# Patent

## Title
Microbiocidal heterobicyclic derivatives

## Abstract

Compounds of the formula I wherein Y—X, R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, Ra and n are as defined in claim 1. Furthermore, the present invention relates to agrochemical compositions which comprise compounds of formula (I), to preparation of these compositions, and to the use of the compounds or compositions in agriculture or horticulture for combating, preventing or controlling infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi.

## Background
RELATED APPLICATION INFORMATION
This application is a 371 of International Application No. PCT/CN2015/072369, filed 6 Feb. 2015, which claims priority to EP Patent Application No. 14154347.0, filed 7 Feb. 2014, the contents of which are incorporated herein by reference herein.
The present invention relates to microbiocidal heterobicyclic derivatives, e.g. as active ingredients, which have microbiocidal activity, in particular fungicidal activity. The invention also relates to preparation of these heterobicyclic derivatives, to intermediates useful in the preparation of these heterobicyclic derivatives, to the preparation of these intermediates, to agrochemical compositions which comprise at least one of the heterobicyclic derivatives, to preparation of these compositions and to the use of the heterobicyclic derivatives or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi.
Certain fungicidal heterobicyclic compounds are described in WO05070917.
It has now surprisingly been found that certain novel heterobicyclic derivatives have favourable fungicidal properties.
The present invention therefore provides compounds of formula I




wherein
each of A1, A2, and A3 independently represents a nitrogen atom or CR7;
Y—X represents a radical selected from G1, G2, G3 and G4:




















G1



 







G2



 







G3



 







G4










R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, in which the alkyl, cycloalkyl, alkenyl and alkynyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or
R1 and R2 together with the carbon atom to which they are attached represent a C3-C10 cycloalkyl group (which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy);
R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, in which the alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or
R3 and R4 together with the carbon atom to which they are attached represent C═O, C═CH2 or C3-C10 cycloalkyl (which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy);
R5 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxyl;
R6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxyl;
each R7 independently represents hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C2-C6 alkynyl, or hydroxyl;
each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CO2H, CO2(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, C(O)NH(C1-C6 alkyl), C(O)NH2, NH(C1-C6 alkylcarbonyl), N(C1-C6 alkylcarbonyl)2, aryl, heteroraryl, aryloxy or heteroraryloxy, in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, C1-C6 alkylthio, C1-C6 alkoxycarbonyl and phenoxy, and the aryl or heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), C1-C6 alkoxy, amino (which itself may be substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkylcarbonyl), nitro, cyano, hydroxyl, mercapto and C1-C6 alkylthio; n is 0, 1, 2, 3 or 4;
Ra is hydrogen, C1-C6 alkylcarbonyl or C1-C6 alkyl, which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or a salt or N-oxide thereof.
In a second aspect the present invention provides an agrochemical composition comprising a compound of formula (I).
Compounds of formula (I) may be used to control phytopathogenic microorganisms. Thus, in order to control a phytopathogen a compound of formula (I), or a composition comprising a compound of formula (I), according to the invention may be applied directly to the phytopathogen, or to the locus of a phytopathogen, in particular to a plant susceptible to attack by phytopathogens.
Thus, in a third aspect the present invention provides the use of a compound of formula (I), or a composition comprising a compound of formula (I), as described herein to control a phytopathogen.
In a further aspect the present invention provides a method of controlling phytopathogens, comprising applying a compound of formula (I), or a composition comprising a compound of formula (I), as described herein to said phytopathogen, or to the locus of said phytopathogen, in particular to a plant susceptible to attack by a phytopathogen.
Compounds of formula (I) are particularly effective in the control of phytopathogenic fungi.
Thus, in a yet further aspect the present invention provides the use of a compound of formula (I), or a composition comprising a compound of formula (I), as described herein to control phytopathogenic fungi.
In a further aspect the present invention provides a method of controlling phytopathogenic fungi, comprising applying a compound of formula (I), or a composition comprising a compound of formula (I), as described herein to said phytopathogenic fungi, or to the locus of said phytopathogenic fungi, in particular to a plant susceptible to attack by phytopathogenic fungi.
Where substituents are indicated as being optionally substituted, this means that they may or may not carry one or more identical or different substituents, e.g. one to three substituents. Normally not more than three such optional substituents are present at the same time. Where a group is indicated as being substituted, e.g. alkyl, this includes those groups that are part of other groups, e.g. the alkyl in alkylthio.
The term “halogen” refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Alkyl substituents may be straight-chained or branched. Alkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the isomers thereof, for example, iso-propyl, iso-butyl, sec-butyl, tert-butyl or iso-amyl.
Alkenyl substituents can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl and allyl. The alkenyl groups are preferably C2-C6, more preferably C2-C4 and most preferably C2-C3 alkenyl groups.
Alkynyl substituents can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are preferably C2-C6, more preferably C2-C4 and most preferably C2-C3 alkynyl groups.
Haloalkyl groups may contain one or more identical or different halogen atoms and, for example, may stand for CH2Cl, CHCl2, CCl3, CH2F, CHF2, CF3, CF3CH2, CH3CF2, CF3CF2 or CCl3CCl2.
Haloalkenyl groups are alkenyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, 2,2-difluorovinyl or 1,2-dichloro-2-fluoro-vinyl.
Haloalkynyl groups are alkynyl groups, respectively, which are substituted with one or more of the same or different halogen atoms and are, for example, 1-chloro-prop-2-ynyl.
Alkoxy means a radical —OR, where R is alkyl, e.g. as defined above. Alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-methylethoxy, propoxy, butoxy, 1-methylpropoxy and 2-methylpropoxy.
Cyano means a —CN group.
Amino means an —NH2 group.
Hydroxyl or hydroxy stands for a —OH group.
Aryl groups (either alone or as part of a larger group, such as e.g. aryloxy, aryl-alkyl) are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heteroaryl groups (either alone or as part of a larger group, such as e.g. heteroaryloxy, heteroaryl-alkyl) are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. [1,2,4]triazolyl), furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
Heterocyclyl groups or heterocyclic rings (either alone or as part of a larger group, such as heterocyclyl-alkyl) are non-aromatic ring structures containing up to 10 atoms including one or more (preferably one, two or three) heteroatoms selected from O, S and N. Examples of monocyclic groups include, oxetanyl, 4,5-dihydro-isoxazolyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, [1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, imidazolidinyl, [1,3,5]oxadiazinanyl, hexahydro-pyrimidinyl, [1,3,5]triazinanyl and morpholinyl or their oxidised versions such as 1-oxo-thietanyl and 1,1-dioxo-thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[1,4]dioxolanyl, benzo[1,3]dioxolanyl, chromenyl, and 2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is preferably substituted by one to four substituents, most preferably by one to three substituents.
The presence of one or more possible asymmetric carbon atoms in a compound of formula I means that the compounds may occur in optically isomeric forms, i.e. enantiomeric or diastereomeric forms. Also atropisomers may occur as a result of restricted rotation about a single bond. Formula I is intended to include all those possible isomeric forms and mixtures thereof. The present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula I. Likewise, formula I is intended to include all possible tautomers. The present invention includes all possible tautomeric forms for a compound of formula I.
In each case, the compounds of formula I according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.
N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
Preferred values of Y—X, R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, Ra and n are, in any combination thereof, as set out below:
Preferably one or more of A1, A2, and A3 represent CR7.
More preferably two or more of A1, A2, and A3 represent CR7.
Even more preferably A1 is a nitrogen atom and A2 and A3 both represent CR7, or A2 is a nitrogen atom and both A1 and A3 represent CR7.
Most preferably all of A1, A2, and A3 represent CR7.
Preferably each R7 independently represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkynyl, or hydroxyl.
More preferably each R7 independently represents hydrogen, halogen, C1-C6 alkyl, or hydroxyl.
Even more preferably each R7 independently represents hydrogen, or halogen.
Most preferably each R7 independently represents hydrogen, fluoro, or chloro, wherein no more than one R7 group is fluoro or chloro.
Preferably Y—X is G1, G2 or G4.
More preferably Y—X is G1 or G2.
Most preferably Y—X is G1.
Preferably R1 and R2 are each independently selected from hydrogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, in which the alkyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group.
More preferably R1 and R2 are each independently selected from C1-C6 alkyl, in which the alkyl group may be optionally substituted with 1 to 3 substituents independently selected from halogen, and C1-C6 alkoxy; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group.
Even more preferably R1 and R2 are each independently selected from C1-C6 alkyl; or R1 and R2 together with the carbon atom to which they are attached represent a cyclopropyl group.
Most preferably R1 and R2 are each independently selected from C1-C2 alkyl.
Preferably R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or C3-C7 cycloalkyl (which may be optionally substituted with 1 to 3 substituents independently selected from halogen).
More preferably R3 and R4 are each independently selected from hydrogen, halogen, C1-C6 alkyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or cyclopropyl.
Even more preferably R3 and R4 are each independently selected from hydrogen, fluoro, or methyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O.
Most preferably R3 and R4 are each independently selected from hydrogen, fluoro, or methyl.
Preferably R5 is hydrogen, halogen, or C1-C6 alkyl.
More preferably R5 is hydrogen, or halogen.
Even more preferably R5 is hydrogen, chloro, or fluoro.
Most preferably R5 is hydrogen.
Preferably R6 is hydrogen, halogen, or C1-C6 alkyl;
More preferably R6 is hydrogen, or C1-C6 alkyl.
Even more preferably R6 is hydrogen, or methyl.
Most preferably R6 is hydrogen.
Preferably each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), or C1-C6 alkoxy; n is 0, 1, 2, or 3.
More preferably each R8 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, or C1-C3 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms); n is 0, 1, or 2.
Even more preferably each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyridyl, phenoxy or pyridyloxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl and pyridyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen; n is 0, 1, or 2.
Most preferably each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen; n is 0, or 1, most preferably 0.
Preferably Ra is hydrogen, or C1-C6 alkyl.
Most preferably Ra is hydrogen, or C1-C2 alkyl.
Embodiments according to the invention are provided as set out below.
Embodiment 1 provides compounds of formula I, or a salt or N-oxide thereof, as defined above.
Embodiment 2 provides compounds according to embodiment 1 wherein one or more of A1, A2, and A3 represent CR7.
Embodiment 3 provides compounds according to embodiment 1 or 2 wherein each R7 independently represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkynyl, or hydroxyl.
Embodiment 4 provides compounds according to any one of embodiments 1, 2 or 3 wherein Y—X is G1, G2 or G4.
Embodiment 5 provides compounds according to any one of embodiments 1, 2, 3 or 4 wherein R1 and R2 are each independently selected from hydrogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, in which the alkyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group.
Embodiment 6 provides compounds according to any one of embodiments 1, 2, 3, 4, or 5 wherein R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or C3-C7 cycloalkyl (which may be optionally substituted with 1 to 3 substituents independently selected from halogen).
Embodiment 7 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, or 6 wherein R5 is hydrogen, halogen, or C1-C6 alkyl.
Embodiment 8 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, or 7 wherein R6 is hydrogen, halogen, or C1-C6 alkyl.
Embodiment 9 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, or 8 wherein each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), or C1-C6 alkoxy; n is 0, 1, 2, or 3.
Embodiment 10 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, or 9 wherein Ra is hydrogen or C1-C6 alkyl when Y—X is G2.
Embodiment 11 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein two or more of A1, A2, and A3 represent CR7.
Embodiment 12 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein each R7 independently represents hydrogen, halogen, C1-C6 alkyl, or hydroxyl.
Embodiment 13 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein Y—X is G1 or G2.
Embodiment 14 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 wherein R1 and R2 are each independently selected from C1-C6 alkyl, in which the alkyl group may be optionally substituted with 1 to 3 substituents independently selected from halogen, and C1-C6 alkoxy; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group.
Embodiment 15 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 wherein R3 and R4 are each independently selected from hydrogen, halogen, C1-C6 alkyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or cyclopropyl.
Embodiment 16 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein R5 is hydrogen, or halogen.
Embodiment 17 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 wherein R6 is hydrogen, or C1-C6 alkyl.
Embodiment 18 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 wherein each R8 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, or C1-C3 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms); n is 0, 1, or 2.
Embodiment 19 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 wherein Ra is hydrogen or C1-C2 alkyl when Y—X is G2.
Embodiment 20 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 wherein A1 is a nitrogen atom and A2 and A3 both represent CR7, or A2 is a nitrogen atom and both A1 and A3 represent CR7.
Embodiment 21 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 wherein each R7 independently represents hydrogen, or halogen.
Embodiment 22 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 wherein R1 and R2 are each independently selected from C1-C6 alkyl; or R1 and R2 together with the carbon atom to which they are attached represent a cyclopropyl group.
Embodiment 23 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 wherein R3 and R4 are each independently selected from hydrogen, fluoro, or methyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O.
Embodiment 24 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 wherein R5 is hydrogen, chloro, or fluoro.
Embodiment 25 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 wherein R6 is hydrogen, or methyl.
Embodiment 26 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 wherein each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyridyl, phenoxy or pyridyloxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl and pyridyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen; n is 0, 1, or 2.
Embodiment 27 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 wherein all of A1, A2, and A3 represent CR7.
Embodiment 28 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 wherein each R7 independently represents hydrogen, fluoro, or chloro, wherein no more than one R7 group is fluoro or chloro.
Embodiment 29 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27 or 28 wherein Y—X is G1 Embodiment 30 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 wherein R1 and R2 are each independently selected from C1-C2 alkyl.
Embodiment 31 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 wherein R3 and R4 are each independently selected from hydrogen, fluoro, or methyl.
Embodiment 32 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 wherein R5 is hydrogen.
Embodiment 33 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 wherein R6 is hydrogen.
Embodiment 34 provides compounds according to any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 wherein each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen; n is 0, or 1, most preferably 0.
A preferred group of compounds according to the invention are those of formula I-1:




wherein R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I.

Another preferred group of compounds according to the invention are those of formula I-2:




wherein R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, Ra and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, Ra and n are as defined for compounds of formula I.

Another preferred group of compounds according to the invention are those of formula I-3:




wherein R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I.

Another preferred group of compounds according to the invention are those of formula I-4:




wherein R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of R1, R2, R3, R4, R5, R6, R7, R8, A1, A2, A3, and n are as defined for compounds of formula I.

Another preferred group of compounds according to the invention are those of formula I-5:




wherein Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I.

Another preferred group of compounds according to the invention are those of formula I-6:




wherein Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I.
Another preferred group of compounds according to the invention are those of formula I-7:




wherein Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I, or a salt or N-oxide thereof. Preferred definitions of Y—X, R1, R2, R3, R4, R5, R6, R7, R8, Ra and n are as defined for compounds of formula I.
A further preferred group of compounds according to the invention are those of formula I-8 which are compounds of formula I wherein one or more of A1, A2, and A3 represent CR7; each R7 independently represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkynyl, or hydroxyl; Y—X is G1, G2 or G4; R1 and R2 are each independently selected from hydrogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, in which the alkyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group; R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or C3-C7 cycloalkyl (which may be optionally substituted with 1 to 3 substituents independently selected from halogen); R5 is hydrogen, halogen, or C1-C6 alkyl; R6 is hydrogen, halogen, or C1-C6 alkyl; each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), or C1-C6 alkoxy; n is 0, 1, 2, or 3; and Ra is hydrogen, or C1-C6 alkyl; or a salt or N-oxide thereof.
A further preferred group of compounds according to the invention are those of formula I-9 which are compounds of formula I wherein two or more of A1, A2, and A3 represent CR7; each R7 independently represents hydrogen, halogen, C1-C6 alkyl, or hydroxyl; Y—X is G1 or G2; R1 and R2 are each independently selected from C1-C6 alkyl, in which the alkyl group may be optionally substituted with 1 to 3 substituents independently selected from halogen, and C1-C6 alkoxy; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group; R3 and R4 are each independently selected from hydrogen, halogen, C1-C6 alkyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or cyclopropyl; R5 is hydrogen, or halogen; R6 is hydrogen, or C1-C6 alkyl; each R8 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, or C1-C3 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms); n is 0, 1, or 2; and Ra is hydrogen, or C1-C2 alkyl; or a salt or N-oxide thereof.
A further preferred group of compounds according to the invention are those of formula I-10 which are compounds of formula I wherein A1 is a nitrogen atom and A2 and A3 both represent CR7, or A2 is a nitrogen atom and both A1 and A3 represent CR7; each R7 independently represents hydrogen, or halogen; Y—X is G1 or G2; R1 and R2 are each independently selected from C1-C6 alkyl; or R1 and R2 together with the carbon atom to which they are attached represent a cyclopropyl group; R3 and R4 are each independently selected from hydrogen, fluoro, or methyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O; R5 is hydrogen, chloro, or fluoro; R6 is hydrogen, or methyl; each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyridyl, phenoxy or pyridyloxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl and pyridyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen; n is 0, 1, or 2; and Ra is hydrogen, or C1-C2 alkyl; or a salt or N-oxide thereof.
A further preferred group of compounds according to the invention are those of formula I-11 which are compounds of formula I wherein all of A1, A2, and A3 represent CR7; each R7 independently represents hydrogen, fluoro, or chloro, wherein no more than one R7 group is fluoro or chloro; Y—X is G1; R1 and R2 are each independently selected from C1-C2 alkyl; R3 and R4 are each independently selected from hydrogen, fluoro, or methyl; R5 is hydrogen; R6 is hydrogen; each R8 independently represents fluoro, chloro, bromo, C1-C3 alkyl, C1-C3 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen; n is 0, or 1, most preferably 0; or a salt or N-oxide thereof.
Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile, improved physico-chemical properties, or increased biodegradability).
Specific examples of compounds of formula I are illustrated in the Tables A1 to A27, B1 to B10, and C1 to C12 below:
Table A1 provides 232 compounds of formula Ia




wherein R6, R7a and R7c are all H and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z below:















TABLE Z





Entry
R1
R2
R3
R4
R8
Y-X
Ra






















1
CH3
CH3
H
H
H [n = 0]
G1
—


2
CH3
CH3
H
H
5-F
G1
—


3
CH3
CH3
H
H
6-F
G1
—


4
CH3
CH3
H
H
7-F
G1
—


5
CH3
CH3
H
H
8-F
G1
—


6
CH3
CH3
H
H
5-Cl
G1
—


7
CH3
CH3
H
H
6-Cl
G1
—


8
CH3
CH3
H
H
7-Cl
G1
—


9
CH3
CH3
H
H
8-Cl
G1
—


10
CH3
CH3
H
H
5-Br
G1
—


11
CH3
CH3
H
H
6-Br
G1
—


12
CH3
CH3
H
H
7-Br
G1
—


13
CH3
CH3
H
H
8-Br
G1
—


14
CH3
CH3
H
H
5-I
G1
—


15
CH3
CH3
H
H
5,6-F2
G1
—


16
CH3
CH3
H
H
5,6-Cl2
G1
—


17
CH3
CH3
H
H
5-F-6-Cl
G1
—


18
CH3
CH3
H
H
5-CH3
G1
—


19
CH3
CH3
H
H
6-CH3
G1
—


20
CH3
CH3
H
H
7-CH3
G1
—


21
CH3
CH3
H
H
8-CH3
G1
—


22
CH3
CH3
H
H
5-CH2CH3
G1
—


23
CH3
CH3
H
H
5-C≡CH
G1
—


24
CH3
CH3
H
H
5-C(H)═CH2
G1
—


25
CH3
CH3
H
H
5-cyclopropyl
G1
—


26
CH3
CH3
H
H
5-CN
G1
—


27
CH3
CH3
H
H
5-OH
G1
—


28
CH3
CH3
H
H
5-OCH3
G1
—


29
CH3
CH3
H
H
5-OC6H5
G1
—


30
CH3
CH3
H
H
5-O-(pyrid-2-yl) 
G1
—


31
CH3
CH3
H
H
5-CH2OCH3
G1
—


32
CH3
CH3
H
H
5-OCHF2
G1
—


33
CH3
CH3
H
H
5-OCF3
G1
—


34
CH3
CH3
H
H
5-OCH2C(H)═CH2
G1
—


35
CH3
CH3
H
H
5-OCH2C≡CH
G1
—


36
CH3
CH3
H
H
5-CF3
G1
—


37
CH3
CH3
H
H
5-CHF2
G1
—


38
CH3
CH3
H
H
5-C6H6
G1
—


39
CH3
CH3
H
H
5-(2-F-C6H5)
G1
—


40
CH3
CH3
H
H
5-(thien-2-y1)
G1
—


41
CH3
CH3
H
H
5-(thiazol-2-y1)
G1
—


42
CH3
CH3
H
H
5-NH2
G1
—


43
CH3
CH3
H
H
5-NHC(O)CH3
G1
—


44
CH3
CH3
H
H
5-O(O)H
G1
—


45
CH3
CH3
H
H
5-C(O)OH
G1
—


46
CH3
CH3
H
H
5-C(O)NH2
G1
—


47
CH3
CH3
H
H
5-C(O)N(CH3)2
G1
—


48
CH3
CH3
H
H
5-COCH3
G1
—


49
CH3
CH3
H
H
H [n = 0]
G2
H


50
CH3
CH3
H
H
5-F
G2
H


51
CH3
CH3
H
H
5-Cl
G2
H


52
CH3
CH3
H
H
5-CH3
G2
H


53
CH3
CH3
H
H
H [n = 0]
G2
CH3


54
CH3
CH3
H
H
5-F
G2
CH3


55
CH3
CH3
H
H
5-Cl
G2
CH3


56
CH3
CH3
H
H
5-CH3
G2
CH3


57
CH3
CH3
H
H
H [n = 0]
G3
—


58
CH3
CH3
H
H
5-F
G3
—


59
CH3
CH3
H
H
5-Cl
G3
—


60
CH3
CH3
H
H
5-CH3
G3
—


61
CH3
CH3
H
H
H [n = 0]
G4
—


62
CH3
CH3
H
H
5-F
G4
—


63
CH3
CH3
H
H
5-Cl
G4
—


64
CH3
CH3
H
H
5-CH3
G4
—


65
CH3
CH3
H
CH3
H [n = 0]
G1
—


66
CH3
CH3
H
CH3
5-F
G1
—


67
CH3
CH3
H
CH3
6-F
G1
—


68
CH3
CH3
H
CH3
5-Cl
G1
—


69
CH3
CH3
H
CH3
6-Cl
G1
—


70
CH3
CH3
H
CH3
5-Br
G1
—


71
CH3
CH3
H
CH3
5-CH3
G1
—


72
CH3
CH3
H
CH3
5-OCH3
G1
—


73
CH3
CH3
H
CH3
5-OC6H5
G1
—


74
CH3
CH3
H
OH
H [n = 0]
G1
—


75
CH3
CH3
H
OH
5-F
G1
—


76
CH3
CH3
H
OH
6-F
G1
—


77
CH3
CH3
H
OH
5-Cl
G1
—


78
CH3
CH3
H
OH
6-Cl
G1
—


79
CH3
CH3
H
OH
5-Br
G1
—


80
CH3
CH3
H
OH
5-CH3
G1
—


81
CH3
CH3
H
OH
5-OCH3
G1
—


82
CH3
CH3
H
OH
5-OC6H5
G1
—


83
CH3
CH3
H
OCH3
H [n = 0]
G1
—


84
CH3
CH3
H
OCH3
5-F
G1
—


85
CH3
CH3
H
OCH3
6-F
G1
—


86
CH3
CH3
H
OCH3
5-Cl
G1
—


87
CH3
CH3
H
OCH3
6-Cl
G1
—


88
CH3
CH3
H
OCH3
5-Br
G1
—


89
CH3
CH3
H
OCH3
5-CH3
G1
—


90
CH3
CH3
H
OCH3
5-OCH3
G1
—


91
CH3
CH3
H
OCH3
5-OC6H5
G1
—


92
CH3
CH3
H
F
H [n = 0]
G1
—


93
CH3
CH3
H
F
5-F
G1
—


94
CH3
CH3
H
F
6-F
G1
—


95
CH3
CH3
H
F
5-CI
G1
—


96
CH3
CH3
H
F
6-CI
G1
—


97
CH3
CH3
H
F
5-Br
G1
—


98
CH3
CH3
H
F
5-CH3
G1
—


99
CH3
CH3
H
F
5-OCH3
G1
—


100
CH3
CH3
H
F
5-OC6H5
G1
—


101
CH3
CH3
CH3
CH3
H [n = 0]
G1
—


102
CH3
CH3
CH3
CH3
5-F
G1
—


103
CH3
CH3
CH3
CH3
6-F
G1
—


104
CH3
CH3
CH3
CH3
5-Cl
G1
—


105
CH3
CH3
CH3
CH3
6-Cl
G1
—


106
CH3
CH3
CH3
CH3
5-Br
G1
—


107
CH3
CH3
CH3
CH3
5,6-F2
G1
—


108
CH3
CH3
CH3
CH3
5,6-Cl2
G1
—


109
CH3
CH3
CH3
CH3
5-F-6-Cl
G1
—


110
CH3
CH3
CH3
CH3
5-CH3
G1
—


111
CH3
CH3
CH3
CH3
5-CH2CH3
G1
—


112
CH3
CH3
CH3
CH3
5-C(O)H
G1
—


113
CH3
CH3
CH3
CH3
5-CN
G1
—


114
CH3
CH3
CH3
CH3
5-OH
G1
—


115
CH3
CH3
CH3
CH3
5-OCH3
G1
—


116
CH3
CH3
CH3
CH3
5-OC6H5
G1
—


117
CH3
CH3
CH3
CH3
5-O-(pyrid-2-yl)
G1
—


118
CH3
CH3
CH3
CH3
5-CH2OCH3
G1
—


119
CH3
CH3
CH3
CH3
5-C6H6
G1
—


120
CH3
CH3
CH3
CH3
5-(2-F-C6H5)
G1
—


121
CH3
CH3
CH3
CH3
5-(thien-2-yl)
G1
—


122
CH3
CH3
CH3
CH3
5-(thiazol-2-yl)
G1
—


123
CH3
CH3
CH3
CH3
5-OCHF2
G1
—


124
CH3
CH3
CH3
CH3
5-OCF3
G1
—


125
CH3
CH3
CH3
CH3
5-OCH2C(H)═CH2
G1
—


126
CH3
CH3
CH3
CH3
5-OCH2C≡CH
G1
—


127
CH3
CH3
CH3
CH3
5-CF3
G1
—


128
CH3
CH3
CH3
CH3
5-CHF2
G1
—


129
CH3
CH3
CH3
CH3
H [n = 0]
G2
H


130
CH3
CH3
CH3
CH3
5-F
G2
H


131
CH3
CH3
CH3
CH3
H [n = 0]
G2
CH3


132
CH3
CH3
CH3
CH3
5-F
G2
CH3


133
CH3
CH3
CH3
CH3
H [n = 0]
G3
—


134
CH3
CH3
CH3
CH3
5-F
G3
—


135
CH3
CH3
CH3
CH3
H [n = 0]
G3
—


136
CH3
CH3
CH3
CH3
5-F
G3
—


137
CH3
CH3
CH3
CH3
H [n = 0]
G4
—


138
CH3
CH3
CH3
CH3
5-F
G4
—


139
CH3
CH3
CH3
CH3
H [n = 0]
G4
—


140
CH3
CH3
CH3
CH3
5-F
G4
—













141
CH3
CH3
═O
H [n = 0]
G1
—


142
CH3
CH3
═O
5-F
G1



143
CH3
CH3
═O
6-F
G1
—


144
CH3
CH3
═O
5-Cl
G1
—


145
CH3
CH3
═O
6-Cl
G1
—


146
CH3
CH3
═O
5-Br
G1
—


147
CH3
CH3
═O
5-CH3
G1
—


148
CH3
CH3
═O
5-OCH3
G1



149
CH3
CH3
═O
5-OC6H5
G1
—














150
CH3
CH3
F
F
H [n = 0]
G1
—


151
CH3
CH3
F
F
5-F
G1
—


152
CH3
CH3
F
F
6-F
G1



153
CH3
CH3
F
F
5-Cl
G1
—


154
CH3
CH3
F
F
6-Cl
G1
—


155
CH3
CH3
F
F
5-Br
G1
—


156
CH3
CH3
F
F
5-CH3
G1
—


157
CH3
CH3
F
F
5-OCH3
G1
—


158
CH3
CH3
F
F
5-OC6H5
G1
—













159
CH3
CH3
cyclol-
H [n = 0]
G1
—





propy





160
CH3
CH3
cyclol-
5-F
G1
—





propy





161
CH3
CH3
cyclo-
H [n = 0]
G1
—





butyl





162
CH3
CH3
cyclo-
5-F
G1
—





butyl





163
CH3
CH3
cyclo-
H [n = 0]
G1
—





pentyl





164
CH3
CH3
cyclo-
5-F
G1
—





pentyl





165
CH3
CH3
cyclo-
H [n = 0]
G1
—





hexyl





166
CH3
CH3
cyclo-
5-F
G1
—





hexyl

















167
CH3
CH2CH3
H
H
H [n = 0]
G1
—


168
CH3
CH2CH3
H
H
5-F
G1
—


169
CH3
CH2CH3
H
H
5-Cl
G1
—


170
CH3
CH2CH3
H
H
5-CH3
G1
—


171
CH3
CH2CH3
H
H
5-OCH3
G1
—


172
CH2-
CH2CH3
H
H
H [n = 0]
G1
— 



CH3








173
CH2-
CH2CH3
H
H
5-F
G1
—



CH3








174
CH2-
CH2CH3
H
H
5-Cl
G1
—



CH3








175
CH3
CF3
H
H
H [n = 0]
G1
— 


176
CH3
CF3
H
H
5-F
G1
—


177
CH3
CF3
H
H
5-Cl
G1
—


178
CH3
CH2Cl
H
H
H [n = 0]
G1
— 


179
CH3
CH2Cl
H
H
5-F
G1
—


180
CH3
CH2Cl
H
H
5-Cl
G1
—


181
CH3
CH2Cl
CH3
CH3
H [n = 0]
G1
— 


182
CH3
CH2Cl
CH3
CH3
5-F
G1
—


183
CH3
CH2Cl
CH3
CH3
5-Cl
G1
—


184
CH3
CH2OCH3
H
H
H [n = 0]
G1
— 


185
CH3
CH2OCH3
H
H
5-F
G1
—


186
CH4
CH2OCH3
H
H
5-Cl
G1
—


187
CH3
CH2OCH3
CH3
CH3
H [n = 0]
G1
— 


188
CH3
CH2OCH3
CH3
CH3
5-F
G1
—


189
CH3
CH2OCH3
CH3
CH3
5-Cl
G1
—


190
CH3
H
H
H
H [n = 0]
G1
— 


191
CH3
H
H
H
5-F
G1
—


192
CH3
H
H
H
5-CH3
G1
—


193
CH3
CH(CH3)2
H
H
H [n = 0]
G1
— 


194
CH3
CH(CH3)2
H
H
5-F
G1
—


195
CH3
CH(CH3)2
H
H
5-Cl
G1
—


196
CH3
CH2-
H
H
H [n = 0]
G1
— 




CH2CH3







197
CH3
CH2-
H
H
5-F
G1
—




CH2CH3







198
CH3
CH2-
H
H
5-Cl
G1
—




CH2CH3


















199
cyclopropyl
H
H
H [n = 0]
G1
—


200
cyclopropyl
CH3
CH3
H [n = 0]
G1
—












201
cyclopropyl
═O
H [n = 0]
G1
—













202
cyclopropyl
F
F
H [n = 0]
G1
—












203
cyclopropyl
cyclo-
H [n = 0]
G1
—




propyl
















204
cyclopropyl
H
H
5-F
G1
—


205
cyclopropyl
CH3
CH3
5-F
G1
—












206
cyclopropyl
═O
5-F
G1
—













207
cyclopropyl
F
F
5-F
G1
—












208
cyclopropyl
cyclo-
5-F
G1
—




propyl
















209
cyclobutyl
H
H
H [n = 0]
G1
—


210
cyclobutyl
CH3
CH3
H [n = 0]
G1
—












211
cyclobutyl
═O
H [n = 0]
G1
—













212
cyclobutyl
F
F
H [n = 0]
G1
—


213
cyclobutyl
H
H
5-F
G1
—


214
cyclobutyl
CH3
CH3
5-F
G1
—












215
cyclobutyl
═O
5-F
G1
—













216
cyclobutyl
F
F
5-F
G1
—


217
cyclopentyl
H
H
H [n = 0]
G1
—


218
cyclopentyl
CH3
CH3
H [n = 0]
G1
—












219
cyclopentyl
═O
H [n = 0]
G1
—













220
cyclopentyl
F
F
H [n = 0]
G1
—


221
cyclopentyl
H
H
5-F
G1
—


222
cyclopentyl
CH3
CH3
5-F
G1
—












223
cyclopentyl
═O
5-F
G1
—













224
cyclopentyl
F
F
5-F
G1
—


225
cyclohexyl
H
H
H [n = 0]
G1
—


226
cyclohexyl
CH3
CH3
H [n = 0]
G1
—












227
cyclohexyl
═O
H [n = 0]
G1
—













228
cyclohexyl
F
F
H [n = 0]
G1
—


229
cyclohexyl
H
H
5-F
G1
—


230
cyclohexyl
CH3
CH3
5-F
G1
—












231
cyclohexyl
═O
5-F
G1
—













232
cyclohexyl
F
F
5-F
G1
—









Table A2 provides 232 compounds of formula Ia wherein R7a, R7c are H, R6 is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A3 provides 232 compounds of formula Ia wherein R7a, R7c are H, R6 is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A4 provides 232 compounds of formula Ia wherein R7a, R7c are H, R6 is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A5 provides 232 compounds of formula Ia wherein R7a, R7c are H, R6 is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A6 provides 232 compounds of formula Ia wherein R6, R7a are H, R7c is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A7 provides 232 compounds of formula Ia wherein R6, R7a are H, R7c is hydroxyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A8 provides 232 compounds of formula Ia wherein R6, R7a are H, R7c is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A9 provides 232 compounds of formula Ia wherein R6, R7a are H, R7c is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A10 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A11 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A12 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A13 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is bromo and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A14 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is cyano and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A15 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is hydroxyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A16 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A17 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is difluoromethyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A18 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is ethynyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A19 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is trifluoromethyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A20 provides 232 compounds of formula Ia wherein R6, R7c are H, R7a is cyclopropyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A21 provides 232 compounds of formula Ia wherein R6 is H, R7c is fluoro, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A22 provides 232 compounds of formula Ia wherein R6 is H, R7c is hydroxyl, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A23 provides 232 compounds of formula Ia wherein R6 is H, R7c is methyl, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A24 provides 232 compounds of formula Ia wherein R6 is all H, R7c is bromo, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A25 provides 232 compounds of formula Ia wherein R6 is all H, R7c is chloro, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A26 provides 232 compounds of formula Ia wherein R6 is methoxy, R7c is H, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table A27 provides 232 compounds of formula Ia wherein R6 is methyl, R7c is H, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B1 discloses 232 compounds of formula Ib





wherein R6 and R7a are H

and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B2 provides 232 compounds of formula Ib wherein wherein R7a is H, R6 is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B3 provides 232 compounds of formula Ib wherein R7a is H, R6 is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B4 provides 232 compounds of formula Ib wherein R7a is H, R6 is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B5 provides 232 compounds of formula Ib wherein R7a is H, R6 is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B6 provides 232 compounds of formula Ib wherein R6 is H, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B7 provides 232 compounds of formula Ib wherein R6 is H, R7a is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B8 provides 232 compounds of formula Ib wherein R6 is H, R7a is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B9 provides 232 compounds of formula Ib wherein R6 is H, R7a is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table B10 provides 232 compounds of formula Ib wherein R6 is methyl, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C1 discloses 232 compounds of formula Ic





wherein R6, R7a, R7c are all H

and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C2 provides 232 compounds of formula Ic wherein R7a, R7c are all H, R6 is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C3 provides 232 compounds of formula Ic wherein R7a, R7c are all H, R6 is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C4 provides 232 compounds of formula Ic wherein R7a, R7c are all H, R6 is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C5 provides 232 compounds of formula Ic wherein R7a, R7c are all H, R6 is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C6 provides 232 compounds of formula Ic wherein R7a, R6 are all H, R7c is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C7 provides 232 compounds of formula Ic wherein R7a, R6 are all H, R7c is hydroxyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C8 provides 232 compounds of formula Ic wherein R7c, R6 are all H, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C9 provides 232 compounds of formula Ic wherein R7c, R6 are all H, R7a is methyl and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C10 provides 232 compounds of formula Ic wherein R7c, R6 are all H, R7a is methoxy and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C11 provides 232 compounds of formula Ic wherein R7c, R6 are all H, R7a is chloro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Table C12 provides 232 compounds of formula Ic wherein R7c is H, R6 is methyl, R7a is fluoro and wherein the values of R1, R2, R3, R4, R8 and the radical Y—X are as defined in Table Z above.

Compounds of the present invention can be made as shown in the following schemes, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
The compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula II, wherein R5, R6, A1, A2 and A3, are as defined for formula I, with a compound of formula III, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, under acidic conditions, e.g. with sulphuric acid, trifluoroacetic acid or trifluoromethansulfonic acid. This is shown in Scheme 1.




The compounds of formula II, wherein R5, R6, A1, A2 and A3, are as defined for formula I, can be obtained by transformation of a compound of formula IV (which are commercially available or easily obtainable by a variety of known methods), wherein A1, A2 and A3, are as defined for formula I, with a compound of formula V, wherein R5 and R6 is as defined for formula I and R9 is C1-C6 alkyl, under acid conditions, e.g. with hydrochloric acid. This is shown in Scheme 2.




Alternatively, the compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula VI, wherein R5, R6, A1, A2 and A3, are as defined for formula I and R10 is hydroxyl or two R10 together with the interjacent boron atom form a five- or sixmembered saturated heterocyclic ring, with a compound of formula VII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I and Hal is halogen, preferably chloro or bromo, under conditions of the Suzuki-Miyaura reaction. This is shown in Scheme 3.




The compounds of formula VII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I and Hal is halogen, preferably chloro or bromo, can be obtained by transformation of a compound of formula VIII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, with a halogenation reagent, such as phosphorus oxychloride phosphorus oxybromide, thionyl chloride, thionyl bromide or Vilsmeier reagent. This is shown in Scheme 4.




The compounds of formula VIII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, can be obtained by transformation of a compound of formula IX, wherein R1, R2, R3, R4, R8 and n are as defined for formula I and R9 is C1-C6 alkyl, with sodium acetate in acetic acid. This is shown in Scheme 5.




The compounds of formula IX, wherein R1, R2, R3, R4, R8 and n are as defined for formula I and R9 is C1-C6 alkyl, can be obtained by transformation of a compound of formula III, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, with a C1-C6 alkyl thiocyanate under acidic conditions, e.g. with sulfuric acid. This is shown in Scheme 6.




Alternatively, the compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula X, wherein R5, R6, A1, A2 and A3, are as defined for formula I and R9 is C1-C6 alkyl, with a compound of formula VII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I and Hal is halogen, preferably chloro or bromo, under conditions of the Stille reaction. This is shown in Scheme 7.




Alternatively, the compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula IV, wherein A1, A2 and A3, are as defined for formula I, with a compound of formula XI, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, under acidic conditions, e.g. with hydrochloric acid. This is shown in Scheme 8.




The compounds of formula XI, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, can be obtained by transformation of a compound of formula XII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, R9 is C1-C6 alkyl and Hal is halogen, preferably chloro or bromo, under aqueous or basic conditions. This is shown in Scheme 9.




The compounds of formula XII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, R9 is C1-C6 alkyl and Hal is halogen, preferably chloro or bromo, can be obtained by transformation of a compound of formula XIII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, R9 is C1-C6 alkyl and Hal is halogen, preferably chloro or bromo, with a phosphorus oxyhalide, such as phosphorus oxychloride or phosphorus oxybromide, and a N,N-di(C1-C6 alkyl)formamide. This is shown in Scheme 10.




The compounds of formula XIII, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, can be obtained by transformation of a compound of formula III, wherein R1, R2, R3, R4, R8 and n are as defined for formula I, with a acetonitrile under acidic conditions, e.g. with sulfuric acid. This is shown in Scheme 11.




The compounds of formula I-2, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, under reductive reaction conditions, e.g. with hydrogen and a catalyst. This is shown in Scheme 12. The ring nitrogen of the tetrahydroisoquinoline in compound I-2 can either be alkylated (Ra=C1-C6 alkyl) by reaction with a C1-C6 alkylhalide and a base, or acylated (Ra=C1-C6 alkylcarbonyl) by transformation with a C1-C6 alkylcarbonylhalide and a base.




The compounds of formula I-3, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, under oxidative reaction conditions, e.g. with meta-chloroperbenzoic acid. This is shown in Scheme 13.




The compounds of formula I-4, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, under oxidative reaction conditions, e.g. with methyltrioxorhenium and urea hydrogen peroxide. This is shown in Scheme 14.




Alternatively, the compounds of formula I-4, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, can be obtained by transformation of a compound of formula I-3, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3, and n are as defined for formula I, under acidic conditions, e.g. with methanesulfonic acid. This is shown in Scheme 15.




The compounds of formula I-1 wherein R3 and R4 are fluoro and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of a compound of formula XIV wherein R3 and R4 together with the carbon atom to which they are attached represent C═O and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I with a fluorinating agent such as diethylaminosulfur trifluoride (DAST) or 2,2-difluoro-1,3-dimethyl-imidazolidine (DFI). This is shown in Scheme 16.




The compounds of formula XIV wherein R3 and R4 together with the carbon atom to which they are attached represent C═O and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of a compound of formula XV wherein R3 is hydrogen and R4 is hydroxy and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I with an oxidizing agent such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol3(1H)-one (Dess-Martin periodinane) or using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine (Swern oxidation). This is shown in Scheme 17.




The compounds of formula XV wherein wherein R3 is hydrogen and R4 is hydroxy and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of a compound of formula XVI wherein R3 is hydrogen and R4 is bromo and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I under hydrolysis conditions.
This is shown in Scheme 18.




The compounds of formula XVI wherein wherein R3 is hydrogen and R4 is bromo and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of a compound of formula XVII wherein R3 and R4 are hydrogen and R1, R2, R5, R6, R8, A1, A2, A3 and n are as defined for formula I with a brominating agent such as N-bromo succinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin in the presence of a radical initiator such as azobisisobutyronitrile (AIBN). This is shown in Scheme 19.




The compounds of formula XVII can be obtained according to the method described in Scheme 1.
Alternatively, the compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of a compound of formula XVIII, wherein R1, R2, R3, R4, R5, R6, A1, A2, A3 and n are as defined for formula I and Z represents bromine or iodine in a solvent, in the presence of or absence of a base, and in the presence of a coupling reagent and a metal catalyst. There are no particular limitations on the coupling agent, catalyst, solvent and bases, provided it is used in ordinary coupling reactions, such as those described in “Cross-Coupling Reactions: A Practical Guide (Topics in Current Chemistry)”, edited by Norio Miyaura and S. L. Buchwald (editions Springer), or “Metal-Catalyzed Cross-Coupling Reactions”, edited by Armin de Meijere and François Diederich (editions WILEY-VCH). This is shown in Scheme 20.




Additionally, certain compounds of formula I-1, wherein R1, R2, R3, R4, R5, R6, R8, A1, A2, A3 and n are as defined for formula I, can be obtained by transformation of another, closely related, compound of formula I-1 using standard synthesis techniques known to the person skilled in the art. Non-exhaustive examples include oxidation reactions, reduction reactions, hydrolysis reactions, coupling reactions, aromatic nucleophilic or electrophilic substitution reactions, nucleophilic substitution reactions, nucleophilic addition reactions, and halogenation reactions.
Certain intermediates described in the above schemes are novel and as such form a further aspect of the invention.
The compounds of formula I can be used in the agricultural sector and related fields of use e.g. as active ingredients for controlling plant pests or on non-living materials for control of spoilage microorganisms or organisms potentially harmful to man. The novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and may be used for protecting numerous cultivated plants. The compounds of formula I can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later e.g. from phytopathogenic microorganisms.
It is also possible to use compounds of formula I as fungicide. The term “fungicide” as used herein means a compound that controls, modifies, or prevents the growth of fungi. The term “fungicidally effective amount” means the quantity of such a compound or combination of such compounds that is capable of producing an effect on the growth of fungi. Controlling or modifying effects include all deviation from natural development, such as killing, retardation and the like, and prevention includes barrier or other defensive formation in or on a plant to prevent fungal infection.
It is also possible to use compounds of formula I as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings (for example rice), for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil. The propagation material can be treated with a composition comprising a compound of formula I before planting: seed, for example, can be dressed before being sown. The compounds of formula I can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation. The composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
Furthermore the compounds according to present invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
In addition, the invention could be used to protect non-living materials from fungal attack, e.g. lumber, wall boards and paint.
Compounds of formula I and fungicidal compositions containing them may be used to control plant diseases caused by a broad spectrum of fungal plant pathogens. They are effective in controlling a broad spectrum of plant diseases, such as foliar pathogens of ornamental, turf, vegetable, field, cereal, and fruit crops.
These fungi and fungal vectors of disease, as well as phytopathogenic bacteria and viruses, which may be controlled are for example:
Absidia corymbifera, Alternaria spp, Aphanomyces spp, Ascochyta spp, Aspergillus spp. including A. flavus, A. fumigatus, A. nidulans, A. niger, A. terrus, Aureobasidium spp. including A. pullulans, Blastomyces dermatitidis, Blumeria graminis, Bremia lactucae, Botryosphaeria spp. including B. dothidea, B. obtusa, Botrytis spp. including B. cinerea, Candida spp. including C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Cephaloascus fragrans, Ceratocystis spp, Cercospora spp. including C. arachidicola, Cercosporidium personatum, Cladosporium spp, Claviceps purpurea, 
Coccidioides immitis, Cochliobolus spp, Colletotrichum spp. including C. musae, 
Cryptococcus neoformans, Diaporthe spp, Didymella spp, Drechslera spp, Elsinoe spp,
Epidermophyton spp, Erwinia amylovora, Erysiphe spp. including E. cichoracearum, 
Eutypa lata, Fusarium spp. including F. culmorum, F. graminearum, F. langsethiae, F. moniliforme, F. oxysporum, F. proliferatum, F. subglutinans, F. solani, Gaeumannomyces graminis, Gibberella fujikuroi, Gloeodes pomigena, Gloeosporium musarum, Glomerella cingulate, Guignardia bidwellii, Gymnosporangium juniperi-virginianae, Helminthosporium spp, Hemileia spp, Histoplasma spp. including H. capsulatum, Laetisaria fuciformis, Leptographium lindbergi, Leveillula taurica, Lophodermium seditiosum, Microdochium nivale, Microsporum spp, Monilinia spp, Mucor spp, Mycosphaerella spp. including M. graminicola, M. pomi, Oncobasidium theobromaeon, Ophiostoma piceae, Paracoccidioides spp, Penicillium spp. including P. digitatum, P. italicum, Petriellidium spp, Peronosclerospora spp. Including P. maydis, P. philippinensis and P. sorghi, Peronospora spp, Phaeosphaeria nodorum, Phakopsora pachyrhizi, Phellinus igniarus, Phialophora spp, Phoma spp, Phomopsis viticola, Phytophthora spp. including P. infestans, Plasmopara spp. including P. halstedii, P. viticola, Pleospora spp., Podosphaera spp. including P. leucotricha, Polymyxa graminis, Polymyxa betae, Pseudocercosporella herpotrichoides, Pseudomonas spp, Pseudoperonospora spp. including P. cubensis, P. humuli, Pseudopeziza tracheiphila, Puccinia Spp. including P. hordei, P. recondita, P. striiformis, P. triticina, Pyrenopeziza spp, Pyrenophora spp, Pyricularia spp. including P. oryzae, Pythium spp. including P. ultimum, Ramularia spp, Rhizoctonia spp, Rhizomucor pusillus, Rhizopus arrhizus, Rhynchosporium spp, Scedosporium spp. including S. apiospermum and S. prolificans, Schizothyrium pomi, 
Sclerotinia spp, Sclerotium spp, Septoria spp, including S. nodorum, S. tritici, Sphaerotheca macularis, Sphaerotheca fusca (Sphaerotheca fuliginea), Sporothorix spp, Stagonospora nodorum, Stemphylium spp. Stereum hirsutum, Thanatephorus cucumeris, Thielaviopsis basicola, Tilletia spp, Trichoderma spp. including T. harzianum, T. pseudokoningii, T. viride, 
Trichophyton spp, Typhula spp, Uncinula necator, Urocystis spp, Ustilago spp, Venturia spp. including V. inaequalis, Verticillium spp, and Xanthomonas spp.
In particular, compounds of formula I and fungicidal compositions containing them may be used to control plant diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and/or Deuteromycete, Blasocladiomycete, Chrytidiomycete, Glomeromycete and/or Mucoromycete classes.
These pathogens may include:
Oomycetes, including Phytophthora diseases such as those caused by Phytophthora capsici, Phytophthora infestans, Phytophthora sojae, Phytophthora fragariae, Phytophthora nicotianae, Phytophthora cinnamomi, Phytophthora citricola, Phytophthora citrophthora and Phytophthora erythroseptica; Pythium diseases such as those caused by Pythium aphanidermatum, Pythium arrhenomanes, Pythium graminicola, Pythium irregulare and Pythium ultimum; diseases caused by Peronosporales such as Peronospora destructor, Peronospora parasitica, Plasmopara viticola, Plasmopara halstedii, Pseudoperonospora cubensis, Albugo candida, Sclerophthora macrospora and Bremia lactucae; and others such as Aphanomyces cochlioides, Labyrinthula zosterae, Peronosclerospora sorghi and Sclerospora graminicola. 
Ascomycetes, including blotch, spot, blast or blight diseases and/or rots for example those caused by Pleosporales such as Stemphylium solani, Stagonospora tainanensis, Spilocaea oleaginea, Setosphaeria turcica, Pyrenochaeta lycoperisici, Pleospora herbarum, Phoma destructiva, Phaeosphaeria herpotrichoides, Phaeocryptocus gaeumannii, Ophiosphaerella graminicola, Ophiobolus graminis, Leptosphaeria maculans, Hendersonia creberrima, Helminthosporium triticirepentis, Setosphaeria turcica, Drechslera glycines, Didymella bryoniae, Cycloconium oleagineum, Corynespora cassficola, Cochliobolus sativus, Bipolaris cactivora, Venturia inaequalis, Pyrenophora teres, Pyrenophora tritici-repentis, Alternaria alternata, Alternaria brassicicola, Alternaria solani and Alternaria tomatophila, Capnodiales such as Septoria tritici, Septoria nodorum, Septoria glycines, Cercospora arachidicola, Cercospora sojina, Cercospora zeae-maydis, Cercosporella capsellae and Cercosporella herpotrichoides, Cladosporium carpophilum, Cladosporium effusum, Passalora fulva, Cladosporium oxysporum, Dothistroma septosporum, Isariopsis clavispora, Mycosphaerella fijiensis, Mycosphaerella graminicola, Mycovellosiella koepkeii, Phaeoisariopsis bataticola, Pseudocercospora vitis, Pseudocercosporella herpotrichoides, Ramularia beticola, Ramularia collo-cygni, Magnaporthales such as Gaeumannomyces graminis, Magnaporthe grisea, Pyricularia oryzae, Diaporthales such as Anisogramma anomala, Apiognomonia errabunda, Cytospora platani, Diaporthe phaseolorum, Discula destructiva, Gnomonia fructicola, Greeneria uvicola, Melanconium juglandinum, Phomopsis viticola, Sirococcus clavigignenti-juglandacearum, Tubakia dryina, Dicarpella spp., Valsa ceratosperma, and others such as Actinothyrium graminis, Ascochyta pisi, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Asperisporium caricae, Blumeriella jaapii, Candida spp., Capnodium ramosum, Cephaloascus spp., Cephalosporium gramineum, Ceratocystis paradoxa, Chaetomium spp., Hymenoscyphus pseudoalbidus, Coccidioides spp., Cylindrosporium padi, Diplocarpon malae, Drepanopeziza campestris, Elsinoe ampelina, Epicoccum nigrum, Epidermophyton spp., Eutypa lata, Geotrichum candidum, Gibellina cerealis, Gloeocercospora sorghi, Gloeodes pomigena, Gloeosporium perennans; Gloeotinia temulenta, Griphospaeria corticola, Kabatiella lini, Leptographium microsporum, Leptosphaerulinia crassiasca, Lophodermium seditiosum, Marssonina graminicola, Microdochium nivale, Monilinia fructicola, Monographella albescens, Monosporascus cannonballus, Naemacyclus spp., Ophiostoma novo-ulmi, Paracoccidioides brasiliensis, Penicillium expansum, Pestalotia rhododendri, Petriellidium spp., Pezicula spp., Phialophora gregata, Phyllachora pomigena, Phymatotrichum omnivora, Physalospora abdita, Plectosporium tabacinum, Polyscytalum pustulans, Pseudopeziza medicaginis, Pyrenopeziza brassicae, Ramulispora sorghi, Rhabdocline pseudotsugae, Rhynchosporium secalis, Sacrocladium oryzae, Scedosporium spp., Schizothyrium pomi, Sclerotinia sclerotiorum, Sclerotinia minor, Sclerotium spp., Typhula ishikariensis, Seimatosporium mariae, Lepteutypa cupressi, Septocyta ruborum, Sphaceloma perseae, Sporonema phacidioides, Stigmina palmivora, Tapesia yallundae, Taphrina bullata, Thielviopsis basicola, Trichoseptoria fructigena, Zygophiala jamaicensis; powdery mildew diseases for example those caused by Erysiphales such as Blumeria graminis, Erysiphe polygoni, Uncinula necator, Sphaerotheca fuligena, Podosphaera leucotricha, Podospaera macularis Golovinomyces cichoracearum, Leveillula taurica, Microsphaera diffusa, Oidiopsis gossypii, Phyllactinia guttata and Oidium arachidis; molds for example those caused by Botryosphaeriales such as Dothiorella aromatica, Diplodia seriata, Guignardia bidwellii, Botrytis cinerea, Botryotinia allii, Botryotinia fabae, Fusicoccum amygdali, Lasiodiplodia theobromae, Macrophoma theicola, Macrophomina phaseolina, Phyllosticta cucurbitacearum; anthracnoses for example those caused by Glommerelales such as Colletotrichum gloeosporioides, Colletotrichum lagenarium, Colletotrichum gossypii, Glomerella cingulata, and Colletotrichum graminicola; and wilts or blights for example those caused by Hypocreales such as Acremonium strictum, Claviceps purpurea, Fusarium culmorum, Fusarium graminearum, Fusarium virguliforme, Fusarium oxysporum, Fusarium subglutinans, Fusarium oxysporum f.sp. cubense, Gerlachia nivale, Gibberella fujikuroi, Gibberella zeae, Gliocladium spp., Myrothecium verrucaria, Nectria ramulariae, Trichoderma viride, Trichothecium roseum, and Verticillium theobromae. 
Basidiomycetes, including smuts for example those caused by Ustilaginales such as Ustilaginoidea virens, Ustilago nuda, Ustilago tritici, Ustilago zeae, rusts for example those caused by Pucciniales such as Cerotelium fici, Chrysomyxa arctostaphyli, Coleosporium ipomoeae, Hemileia vastatrix, Puccinia arachidis, Puccinia cacabata, Puccinia graminis, Puccinia recondita, Puccinia sorghi, Puccinia hordei, Puccinia striiformis f.sp. Hordei, Puccinia striiformis f.sp. Secalis, Pucciniastrum coryli, or Uredinales such as Cronartium ribicola, Gymnosporangium juniperi-viginianae, Melampsora medusae, Phakopsora pachyrhizi, Phragmidium mucronatum, Physopella ampelosidis, Tranzschelia discolor and Uromyces viciae-fabae; and other rots and diseases such as those caused by Cryptococcus spp., Exobasidium vexans, Marasmiellus inoderma, Mycena spp., Sphacelotheca reiliana, Typhula ishikariensis, Urocystis agropyri, Itersonilia perplexans, Corticium invisum, Laetisaria fuciformis, Waitea circinata, Rhizoctonia solani, Thanetephorus cucurmeris, Entyloma dahliae, Entylomella microspora, Neovossia moliniae and Tilletia caries. 
Blastocladiomycetes, such as Physoderma maydis. 
Mucoromycetes, such as Choanephora cucurbitarum; Mucor spp.; Rhizopus arrhizus, 
As well as diseases caused by other species and genera closely related to those listed above.
In addition to their fungicidal activity, the compounds and compositions comprising them may also have activity against bacteria such as Erwinia amylovora, Erwinia caratovora, Xanthomonas campestris, Pseudomonas syringae, Strptomyces scabies and other related species as well as certain protozoa.
Within the scope of present invention, target crops and/or useful plants to be protected typically comprise perennial and annual crops, such as berry plants for example blackberries, blueberries, cranberries, raspberries and strawberries; cereals for example barley, maize (corn), millet, oats, rice, rye, sorghum triticale and wheat; fibre plants for example cotton, flax, hemp, jute and sisal; field crops for example sugar and fodder beet, coffee, hops, mustard, oilseed rape (canola), poppy, sugar cane, sunflower, tea and tobacco; fruit trees for example apple, apricot, avocado, banana, cherry, citrus, nectarine, peach, pear and plum; grasses for example Bermuda grass, bluegrass, bentgrass, centipede grass, fescue, ryegrass, St. Augustine grass and Zoysia grass; herbs such as basil, borage, chives, coriander, lavender, lovage, mint, oregano, parsley, rosemary, sage and thyme; legumes for example beans, lentils, peas and soya beans; nuts for example almond, cashew, ground nut, hazelnut, peanut, pecan, pistachio and walnut; palms for example oil palm; ornamentals for example flowers, shrubs and trees; other trees, for example cacao, coconut, olive and rubber; vegetables for example asparagus, aubergine, broccoli, cabbage, carrot, cucumber, garlic, lettuce, marrow, melon, okra, onion, pepper, potato, pumpkin, rhubarb, spinach and tomato; and vines for example grapes.
The useful plants and/or target crops in accordance with the invention include conventional as well as genetically enhanced or engineered varieties such as, for example, insect resistant (e.g. Bt. and VIP varieties) as well as disease resistant, herbicide tolerant (e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®) and nematode tolerant varieties. By way of example, suitable genetically enhanced or engineered crop varieties include the Stoneville 5599BR cotton and Stoneville 4892BR cotton varieties.
The term “useful plants” and/or “target crops” is to be understood as including also useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as, for example, HPPD inhibitors, ALS inhibitors, for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.
The term “useful plants” and/or “target crops” is to be understood as including those which naturally are or have been rendered resistant to harmful insects. This includes plants transformed by the use of recombinant DNA techniques, for example, to be capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria. Examples of toxins which can be expressed include δ-endotoxins, vegetative insecticidal proteins (Vip), insecticidal proteins of bacteria colonising nematodes, and toxins produced by scorpions, arachnids, wasps and fungi. An example of a crop that has been modified to express the Bacillus thuringiensis toxin is the Bt maize KnockOut® (Syngenta Seeds). An example of a crop comprising more than one gene that codes for insecticidal resistance and thus expresses more than one toxin is VipCot® (Syngenta Seeds). Crops or seed material thereof can also be resistant to multiple types of pests (so-called stacked transgenic events when created by genetic modification). For example, a plant can have the ability to express an insecticidal protein while at the same time being herbicide tolerant, for example Herculex I® (Dow AgroSciences, Pioneer Hi-Bred International).
The term “useful plants” and/or “target crops” is to be understood as including also useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
Toxins that can be expressed by transgenic plants include, for example, insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as δ-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1, Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins and other insect-specific neurotoxins; toxins produced by fungi, such as Streptomycetes toxins, plant lectins, such as pea lectins, barley lectins or snowdrop lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroidoxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such as blockers of sodium or calcium channels, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, bibenzyl synthase, chitinases and glucanases.
Further, in the context of the present invention there are to be understood by δ-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Viol, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3A toxin (see WO03/018810).
More examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-A-0 374 753, WO93/07278, WO95/34656, EP-A-0 427 529, EP-A-451 878 and WO03/052073.
The processes for the preparation of such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above. Cryl-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.
The toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects. Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and butterflies (Lepidoptera).
Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a Cry1Ac toxin); Bollgard I® (cotton variety that expresses a Cry1Ac toxin); Bollgard II® (cotton variety that expresses a Cry1Ac and a Cry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and a Cry1Ab toxin); NewLeaf® (potato variety that expresses a Cry3A toxin); NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.
Further examples of such transgenic crops are:
1. Bt11 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays which has been rendered resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
2. Bt176 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays which has been rendered resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a Cry1Ab toxin. Bt176 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
3. MIR604 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Maize which has been rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3A055 modified by insertion of a cathepsin-G-protease recognition sequence. The preparation of such transgenic maize plants is described in WO 03/018810.
4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.
5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/ES/96/02.
6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-1160 Brussels, Belgium, registration number C/NL/00/10. Genetically modified maize for the expression of the protein Cry1F for achieving resistance to certain Lepidoptera insects and of the PAT protein for achieving tolerance to the herbicide glufosinate ammonium.
7. NK603×MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of conventionally bred hybrid maize varieties by crossing the genetically modified varieties NK603 and MON 810. NK603×MON 810 Maize transgenically expresses the protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a Cry1Ab toxin obtained from Bacillus thuringiensis subsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.
The term “locus” as used herein means fields in or on which plants are growing, or where seeds of cultivated plants are sown, or where seed will be placed into the soil. It includes soil, seeds, and seedlings, as well as established vegetation.
The term “plants” refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage, and fruits.
The term “plant propagation material” is understood to denote generative parts of the plant, such as seeds, which can be used for the multiplication of the latter, and vegetative material, such as cuttings or tubers, for example potatoes. There may be mentioned for example seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes and parts of plants. Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants may be protected before transplantation by a total or partial treatment by immersion. Preferably “plant propagation material” is understood to denote seeds.
Pesticidal agents referred to herein using their common name are known, for example, from “The Pesticide Manual”, 15th Ed., British Crop Protection Council 2009.
The compounds of formula I may be used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they may be conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
Suitable carriers and adjuvants, e.g. for agricultural use, can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.
Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers. The particles contain the active ingredient retained in a solid matrix. Typical solid matrices include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain from 5% to 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.
Emulsifiable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.
Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which treatment is required. Typical carriers for granular formulations include sand, fuller's earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound. Granular formulations normally contain 5% to 25% of active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.
Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers.
Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically 1 to 50 microns in diameter. The enclosed liquid typically constitutes 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound. Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores. Granules typically range from 1 millimeter to 1 centimeter and preferably 1 to 2 millimeters in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust and granular carbon. Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.
Other useful formulations for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurised sprayers, wherein the active ingredient is dispersed in finely-divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.
Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to those skilled in the art.
Liquid carriers that can be employed include, for example, water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethyl formamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol diacetate, glycerol monoacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropyl benzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG400), propionic acid, propylene glycol, propylene glycol monomethyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, methanol, ethanol, isopropanol, and higher molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, etc., ethylene glycol, propylene glycol, glycerine and N-methyl-2-pyrrolidinone. Water is generally the carrier of choice for the dilution of concentrates.
Suitable solid carriers include, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour and lignin.
A broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. These agents, when used, normally comprise from 0.1% to 15% by weight of the formulation. They can be anionic, cationic, non-ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes. Typical surface active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub. 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C.sub. 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.
Other adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants and sticking agents.
In addition, further, other biocidally active ingredients or compositions may be combined with the compositions of the invention and used in the methods of the invention and applied simultaneously or sequentially with the compositions of the invention. When applied simultaneously, these further active ingredients may be formulated together with the compositions of the invention or mixed in, for example, the spray tank. These further biocidally active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.
In addition, the compositions of the invention may also be applied with one or more systemically acquired resistance inducers (“SAR” inducer). SAR inducers are known and described in, for example, U.S. Pat. No. 6,919,298 and include, for example, salicylates and the commercial SAR inducer acibenzolar-S-methyl.
The compounds of formula I are normally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds. These further compounds can be e.g. fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides or non-selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
The compounds of formula I may be used in the form of (fungicidal) compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula I or of at least one preferred individual compound as above-defined, in free form or in agrochemically usable salt form, and at least one of the above-mentioned adjuvants.
The invention therefore provides a composition, preferably a fungicidal composition, comprising at least one compound formula I an agriculturally acceptable carrier and optionally an adjuvant. An agricultural acceptable carrier is for example a carrier that is suitable for agricultural use. Agricultural carriers are well known in the art. Preferably said composition may comprise at least one or more pesticidally active compounds, for example an additional fungicidal active ingredient in addition to the compound of formula I.
The compound of formula (I) may be the sole active ingredient of a composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may, in some cases, result in unexpected synergistic activities.
Examples of suitable additional active ingredients include the following acycloamino acid fungicides, aliphatic nitrogen fungicides, amide fungicides, anilide fungicides, antibiotic fungicides, aromatic fungicides, arsenical fungicides, aryl phenyl ketone fungicides, benzamide fungicides, benzanilide fungicides, benzimidazole fungicides, benzothiazole fungicides, botanical fungicides, bridged diphenyl fungicides, carbamate fungicides, carbanilate fungicides, conazole fungicides, copper fungicides, dicarboximide fungicides, dinitrophenol fungicides, dithiocarbamate fungicides, dithiolane fungicides, furamide fungicides, furanilide fungicides, hydrazide fungicides, imidazole fungicides, mercury fungicides, morpholine fungicides, organophosphorous fungicides, organotin fungicides, oxathiin fungicides, oxazole fungicides, phenylsulfamide fungicides, polysulfide fungicides, pyrazole fungicides, pyridine fungicides, pyrimidine fungicides, pyrrole fungicides, quaternary ammonium fungicides, quinoline fungicides, quinone fungicides, quinoxaline fungicides, strobilurin fungicides, sulfonanilide fungicides, thiadiazole fungicides, thiazole fungicides, thiazolidine fungicides, thiocarbamate fungicides, thiophene fungicides, triazine fungicides, triazole fungicides, triazolopyrimidine fungicides, urea fungicides, valinamide fungicides, and zinc fungicides.
Examples of suitable additional active ingredients also include the following: 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-amide, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (2-dichloromethylene-3-ethyl-1-methyl-indan-4-yl)-amide (1072957-71-1), 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid (4′-methylsulfanyl-biphenyl-2-yl)-amide, 1-methyl-3-difluoromethyl-4H-pyrazole-4-carboxylic acid [2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethyl]amide, (5-Chloro-2,4-dimethyl-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)-methanone, (5-Bromo-4-chloro-2-methoxy-pyridin-3-yl)-(2,3,4-trimethoxy-6-methyl-phenyl)methanone, 2-{2-[(E)-3-(2,6-Dichloro-phenyl)-1-methyl-prop-2-en-(E)-ylideneaminooxymethyl]-phenyl}-2-[(Z)-methoxyimino]-N-methyl-acetamide, 3-[5-(4-Chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine, (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoacetamide, 4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethylbenzimidazole-1-sulphonamide, a-[N-(3-chloro-2, 6-xylyl)-2-methoxyacetamido]-y-butyrolactone, 4-chloro-2-cyano-N,-dimethyl-5-p-tolylimidazole-1-sulfonamide, N-allyl-4,5,-dimethyl-2-trimethylsilylthiophene-3-carboxamide, N-(I-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy) propionamide, N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide, (.+-.)-cis-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)-cycloheptanol, 2-(1-tert-butyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol, 2′,6′-dibromo-2-methyl-4-trifluoromethoxy-4′-trifluoromethyl-1,3-thiazole-5-carboxanilide, 1-imidazolyl-1-(4′-chlorophenoxy)-3,3-dimethylbutan-2-one, methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]3-methoxyacrylate, methyl (E)-2-[2-[6-(2-thioamidophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[6-(2,6-difluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[3-(pyrimidin-2-yloxy)phenoxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[3-(5-methylpyrimidin-2-yloxy)-phenoxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[3-(phenyl-sulphonyloxy)phenoxy]phenyl-3-methoxyacrylate, methyl (E)-2-[2-[3-(4-nitrophenoxy)phenoxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-phenoxyphenyl]-3-methoxyacrylate, methyl (E)-2-[2-(3,5-dimethyl-benzoyl)pyrrol-1-yl]-3-methoxyacrylate, methyl (E)-2-[2-(3-methoxyphenoxy)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(2-phenylethen-1-yl)-phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(3,5-dichlorophenoxy)pyridin-3-yl]-3-methoxyacrylate, methyl (E)-2-(2-(3-(1,1,2,2-tetrafluoroethoxy)phenoxy)phenyl)-3-methoxyacrylate, methyl (E)-2-(2-[3-(alpha-hydroxybenzyl)phenoxy]phenyl)-3-methoxyacrylate, methyl (E)-2-(2-(4-phenoxypyridin-2-yloxy)phenyl)-3-methoxyacrylate, methyl (E)-2-[2-(3-n-propyloxy-phenoxy)phenyl]3-methoxyacrylate, methyl (E)-2-[2-(3-isopropyloxyphenoxy)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[3-(2-fluorophenoxy)phenoxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(3-ethoxyphenoxy)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(4-tert-butyl-pyridin-2-yloxy)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[3-(3-cyanophenoxy)phenoxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[(3-methyl-pyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[6-(2-methyl-phenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(5-bromo-pyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-(3-(3-iodopyridin-2-yloxy)phenoxy)phenyl]-3-methoxyacrylate, methyl (E)-2-[2-[6-(2-chloropyridin-3-yloxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate, methyl (E),(E)-2-[2-(5,6-dimethylpyrazin-2-ylmethyloximinomethyl)phenyl]-3-methoxyacrylate, methyl (E)-2-{2-[6-(6-methylpyridin-2-yloxy)pyrimidin-4-yloxy]phenyl}-3-methoxy-acrylate, methyl (E),(E)-2-{2-(3-methoxyphenyl)methyloximinomethyl]-phenyl}-3-methoxyacrylate, methyl (E)-2-{2-(6-(2-azidophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate, methyl (E),(E)-2-{2-[6-phenylpyrimidin-4-yl)-methyloximinomethyl]phenyl}-3-methoxyacrylate, methyl (E),(E)-2-{2-[(4-chlorophenyl)-methyloximinomethyl]-phenyl}-3-methoxyacrylate, methyl (E)-2-{2-[6-(2-n-propylphenoxy)-1,3,5-triazin-4-yloxy]phenyl}-3-methoxyacrylate, methyl (E),(E)-2-{2-[(3-nitrophenyl)methyloximinomethyl]phenyl}-3-methoxyacrylate, 3-chloro-7-(2-aza-2,7,7-trimethyl-oct-3-en-5-ine), 2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide, 3-iodo-2-propinyl alcohol, 4-chlorophenyl-3-iodopropargyl formal, 3-bromo-2,3-diiodo-2-propenyl ethylcarbamate, 2,3,3-triiodoallyl alcohol, 3-bromo-2,3-diiodo-2-propenyl alcohol, 3-iodo-2-propinyl n-butylcarbamate, 3-iodo-2-propinyl n-hexylcarbamate, 3-iodo-2-propinyl cyclohexyl-carbamate, 3-iodo-2-propinyl phenylcarbamate; phenol derivatives, such as tribromophenol, tetrachlorophenol, 3-methyl-4-chlorophenol, 3,5-dimethyl-4-chlorophenol, phenoxyethanol, dichlorophene, o-phenylphenol, m-phenylphenol, p-phenylphenol, 2-benzyl-4-chlorophenol, 5-hydroxy-2(5H)-furanone; 4,5-dichlorodithiazolinone, 4,5-benzodithiazolinone, 4,5-trimethylenedithiazolinone, 4,5-dichloro-(3H)-1,2-dithiol-3-one, 3,5-dimethyl-tetrahydro-1,3,5-thiadiazine-2-thione, N-(2-p-chlorobenzoylethyl)-hexaminium chloride, acibenzolar, acypetacs, alanycarb, albendazole, aldimorph, allicin, allyl alcohol, ametoctradin, amisulbrom, amobam, ampropylfos, anilazine, asomate, aureofungin, azaconazole, azafendin, azithiram, azoxystrobin, barium polysulfide, benalaxyl, benalaxyl-M, benodanil, benomyl, benquinox, bentaluron, benthiavalicarb, benthiazole, benzalkonium chloride, benzamacril, benzamorf, benzohydroxamic acid, berberine, bethoxazin, biloxazol, binapacryl, biphenyl, bitertanol, bithionol, bixafen, blasticidin-S, boscalid, bromothalonil, bromuconazole, bupirimate, buthiobate, butylamine calcium polysulfide, captafol, captan, carbamorph, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chitosan, chlobenthiazone, chloraniformethan, chloranil, chlorfenazole, chloroneb, chloropicrin, chlorothalonil, chlorozolinate, chlozolinate, climbazole, clotrimazole, clozylacon, copper containing compounds such as copper acetate, copper carbonate, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper oxyquinolate, copper silicate, copper sulphate, copper tallate, copper zinc chromate and Bordeaux mixture, cresol, cufraneb, cuprobam, cuprous oxide, cyazofamid, cyclafuramid, cycloheximide, cyflufenamid, cymoxanil, cypendazole, cyproconazole, cyprodinil, dazomet, debacarb, decafentin, dehydroacetic acid, di-2-pyridyl disulphide 1, 1′-dioxide, dichlofluanid, diclomezine, dichlone, dicloran, dichlorophen, dichlozoline, diclobutrazol, diclocymet, diethofencarb, difenoconazole, difenzoquat, diflumetorim, O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetachlone, dimetconazole, dimethomorph, dimethirimol, diniconazole, diniconazole-M, dinobuton, dinocap, dinocton, dinopenton, dinosulfon, dinoterbon, diphenylamine, dipyrithione, disulfiram, ditalimfos, dithianon, dithioether, dodecyl dimethyl ammonium chloride, dodemorph, dodicin, dodine, doguadine, drazoxolon, edifenphos, enestroburin, epoxiconazole, etaconazole, etem, ethaboxam, ethirimol, ethoxyquin, ethilicin, ethyl (Z)-N-benzyl-N([methyl (methyl-thioethylideneamino-oxycarbonyl) amino]thio)-β-alaninate, etridiazole, famoxadone, fenamidone, fenaminosulf, fenapanil, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenitropan, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fenpyrazamine, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, flupicolide, fluopyram, fluoroimide, fluotrimazole, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutanil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, fosetyl, fuberidazole, furalaxyl, furametpyr, furcarbanil, furconazole, furfural, furmecyclox, furophanate, glyodin, griseofulvin, guazatine, halacrinate, hexa chlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexylthiofos, hydrargaphen, hydroxyisoxazole, hymexazole, imazalil, imazalil sulphate, imibenconazole, iminoctadine, iminoctadine triacetate, inezin, iodocarb, ipconazole, iprobenfos, iprodione, iprovalicarb, isopropanyl butyl carbamate, isoprothiolane, isopyrazam, isotianil, isovaledione, izopamfos, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY248908, mancozeb, mandipropamid, maneb, mebenil, mecarbinzid, mefenoxam, mepanipyrim, mepronil, mercuric chloride, mercurous chloride, meptyldinocap, metalaxyl, metalaxyl-M, metam, metazoxolon, metconazole, methasulfocarb, methfuroxam, methyl bromide, methyl iodide, methyl isothiocyanate, metiram, metiram-zinc, metominostrobin, metrafenone, metsulfovax, milneb, moroxydine, myclobutanil, myclozolin, nabam, natamycin, neoasozin, nickel dimethyldithiocarbamate, nitrostyrene, nitrothal-iso-propyl, nuarimol, octhilinone, ofurace, organomercury compounds, orysastrobin, osthol, oxadixyl, oxasulfuron, oxine-copper, oxolinic acid, oxpoconazole, oxycarboxin, parinol, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, penthiopyrad, phenamacril, phenazin oxide, phosdiphen, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin, piperalin, polycarbamate, polyoxin D, polyoxrim, polyram, probenazole, prochloraz, procymidone, propamidine, propamocarb, propiconazole, propineb, propionic acid, proquinazid, prothiocarb, prothioconazole, pyracarbolid, pyraclostrobin, pyrametrostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyridinitril, pyrifenox, pyrimethanil, pyriofenone, pyroquilon, pyroxychlor, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinacetol, quinazamid, quinconazole, quinomethionate, quinoxyfen, quintozene, rabenzazole, santonin, sedaxane, silthiofam, simeconazole, sipconazole, sodium pentachlorophenate, solatenol, spiroxamine, streptomycin, sulphur, sultropen, tebuconazole, tebfloquin, tecloftalam, tecnazene, tecoram, tetraconazole, thiabendazole, thiadifluor, thicyofen, thifluzamide, 2-(thiocyanomethylthio) benzothiazole, thiophanate-methyl, thioquinox, thiram, tiadinil, timibenconazole, tioxymid, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triamiphos, triarimol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumazole, triforine, triflumizole, triticonazole, uniconazole, urbacide, validamycin, valifenalate, vapam, vinclozolin, zarilamid, zineb, ziram, and zoxamide.
The compounds of the invention may also be used in combination with anthelmintic agents. Such anthelmintic agents include, compounds selected from the macrocyclic lactone class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin derivatives as described in EP-357460, EP-444964 and EP-594291. Additional anthelmintic agents include semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those described in U.S. Pat. No. 5,015,630, WO-9415944 and WO-9522552. Additional anthelmintic agents include the benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of the class. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole, levamisole, pyrantel pamoate, oxantel or morantel. Additional anthelmintic agents include flukicides, such as triclabendazole and clorsulon and the cestocides, such as praziquantel and epsiprantel.
The compounds of the invention may be used in combination with derivatives and analogues of the paraherquamide/marcfortine class of anthelmintic agents, as well as the antiparasitic oxazolines such as those disclosed in U.S. Pat. No. 5,478,855, U.S. Pat. No. 4,639,771 and DE-19520936.
The compounds of the invention may be used in combination with derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as described in WO-9615121 and also with anthelmintic active cyclic depsipeptides such as those described in WO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334, EP-382173, and EP-503538.
The compounds of the invention may be used in combination with other ectoparasiticides; for example, fipronil; pyrethroids; organophosphates; insect growth regulators such as lufenuron; ecdysone agonists such as tebufenozide and the like; neonicotinoids such as imidacloprid and the like.
The compounds of the invention may be used in combination with terpene alkaloids, for example those described in International Patent Application Publication Numbers WO95/19363 or WO04/72086, particularly the compounds disclosed therein.
Other examples of such biologically active compounds that the compounds of the invention may be used in combination with include but are not restricted to the following:
Organophosphates: acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, bromophos, bromophos-ethyl, cadusafos, chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton, demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate, isoxathion, malathion, methacriphos, methamidophos, methidathion, methyl-parathion, mevinphos, monocrotophos, naled, omethoate, oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate, phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate, phoxim, pirimiphos, pirimiphos-methyl, profenofos, propaphos, proetamphos, prothiofos, pyraclofos, pyridapenthion, quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thimeton, triazophos, trichlorfon, vamidothion.
Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate, benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb, ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801, isoprocarb, indoxacarb, methiocarb, methomyl, 5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, UC-51717.
Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, beta-cyfluthrin, cyfluthrin, a-cypermethrin, beta-cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin, lambda-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin, theta-cypermethrin, silafluofen, t-fluvalinate, tefluthrin, tralomethrin, Zeta-cypermethrin.
Arthropod growth regulators: a) chitin synthesis inhibitors: benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide, tebufenozide; c) juvenoids: pyriproxyfen, methoprene (including S-methoprene), fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.
Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl, bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin, dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196, neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen, NC-1111, R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601, silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon, tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301.
Biological agents: Bacillus thuringiensis ssp aizawai, kurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenic bacteria, virus and fungi.
Bactericides: chlortetracycline, oxytetracycline, streptomycin.
Other biological agents: enrofloxacin, febantel, penethamate, moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin, ceftiour, carprofen, metaflumizone, praziquarantel, triclabendazole.
The following mixtures of the compounds of formula I with active ingredients are preferred (the abbreviation “TX” means “one compound selected from the group consisting of the compounds described in Tables A1 to A27, B1 to B10, and C1 to C12 (above) of the present invention”):
an adjuvant selected from the group of substances consisting of petroleum oils (alternative name) (628)+TX,
an acaricide selected from the group of substances consisting of 1,1-bis(4-chloro-phenyl)-2-ethoxyethanol (IUPAC name) (910)+TX, 2,4-dichlorophenyl benzenesulfonate (IUPAC/Chemical Abstracts name) (1059)+TX, 2-fluoro-N-methyl-N-1-naphthylacetamide (IUPAC name) (1295)+TX, 4-chlorophenyl phenyl sulfone (IUPAC name) (981)+TX, abamectin (1)+TX, acequinocyl (3)+TX, acetoprole [CCN]+TX, acrinathrin (9)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, alpha-cypermethrin (202)+TX, amidithion (870)+TX, amidoflumet [CCN]+TX, amidothioate (872)+TX, amiton (875)+TX, amiton hydrogen oxalate (875)+TX, amitraz (24)+TX, aramite (881)+TX, arsenous oxide (882)+TX, AVI 382 (compound code)+TX, AZ 60541 (compound code)+TX, azinphos-ethyl (44)+TX, azinphos-methyl (45)+TX, azobenzene (IUPAC name) (888)+TX, azocyclotin (46)+TX, azothoate (889)+TX, benomyl (62)+TX, benoxafos (alternative name) [CCN]+TX, benzoximate (71)+TX, benzyl benzoate (IUPAC name) [CCN]+TX, bifenazate (74)+TX, bifenthrin (76)+TX, binapacryl (907)+TX, brofenvalerate (alternative name)+TX, bromocyclen (918)+TX, bromophos (920)+TX, bromophos-ethyl (921)+TX, bromopropylate (94)+TX, buprofezin (99)+TX, butocarboxim (103)+TX, butoxycarboxim (104)+TX, butylpyridaben (alternative name)+TX, calcium polysulfide (IUPAC name) (111)+TX, camphechlor (941)+TX, carbanolate (943)+TX, carbaryl (115)+TX, carbofuran (118)+TX, carbophenothion (947)+TX, CGA 50′439 (development code) (125)+TX, chinomethionat (126)+TX, chlorbenside (959)+TX, chlordimeform (964)+TX, chlordimeform hydrochloride (964)+TX, chlorfenapyr (130)+TX, chlorfenethol (968)+TX, chlorfenson (970)+TX, chlorfensulfide (971)+TX, chlorfenvinphos (131)+TX, chlorobenzilate (975)+TX, chloromebuform (977)+TX, chloromethiuron (978)+TX, chloropropylate (983)+TX, chlorpyrifos (145)+TX, chlorpyrifos-methyl (146)+TX, chlorthiophos (994)+TX, cinerin I (696)+TX, cinerin II (696)+TX, cinerins (696)+TX, clofentezine (158)+TX, closantel (alternative name) [CCN]+TX, coumaphos (174)+TX, crotamiton (alternative name) [CCN]+TX, crotoxyphos (1010)+TX, cufraneb (1013)+TX, cyanthoate (1020)+TX, cyflumetofen (CAS Reg. No.: 400882-07-7)+TX, cyhalothrin (196)+TX, cyhexatin (199)+TX, cypermethrin (201)+TX, DCPM (1032)+TX, DDT (219)+TX, demephion (1037)+TX, demephion-O (1037)+TX, demephion-S(1037)+TX, demeton (1038)+TX, demeton-methyl (224)+TX, demeton-O (1038)+TX, demeton-O-methyl (224)+TX, demeton-S (1038)+TX, demeton-S-methyl (224)+TX, demeton-S-methylsulfon (1039)+TX, diafenthiuron (226)+TX, dialifos (1042)+TX, diazinon (227)+TX, dichlofluanid (230)+TX, dichlorvos (236)+TX, dicliphos (alternative name)+TX, dicofol (242)+TX, dicrotophos (243)+TX, dienochlor (1071)+TX, dimefox (1081)+TX, dimethoate (262)+TX, dinactin (alternative name) (653)+TX, dinex (1089)+TX, dinex-diclexine (1089)+TX, dinobuton (269)+TX, dinocap (270)+TX, dinocap-4 [CCN]+TX, dinocap-6 [CCN]+TX, dinocton (1090)+TX, dinopenton (1092)+TX, dinosulfon (1097)+TX, dinoterbon (1098)+TX, dioxathion (1102)+TX, diphenyl sulfone (IUPAC name) (1103)+TX, disulfiram (alternative name) [CCN]+TX, disulfoton (278)+TX, DNOC (282)+TX, dofenapyn (1113)+TX, doramectin (alternative name) [CCN]+TX, endosulfan (294)+TX, endothion (1121)+TX, EPN (297)+TX, eprinomectin (alternative name) [CCN]+TX, ethion (309)+TX, ethoate-methyl (1134)+TX, etoxazole (320)+TX, etrimfos (1142)+TX, fenazaflor (1147)+TX, fenazaquin (328)+TX, fenbutatin oxide (330)+TX, fenothiocarb (337)+TX, fenpropathrin (342)+TX, fenpyrad (alternative name)+TX, fenpyroximate (345)+TX, fenson (1157)+TX, fentrifanil (1161)+TX, fenvalerate (349)+TX, fipronil (354)+TX, fluacrypyrim (360)+TX, fluazuron (1166)+TX, flubenzimine (1167)+TX, flucycloxuron (366)+TX, flucythrinate (367)+TX, fluenetil (1169)+TX, flufenoxuron (370)+TX, flumethrin (372)+TX, fluorbenside (1174)+TX, fluvalinate (1184)+TX, FMC 1137 (development code) (1185)+TX, formetanate (405)+TX, formetanate hydrochloride (405)+TX, formothion (1192)+TX, formparanate (1193)+TX, gamma-HCH (430)+TX, glyodin (1205)+TX, halfenprox (424)+TX, heptenophos (432)+TX, hexadecyl cyclopropanecarboxylate (IUPAC/Chemical Abstracts name) (1216)+TX, hexythiazox (441)+TX, iodomethane (IUPAC name) (542)+TX, isocarbophos (alternative name) (473)+TX, isopropyl O-(methoxyaminothiophosphoryl)salicylate (IUPAC name) (473)+TX, ivermectin (alternative name) [CCN]+TX, jasmolin I (696)+TX, jasmolin II (696)+TX, jodfenphos (1248)+TX, lindane (430)+TX, lufenuron (490)+TX, malathion (492)+TX, malonoben (1254)+TX, mecarbam (502)+TX, mephosfolan (1261)+TX, mesulfen (alternative name) [CCN]+TX, methacrifos (1266)+TX, methamidophos (527)+TX, methidathion (529)+TX, methiocarb (530)+TX, methomyl (531)+TX, methyl bromide (537)+TX, metolcarb (550)+TX, mevinphos (556)+TX, mexacarbate (1290)+TX, milbemectin (557)+TX, milbemycin oxime (alternative name) [CCN]+TX, mipafox (1293)+TX, monocrotophos (561)+TX, morphothion (1300)+TX, moxidectin (alternative name) [CCN]+TX, naled (567)+TX, NC-184 (compound code)+TX, NC-512 (compound code)+TX, nifluridide (1309)+TX, nikkomycins (alternative name) [CCN]+TX, nitrilacarb (1313)+TX, nitrilacarb 1:1 zinc chloride complex (1313)+TX, NNI-0101 (compound code)+TX, NNI-0250 (compound code)+TX, omethoate (594)+TX, oxamyl (602)+TX, oxydeprofos (1324)+TX, oxydisulfoton (1325)+TX, pp′-DDT (219)+TX, parathion (615)+TX, permethrin (626)+TX, petroleum oils (alternative name) (628)+TX, phenkapton (1330)+TX, phenthoate (631)+TX, phorate (636)+TX, phosalone (637)+TX, phosfolan (1338)+TX, phosmet (638)+TX, phosphamidon (639)+TX, phoxim (642)+TX, pirimiphos-methyl (652)+TX, polychloroterpenes (traditional name) (1347)+TX, polynactins (alternative name) (653)+TX, proclonol (1350)+TX, profenofos (662)+TX, promacyl (1354)+TX, propargite (671)+TX, propetamphos (673)+TX, propoxur (678)+TX, prothidathion (1360)+TX, prothoate (1362)+TX, pyrethrin I (696)+TX, pyrethrin II (696)+TX, pyrethrins (696)+TX, pyridaben (699)+TX, pyridaphenthion (701)+TX, pyrimidifen (706)+TX, pyrimitate (1370)+TX, quinalphos (711)+TX, quintiofos (1381)+TX, R-1492 (development code) (1382)+TX, RA-17 (development code) (1383)+TX, rotenone (722)+TX, schradan (1389)+TX, sebufos (alternative name)+TX, selamectin (alternative name) [CCN]+TX, SI-0009 (compound code)+TX, sophamide (1402)+TX, spirodiclofen (738)+TX, spiromesifen (739)+TX, SSI-121 (development code) (1404)+TX, sulfiram (alternative name) [CCN]+TX, sulfluramid (750)+TX, sulfotep (753)+TX, sulfur (754)+TX, SZI-121 (development code) (757)+TX, tau-fluvalinate (398)+TX, tebufenpyrad (763)+TX, TEPP (1417)+TX, terbam (alternative name)+TX, tetrachlorvinphos (777)+TX, tetradifon (786)+TX, tetranactin (alternative name) (653)+TX, tetrasul (1425)+TX, thiafenox (alternative name)+TX, thiocarboxime (1431)+TX, thiofanox (800)+TX, thiometon (801)+TX, thioquinox (1436)+TX, thuringiensin (alternative name) [CCN]+TX, triamiphos (1441)+TX, triarathene (1443)+TX, triazophos (820)+TX, triazuron (alternative name)+TX, trichlorfon (824)+TX, trifenofos (1455)+TX, trinactin (alternative name) (653)+TX, vamidothion (847)+TX, vaniliprole [CCN] and YI-5302 (compound code)+TX,
an algicide selected from the group of substances consisting of bethoxazin [CCN]+TX, copper dioctanoate (IUPAC name) (170)+TX, copper sulfate (172)+TX, cybutryne [CCN]+TX, dichlone (1052)+TX, dichlorophen (232)+TX, endothal (295)+TX, fentin (347)+TX, hydrated lime [CCN]+TX, nabam (566)+TX, quinoclamine (714)+TX, quinonamid (1379)+TX, simazine (730)+TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347)+TX,
an anthelmintic selected from the group of substances consisting of abamectin (1)+TX, crufomate (1011)+TX, doramectin (alternative name) [CCN]+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, eprinomectin (alternative name) [CCN]+TX, ivermectin (alternative name) [CCN]+TX, milbemycin oxime (alternative name) [CCN]+TX, moxidectin (alternative name) [CCN]+TX, piperazine [CCN]+TX, selamectin (alternative name) [CCN]+TX, spinosad (737) and thiophanate (1435)+TX,
an avicide selected from the group of substances consisting of chloralose (127)+TX, endrin (1122)+TX, fenthion (346)+TX, pyridin-4-amine (IUPAC name) (23) and strychnine (745)+TX,
a bactericide selected from the group of substances consisting of 1-hydroxy-1H-pyridine-2-thione (IUPAC name) (1222)+TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748)+TX, 8-hydroxyquinoline sulfate (446)+TX, bronopol (97)+TX, copper dioctanoate (IUPAC name) (170)+TX, copper hydroxide (IUPAC name) (169)+TX, cresol [CCN]+TX, dichlorophen (232)+TX, dipyrithione (1105)+TX, dodicin (1112)+TX, fenaminosulf (1144)+TX, formaldehyde (404)+TX, hydrargaphen (alternative name) [CCN]+TX, kasugamycin (483)+TX, kasugamycin hydrochloride hydrate (483)+TX, nickel bis(dimethyldithiocarbamate) (IUPAC name) (1308)+TX, nitrapyrin (580)+TX, octhilinone (590)+TX, oxolinic acid (606)+TX, oxytetracycline (611)+TX, potassium hydroxyquinoline sulfate (446)+TX, probenazole (658)+TX, streptomycin (744)+TX, streptomycin sesquisulfate (744)+TX, tecloftalam (766)+TX, and thiomersal (alternative name) [CCN]+TX,
a biological agent selected from the group of substances consisting of Adoxophyes orana GV (alternative name) (12)+TX, Agrobacterium radiobacter (alternative name) (13)+TX, Amblyseius spp. (alternative name) (19)+TX, Anagrapha falcifera NPV (alternative name) (28)+TX, Anagrus atomus (alternative name) (29)+TX, Aphelinus abdominalis (alternative name) (33)+TX, Aphidius colemani (alternative name) (34)+TX, Aphidoletes aphidimyza (alternative name) (35)+TX, Autographa californica NPV (alternative name) (38)+TX, Bacillus firmus (alternative name) (48)+TX, Bacillus sphaericus Neide (scientific name) (49)+TX, Bacillus thuringiensis Berliner (scientific name) (51)+TX, Bacillus thuringiensis subsp. aizawai (scientific name) (51)+TX, Bacillus thuringiensis subsp. israelensis (scientific name) (51)+TX, Bacillus thuringiensis subsp. japonensis (scientific name) (51)+TX, Bacillus thuringiensis subsp. kurstaki (scientific name) (51)+TX, Bacillus thuringiensis subsp. tenebrionis (scientific name) (51)+TX, Beauveria bassiana (alternative name) (53)+TX, Beauveria brongniartii (alternative name) (54)+TX, Chrysoperla carnea (alternative name) (151)+TX, Cryptolaemus montrouzieri (alternative name) (178)+TX, Cydia pomonella GV (alternative name) (191)+TX, Dacnusa sibirica (alternative name) (212)+TX, Diglyphus isaea (alternative name) (254)+TX, Encarsia formosa (scientific name) (293)+TX, Eretmocerus eremicus (alternative name) (300)+TX, Helicoverpa zea NPV (alternative name) (431)+TX, Heterorhabditis bacteriophora and H. megidis (alternative name) (433)+TX, Hippodamia convergens (alternative name) (442)+TX, Leptomastix dactylopii (alternative name) (488)+TX, Macrolophus caliginosus (alternative name) (491)+TX, Mamestra brassicae NPV (alternative name) (494)+TX, Metaphycus helvolus (alternative name) (522)+TX, Metarhizium anisopliae var. acridum (scientific name) (523)+TX, Metarhizium anisopliae var. anisopliae (scientific name) (523)+TX, Neodiprion sertifer NPV and N. lecontei NPV (alternative name) (575)+TX, Orius spp. (alternative name) (596)+TX, Paecilomyces fumosoroseus (alternative name) (613)+TX, Phytoseiulus persimilis (alternative name) (644)+TX, Spodoptera exigua multicapsid nuclear polyhedrosis virus (scientific name) (741)+TX, Steinernema bibionis (alternative name) (742)+TX, Steinernema carpocapsae (alternative name) (742)+TX, Steinernema feltiae (alternative name) (742)+TX, Steinernema glaseri (alternative name) (742)+TX, Steinernema riobrave (alternative name) (742)+TX, Steinernema riobravis (alternative name) (742)+TX, Steinernema scapterisci (alternative name) (742)+TX, Steinernema spp. (alternative name) (742)+TX, Trichogramma spp. (alternative name) (826)+TX, Typhlodromus occidentalis (alternative name) (844) and Verticillium lecanii (alternative name) (848)+TX,
a soil sterilant selected from the group of substances consisting of iodomethane (IUPAC name) (542) and methyl bromide (537)+TX,
a chemosterilant selected from the group of substances consisting of apholate [CCN]+TX, bisazir (alternative name) [CCN]+TX, busulfan (alternative name) [CCN]+TX, diflubenzuron (250)+TX, dimatif (alternative name) [CCN]+TX, hemel [CCN]+TX, hempa [CCN]+TX, metepa [CCN]+TX, methiotepa [CCN]+TX, methyl apholate [CCN]+TX, morzid [CCN]+TX, penfluron (alternative name) [CCN]+TX, tepa [CCN]+TX, thiohempa (alternative name) [CCN]+TX, thiotepa (alternative name) [CCN]+TX, tretamine (alternative name) [CCN] and uredepa (alternative name) [CCN]+TX,
an insect pheromone selected from the group of substances consisting of (E)-dec-5-en-1-yl acetate with (E)-dec-5-en-1-ol (IUPAC name) (222)+TX, (E)-tridec-4-en-1-yl acetate (IUPAC name) (829)+TX, (E)-6-methylhept-2-en-4-ol (IUPAC name) (541)+TX, (E,Z)-tetradeca-4,10-dien-1-yl acetate (IUPAC name) (779)+TX, (Z)-dodec-7-en-1-yl acetate (IUPAC name) (285)+TX, (Z)-hexadec-11-enal (IUPAC name) (436)+TX, (Z)-hexadec-11-en-1-yl acetate (IUPAC name) (437)+TX, (Z)-hexadec-13-en-11-yn-1-yl acetate (IUPAC name) (438)+TX, (Z)-icos-13-en-10-one (IUPAC name) (448)+TX, (Z)-tetradec-7-en-1-al (IUPAC name) (782)+TX, (Z)-tetradec-9-en-1-ol (IUPAC name) (783)+TX, (Z)-tetradec-9-en-1-yl acetate (IUPAC name) (784)+TX, (7E,9Z)-dodeca-7,9-dien-1-yl acetate (IUPAC name) (283)+TX, (9Z,11E)-tetradeca-9,11-dien-1-yl acetate (IUPAC name) (780)+TX, (9Z,12E)-tetradeca-9,12-dien-1-yl acetate (IUPAC name) (781)+TX, 14-methyloctadec-1-ene (IUPAC name) (545)+TX, 4-methylnonan-5-ol with 4-methylnonan-5-one (IUPAC name) (544)+TX, alpha-multistriatin (alternative name) [CCN]+TX, brevicomin (alternative name) [CCN]+TX, codlelure (alternative name) [CCN]+TX, codlemone (alternative name) (167)+TX, cuelure (alternative name) (179)+TX, disparlure (277)+TX, dodec-8-en-1-yl acetate (IUPAC name) (286)+TX, dodec-9-en-1-yl acetate (IUPAC name) (287)+TX, dodeca-8+TX, 10-dien-1-yl acetate (IUPAC name) (284)+TX, dominicalure (alternative name) [CCN]+TX, ethyl 4-methyloctanoate (IUPAC name) (317)+TX, eugenol (alternative name) [CCN]+TX, frontalin (alternative name) [CCN]+TX, gossyplure (alternative name) (420)+TX, grandlure (421)+TX, grandlure I (alternative name) (421)+TX, grandlure II (alternative name) (421)+TX, grandlure III (alternative name) (421)+TX, grandlure IV (alternative name) (421)+TX, hexalure [CCN]+TX, ipsdienol (alternative name) [CCN]+TX, ipsenol (alternative name) [CCN]+TX, japonilure (alternative name) (481)+TX, lineatin (alternative name) [CCN]+TX, litlure (alternative name) [CCN]+TX, looplure (alternative name) [CCN]+TX, medlure [CCN]+TX, megatomoic acid (alternative name) [CCN]+TX, methyl eugenol (alternative name) (540)+TX, muscalure (563)+TX, octadeca-2,13-dien-1-yl acetate (IUPAC name) (588)+TX, octadeca-3,13-dien-1-yl acetate (IUPAC name) (589)+TX, orfralure (alternative name) [CCN]+TX, oryctalure (alternative name) (317)+TX, ostramone (alternative name) [CCN]+TX, siglure [CCN]+TX, sordidin (alternative name) (736)+TX, sulcatol (alternative name) [CCN]+TX, tetradec-11-en-1-yl acetate (IUPAC name) (785)+TX, trimedlure (839)+TX, trimedlure A (alternative name) (839)+TX, trimedlure B1 (alternative name) (839)+TX, trimedlure B2 (alternative name) (839)+TX, trimedlure C (alternative name) (839) and trunc-call (alternative name) [CCN]+TX,
an insect repellent selected from the group of substances consisting of 2-(octylthio)-ethanol (IUPAC name) (591)+TX, butopyronoxyl (933)+TX, butoxy(polypropylene glycol) (936)+TX, dibutyl adipate (IUPAC name) (1046)+TX, dibutyl phthalate (1047)+TX, dibutyl succinate (IUPAC name) (1048)+TX, diethyltoluamide [CCN]+TX, dimethyl carbate [CCN]+TX, dimethyl phthalate [CCN]+TX, ethyl hexanediol (1137)+TX, hexamide [CCN]+TX, methoquin-butyl (1276)+TX, methylneodecanamide [CCN]+TX, oxamate [CCN] and picaridin [CCN]+TX,
an insecticide selected from the group of substances consisting of 1-dichloro-1-nitroethane (IUPAC/Chemical Abstracts name) (1058)+TX, 1,1-dichloro-2,2-bis(4-ethylphenyl)ethane (IUPAC name) (1056), +TX, 1,2-dichloropropane (IUPAC/Chemical Abstracts name) (1062)+TX, 1,2-dichloropropane with 1,3-dichloropropene (IUPAC name) (1063)+TX, 1-bromo-2-chloroethane (IUPAC/Chemical Abstracts name) (916)+TX, 2,2,2-trichloro-1-(3,4-dichlorophenyl)ethyl acetate (IUPAC name) (1451)+TX, 2,2-dichlorovinyl 2-ethylsulfinylethyl methyl phosphate (IUPAC name) (1066)+TX, 2-(1,3-dithiolan-2-yl)phenyl dimethylcarbamate (IUPAC/Chemical Abstracts name) (1109)+TX, 2-(2-butoxyethoxy)ethyl thiocyanate (IUPAC/Chemical Abstracts name) (935)+TX, 2-(4,5-dimethyl-1,3-dioxolan-2-yl)phenyl methylcarbamate (IUPAC/Chemical Abstracts name) (1084)+TX, 2-(4-chloro-3,5-xylyloxy)ethanol (IUPAC name) (986)+TX, 2-chlorovinyl diethyl phosphate (IUPAC name) (984)+TX, 2-imidazolidone (IUPAC name) (1225)+TX, 2-isovalerylindan-1,3-dione (IUPAC name) (1246)+TX, 2-methyl(prop-2-ynyl)aminophenyl methylcarbamate (IUPAC name) (1284)+TX, 2-thiocyanatoethyl laurate (IUPAC name) (1433)+TX, 3-bromo-1-chloroprop-1-ene (IUPAC name) (917)+TX, 3-methyl-1-phenylpyrazol-5-yl dimethylcarbamate (IUPAC name) (1283)+TX, 4-methyl(prop-2-ynyl)amino-3,5-xylyl methylcarbamate (IUPAC name) (1285)+TX, 5,5-dimethyl-3-oxocyclohex-1-enyl dimethylcarbamate (IUPAC name) (1085)+TX, abamectin (1)+TX, acephate (2)+TX, acetamiprid (4)+TX, acethion (alternative name) [CCN]+TX, acetoprole [CCN]+TX, acrinathrin (9)+TX, acrylonitrile (IUPAC name) (861)+TX, alanycarb (15)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, aldrin (864)+TX, allethrin (17)+TX, allosamidin (alternative name) [CCN]+TX, allyxycarb (866)+TX, alpha-cypermethrin (202)+TX, alpha-ecdysone (alternative name) [CCN]+TX, aluminium phosphide (640)+TX, amidithion (870)+TX, amidothioate (872)+TX, aminocarb (873)+TX, amiton (875)+TX, amiton hydrogen oxalate (875)+TX, amitraz (24)+TX, anabasine (877)+TX, athidathion (883)+TX, AVI 382 (compound code)+TX, AZ 60541 (compound code)+TX, azadirachtin (alternative name) (41)+TX, azamethiphos (42)+TX, azinphos-ethyl (44)+TX, azinphos-methyl (45)+TX, azothoate (889)+TX, Bacillus thuringiensis delta endotoxins (alternative name) (52)+TX, barium hexafluorosilicate (alternative name) [CCN]+TX, barium polysulfide (IUPAC/Chemical Abstracts name) (892)+TX, barthrin [CCN]+TX, Bayer 22/190 (development code) (893)+TX, Bayer 22408 (development code) (894)+TX, bendiocarb (58)+TX, benfuracarb (60)+TX, bensultap (66)+TX, beta-cyfluthrin (194)+TX, beta-cypermethrin (203)+TX, bifenthrin (76)+TX, bioallethrin (78)+TX, bioallethrin S-cyclopentenyl isomer (alternative name) (79)+TX, bioethanomethrin [CCN]+TX, biopermethrin (908)+TX, bioresmethrin (80)+TX, bis(2-chloroethyl) ether (IUPAC name) (909)+TX, bistrifluron (83)+TX, borax (86)+TX, brofenvalerate (alternative name)+TX, bromfenvinfos (914)+TX, bromocyclen (918)+TX, bromo-DDT (alternative name) [CCN]+TX, bromophos (920)+TX, bromophos-ethyl (921)+TX, bufencarb (924)+TX, buprofezin (99)+TX, butacarb (926)+TX, butathiofos (927)+TX, butocarboxim (103)+TX, butonate (932)+TX, butoxycarboxim (104)+TX, butylpyridaben (alternative name)+TX, cadusafos (109)+TX, calcium arsenate [CCN]+TX, calcium cyanide (444)+TX, calcium polysulfide (IUPAC name) (111)+TX, camphechlor (941)+TX, carbanolate (943)+TX, carbaryl (115)+TX, carbofuran (118)+TX, carbon disulfide (IUPAC/Chemical Abstracts name) (945)+TX, carbon tetrachloride (IUPAC name) (946)+TX, carbophenothion (947)+TX, carbosulfan (119)+TX, cartap (123)+TX, cartap hydrochloride (123)+TX, cevadine (alternative name) (725)+TX, chlorbicyclen (960)+TX, chlordane (128)+TX, chlordecone (963)+TX, chlordimeform (964)+TX, chlordimeform hydrochloride (964)+TX, chlorethoxyfos (129)+TX, chlorfenapyr (130)+TX, chlorfenvinphos (131)+TX, chlorfluazuron (132)+TX, chlormephos (136)+TX, chloroform [CCN]+TX, chloropicrin (141)+TX, chlorphoxim (989)+TX, chlorprazophos (990)+TX, chlorpyrifos (145)+TX, chlorpyrifos-methyl (146)+TX, chlorthiophos (994)+TX, chromafenozide (150)+TX, cinerin I (696)+TX, cinerin II (696)+TX, cinerins (696)+TX, cis-resmethrin (alternative name)+TX, cismethrin (80)+TX, clocythrin (alternative name)+TX, cloethocarb (999)+TX, closantel (alternative name) [CCN]+TX, clothianidin (165)+TX, copper acetoarsenite [CCN]+TX, copper arsenate [CCN]+TX, copper oleate [CCN]+TX, coumaphos (174)+TX, coumithoate (1006)+TX, crotamiton (alternative name) [CCN]+TX, crotoxyphos (1010)+TX, crufomate (1011)+TX, cryolite (alternative name) (177)+TX, CS 708 (development code) (1012)+TX, cyanofenphos (1019)+TX, cyanophos (184)+TX, cyanthoate (1020)+TX, cyclethrin [CCN]+TX, cycloprothrin (188)+TX, cyfluthrin (193)+TX, cyhalothrin (196)+TX, cypermethrin (201)+TX, cyphenothrin (206)+TX, cyromazine (209)+TX, cythioate (alternative name) [CCN]+TX, d-limonene (alternative name) [CCN]+TX, d-tetramethrin (alternative name) (788)+TX, DAEP (1031)+TX, dazomet (216)+TX, DDT (219)+TX, decarbofuran (1034)+TX, deltamethrin (223)+TX, demephion (1037)+TX, demephion-O (1037)+TX, demephion-S(1037)+TX, demeton (1038)+TX, demeton-methyl (224)+TX, demeton-O (1038)+TX, demeton-O-methyl (224)+TX, demeton-S(1038)+TX, demeton-S-methyl (224)+TX, demeton-S-methylsulphon (1039)+TX, diafenthiuron (226)+TX, dialifos (1042)+TX, diamidafos (1044)+TX, diazinon (227)+TX, dicapthon (1050)+TX, dichlofenthion (1051)+TX, dichlorvos (236)+TX, dicliphos (alternative name)+TX, dicresyl (alternative name) [CCN]+TX, dicrotophos (243)+TX, dicyclanil (244)+TX, dieldrin (1070)+TX, diethyl 5-methylpyrazol-3-yl phosphate (IUPAC name) (1076)+TX, diflubenzuron (250)+TX, dilor (alternative name) [CCN]+TX, dimefluthrin [CCN]+TX, dimefox (1081)+TX, dimetan (1085)+TX, dimethoate (262)+TX, dimethrin (1083)+TX, dimethylvinphos (265)+TX, dimetilan (1086)+TX, dinex (1089)+TX, dinex-diclexine (1089)+TX, dinoprop (1093)+TX, dinosam (1094)+TX, dinoseb (1095)+TX, dinotefuran (271)+TX, diofenolan (1099)+TX, dioxabenzofos (1100)+TX, dioxacarb (1101)+TX, dioxathion (1102)+TX, disulfoton (278)+TX, dithicrofos (1108)+TX, DNOC (282)+TX, doramectin (alternative name) [CCN]+TX, DSP (1115)+TX, ecdysterone (alternative name) [CCN]+TX, El 1642 (development code) (1118)+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, EMPC (1120)+TX, empenthrin (292)+TX, endosulfan (294)+TX, endothion (1121)+TX, endrin (1122)+TX, EPBP (1123)+TX, EPN (297)+TX, epofenonane (1124)+TX, eprinomectin (alternative name) [CCN]+TX, esfenvalerate (302)+TX, etaphos (alternative name) [CCN]+TX, ethiofencarb (308)+TX, ethion (309)+TX, ethiprole (310)+TX, ethoate-methyl (1134)+TX, ethoprophos (312)+TX, ethyl formate (IUPAC name) [CCN]+TX, ethyl-DDD (alternative name) (1056)+TX, ethylene dibromide (316)+TX, ethylene dichloride (chemical name) (1136)+TX, ethylene oxide [CCN]+TX, etofenprox (319)+TX, etrimfos (1142)+TX, EXD (1143)+TX, famphur (323)+TX, fenamiphos (326)+TX, fenazaflor (1147)+TX, fenchlorphos (1148)+TX, fenethacarb (1149)+TX, fenfluthrin (1150)+TX, fenitrothion (335)+TX, fenobucarb (336)+TX, fenoxacrim (1153)+TX, fenoxycarb (340)+TX, fenpirithrin (1155)+TX, fenpropathrin (342)+TX, fenpyrad (alternative name)+TX, fensulfothion (1158)+TX, fenthion (346)+TX, fenthion-ethyl [CCN]+TX, fenvalerate (349)+TX, fipronil (354)+TX, flonicamid (358)+TX, flubendiamide (CAS. Reg. No.: 272451-65-7)+TX, flucofuron (1168)+TX, flucycloxuron (366)+TX, flucythrinate (367)+TX, fluenetil (1169)+TX, flufenerim [CCN]+TX, flufenoxuron (370)+TX, flufenprox (1171)+TX, flumethrin (372)+TX, fluvalinate (1184)+TX, FMC 1137 (development code) (1185)+TX, fonofos (1191)+TX, formetanate (405)+TX, formetanate hydrochloride (405)+TX, formothion (1192)+TX, formparanate (1193)+TX, fosmethilan (1194)+TX, fospirate (1195)+TX, fosthiazate (408)+TX, fosthietan (1196)+TX, furathiocarb (412)+TX, furethrin (1200)+TX, gamma-cyhalothrin (197)+TX, gamma-HCH (430)+TX, guazatine (422)+TX, guazatine acetates (422)+TX, GY-81 (development code) (423)+TX, halfenprox (424)+TX, halofenozide (425)+TX, HCH (430)+TX, HEOD (1070)+TX, heptachlor (1211)+TX, heptenophos (432)+TX, heterophos [CCN]+TX, hexaflumuron (439)+TX, HHDN (864)+TX, hydramethylnon (443)+TX, hydrogen cyanide (444)+TX, hydroprene (445)+TX, hyquincarb (1223)+TX, imidacloprid (458)+TX, imiprothrin (460)+TX, indoxacarb (465)+TX, iodomethane (IUPAC name) (542)+TX, IPSP (1229)+TX, isazofos (1231)+TX, isobenzan (1232)+TX, isocarbophos (alternative name) (473)+TX, isodrin (1235)+TX, isofenphos (1236)+TX, isolane (1237)+TX, isoprocarb (472)+TX, isopropyl O-(methoxy-aminothiophosphoryl)salicylate (IUPAC name) (473)+TX, isoprothiolane (474)+TX, isothioate (1244)+TX, isoxathion (480)+TX, ivermectin (alternative name) [CCN]+TX, jasmolin I (696)+TX, jasmolin II (696)+TX, jodfenphos (1248)+TX, juvenile hormone I (alternative name) [CCN]+TX, juvenile hormone II (alternative name) [CCN]+TX, juvenile hormone III (alternative name) [CCN]+TX, kelevan (1249)+TX, kinoprene (484)+TX, lambda-cyhalothrin (198)+TX, lead arsenate [CCN]+TX, lepimectin (CCN)+TX, leptophos (1250)+TX, lindane (430)+TX, lirimfos (1251)+TX, lufenuron (490)+TX, lythidathion (1253)+TX, m-cumenyl methylcarbamate (IUPAC name) (1014)+TX, magnesium phosphide (IUPAC name) (640)+TX, malathion (492)+TX, malonoben (1254)+TX, mazidox (1255)+TX, mecarbam (502)+TX, mecarphon (1258)+TX, menazon (1260)+TX, mephosfolan (1261)+TX, mercurous chloride (513)+TX, mesulfenfos (1263)+TX, metaflumizone (CCN)+TX, metam (519)+TX, metam-potassium (alternative name) (519)+TX, metam-sodium (519)+TX, methacrifos (1266)+TX, methamidophos (527)+TX, methanesulfonyl fluoride (IUPAC/Chemical Abstracts name) (1268)+TX, methidathion (529)+TX, methiocarb (530)+TX, methocrotophos (1273)+TX, methomyl (531)+TX, methoprene (532)+TX, methoquin-butyl (1276)+TX, methothrin (alternative name) (533)+TX, methoxychlor (534)+TX, methoxyfenozide (535)+TX, methyl bromide (537)+TX, methyl isothiocyanate (543)+TX, methylchloroform (alternative name) [CCN]+TX, methylene chloride [CCN]+TX, metofluthrin [CCN]+TX, metolcarb (550)+TX, metoxadiazone (1288)+TX, mevinphos (556)+TX, mexacarbate (1290)+TX, milbemectin (557)+TX, milbemycin oxime (alternative name) [CCN]+TX, mipafox (1293)+TX, mirex (1294)+TX, monocrotophos (561)+TX, morphothion (1300)+TX, moxidectin (alternative name) [CCN]+TX, naftalofos (alternative name) [CCN]+TX, naled (567)+TX, naphthalene (IUPAC/Chemical Abstracts name) (1303)+TX, NC-170 (development code) (1306)+TX, NC-184 (compound code)+TX, nicotine (578)+TX, nicotine sulfate (578)+TX, nifluridide (1309)+TX, nitenpyram (579)+TX, nithiazine (1311)+TX, nitrilacarb (1313)+TX, nitrilacarb 1:1 zinc chloride complex (1313)+TX, NNI-0101 (compound code)+TX, NNI-0250 (compound code)+TX, nornicotine (traditional name) (1319)+TX, novaluron (585)+TX, noviflumuron (586)+TX, O-5-dichloro-4-iodophenyl O-ethyl ethylphosphonothioate (IUPAC name) (1057)+TX, O,O-diethyl O-4-methyl-2-oxo-2H-chromen-7-yl phosphorothioate (IUPAC name) (1074)+TX, O,O-diethyl O-6-methyl-2-propylpyrimidin-4-yl phosphorothioate (IUPAC name) (1075)+TX, O,O,O′,O′-tetrapropyl dithiopyrophosphate (IUPAC name) (1424)+TX, oleic acid (IUPAC name) (593)+TX, omethoate (594)+TX, oxamyl (602)+TX, oxydemeton-methyl (609)+TX, oxydeprofos (1324)+TX, oxydisulfoton (1325)+TX, pp′-DDT (219)+TX, para-dichlorobenzene [CCN]+TX, parathion (615)+TX, parathion-methyl (616)+TX, penfluron (alternative name) [CCN]+TX, pentachlorophenol (623)+TX, pentachlorophenyl laurate (IUPAC name) (623)+TX, permethrin (626)+TX, petroleum oils (alternative name) (628)+TX, PH 60-38 (development code) (1328)+TX, phenkapton (1330)+TX, phenothrin (630)+TX, phenthoate (631)+TX, phorate (636)+TX, phosalone (637)+TX, phosfolan (1338)+TX, phosmet (638)+TX, phosnichlor (1339)+TX, phosphamidon (639)+TX, phosphine (IUPAC name) (640)+TX, phoxim (642)+TX, phoxim-methyl (1340)+TX, pirimetaphos (1344)+TX, pirimicarb (651)+TX, pirimiphos-ethyl (1345)+TX, pirimiphos-methyl (652)+TX, polychlorodicyclopentadiene isomers (IUPAC name) (1346)+TX, polychloroterpenes (traditional name) (1347)+TX, potassium arsenite [CCN]+TX, potassium thiocyanate [CCN]+TX, prallethrin (655)+TX, precocene I (alternative name) [CCN]+TX, precocene II (alternative name) [CCN]+TX, precocene III (alternative name) [CCN]+TX, primidophos (1349)+TX, profenofos (662)+TX, profluthrin [CCN]+TX, promacyl (1354)+TX, promecarb (1355)+TX, propaphos (1356)+TX, propetamphos (673)+TX, propoxur (678)+TX, prothidathion (1360)+TX, prothiofos (686)+TX, prothoate (1362)+TX, protrifenbute [CCN]+TX, pymetrozine (688)+TX, pyraclofos (689)+TX, pyrazophos (693)+TX, pyresmethrin (1367)+TX, pyrethrin I (696)+TX, pyrethrin II (696)+TX, pyrethrins (696)+TX, pyridaben (699)+TX, pyridalyl (700)+TX, pyridaphenthion (701)+TX, pyrimidifen (706)+TX, pyrimitate (1370)+TX, pyriproxyfen (708)+TX, quassia (alternative name) [CCN]+TX, quinalphos (711)+TX, quinalphos-methyl (1376)+TX, quinothion (1380)+TX, quintiofos (1381)+TX, R-1492 (development code) (1382)+TX, rafoxanide (alternative name) [CCN]+TX, resmethrin (719)+TX, rotenone (722)+TX, RU 15525 (development code) (723)+TX, RU 25475 (development code) (1386)+TX, ryania (alternative name) (1387)+TX, ryanodine (traditional name) (1387)+TX, sabadilla (alternative name) (725)+TX, schradan (1389)+TX, sebufos (alternative name)+TX, selamectin (alternative name) [CCN]+TX, SI-0009 (compound code)+TX, SI-0205 (compound code)+TX, SI-0404 (compound code)+TX, SI-0405 (compound code)+TX, silafluofen (728)+TX, SN 72129 (development code) (1397)+TX, sodium arsenite [CCN]+TX, sodium cyanide (444)+TX, sodium fluoride (IUPAC/Chemical Abstracts name) (1399)+TX, sodium hexafluorosilicate (1400)+TX, sodium pentachlorophenoxide (623)+TX, sodium selenate (IUPAC name) (1401)+TX, sodium thiocyanate [CCN]+TX, sophamide (1402)+TX, spinosad (737)+TX, spiromesifen (739)+TX, spirotetrmat (CCN)+TX, sulcofuron (746)+TX, sulcofuron-sodium (746)+TX, sulfluramid (750)+TX, sulfotep (753)+TX, sulfuryl fluoride (756)+TX, sulprofos (1408)+TX, tar oils (alternative name) (758)+TX, tau-fluvalinate (398)+TX, tazimcarb (1412)+TX, TDE (1414)+TX, tebufenozide (762)+TX, tebufenpyrad (763)+TX, tebupirimfos (764)+TX, teflubenzuron (768)+TX, tefluthrin (769)+TX, temephos (770)+TX, TEPP (1417)+TX, terallethrin (1418)+TX, terbam (alternative name)+TX, terbufos (773)+TX, tetrachloroethane [CCN]+TX, tetrachlorvinphos (777)+TX, tetramethrin (787)+TX, theta-cypermethrin (204)+TX, thiacloprid (791)+TX, thiafenox (alternative name)+TX, thiamethoxam (792)+TX, thicrofos (1428)+TX, thiocarboxime (1431)+TX, thiocyclam (798)+TX, thiocyclam hydrogen oxalate (798)+TX, thiodicarb (799)+TX, thiofanox (800)+TX, thiometon (801)+TX, thionazin (1434)+TX, thiosultap (803)+TX, thiosultap-sodium (803)+TX, thuringiensin (alternative name) [CCN]+TX, tolfenpyrad (809)+TX, tralomethrin (812)+TX, transfluthrin (813)+TX, transpermethrin (1440)+TX, triamiphos (1441)+TX, triazamate (818)+TX, triazophos (820)+TX, triazuron (alternative name)+TX, trichlorfon (824)+TX, trichlormetaphos-3 (alternative name) [CCN]+TX, trichloronat (1452)+TX, trifenofos (1455)+TX, triflumuron (835)+TX, trimethacarb (840)+TX, triprene (1459)+TX, vamidothion (847)+TX, vaniliprole [CCN]+TX, veratridine (alternative name) (725)+TX, veratrine (alternative name) (725)+TX, XMC (853)+TX, xylylcarb (854)+TX, YI-5302 (compound code)+TX, zeta-cypermethrin (205)+TX, zetamethrin (alternative name)+TX, zinc phosphide (640)+TX, zolaprofos (1469) and ZXI 8901 (development code) (858)+TX, cyantraniliprole [736994-63-19+TX, chlorantraniliprole [500008-45-7]+TX, cyenopyrafen [560121-52-0]+TX, cyflumetofen [400882-07-7]+TX, pyrifluquinazon [337458-27-2]+TX, spinetoram [187166-40-1+187166-15-0]+TX, spirotetramat [203313-25-1]+TX, sulfoxaflor [946578-00-3]+TX, flufiprole [704886-18-0]+TX, meperfluthrin [915288-13-0]+TX, tetramethylfluthrin [84937-88-2]+TX, triflumezopyrim (disclosed in WO 2012/092115)+TX,
a molluscicide selected from the group of substances consisting of bis(tributyltin) oxide (IUPAC name) (913)+TX, bromoacetamide [CCN]+TX, calcium arsenate [CCN]+TX, cloethocarb (999)+TX, copper acetoarsenite [CCN]+TX, copper sulfate (172)+TX, fentin (347)+TX, ferric phosphate (IUPAC name) (352)+TX, metaldehyde (518)+TX, methiocarb (530)+TX, niclosamide (576)+TX, niclosamide-olamine (576)+TX, pentachlorophenol (623)+TX, sodium pentachlorophenoxide (623)+TX, tazimcarb (1412)+TX, thiodicarb (799)+TX, tributyltin oxide (913)+TX, trifenmorph (1454)+TX, trimethacarb (840)+TX, triphenyltin acetate (IUPAC name) (347) and triphenyltin hydroxide (IUPAC name) (347)+TX, pyriprole [394730-71-3]+TX,
a nematicide selected from the group of substances consisting of AKD-3088 (compound code)+TX, 1,2-dibromo-3-chloropropane (IUPAC/Chemical Abstracts name) (1045)+TX, 1,2-dichloropropane (IUPAC/Chemical Abstracts name) (1062)+TX, 1,2-dichloropropane with 1,3-dichloropropene (IUPAC name) (1063)+TX, 1,3-dichloropropene (233)+TX, 3,4-dichlorotetrahydrothiophene 1,1-dioxide (IUPAC/Chemical Abstracts name) (1065)+TX, 3-(4-chlorophenyl)-5-methylrhodanine (IUPAC name) (980)+TX, 5-methyl-6-thioxo-1,3,5-thiadiazinan-3-ylacetic acid (IUPAC name) (1286)+TX, 6-isopentenylaminopurine (alternative name) (210)+TX, abamectin (1)+TX, acetoprole [CCN]+TX, alanycarb (15)+TX, aldicarb (16)+TX, aldoxycarb (863)+TX, AZ 60541 (compound code)+TX, benclothiaz [CCN]+TX, benomyl (62)+TX, butylpyridaben (alternative name)+TX, cadusafos (109)+TX, carbofuran (118)+TX, carbon disulfide (945)+TX, carbosulfan (119)+TX, chloropicrin (141)+TX, chlorpyrifos (145)+TX, cloethocarb (999)+TX, cytokinins (alternative name) (210)+TX, dazomet (216)+TX, DBCP (1045)+TX, DCIP (218)+TX, diamidafos (1044)+TX, dichlofenthion (1051)+TX, dicliphos (alternative name)+TX, dimethoate (262)+TX, doramectin (alternative name) [CCN]+TX, emamectin (291)+TX, emamectin benzoate (291)+TX, eprinomectin (alternative name) [CCN]+TX, ethoprophos (312)+TX, ethylene dibromide (316)+TX, fenamiphos (326)+TX, fenpyrad (alternative name)+TX, fensulfothion (1158)+TX, fosthiazate (408)+TX, fosthietan (1196)+TX, furfural (alternative name) [CCN]+TX, GY-81 (development code) (423)+TX, heterophos [CCN]+TX, iodomethane (IUPAC name) (542)+TX, isamidofos (1230)+TX, isazofos (1231)+TX, ivermectin (alternative name) [CCN]+TX, kinetin (alternative name) (210)+TX, mecarphon (1258)+TX, metam (519)+TX, metam-potassium (alternative name) (519)+TX, metam-sodium (519)+TX, methyl bromide (537)+TX, methyl isothiocyanate (543)+TX, milbemycin oxime (alternative name) [CCN]+TX, moxidectin (alternative name) [CCN]+TX, Myrothecium verrucaria composition (alternative name) (565)+TX, NC-184 (compound code)+TX, oxamyl (602)+TX, phorate (636)+TX, phosphamidon (639)+TX, phosphocarb [CCN]+TX, sebufos (alternative name)+TX, selamectin (alternative name) [CCN]+TX, spinosad (737)+TX, terbam (alternative name)+TX, terbufos (773)+TX, tetrachlorothiophene (IUPAC/Chemical Abstracts name) (1422)+TX, thiafenox (alternative name)+TX, thionazin (1434)+TX, triazophos (820)+TX, triazuron (alternative name)+TX, xylenols [CCN]+TX, YI-5302 (compound code) and zeatin (alternative name) (210)+TX, fluensulfone [318290-98-1]+TX,
a nitrification inhibitor selected from the group of substances consisting of potassium ethylxanthate [CCN] and nitrapyrin (580)+TX,
a plant activator selected from the group of substances consisting of acibenzolar (6)+TX, acibenzolar-S-methyl (6)+TX, probenazole (658) and Reynoutria sachalinensis extract (alternative name) (720)+TX,
a rodenticide selected from the group of substances consisting of 2-isovalerylindan-1,3-dione (IUPAC name) (1246)+TX, 4-(quinoxalin-2-ylamino)benzenesulfonamide (IUPAC name) (748)+TX, alpha-chlorohydrin [CCN]+TX, aluminium phosphide (640)+TX, antu (880)+TX, arsenous oxide (882)+TX, barium carbonate (891)+TX, bisthiosemi (912)+TX, brodifacoum (89)+TX, bromadiolone (91)+TX, bromethalin (92)+TX, calcium cyanide (444)+TX, chloralose (127)+TX, chlorophacinone (140)+TX, cholecalciferol (alternative name) (850)+TX, coumachlor (1004)+TX, coumafuryl (1005)+TX, coumatetralyl (175)+TX, crimidine (1009)+TX, difenacoum (246)+TX, difethialone (249)+TX, diphacinone (273)+TX, ergocalciferol (301)+TX, flocoumafen (357)+TX, fluoroacetamide (379)+TX, flupropadine (1183)+TX, flupropadine hydrochloride (1183)+TX, gamma-HCH (430)+TX, HCH (430)+TX, hydrogen cyanide (444)+TX, iodomethane (IUPAC name) (542)+TX, lindane (430)+TX, magnesium phosphide (IUPAC name) (640)+TX, methyl bromide (537)+TX, norbormide (1318)+TX, phosacetim (1336)+TX, phosphine (IUPAC name) (640)+TX, phosphorus [CCN]+TX, pindone (1341)+TX, potassium arsenite [CCN]+TX, pyrinuron (1371)+TX, scilliroside (1390)+TX, sodium arsenite [CCN]+TX, sodium cyanide (444)+TX, sodium fluoroacetate (735)+TX, strychnine (745)+TX, thallium sulfate [CCN]+TX, warfarin (851) and zinc phosphide (640)+TX,
a synergist selected from the group of substances consisting of 2-(2-butoxyethoxy)-ethyl piperonylate (IUPAC name) (934)+TX, 5-(1,3-benzodioxol-5-yl)-3-hexylcyclohex-2-enone (IUPAC name) (903)+TX, farnesol with nerolidol (alternative name) (324)+TX, MB-599 (development code) (498)+TX, MGK 264 (development code) (296)+TX, piperonyl butoxide (649)+TX, piprotal (1343)+TX, propyl isomer (1358)+TX, S421 (development code) (724)+TX, sesamex (1393)+TX, sesasmolin (1394) and sulfoxide (1406)+TX,
an animal repellent selected from the group of substances consisting of anthraquinone (32)+TX, chloralose (127)+TX, copper naphthenate [CCN]+TX, copper oxychloride (171)+TX, diazinon (227)+TX, dicyclopentadiene (chemical name) (1069)+TX, guazatine (422)+TX, guazatine acetates (422)+TX, methiocarb (530)+TX, pyridin-4-amine (IUPAC name) (23)+TX, thiram (804)+TX, trimethacarb (840)+TX, zinc naphthenate [CCN] and ziram (856)+TX,
a virucide selected from the group of substances consisting of imanin (alternative name) [CCN] and ribavirin (alternative name) [CCN]+TX,
a wound protectant selected from the group of substances consisting of mercuric oxide (512)+TX, octhilinone (590) and thiophanate-methyl (802)+TX,
and biologically active compounds selected from the group consisting of azaconazole (60207-31-0]+TX, bitertanol [70585-36-3]+TX, bromuconazole [116255-48-2]+TX, cyproconazole [94361-06-5]+TX, difenoconazole [119446-68-3]+TX, diniconazole [83657-24-3]+TX, epoxiconazole [106325-08-0]+TX, fenbuconazole [114369-43-6]+TX, fluquinconazole [136426-54-5]+TX, flusilazole [85509-19-9]+TX, flutriafol [76674-21-0]+TX, hexaconazole [79983-71-4]+TX, imazalil [35554-44-0]+TX, imibenconazole [86598-92-7]+TX, ipconazole [125225-28-7]+TX, metconazole [125116-23-6]+TX, myclobutanil [88671-89-0]+TX, pefurazoate [101903-30-4]+TX, penconazole [66246-88-6]+TX, prothioconazole [178928-70-6]+TX, pyrifenox [88283-41-4]+TX, prochloraz [67747-09-5]+TX, propiconazole [60207-90-1]+TX, simeconazole [149508-90-7]+TX, tebuconazole [107534-96-3]+TX, tetraconazole [112281-77-3]+TX, triadimefon [43121-43-3]+TX, triadimenol [55219-65-3]+TX, triflumizole [99387-89-0]+TX, triticonazole [131983-72-7]+TX, ancymidol [12771-68-5]+TX, fenarimol [60168-88-9]+TX, nuarimol [63284-71-9]+TX, bupirimate [41483-43-6]+TX, dimethirimol [5221-53-4]+TX, ethirimol [23947-60-6]+TX, dodemorph [1593-77-7]+TX, fenpropidine [67306-00-7]+TX, fenpropimorph [67564-91-4]+TX, spiroxamine [118134-30-8]+TX, tridemorph [81412-43-3]+TX, cyprodinil [121552-61-2]+TX, mepanipyrim [110235-47-7]+TX, pyrimethanil [53112-28-0]+TX, fenpiclonil [74738-17-3]+TX, fludioxonil [131341-86-1]+TX, benalaxyl [71626-11-4]+TX, furalaxyl [57646-30-7]+TX, metalaxyl [57837-19-1]+TX, R-metalaxyl [70630-17-0]+TX, ofurace [58810-48-3]+TX, oxadixyl [77732-09-3]+TX, benomyl [17804-35-2]+TX, carbendazim [10605-21-7]+TX, debacarb [62732-91-6]+TX, fuberidazole [3878-19-1]+TX, thiabendazole [148-79-8]+TX, chlozolinate [84332-86-5]+TX, dichlozoline [24201-58-9]+TX, iprodione [36734-19-7]+TX, myclozoline [54864-61-8]+TX, procymidone [32809-16-8]+TX, vinclozoline [50471-44-8]+TX, boscalid [188425-85-6]+TX, carboxin [5234-68-4]+TX, fenfuram [24691-80-3]+TX, flutolanil [66332-96-5]+TX, mepronil [55814-41-0]+TX, oxycarboxin [5259-88-1]+TX, penthiopyrad [183675-82-3]+TX, thifluzamide [130000-40-7]+TX, guazatine [108173-90-6]+TX, dodine [2439-10-3] [112-65-2] (free base)+TX, iminoctadine [13516-27-3]+TX, azoxystrobin [131860-33-8]+TX, dimoxystrobin [149961-52-4]+TX, enestroburin {Proc. BCPC, Int. Congr., Glasgow, 2003, 1, 93}+TX, fluoxastrobin [361377-29-9]+TX, kresoxim-methyl [143390-89-0]+TX, metominostrobin [133408-50-1]+TX, trifloxystrobin [141517-21-7]+TX, orysastrobin [248593-16-0]+TX, picoxystrobin [117428-22-5]+TX, pyraclostrobin [175013-18-0]+TX, ferbam [14484-64-1]+TX, mancozeb [8018-01-7]+TX, maneb [12427-38-2]+TX, metiram [9006-42-2]+TX, propineb [12071-83-9]+TX, thiram [137-26-8]+TX, zineb [12122-67-7]+TX, ziram [137-30-4]+TX, captafol [2425-06-1]+TX, captan [133-06-2]+TX, dichlofluanid [1085-98-9]+TX, fluoroimide [41205-21-4]+TX, folpet [133-07-3]+TX, tolylfluanid [731-27-1]+TX, bordeaux mixture [8011-63-0]+TX, copperhydroxid [20427-59-2]+TX, copperoxychlorid [1332-40-7]+TX, coppersulfat [7758-98-7]+TX, copperoxid [1317-39-1]+TX, mancopper [53988-93-5]+TX, oxine-copper [10380-28-6]+TX, dinocap [131-72-6]+TX, nitrothal-isopropyl [10552-74-6]+TX, edifenphos [17109-49-8]+TX, iprobenphos [26087-47-8]+TX, isoprothiolane [50512-35-1]+TX, phosdiphen [36519-00-3]+TX, pyrazophos [13457-18-6]+TX, tolclofos-methyl [57018-04-9]+TX, acibenzolar-S-methyl [135158-54-2]+TX, anilazine [101-05-3]+TX, benthiavalicarb [413615-35-7]+TX, blasticidin-S [2079-00-7]+TX, chinomethionat [2439-01-2]+TX, chloroneb [2675-77-6]+TX, chlorothalonil [1897-45-6]+TX, cyflufenamid [180409-60-3]+TX, cymoxanil [57966-95-7]+TX, dichlone [117-80-6]+TX, diclocymet [139920-32-4]+TX, diclomezine [62865-36-5]+TX, dicloran [99-30-9]+TX, diethofencarb [87130-20-9]+TX, dimethomorph [110488-70-5]+TX, SYP-LI90 (Flumorph) [211867-47-9]+TX, dithianon [3347-22-6]+TX, ethaboxam [162650-77-3]+TX, etridiazole [2593-15-9]+TX, famoxadone [131807-57-3]+TX, fenamidone [161326-34-7]+TX, fenoxanil [115852-48-7]+TX, fentin [668-34-8]+TX, ferimzone [89269-64-7]+TX, fluazinam [79622-59-6]+TX, fluopicolide [239110-15-7]+TX, flusulfamide [106917-52-6]+TX, fenhexamid [126833-17-8]+TX, fosetyl-aluminium [39148-24-8]+TX, hymexazol [10004-44-1]+TX, iprovalicarb [140923-17-7]+TX, IKF-916 (Cyazofamid) [120116-88-3]+TX, kasugamycin [6980-18-3]+TX, methasulfocarb [66952-49-6]+TX, metrafenone [220899-03-6]+TX, pencycuron [66063-05-6]+TX, phthalide [27355-22-2]+TX, polyoxins [11113-80-7]+TX, probenazole [27605-76-1]+TX, propamocarb [25606-41-1]+TX, proquinazid [189278-12-4]+TX, pyroquilon [57369-32-1]+TX, quinoxyfen [124495-18-7]+TX, quintozene [82-68-8]+TX, sulfur [7704-34-9]+TX, tiadinil [223580-51-6]+TX, triazoxide [72459-58-6]+TX, tricyclazole [41814-78-2]+TX, triforine [26644-46-2]+TX, validamycin [37248-47-8]+TX, zoxamide (RH7281) [156052-68-5]+TX, mandipropamid [374726-62-2]+TX, isopyrazam [881685-58-1]+TX, sedaxane [874967-67-6]+TX, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide (disclosed in WO 2007/048556)+TX, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3′,4′,5′-trifluoro-biphenyl-2-yl)-amide (disclosed in WO 2006/087343)+TX, [(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-3-[(cyclopropylcarbonyl)oxy]-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-6,12-dihydroxy-4,6a,12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,11Hnaphtho[2,1-b]pyrano[3,4-e]pyran-4-yl]methyl-cyclopropanecarboxylate [915972-17-7]+TX and 1,3,5-trimethyl-N-(2-methyl-1-oxopropyl)-N-[3-(2-methylpropyl)-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]-1H-pyrazole-4-carboxamide [926914-55-8]+TX.
The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual—A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright© 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “develoment code” is used or, if neither one of those designations nor a “common name” is used, an “alternative name” is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.
The active ingredient mixture of the compounds of formula I selected from Tables A1 to A27, B1 to B10, and C1 to C12 (above) with active ingredients described above comprises a compound selected from Tables A1 to A27, B1 to B10, and C1 to C12 (above) and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 and 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are by weight.
The mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
The mixtures comprising a compound of formula I selected from Tables A1 to A27, B1 to B10, and C1 to C12 (above) and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I selected from Tables A1 to A27, B1 to B10, and C1 to C12 (above) and the active ingredients as described above is not essential for working the present invention.
The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.
Another aspect of invention is related to the use of a compound of formula I or of a preferred individual compound as above-defined, of a composition comprising at least one compound of formula I or at least one preferred individual compound as above-defined, or of a fungicidal or insecticidal mixture comprising at least one compound of formula I or at least one preferred individual compound as above-defined, in admixture with other fungicides or insecticides as described above, for controlling or preventing infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or non-living materials by insects or by phytopathogenic microorganisms, preferably fungal organisms.
A further aspect of invention is related to a method of controlling or preventing an infestation of plants, e.g. useful plants such as crop plants, propagation material thereof, e.g. seeds, harvested crops, e.g. harvested food crops, or of non-living materials by insects or by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula I or of a preferred individual compound as above-defined as active ingredient to the plants, to parts of the plants or to the locus thereof, to the propagation material thereof, or to any part of the non-living materials.
Controlling or preventing means reducing infestation by insects or by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
A preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, or insects which comprises the application of a compound of formula I, or an agrochemical composition which contains at least one of said compounds, is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen or insect. However, the compounds of formula I can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of formula I may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
A formulation, e.g. a composition containing the compound of formula I, and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula I, may be prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is preferably 1 g to 2000 g of active ingredient per hectare, more preferably 10 to 1000 g/ha, most preferably 10 to 600 g/ha. When used as seed drenching agent, convenient dosages are from 10 mg to 1 g of active substance per kg of seeds.
When the combinations of the present invention are used for treating seed, rates of 0.001 to 50 g of a compound of formula I per kg of seed, preferably from 0.01 to 10 g per kg of seed are generally sufficient.
Suitably, a composition comprising a compound of formula (I) according to the present invention is applied either preventative, meaning prior to disease development or curative, meaning after disease development.
The compositions of the invention may be employed in any conventional form, for example in the form of a twin pack, a powder for dry seed treatment (DS), an emulsion for seed treatment (ES), a flowable concentrate for seed treatment (FS), a solution for seed treatment (LS), a water dispersible powder for seed treatment (WS), a capsule suspension for seed treatment (CF), a gel for seed treatment (GF), an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
Such compositions may be produced in conventional manner, e.g. by mixing the active ingredients with appropriate formulation inerts (diluents, solvents, fillers and optionally other formulating ingredients such as surfactants, biocides, anti-freeze, stickers, thickeners and compounds that provide adjuvancy effects). Also conventional slow release formulations may be employed where long lasting efficacy is intended. Particularly formulations to be applied in spraying forms, such as water dispersible concentrates (e.g. EC, SC, DC, OD, SE, EW, EO and the like), wettable powders and granules, may contain surfactants such as wetting and dispersing agents and other compounds that provide adjuvancy effects, e.g. the ondensation product of formaldehyde with naphthalene sulphonate, an alkylarylsulphonate, a lignin sulphonate, a fatty alkyl sulphate, and ethoxylated alkylphenol and an ethoxylated fatty alcohol.
A seed dressing formulation is applied in a manner known per se to the seeds employing the combination of the invention and a diluent in suitable seed dressing formulation form, e.g. as an aqueous suspension or in a dry powder form having good adherence to the seeds. Such seed dressing formulations are known in the art. Seed dressing formulations may contain the single active ingredients or the combination of active ingredients in encapsulated form, e.g. as slow release capsules or microcapsules.
In general, the formulations include from 0.01 to 90% by weight of active agent, from 0 to 20% agriculturally acceptable surfactant and 10 to 99.99% solid or liquid formulation inerts and adjuvant(s), the active agent consisting of at least the compound of formula I together with component (B) and (C), and optionally other active agents, particularly microbiocides or conservatives or the like. Concentrated forms of compositions generally contain in between about 2 and 80%, preferably between about 5 and 70% by weight of active agent. Application forms of formulation may for example contain from 0.01 to 20% by weight, preferably from 0.01 to 5% by weight of active agent. Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ diluted formulations.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.


EXAMPLES
The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the methods used are as follows:
Method G:
Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85
Method H:
Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85
Method J:
Measurement were done on SPD-20A from Shimadzu:
Solvent degasser, binary pump, heated column, heated column compartment and ultraviolet detector. Column:Diamonsil C18 (2) 5u 150*4.6 mm. Oven Temperature (° C.): 40.0. Maximum Temperature (° C.): 80.0. SPD-20A Wavelength range (nm): 210 to 500. Solvent Gradient: A=H2O+0.1% TFA, B=ACN+0.1% TFA















Time
A %
B %
Flow (ml/min)








 0.00
90
10
1.00



15.00
 0
100 
1.00



25.00
 0
100 
1.00



27.00
90
10
1.00



36.00
90
10
1.00









FORMULATION EXAMPLES













Wettable powders
a)
b)
c)







active ingredient [compound of formula (I)]
25% 
50% 
75%


sodium lignosulfonate
5%
5%
—


sodium lauryl sulfate
3%
—
 5%


sodium diisobutylnaphthalenesulfonate
—
6%
10%


phenol polyethylene glycol ether
—
2%
—


(7-8 mol of ethylene oxide)





highly dispersed silicic acid
5%
10% 
10%


Kaolin
62% 
27% 
—









The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.














Powders for dry seed treatment
a)
b)
c)







active ingredient [compound of formula (I)]
25% 
50% 
75%


light mineral oil
5%
5%
 5%


highly dispersed silicic acid
5%
5%
—


Kaolin
65% 
40% 
—


Talcum
—

20 









The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

Emulsifiable Concentrate

    
    
        aclive ingredient [compound of formula (I)]10%
        oclylphenol polyethylene glycol ether 3%
        (4-5 mol of ethylene oxide)
        calcium dodecylbenzenesulfonate 3%
        castor oil polyglycol ether (35 mol of ethylene oxide) 4%
        Cyclohexanone 30%
        xylene mixture 50%

Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

    
    















Dusts
a)
b)
c)







Active ingredient [compound of formula (I)]
 5%
 6%
 4%


talcum
95%
—
—


Kaolin
—
94%
—


mineral filler
—
—
96%









Ready-for-use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

Extruder Granules

    
    
        Active ingredient [compound of formula (I)]15%

The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

Coated Granules

        Active ingredient [compound of formula (I)]8%
        polyethylene glycol (mol. wt. 200) 3%
        Kaolin 89%

The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

Suspension Concentrate

        active ingredient [compound of formula (I)]40%
        propylene glycol 10%
        nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6 %
        Sodium lignosulfonate 10%
        carboxymethylcellulose 1%
        silicone oil (in the form of a 75% emulsion in water) 1%
        Water 32%

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

Flowable Concentrate for Seed Treatment

        active ingredient [compound of formula (I)]40%
        propylene glycol 5%
        copolymer butanol PO/EO 2%
        tristyrenephenole with 10-20 moles EO 2%
        1,2-benzisothiazolin-3-one (in the form of a 20% solution in water) 0.5%
        monoazo-pigment calcium salt 5%

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

Slow Release Capsule Suspension

28 parts of a combination of the compound of formula I are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.

The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.

The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

    
    


PREPARATION EXAMPLES
Example 1
This example illustrates the preparation of 5-fluoro-1-(7-fluoro-pyrrolo[1,2-b]pyridazin-3-yl)-3,3-dimethyl-3,4-dihydro-isoquinoline
a) Preparation of pyrrolo[1,2-b]pyridazine-3-carbonitrile
To a suspension of sodium (E)-2-cyano-3,3-dimethoxy-prop-1-en-1-olate (1.80 equiv., 0.877 mol, 144.8 g) in MeOH (1.62 L, 0.54 mol/L) was added concentrated hydrochloric acid (12 mol/L, 7.00 equiv., 3.41 mmol, 284 mL) slowly so that the temperature does not exceed 20° C. and the mixture was stirred at room temperature for 20 min. Then, a solution of 1-aminopyrrole (1.00 equiv., 0.487 mol, 40.0 g) in 150 mL of MeOH was added slowly over 2 hours and the mixture was heated at reflux for another 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to 1⁄3 the original volume and then neutralized by the addition of sat. aq. NaHCO3. The mixture was extracted with TBME, and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give 100 mg of an orange residue, which was purified by flash chromatography (30% EtOAc in heptane) to give pyrrolo[1,2-b]pyridazine-3-carbonitrile (0.293 mol, 44.3 g, 59% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm)=6.87 (1H, dd, J=4.58, 1.28 Hz), 7.08 (1H, dd, J=4.58, 2.75 Hz), 7.93-8.01 (1H, m), 8.13-8.17 (2H, m); LC-MS, UV Detection: 220 nm; Rt=0.89, MS: (M+1)=144.1
b) Preparation of 7-fluoropyrrolo[1,2-b]pyridazine-3-carbonitrile
To a suspension of pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.00 equiv., 69.9 mmol, 10.0 g) in water (1.00 L, 0.07 mol/L) was added Selectfluor® (1.50 equiv., 105 mmol, 37.1 g) and the mixture was heated at 50° C. (bath temperature 60° C.) for 2 hours. The reaction mixture was allowed to cool to room temperature and then extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give 8.1 g of a dark green residue, which was purified by flash chromatography (0-25% EtOAc in cyclohexane) to give 7-fluoropyrrolo[1,2-b]pyridazine-3-carbonitrile (24.8 mmol, 4.00 g, 35% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm)=6.66 (1H, dd, J=4.77, 3.30 Hz), 6.80 (1H, t, J=4.95 Hz), 8.10 (1H, t, J=2.20 Hz), 8.19 (1H, d, J=2.20 Hz); 19F-NMR (377 MHz, CDCl3): δ (ppm)=−135.81 (1F, s); LC-MS, UV Detection: 220 nm; Rt=0.95, MS: (M+1)=162
c) Preparation of 5-fluoro-1-(7-fluoro-pyrrolo[1,2-b]pyridazin-3-yl)-3,3-dimethyl-3,4-dihydro-isoquinoline
To a solution of 7-fluoropyrrolo[1,2-b]pyridazine-3-carbonitrile (1.0 equiv., 3.10 mmol, 0.500 g) in 1,2-dichloroethane (31 mL, 0.1 mol/L) and trifluoromethanesulfonic acid (25 equiv., 78 mmol, 6.9 mL) at room temperature was added 1-(2-fluorophenyl)-2-methyl-propan-2-ol (3.0 equiv., 9.3 mmol, 1.6 g) in 6 portions over a period of 2 hours and 30 minutes. The reaction mixture was stirred at room temperature for 19 hours, then poured slowly into sat. aq. NaHCO3. The mixture was extracted with DCM, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.6 g of a dark yellow residue, which was purified by flash chromatography (0-25% EtOAc in cyclohexane) to give 5-fluoro-1-(7-fluoro-pyrrolo[1,2-b]pyridazin-3-yl)-3,3-dimethyl-3,4-dihydro-isoquinoline (1.6 mmol, 0.50 g, 50% yield) as a greenish yellow gum. 1H-NMR (400 MHz, CDCl3): δ (ppm)=1.32 (6H, s), 2.84 (2H, s), 6.46 (1H, dd, J=4.77, 3.30 Hz), 6.50-6.54 (1H, m), 7.17-7.25 (2H, m), 7.26-7.33 (1H, m), 7.93 (1H, t, J=2.38 Hz), 8.42 (1H, d, J=2.20 Hz); 19F-NMR (377 MHz, CDCl3): δ (ppm)=−141.68 (1F, s), −120.31 (1F, s); LC-MS, UV Detection: 220 nm; Rt=1.08, MS: (M+1)=312
Example 2
This example illustrates the preparation of 3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline
a) Preparation of 1,3,3-trimethyl-4H-isoquinoline
Acetonitrile (1.5 g, 37 mmol) was slowly added to 98% sulfuric acid (50 g, 0.5 mol) at 0° C. Then 2-methyl-1-phenyl-propan-2-ol (5.0 g, 33 mmol) was added to this solution at 0° C. The reaction mixture was allowed to reach room temperature, stirred for 1 h at this temperature and poured on aqueous sodium hydroxide solution of pH 9. The mixture was extracted with ethyl acetate, the organic layer washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to obtain 1,3,3-trimethyl-4H-isoquinoline (4.3 g, 25 mmol, 74%), which was pure enough to be directly used in the next step. 1H-NMR (400 MHz, CDCl3): δ (ppm)=1.20 (s, 6H), 2.37 (s, 3H), 2.69 (s, 2H), 7.14 (d, 1H), 7.27-7.36 (m, 2H), 7.48 (d, 1H).
b) Preparation of 2-(3,3-dimethyl-2,4-dihydroisoquinolin-1-ylidene)propanedial
Dimethylformamide (1.3 g, 18 mmol) was added to 14 ml of xylene and this mixture was cooled to 0° C. Phosporus oxychloride (2.2 g, 14 mmol) was added dropwise, the resulting mixture was stirred for further 30 min at 0° C. and then allowed to reach room temperature. Subsequently a solution of 1,3,3-trimethyl-4H-isoquinoline (1.0 g, 5.8 mmol) in 2 ml of xylene was added, the resulting mixture was heated to 90° C. for 20 h and subsequently cooled to room temperature. The reaction mixture was added slowly to 10 ml of a 20% aqueous sodium hydroxide solution under external cooling, then stirred at 60° C. and 250 mbar for 1 h, then at 80° c. and 200 mbar for 6 h to remove water and dimethylamine. The resulting suspension is then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder was purified by chromatography on silica gel, using ethyl acetate and heptane as eluents to deliver 2-(3,3-dimethyl-2,4-dihydroisoquinolin-1-ylidene)propanedial (0.9 g, 3.7 mmol, 64%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm)=1.32 (s, 6H), 2.91 (s, 2H), 7.29 (d, 1H), 7.39 (t, 1H), 7.54 (t, 1H), 7.65 (d, 1H), 9.80 (s, 2H), 12.11 (bs, 1H).
c) Preparation of 3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline
Hydrochloric acid (93 mg, 2.5 mmol) was added to a solution of 2-(3,3-dimethyl-2,4-dihydroisoquinolin-1-ylidene)propanedial (80 mg, 0.3 mmol) and 1-aminopyrrole (30 mg, 0.4 mmol) in 3 ml of methanol at room temperature. The reaction mixture was heated to reflux for 2 h, cooled to room temperature and poured on saturated aquoues sodium carbonate solution. This mixture was extracted with ethyl acetate, the organic phase washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder was purified by chromatography on silica gel, using ethyl acetate and heptane as eluents to deliver 3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline(80 mg, 0.3 mmol, 80%). 1H-NMR (400 MHz, CDCl3): δ (ppm)=1.27 (s, 6H), 2.80 (s, 2H), 6.59 (d, 1H), 6.90 (d, 1H), 7.23-7.42 (m, 4H), 7.81 (t, 1H), 7.96 (d, 1H), 8.38 (d, 1H).
Example 3
This example illustrates the preparation of 3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile
a) Preparation of 5-fluoro-3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline
To a solution of pyrrolo[1,2-b]pyridazine-3-carbonitrile (7.00 mmol, 1.00 g) in 1,2-dichloroethane (0.10 M, 70 mL) at room temperature was added trifluromethanesulfonic acid (25 equiv., 170 mmol, 15 mL) followed by portionwise addition of 1-(2-fluorophenyl)-2-methyl-propan-2-ol (3.00 equiv., 21.0 mmol, 3.50 g) (6 portions over a period of 5 hours) and the reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was carefully poured on a cooled saturated aqueous NaHCO3 solution and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 5-fluoro-3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline (0.84 g, 41% yield) as an orange oil which crystallized upon standing: mp 213-214° C.; 1H NMR (400 MHz, CDCl3) δ (ppm)=1.26-1.39 (m, 6H) 2.85 (s, 2H) 6.64 (dd, J=4.80 Hz, 1H) 6.84-7.05 (m, 1H) 7.15-7.35 (m, 3H) 7.79-7.91 (m, 1H) 7.98 (s, J=5.66 Hz, 1H) 8.39 (d, J=5.54 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−120.48 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.00; MS: (M+1)=294.
b) Preparation of 1-(7-bromopyrrolo[1,2-b]pyridazin-3-yl)-5-fluoro-3,3-dimethyl-4H-isoquinoline
To a cooled solution (0° C.) of 5-fluoro-3,3-dimethyl-1-pyrrolo[1,2-b]pyridazin-3-yl-4H-isoquinoline (2.2 mmol, 660 mg) in MeCN (0.10 M, 23 mL) was added N-bromosuccinimide (1.0 equiv., 2.2 mmol, 0.40 g) and the reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was poured on ice water and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 1-(7-bromopyrrolo[1,2-b]pyridazin-3-yl)-5-fluoro-3,3-dimethyl-4H-isoquinoline (0.74 g, 84% yield) as an orange oil: 1H NMR (400 MHz, CDCl3) δ (ppm)=1.29-1.32 (m, 6H) 2.83 (s, 2H) 6.71 (d, J=4.77 Hz, 1H) 6.97 (d, J=4.40 Hz, 1H) 7.14-7.26 (m, 3H) 7.98 (d, J=2.20 Hz, 1H) 8.48 (d, J=2.20 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−118.82 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.35; MS: (M+1)=372-374.
c) Preparation of 3-(5-fluoro-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile
To a solution of 1-(7-bromopyrrolo[1,2-b]pyridazin-3-yl)-5-fluoro-3,3-dimethyl-4H-isoquinoline (0.27 mmol, 100 mg) in DMF (0.20 M, 1.3 mL) at room temperature was added zinc cyanide (2.0 equiv., 0.54 mmol, 63 mg) and Pd(Ph3P)4 (0.10 equiv., 0.027 mmol, 31 mg) and the reaction mixture was heated in a microwave at 160° C. for 30 minutes. The reaction mixture was allowed to cool down to room temperature, diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 3-(5-fluoro-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (70 mg, 80% yield) as an orange solid: mp 118-136° C.; 1H NMR (400 MHz, CDCl3) δ (ppm)=1.29-1.34 (m, 6H) 2.84 (s, 2H) 6.64 (d, J=4.40 Hz, 1H) 7.11 (dd, J=7.70, 1.10 Hz, 1H) 7.20-7.26 (m, 1H) 7.26-7.29 (m, 1H) 7.39 (d, J=4.77 Hz, 1H) 8.07 (d, J=2.20 Hz, 1H) 8.60 (d, J=2.20 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−119.72 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.55; MS: (M+1)=319.
d) Preparation of 5-bromo-3-(5-fluoro-4-hydroxy-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile
To a solution of 3-(5-fluoro-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (0.35 mmol, 140 mg) in CCl4 (0.20 M, 1.8 mL) at room temperature was added N-bromosuccinimide (2.0 equiv., 0.70 mmol, 126 mg) and AIBN (0.05 equiv., 0.018 mmol, 2.9 mg) and the reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature, diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated to give 5-bromo-3-(4-bromo-5-fluoro-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (180 mg) as a orange solid which was used directly in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ (ppm)=1.66 (s, 6H) 2.71 (s, 1H) 7.14 (d, J=7.22 Hz, 1H) 7.21-7.28 (m, 1H) 7.35 (s, 2H) 8.00 (br. s., 1H) 8.58 (d, J=1.83 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−118.82 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=2.06; MS: (M+1)=477.
A solution of 5-bromo-3-(4-bromo-5-fluoro-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (180 mg) in a mixture of water (1.9 mL) and dioxane (1.9 mL, total conc. 0.10 M) was stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 5-bromo-3-(5-fluoro-4-hydroxy-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (70 mg, 40% yield) as a yellow resin: 1H NMR (400 MHz, CDCl3) δ (ppm)=1.04 (s, 3H) 1.70-1.79 (m, 3H) 1.88-2.02 (m, 1H) 4.91 (br. s., 1H) 7.21 (d, J=7.70 Hz, 1H) 7.34 (t, J=8.62 Hz, 1H) 7.42-7.54 (m, 2H) 8.09 (d, J=1.83 Hz, 1H) 8.64-8.71 (m, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−121.29 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.51; MS: (M+1)=413-415.
e) Preparation of 5-bromo-3-(5-fluoro-3,3-dimethyl-4-oxo-1-isoquinolyl)pyrrolo [1,2-b]pyridazine-7-carbonitrile
To a solution of 5-bromo-3-(5-fluoro-4-hydroxy-3,3-dimethyl-4H-isoquinolin-1-yl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (0.15 mmol, 60 mg) in a mixture of DMSO (0.3 mL) and dichloromethane (1.0 mL, total conc. 0.15 M) at room temperature was added triethylamine (5.0 equiv., 0.73 mmol, 0.10 mL) followed by SO3.pyridine complex (3.0 equiv., 0.44 mmol, 69 mg) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by the addition of a 0.5 M aqueous citric acid solution and was stirred vigorously for 1 h. The 2 phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 5-bromo-3-(5-fluoro-3,3-dimethyl-4-oxo-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (30 mg, 50% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ (ppm)=1.61 (s, 6H) 7.29 (s, 1H) 7.42-7.52 (m, 2H) 7.80 (td, J=8.07, 4.77 Hz, 1H) 8.08 (d, J=1.83 Hz, 1H) 8.59 (d, J=1.83 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−109.82 (s, 1F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.75; MS: (M+1)=413.
f) Preparation of 5-bromo-3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile
A solution of 5-bromo-3-(5-fluoro-3,3-dimethyl-4-oxo-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (0.24 mmol, 100 mg) in 2,2-difluoro-1,3-dimethyl-imidazolidine (10.0 equiv., 2.4 mmol, 0.3 mL) was stirred at 105° C. overnight. The reaction mixture was allowed to cool down to room temperature, diluted with dichloromethane then quenched by the slow addition of a saturated aqueous NaHCO3 solution. The pH was adjusted to 8-9 by the addition of 1 M NaOH solution and the 2 phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to give 5-bromo-3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (80 mg, 80% yield) as a light yellow solid: mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ (ppm)=1.49 (s, 6H) 7.21-7.26 (m, 1H) 7.40-7.47 (m, 2H) 7.65 (td, J=8.07, 4.77 Hz, 1H) 8.06 (d, J=2.20 Hz, 1H) 8.63 (d, J=2.20 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−111.84 (t, J=30.00 Hz, 1F) −109.38 (d, J=30.04 Hz, 2F); LC-MS (Method H) UV Detection: 220 nm, Rt=2.03; MS: (M+1)=435.
g) Preparation of 3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile
To a solution of 5-bromo-3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (0.092 mmol, 40 mg) in toluene (1 M, 0.92 mL) at room temperature was added tris(trimethylsilylsilane) (3.0 equiv., 0.27 mmol, 69 mg) and AIBN (0.25 equiv., 0.023 mmol, 3.9 mg) and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature then concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-(4,4,5-trifluoro-3,3-dimethyl-1-isoquinolyl)pyrrolo[1,2-b]pyridazine-7-carbonitrile (4.8 mg, 13% yield) as a yellow solid: mp 214-216° C.; 1H NMR (400 MHz, CDCl3) δ (ppm)=1.37 (s, 6H) 6.59 (d, J=4.77 Hz, 1H) 7.13 (dd, J=7.70, 1.10 Hz, 1H) 7.27-7.34 (m, 2H) 7.48-7.55 (m, 1H) 7.98 (d, J=2.20 Hz, 1H) 8.51 (d, J=1.83 Hz, 1H); 19F NMR (377 MHz, CDCl3) δ (ppm)=−111.99 (t, J=30.00 Hz, 1F) −109.43 (d, J=31.47 Hz, 2F); LC-MS (Method H) UV Detection: 220 nm, Rt=1.82; MS: (M+1)=355.
Example 4
This example illustrates the preparation of 5-fluoro-3,3,4,4-tetramethyl-1-(4-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline
a) Preparation of ethyl 4-methylpyrrolo[1,2-b]pyridazine-3-carboxylate
A mixture of 1-aminopyrrole (30.9 g, 0.376 mol) and ethyl (2Z)-2-(ethoxymethylene)-3-oxo-butanoate (70 g, 0.376 mol) was stirred at r.t. for 10 min. A quick and exothermic reaction happened. The reaction mixture precipitated a solid material, which was washed with petroleum ether. To a solution of the precipitated solid material in EtOH (500 ml) was added hydrochloric acid (165 ml). The resulting solution was heated to 80° C. and stirred at 80° C. for 16 h. After cooling, the solution was poured into water, extracted with dichloromethane, dried over MgSO4, evaporated concentrated in vacuum, and further purified by chromatography on silica gel to afford 37 g of compound 4 in 37% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm)=8.45 (s, 1H), 8.00 (dd, J=2.6, 1.5 Hz, 1H), 7.02 (dd, J=4.5, 1.5 Hz, 1H), 6.96 (dd, J=4.4, 2.7 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.75 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
b) Preparation of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid
To a stirred solution of ethyl 4-methylpyrrolo[1,2-b]pyridazine-3-carboxylate (38 g, 186 mmol) in a mixture of MeOH (200 ml) and THF (200 ml) at r.t. was added 300 ml of 10% aqueous NaOH solution. The reaction mixture was stirred at 60° C. for 2 h. After cooling, the reaction solution was poured into water, acidified pH to 2 with concentrated hydrochloric acid. The precipitate was filtered, washed with EA and dried under vacuum to afford 27 g of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid in 75% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm)=13.01 (s, 1H), 8.44 (s, 1H), 8.11-7.68 (m, 1H), 6.98 (dd, J=4.4, 1.3 Hz, 1H), 6.94 (dd, J=4.4, 2.6 Hz, 1H), 2.75 (s, 3H).
c) Preparation of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxamide
To a mixture of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxylic acid (13 g, 66.7 mmol) and POCl3 (204 g, 133.3 mmol) was added Et3N (7.4 g, 73.4 mmol) dropwise at r.t. The reaction mixture was then heated to 90° C. and stirred for 16 h. The excess POCl3 was removed under vacuum to give the crude acyl chloride, which was directly used in the next step without any further purification.
A solution of the acyl chloride in 50 ml of dichloromethane was slowly added to 500 ml of aqueous ammonia at 0° C. within 0.5 h. After stirred for 1 h, the reaction solution was concentrated and 200 ml of water was added. The precipitate was filtered, washed with water, dried under vacuum to afford 9 g of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxamide in 70% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm)=8.22 (s, 1H), 7.95 (d, J=2.9 Hz, 2H), 7.34 (d, J=2.8 Hz, 1H), 6.14 (s, 2H), 2.70 (s, 3H).
d) Preparation of 4-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile
To a suspension of 4-methylpyrrolo[1,2-b]pyridazine-3-carboxamide (9 g, 51.4 mmol) in toluene (500 ml), was added POCl3 (40 ml) was added. After addition, the reaction was then heated to 50° C. and stirred for 2 h. After cooling, the reaction solution mixture was poured into ice water and, extracted with CH2Cl2, The organic phase was dried over MgSO4, evaporated concentrated in vacuum and further purified by chromatography on silica gel to afford 3 g of 4-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile in 37% yield. 1H NMR (400 MHz, DMSO-d6dmso) δ (ppm)=8.35 (s, 1H), 8.09-7.97 (m, 1H), 7.14-6.86 (m, 2H), 2.63 (s, 3H).
e) Preparation of 5-fluoro-3,3,4,4-tetramethyl-1-(4-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline
To a solution of 4-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile (1.57 g, 10 mmol), TFA (18.7 ml, 200 mmol) and Tf2O (0.33 ml, 2 mmol) in dichloromethane (40 ml), at 0° C. was added 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol (6 g, 30 mmol) and the reaction mixture was stirred at 0° C. for 2 h. The reaction solution mixture was poured into ice water and basified with aq. NaHCO3. The aqueous phase was extracted with dichloromethane, and the combined organic extract was dried over MgSO4, concentrated in vacuum and purified by chromatography on silica gel to afford 5-fluoro-3,3,4,4-tetramethyl-1-(4-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline. 1H NMR (400 MHz, CDCl3) δ (ppm)=7.69 (s, 1H), 7.61 (s, 1H), 7.15-7.10 (dd, 2H), 6.87-6.85 (dd, 1H), 6.81-6.79 (dd, 1H), 6.49-6.48 (dd, 1H), 2.26 (s, 3H).), 1.44-1.43 (d, 6H), 0.1.29 (s, 6H).
Example 5
This example illustrates the preparation of 5-fluoro-3,3,4,4-tetramethyl-1-(2-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline
a) Preparation of 2-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile
To a suspension of NaH (11.4 g, 286 mmol, 60%) in 500 ml of dry Et2O at r.t., 3,3-dimethoxypropanenitrile compound 1 (30 g, 260 mmol) was added dropwise. at r.t. followed by dropwise addition of CH3CO2Me (45.6 g, 250 mmol). The reaction mixture was then stirred at r.t. for 2 days. The precipitate was filtered, washed with Et2O, and dried in vacuo to afford 26 g of 2-(dimethoxymethyl)-3-oxo-butanenitrile as a sodium salt in 65% yield.
To a solution of the sodium salt of 2-(dimethoxymethyl)-3-oxo-butanenitrile (26 g, 165.6 mmol) in EtOH (500 ml) at r.t., were added hydrochloric acid (30 ml) and 1-aminopyrrole (13.6 g, 165.6 mmol). The reaction was then heated to 80° C. and stirred for 2 h. Hydrochloric acid (40 ml) and EtOH (40 ml) were added at 80° C. After stirring for 12 h, the reaction mixture was allowed to cool down to r.t. and poured into water. The aqueous phase was extracted with dichloromethane, dried over MgSO4, evaporated in vacuum, and further purified by chromatography on silica gel to afford 8 g of 2-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile in 25% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm)=8.60 (s, 1H), 8.02 (s, 1H), 6.97 (dd, J=4.5, 2.6 Hz, 1H), 6.82 (dd, J=4.5, 1.1 Hz, 1H), 2.48 (s, 3H).
a) Preparation of 5-fluoro-3,3,4,4-tetramethyl-1-(2-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline
To a solution of 2-methylpyrrolo[1,2-b]pyridazine-3-carbonitrile (1.57 g, 10 mmol) in conc. H2SO4 (21 ml), at 0° C. was added 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol (6 g, 30 mmol) and the reaction mixture was stirred at 0° C. for 5 h. The reaction mixture was poured into ice water and basified with aq. NaHCO3. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over MgSO4, evaporated in vacuum, and purified by chromatography on silica gel to afford 5-fluoro-3,3,4,4-tetramethyl-1-(2-methylpyrrolo[1,2-b]pyridazin-3-yl)isoquinoline. 1H NMR (400 MHz, CDCl3) δ (ppm)=7.87 (s, 1H), 7.75-7.74 (d, 1H), 7.15-7.11 (dd, 2H), 6.87-6.84 (dd, 2H), 6.58-6.57 (dd, 1H), 2.28 (s, 3H). 1.45-1.44 (d, 6H), 0.1.31 (s, 6H).







TABLE E





Physical data of compounds of formula I























[M + H]
LC-MS



No.
Compound
RT (min)
(measured)
Method
MP ° C.





E 1




1.19
322
H
121-125


 


E 2




1.29
340
H
112-115


 


E 3




0.78
294
G



 


E 4




0.78
290
G



 


E 5




0.87
356
G



 


E 6




0.88
310
G



 


E 7




1.08
312
H



 


E 8




0.91
294
H



 


E 9




1.31
372
H



 


E 10




0.88
276
H



 


E 11




0.89
330
G
114-115


 


E 12




0.98
358
G
126-127


 


E 13




1.50
356
H
126-129


 


E 14




1.42
434
H



 


E 15




1.64
392
H



 


E 16




1.68
356
H



 


E 17




1.35
374
H



 


E 18




1.15
326
H



 


E 19




0.58
351
G



 


E 20




0.71
278
G



 


E 21




0.73
296
G



 


E 22




0.87
319
G



 


E 23




0.76
324
G



 


E 24




1.86
466
H



 


E 25




1.89
365
H
128-130


 


E 26




1.11
308
H



 


E 27




0.81
318
G



 


E 28




0.94
388
G



 


E 29




0.91
402
G



 


E 30




1.56
319
H
118-136


 


E 31




0.79
369
G



 


E 32




0.81
326
G



 


E 33




0.69
304
G
64-66


 


E 34




0.65
292
G
221-224


 


E 35




2.20
408
H



 


E 36




2.45
458
H



 


E 37




1.57
448
H



 


E 38




2.15
574
H



 


E 39




0.81
342
G



 


E 40




1.77
364
H



 


E 41




1.26
470
G
50-53


 


E 42




1.52
400
H
136-139


 


E 43




2.03
390
H



 


E 44




2.11
480
H
110-135


 


E 45




1.19
322
H



 


E 46




1.19
322
H



 


E 47




1.19
322
H



 


E 48




1.19
322
H



 


E 49




1.19
322
H



 


E 50




1.19
322
H



 


E 51




1.19
322
H



 


E 52




1.78
347
H
177-180


 


E 53




1.27
336
H
117-120


 


E 54




0.78
330
G



 


E 55




0.70
318
G



 


E 56




0.82
347
G



 


E 57




0.79
347
G



 


E 58




0.81
301
G
139-142


 


E 59




0.87
316
G



 


E 60




0.96
368
G



 


E 61




1.00
304
H



 


E 62




1.50
346
H



 


E 63




1.75
413
H



 


E 64




2.03
435
H
190-192


 


E 65




1.06
354
H



 


E 66




1.81
355
H
214-216


 


E 67




1.82
368
H
148-150


 


E 68




1.28
329
H



 


E 69




2.03
390
H
130-133


 


E 70




2.12
390
H



 


E 71




1.35
312
H



 


E 72




0.74
322
G
57-60


 


E 73




0.88
340
G
87-89


 


E 74




0.95
340
G
128-130


 


E 75




1.03
358
G
152-154


 


E 76




1.50
356
H



 


E 77




1.29
340
H



 


E 78




0.83
336
G



 


E 79




0.99
336
G



 


E 80




0.96
354
G
94-97


 


E 81




1.02
354
G



 


E 82




1.09
414
G
104-106


 


E 83




1.12
361
G
174-176


 


E 84




1.11
414
G
121-123


 


E 85




0.92
323
G
177-180


 


E 86




0.81
295
G
153-155


 


E 87




0.92
388
G
68-70


 


E 88




1.01
356
G
168-170


 


E 89




0.93
331
G
152-155


 


E 90




0.96
345
G
150-152


 


E 91




1.06
410
G
172-175


 


E 92




0.93
336
G



 


E 93




0.93
336
G
118-121


 


E 94




1.02
356
G
150-153


 


E 95




0.99
354
G
122-124


 


E 96




0.84
308
G
104-106


 


E 97




1.13
361
G
174-176


 


E 98




0.98
354
G
121-123


 


E 99




0.82
336
G



 


E 100




0.88
337
G












No.
Compound
NMR





E 101




1H NMR (400 MHz, CDCl3) δ (ppm) 8.25 (s, 1H), 7.81 (s, 1H), 7.25-7.19 (m, 1H), 7.18-7.07 (m, 2H), 6.50 (s, 1H), 6.28 (d, J = 3.9 Hz, 1H), 4.12 (s, 3H), 1.41 (s, 6H), 1.26 (s, 6H). 19F NMR (376 MHz, CDCl3) δ (ppm) −110.50 (1F, s).


 


E 102




1H NMR (400 MHz, CDCl3) δ (ppm) 8.37 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.29-7.13 (m, 3H), 6.98- 6.84 (m, 1H), 6.60 (d, J = 4.2 Hz, 1H), 2.87-2.69 (m, 2H), 1.78-1.52 (m, 2H), 1.19 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm) −116.48 (1F, s).


 


E 103




1H NMR (400 MHz, CDCl3) δ (ppm) 8.41 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.30-7.12 (m, 3H), 6.93-6.87 (m, 1H), 6.62 (d, J = 3.3 Hz, 1H), 2.80 (s, 2H), 1.93-1.39 (m, 10H). 19F NMR (376 MHz, CDCl3) δ (ppm) −116.43 (1F, s).


 


E 104




1H NMR (400 MHz, CDCl3) δ (ppm) 8.39 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.28-7.09 (m, 3H), 6.89 (s, 1H), 6.60 (d, J = 3.9 Hz, 1H), 2.76 (s, 2H), 1.72-1.40 (m, 4H), 0.94 (t, J = 7.4 Hz, 6H).


 


E 105




1H NMR (400 MHz, CDCl3) δ (ppm) 8.36 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.31-7.12 (m, 3H), 6.90 (s, 1H), 6.61 (d, J = 3.5 Hz, 1H), 2.79 (q, J = 16.2 Hz, 2H), 1.71-1.32 (m, 4H), 1.22 (s, 3H), 0.92 (t, J = 6.6 Hz, 3H).


 


E 106




1H NMR (400 MHz, DMSO) δ (ppm) 8.31 (s, 1H), 8.01 (s, 1H), 7.31-7.21 (m, 2H), 7.10 (d, J = 4.5 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 4.5 Hz, 1H), 1.42 (d, J = 5.3 Hz, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.16 (s, 3H).


 


E 107




1H NMR (400 MHz, CDCl3) δ (ppm) 8.28 (s, 1H), 8.10 (s, 1H), 7.21-7.12 (m, 1H), 7.05 (dd, J = 12.1, 8.3 Hz, 1H), 6.95 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 4.5 Hz, 1H), 1.50 (s, 12H).









BIOLOGICAL EXAMPLES
Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
Compounds E 1, E 2, E 3, E 4, E 5, E 6, E 7, E 8, E 9, E 10, E 11, E 12, E 13, E 15, E 16, E 17, E 18, E 20, E 21, E 22, E 23, E 24, E 25, E 26, E 27, E 28, E 29, E 30, E 31, E 32, E 34, E 35, E 36, E 37, E 38, E 39, E 40, E 41, E 42, E 43, E 44, E 45, E 46, E 47, E 48, E 49, E 50, E 51, E 52, E 53, E 54, E 56, E 57, E 58, E 59, E 60, E 61, E 62, E 65, E 66, E 68, E 69, E 70, E 71, E 72, E 73, E 74, E 75, E 76, E 77, E 78, E 79, E 80, E 81, E 82, E 83, E 84, E 85, E 86, E 88, E 89, E 90, E 91, E 92, E 93, E 94 and E 95 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Fusarium culmorum/Liquid Culture (Head Blight)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
Compounds E 1, E 2, E 3, E 5, E 6, E 7, E 9, E 12, E 13, E 22, E 24, E 26, E 27, E 29, E 30, E 32, E 42, E 45, E 46, E 47, E 48, E 49, E 50, E 51, E 52, E 53, E 58, E 60, E 61, E 66, E 71, E 72, E 73, E 74, E 75, E 76, E 77, E 78, E 79, E 80, E 81, E 84 and E 90 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Gaeumannomyces graminis/Liquid Culture (Take-All of Cereals)
Mycelial fragments of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
Compounds E 1, E 2, E 3, E 15, E 17, E 18, E 21, E 27, E 30, E 31, E 42, E 54, E 75, E 76, E 77 and E 84 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Glomerella lagenarium (Colletotrichum lagenarium)/Liquid Culture (Anthracnose)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is measured photometrically 3-4 days after application.
Compounds E 1, E 2, E 3, E 4, E 5, E 6, E 7, E 8, E 9, E 10, E 11, E 12, E 13, E 15, E 16, E 17, E 18, E 21, E 22, E 23, E 24, E 25, E 26, E 27, E 28, E 29, E 30, E 32, E 34, E 35, E 37, E 40, E 42, E 43, E 45, E 46, E 47, E 48, E 49, E 50, E 51, E 52, E 53, E 56, E 57, E 58, E 60, E 61, E 62, E 66, E 67, E 68, E 69, E 70, E 71, E 72, E 73, E 74, E 75, E 76, E 77, E 78, E 79, E 80, E 81, E 82, E 83, E 84, E 85, E 89, E 90, E 92, E 93, E 94 and E 95 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
Compounds E 1, E 2, E 3, E 4, E 5, E 6, E 7, E 8, E 9, E 10, E 13, E 15, E 17, E 18, E 22, E 24, E 25, E 26, E 27, E 29, E 30, E 32, E 37, E 38, E 41, E 42, E 43, E 45, E 46, E 47, E 48, E 49, E 50, E 51, E 52, E 53, E 60, E 62, E 65, E 66, E 67, E 69, E 70, E 71, E 72, E 73, E 74, E 76, E 77, E 80, E 82, E 84, E 85 and E 90 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.
Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch)
Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
Compounds E 3, E 5, E 15, E 18, E 24, E 27, E 29, E 30, E 38, E 60 and E 76 of Table E at 200 ppm give at least 80% disease control in this test when compared to untreated control leaf disks under the same conditions, which show extensive disease development.

## Claims

1. A compound of formula I:



wherein
each of A1, A2, and A3 independently represents a nitrogen atom or CR7;
Y—X represents a radical selected from G1, G2, G3 and G4:
















R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, in which the alkyl, cycloalkyl, alkenyl and alkynyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or
R1 and R2 together with the carbon atom to which they are attached represent a C3-C10 cycloalkyl group (which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy);
R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, in which the alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or
R3 and R4 together with the carbon atom to which they are attached represent C═O, C═CH2 or C3-C10 cycloalkyl (which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, C1-C6 alkyl, C1-C6 alkoxy and phenoxy);
R5 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxyl;
R6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxyl;
each R7 independently represents hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C2-C6 alkynyl, or hydroxyl;
each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CO2H, CO2(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2, C(O)NH(C1-C6 alkyl), C(O)NH2, NH(C1-C6 alkylcarbonyl), N(C1-C6 alkylcarbonyl)2, aryl, heteroraryl, aryloxy or heteroraryloxy, in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, C1-C6 alkylthio, C1-C6 alkoxycarbonyl and phenoxy, and the aryl or heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), C1-C6 alkoxy, amino (which itself may be substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6 alkylcarbonyl), nitro, cyano, hydroxyl, mercapto and C1-C6 alkylthio; n is 0, 1, 2, 3 or 4;
Ra is hydrogen, C1-C6 alkylcarbonyl or C1-C6 alkyl, which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 alkylthio and phenoxy; or a salt or N-oxide thereof.

2. A compound according to claim 1 wherein one or more of A1, A2, and A3 represents CR7.

3. A compound according to claim 1 wherein each R7 independently represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkynyl, or hydroxyl.

4. A compound according to claim 1, wherein Y—X is G1, G2 or G4.

5. A compound according to claim 1, wherein R1 and R2 are each independently selected from hydrogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, in which the alkyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group.

6. A compound according to claim 1, wherein R3 and R4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C6 alkoxy, and C1-C6 alkylthio; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or C3-C7 cycloalkyl, which may be optionally substituted with 1 to 3 substituents independently selected from halogen.

7. A compound according to claim 1, wherein R5 is hydrogen, halogen, or C1-C6 alkyl.

8. A compound according to claim 1, wherein R6 is hydrogen, halogen, or C1-C6 alkyl.

9. A compound according to claim 1, wherein each R8 independently represents hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C2-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylthio, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl, or oxazolyl), in which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkoxy, hydroxyl, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms), or C1-C6 alkoxy; n is 0, 1, 2, or 3.

10. A compound according to claim 1, wherein Ra is hydrogen or C1-C6 alkyl when Y—X is G2.

11. A compound according to claim 1 wherein two or more of A1, A2, and A3 represent CR7; each R7 independently represents hydrogen, halogen, C1-C6 alkyl, or hydroxyl; Y—X is G1; R1 and R2 are each independently selected from C1-C6 alkyl, in which the alkyl group may be optionally substituted with 1 to 3 substituents independently selected from halogen, and C1-C6 alkoxy; or R1 and R2 together with the carbon atom to which they are attached represent a C3-C6 cycloalkyl group; R3 and R4 are each independently selected from hydrogen, halogen, C1-C6 alkyl; or R3 and R4 together with the carbon atom to which they are attached represent C═O, or cyclopropyl; R5 is hydrogen, or halogen; R6 is hydrogen, or C1-C6 alkyl; each R8 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is pyridyl, thiophenyl or thiazolyl), in which the alkyl and alkoxy groups may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and the phenyl, phenoxy and heteroaryl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, or C1-C3 alkyl (which itself may be optionally substituted with 1 to 3 halogen atoms); n is 0, 1, or 2; and Ra is hydrogen, or C1-C2 alkyl; or a salt or N-oxide thereof.

12. A method of combating phytopathogenic diseases which comprises applying to a phytopathogen, to the locus of a phytopathogen, or to a plant susceptible to attack by a phytopathogen, or to propagation material thereof, a fungicidally effective amount of a compound of formula (I) as defined in claim 1 or a composition comprising a fungicidally effective amount of said compound.

13. A composition comprising a fungicidally effective amount of a compound of formula (I) as defined in claim 1.

14. A composition according to claim 13, wherein the composition further comprises at least one additional active ingredient and/or a diluent.