth in liquid culture assay. The compounds were added in the desired concentration to the culture medium with spores. After 6 days incubation, fungi-toxicity of compounds was determined by spectrometric measurement of mycelium growth. Inhibition of fungal growth was determined by comparing the absorbance values in wells containing the fungicides with the absorbance in control wells without fungicides.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 20 ppm of active ingredient: I-083; I-132; I-185; I-234
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 20 ppm of active ingredient: I-126; I-134; I-180; I-194; I-206; I-227; I-235
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 20 ppm of active ingredient: I-001; I-002; I-003; I-004; I-005; I-006; I-007; I-008; I-009; I-010; I-011; I-012; I-013; I-014; I-015; I-016; I-017; I-018; I-019; I-020; I-021; I-022; I-023; I-024; I-025; I-026; I-027; I-028; I-029; I-030; I-031; I-032; I-033; I-034; I-035; I-036; I-037; I-038; I-039; I-040; I-041; I-042; I-043; I-044; I-045; I-046; I-047; I-048; I-049; I-050; I-051; I-052; I-053; I-054; I-055; I-056; I-057; I-058; I-059; I-060; I-061; I-063; I-064; I-065; I-066; I-067; I-068; I-069; I-070; I-071; I-072; I-073; I-074; I-075; I-076; I-077; I-078; I-079; I-080; I-081; I-082; I-084; I-085; I-086; I-087; I-088; I-089; I-090; I-091; I-092; I-093; I-094; I-097; I-098; I-099; I-100; I-101; I-102; I-103; I-104; I-105; I-106; I-107; I-108; I-109; I-110; I-111; I-112; I-113; I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122; I-123; I-124; I-125; I-127; I-128; I-129; I-130; I-133; I-135; I-136; I-137; I-138; I-139; I-140; I-141; I-142; I-143; I-144; I-145; I-146; I-147; I-148; I-149; I-150; I-151; I-152; I-153; I-154; I-155; I-156; I-157; I-158; I-159; I-160; I-161; I-162; I-163; I-164; I-165; I-166; I-167; I-168; I-169; I-170; I-171; I-172; I-173; I-174; I-175; I-176; I-177; I-179; I-181; I-182; I-183; I-186; I-187; I-188; I-189; I-190; I-191; I-192; I-193; I-195; I-196; I-197; I-198; I-199; I-200; I-201; I-202; I-203; I-204; I-205; I-207; I-208; I-210; I-211; I-212; I-213; I-214; I-216; I-217; I-218; I-219; I-220; I-221; I-222; I-223; I-224; I-225; I-226; I-228; I-229; I-230; I-231; I-232; I-233; I-236; I-237; I-238; I-239; I-240; I-241; I-242; I-243; I-244; I-245; I-246; I-247; I-248; I-249; I-250; I-251; I-252; I-253; I-254; I-255; I-256; I-257; I-258; I-259; I-260; I-261; I-262; I-263; I-264; I-265; I-266; I-267; I-268; I-269; I-270; I-271; I-272; I-273; I-274; I-275; I-276; I-277; I-278; I-279; I-280; I-281; I-282; I-283; I-284; I-285; I-286; I-287; I-288; I-289; I-290; I-291; I-292; I-293; I-294; I-295; I-296; I-297; I-298; I-299; I-300; I-301; I-302; I-303; I-304; I-305; I-306; I-307; I-308; I-309; I-310; I-311; I-312; I-313; I-315; I-316; I-317; I-318; I-319; I-347
Fungicides were solubilized in DMSO and the solution used to prepare the required range of concentrations. The final concentration of DMSO used in the assay was ≤1%.
A spore suspension of Septoria tritici was prepared and diluted to the desired spore density.
Fungicides were evaluated for their ability to inhibit spore germination and mycelium growth in liquid culture assay. The compounds were added in the desired concentration to the culture medium with spores. After 7 days incubation, fungi-toxicity of compounds was determined by spectrometric measurement of mycelium growth. Inhibition of fungal growth was determined by comparing the absorbance values in wells containing the fungicides with the absorbance in control wells without fungicides.
In this test the following compounds according to the invention showed efficacy between 70% and 79% at a concentration of 20 ppm of active ingredient: I-005; I-024; I-066; I-104; I-123; I-132; I-142; I-146; I-148; I-198; I-248; I-249; I-291; I-343
In this test the following compounds according to the invention showed efficacy between 80% and 89% at a concentration of 20 ppm of active ingredient: I-008; I-018; I-020; I-026; I-048; I-067; I-070; I-072; I-086; I-089; I-097; I-109; I-110; I-111; I-112; I-113; I-124; I-127; I-128; I-138; I-140; I-143; I-152; I-157; I-174; I-175; I-188; I-190; I-193; I-196; I-197; I-199; I-200; I-201; I-207; I-225; I-233; I-241; I-247; I-250; I-252; I-255; I-256; I-278; I-279; I-283; I-284; I-285; I-286; I-288; I-289; I-290; I-294
In this test the following compounds according to the invention showed efficacy between 90% and 100% at a concentration of 20 ppm of active ingredient: I-001; I-003; I-004; I-007; I-009; I-011; I-013; I-016; I-017; I-019; I-021; I-022; I-023; I-025; I-027; I-028; I-030; I-032; I-035; I-036; I-038; I-043; I-045; I-050; I-052; I-053; I-054; I-055; I-059; I-075; I-076; I-082; I-084; I-085; I-130; I-147; I-153; I-155; I-159; I-161; I-163; I-165; I-166; I-170; I-172; I-186; I-189; I-195; I-205; I-218; I-226; I-236; I-239; I-259; I-260; I-261; I-273; I-275; I-280; I-281; I-298; I-299; I-300; I-301; I-302; I-303; I-305; I-306; I-307; I-308; I-320; I-323; I-342
| Number | Date | Country | Kind |
|---|---|---|---|
| 18214866.8 | Dec 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/086373 | 12/19/2019 | WO |
