WO2015040352A1 - Agricultural chemicals - Google Patents

Abstract

The present invention relates to compounds which are of use in the field of agriculture as fungicides. The compounds are derivatives of succinate dehydrogenase inhibitors (SDHIs) which comprise different linker groups in place of the SDHI central amide. The invention also relates to uses, methods of use and compositions comprising said SDHI derivatives.

Description

Agricultural Chemicals

The present invention relates to compounds which are of use in the field of agriculture as fungicides.

Given the global increase in demand for food, there is an international need for new treatments to reduce food crop losses to disease, insects and weeds. Over 40% of crops are lost before harvest, and 10% post harvest, worldwide. Losses have actually increased since the mid-1990s.

A new threat contributing to this is the emergence of chemical-resistant organisms, for example, glyphosate-resistant weeds in USA and strobilurin-resistant strains of septoria fungal species.

Recent research also suggests that the geographical spread of many crop pests and diseases is increasing, possibly as a result of global warming.

An aim of the present invention is to provide pesticides (e.g. fungicides) which have activity either non-selectively, i.e. broad spectrum activity, or which are active specifically against selective target organisms.

An aim of the present invention is to provide compounds which are less persistent in the environment after use than prior art compounds.

Alternatively or additionally the compounds of the present invention are less prone to bioaccumulation once in the food chain than prior art compounds.

Another aim of the invention is to provide compounds which are less harmful to humans than prior art compounds.

Alternatively or additionally, the compounds of the invention may be less harmful than prior art compounds to one or more of the following groups: amphibians, fish, mammals (including domesticated animals such as dogs, cats, cows, sheep, pigs, goats, etc), reptiles, birds, and beneficial invertebrates (e.g. bees and other insects, or worms), beneficial nematodes, beneficial fungi and nitrogen-fixing bacteria. The compounds of the invention may be as active or more active than prior art compounds. They may have activity against organisms which have developed a resistance to prior art compounds. However, the present invention also concerns compounds which have a lower level of activity relative to known SDHIs. These lower activity compounds are still effective as fungicides but have other advantages relative to existing compounds such as, for example, a reduced environmental impact.

The compounds of the invention may be more selective than the parent, i.e. they may have better, similar or even slightly lower activity than known SDHIs against target species but have a significantly lower activity against non-target species (e.g. the crops which are being protected).

This invention provides compounds that achieve one or more of the above aims. The compounds may be active in their own right or may metabolise or react in aqueous media to yield an active compound.

Summary of the Invention

In a first aspect of the invention is provided a compound which is a derivative of a succinate dehydrogenase inhibitor (SDHI) wherein the SDHI incorporates an amide group and has the form A-C(0)-NH-B, wherein A and B are the residual parts of the structure of the SDHI to which the amide group is bound and wherein the compound has a structure A-L-B

wherein -L- is selected from: -CR²R²-NR¹-, -CR²R²-0-, - C(0)-0-, - CR¹=N-, and -CR¹=N-0-; R¹ is independently selected from H, C₁-C4 alkyl and C₁-C4 haloalkyl; and

R² is independently selected at each occurrence from H, fluorine, C₁-C4 alkyl and C₁-C4 haloalkyl;

or an agronomically acceptable salt or N-oxide thereof.

In an embodiment, the SDHI is selected from benodanil, flutolanil, mepronil, isofetamid, fluopyram, fenfuram, carboxin, oxycarboxin, thifluzamide, boscalid, benzovindiflupyr, bixafen, fluxapyroxad, furametpyr, isopyrazam, penflufen, penthiopyrad and sedaxane.

The compound of the invention may therefore be a compound of any of formulae I to XVIII:

wherein -L- is selected from : -CR²R²-N R¹-, -CR²R²-0-, - C(0)-0-, - CR¹ =N-, and -CR¹=N-

R¹ is independently selected from H , C1-C4 alkyl and C1-C4 haloalkyl; and

R² is independently selected at each occurrence from H, fluorine, C C alkyl and C C₄ haloalkyl;

or an agronomically acceptable salt or N-oxide thereof.

Thus, it can be seen that compounds of the invention may have the structure A-L-B, in which A is the portion of the structures of formulae I to XVIII which are to the left of the L as depicted above and B is the the portion of the structures of formulae I to XVIII which are to the right of the L as depicted above.

I n an embodiment, the compound is selected from compounds of formulae XI to XVIII. Specifically, the compound may be a compound of formula XI.

Alternatively, the compounds may be a compound of formula X.

I n a second aspect of the invention, is provided a compound of formula XIX:

XIX

wherein -L- is selected from: -CR²R²-NR¹-, -CR²R²-0-, -C(0)-0-, - CR¹=N-, and -CR¹=N-0-;

R¹ is independently selected from H, C C₄ alkyl and C₁-C4 haloalkyi; and

R² is independently selected at each occurrence from H, fluorine, C C₄ alkyl and C C₄ haloalkyi;

R³ is independently selected from H, C C₄ alkyl, C₃-C₅-cycloalkyl and C C₄ haloalkyi;

R⁴ and R⁵ are each independently selected from H, halogen, C C₄ alkyl and C C₄ haloalkyi;

R⁶ is independently phenyl, biphenyl or heteroaryl,

wherein in any R⁶ group is unsubstituted or is substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a; C0₂R^a; C(0)R^a;

CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

wherein R^a is selected from H, C C₆ alkyl, C₃-C₆ cycloalkyi or bicycloalkyi and Ci-C₄ haloalkyi; and wherein, in the case of an aryl group (including phenyl, biphenyl and naphthyl) or heteroaryl group, any two of these substituents (e.g. NR^aR^a, OR^a, SR^a, R^a) when present on neighbouring atoms in the aryl or heteroaryl group may, where chemically possible, together with the atoms to which they are attached form a mono or bicyclic carbocyclic or heterocyclic ring system which is fused to the aryl or heteroaryl group and which may likewise be substituted by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a C0₂R^a _; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

or an agronomically acceptable salt or N-oxide thereof.

In an embodiment, the compound of formula XIX is a compound of formula XX:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as described above for compounds of formula XIX. In an embodiment, the compound of formula XIX is a compound of formula XXI:

wherein R², R³, R⁴, R⁵ and R⁶ are as described above for compounds of formula XIX.

In an embodiment, the compound of formula XIX is a compound of formula XXII:

II

wherein R³, R⁴, R⁵ and R⁶ are as described above for compounds of formula XIX.

In an embodiment, the compound of formula XIX is a compound of formula XXIII:

III

wherein R¹ , R³, R⁴, R⁵ and R^s are as described above for compounds of formula XIX.

In an embodiment, the compound of formula XIX is a compound of formula XXIV:

XXIV

wherein R , R , R , R and R are as described above for compounds of formula XIX. ed a compound of formula XXV:

wherein -L- is selected from:- CR²R²-NR¹-, -CR²R²-0-, - C(0)-0-, -CR¹=N-, and -CR¹=N-0-; X is selected from N and NO; R¹ is independently selected from H , C1-C4 alkyl and C1-C4 haloalkyl; and

R² is independently selected at each occurrence from H, fluorine, C C alkyl and C C₄ haloalkyl;

R⁷ and R⁸ are each independently selected from H , halogen, C C₄ alkyl and C C₄ haloalkyl; n is an integer selected from 0, 1 , 2, 3, 4 and 5; and

m is an integer selected from 0, 1 , 2, 3 and 4

wherein in any R¹ , R², R⁷or R⁸ group is unsubstituted or is substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; N R^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a; C0₂R^a; C(0)R^a; CON R^aR^a; CH₂N R^aR^a; CH₂OR^a and OR^a;

wherein R^a is selected from H, CrC₆ alkyl, C₃-C₆ cycloalkyl or bicycloalkyl and Ci-C₄ haloalkyl; and wherein, in the case of an aryl group (including phenyl, biphenyl and naphthyl) or heteroaryl group, any two of these substituents (e.g. N R^aR^a, OR^a, SR^a, R^a) when present on neighbouring atoms in the aryl or heteroaryl group may, where chemically possible, together with the atoms to which they are attached form a mono or bicyclic carbocyclic or heterocyclic ring system which is fused to the aryl or heteroaryl group and which may likewise be substituted by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; N R^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a C0₂R^a _; C(0)R^a; CON R^aR^a; CH₂N R^aR^a; CH₂OR^a and OR^a;

or an agronomically acceptable salt or N-oxide thereof.

The following embodiments apply to compounds of any of formulae (l)-(XXV). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.

Preferably R² and R¹ are each at each occurrence H .

In an embodiment, -L- is - CR²R²- N R¹-. Thus, -L- may be -CH₂-NH-.

In another embodiment, -L- is - CR²R²- 0-. Thus, -L- may be CH₂0.

In yet another embodiment, -L- is -C(0)-0-. In a yet further embodiment, -L- is -CR¹=N-. Thus, -L- may be -CH=N-. In yet another embodiment, -L- is -CR¹=N-0-. Thus, -L- may be -CH=N-0-. In an embodiment, R³ is C1-C4 alkyl, e.g. methyl.

In an embodiment, R⁴ is H. In another embodiment, R⁴ is halogen. Thus, R⁴ may be F.

Alternatively, R⁴ may be CI.

In an embodiment, R⁵ is independently selected from CrC₄-alkyl and C1-C4 haloalkyl.

Preferably, R⁵ is independently selected from Ci alkyl and Ci haloalkyl. Thus, R⁵ may be methyl, fluoromethyl, difluoromethyl or trifluoromethyl. In an embodiment, R⁵ is CrC₄-alkyl, e.g. methyl. In an embodiment, R⁵ is C C haloalkyl, e.g. R⁵ is selected from difluoromethyl or trifluoromethyl.

Thus, in a specific embodiment, the pyrazole to which R³, R⁴ and R⁵ are attached, is selected

from:

In an embodiment, R is selected from phenyl, biphenyl and 5-membered heteroaromatic (e.g. a 5-membered heteroaromatic comprising 1 heteroatom in the ring), any of which may be substituted or unsubstituted. In an embodiment, R⁶ is selected from phenyl, biphenyl and thiophenyl, any of which may be substituted or unsubstituted. In an embodiment, R⁶ is substituted or unsubstituted phenyl. Alternatively, R⁶ may be substituted or unsubstituted biphenyl. In a further alternative, R^B is substituted or unsubstituted thiophenyl.

In an embodiment, R⁶ is selected from the following structures:

In an embodiment, X is NO. Preferably, X is N.

In an embodiment, n is 1. In embodiments in which n is not 0, the group R⁷ is at one occurence in the 2-position relative to the rest of the molecule. Thus, the phenyl ring to which

the R⁷ group is attached may take the form:

. In an embodiment, R⁷ is CrC₄- haloalkyl. Thus, R² may be independently selected from CrC₄-fluoroalkyl. In a preferred embodiment, R⁷ is CF₃. Thus, the phenyl ring to which the R⁷ group is attached may take the

form:

In an embodiment, m is 2. In embodiments in which m is not 0, the group R is at one occurence in the 3-position relative to X (e.g. the pyridine N). In embodiments in which m is not 0, the group R⁸ is at one occurence in the 5-position relative to X (e.g. the pyridine N). Thus, the ring to which the R groups are attached may take the form:

e.g.

In an embodiment, R is at one occurrence halo. In an embodiment, R is at one occurrence

In an embodiment, R is at one occurrence CrC₄-haloalkyl. In an embodiment, R is at one occurrence CrC₄-fluoroalkyl. In a preferred embodiment, R⁸ is at one occurrence CF₃.

Thus, the ring to which the R groups are attached may take the form

e.g.

In any of the above aspects and embodiments, heteroaryl groups may be any aromatic (i.e. a ring system containing 2(2n + 1)π electrons) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the

heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 -3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10- membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1- 4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.

In any of the above aspects and embodiments, a heterocycloalkyl group is a 3-8 membered saturated or partially saturated ring comprising 1 or 2 heteroatoms independently selected from O, S and N (in other words from 1 to 2 of the atoms forming the ring system are selected from O, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to rings with from 5 to 8 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran,

tetrahydropyran, dihydropyran, dioxane, azepine.

In any of the above aspects and embodiments, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen substituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.

In an embodiment, in any R¹-R⁸ group which contains an aryl or heteroaryl group, that aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a _; C0₂R^a _; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a; and OR^a; wherein R^a is selected from H, C C₄ alkyl and C C₄ haloalkyl; and wherein any two substituents on neighbouring atoms and comprising R^a groups may join up to form a ring.

In an embodiment, in any R¹-R⁸ group which contains an alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl group, that alkyl, haloalkyl, cycloalkyl or heterocycloalkyl group is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: oxo; =NR^a; =NOR^a; R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a _; C0₂R^a _; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a; and OR^a; wherein R^a is selected from H, Ci-C₄ alkyl and C C₄ haloalkyl.

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

The compounds of the invention may be obtained, stored and/or used in the form of an agronomically acceptable salt. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of agronomically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,

benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable salts also include salts of inorganic and organic bases, e.g. counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium. The compounds may also be obtained, stored and/or used in the form of an N-oxide.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).

The activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.

The present invention also includes all environmentally acceptable isotopically-labelled compounds of formulae I to XXV and their syntheses, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ^3SCI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

Throughout this specification these abbreviations have the following meanings:

DCE - dichloromethane

DCM - dichloromethane

MS - molecular sieves

THF - tetrahydrofuran TLC - thin layer chromatography

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

If appropriate, the compounds of the invention can, at certain concentrations or application rates, be used as fungicides.

According to another aspect of the present invention, there is provided a method for controlling fungal diseases of plants, the method comprising applying an agronomically effective and substantially non-phytotoxic (to the crop plant) quantity of a compound of the invention to the seeds of the plants, to the plants themselves or to the area where it is intended that the plants will grow.

The pesticide may be applied as a seed treatment, foliar application, stem application, drench or drip application (chemigation) to the seed, the plant or to the fruit of the plant or to soil or to inert substrate (e.g. inorganic substrates like sand, rockwool, glasswool; expanded minerals like perlite, vermiculite, zeolite or expanded clay), Pumbe, Pyroclastic materials or stuff, synthetic organic substrates (e.g. polyurethane) organic substrates (e.g. peat, composts, tree waste products like coir, wood fibre or chips, tree bark) or to a liquid substrate (e.g. floating hydroponic systems, Nutrient Film Technique, Aeroponics).

In a further aspect, the present invention also relates to a fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of the invention. The composition may further comprise one or more additional fungicides. The term "effective and non-phytotoxic amount" means an amount of pesticide according to the invention which is sufficient to control or destroy any of the targeted pests present or liable to appear in the crops and which does not have any significant detrimental effect on the crops or indeed has a positive effect on plant vigour and yield in the absence of target organism. The amount will vary depending on the pest to be controlled, the type of crop, the climatic conditions and the compounds included in the pesticidal composition. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art.

Depending on their particular physical and/or chemical properties, the active compounds of the invention can be formulated as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, microencapsulations in polymeric substances and in coating materials for seed, and also as ULV cold and warm fogging formulations.

The active compounds can be used neat, or in the form of a formulation, e.g. ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural substances impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances. Application may be carried out, for example, by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is also possible to apply the active compounds by the ultra-low volume method or to inject the preparation of active compound or the active compound itself into the soil. It is also possible to treat the seed of the plants.

Formulations containing the compounds of the invention are produced in a known manner, for example by mixing the compounds with extenders (e.g. liquid solvents and/or solid carriers), optionally with the use of surfactants (e.g. emulsifiers and/or dispersants and/or foam-formers). The formulations are prepared either in factories/production plants or alternatively before or during the application.

Auxiliaries are substances which are suitable for imparting to the composition itself and/or to preparations derived therefrom (for example spray liquors, seed dressings) particular properties such as certain technical properties and/or also particular biological properties. Typical suitable auxiliaries are: extenders, solvents and carriers.

Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and non-aromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulphones and sulphoxides (such as dimethyl sulphoxide).

If the extender used is water, it is also possible to use, for example, organic solvents as auxiliary solvents. Essentially, suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, alcohols such as butanol or glycol and also their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulphoxide.

Suitable solid carriers are: for example, ammonium salts and ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and ground synthetic minerals, such as finely divided silica, alumina and silicates; suitable solid carriers for granules are: for example, crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic meals, and granules of organic material such as paper, sawdust, coconut shells, maize cobs and tobacco stalks; suitable emulsifiers and/or foam-formers are: for example, nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates,

arylsulphonates and also protein hydrolysates; suitable dispersants are nonionic and/or ionic substances, for example from the classes of the alcohol-POE and/or -POP ethers, acid and/or POP-POE esters, alkylaryl and/or POP-POE ethers, fat- and/or POP-POE adducts, POE- and/or POP-polyol derivatives, POE- and/or POP-sorbitan- or -sugar adducts, alkyl or aryl sulphates, alkyl- or arylsulphonates and alkyl or aryl phosphates or the corresponding PO- ether adducts. Furthermore, suitable oligo- or polymers, for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulphonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulphonic acids and their adducts with formaldehyde.

Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, as well as natural phospholipids such as cephalins and lecithins, and synthetic phospholipids, can be used in the formulations.

Further additives may be mineral and vegetable oils. It is also possible to add colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc. Other possible additives are perfumes, mineral or vegetable, optionally modified oils and waxes.

The formulations may also comprise stabilizers, e.g. low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability.

The formulations generally comprise between 0.01 and 98% by weight of active compound, preferably between 0.1 and 95% and particularly preferably between 0.5 and 90%.

The active compounds of the invention can also be used as a mixture with other known fungicides, for example, to improve the activity spectrum or to reduce or slow the development of resistance. A mixture with other known active compounds such as nematicides, herbicides, insecticides, acaricides, or bactericides, or with fertilizers and growth regulators, safeners or semiochemicals is also possible.

Exemplary application rates of the active compounds according to the invention are: when treating leaves: from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used); when treating seed: from 2 to 200 g per 100 kg of seed, preferably from 2.5 to 150 g per 100 kg of seed, and particularly preferably from 2.5 to 25 g per 100 kg of seed, very particularly preferably from 2.5 to 12.5 g per 100 kg of seed; when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.

The compositions according to the invention are suitable for protecting any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture and, in particular, cereals (e.g. wheat, barley, rye, millet and oats), maize, cotton, soya beans, rice, potatoes, sunflowers, beans, coffee, beet (for example sugar beet and fodder beet), peanuts, vegetables (e.g. tomatoes, cucumbers, onions and lettuce), lawns, fruit and nut trees (e.g. apples pears peaches nectarines, apricots, hazelnut, pecan, macadamia, pistachio), soft fruit (e.g. strawberries, raspberries, blackcurrants, redcurrants), grapevines, bananas, cocoa and ornamental plants.

The active compounds of the invention, in combination with good plant tolerance and favourable toxicity to warm-blooded animals and being tolerated well by the environment, are suitable for protecting plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested material and for controlling pests, in particular fungal diseases, which are encountered in agriculture, in horticulture, in animal husbandry, in forests, in gardens and leisure facilities, in the protection of stored products and of materials, and in the hygiene sector. They may be preferably employed as crop protection agents.

SDHIs

Many of the compounds of the invention are defined in relation to SDHI inhibitors. An SDHI can be identified by testing a compound against one of a number of assays which will be known to the person skilled in the art. An illustrative example is that described in D. Kriegel et al, 'Succinate Dehydrogenase Activity Assay in situ with Blue Tetrazolium Salt in Crabtree- Positive Saccharomyces cerevisae Strain' (Food Technol. Biotechnol. 46 (4) 376-380 (2008)).

In an embodiment, the SDHI is a compound which was known (i.e. reported as such) to be an SDHI on 1 September 2013.

In another embodiment, the SDHI is a compound which has been approved as an SDHI for agricultural use in Europe and/or North America on or before 1 September 2013.

Use as fungicides

The compounds of the invention have activity as fungicides.

The following are illustrative examples of agricultural pests that may be controlled by fungicidal compounds:

Powdery mildew diseases such as: Blumeria diseases, caused for example by Blumeria graminis; Podosphaera diseases, caused for example by Podosphaera leucotheca;

Sphaerotheca diseases, caused for example by Sphaerotheca fuliginea; Uncinula diseases, caused for example by Uncinula necator;

Rust diseases such as: Gymnosporangium diseases, caused for example by

Gymnosporangium sabinae; Hemileia diseases, caused for example by Hemileia vastatix; Phakopsora diseases, caused for example by Phakopsora pachyrhizi or Phakopsora meibomiae; Puccinia diseases, caused for example by Puccinia recondita; Uromyces diseases, caused for example by Uromyces appendiculatus;

Oomycete diseases such as: Albugo diseases caused for example by Albugo Candida;

Bremia diseases, caused for example by Bremia lactucae; Peronospora diseases, caused for example by Peronospora pisi or P. brassicae; Phytophthora diseases, caused for example by Phytophthora infestans; Plasmopara diseases, caused for example by Plasmopara viticola; Pseudoperonospora diseases, caused for example by Pseudoperonospora humuli or

Pseudoperonospora cubensis; Pythium diseases, caused for example by Pythium ultimum; Leafspot, leaf blotch and leaf blight diseases such as: Alternaria diseases, caused for example by Alternaria solani; Cercospora diseases, caused for example by Cercospora beticola;

Cladiosporum diseases, caused for example by Cladiosporium cucumerinum; Cochliobolus diseases, caused for example by Cochliobolus sativus; Colletotrichum diseases, caused for example by Colletotrichum lindemuthanium; Cycloconium diseases, caused for example by Cycloconium oleaginum; Diaporthe diseases, caused for example by Diaporthe citri;

Drechslera, Syn: Helminthosporium) or Cochliobolus miyabeanus; Elsinoe diseases, caused for example by Elsinoe fawcettii; Gloeosporium diseases, caused for example by

Gloeospo[eta]um laeticolor; Glomerella diseases, caused for example by Glomerella cingulata; Guignardia diseases, caused for example by Guignardia bidwelli; Leptosphaeria diseases, caused for example by Leptosphaeria maculans; Leptosphaeria nodorum; Magnaporthe diseases, caused for example by Magnaporthe grisea; Mycosphaerella diseases, caused for example by Mycosphaerella graminicola; Mycosphaerella arachidtola; Mycosphaerella fibensis; Phaeosphaeria diseases, caused for example by Phaeosphaera nodorum; Pyrenophora diseases, caused for example by Pyrenophora teres; Ramularia diseases, caused for example by Ramularia collo-cygni; Rhynchosporium diseases, caused for example by Rhynchosporium secalis; Septoria diseases, caused for example by Septoria apii or Septoria lycopercisi;

Typhula diseases, caused for example by Typhula incarnata; Venturia diseases, caused for example by Venturia inaequalis;

Root and stem diseases such as: Corticium diseases, caused for example by Corticium graminearum; Fusarium diseases, caused for example by Fusa[eta]um oxysporum;

Gaeumannomyces diseases, caused for example by Gaeumannomyces graminis; Rhizoctonia diseases, caused for example by Rhizoctonia solani; Sarocladium diseases caused for example by Sarocladium oryzae; Sclerotium diseases caused for example by Sclerotium oryzae; Tapesia diseases, caused for example by Tapesia acuformis; Thielavbpsis diseases, caused for example by Thielaviopsis basicola;

Ear and panicle diseases including maize cob, such as: Alternaria diseases, caused for example by Alternaria spp.; Aspergillus diseases, caused for example by Aspergillus flavus; Cladosporium diseases, caused for example by Cladosporium spp.; Claviceps diseases, caused for example by Claviceps purpurea; Fusarium diseases, caused for example by Fusarium culmorum; Gibberella diseases, caused for example by Gibberella zeae;

Monographella diseases, caused for example by Monographella nivalis;

Smut and bunt diseases such as: Sphacelotheca diseases, caused for example by

Sphacelotheca reiliana; Tilletia diseases, caused for example by Tilletia caries;

Urocystis diseases, caused for example by Urocystis occulta; Ustilago diseases, caused for example by Ustilago nuda;

Fruit rot and mould diseases such as: Aspergillus diseases, caused for example by Aspergillus flavus; Botrytis diseases, caused for example by Botrytis cinerea; Penicillium diseases, caused for example by Penicillium expansum; Rhizopus diseases caused by example by Rhizopus stolonifer; Sclerotinia diseases, caused for example by Sclerotinia sclerotiorum;

Verticilium diseases, caused for example by Verticilium alboatrum;

Seed and soil borne decay, mould, wilt, rot and dampingoff diseases such as: Alternaria diseases, caused for example by Alternaria brassicicola; Aphanomyces diseases, caused for example by Aphanomyces euteiches; Ascochyta diseases, caused for example by Ascochyta lentis Aspergillus diseases, caused for example by Aspergillus flavus; Cladosporium diseases, caused for example by Cladosporium herbarum; Cochliobolus diseases, caused for example by Cochliobolus sativus (Conidiaform: Drechslera, Bipolaris Syn: Helminthosporium);

Colletotrichum diseases, caused for example by Colletotrichum coccodes; Fusarium diseases, caused for example by Fusa[eta]um culmorum; Gibberella diseases, caused for example by Gibberella zeae; Macrophomina diseases, caused for example by Macrophomina phaseolina Monographella diseases, caused for example by Monographella nivalis; Penicillium diseases, caused for example by Penicillium expansum; Phoma diseases, caused for example by Phoma lingam; Phomopsis diseases, caused for example by Phomopsis sojae; Phytophthora diseases, caused for example by Phytophthora cactorum; Pyrenophora diseases, caused for example by Pyrenophora graminea Pyricularia diseases, caused for example by Pyricularia oryzae; Pythium diseases, caused for example by Pythium ultimum; Rhizoctonia diseases, caused for example by Rhizoctonia solani; Rhizopus diseases, caused for example by Rhizopus oryzae; Sclerotium diseases, caused for example by Sclerotium rolfsii; Septoria diseases, caused for example by Septoria nodorum; Typhula diseases, caused for example by Typhula incarnata; Verticillium diseases, caused for example by Verticillium dahliae;

Canker, broom and dieback diseases such as: Nectria diseases, caused for example by Nectria galligena;

Blight diseases such as:

Monilinia diseases, caused for example by Monilinia laxa;

Leaf blister or leaf curl diseases such as: Exobasidium diseases caused for example by Exobasidium vexans; Taphrina diseases, caused for example by Taphrina deformans; - Decline diseases of wooden plants such as:

Esca diseases, caused for example by Phaemoniella clamydospora, Phaeomoniella clamydospora, Phaeoacremonium aleophilum and Fomitiporia mediterranea;

Eutypa dyeback, caused for example by Eutypa lata; Dutch elm disease, caused for example by Ceratocystsc ulmi; Ganoderma diseases caused by example by Ganoderma boninense;

Diseases of flowers and seeds such as: Botrytis diseases, caused for example by Botrytis cinerea;

Diseases of tubers such as: Rhizoctonia diseases, caused for example by Rhizoctonia solani Helminthosporium diseases, caused for example by Helminthospohum solani.

Diseases of Tubers such as

Rhizoctonia diseases caused for example by Rhizoctonia solani; Helminthosporium diseases caused for example by Helminthospohum solani;

Club root diseases such as

Plasmodiophora diseases, caused for example by Plamodiophora brassicae.

The compounds of the invention may be active against a broad spectrum of fungal diseases. Alternatively they may be active specifically against cereal fungal diseases or they may be specifically active against oomycete diseases.

Notable cereal fungal diseases are:

Erisyphe graminis (now Blumeria)

Septoria nodorum

Septoria tritici

Fusarium oxysporum

Rhychosporium secalis

Pyrenophora teres

Notable oomycete fungal diseases are:

Plamopara viticola

Phytophthora infestans

Pythium ultimum

Bremia lactuca

Peronospora spp

In additional to their fungicidal acitivity, the compounds of the invention may also have some activity against other microbes, e.g. bacteria. The fungicidal compounds of the invention may also be used in the treatment of fungal diseases of humans and animals (e.g. mammals). Likewise, the bactericidal compounds of the invention may be used in the treatment of bacterial diseases of humans and animals. Thus, the invention includes a method of treating a fungal or bacterial disease, the method comprising administering a therapeutic amount of an antifungal agent of the invention to a subject (e.g. a human subject) in need thereof. The compound may be formulated for topical administration to the infected area of the body or it may be formulated for oral or parenteral administration.

Detailed Description - Synthesis

The skilled man will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions); "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later); "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions); "Organic Synthesis - The

Disconnection Approach", S Warren (Wiley), (1982 or later editions); "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions); "Heterocyclic Chemistry", J. Joule (Wiley 2010 edition or later); ("Guidebook To Organic Synthesis" RK Mackie and DM Smith

(Longman) (1982 or later editions), etc., and the references therein as a guide.

The skilled person is familiar with a range of strategies for synthesising organic and particularly heterocyclic molecules and these represent common general knowledge as set out in text books such as Warren Organic Synthesis: The Disconnection Approach"; Mackie and Smith "Guidebook to Organic Chemistry"; and Clayden, Greeves, Warren and Wothers "Organic Chemistry".

The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.

Example 1 - Fluopyram analogues

2-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifiuom

A solution of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanamine (400 mg, 1.78 mmol) and 2- (trifluoromethyl)benzaldehyde (310 mg, 1.78 mmol) in 1 ,2-dichloroethane (6 ml.) was stirred at room temperature over 4A MS for 16h. The reaction mixture was filtered and the solvent removed in vacuo to afford the product (572 mg, 85%) as a yellow solid.

1 H NMR 5_H (300 MHz, CDCI3); 8.64 (s, 1 H), 8.57 (s, 1 H), 8.08 (d, J = 7.5 Hz, 1 H), 7.80 (s, 1 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.56-7.39 (m, 2H), 4.08 (t, J = 7.0 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H); ESI-MS 381.4 [MH⁺].

N-[[3-chloro-5-(trifluoromethyl)-2-pyridyl]methoxy]-1-[2-(trifluoromethyl)

phenyljmethanimine 2

A solution of 0-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)hydroxylamine (180 mg, 0.795 mmol) and 2-(trifluoromethyl)benzaldehyde (138 mg, 0.795 mmol) in 1 ,2-dichloroethane (4 mL) was heated at 80 °C over 4A MS. After 4 h the reaction mixture was allowed to cool and was stirred at room temperature for 18 h. The mixture was filtered and concentrated to give the internal oxime (240 mg, 79%) as a colourless liquid.

¹ H NMR 5_H (300 MHz, CDCI₃); 8.72 (s, 1 H), 8.50 (s, 1 H), 7.92-7.82 (m, 2H), 7.57 (d, J = 7.5 Hz, 1 H), 7.45-7.34 (m, 2H), 5.45 (s, 2H); ESI-MS 383.1 [MH⁺].

2-[3-Chloro-5-(trifluoromethyl)-2-pyridyl]-N-[[2-(trifluor^

methyljethanamine 3

3-Chloro-5-(trifluoromethyl)-2-ethylaminepyridinyl.HCI (200 mg, 0.89 mmol) and 2- trifluoromethyl benzaldehyde (0.12ml_, 0.89 mmol) were stirred in DCE (2 mL) for 16 h at ambient temperature in the presence of 4 A molecular sieves, after which time TLC showed the complete consumption of the starting materials. The reaction mixture was then cooled to 0 °C and sodium borohydride (34 mg, 0.89 mmol) was added portionwise before being stirred for a further 16 h at ambient temperature. The reaction was quenched with H₂0 (2 mL), the organic layer separated and dried over MgS0₄ before the solvent was removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 98:2 DCM:MeOH) to afford the desired product as a colourless oil (50 mg, 15%).

¹ H NMR δ_Η (CDCIs, 300 MHz): 8.61 (s, 1 H), 7.81 (s, 1 H), 7.55 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1 H), 7.26 (t, J = 7.5 Hz, 1 H), 3.94 (s, 2H), 3.17 (t, J = 6.5 Hz, 2H), 3.04 (t, J = 4.0 Hz, 2H). ESI-MS 383.0 [MH]⁺.

2-[3-Chloro-5-(trifluoromethyl)-2-pyridyl]ethyl 2-(trifluoromethyl)benzoate 4

To a solution of 2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]ethanol (199 mg, 0.88 mmol) in THF (1.5 ml.) was added a solution of 2-(trifluoromethyl)benzoyl chloride (184 mg, 0.88 mmol) in THF (1.5 ml.) and triethylamine (0.12 ml_, 0.88 mmol) and the mixture was stirred at ambient temperature for 16 h. A further 0.25 equivalents of the acid chloride (46 mg, 0.22 mmol) and triethylamine (30 μΙ_, 0.22 mmol) was added and stirring was continued for a further 16 h, after which time TLC showed complete consumption of the starting alcohol. The reaction mixture was diluted with H₂0 (1 ml.) and extracted with EtOAc (5 ml.) before being dried over MgSC and the solvent removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 90: 10 Hexane:EtOAc) to afford the desired product as a colourless oil (100 mg, 28%).

¹ H NMR δ_Η (CDCIs, 300 MHz): 8.74 (s, 1 H), 7.93 (s, 1 H), 7.78 - 7.71 (m, 2H), 7.64 - 7.60 (m, 2H), 4.87 (t, J = 6.5 Hz, 2H), 3.49 (t, J = 6.5 Hz, 2H). ESI-MS 398.0 [MH]⁺.

Example 2 - Bixafen Analogues

N-[2-(3,4-dichlorophenyl)-4-fluoro-phenyl]-1-[3-(difluoromethyl)-1 -methyl^

yljmethanimine 5

To a solution of 2-(3,4-dichlorophenyl)-4-fluoro-aniline (1 11 mg, 0.44 mmol) in CHCI₃ (3 ml.) was added 3-(difluoromethyl)-1-methyl-pyrazole-4-carbaldehyde (70 mg, 0.44 mmol) and 4A MS and the mixture stirred for 16h at room temperature. The reaction mixture was filtered and the solvent removed in vacuo to afford the product (169 mg, 97%) as a pale yellow oil which solidified on standing.

¹ H NMR δ_Η (CDCIs, 300 MHz): 8.42 (s, 1 H), 7.75 (s, 1 H), 7.51 (d, J = 2.1 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.20 (dd, J = 8.3, 2.1 Hz, 1 H), 7.05-6.96 (m, 3H), 6.78 (t, = 54.1 Hz, 1 H), 3.88 (s, 3H); ESI-MS 397.9 [M]⁺

2-(3,4-dichlorophenyl)-N-[[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]met^

aniline 6

To a solution of 2-(3,4-dichlorophenyl)-4-fluoro-aniline (470 mg, 1.8 mmol) in DCE (5 mL) was added 3-(difluoromethyl)-1-methyl-pyrazole-4-carbaldehyde (295 mg, 1.8 mmol) and 4A MS and the mixture stirred for 16h at room temperature. Sodium triacetoxyborohydride (234 mg, 3.6 mmol) was then added and the mixture stirred for a further 16h after which time the reaction mixture was filtered, diluted with dichloromethane (10 mL), washed with H₂0 (10 mL) and the solvent removed in vacuo. The resulting residue was purified by column

chromatography, eluting with 8:2 hexane/ethyl acetate moving to 6:4 hexane/ethyl acetate to afford the product (310 mg, 42%) as a clear oil which solidified on standing.

1 H NMR δ_Η (CDCI₃, 300 MHz): 7.42 (d, J = 8.2 Hz, 1 H), 7.41 (d, J = 2.0 Hz, 1 H), 7.18 (s, 1 H), 7.16 (dd, J = 8.3 Hz, 2.0 Hz, 1 H), 6.88 (m, 1 H), 6.74 (dd, J = 8.9, 3.0 Hz, 1 H), 6.58 (dd, J = 8.9, 4.6 Hz, 1 H), 6.58 (overlapping t, J = 54.4 Hz, 1 H), 4.18 (s, 2H), 3.78 (s, 3H). ESI-MS 400.0 [M]⁺

Example 3 - Isopyrazam Derivatives

(E)-N-((3-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)methylene)-9-isopropyl-1, 2,3,4- tetrah dro-1,4-methanonaphthalen-5-amine 7

7 A solution of 3-(difluoromethyl)-1-methyl-pyrazole-4-carbaldehyde (130 mg, 0.81 mmol) and 5- amino-9-isopropylbenzyl norbornene (163 mg, 0.81 mmol) in DCM (2 mL) was stirred under nitrogen in the presence of molecular sieves. After 22.5 h TLC showed complete consumption of the starting material. The reaction mixture was filtered and the solvent removed in vacuo to provide the product as an off-white solid (225 mg, 81%).

NMR δ_Η (CDCI₃, 300 MHz): 8.40 (s, 1 H), 7.92 (s, 1 H), 7.08 - 6.75 (m, 4H), 3.90 (s, 3H), 3.16 (s, 1 H), 3.07 (s, 1 H), 1.90 - 1.87 (m, 2H), 1.55 - 1.47 (m, 2H), 1.21 - 1.06 (m, 2H), 1.06 - 0.72 (m, 6H). EI-MS 344.2 [MH]⁺.

N-((3-(Difluoromethyl)-1 -methyl-1 H-pyrazol-4-yl)methyl)-9-isopropyl-1 ,2,3,4-tetrahydro-1 ,4- 8

Sodium triacetoxyborohydride (119 mg, 0.56 mmol) was added to a solution of 3- (difluoromethyl)-1-methyl-pyrazole-4-carbaldehyde (64 mg, 0.40 mmol) and 5-amino-9- isopropylbenzyl norbornene (81 mg, 0.40 mmol) in DCE (2 mL) under nitrogen in the presence of molecular sieves. The reaction mixture was stirred at ambient temperature for 23 h, after which time TLC analysis showed complete consumption of the starting material. The reaction mixture was filtered, then H₂0 (25 mL) was added, extracted with DCM (3 x 10 mL) and washed with brine (2 x 20 mL) before being dried over MgS0₄ and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 70:30 hexane/EtOAc) followed by trituration (solvent hexane) to afford the product as a white solid (88 mg, 64%).

NMR δ_Η (CDCI₃, 300 MHz): 7.24 (s, 1 H), 6.91 (t, J = 7.5 Hz, 1 H), 6.63 (t, J = 54.5 Hz, 1 H), 6.57 (d, J = 7.0 Hz, 1 H), 6.44 (d, J = 7.0 Hz, 1 H), 4.27 (s, 2H), 3.82 (s, 3H), 3.08 (s, 2H), 1.89 - 1.82 (m, 2H), 1.46 - 1.43 (m, 2H), 1.12 - 1.02 (m, 2H), 0.94 - 0.72 (m, 6H). ESI-MS 346.1 [MH]⁺.

Example 4 - Testing the fungicidal activity of compounds of the invention

An assay was carried out to determine the in vitro fungicide activity of 8 compounds of the invention.

Experimental Conditions The biological evaluation was undertaken in vitro using a Microtitre Plate Assay (MTP).

Appropriate concentrations range (8 concentrations, depending on the pathogen) of technical or formulated fungicide were tested on a defined fungal spore suspension or a ground mycelium suspension. Three repetitions (wells) were undertaken.

In the tables below C represents a percentage inhibition of 0.1 -50; B represents a percentage inhibition of 50-80; and A represents a percentage inhibition of 80-100.

Results

Alternaria solani Hst: Optical density (OD) measured at 590 nm after 3 days of incubation at 19°C in darkness

Botryris cinerea Hst: Optical density (OD) measured at 590 nm after 5 days of incubation at 19°C in darkness

Venturia inaequalis 1694: Optical density (OD) measured at 590 nm after 7 days of incubation at 19°C in darkness

Fusarium graminearum Fgl: Optical density (OD) measured at 590 nm after 3 days of incubation at 19°C in darkness

Compound Concentration ^g a.i./ml) 0.16 0.8 4 20

Percentage of inhibition ( of the untreated control)

5 C C c A

6 c c c C

7 C c c C

8 C c c C

Mycosphaerella graminicola StA: Optical density (OD) measured at 590 nm after 7 days of incubation at 19°C in darkness

Rhynchosporium secalis SI: Optical density (OD) measured at 590 nm after 5 days of incubation at 19°C in darkness

Rhizoctonia solani AG4: Optical density (OD) measured at 590 nm after 3 days of incubation at 19°C in darkness

This shows that the compounds of the invention have activity against a range of fungal plant pathogens.

Claims

Claims

1. A compound which is a derivative of a succinate dehydrogenase inhibitor (SDHI) wherein the SDHI incorporates an amide group and has the form A-C(0)-NH-B, wherein A and B are the residual parts of the structure of the SDHI to which the amide group is bound and wherein the compound has a structure A-L-B

wherein -L- is selected from: -CR²R²-NR¹-, -CR²R²-0-, - C(0)-O, - CR¹=N-, and -CR¹=N-0-;

R¹ is independently selected from H, C C₄ alkyl and C1 -C4 haloalkyl; and

R² is independently selected at each occurrence from H, fluorine, C C₄ alkyl and C C₄ haloalkyl;

or an agronomically acceptable salt or N-oxide thereof.

2. A compound of claim 1 , wherein the SDHI is selected from benodanil, flutolanil, mepronil, isofetamid, fluopyram, fenfuram, carboxin, oxycarboxin, thifluzamide, boscalid, benzovindiflupyr, bixafen, fluxapyroxad, furametpyr, isopyrazam, penflufen, penthiopyrad and sedaxane.

wherein -L- is selected from: -CR²R²-NR¹-, -CR²R²-0-, - C(0)-0-, - CR¹=N-, and -CR¹=N-0-; R¹ is independently selected from H, C1-C4 alkyl and C1-C4 haloalkyi; and R² is independently selected at each occurrence from H, fluorine, C C₄ alkyl and C C₄ haloalkyi;

or an agronomically acceptable salt or N-oxide thereof.

4. A compound of formula XIX:

wherein -L- is selected from: -CR²R²-NR¹-, -CR²R²-0-, -C(0)-0-, - CR¹=N-, and -CR¹=N-0-;

R¹ is independently selected from H, C1-C4 alkyl and C1-C4 haloalkyi; and

R² is independently selected at each occurrence from H, fluorine, C1-C4 alkyl and C1-C4 haloalkyi;

R³ is independently selected from H, C C₄ alkyl, C₃-C₃-cycloalkyl and C C₄ haloalkyi;

R⁴ and R⁵ are each independently selected from H, halogen, C C₄ alkyl and C C₄ haloalkyi;

R⁶ is independently phenyl, biphenyl or heteroaryl,

wherein in any R⁶ group is unsubstituted or is substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a _; C0₂R^a; C(0)R^a;

CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

wherein R^a is selected from H, C C₆ alkyl, C₃-C₆ cycloalkyi or bicycloalkyi and C1-C4 haloalkyi; and wherein, in the case of an aryl group or heteroaryl group, any two of these substituents when present on neighbouring atoms in the aryl or heteroaryl group may, where chemically possible, together with the atoms to which they are attached form a mono or bicyclic carbocyclic or heterocyclic ring system which is fused to the aryl or heteroaryl group and which may likewise be substituted by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a _; C0₂R^a; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

or an agronomically acceptable salt or N-oxide thereof.

5. A compound of claim 4, wherein R³ is C C₄ alkyl, optionally wherein R³ is methyl.

6. A compound of claim 4 or claim 5, wherein R⁴ is H.

7. A compound of claim 4 or claim 5, wherein R⁴ is halogen, optionally wherein R⁴ is F or

CI.

8. A compound of any one of claims 4 to 7, wherein R⁵ is CrC₄-alkyl optionally wherein is methyl.

9. A compound of any one of claims 4 to 7, wherein R⁵ is C C₄ haloalkyi optionally wherein R⁵ is selected from difluoromethyl or trifluoromethyl.

10. A compound of any one of claims 4 to 9, wherein R^s is substituted or unsubstituted phenyl or substituted or unsubstituted biphenyl.

11. A compound of any one of claims 4 to 9, wherein R^s is thiophenyl.

wherein -L- is selected from:- CR²R²-NR¹-, -CR²R²-0-, - C(0)-0-, -CR¹=N-, and -CR¹=N-0-; X is selected from N and NO;

R¹ is independently selected from H, CrC₄ alkyl and C₁-C4 haloalkyi; and

R² is independently selected at each occurrence from H, fluorine, d-C alkyl and Ci-C haloalkyi;

R⁷ and R⁸ are each independently selected from H, halogen, C C alkyl and C C₄ haloalkyi; n is an integer selected from 0, 1 , 2, 3, 4 and 5; and

m is an integer selected from 0, 1 , 2, 3 and 4

wherein in any R¹, R², R⁷or R⁸ group is unsubstituted or is substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a; S0₂NR^aR^a _; C0₂R^a; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

wherein R^a is selected from H, C C₆ alkyl, C₃-C₆ cycloalkyi or bicycloalkyi and C C₄ haloalkyi; and wherein, in the case of an aryl group or heteroaryl group, any two of these substituents when present on neighbouring atoms in the aryl or heteroaryl group may, where chemically possible, together with the atoms to which they are attached form a mono or bicyclic carbocydic or heterocyclic ring system which is fused to the aryl or heteroaryl group and which may likewise be substituted by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: R^a; halo; nitro; cyano; NR^aR^a; S0₃R^a; S0₂R^a;

S0₂NR^aR^a _; C0₂R^a; C(0)R^a; CONR^aR^a; CH₂NR^aR^a; CH₂OR^a and OR^a;

or an agronomically acceptable salt or N-oxide thereof.

13. A compound of claim 12, wherein X is N. 13, wherein the phenyl ring to which the R⁷ group is

15. A compound of a to 14, wherein the ring to which the R groups are

attached takes the form:

16. A compound according to any preceeding claim, wherein -L- is -CR²R²-NR¹.

17. A compound according to any one of claims 1 to 15, wherein -L- is -CR²R²-0-.

18. A compound according to any one of claims 1 to 15, wherein -L- is -C(0)-0-.

19. A compound according to any one of claims 1 to 15, wherein -L- is -CR¹=N-.

20. A compound according to any one of claims 1 to 15, wherein -L- is -CR¹=N-0-

A compound according to any preceding claim, wherein R² and R¹ are each at each

22. A method for controlling fungal diseases of plants, the method comprising applying an agronomically effective and substantially non-phytotoxic quantity of a compound of any preceding claim to the seeds of the plants, to the plants themselves or to the area where it is intended that the plants will grow.

23. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any preceding claim.