WO2015040405A2 - Agricultural chemicals - Google Patents

Abstract

The present invention relates to compounds which are of use in the field of agriculture as nematicides, fungicides, insecticides and/or acaricides. The compounds of the invention are pyridine or pyrimidine substituted with both an amine and an amide substituent group. The invention also relates to compositions comprising said compounds and methods of using said compounds.

Description

Agricultural Chemicals

The present invention relates to compounds which are of use in the field of agriculture as nematicides, fungicides, insecticides and/or acaricides.

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 that of prior art compoundscompound. These lower activity compounds are still effective as nematicides, fungicides, insecticides and/or acaricides 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 prior art compounds, i .e. they may have better, similar or even slightly lower activity than prior art compoundsagainst 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 of formula I:

wherein

X is independently selected from N and CR⁵;

R¹ and R² are independently selected from the group comprising: H, Ci-Ce alkyl, -(CR⁸R⁸) heteroaryl, -(CR⁸R⁸)_n-aryl , -(CR⁸R⁸)_n-aryl-Z-A, -(CR⁸R⁸)_n-heteroaryl-Z-A, -(CR⁸R⁸)_n-C₃-C cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl and Ci-C₈-haloalkyl;

R³, R⁴ and R⁵ are independently selected from the group comprising: H, C1-C4 alkyl, -(CR⁸R⁸) heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n- C₃-C₆-cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl, C1-C haloalkyl , bromo, nitro, OR⁹, SR⁹, cyano, C2-C4 alkenyl, C2-C4 alkynyl and NR⁹R⁹;

R⁶ is independently selected from the group comprising: H, -(CR¹⁰R¹⁰)_mR¹¹ and C(0)R¹²;

R⁷ is independently selected from: H , C1-C4 alkyl, C3-Cs-cycloalkyl and benzyl;

Z is independently selected from O, S and NR⁹;

A is independently selected from aryl and heteroaryl;

R⁸ is independently at each occurrence selected from H, F, C1-C4 alkyl and C1-C4 haloalkyl; R⁹ is independently at each occurrence selected from H, C1-C4 alkyl, C(0)-Ci-C4 alkyl, and Ci- C4 haloalkyi;

R¹⁰ is independently at each occurrence selected from H, F, C1-C4 alkyl and C1-C4 haloalkyi R¹ is independently at each occurrence selected from the group comprising: H, Ci-Ce alkyl, - (CR⁸R⁸)_P-heteroaryl, -(CR⁸R⁸)_P-aryl, -(CR⁸R⁸)_P-aryl-Z-A, -(CR⁸R⁸)_P-heteroaryl-Z-A, -(CR⁸R⁸)_P- C₃- Ce-cycloalkyl, -(CR⁸R⁸)_p-heterocycloalkyl and Ci-Cs-haloalkyl;

R¹² is independently selected from H, C1-C4 alkyl, C1-C4 haloalkyi, C3-C5 cycloalkyi;

n is an integer independently at each occurrence selected from 0, 1 , 2 and 3;

m is an integer independently at each occurrence selected from 0 and 1 ;

p is an integer independently at each occurrence selected from 0 and 1 ;

wherein in any R -R¹² group which contains an alkyl, haloalkyi, cycloalkyi, heterocycloalkyl, aryl or heteroaryl group, that alkyl, haloalkyi, cycloalkyi, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or 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; Ch OR³ and OR^a; wherein R^a is selected from H, C1-C4 alkyl and CF3; and wherein, in the case of an aryl group 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 ring which is fused to the aryl or heteroaryl group;

or an agronomically acceptable salt or N-oxide thereof.

The compound may be a compound of formula la:

wherein

X is independently selected from N and CR⁵;

R¹ and R² are independently selected from the group comprising: H, Ci-Ce alkyl, -(CR⁸R⁸)_n- heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n-aryl-Z-A, -(CR⁸R⁸)_n-heteroaryl-Z-A, -(CR⁸R⁸)_n-C₃-C₆- cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl and Ci-Ce-haloalkyl;

R³, R⁴ and R⁵ are independently selected from the group comprising: H, C1-C4 alkyl, -(CR⁸R⁸)_n- heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n- C₃-C₆-cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl, C1-C4- haloalkyl, halogen, nitro, OR⁹, SR⁹, cyano, C₂-C₄ alkenyl, C₂-C₄ alkynyl and NR⁹R⁹;

R⁶ and R⁷ are independently selected from the group comprising: H and -(CR¹⁰R¹⁰)_mR^{1 1} ; Z is independently selected from O, S and NR⁹;

A is independently selected from aryl and heteroaryl;

R⁸ is independently at each occurrence selected from H, C1-C4 alkyl and C1-C4 haloalkyi;

R⁹ is independently at each occurrence selected from H, C1-C4 alkyl, C(0)-O-C4 alkyl, and O-

C haloalkyi;

R¹⁰ is independently at each occurrence selected from H, C1-C4 alkyl and C1-C4 haloalkyi; or wherein two R ⁰ groups which are attached to the same carbon form an oxo group;

R¹ is independently at each occurrence selected from the group comprising: H, O-Ce alkyl, -

(CR⁸R⁸)p-heteroaryl, -(CR⁸R⁸)_P-aryl, -(CR⁸R⁸)_P-aryl-Z-A, -(CR⁸R⁸)_P-heteroaryl-Z-A, -(CR⁸R⁸)_P- C₃-

C6-cycloalkyl, -(CR⁸R⁸)_P-heterocycloalkyl and Ci-Cs-haloalkyl;

n is an integer independently at each occurrence selected from 0, 1 , 2 and 3;

m is an integer independently at each occurrence selected from 0 and 1 ;

p is an integer independently at each occurrence selected from 0 and 1 ;

wherein in any R -R¹¹ group which contains an alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group, that alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is unsubstituted or 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;

ChbOR⁸ and OR^a; wherein R^a is selected from H, C1-C4 alkyl and C1-C4 haloalkyi; and wherein, in the case of an aryl group 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 ring which is fused to the aryl or heteroaryl group;

or an agronomical ly acceptable salt or N-oxide thereof.

In an embodiment, the compound of formula I or la is a compound of formula II:

wherein R\ R², R³, R⁴, R⁶ and R⁷ are as described above for compounds of formula I or formula 1a.

In an embodiment, the compound of formula I is a compound of formula III:

wherein R¹ , R², R³, R⁴, R⁵, R⁵ and R⁷ are as described above for compounds of formula I or formula la.

In an embodiment, the compound of formula I or formula la is a compound of formula IV:

wherein R\ R², R⁶ and R⁷ are as described above for compounds of formula I or formula la and wherein R³ is independently selected from the group comprising: C1-C4 alkyl, Ci-C4-haloalkyl, bromo, cyano, C2-C4 alkenyl and C2-C4 alkynyl. It may be that R³ is independently selected from the group comprising: C1-C4 alkyl, -(CR⁸R⁸)_n-heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_r- cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl, Ci-C4-haloalkyl, halogen, nitro, OR⁹, SR⁹, cyano, C2-C4 alkenyl, C2-C4 alkynyl and NR⁹R⁹.

In an embodiment, the compound of formula I or formula la is a compound of formula V:

wherein R\ R², R⁶ and R⁷ are as described above for compounds of formula I or formula la and wherein R³ is as described above for compounds of formula IV.

In an embodiment, the compound of formula I or formula la is a compound of formula VI :

wherein R¹ , R², R⁶ and R⁷ are as described above for compounds of formula I or formula la and wherein R³ is as described above for compounds of formula IV. The following embodiments apply to compounds of any of formulae (l)-(VI) (including la). 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.

In an embodiment, X is N Alternatively, X is CR⁵

Preferably, only one of R and R² is H. Preferably, R and R² are not both H. Thus, it may be that R is independently selected from the group comprising: Ci-Cs alkyl, -(CR⁸R⁸)_n-heteroaryl, - (CR⁸R⁸)n-aryl, -(CR⁸R⁸)_n-aryl-Z-A, -(CR⁸R⁸)_n-heteroaryl-Z-A, -(CR⁸R⁸)_n- C₃-C₆-cycloalkyl, - (CR⁸R⁸)n-heterocycloalkyl and Ci-Cs-haloalkyl. In a further embodiment, R¹ is independently selected from the group comprising: d-Cs alkyl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n-aryl-Z-A and - (CR⁸R⁸)_n- Cs-Ce-cycloalkyl.

In some embodiments in which R¹ contains -(CR⁸R⁸)_n-, n is 0. In alternative embodiments in which R¹ contains -(CR⁸R⁸)_n-, n is 1 or n is 2. In some embodiments (where n is 1 , 2 or 3), the -(CR⁸R⁸)- group adjacent to the N to which R is attached may be -CH(Me)-.

R¹ may be -(CR⁸R⁸)_n-aryl, e.g. -(CR⁸R⁸)_n-phenyl. Thus, by reference to the previous paragraph, R¹ may be -CH(Me)Ph.

R¹ may also be -(CR⁸R⁸V Cs-Cs-cycloalkyl, e.g. -(CR⁸RV Cs-Cs-cycloalkyl. R may be selected from -(CR⁸R⁸)_n-cyclobutyl, -(CR⁸R⁸)„-c or -(CR³R⁸)_n-cyclopentyl. Thus, by

reference to the previous paragraph, R¹ may be

(an illustrative example of a group in which n is 1) or

(an illustrative example of a group in which n is 2).

Alternatively, R¹ may be cycloalkyl (i.e. n is 0), e.g. R¹ may be cyclopentyl.

In other embodiments, R¹ may be Ci-Cs-alkyl. Thus, R¹ may be propyl, butyl, pentyl, hexyl, heptyl or octyl. These R¹ groups may be branched, and in some embodiments have a methyl group branching out from the carbon adjacent to the N to which R¹ is attached. Thus, for example, R may be heptyl and more specifically R¹ may be n-heptyl or R may be

In another embodiment, R is -(CR⁸R⁸)_n-aryl-Z-A or -(CR⁸R⁸)_n-heteroaryl-Z-A. n is preferably 0. Thus, R¹ may be phenyl-Z-A or pyridyl-Z-A. I n these embodiments, the Z-A is preferably at the para position of the phenyl or pyridyl ring relative to the N to which (CR⁸R⁸)_n is attached. Z is preferably O. A may be phenyl, which may be substituted, e.g. at the para-position. Thus, A may be 4-trifluoromethylphenyl. I n a specific embodiment, R¹ may be

R² may be selected from: H and C1-C4 alkyl. In a preferred embodiment, R² is H.

It may be that R³, R⁴ and R⁵ are independently selected from the group comprising: H , C1-C4 alkyl, Ci-C4-haloalkyl, bromo, cyano, C2-C4 alkenyl and C2-C4 alkynyl. Thus, R³ may be independently selected from the group comprising: H, C1-C4 alkyl, Ci-C4-haloalkyl, bromo, cyano, C2-C4 alkenyl and C2-C4 alkynyl.

Preferably, R³ is not H . Thus, it may be that R³ is independently selected from the group comprising: d-C₄ alkyl, -(CR⁸R⁸)_n-heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n-cycloalkyl, -(CR⁸R⁸)_n- heterocycloalkyl, CrC4-haloalkyl, halogen, nitro, OR⁹, SR⁹, cyano, C2-C4 alkenyl, C2-C4 alkynyl and NR⁹R⁹. R³ may be selected from the group comprising: H, C1-C4 alkyl, CrC4-haloalkyl, bromo, cyano, C2-C4 alkenyl and C2-C4 alkynyl.

In another embodiment, R³ is independently selected from the group comprising: C1-C4 alkyl, heteroaryl, phenyl, cydoalkyi, heterocycloalkyl, Ci-C4-haloalkyl, halogen, nitro, OR⁹ and NR⁹R⁹ In a further embodiment, R³ is independently selected from halo (e.g. bromo) and C1-C4 alkyl. Thus, R³ may be halo (e.g. bromo). Alternatively, R³ may be C1-C4 alkyl and, more particularly R³ may be C1-C2 alkyl (e.g. methyl).

Preferably, R⁴ is H.

In some embodiments, R⁵ is H. Thus, it may be that X is CH.

Preferably, only one of R⁶ and R⁷ is H. Preferably, R⁶ and R⁷ are not both H . Thus, it may be that R⁶ is selected from -(CR ⁰R ⁰)_mR^{1 1} and C(0)R¹². R⁶ may be independently selected from the group comprising: -C(0)H, -(CR ⁰R ⁰)_m-Ci-C6 alkyl, -(CR¹⁰R¹⁰)_m-heteroaryl, -(CR¹⁰R¹⁰)_m-aryl, -(CR ⁰R ⁰)_m-aryl-Z-A, -(CR ⁰R ⁰)_m-heteroaryl-Z-A, - (CR ⁰R ⁰)_m-cycloalkyl, -(CR ⁰R¹⁰)_m-heterocycloalkyl and -(CR¹⁰R¹⁰)_m-Ci-C₃-haloalkyl. R^s may be independently selected from the group comprising: -(CR ⁰R ⁰)m-Ci-Ce alkyl, -(CR¹⁰R¹⁰)_m- heteroaryl, -(CR¹⁰R¹⁰)_m-aryl, -(CR¹⁰R¹⁰)_m-aryl-Z-A, -(CR¹⁰R¹⁰)_m-heteroaryl-Z-A, -(CR¹⁰R¹⁰)_m- cycloalkyl, -(CR¹⁰R ⁰)_m-heterocycloalkyl and -(CR¹⁰R^{1 0})m-Ci-C₆-haloalkyl. R¹ may be selected from: Ci-C₈ alkyl, -(CR⁸R⁸)_P-heteroaryl, -(CR^BR⁸)_P-aryl, -(CR⁸R⁸)_P-aryl-Z-A, -(CR⁸R⁸)_P-heteroaryl- Z-A, -(CR⁸R⁸)_P-cycloalkyl, -(CR⁸R⁸)_P-heterocycloalkyl and Ci-Ce-haloalkyl.

Preferably, m is 0.

Alternatively, m may be 1.

When m is 1 , preferably the two R^{1 D} groups which are attached to the same carbon form an oxo group. In other words -(CR¹⁰R¹⁰)_m- may be -C(O)-.

R⁶ may be -(CR ⁰R¹⁰)_m-aryl, e.g. -(CR ⁰R ⁰)_m-phenyl. Thus, R⁶ may be phenyl. Said phenyl group may be substituted or unsubstituted. R^B may be a phenyl group substituted with from 1 to 4 substituents selected from halo, C1-C4 alkyl, C1-C4 haloalkyl. R⁶ may be a halo, dihalo or trihalo substituted phenyl group, e.g. a 2,5-dihalophenyl group or a 2,6-dihalophenyl group. Alternatively, R⁶ may be a phenyl ring to which a heterocyclic ring is fused, e.g. a 1 ,3-

benzodioxole. In a specific embodiment, R⁶ may be

. In an alternative embodiment, R⁶ is unsubstituted phenyl.

R⁶ may be C(0)R¹². R ² may be independently selected from C1-C4 alkyl, C1 -C4 haloalkyl, C3-C5 cycloalkyl. R¹² may be independently selected from Me, Et, i-Pr, CF3 and cyclopropyl.

Alternatively, R¹² may be H , i.e R⁶ may be C(0)H.

In an embodiment, R⁷ is H.

It may be that R⁸ is independently at each occurrence selected from H, C1 -C4 alkyl and C1 -C4 haloalkyl. It may be that R⁸ is independently at each occurrence selected from: H, F, methyl and CF₃. In any of the above aspects and embodiments, heteroaryl groups may be any aromatic (i.e. a ring system containing 2(n + 1) π- or n- 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. Heteroaryl groups may also be 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1 heteroatomic group independently selected from O, S and NH and the ring also comprises a carbonyl group. Such groups include pyridones and pyranones.

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 4 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 haloalkyi 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-R¹² 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, C1-C4 alkyl and C1-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-R¹² 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, C1-C4 alkyl and C1-C4 haloalkyl.

A group which is represented as SO3R is typically a group having the form S(0)₂OR. A group which is represented as S0₂R is typically a group having the form S(0)₂R. A group which is represented as S0₂NR^aR^a is typically a group having the form S(0)₂NRR.

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. 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 VI (including formula la) 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 ¹C, ¹³C and C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l , nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ⁵0, ¹⁷0 and ⁸0, 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:

BINAP - 2,2'-bis(diphenylphosphino)-1 , 1'-binaphthyl)

DCC - Λ/,Λ/'-dicyclohexylcarbodiimide DCM - dichloromethane

DIPEA - diisopropylethylamine DMF - N,N-dimethylformamide

D AP - Λ/,/V-dimethylaminopyridine DMSO - dimethylsulfoxide

HATU - 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid

hexafluorophosphate

IMS - industrial methylated spirits LDA - lithium diisopropylamide

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, insecticides, acaricides and nematicides.

According to another aspect of the present invention, there is provided a method for controlling nematodes, insect or aracnid pests and/or fungal diseases, 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 nematicidal, fungicidal, acaricidal and/or insecticidal composition comprising an effective and non-phytotoxic amount of an active compound of the invention. The composition may further comprise one or more additional nematicides, fungicides, insecticides and/or acaricides.

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, alkyi 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, alkyi or aryl sulphates, alkyi- or arylsulphonates and alkyi 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 nematicides, fungicides, insecticides and/or acaricides, 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 herbicides 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.

A formulation which could be used to administer the compounds, particularly in the context of testing for activity, would be to supply all compounds as a 10% solution in DMSO. If there are solubility problems this can be helped by adding acetone (e.g. to dilute a DMSO

solution/suspension by 50% resulting in a 5% solution of the compound in DMSO/acetone. The administration formulation is then obtained by adding the DMSO (or DMSO/acetone) solution to a 0. % solution of Tween 20™ in water to give the required concentration. The result is likely to be an emulsion that can be sprayed. If crystallisation occurs, resulting in inconsistent results, further DMSO can be added to the test solution.

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 nematodes, insects, aracnids and 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.

Use as insecticides/acaricides

The compounds of the invention have activity as insecticides/acaricides.

They may be active against normally sensitive and resistant species of pests and against all or some stages of development. The following are illustrative examples of pests that may be controlled by insecticidal/acahcidal compounds: from the order of the Anoplura (Phthiraptera), for example, Damalinia spp., Haematopinus spp. , Linognathus spp., Pediculus spp. ,

Trichodectes spp; from the class of the Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp., Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp. , Eriophyes spp., Hemitarsonemus spp. , Hyalomma spp., Ixodes spp., Latrodectus mactans, etatetranychus spp. , Oligonychus spp. , Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora, Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici; from the class of the Bivalva, for example, Dreissena spp; from the order of the Chilopoda, for example, Geophilus spp. , Scutigera spp; from the order of the Coleoptera, for example, Acanthoscelides obtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora spp. , Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidius obtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp., Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp. , Lachnostema consanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, elolontha melolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus, Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodes chrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica, Sitophilus spp. , Sphenophorus spp., Sternechus spp., Symphyletes spp., Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp. , Xylotrechus spp. , Zabrus spp; from the order of the Collembola, for example, Onychiurus armatus; from the order of the Dermaptera, for example, Forficula auricularia; from the order of the Diplopoda, for example, Blaniulus guttulatus; from the order of the Diptera, for example, Aedes spp., Anopheles spp. , Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp. , Fannia spp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp., Liriomyza spp. , Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyoscyami, Phorbia spp. , Stomoxys spp., Tabanus spp., Tannia spp., Tipula paludosa, Wohlfahrtia spp; from the class of the Gastropoda, for example, Arion spp. ,

Biomphalaria spp., Bulinus spp., Deroceras spp., Galba spp. , Lymnaea spp., Oncomelania spp., Succinea spp; from the class of the helminths, for example, Ancylostoma duodenale, Ancylostoma ceylanicum, Acylostoma braziliensis, Ancylostoma spp. , Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp., Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa, Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongyloides fuelleborni,

Strongyloides stercoralis, Stronyloides spp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella nativa, Trichinella britovi, Trichinella nelsoni, Trichinella pseudopsiralis,

Trichostrongulus spp., Trichuris trichuria, Wuchereria bancrofti.

When used as insecticides, the active compounds according to the invention can furthermore be present in their commercially available formulations and in the use forms, prepared from these formulations, as a mixture with inhibitors which reduce degradation of the active compound after use in the environment of the plant, on the surface of parts of plants or in plant tissues. The active compound content of the use forms prepared from the commercially available formulations can vary within wide limits. The active compound concentration of the use forms can be from 0.00000001 to 95% by weight of active compound, preferably between 0.00001 and 1 % by weight. The compounds are employed in a customary manner appropriate for the use forms.

The active compounds according to the invention may act not only against plant, hygiene and stored product pests, but also in the veterinary medicine sector against animal parasites (ecto- and endoparasites), such as hard ticks, soft ticks, mange mites, leaf mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, feather lice and fleas. The following are illustrative examples of parasites that may be controlled by insecticidal/acaricidal compounds: from the order of the Anoplurida, for example, Haematopinus spp., Linognathus spp., Pediculus spp. , Phtirus spp., Solenopotes spp; from the order of the Mallophagida and the suborders

Amblycerina and Ischnocerina, for example, Trimenopon spp. , Menopon spp. , Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp. , Felicola spp; diptera and the suborders Nematocerina and Brachycerina, for example, Aedes spp. , Anopheles spp., Culex spp. , Simulium spp., Eusimulium spp., Phlebotomus spp. , Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp. ,

Haematopota spp., Philipomyia spp., Braula spp. , Musca spp. , Hydrotaea spp. , Stomoxys spp. , Haematobia spp., orellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp. , Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp., Melophagus spp; from the order of the Siphonapterida, for example, Pulex spp., Ctenocephalides spp., Xenopsylla spp. , Ceratophyllus spp; from the order of the Heteropterida, for example, Cimex spp. , Triatoma spp., Rhodnius spp., Panstrongylus spp; from the order of the Blattarida, for example, Blatta orientalis, Periplaneta americana, Blattela germanica, Supella spp; from the subclass of the Acari (Acarina) and the orders of the Meta- and Mesostigmata, for example, Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp. , Boophilus spp., Dermacentor spp., Haemophysalis spp. , Hyalomma spp., Rhipicephalus spp. , Dermanyssus spp., Raillietia spp. , Pneumonyssus spp., Sternostoma spp., Varroa spp; from the order of the Actinedida

(Prostigmata) and Acaridida (Astigmata), for example, Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp. , Demodex spp., Trombicula spp. , Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp. , Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp. , Notoedres spp., Knemidocoptes spp. , Cytodites spp., Laminosioptes spp. Each compound of the invention may have activity against one or more than one of the above organisms.

The active compounds according to the invention may also be suitable for controlling arthropods which infest agricultural productive livestock, such as, for example, cattle, sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, chickens, turkeys, ducks, geese and bees, pets, such as, for example, dogs, cats, caged birds and aquarium fish, and also so-called test animals, such as, for example, hamsters, guinea pigs, rats and mice. By controlling these arthropods, cases of death and reductions in productivity (for meat, milk, wool, hides, eggs, honey etc.) should be diminished, so that more economic and easier animal husbandry is possible by use of the active compounds according to the invention.

The insecticidal/acaricidal compounds may be used in the veterinary sector and in animal husbandry in a known manner by enteral administration in the form of, for example, tablets, capsules, potions, drenches, granules, pastes, boluses, the feed-through process and suppositories, by parenteral administration, such as, for example, by injection (intramuscular, subcutaneous, intravenous, intraperitoneal and the like), implants, by nasal administration, by dermal use in the form, for example, of dipping or bathing, spraying, pouring on and spotting on, washing and powdering, and also with the aid of moulded articles containing the active compound, such as collars, ear marks, tail marks, limb bands, halters, marking devices and the like.

When used for cattle, poultry, pets and the like, the insecticidal/acaricidal compounds can be used as formulations (for example powders, emulsions, free-flowing compositions), which comprise the active compounds in an amount of 1 to 80% by weight, directly or after 100- to 10 000-fold dilution, or they can be used as a chemical bath.

The insecticidal/acaricidal compounds of the invention may be used in the treatment of human disease, particularly parasitic infections e.g. those caused by mites, insects, helminths etc. Thus, the invention includes a method of treating a disease (e.g. a parasitic 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.

The insecticidal/acaricidal compounds may also have activity against insects which destroy industrial materials. The following are illustrative examples of pests that may be controlled by insecticidal/acaricidal compounds:: Beetles, such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinus pecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthes rugicollis, Xyleborus spec.

Tryptodendron spec. Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec. Dinoderus minutus; Hymenopterons, such as Sirex juvencus, Urocerus gigas, Urocerus gigas taignus, Urocerus augur; Termites, such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis,

Reticulitermes lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis, Coptotermes formosanus; Bristletails, such as Lepisma saccharina. Each compound of the invention may have activity against one or more than one of the above organisms.

Industrial materials in the present connection are to be understood as meaning non-living materials, such as, preferably, plastics, adhesives, sizes, papers and cardboards, leather, wood and processed wood products and coating compositions.

In domestic, hygiene and stored-product protection, the insecticidal/acaricidal compounds may also be suitable for controlling animal pests, in particular insects, arachnids and mites, which are found in enclosed spaces, for example, dwellings, factory halls, offices, vehicle cabins and the like. They can be employed alone or in combination with other active compounds and auxiliaries in domestic insecticide products for controlling these pests. They are active against sensitive and resistant species and against all developmental stages.

The following are illustrative examples of pests that may be controlled by insecticidal/acaricidal compounds: from the order of the Scorpionidea, for example, Buthus occitanus; from the order of the Acarina, for example, Argas persicus, Argas reflexus, Bryobia ssp. , Dermanyssus gallinae, Glyciphagus domesticus, Ornithodorus moubat, Rhipicephalus sanguineus,

Trombicula alfreddugesi, Neutrombicula autumnalis, Dermatophagoides pteronissimus, Dermatophagoides forinae; from the order of the Araneae, for example, Aviculariidae,

Araneidae; from the order of the Opiliones, for example, Pseudoscorpiones chelifer,

Pseudoscorpiones cheiridium, Opiliones phalangium; from the order of the Isopoda, for example, Oniscus asellus, Porcellio scaber; from the order of the Diplopoda, for example, Blaniulus guttulatus, Polydesmus spp; from the order of the Chilopoda, for example, Geophilus spp; from the order of the Zygentoma, for example, Ctenolepisma spp., Lepisma saccharina, Lepismodes inquilinus; from the order of the Blattaria, for example, Blatta orientalies, Blattella germanica, Blattella asahinai, Leucophaea maderae, Panchlora spp. , Parcoblatta spp. , Periplaneta australasiae, Periplaneta americana, Periplaneta brunnea, Periplaneta fuliginosa, Supella longipalpa; from the order of the Saltatoria, for example, Acheta domesticus; from the order of the Dermaptera, for example, Forficula auricularia; from the order of the Isoptera, for example, Kalotermes spp. , Reticulitermes spp; from the order of the Psocoptera, for example, Lepinatus spp. , Liposcelis spp; from the order of the Coleoptera, for example, Anthrenus spp. , Attagenus spp., Dermestes spp. , Latheticus oryzae, Necrobia spp., Ptinus spp., Rhizopertha dominica, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum; from the order of the Diptera, for example, Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles spp., Calliphora erythrocephala, Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Drosophila spp. , Fannia canicularis, usca domestica, Phlebotomus spp., Sarcophaga carnaria, Simulium spp., Stomoxys calcitrans, Tipula paludosa; from the order of the Lepidoptera, for example, Achroia grisella, Galleria mellonella, Plodia interpunctella, Tinea doacella, Tinea pellionella, Tineola bisselliella; from the order of the Siphonaptera, for example, Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsylla cheopis; from the order of the Hymenoptera, for example, Camponotus herculeanus, Lasius fuliginosus, Lasius niger, Lasius umbratus, Monomorium pharaonis, Paravespula spp., Tetramorium caespitum; from the order of the Anoplura, for example, Pediculus humanus capitis, Pediculus humanus corporis, Pemphigus spp., Phylloera vastatrix, Phthirus pubis; from the order of the Heteroptera, for example, Cimex hemipterus, Cimex lectularius, Rhodinus prolixus, Triatoma infestans. Each compound of the invention may have activity against one or more than one of the above organisms.

In the field of household insecticides, they may be used alone or in combination with other suitable active compounds, such as phosphoric esters, carbamates, pyrethroids,

neonicotinoids, growth regulators or active compounds from other known classes of insecticides. They are used in aerosols, pressure-free spray products, for example pump and atomizer sprays, automatic fogging systems, foggers, foams, gels, evaporator products with evaporator tablets made of cellulose or polymer, liquid evaporators, gel and membrane evaporators, propeller-driven evaporators, energy-free, or passive, evaporation systems, moth papers, moth bags and moth gels, as granules or dusts, in baits for spreading or in bait stations.

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 Gloeosporium 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 Fusarium culmorum; Gibberella diseases, caused for example by Gibberella zeae; Macrophomina diseases, caused for example by Macrophomina phaseolina Monographella diseases, caused for example by onographella 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; hizoctonia 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 onilinia 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.

The following paragraphs describe illustrative protocols useful for assessing the fungicidal activity of compounds:

In vivo test on Venturis inaequalis in apples

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 24.5 parts by weight of acetone, 24.5 parts by weight of Ν, Ν-dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound at the stated rate of application. After the spray coating has dried on, the plants are inoculated with an aqueous conidia suspension of the causal agent of apple scab (Venturia inaequalis) and then remain for 1 day in an incubation cabinet at approximately 20 °C and a relative atmospheric humidity of 100%. The plants are then placed in a greenhouse at approximately 21 °C and a relative atmospheric humidity of approximately 90%. The test is evaluated 10 days after the inoculation.

In viva test on Botrytis cinerea in beans

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 24.5 parts by weight of acetone, 24.5 parts by weight of Ν, Ν-dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound. After the spray coating has dried on, 2 small pieces of agar covered with growth of Botrytis cinerea are placed on each leaf. The inoculated plants are placed in a darkened chamber at 20 °C and a relative atmospheric humidity of 100%. 2 days after the inoculation, the size of the lesions on the leaves is evaluated.

In vivo test on Sphaerotheca fuliginea in cucumber

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 49 parts by weight of DMF and 1 part by weight of alkylarylpolyglycolether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of

Sphaerotheca fuliginea. Then the plants are placed in a greenhouse at approximately 23 °C and a relative atmospheric humidity of approximately 70%. The test is evaluated 7 days after the inoculation.

In vivo test on Leptosphaeria nodorum in wheat

To produce a suitable formulation of active compound, 1 part by weight of active compound or the compound combination is mixed with 50 parts by weight of Ν ,Ν-dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate is diluted with water to the desired concentration. To test for protective activity, young plants are sprayed with a formulation of active compound or active compound combination at the stated rate of application. After the spray coating has dried on, the plants are sprayed with a spore suspension of Leptosphaeria nodorum. The plants remain for 48 hours in an incubation cabinet at 20 °C and a relative atmospheric humidity of 100%. The plants are placed in a greenhouse at a temperature of approximately 15 °C and a relative atmospheric humidity of approximately 80%. The test is evaluated 10 days after the inoculation.

In vivo test on Pyrenophora teres in barley

To produce a suitable formulation of active compound, 1 part by weight of active compound or the compound combination is mixed with 50 parts by weight of N ,N-dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with a formulation of active compound at the stated rate of application. After the spray coating has dried on, the plants are sprayed with a conidia suspension of Pyrenophora teres. The plants remain for 48 hours in an incubation cabinet at 20 °C and a relative atmospheric humidity of 100%.

The plants are placed in a greenhouse at a temperature of approximately 20 °C and a relative atmospheric humidity of approximately 80%. The test is evaluated 10 days after the inoculation.

In vivo protective test on Pyricularia oryzae in rice

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 28.5 parts by weight of acetone and 1.5 parts by weight of polyoxyethylene alkyl phenyl ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with an aqueous spore suspension of the causal agent of rice blast Pyricularia oryzae. The plants are then placed in an incubator at approximately 25 °C and a relative atmospheric humidity of approximately 100% for 1 day. The test is evaluated 7 days after the inoculation.

In vivo protective test on Rhizoctonia solani in rice

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 28.5 parts by weight of acetone and 1.5 parts by weight of polyoxyethylene alkyl phenyl ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with a hypha of the causal agent of rice sheath blight Rhizoctonia solani. The plants are then placed in an incubator at approximately 25 °C and a relative atmospheric humidity of approximately 100%.

In vivo protective test on Cochliobolus miyabeanus in rice

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 28.5 parts by weight of acetone and 1.5 parts by weight of polyoxyethylene alkyl phenyl ether, and the concentrate is diluted with water to the desired concentration. To test for activity, young plants are sprayed with the formulation of active compound at the stated rate of application. One day after spraying, the plants are inoculated with an aqueous spore suspension of the causal agent of rice brown spot Cochliobolus miyabeanus. The plants are then placed in an incubator at approximately 25 °C and a relative atmospheric humidity of approximately 100% for 1 day. The test is evaluated 4 days after the inoculation. Use as Nematicides

The compounds of the invention can be used as nematicides.

Phytoparasitic nematodes include, for example, Anguina spp., Aphelenchoides spp.,

Belonoaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp.,

Heliocotylenchus spp., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.

The following paragraph describes an illustrative protocols useful for assessing the nematicidal activity of compounds:

Meloidogyne test

To produce a suitable formulation of active compound, 1 part by weight of active compound is mixed with 80.0 parts by weight of acetone, and the concentrate is diluted with emulsifier- containing water to the desired concentration. Vessels are filled with sand, a solution of the active ingredient, a suspension containing eggs and larvae of Meloidogyne incognita and lettuce seeds. The lettuce seeds germinate and the seedlings grow. Galls develop in the roots. After 14 days the nematicidal activity is determined on the basis of the percentage of gall formation.

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.

Certain compounds of the invention can be synthesised according to the following general synthetic schemes. Other compounds of the invention can be made according to or analogously to the methods described in Example 1.

General Synthetic Schemes

One method for synthesizing the compounds of the invention is provided in Scheme 1.

Scheme

A typical synthesis starts from an appropriately substituted pyridinyl or pyrimidinyl acid. Where the starting material is not commercially available, the range of methods available for the synthesis of polysubstituted pyridines and pyrimidines is well known to those skilled in the art.

The amide coupling to form amide C can be achieved using any conventional means. One method would be by mixing acid A with amine B in the presence of an activating agent (e.g. DCC) and a nucleophilic catalyst (e.g. D AP). Alternatively, a mixed anhydride (using e.g. EtOCOCI and NEt₃ at 0 °C) can be formed and this can be treated with amine B (e.g. at 0 °C). The amine coupling step can be achieved by mixing amide C with amine D. Exemplary reaction conditions for this coupling step is to perform the reaction in a dioxane/water mixture optionally in the presence of CuS0₄ (the presence of the CuS0 is preferred for instances in which Hal is Br or I) at 80 °C.

An alternative synthetic approach is described in Scheme 2.

Again, a typical synthesis starts from an appropriately substituted pyridinyl or pyrimidinyl acid F. Amide coupling and amine addition steps are then performed similarly to the corresponding steps described for Scheme 1 above. The pyridine or pyrimidine ring can then be deprotonated using a base (e.g. LDA in THF and hexane at -70 °C) and alkylated with alkylating agent J (e.g. at -70 °C)

Example 1 - Synthesis

Flash chromatography was carried out using silica gel (40-63 μηι particles). Thin layer chromatography was carried out on pre-coated aluminium backed plates (Merck silica Keiselgel 60 F254) . Visualisation was carried out with UV light (254 nm) and by staining with either potassium permanganate, phosphomolybdic acid (PMA) or ninhydrin solutions. Where hexane is specified as a flash chromatography solvent, petroleum ether (b.p. 40-60 °C) can be used as an alternative.

All H NM R spectra were obtained using either a Bruker Ultrashield 300 spectrometer or Bruker DPX300 spectrometer. Chemical shifts are expressed in parts per million (δ) and are referenced to the solvent. Coupling constants J are expressed in Hertz (Hz).

ESI mass spectrometry was performed using a Bruker HCT Ultra LCMS instrument (Agilent 1200 Series LC with diode array detector and Bruker HCT Ultra Ion Trap MS) using a

Phenomenex Luna 5u C18(2) 100A, 50 ^χ 2.00 mm 5 micron LC column (solvent: 5-90% gradient of acetonitrile in water (with 1 % formic acid). Flow rate 1.2 mL/min). El mass spectrometry was performed using a Varian Saturn 2100T GC/MS instrument with a FactorFour VF-5MS 30 m ^χ 0.25 mm capillary column. High resolution mass spectrometry (ESI) was performed using a Dionex UltiMate 3000 system.

All reagents were obtained from commercial suppliers and used as supplied unless otherwise stated.

Meth l 6-anilino-3-methyl-pyridine-2-carboxylate 9

To a flask charged with methyl 6-chloro-3-methyl-pyridine-2-carboxylate (557 mg, 3.00 mmol), Pd(OAc)₂ (67 mg, 0.3 mmol), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (187 mg, 0.3 mmol) and caesium carbonate (1.27 g, 3.60 mmol) was added toluene (6 mL) followed by aniline (0.33 mL, 3.60 mmol) and the mixture was heated at 90 °C. After 18 hours, the reaction was quenched with sat. ammonium acetate^) (10 mL) and water (15 mL) then extracted with EtOAc ( 3 x 20 mL) before the combined organics were washed with brine (2 x 25 mL), dried over MgS04 and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 30% EtOAc/hexane) to afford the title compound as a yellow solid (654 mg, 90%).

¹ H NMR 5H (CDC , 300 MHz): 7.44 (d, J = 9.0 Hz, 1 H), 7.38 - 7.33 (m, 2H), 7.30 - 7.25 (m, 3H), 7.05 (d, J = 9.0 Hz, 1 H), 3.99 (s, 3H), 2.49 (s, 3H) ppm. ESI-MS 243.0 [MH]⁺.

6-Anilino-3-meth l-pyridine-2-carboxylic acid 10

Lithum hydroxide [1 M in H2O] (2.84 mL, 2.84 mmol) was added to a solution of methyl 6- anilino-3-methyl-pyridine-2-carboxylate 9 (625 mg, 2.58 mmol) in THF (6.5 mL) and heated at 60 °C. After 40 hours, the reaction was cooled to rt before being adjusted to pH 2 using 2 M HCI(ag). The volume of the solution was halved by evaporation before being extracted with EtOAc (3x20 mL), the combined organics washed with brine, dried over MgSC and the solvent removed in vacuo to afford the title compound as a white solid (353 mg, 60%).

Ή NMR δ_Η (CDCb, 300 MHz): 7.56 (d, J = 9.0 Hz, 1 H), 7.37 - 7.28 (m, 4H), 7.20 - 7.12 (m, 1 H), 7.07 (d, J = 9.0 Hz, 1 H), 2.60 (s, 3H) ppm. ESI-MS 229.0 [MH]⁺.

6-Anilino-3-methyl-/V-(1-phenylethyl)pyridine-2-carboxylamide 11

/V-Ethyldiisopropylamine (0.46 mL, 2.64 mmol) was added to a suspension of 6-anilino-3- methyl-pyiridine-2-carboxylic acid 10 (200 mg, 0.88 mmol), 4-(dimethylamino)pyridine (161 mg, 1.32 mmol) and A/-(3-dimethylaminopropyl)-A7'-ethylcarbodiimide hydrochloride (253 mg, 1.32 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 10 minutes before a solution of omethylbenzylamine (0.17 mL, 1.32 mmol) in DCM (4 mL) was added and stirring was continued for 20 h, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with 2M HCI^ (5 mL) and water (10 mL) then extracted with EtOAc (3 x 25 mL) before the organics were washed with brine (2 x 25 mL), dried over MgSCU and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 30% EtOAc/hexane) to afford the title compound as a white solid (160 mg, 55%).

Ή NMR δ_Η (CDCI3, 300 MHz): 8.29 - 8.26 (m, 1 H), 7.34 - 7.17 (m, 10H), 7.02 - 6.95 (m, 1 H), 6.78 (d, J = 9.0 Hz, 1 H), 6.37 (br, 1 H), 5.23 - 5.12 (m, 1 H), 2.56 (s, 3H), 1.50 (d, J = 6.0 Hz, 3H). ESI-MS 332.1 [MH]⁺.

6-Anilino-N- 1-cyclobutylethyl)-3-methyl-pyridine-2-carboxamide 12

/V-Ethyldiisopropylamine (0.69 mL, 3.94 mmol) was added to a suspension of 6-anilino-3- methyl-pyiridine-2-carboxylic acid 10 (300 mg, 1.31 mmol), 4-(dimethylamino)pyridine (242 mg, 1.97 mmol) and A/-(3-dimethylaminopropyl)-A '-ethylcarbodiimide hydrochloride (380 mg, 1.97 mmol) in DCM (5 mL). The reaction was stirred at ambient temperature, under nitrogen, for 10 minutes before a solution of 1-cyclobutylethylamine (196 mg, 1.97 mmol) in DCM (5 mL) was added and stirring was continued for 16 h. Further portions of 1-cyclobutylethylamine (40 mg, 0.40 mmol), 4-(dimethylamino)pyridine (48 mg, 0.39 mmol), A/-(3-dimethylaminopropyl)-/V - ethylcarbodiimide hydrochloride (76 mg, 0.39 mmol) and /V-ethyldiisopropylamine (0.14 mL, 0.79 mmol) were then added and stirring was continued for 8 h. The reaction mixture was quenched with 2M HCI(ag) (5 mL) and water (10 mL) then extracted with EtOAc (3 x 25 mL) before the organics were washed with brine (2 x 25 mL), dried over MgSC and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 70% hexane/EtOAc) to afford the title compound as a yellow oil (174 mg, 43%).

1 H NMR 5_H (CDCI3, 300 MHz): 7.83 - 7.80 (m, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.37 - 7.28 (m, 4H), 7.12 - 7.05 (m, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 6.42 (br, 1 H), 4.18 - 4.11 (m, 1 H), 2.66 (s, 3H), 2.41 - 2.36 (m, 1 H), 2.10 - 2.03 (m, 2H), 1.93 - 1.79 (m, 4H), 1.15 (d, J ESI-MS 310.1 [MH]⁺.

Meth l 6-[(2,6-difluorophenyl)amino]-3-methyl-pyridine-2-carboxylate 13

To a flask charged with methyl 6-chloro-3-methyl-pyridine-2-carboxylate (278 mg, 1 .50 mmol), Pd(OAc)₂ (34 mg, 0.15 mmol), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (93 mg, 0.15 mmol) and caesium carbonate (635 mg, 1.80 mmol) was added toluene (3 mL) followed by 2,6- difluoroaniline (0.19 mL, 1.80 mmol) and the mixture was heated at 90 °C. After 18 hours, the reaction was quenched with sat. ammonium acetate^) (10 mL) and water (15 mL) then extracted with EtOAc ( 3 x 20 mL) before the combined organics were washed with brine (2 x 25 mL), dried over MgSC and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 40% EtOAc/hexane to afford the title compound as a yellow oil (313 mg, 75%).

Ή NMR 5_H (CDCb, 300 MHz): 7.46 (d, J = 9.0 Hz, 1 H), 7.18 - 7.10 (m, 1 H), 7.03 - 6.96 (m, 2H), 6.59 - 6.54 (m, 1 H), 6.37 (br, 1 H), 3.99 (s, 3H), 2.50 (s, 3H) ppm. ESI-MS 279.0 [MH]⁺.

6-[(2, 6-Difluorophenyl)amino]-3-methyl-pyridine-2-carboxylic acid 14

Lithum hydroxide [1 M in H₂0] (1.88 mL, 1.88 mmol) was added to a solution of methyl 6-[(2,6- difluorophenyl)amino]-3-methyl-pyridine-2-carboxylate 13 (476 mg, 1.71 mmol) in THF (4 mL) and heated at 60 °C. After 40 hours, the reaction was cooled and adjusted to pH 2 using 2 M HCI(ag). The volume of the solution was reduced to half before being extracted with EtOAc before the combined organics were washed with brine, dried over MgSC>4 and the solvent removed in vacuo to afford the title compound as a white solid (336 mg, 74%).

1 H NMR 5_H (CDCb, 300 M Hz): 7.78 (br, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.19 - 7.10 (m, 1 H), 7.06 - 6.93 (m, 2H), 6.68 (d, J = 9.0 Hz, 1 H), 2.59 (s, 3H) ppm. ESI-MS 265.0 [MH]⁺.

6-[(2,6-Difluoropheny0amino]-3-methyl-N-[4-[4-(trifluoromethyl)phen

2-carboxamide 15

/V-Ethyldiisopropylamine (0.32 mL, 1.82 mmol) was added to a suspension of 6-[(2,6- difluorophenyl)amino]-3-methyl-pyridine-2-carboxylic acid 14 (160 mg, 0.61 mmol), 4- (dimethylamino)pyridine (111 mg, 0.91 mmol) and /V-(3-dimethylaminopropyl)-A/'- ethylcarbodiimide hydrochloride (174 mg, 0.91 mmol) in DCM (2 mL). The reaction was stirred at ambient temperature, under nitrogen, for 10 minutes before a solution of 4-(4- trifluoromethylphenoxy)aniline (230 mg, 0.91 mmol) in DCM (2 mL) was added and stirring was continued for 24 h, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with 2M

(5 mL) and water (10 mL) then extracted with EtOAc (3 x 25 mL) before the organics were washed with brine (2 x 25 mL), dried over MgSC and the solvent removed in vacuo. The crude material was purified by flash

chromatography on silica gel (solvent 80% hexane/EtOAc) to afford the title compound as a white solid (201 mg, 66%).

Ή NMR 5_H (CDC , 300 MHz): 9.94 (s, 1 H), 7.61 (d, J = 9.0 Hz, 2H), 7.54 - 7.43 (m, 3H), 7.18 - 7.08 (m, 1 H), 7.02 - 6.94 (m, 6H), 6.69 (d, J = 9.0 Hz, 1 H), 6.15 (br, 1 H), 2.64 (s, 3H). ESI- MS 500.1 [MH]⁺.

6-Chloro-3-meth l-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyridine-2-carboxamide 16

/V-Ethyldiisopropylamine (0.69 mL, 3.95 mmol) was added to a suspension of 6-chloro-3- methyl-pyridine-2-carboxylic acid (271 mg, 1.58 mmol), 4-(dimethylamino)pyridine (241 mg, 1.97 mmol) and N-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride (379 mg, 1.97 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 10 minutes before a solution of 4-(4-trifluoromethylphenoxy)aniline (500 mg, 1.97 mmol) in DCM (5 mL) was added and stirring was continued for 24 h. The reaction mixture was quenched with 2M

(5 mL) and extracted with chloroform (3x15 mL) before the organics were washed with brine, dried over MgSCU and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 15% EtOAc/hexane) to afford the title compound as a white solid (302 mg, 38%).

¹ H NMR 5_H (CDCb, 300 M Hz): 9.90 (br, 1 H), 7.79 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1 H), 7.12 - 7.05 (m, 4H), 2.81 (s, 3H) ppm. 2-Amino-5-meth l-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrimidine-4-carboxamide 17

To a solution of 2-chloro-5-methyl-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrirnidine-4- carboxamide (300 mg, 0.6 mmol) in IMS (3 mL) was added ammonium hydroxide (30 %, 3 mL) solution and the mixture was heated under microwave conditions at 140 °C for 30 min. Water (6 mL) was added and the mixture was extracted with dichloromethane (3x20 mL). The combined organic extracts were dried over MgSC , the solvent removed in vacuo the crude material recrystallised from hot IMS to afford the title compound (186 mg, 65 %).

1 H NMR 5_H (CDCb, 300 M Hz): 9.85 (br s, 1 H), 8.28 (s, 1 H),

7.70 (d, J = 9.0 Hz, 2 H), 7.51 (d, J = 9.0 Hz, 2 H), 7.01 (m, 4 H), 4.98 (br s, 2 H), 2.52 (s, 3 H). ESI-MS 389.0 [MH] ⁺.

6-Formamido-3-methy N-[4-[4-(trifluoromethyl)phenoxy]phenylJpyridine-2-carboxamide 1

Acetic formic anhydride (18 μί, 0.26 mmol) was added to a solution of 6-amino-3-methyl-W-[4- [4-(trifluoromethyl)phenoxy]phenyl]pyridine-2-carboxamide 17 (67 mg, 0.17 mmol) in THF (2 mL). The reaction was stirred at ambient temperature, under nitrogen, for 1 h, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with water (5 mL) then extracted with EtOAc (3 x 5 mL) before the organics were dried over MgSC and the solvent removed in vacuo to afford the title compound as a yellow solid (65 mg, 92%).

Ή NMR 5_H (CDCb, 300 MHz): 9.68 (br, 1 H), 9.66 (br) + 9.23 (d, J = 11 .0 Hz) + 8.45 (br) + 8.20 (d, J = 8.4 Hz) (2H), 7.70 - 7.59 (m, 3H), 7.51 (d, J = 8.8 Hz, 2H), 7.04 - 6.92 (m, 5H), 2.70 (s, 3H). ESI-MS 416.1 [MH]⁺.

6-Chloro-N-c clopentyl-3-methyl-pyridine-2-carboxamide 19

/V-Ethyldiisopropylamine (2.28 mL, 13.11 mmol) was added to a suspension of 6-chloro-3- methyl-pyridine-2-carboxylic acid (750 mg, 4.37 mmol), 4-(dimethylamino)pyridine (801 mg, 6.56 mmol) and A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride (1.26 g, 6.56 mmol) in DCM (10 mL). The mixture was stirred at rt for 10 minutes before a solution of cyclopentylamine (0.65 mL, 6.56 mmol) in DCM (10 mL) was added and the mixture stirred for a further 24h. The reaction was quenched by the addition of 2M HCI(at?; (10 mL) and water (15 mL) and extracted with EtOAc (2 x 25 mL) before the combined organics were washed with brine (2 x 25 mL), dried over MgSC and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 25% EtOAc/hexane) to afford the title compound as a white solid (172 mg, 16%).

Ή NMR 5_H (CDC , 300 M Hz): 7.75 (br, 1 H), 7.48 (d, J = 9.0 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H), 4.32 - 4.20 (m, 1 H), 2.65 (s, 3H), 2.06 - 1.96 (m, 2H), 1.76 - 1.42 (m, 6H) ppm.

6- 1,3-Benzodioxol-4-ylamino)-N-cyclopentyl-3-methyl-pyridine-2-carboxamide 20

A solution of 1 ,3-benzodioxol-4-amine (114 mg, 0.83 mmol) in toluene (2 mL) was added to a suspension of 6-chloro-/V-cyclopentyl-3-methyl-pyridine-2-carboxamide 19 (165 mg, 0.69 mmol), palladium(ll) acetate (16 mg, 0.07 mmol), rac-2,2'-bis(diphenylphosphino)-1 , - binaphthalene (43 mg, 0.07 mmol) and caesium carbonate (293 mg, 0.83 mmol). The reaction was heated at 90 °C, under nitrogen, for 24 h, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with sat N^CI^₎ (5 mL) and water (10 mL) then extracted with EtOAc (3 x 25 mL) before the organics were washed with brine (2 x 25 mL), dried over MgSC and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 75% hexane/EtOAc) to afford the title compound as a white solid (142 mg, 61%).

¹ H NMR 5_H (CDCb, 300 MHz): 8.00 - 7.97 (m, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 1 H), 6.87 - 6.78 (m, 2H), 6.64 (dd, J = 1.0, 8.0 Hz, 1 H), 6.26 (br, 1 H), 6.00 (s, 2H), 4.41 - 4.30 (m, 1 H), 2.66 (s, 3H), 2.10 - 2.01 (m, 2H), 1.79 - 1 .62 (m, 4H), 1.59 - 1.51 (m, 2H). ESI-MS 340.1 [ H]⁺.

2-Chloro-5-meth l-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrimidine-4-carboxamide 21

To a stirred suspension of 2-chloro-5-methylpyrimidine-4-carboxylic acid (0.5 g, 2.9 mmol) in dichloromethane (10 mL) was added A/.W-dimethylformamide (0.01 mL) and oxalyl chloride (0.55 g, 0.37 mL, 4.35 mmol) dropwise. Stirring was continued at room temperature for 1 h after which time the volatiles were removed in vacuo. The solid was taken up in dichloromethane (20 mL) before triethylamine (0.73 g, 1.0 mL, 7.25 mmol) and 4-(4-trifluoromethylphenoxy)aniline (550 mg, 2. 8 mmol) were added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane (30 mL), washed with sat.

aqueous sodium bicarbonate (50 mL), 0.2 M hydrochloric acid (50 mL), dried over gSC the solvent removed in vacuo to afford the title compound as a brown oil that solidified upon standing (892 mg, quant ).

Ή NMR 5_H (CDC , 300 M Hz): 9.71 (br s, 1 H), 8.60 (s, 1 H), 7.70 (d, J = 9.1 Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.01 (m, 4 H), 2.69 (s, 3 H). ESI-MS 408.0 [MH] ⁺.

2-Amino-5-meth l-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrimidine-4-carboxa 22

To a solution of 2-chloro-W-cyclopentyl-5-methyl-pyrimidine-4-carboxamide 21 (300 mg, 0.6 mmol) in IMS (3 mL) was added ammonium hydroxide (30 %, 3 mL) solution and the mixture was heated under microwave conditions at 140 °C for 30 min. Water (6 mL) was added and the mixture was extracted with dichloromethane (3x20 mL). The combined organic extracts were dried over MgSC , the solvent removed in vacuo the crude material recrystallised from hot IMS to afford the title compound (186 mg, 65 %).

1 H NMR 5_H (CDCI3, 300 M Hz): 9.85 (br s, 1 H), 8.28 (s, 1 H),

7.70 (d, J = 9.0 Hz, 2 H), 7.51 (d, J = 9.0 Hz, 2 H), 7.01 (m, 4 H), 4.98 (br s, 2 H), 2.52 (s, 3 H). ESI-MS 389.0 [MH] ⁺.

2-Formamido-5-methy N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrimidine-4-

To a solution of 2-amino-5-methyl-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrimidine-4- carboxamide 22 (80mg, 0.2mmol) in THF (0.5mL) was added freshly prepared acetic formic anhydride (88pL, 1.2mmol) and the solution stirred at RT for 16h before the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent 2%MeOH/DCM) to afford the title compound as a yellow solid (86mg, 98%). ¹ H NMR 5_H (CDC , 300 M Hz): 9.59 (s, 1 H), 9.48 (br d, J = 10.6 Hz, 1 H), 8.52 (s, 1 H), 8.26 (br d, J = 10.5 Hz, 1 H), 7.67 (d, J - 9.0 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.04 (d, J - 9.0 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 2.65 (s, 3H). ESI-MS 417.1 [MH]⁺.

2-[(2,6-Difluorophenyl)amina]-5-methyl-N-[4-[4- (trifluarometh l)phenoxy]phenyl]pyrimidine-4-carboxamide 24

To a solution of 2-chloro-5-methyl-N-[4-[4-(trifluoromethyl)phenoxy]phenyl]pyrirnidine-4- carboxamide 21 (285mg, 0.70mmol) in toluene (2mL) was added palladium acetate (16mg, 0.07mmol), BINAP (44mg, 0.07mmol), caesium carbonate (274mg, 0.84mmol) and 2,6- difluoroaniline (90μΙ_, 0.84mmol) and the mixture was heated at 90°C for 16h. Analysis by TLC showed unreacted starting material so a further portion of 2,6-difluoroaniline (90μΙ_,

0.84mmol) was added and heating continued at 90°C for a further 24h. Additional palladium acetate (16mg, 0.07mmol), BINAP (44mg, 0.07mmol) and caesium carbonate (274mg, 0.84mmol) was added and the mixture heated at 90 °C for a further 18 h. The reaction mixture was cooled to room temperature and EtOAc (30 ml_) and sat. aq. NH4CI (30 ml.) were added. The aqueous phase was extracted with ethyl acetate (2 * 30 ml_), the combined organic fractions dried over MgSC and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (solvent 15% EtOAc/hexane moving to 25%

EtOAc/hexane) to afford the title compound as a pale brown solid (102mg, 29% yield).

1 H NMR 5_H (CDCb, 300 MHz): 9.77 (s, 1 H), 8.38 (s, 1 H), 7.56 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.23-7.13 (m, 1 H) 7.04 - 6.95 (m, 6H), 6.69 (s, 1 H), 2.57 (s, 3H).

ESI-MS 501.2[MH]^†.

2-Chloro-5-methyl-N-(1-phenylethyl)pyrimidine-4-carboxamide 25

To a stirred suspension of 2-chloro-5-methylpyrimidine-4-carboxylic acid (0.5 g, 2.9 mmol) in dichloromethane (10 ml_) was added /V,A/-dimethylformamide (0.01 ml_) and oxalyl chloride (0.55 g, 0.37 ml_, 4.35 mmol) dropwise. Stirring was continued at room temperature for 1.5 h after which time the volatiles were removed in vacuo. The solid was taken up in

dichloromethane (20 ml_) before triethylamine (0.73 g, 1.0 ml_, 7.25 mmol) and a- methylbenzylamine (422 mg, 443 μΙ, 3.48 mmol) were added dropwise and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with dichloromethane (30 mL), washed with sat. aqueous sodium bicarbonate (50 mL), 0.1 M hydrochloric acid (50 mL), dried over MgSCU and the solvent removed in vacuo to afford the title compound as a pale brown oil that crystallised on standing (0.59 g, 73 %).

¹ H NMR 5_H (CDC , 300 M Hz): 8.51 (s, 1 H), 8.07 (br d, J - 6.6 Hz, 1 H), 7.28 (m, 5 H), 5.18 (m, 1 H), 2.60 (s, 3 H), 1.55 (d, J = 6.9 Hz, 3 H). ESI-MS 298.0 [MNa] ⁺.

2-Anilino-5-meth l-N-(1-phenylethyl)pyrimidine-4-carboxamide 26

To a solution of 2-chloro-5-methyl-N-(1-phenylethyl)pyrimidine-4-carboxamide 25 (480mg, 1.74mmol) in toluene (5mL) was added palladium acetate (40mg, 0.18mmol), BINAP ( 12mg, 0.18mmol) and aniline (192μί, 2.10mmol) and the mixture heated to 90°C for 18 h. The reaction mixture was cooled to room temperature and ethyl acetate (40 mL) and sat. aq. NH4CI (40 mL) were added. The aqueous phase was extracted with EtOAc (2 * 40 mL), the combined organic fractions dried over MgSC and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (solvent 20%EtOAc/hexane moving to 25% EtOAc/hexane) to give the title compound as a pale yellow solid (373mg, 64% yield).

Ή NMR 5_H (CDCI3, 300 M Hz): 8.31 (s, 1 H), 8.14 (br d, J = 8.1 Hz, 1 H), 7.50 - 7.39 (m, 2H), 7.37 - 7.15 (m, 7H), 7.06 - 6.93 (m, 2H), 5.23 - 5.07 (m, 1 H), 2.49 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H). ESI-MS 333.1 [MH]⁺.

2-Chloro-N-c clopentyl-5-methyl-pyrimidine-4-carboxamide 27

To a stirred suspension of 2-chloro-5-methylpyrimidine-4-carboxylic acid (0.5 g, 2.9 mmol) in dichloromethane (10 mL) was added /V,A/-dimethylformamide (0.01 mL) and oxalyl chloride (0.55 g, 0.37 mL, 4.35 mmol) dropwise. Stirring was continued at room temperature for 1 h after which time the volatiles were removed in vacuo. The solid was taken up in dichloromethane (20 mL) before triethylamine (0.73 g, 1.0 mL, 7.25 mmol) and cyclopentylamine (249 mg, 343 μΙ, 3.48 mmol) were added dropwise and the mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (30 mL), washed with sat. aqueous sodium bicarbonate (50 mL), 0.2 M hydrochloric acid (50 mL), dried over MgSCU and the solvent removed in vacuo to afford the title compound as a brown solid (481 mg, 69 %). ¹ H NMR 5_H (CDC , 300 M Hz): 8.50 (s, 1 H), 7.73 (br s, 1 H), 4.28 (p, J = 7.2 Hz, 1 H), 2.62 (s, 3 H), 2.01 (m, 2 H), 1.71 (m, 6 H). ESI-MS 240.0 [MH] ⁺.

2- 1,3-Benzodioxol-4-ylamino)-N-cyclopentyl-5-methyl-pyrimidine-4-carboxamide 28

To a solution of 2-chloro-N-cyclopentyl-5-methyl-pyrimidine-4-carboxamide 27 (250mg, 1.04mmol) in toluene (3mL) was added palladium acetate (25mg, 0.11 mmol), BINAP (70mg, 0.11 mmol), caesium carbonate (443mg, 1 .36mmol) and 1 ,3-benzodioxol-4-amine (187mg, 1.36mmol) and the mixture heated to 90°C for 18 h. The reaction mixture was cooled to room temperature and EtOAc (50 mL) and sat. aq. N H4CI (50 mL) were added. The aqueous phase was extracted with EtOAc (2 ^χ 50 mL), the combined organic fractions dried over MgSCU and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (solvent 20% EtOAc/hexane moving to 30% EtOAc/hexane) to give the title compound as a brown oil that solidified upon standing (251 mg, 70% yield).

Ή NMR 5_H (CDCI3, 300 M Hz): 8.40 (s, 1 H), 7.88 (br d, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.5, 1.0 Hz, 1 H), 6.87 (apr t, J = 8.1 Hz, 1 H), 6.65 (dd, J = 7.8, 1.0 Hz, 1 H), 6.02 (s, 2H), 4.41-4.29 (m, 1 H), 2.59 (s, 3H), 2.16 - 2.00 (m, 2H), 1.82 - 1.61 (m, 4H), 1.61 - 1.48 (m, 2H). ESI-MS

341 .1 [MH]⁺.

2- hloro-N-(1-cyclobutylethyl)-5-methyl-pyrimidine-4-carboxamide 29

To a stirred suspension of 2-chloro-5-methylpyrimidine-4-carboxylic acid (0.5 g, 2.9 mmol) in dichloromethane (10 mL) was added /V,A/-dimethylformamide (0.01 mL) and oxalyl chloride (0.55 g, 0.37 mL, 4.35 mmol) dropwise. Stirring was continued at room temperature for 1 h after which time the volatiles were removed in vacuo. The solid was taken up in dichloromethane (20 mL) before triethylamine (1.03 g, 1.42 mL, 10.2 mmol) and a-methyl cyclobutylmethylamine hydrochloride (472mg, 3.48 mmol) were added and the mixture was stirred at room

temperature for 18 h. The mixture was diluted with dichloromethane (30 mL), washed with sat. aqueous sodium bicarbonate (50 mL), 0.2 M hydrochloric acid (50 mL), dried over gS0₄ and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent 20 % EtOAc/hexane) to afford the title compound as a colourless solid (218 mg, 30 %). ¹ H NMR 5H (CDC , 300 M Hz): 8.60 (s, 1 H), 7.73 (br, 1 H), 4.12 (m, 1 H), 2.70 (s, 3 H), 2.40 (m, 1 H), 2.10 (m, 2 H), 1.87 (m, 4 H), 1.78 (d, J = 3.0 Hz, 3 H). ESI-MS 254.0 [MH] ⁺.

2-Anilino-N- 1-cyclobutylet yl)-5-methyl-pyrimidine- -carboxamide 30

To a solution of 2-chloro-N-(1 -cyclobutylethyl)-5-methyl-pyrimidine-4-carboxamide 29 (215mg, 0.85mmol) in toluene (2.5mL) was added palladium acetate (20mg, 0.09mmol), BINAP (62mg, 0.09mmol), caesium carbonate (355mg, 1 .09mmol) and aniline (192μΙ_, 1.08mmol) and the mixture heated to 90°C for 16h. The reaction mixture was cooled to room temperature and EtOAc (40 mL) and sat. aq. NH4CI (40 mL) were added. The aqueous phase was extracted with EtOAc (2 40 mL), the combined organic layers dried over gSCU and the solvent removed in vacuo. The crude product was purified by column chromatography (solvent 15% EtOAc/hexane moving to 25% EtOAc/hexane) to give the title compound as a yellow oil that solidified upon standing (160mg, 61 % yield).

Ή NMR 5_H (CDCI3, 300 M Hz): 8.29 (s, 1 H), 7.61 (br d, J = 9.0 Hz, 1 H), 7.58 - 7.41 (m, 2H), 7.35 - 7.25 (m, 2H), 7.22 (s, H), 7.04-6.98 (m, 1 H), 3.99 (m, 1 H), 2.49 (s, 3H), 2.38-2.24 (m, 1 H), 2.02 - 1.92 (m, 2H), 1.82 - 1.64 (m, 4H), 1.05 (d, J = 6.6 Hz, 3H). ESI-MS 31 1.1 [MH]⁺.

2-Anilino-5-methyl-N-(1-phenylethyl)thiazole-4-carboxamide 31

To a solution of 2-anilino-5-methyl-thiazole-4-carboxylic acid (400mg, 1.7mmol) in DMF (10mL) was added HATU (649mg, 1.7mmol), DIPEA (0.45mL, 2.6mmol) and 1 -phenylethanamine (0.2mL, 1.7mmol) and the mixture stirred at RT for 16h after which time the reaction was poured into water and extracted with Et₂0 before being dried over MgSC>4 and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent 20% EtOAc/hexane) to afford the title compound as a clear oil which foamed and solidified under high vacuum (504mg, 84%).

Ή NMR 5_H (CDCb, 300 MHz): 7.48 (br d, J = 8.2Hz, 1 H), 7.32 - 7.14 (m, 9H), 7.07 (s, 1 H), 7.02 - 6.97 (m, 1 H), 5.20 - 5.10 (m, 1 H), 2.62 (s, 3H), 1.49 (d, J = 7.0Hz, 3H). ESI-MS 338.2[MH]^†.

Compound 31 is a compound of the prior art (WO2010/012793) and is included for reference purposes only. Example 2 - Testing the insecticidal and acaricidal activity of compounds of the invention.

A laboratory bioassay can be conducted to screen the compounds of the invention for biocidal activity against target species (examples might be: aphids (Myzus persicae), mosquito larvae (Aedes aegypti) cabbage moth larvae (Mamestra brassicae), and two-spotted spider mites ( Tetranychus urticae), in terms of knockdown and mortality. Compounds are diluted in DMSO containing 1 % Tween (the Tween is optional but has been used for testing the compounds of the invention) and assessed at a range of concentrations (e.g. from 0.5% to 0.00001%). A DMSO only negative control is also included for comparative purposes. These are applied directly onto the insects/mites and assessments of knockdown and mortality are conducted at 24 and 48 hours post treatment.

Test system

Aphids, Myzus persicae, can be maintained on Chinese cabbage plants. Mixed sex and age aphids are used in the experiments.

Mosquitoes, Aedes aegypti, can be obtained as eggs and reared to 3^rd instar larvae, prior to use in the experiments.

Cabbage moths, Mamestra brassicae, can be obtained as eggs and reared on Chinese cabbage plants to 2^nd instar larvae, prior to use in the experiments. Lacanobia oleracea caterpillars can also be used.

Two-spotted spider mites, Tetranychus urticae, can be obtained from a standard susceptible laboratory culture. Mixed sex and age mites are used in the experiments.

The temperature should be maintained between about 22 °C and about 25 °C and the relative humidity should range from about 25 % to about 45%. Arthropods are maintained on a 16:8 hour (light: dark) photoperiod post treatment.

Test treatments and application

The test compounds are dissolved in DMSO and diluted at a range of six concentrations (e.g.

0.5%, 0.1 %, 0.01 %, 0.001%, 0.0001 % and 0.00001 %). In the field, 0.05% represents the normal approximate dosage applied. Activity at this level or at dilutions less than this is thus indicative of an effective compound. The concentrates are prepared at room temperature and stirred for approximately 15 minutes, using a vortex mixer. A negative control (DMSO only) is also included in the testing for comparative purposes. Treatments are applied directly onto the arthropods within Petri dishes, using a Potter tower, at a rate of 0.2 ml per replicate.

Experimental design

The targets (except mosquito larvae) are counted into a 55 mm diameter Petri dish lined with a leaf disc (abaxial surface upwards) mounted on damp cotton wool. For moth larvae and aphids, leaf discs should be cut from round cabbage, for mites, leaf discs should be cut from dwarf French bean plants. Mosquito larvae should be placed into an 11 cm diameter plastic container, filled with approximately 150 ml of de-chlorinated tap water, using a pipette.

The targets are sprayed using the Potter tower or in the case of mosquito larvae, a Gilson pipette. The number of knocked down and dead insects or arthropods is assessed at 24 and 48 hours post treatment.

Three to five replicates should be performed for each treatment, for each species.

The above protocol was used to test the activity of certain compounds of the invention against aphids (Myzus persicae caterpillars (Mamestra brassicae and Lacanobia oleracea), and two- spotted spider mites (Tetranychus urticae) as shown in table 1. Five replicates were performed per species.

A number of compounds of the invention achieved excellent control over spider mites. Indeed, compounds 11 , 30, 24, 20 and 28 were considerably more active against spider mites than the reference compound 31. Compound 20 also achieved greater than 50% control over both aphids and caterpillars at the highest concentrations tested, again better than the reference compound 31 .

Table 1

Average of % corrected affected

31 11 26 18 23 12 30 15 24 20 28

Compound

Aphids

0.25 %w/v D D D D C 0 D C C B D

Caterpillars

0.015625 D D D D D D D C D D D

0.03125 D D D D D D D D D 0 D

0.0625 D D D D D D D D D D D

0.125 D D D D C C D D D D D

0.25 D C D D D D D D D B C

Spider mites

0.015625 C c 0 0 0 C B B B A

0.03125 C c 0 D D C B A B A

0.0625 c B 0 0 D C C C A A A 0.125 B B D 0 D C B B A A

Compounds exhibiting a percentage control at a given concentration between 1 % and 19% were assigned a rating of D; compounds exhibiting a percentage control between 20% and 49% were assigned a rating of C; compounds exhibiting a percentage control from 50% to 70% were assigned a rating of B; compounds exhibiting a percentage control greater than 70% were assigned a rating of A.

Example 3 - Testing the fungicidal activity of compounds of the invention

The fungicidal activity of the compounds of the invention was tested against a range of fungal plant pathogens. ECso were determined for each fungicide tested by measuring the Optical Density at 590 nm of each well of the microtitre plate after 3 days of incubation (F.

graminearum and R. solani), 5 days of incubation (B. cinerea) or 7 days of incubation (M. graminicola and V. ineaqualis) at 19°C in darkness. The results are presented in Table 2:

In table 2, a compound for which an EC50 could not be determined for that pathogen (because the percentage of inhibition obtained at the highest concentration of fungicide tested (40 Mg/ml) is lower than 50 %) was not assigned a star rating; a compound having an EC50 between 18 and 40 μg/ml was assigned a rating of one star; a compound having an EC50 between 5 and 18 pg/ml was assigned a rating of two stars; and a compound having an EC50 below 5 μg/ml was assigned a rating of three stars.

Many of the compounds of the invention showed significant fungicidal activity. In particular, compounds 1 1 , 12 and 20 showed excellent activity against a number of fungal pathogens.

Claims

Claims la I:

wherein

X is independently selected from N and CR⁵;

R¹ and R² are independently selected from the group comprising: H, C C₈ alkyl, -(CR⁸R⁸)_n- heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n-aryl-Z-A, -(CR⁸R⁸)_n-heteroaryl-Z-A, -(CR⁸R⁸)_n-C₃-C₆- cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl and CrCs-haloalkyl;

R³, R⁴ and R⁵ are independently selected from the group comprising: H, C_rC₄ alkyl, -

(CR⁸R⁸)_n-heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n- C₃-C₆-cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl,

C_rC₄-haloalkyl, bromo, nitro, OR⁹, SR⁹, cyano, C₂-C₄ alkenyl, C₂-C₄ alkynyl and NR⁹R⁹;

R⁶ is independently selected from the group comprising: H, -(CR¹⁰R¹⁰)_mR¹¹ and C(0)R¹²;

R⁷ is independently selected from: H, C C₄ alkyl, C₃-C₅-cycloalkyl and benzyl;

Z is independently selected from O, S and NR⁹;

A is independently selected from aryl and heteroaryl;

R⁸ is independently at each occurrence selected from H, F, C C₄ alkyl and C C₄ haloalkyi; R⁹ is independently at each occurrence selected from H, Ci-C₄ alkyl, C(0)-Ci-C₄ alkyl, and C₁-C4 haloalkyi;

R¹⁰ is independently at each occurrence selected from H, F, C₁-C4 alkyl and C₁-C4 haloalkyi

R¹¹ is independently at each occurrence selected from the group comprising: H, CrC₈ alkyl,

-(CR⁸R⁸)_p-heteroaryl, -(CR⁸R⁸)_p-aryl, -(CR⁸R⁸)_p-aryl-Z-A, -(CR⁸R⁸)_p-heteroaryl-Z-A, -

(CR⁸R⁸)_P- C₃-Ce-cycloalkyl, -(CR⁸R⁸)_p-heterocycloalkyl and CrC₈-haloalkyl;

R¹² is independently selected from H, C C₄ alkyl, C C₄ haloalkyi, C₃-C₅ cycloalkyi;

n is an integer independently at each occurrence selected from 0, 1 , 2 and 3;

m is an integer independently at each occurrence selected from 0 and 1 ;

p is an integer independently at each occurrence selected from 0 and 1 ;

wherein in any R¹-R¹² group which contains an alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group, that alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is unsubstituted or 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 , C C₄ alkyl and CF₃; and wherein, in the case of an aryl group 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 ring which is fused to the aryl or heteroaryl group;

or an agronomically acceptable salt or N-oxide thereof.

2. A compound of claim 1 , wherein X is N.

3. A compound of claim 1 , wherein X is CR⁵.

4. A compound of claim 3, wherein R⁵ is H.

5. A compound of any preceding claim, wherein R⁴ is H.

6. A compound of any preceding claim, wherein R³ is bromo.

7. A compound of any one of claims 1 to 5, wherein R³ is C1-C4 alkyl and, optionally wherein R³ is methyl.

8. A compound of any preceding claim, wherein R¹ is independently selected from the group comprising: C C₈ alkyl, -(CR⁸R⁸)_n-heteroaryl, -(CR⁸R⁸)_n-aryl, -(CR⁸R⁸)_n-aryl-Z-A, - (CR⁸R⁸)n-heteroaryl-Z-A, -(CR⁸R⁸)_n- C₃-C₆-cycloalkyl, -(CR⁸R⁸)_n-heterocycloalkyl and C C₈- haloalkyl.

9. A compound of any preceding claim, wherein R² is H.

10. A compound of any preceding claim, wherein R⁶ is independently selected from the group comprising: -(CR¹⁰R¹⁰)_m-C C₆ alkyl, -(CR¹⁰R¹⁰)_m-heteroaryl, -(CR¹⁰R¹⁰)_m-aryl, - (CR¹⁰R¹⁰)_m-aryl-Z-A, -(CR¹⁰R¹⁰)_m-heteroaryl-Z-A, -(CR¹⁰R¹⁰)_m-cycloalkyl, -(CR¹⁰R¹⁰)_m- heterocycloalkyl and -(CR¹⁰R¹⁰)_m-C₁-C₃-haloalkyl.

11. A compound of any preceding claim, wherein R⁷ is H.

12. A method for controlling nematodes the method comprising applying an

agronomically effective and substantially non-phytotoxic (to the crop plant) 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.

13. A nematicidal composition comprising an effective and non-phytotoxic amount (to the crop plant) of an active compound of any preceding claim.

14. A method for controlling insect or aracnid pests, the method comprising applying an agronomically effective and substantially non-phytotoxic (to the crop plant) 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.

15. An acaricidal and/or insecticidal composition comprising an effective and non- phytotoxic amount of an active compound of any preceding claim.

16. A method for controlling fungal diseases, the method comprising applying an agronomically effective and substantially non-phytotoxic (to the crop plant) 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.

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