WO2016055802A1

WO2016055802A1 - Agricultural chemicals

Info

Publication number: WO2016055802A1
Application number: PCT/GB2015/052958
Authority: WO
Inventors: William Thompson; Christopher URCH
Original assignee: Redag Crop Protection Ltd
Priority date: 2014-10-10
Filing date: 2015-10-09
Publication date: 2016-04-14
Also published as: GB201417950D0

Abstract

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

Description

Agricultural Chemicals

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

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

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

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

An aim of certain embodiments of the present invention is to provide pesticides (e.g.

nematicides, acaricides, insecticides and fungicides) which have activity either non-selectively, i.e. broad spectrum activity, or which are active specifically against selective target organisms.

An aim of certain embodiments 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 may be less prone to bioaccumulation once in the food chain than prior art compounds.

Another aim of certain embodiments 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.

Certain 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, certain embodiments of the present invention may also concern compounds which have a lower level of activity relative to prior art compounds. These lower activity compounds are still effective as fungicides but have other advantages relative to existing compounds such as, for example, a reduced environmental impact.

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

Certain embodiments of the invention provide 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 CH; Y is independently selected from: O and NR⁵; A is a 5- or 6- membered heteroaryl group; B is a tetrazole group;

R¹ is independently selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, and C3-C6-cycloalkyl;

R² and R⁶ are each independently at each occurrence selected from: H, halo, Ci-C4-alkyl and Ci-C₄-haloalkyl;

R³ is independently selected from H, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -(CR⁶R⁶)_q-Z- (CR⁶R⁶)rR⁷; Z is selected from: a bond, S, O and NR⁸;

R⁴ is independently at each occurrence selected from: halo, nitro, cyano, NR⁹R⁹, NR⁸S(0)2R⁸, NR⁸C(0)R⁸, NR⁸CONR⁸R⁸, NR⁸C0₂R⁸, OR⁸; SR⁸, S(0)R⁸, S(0)₂OR⁸, S(0)₂R⁸, S(0)₂NR⁸R⁸, C0₂R⁸ C(0)R⁸, CONR⁸R⁸, CR⁸R⁸NR⁹R⁹, CR⁸R⁸OR⁸, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄ ^"haloalkyl;

R⁵ and R⁸ are independently at each occurrence selected from: H, Ci-C₄-alkyl, and Ci-C₄- haloalkyl;

R⁷ is independently selected from: H, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl;

R⁹ is independently selected from: H, Ci-C₄-alkyl, C(0)-Ci-C₄-alkyl and Ci-C₄-haloalkyl; n is an integer independently selected from 0, 1 and 2; p is an integer independently selected from 0, 1 , 2, 3 and 4; q and r are each an integer selected from 0, 1 , 2 and 3; wherein in any R¹-R⁹ group is an alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, that alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: oxo, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, Ci-C₄ alkyl and Ci-C₄-haloalkyl; and R^b is independently at each occurrence selected from H, halogen, Ci-C₄-alkyl and Ci-C₄-haloalkyl; or an agronomically acceptable salt or N-oxide thereof.

B is a tetrazole group which is linked to the rest of the molecule at X and is substituted with a substituent R¹. Where X is CH (e.g. compounds of formula III below), B can be linked to the rest of the molecule via the carbon of the tetrazole ring or via one of the nitrogen atoms. Where X is N (e.g. compounds of formula II below), B can be linked to the rest of the molecule via the carbon atom of the tetrazole ring and not via one of the nitrogen atoms. The group R¹ is attached to the remaining free site of the tetrazole ring. B and R¹ can thus adopt a number of different orientations:

preferred.

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

wherein R¹ , R², R³, R⁴, n, p, Y, A and B are as described above for compounds of formula I.

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

wherein R¹ , R , R³, R⁴, n, p, Y, A and B are as described above for compounds of formula I.

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

wherein R¹ , R², R³, R⁴, n, p, B, X and Y are as described above for compounds of formula I; and wherein R¹⁰ is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂- C₄-alkynyl and Ci-C₄-haloalkyl; and s is an integer selected from 0, 1 , 2 and 3. la I is a compound of formula V:

V

wherein R¹, R², R³, R⁴, n, p, B, X and Y are as described above for compounds of formula I; where R¹¹ is independently selected from: halo, nitro, cyano, NR^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄- haloalkyl.

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

wherein R¹, R³, R⁴, A, B, p, X and Y are as described above for compounds of formula I.

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

wherein R¹, R³, R⁴, A, B, p and X are as described above for compounds of formula I. In an embodiment, the compound of formula I is a compound of formula VIII:

wherein R¹ , R³, R⁴, A, B, p and X are as described above for compounds of formula I and R¹⁰ and s are as described above for compounds of formula IV. In certain preferred embodiments, X is N.

The following embodiments apply to compounds of any of formulae (l)-(VIII). 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.

X may be N. Alternatively, X may be CH.

Y may be O. Alternatively, Y may be NR⁵. It may be that R⁵ is H. Thus, Y may be NH.

Alternatively, it may be that R⁵ is not H, i.e. R⁵ may be Ci-C4-alkyl.

It may be that Y is O and n is 1.

R¹-B- may be N

Preferably, R¹-B- is

R¹ may be independently selected from Ci-C4-alkyl and C3-C6-cycloalkyl. Thus, R¹ may be Ci- C4-alkyl. Preferably, R¹ is methyl. These embodiments are particularly preferred when B is linked to the rest of the molecule via the carbon atom of the tetrazole ring (i.e. when R¹ is

attached to a nitrogen of the tetrazole), e.g. when

Alternatively, R¹ may be H.

Preferably, n is 1. Preferably, R² is at each occurrence selected from H, F and Me. R² may, at each occurrence be H. Most preferably -(CR²R²)_n- is -CH2-.

A may be a 6-membered heteroaryl group. Thus, A may be selected from pyridine, pyrimidine, pyridazine or pyrazine. In certain preferred examples, A is pyridine. Where A is pyridine it is preferably linked to (-CR2R2)n- (e.g. -CH2-) at the 2-position of the pyridine ring. Likewise, where A is pyridine it is preferably linked to NHC(0)R³ at the 6-position of the pyridine ring.

Thus, the group

where R¹⁰ is independently at each occurrence selected from: halo, nitro, cyano, NR^aR^a, NR^aS(0)2R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄-haloalkyl; and s is an integer selected from 0, 1 , 2 and 3. s may be 1. R¹⁰ may be independently at each occurrence selected from: Ci-C₄-alkyl, Ci-C₄- haloalkyl, halogen, nitro and cyano, e.g. selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl and halogen. Preferably, however, s is 0.

Thus, the group H may be

Alternatively, A may be a 5-membered heteroaryl group. Thus, A may be selected from furan, thiophene, pyrrole, isoxazole, oxazole, pyrazole, imidazole, thiazole or isothiazole. A may be selected from isoxazole, oxazole, thiazole and isothiazole. In certain preferred examples, A is thiazole. Where A is thiazole it is preferably linked to (-CR2R2)n- (e.g. -CH2-) at the 4-position of the thiazole ring. Likewise, where A is thiazole it is preferably linked to NHC(0)R³ at the 2- position of the thiazole ring. Thus, the group

is preferably

where R^{1 1} is independently at each occurrence selected from: H, halo, nitro, cyano, NR^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C4-alkyl, C₂-C4-alkenyl, C₂-C4-alkynyl and Ci-C4-haloalkyl.

R^{1 1} may be independently selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro and cyano, e.g. from Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro and cyano. R^{1 1} may be

independently selected from: H, C1-C4 alkyl, Ci-C4-haloalkyl and halogen, e.g. from Ci-C4-alkyl, Ci-C4-haloalkyl and halogen. Preferably, however, R^{1 1} is H.

Thus, the group H may be H

R³ may be H. It may be that R³ is not H, i.e. it may be that R³ is independently selected from Ci-C_e alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl and -(CR⁶R⁶)_q-Z-(CR⁶R⁶)_rR⁷.

R³ may be selected from: d-Ce-alkyl, C₂-C6-alkenyl and C₂-C6-alkynyl.

Preferably, however R³ is -(CR⁶R⁶)_q-Z-(CR⁶R⁶)_r-R⁷.

It may be that q, Z and r are chosen such that the total length in terms of the number of atoms of the chain -(CR⁶R⁶)_q-Z-(CR⁶R⁶)_r- is no more than 4, e.g. the total length of the chain is 1 , 2 or 3 atoms. q may be 0, but is preferably 1. r may be selected from 0, 1 and 2. Thus in certain preferred embodiments r is 0. In other preferred embodiments, r is 1. R⁶ is preferably at all occurrences independently selected from F, H and Me. R⁶ may at all occurrences be selected from F and H. R⁶ may at all occurrences be H. R⁶ may at all occurrences be F.

R⁷ may be selected from C3-C7 cycloalkyi, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl. These R⁷ groups may be substituted or unsubstituted. R⁷ may be C3- C7-cycloalkyl, e.g. unsubstituted C3-C7-cycloalkyl. R⁷ may also be a phenyl group. Thus, R⁷ may be unsubstituted phenyl. R⁷ may be phenyl substituted with from 1-3 groups selected from H, halogen, Ci-C4-alkyl and Ci-C4-haloalkyl.

Z may be a bond. Where Z is a bond, it may be that at least one of q and r is an integer selected from 1 , 2 and 3 and R⁷ is selected from C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl. Where Z is a bond, R⁷ may be selected from C3-C7- cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl and q is preferably 0.

It may be that Z is a bond and q and r are both 0. Preferably, in this instance R⁷ is selected from where, if Z is a bond, at least one of q and r is an integer selected from 1 , 2 and 3 and R⁷ is selected from C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl.

Z may be NR⁸, e.g. NH. Where Z is NR⁸, e.g. NH, it may be that q is 1 and r is selected from 0, 1 and 2. r may be 1. Where Z is NR⁸, e.g. NH, it may be that R⁷ is H, but preferably R⁷ is selected from C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl. In these embodiments, preferably R⁶ is at all occurences independently selected from F, H and Me. R⁶ may at all occurences be H. R⁶ may at all occurences be F.

Z may be S. Where Z is S, it may be that q is 1 and r is selected from 0, 1 and 2. r may be 1. Where Z is S, it may be that R⁷ is H, but preferably R⁷ is selected from C3-C7-cycloalkyl, C3-C7- heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl. In these embodiments, preferably R⁶ is at all occurences independently selected from F, H and Me. R⁶ may at all occurences be H. R⁶ may at all occurences be F.

Preferably, Z is O. Where Z is O, it may be that q is 1 and r is selected from 0, 1 and 2. r may be 1. Where Z is O, it may be that R⁷ is H, but preferably R⁷ is selected from C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl. In these embodiments, preferably R⁶ is at all occurences independently selected from F, H and Me. R⁶ may at all occurences be H. R⁶ may at all occurences be F. In certain specific embodiments, -(CR⁶R⁶)_q- is -CF2-. In other specific embodiments, -(CR²R²)_q- is -CH2-. In yet further specific embodiments, -(CR⁶R⁶)_q- is -C(Me)H-. The embodiments are particularly preferred where Z is O or when Z is NR⁸, e.g. NH.

In certain specific embodiments, -(CR⁶R⁶)_r- is -CH2-. In other specific embodiments, -(CR⁶R⁶)_r is -CH2CH2-. The embodiments are particularly preferred where Z is O or when Z is NR⁸, e.g. NH.

In certain specific embodiments, R³ is CF20Ph.

R⁴ may independently at each occurrence be selected from: halo, nitro, cyano, NR⁹R⁹, OR⁸; Ci- C₄-alkyl, C2-C₄-alkenyl, C2-C₄-alkynyl and Ci-C₄-haloalkyl. Preferably, R⁴ is independently at each occurrence be selected from: halo, nitro, cyano, Ci-C₄-alkyl and Ci-C₄-haloalkyl, e.g. from halo, Ci-C₄-alkyl and Ci-C₄-haloalkyl. p may be an integer selected from 1 or 2. In certain embodiments, however, p is 0.

In an embodiment, the compound of formula I is selected from those compounds tested in Example 2.

The term C_m-C_n refers to a group with m to n carbon atoms.

The term "alkyl" refers to a linear or branched saturated hydrocarbon chain. For example, Ci- C6-alkyl may refer to methyl, ethyl, n-propyl, /^'so-propyl, n-butyl, sec-butyl, te/f-butyl, n-pentyl and n-hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be fluorine, OR^a or NHR^a.

The term "haloalkyi" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6- haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1- chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2- trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyi group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom. Thus, 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.

The term "alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be fluorine, OR^a or NHR^a.

The term "alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, "C2-C6-alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be fluorine, OR^a or NHR^a.

The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, "C3-C6-cycloalkyl" may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be fluorine, OR^a or NHR^a.

In any of the above aspects and embodiments, heteroaryl groups may be any aromatic (i.e. a ring system containing 2(2n + 1)π electrons) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from O, S and N (in other words from 1 to 4 of the atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.

In any of the above aspects and embodiments, a heterocycloalkyl group is a 3-7 membered saturated or partially saturated ring comprising 1 or 2 heteroatoms independently selected from O, S and N (in other words from 1 to 2 of the atoms forming the ring system are selected from O, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to rings with from 5 to 7 members. A 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.

Where any R¹-R¹¹ group is an aryl or heteroaryl group, that aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: halo, nitro, cyano, NR^aR^a, NR^aS(0)2R^a, NR^aC(0)R^a,

NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄ haloalkyl; wherein R^a is independently at each occurrence selected from H, Ci-C₄ alkyl and Ci- C₄ haloalkyl; and R^b is independently at each occurrence selected from H, halogen, Ci-C₄ alkyl and Ci-C₄ haloalkyl.

Where any R¹-R¹¹ group is an alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl group, that alkyl, haloalkyl, cycloalkyl or heterocycloalkyl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: oxo, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄ haloalkyl; wherein R^a is independently at each occurrence selected from H, Ci-C₄ alkyl and Ci-C₄ haloalkyl; and R^b is independently at each occurrence selected from H, halogen, Ci-C₄ alkyl and Ci-C₄ haloalkyl.

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

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

The compounds of the invention may be obtained, stored and/or used in the form of an agronomically acceptable salt. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of agronomically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable salts also include salts of inorganic and organic bases, e.g. counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium. The compounds may also be obtained, stored and/or used in the form of an N-oxide.

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

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

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

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

While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994). The activity of the compounds of the present invention can be assessed by a variety of in silico, in vitro and in vivo assays. In silico analysis of a variety of compounds has been demonstrated to be predictive of ultimate in vitro and even in vivo activity.

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

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

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

Throughout this specification these abbreviations have the following meanings:

CDI -carbonyl diimidazole DCM - dichloromethane

DMAP - A/,A/-dimethyl-4-aminopyridine DMF - N,N-dimethylformamide

DMSO - dimethylsulfoxide

EDCI - 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOAT - 1 -Hydroxy- 7-azabenzotriazole IMS - industrial methylated spirits

LDA - Lithium diisopropylamide pyr - pyridine

Selectfluor™ - 1-Chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) Tf - trifluoromethylsulfonyl TBAF - tetrabutylammonium fluoride

THF - tetrahydrofuran

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

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

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

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

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

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

In a further aspect, the present invention also relates to a fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of the invention. The composition may further comprise one or more additional fungicides.

The term "effective and non-phytotoxic amount" means an amount of pesticide according to the invention which is sufficient to control or destroy any of the targeted pests present or liable to appear on 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 according to the invention can also be used as a mixture with other known fungicides, for example, to improve the activity spectrum or to reduce or slow the development of resistance.

A mixture with other known active compounds such as nematicides, acaricides, herbicides, insecticides 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 very basic 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 0.1 % 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 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 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 Fusarium 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 damping off 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 Monographella nivalis; Penicillium diseases, caused for example by Penicillium expansum; Phoma diseases, caused for example by Phoma lingam; Phomopsis diseases, caused for example by Phomopsis sojae; Phytophthora diseases, caused for example by Phytophthora cactorum; Pyrenophora diseases, caused for example by Pyrenophora graminea Pyricularia diseases, caused for example by Pyricularia oryzae; Pythium diseases, caused for example by Pythium ultimum; Rhizoctonia diseases, caused for example by Rhizoctonia solani; Rhizopus diseases, caused for example by Rhizopus oryzae; Sclerotium diseases, caused for example by Sclerotium rolfsii; Septoria diseases, caused for example by Septoria nodorum; Typhula diseases, caused for example by Typhula incarnata; Verticillium diseases, caused for example by Verticillium dahliae;

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

Blight diseases such as:

Monilinia diseases, caused for example by Monilinia laxa;

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

Esca diseases, caused for example by Phaemoniella clamydospora, Phaeomoniella

clamydospora, Phaeoacremonium aleophilum and Fomitiporia mediterranea;

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

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

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

Diseases of Tubers such as

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

Club root diseases such as

Plasmodiophora diseases, caused for example by Plamodiophora brassicae.

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

Erisyphe graminis (now Blumeria)

Septoria nodorum

Septoria tritici

Fusarium oxysporum

Rhychosporium secalis

Pyrenophora teres

Notable oomycete fungal diseases are:

Plamopara viticola

Phytophthora infestans

Pythium ultimum

Bremia lactuca

Peronospora spp

In additional to their fungicidal activity, 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.

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 are exemplary methodologies for testing the fungicidal activities of compounds of the invention:

In vivo test on Venturia inaequalis in apples

To produce a suitable formulation of active compound, 1 part by weight of active compound may be mixed with 24.5 parts by weight of acetone, 24.5 parts by weight of N,N- dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate may be diluted with water to the desired concentration. To test for activity, young plants may be sprayed with the formulation of active compound at the stated rate of application. After the spray coating has dried on, the plants may be 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 may then be placed in a greenhouse at approximately 21 °C and a relative atmospheric humidity of approximately 90%. The test may be evaluated 10 days after the inoculation.

In vivo test on Botrytis cinerea in beans

To produce a suitable formulation of active compound, 1 part by weight of active compound may be mixed with 24.5 parts by weight of acetone, 24.5 parts by weight of N,N- dimethylacetamide and 1 part by weight of alkylaryl polyglycol ether, and the concentrate may be diluted with water to the desired concentration. To test for activity, young plants may be 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 may be 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 may be evaluated.

In vivo test on Sphaerotheca fuliginea in cucumber

To produce a suitable formulation of active compound, 1 part by weight of active compound may be mixed with 49 parts by weight of DMF and 1 part by weight of alkylarylpolyglycolether, and the concentrate may be diluted with water to the desired concentration. To test for activity, young plants may be sprayed with the formulation of active compound at the stated rate of application. One day after this treatment, the plants may be inoculated with an aqueous spore suspension of Sphaerotheca fuliginea. Then the plants may be placed in a greenhouse at approximately 23 °C and a relative atmospheric humidity of approximately 70%. The test may be evaluated 7 days after the inoculation

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 made according to the general synthetic schemes below. Certain compounds of the invention can be made according to or by methods analogous to the methods described in Example 1. General Synthetic Schemes

Scheme A shows a route which can be particularly useful in preparing compounds of formulae I, III, IV, V and VI in which X is CH and Y is NH.

Scheme A

A typical synthesis according to Scheme A starts from an carboxylic acid A, which can be converted to the amide C by reaction (e.g. using benzotriazole and CDI optionally in DMF at room temperature) with amine B, a specific example of which is amine D. Acylation of amide C with acid chloride E (e.g. in the presence of triethylamine and DMAP optionally in DCM at 0 °C) will provide compounds of formula F.

Scheme B shows a route which can be particularly useful in preparing compounds of formulae I, III, IV, V and VI in which X is CH and Y is O.

Scheme B

In an alternative approach, shown in Scheme B, acid A is coupled (e.g. by converting acid A to the acid chloride using SOC and triethylamine optionally in DCM at room temperature; and then adding the alcohol in the presence of pyridine optionally in DCM at room temperature) directly with an alcohol G, a specific subset of which is alcohol H, which has already been acylated.

Scheme B shows a route which can be particularly useful in preparing compounds of formulae I, II, IV, V and VI in which X is N.

Scheme C

Compounds of formula K can be converted into carbamoyl chlorides L (e.g. using phosgene in

DCM at room temperature). Carbamoyl chlorides L can be converted into compounds of formulae N and O through reaction with alcohol G or amine M respectively (e.g. in the presence of pyridine optionally in DCM at room temperature).

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 ¹ H NMR 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 x 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. tert-Butyl (6-((2-(1-methyl-1H-tetrazol-5-yl)-2-phenylacetamido)methyl)pyridin-2- yl)carbamate 1

To a solution of 5-benzyl-1-methyltetrazole (871 mg, 5 mmol) in THF (25 mL) at -78 °C was added n-BuLi [1.5 M in hexanes] (4.20 mL, 6.25 mmol) dropwise. After 30 minutes, C02(_g> was bubbled through the mixture while the reaction was simultaneously warmed to room

temperature over 30 minutes. The reaction mixture was quenched with water (20 mL), acidified to pH 2 with 2 M HCI(_a(?) and extracted with EtOAc (3x30 mL) before the organics were dried over MgS0₄ and the solvent removed in vacuo. The residue was dissolved in DCM (25 mL) before EDCI.HCI (1.44 g, 7.50 mmol), 4-(dimethylamino)pyridine (916 mg, 7.50 mmol) and N- ethyldiisopropylamine (2.60 mL, 15.00 mmol) were added. After 10 minutes, a solution of tert- butyl (6-(aminomethyl)pyridine-2-yl)carbamate (837 mg, 3.75 mmol) in DCM (25 mL) was added and the mixture was stirred at room temperature for 22 hours. The reaction mixture was quenched with water (15 mL) and extracted with CHCb (3x25 mL) before the organics were washed with brine, dried over MgS0₄ and the solvent removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 80% EtOAc/hexane) to afford the title compound as an off-white solid (148 mg, 7%).

¹ H NMR δ_Η (CDCb, 300 MHz): 7.99 (br, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.37 - 7.32 (m, 5H), 6.93 (br, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 5.20 (s, 1 H), 4.41 (d, J = 5.0 Hz, 2H), 3.88 (s, 3H), 1.46 (s, 9H). ESI-MS 424.1 [MH]⁺.

N-((6-Aminopyridin-2-yl)methyl)-2-(1 -methyl-1 H-tetrazol-5-yl)-2-phenylacetamide 2

To a solution of te/f-butyl (6-((2-(1 -methyl- 1/-/-tetrazol-5-yl)-2-phenylacetamido)methyl)pyridin-2- yl)carbamate (145 mg, 0.34 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (0.26 mL, 3.40 mmol) dropwise and the mixture was stirred at rt for 3 hours. The reaction mixture was diluted with DCM (3 mL) and water (3 mL), neutralised with sat. NaHC03(_a(7), and the separated aqueous layer extracted with DCM (2x5 mL) before the combined organics were dried over MgS0₄ and the solvent removed in vacuo to afford the title compound as an off-white solid (64 mg, 58%).

¹ H NMR δ_Η (CDCb, 300 MHz): 8.19 (br, 1 H), 7.37 - 7.32 (m, 6H), 6.49 (d, J = 7.5 Hz, 1 H), 6.45 (d, J = 8.0 Hz, 1 H), 5.26 (s, 1 H), 4.80 (br, 2H), 4.37 - 4.35 (m, 2H), 3.85 (s, 3H) ppm.

2,2^ifluoro-N-[6-[[[2-(1-methyl-1H-tetrazol-5-yl)-2-phenyl-acetyl]ami

pyridyl]-2-phenoxy-acetamide 3

To a solution of 2,2-difluoro-2-phenoxy acetic acid (52 mg, 0.28 mmol) in DCM (1 mL) and DMF (3 drops) was added oxalyl chloride (37 μί, 0.44 mmol) dropwise and the reaction was stirred at room temperature for 1 hour before the volatiles were removed in vacuo. The residue was dissolved in toluene (2 mL) and added to a solution of A/-[(6-amino-2-pyridyl)methyl]-2-(1- methyl-1 /-/-tetrazol-5-yl)-2-phenyl-acetamide (64 mg, 0.20 mmol) and /V-ethyldiisopropylamine (0.17 mL, 0.99 mmol) in toluene (2 mL). 4-(Dimethylamino)pyridine (29 mg, 0.24 mmol) was added and the mixture was heated at 90 °C for 20 hours, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with water (10 mL), neutralised with sat. NH₄CI(_a(7) and extracted with EtOAc (3 x 10 mL) before the organics were washed with brine (2 x 10 mL), dried over MgS0₄ and the solvent removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 80% EtOAc/hexane) to afford the title compound as a yellow oil (51 mg, 51 %).

1 H NMR δ_Η (CDCb, 300 MHz): 8.57 (br, 1 H), 8.18 (br, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.39 - 7.24 (m, 10H), 6.98 (d, J = 8.0 Hz, 1 H), 5.21 (s, 1 H), 4.51 - 4.40 (m, 2H), 3.87 (s, 3H) ppm. ESI-MS 494.2 [MH]⁺.

Methyl 2-phenyl-2-(1H-tetrazol-5-yl)acetate 4

To a solution of methyl 2-cyano-2-phenylacetate (1.75 g, 10.00 mmol) in toluene (25 mL) was added trimethylsilylazide (2.30 mL, 17.00 mmol) and dibutyltin oxide (249 mg, 1.00 mmol) and the mixture was heated at 85 °C for 3 hours. The volatiles were removed in vacuo before being dissolved in MeOH and the solvent removed in vacuo. The crude product was dissolved in EtOAc (50 mL), washed with 2 M HCI_(a(7) (20 mL) and brine (2 x 20 mL), dried over MgS0 and the solvent removed in vacuo. The resulting product was suspended in Et20 and the solid collected by filtration to afford the title compound as an off-white solid (1.13 g, 52%).

1 H NMR δ_Η (CDCb, 300 MHz): 7.38 - 7.20 (m, 5H), 5.49 (s, 1 H), 3.74 (s, 3H) ppm.

Methyl 2-(2-methyl-2H-tetrazol-5-yl)-2-phenylacetate 5

To a suspension of methyl 2-phenyl-2-(1 /-/-tetrazol-5-yl)acetate (1.09 g, 5.00 mmol) and potassium carbonate (690 mg, 5.00 mmol) in acetonitrile (50 mL) was added methyl iodide (0.31 mL, 5.00 mmol)and the mixture was heated at 60 °C for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with CHCb (3 x 25 mL) before the organics were washed with brine (2 x 25 mL), dried over MgS0₄ and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (solvent 40% EtOAc/hexane) to afford the title compound as an orange solid (486 mg, 42%). 494 mg (43%) of methyl 2-(1- methyl-1 /-/-tetrazol-5-yl)-2-phenylacetate was also isolated from the reaction.

1 H NMR δ_Η (CDCb, 300 MHz): 7.43 - 7.39 (m, 2H), 7.33 - 7.23 (m, 3H) 5.29 (s, 1 H), 4.26 (s, 3H), 3.68 (s, 3H) ppm. ESI-MS 255.1 [M+Na]⁺.

2- 2-Methyl-2H-tetrazol-5-yl)-2-phenylacetic acid 6

To a solution of methyl 2-(2-methyl-2/-/-tetrazol-5-yl)phenylacetate (470 mg, 2.02 mmol) in THF (20 ml_) was added lithium hydroxide [1 M in H2O] (10.00 ml_, 10.00 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified with 2M HCI(_a(?) and extracted with EtOAc (3x20 ml_) before the organics were dried over MgS0₄ and the solvent removed in vacuo to afford the title compound as a yellow solid (433 mg, 98%).

1 H NMR δ_Η (CDCb, 300 MHz): 7.45 - 7.40 (m, 2H), 7.34 - 7.27 (m, 3H) 5.33 (s, 1 H), 4.27 (s, 3H) ppm. ESI-MS 241.1 [M+Na]⁺. tert-Butyl (6-((2-(2-methyl-2H-tetrazol-5-yl)-2-phenylacetamido)methyl)pyridin-2- yl)carbamate 7

To a solution of 2-(2-methyl-2/-/-tetrazol-5-yl)-2-phenylacetic acid (364 mg, 1.67 mmol) in DCM (15 ml_) was added EDCI.HCI (479 mg, 2.50 mmol), 4-(dimethylamino)pyridine (305 mg, 2.50 mmol) and /V-ethyldiisopropylamine (0.87 ml_, 5.00 mmol). After 10 minutes, a solution of tert- butyl (6-(aminomethyl)pyridine-2-yl)carbamate (446 mg, 2.00 mmol) in DCM (15 ml_) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 2 M HCI(_a(?) (10 ml_) and extracted with DCM (2 x 15 ml_) before the combined organics were dried over MgS0₄ and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent 80% EtOAc/hexane) to afford the title compound as a white solid (327 mg, 46%).

¹ H NMR 5_H (CDCb, 300 MHz): 8.04 (br, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.62 - 7.55 (m, 3H), 7.48 - 7.38 (m, 4H), 6.90 (br, 1 H), 6.84 (d, J = 7.5 Hz, 1 H) 5.40 (s, 1 H), 4.48 (d, J = 5.0 Hz, 2H), 4.38 (s, 3H), 1.55 (s, 9H). N-((6-Aminopyn^'din-2-yl)methyl)-2-(2-methyl-2H-tetrazol-5-yl)-2-phenylacetamide 8

To a solution of te/f-butyl (6-((2-(2-methyl-2/-/-tetrazol-5-yl)-2-phenylacetamido)methyl)pyridin-2- yl)carbamate (310 mg, 0.73 mmol) in DCM (1.5 ml_) was added trifluoroacetic acid (0.56 ml_, 7.31 mmol) dropwise and the mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with DCM (2 ml_) and water (2 ml_), neutralised with sat.

NaHC03(_a(7) and the separated aqueous layer was extracted with DCM (2 x 5 ml_) before the combined organics were dried over MgS0₄ and the solvent removed in vacuo to afford the title compound as a pale yellow foam (183 mg, 78%).

¹ H NMR δ_Η (CDC , 300 MHz): 7.86 (br m, 1 H), 7.62 - 7.56 (m, 1 H), 7.35 - 7.23 (m, 5H), 6.69 (d, J = 7.5 Hz, 1 H), 6.59 (d, J = 9.0 Hz, 1 H), 5.25 (s, 1 H), 4.38 (d, J = 6.0 Hz, 2H), 4.25 (s, 3H) ppm. ESI-MS 324.1 [MH]⁺.

2,2-Difluoro-N-[6-[[[2-(2-methy-2H-ltetrazol-5-yl)-2-phenyl-acetyl]am

pyridyl]-2-phenoxy-acetamide 9

To a solution of 2,2-difluoro-2-phenoxy acetic acid (147 mg, 0.78 mmol) in DCM (2 ml_) and DMF (5 drops) was added oxalyl chloride (1 10 μΙ_, 1.23 mmol) dropwise and the reaction was stirred at room temperature for 1 hour before the volatiles were removed in vacuo. The residue was dissolved in toluene (4 ml_) and added to a solution of A/-[(6-amino-2-pyridyl)methyl]-2-(2- methyl-2H-tetrazol-5-yl)-2-phenyl-acetamide (180 mg, 0.56 mmol) and /V-ethyldiisopropylamine (0.48 ml_, 2.78 mmol) in toluene (4 ml_). 4-(Dimethylamino)pyridine (82 mg, 0.67 mmol) was added and the mixture was heated at 90 °C for 16 hours, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with water (25 ml_), neutralised with 2M HCI(_a(?) and extracted with EtOAc (3 x 25 ml_) before the organics were washed with brine (2 x 25 ml_), dried over MgS0₄ and the solvent removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 75%

EtOAc/hexane) to afford the title compound as a yellow solid (123 mg, 45%). ¹ H NMR δ_Η (CDCb, 300 MHz): 8.46 (br, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.4 - 7.44 (m, 3H), 7.40 - 7.17 (m, 7H), 6.98 (d, J = 8.0 Hz, 1 H) 5.31 (s, 1 H), 4.49 - 4.47 (m, 2H), 4.24 (s, 3H) ppm. ESI-MS 494.2 [MH]⁺.

N-(4-(((tert-Butyldimethylsilyl)oxy)methy)thiazol-2-yl)-2,2-difluoro-2-phen

10

To a solution of 2,2-difluoro-2-phenoxy acetic acid (658 mg, 3.5 mmol) in DCM (10 mL) and DMF (5 drops) was added oxalyl chloride (0.47 mL, 5.50 mmol) dropwise and the reaction was stirred at room temperature for 2 hours before the volatiles were removed in vacuo. The residue was dissolved in toluene (10 mL) and added to a solution of 4-(((tert- butyldimethylsilyl)oxy)methyl)thiazol-2-amine (610 mg, 2.50 mmol) and /V-ethyldiisopropylamine (2.18 mL, 12.50 mmol) in toluene (10 mL). 4-(Dimethylamino)pyridine (366 mg, 3.00 mmol) was added and the mixture was heated at 90 °C for 19 hours. The reaction mixture was quenched with water (25 mL), neutralised with sat. NH₄CI(_a(7) and extracted with EtOAc (3 x 25 mL) before the organics were dried over MgS0₄ and the solvent removed in vacuo. The resulting product was purified by flash chromatography on silica gel (solvent 20% EtOAc/hexane) to afford the title compound as a yellow oil (437 mg, 42%).

¹ H NMR δ_Η (CDCb, 300 MHz): 7.46 - 7.41 (m, 2H), 7.36 - 7.33 (m, 1 H), 7.29 - 7.26 (m, 2H), 7.00 (t, J = 1.0 Hz, 1 H), 4.73 (d, J = 1.0 Hz, 2H), 0.94 (s, 9H), 0.13 (s, 6H). ESI-MS 415.5

[MH]⁺.

2, 2-Difluoro-N-(4-(hydroxymethyl)thiazol-2-yl)-2-phenoxyacetamide 11

To a solution of A/-(4-(((te/f-butyldimethylsilyl)oxy)methy)thiazol-2-yl)-2,2-difluoro-2- phenoxyacetamide (414 mg, 1.00 mmol) in THF (10 mL) was added TBAF [1 M in THF] (1.20 mL, 1.20 mmol) dropwise and the mixture was stirred for 90 minutes at room temperature before further TBAF [1 M in THF] (1.20 mL, 1.20 mmol) was added. After stirring for a further 3 hours the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 20 mL) before the organics were washed with brine (50 mL), dried over MgS0₄ and the solvent removed in vacuo. The crude material was purified by flash chromatography on silica gel (solvent EtOAc) to afford the title compound as a colourless oil (290 mg, 97%).

1 H NMR δ_Η (CDCb, 300 MHz): 7.46 - 7.41 (m, 2H), 7.38 - 7.26 (m, 3H), 6.97 (s, 1 H), 4.73 (s, 2H) ppm. ESI-MS 300.9 [MH]⁺.

[2-[(2,2-Difluoro-2-phenoxy-acetyl)amino]thiazol-4-yl]methyl 2-(2-methyl-2H-tetrazol-5-yl)- 2-phenyl-acetate 12

A solution of 2,2-difluoro-/V-[4-(hydroxymethyl)thiazol-2-yl]-2-phenoxy-acetamide (220 mg, 0.73 mmol) in DCM (5 ml_) was added to a solution of 2-(2-methyl-2H-tetrazol-5-yl)-2-phenyl-acetic acid (192 mg, 0.88 mmol), Λ/,Λ/'-dicyclohexylcarbodiimide (181 mg, 0.88 mmol) and 4- (dimethylamino)pyridine (107 mg, 0.88 mmol) in DCM (5 ml_). The reaction was stirred at room temperature for 18 hours, after which time TLC showed complete consumption of the starting material. The reaction mixture was quenched with water (50 ml_) and extracted with CHCb (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 resulting product was purified by flash chromatography on silica gel (solvent 50% EtOAc/hexane) to afford a white solid. The solid was dissolved in a minimum amount of Et20 and left to precipitate a white solid which was removed by filtration before the filtrate was dried in vacuo to afford the title compound as a white solid (156 mg, 35%).

1 H NMR 5_H (CDCb, 300 MHz): 9.65 (br, 1 H), 7.42 - 7.15 (m, 10H), 6.87 (s, 1 H) 5.36 (s, 1 H), 5.15 (s, 2H), 4.23 (s, 3H) ppm. ESI-MS 501.1 [MH]⁺. tert-Butyl N-tert-butoxycarbonyl-N-[4-[(tert-butyl(dimethyl)silyl)oxymethyl]thiazol-2- yl] carbamate 13

To a solution of 4-[(te/f-butyl(dimethyl)silyl)oxymethyl]thiazol-2-amine (2.44 g, 10 mmol) in dichloromethane (20 ml_) was added 4-dimethylaminopyridine (25 mg, 0.2 mmol) and di-te/f- butyl dicarbonate (4.58 g, 21 mmol) and the mixture was stirred at rt for 16h. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (100 mL), dried over

MgSCU and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent 20 % EtOAc/hexane) to give the title compound (4.41 g, 99 %).

¹ H NMR δ_Η (CDCb, 300 MHz): 7.06 (s, 1 H), 4.80 (s, 2H), 1.54 (s, 18H), 0.97 (s, 9H), 0.15 (s,

6H). tert-Butyl N-tert-butoxycarbonyl-N-[4-(hydroxymethyl)thiazol-2-yl]carbamate 14

To a solution of te/f-butyl A/-te/f-butoxycarbonyl-/\/-[4-[(fe/f-butyl(dimethyl)silyl)oxymethyl]thiazol- 2-yl]carbamate (4.41 g, 9.9 mmol) in THF (50 mL) at 0 °C was added tetrabutylammonium fluoride (1.0 M in THF, 10.5 mL, 10 mmol) dropwise and the mixture was stirred for 4 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL), dried over MgSCU and the solvent removed in vacuo to afford the title compound (3.27 g, 77%) that was used in the next step without further purification.

¹ H NMR δ_Η (CDCb, 300 MHz): 6.99 (s, 1 H), 4.67 (s, 2H), 3.38 (br s, 1 H), 1.51 (s, 18H).

[2-(bis(tert-Butoxycarbonyl)amino)thiazol-4-yl]methyl methanesulfonate 15

o

To a solution of te/f-butyl A/-te/f-butoxycarbonyl-/\/-[4-(hydroxymethyl)thiazol-2-yl]carbamate (3.27 g, 9.9 mmol) in dichloromethane (50 mL) at 0 °C was added triethylamine (2.00 g, 2.76 mL, 19.8 mmol) and methanesulfonyl chloride (2.27 g, 1.53 mL, 19.8 mmol) and the mixture was stirred for 10 min. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL), dried over MgS04 and the solvent removed in vacuo to afford the title compound (4.04 g, quant.) that was used in the next step without further purification.

1 H NMR δ_Η (CDCb, 300 MHz): 7.17 (s, 1 H), 5.22 (s, 2H), 3.00 (s, 3H), 1.55 (s, 18H). tert-Butyl N-tert-butoxycarbonyl-N-[4-[ (1,3-dioxoisoindolin-2-yl)methyl]thiazol-2- yl] carbamate 16

To a solution of [2-(bis(te/f-butoxycarbonyl)amino)thiazol-4-yl]methyl methanesulfonate (4.04 g, 9.9 mmol) in Λ/,Λ/'-dimethylformamide (20 ml_) was added potassium phthalimide (2.75 g, 15 mmol) and the solution heated to 90 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (250 ml_), washed with water (250 ml_), dried over MgSCU and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (30 % Et₂0/hexane) to afford the title compound (940mg, 21 %).

¹ H NMR δ_Η (CDCb, 300 MHz): 7.88-7.84 (m, 2H), 7.76-7.72 (m, 2H), 6.98 (s, 1 H), 4.91 (s, 2H), 1.47 (s, 18H). tert-But l N-[4-(aminomethyl)thiazol-2-yl]carbamate 17

To a solution of te/f-butyl A/-te/f-butoxycarbonyl-/\/-[4-[(1 ,3-dioxoisoindolin-2-yl)methyl]thiazol-2- yl]carbamate (0.94 g, 2.0 mmol) in IMS (10 ml_) was added hydrazine hydrate (410 mg, 400 μηιοΙ, 8.2 mmol) and the mixture was stirred for 3 h at room temperature. The reaction mixture was filtered and the solvent removed in vacuo to give a solid which was suspended in IMS (5 ml_) and refiltered. The filtrate was concentrated in vacuo to give the title compound (229mg, 49%) that was used in the next step without further purification.

¹ H NMR δ_Η (CDCb, 300 MHz): 6.57 (s, 1 H), 3.77 (s, 2H), 1.48 (s, 9H). ESI-MS 252.0 [M+Na]⁺ tert-Butyl N-[4-[[[ ( 1 -methyl- 1 H-tetrazol-5-yl)-phenyl-carbamoyl]amino]methyl]thiazol-2- yl] carbamate 18

To a solution of 1-methyl-N-phenyl-1 H-tetrazol-5-amine (250 mg, 1.4mmol) in DCM (3 ml_) at

0°C was added trichloromethyl chloroformate (190 μΙ_, 1.6 mmol) and pyridine (231 μΙ_, 2.8 mmol) and the mixture was allowed to warm to room temperature over 16h. The solvent was removed in vacuo and the residue redissolved in DCM (5 mL) before being added to a solution of te/f-butyl N-[4-(aminomethyl)thiazol-2-yl]carbamate (229 mg, 1.0 mmol) and triethylamine (360 μΙ_, 2.6 mmol) in DCM (5 mL). The mixture was stirred for 16h before being diluted with water (5 mL) and DCM (5 mL). The aqueous layer was separated and extracted with DCM (2x10 mL) before the combined organics were dried over MgS0₄ and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (solvent 1 % MeOH/DCM) to afford the title compound as a yellow foam (360 mg, 84%).

1 H NMR δ_Η (CDC , 300 MHz): 7.43-7.35 (m, 5H), 6.75 (s, 1 H), 6.65 (br s, 1 H), 4.44 (d, J = 5.4 Hz, 2H), 3.75 (s, 3H). ESI-MS 431.1 [MH]⁺.

3-[(2-Aminothiazol-4-yl)methyl]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-urea 19

To a solution of tert-butyl N-[4-[[[(1-methyl-1 H-tetrazol-5-yl)-phenyl- carbamoyl]amino]methyl]thiazol-2-yl]carbamate (320 mg, 0.06 mmol) in DCM (12 mL) at 0°C was added trifluoroacetic acid (6 mL) dropwise and the mixture stirred for 3h at room

temperature. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica gel (solvent 5% MeOH/DCM) to afford the title compound as a white solid (227 mg, 92%).

¹ H NMR δ_Η (Methanol-^, 300 MHz): 7.44-7.31 (m, 5H), 5.98 (s, 1 H), 4.11 (s, 2H), 3.85 (s, 3H). ESI-MS 331.0 [MH]⁺.

2, 2-Difluoro-N-[4-[[[ ( 1 -methyl-1H-tetrazol-5-yl)-phenyl-carbamoyl]amino]methyl]thiazol-2- yl]-2-phenoxy-acetamide 20

To a solution of 2,2-difluoro-2-phenoxy-acetic acid (292mg, 1.54 mmol) in DCM (5mL) was added DMF (0.1 mL) and oxalyl chloride (140μί, 1.6 mmol) dropwise and the mixture was stirred at room temperature for 3h before the solvent was removed in vacuo. The residue was re-dissolved in DCM (5mL) and filtered before being added to a solution of 3-[(2-aminothiazol-4- yl)methyl]-1-(1-methyl-1 H-tetrazol-5-yl)-1-phenyl-urea (230mg, 0.7 mmol) and triethylamine (214μΙ_, 1.5 mmol) and the mixture was stirred at RT for 16h. H2O (5ml_) was added, the layers separated and the aqueous fraction was extracted with DCM (2x1 OmL). The combined organic solvents were dried over MgSCU, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (solvent 70% EtOAc/hexane) to afford the title compound (69mg, 20%).

¹ H NMR δ_Η (CDCb, 300 MHz): 9.83 (s, 1 H), 7.50-7.30 (m, 9H), 7.24 (s, 1 H), 7.00 (br t, J = 6 Hz, 1 H), 6.94 (s, 1 H). 4.49 (d, J = 5.7 Hz, 2H), 3.65 (s, 3H).

ESI-MS 501.1 [MH]⁺.

N-[6-[(tert-Butyl(dimethyl)silyl)oxymethyl]-2-pyridyl]-2,2-difluoro-2-phenoxy-acetami 20

To a solution of 2,2-difluoro-2-phenoxy acetic acid (284 mg, 1.51 mmol) in DCM (5 ml_) and DMF (2 drops) was added oxalyl chloride (0.24 ml_, 2.77 mmol) dropwise and the mixture was stirred at room temperature for 90 minutes before the volatiles were removed in vacuo. The residue was dissolved in toluene (2.5 ml_) and added to a solution of 6-[(tert- butyl(dimethyl)silyl)oxymethyl]pyridin-2-amine (300 mg, 1.26 mmol) and N- ethyldiisopropylamine (1.10 ml_, 6.29 mmol) in toluene (2.5 ml_). 4-(Dimethylamino)pyridine (184 mg, 1.51 mmol) was added and the mixture was heated at 90 °C for 24 hours. The reaction mixture was neutralised with 2 M HCI(_a(?) and extracted with EtOAc (3x5 ml_) before the organics were washed with brine, dried over MgSCU and the solvent removed in vacuo. The resulting oil was triturated with Et20 to precipitate a brown solid which was removed by filtration and purified by flash chromatography on silica gel (solvent 20% EtOAc/hexane) to afford the title compound as a yellow oil (234 mg, 45%).

¹ H NMR δ_Η (CDCb, 300 MHz): 8.60 (br, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H), 7.36 - 7.22 (m, 6H), 4.67 (s, 2H), 0.89 (s, 9H), 0.06 (s, 6H) ppm. ESI-MS 409.1 [MH]⁺.

2,2-Difluoro-N-[6-(hydroxymethyl)-2-pyridyl]-2-phenoxy-acetamide 21

To a solution of A/-[6-[(fe/f-butyl(dimethyl)silyl)oxymethyl]-2-pyridyl]-2,2-difluoro-2-phenoxy- acetamide (785 mg, 1.92 mmol) in THF (20 mL) was added TBAF [1 M in THF] (2.30 mL, 2.30 mmol) dropwise and the reaction was stirred for 17 hours at room temperature. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 25 mL) before the 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 50% EtOAc/hexane) to afford the title compound as a white solid (342 mg, 60%).

1 H NMR δ_Η (CDCb, 300 MHz): 8.86 (br, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.74 (t, J = 1.0 Hz, 1 H), 7.37 - 7.32 (m, 2H), 7.26 - 7.19 (m, 3H), 7.05 (d, J = 7.5 Hz, 1 H), 4.67 (s, 2H), 3.19 (br, 1 H) ppm.

[6-[(2,2-Difluoro-2-phenoxy-acetyl)amino]-2-pyridyl] methyl N-(1-methyl-1H-tetrazol-5-yl)- N-phenyl-carbamate 22

To a solution of 1-methyl-N-phenyl-1 H-tetrazol-5-amine (250mg, 1.4 mmol) in DCM (3mL) at 0°C was added trichloromethyl chloroformate (190μί, 1.6 mmol) and pyridine (231 μί, 2.8 mmol) dropwise and the mixture was allowed to warm to rt over 16h at which point the solvent was removed in vacuo. The residue was re-dissolved in DCM (5mL) and filtered before being added to a solution of 2,2-difluoro-N-[6-(hydroxymethyl)-2-pyridyl]-2-phenoxy-acetamide (378mg, 1.3 mmol) and triethylamine (358μί, 2.6 mmol) in DCM (3mL) and the mixture was stirred at RT for 16h. H2O (5mL) was added, the layers separated and the aqueous fraction was extracted with DCM (2x1 OmL). The combined organic solvents were dried over MgS0₄, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (solvent 50% EtOAc/hexane) to afford the title compound (212mg, 33%).

1 H NMR δ_Η (CDCb, 300 MHz): 8.84 (s, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.45-7.25 (m, 10H), 7.04 (apr t, J = 7.5 Hz, 1 H), 5.28 (s, 2H), 3.95 (s, 3H).

ESI-MS 496.1 [MH]⁺.

Example 2 - Testing the fungicidal activity of compounds of the invention Amended agar assay

Testing was carried out on potato dextrose agar (PDA) amended with each compound at test concentrations of 20, 4 and 0.8. Amended agar at each test concentration was poured into three replicate 9 cm petri dishes. Each replicate dish was inoculated in the centre with a 5 mm agar plug taken from the leading edge of a culture aged between 2 and 7 days old; the age of the culture was dependant on the growth rate of the pathogen being tested. The test pathogens were Pythium ultimum, Phytophthora cinnamomi, Botrytis cinerea, an Alternaria species and Rhizoctonia cerealis. Plates were incubated at 18°C and the diameter of each colony measured before growth on the fastest growing plate reached the plate edge. This varied between 2 and 7 days depending on the growth rate of test pathogens. The % reduction in colony growth compared to the control was calculated for each test concentration and pathogen combination.

Photometric assay

The effect of fungicides on germination of Septoria tritici spores was determined using a photometric technique adapted from Pijls et al. (Pijls CFN, Shaw MW, Parker A (1994). A rapid test to evaluate in vitro sensitivity of Septoria tritici to flutriafol using a microtitre plate reader. Plant Pathology, 43, 726-32), which used optical densitometry to measure levels of spore germination. Each compound was tested at concentrations of 100, 10, 1 , 0.1 , 0.01 , 0.001 , 0.0001 and 0 ppm with three replicates and controls.

Dilutions of each fungicide were prepared in a glucose-peptone growth medium (GPM) and 100 μΙ of each pippetted into wells of a flat-bottomed microtitre plate (96 well). 100 μΙ of non- amended GPM was used as the control. 150 μΙ of a conidial spore suspension (at 10⁴ spores ml^-1) was pippetted in each treatment well and 150 μΙ GPM only into control wells. For each test, conidia were obtained from a 5 day old culture of a Septoria (growing on PDA). The isolate used was collected during 2014 and taken from the Fera culture collection (isolate number 2014/162)

Plate absorbance was read at 405 nm immediately after the addition of spores and then again 6 days later. The difference in absorbance readings was used to calculate the average control at any given dosage for each compound.

The results are shown in Table 1 in which * represents an average control of up to 40% at said dosage; ** represents an average control of 40% or greater but less than 80% at said dosage; and *** represents an average control of 80% or greater at said dosage Table 1 - average % control at given dosage-

P. cinnamomi Pythium Septoria

Pathogen

Dose 0.8 4 20 0.8 4 20 1 10 100

20 * ** ** * * * * ** *

22 ** ** ** ** ** * * **

3 * ** ** * * ** *

9 * * * * * * *

12 * * * * * * * * *

All compounds tested exhibited antifungal activity. In particular, compound 22 exhibited good control over certain pathogens.

Claims

1. A compound of formula I

wherein

X is independently selected from: N and CH ;

Y is independently selected from: O and NR⁵; A is a 5- or 6- membered heteroaryl group; B is a tetrazole group;

R¹ is independently selected from: H , Ci-C4-alkyl, Ci-C4-haloalkyl, and C3-C6-cycloalkyl;

R³ is independently selected from H, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and -(CR⁶R⁶)_q-Z- (CR⁶R⁶)rR⁷;

Z is selected from: a bond, S, O and NR⁸;

R⁴ is independently at each occurrence selected from: halo, nitro, cyano, NR⁹R⁹, NR⁸S(0)2R⁸, NR⁸C(0)R⁸, NR⁸CONR⁸R⁸, NR⁸C0₂R⁸, OR⁸; SR⁸, S(0)R⁸, S(0)₂OR⁸, S(0)₂R⁸, S(0)₂NR⁸R⁸, C0₂R⁸, C(0)R⁸, CONR⁸R⁸, CR⁸R⁸NR⁹R⁹, CR⁸R⁸OR⁸, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C4-haloalkyl;

R⁵ and R⁸ are independently at each occurrence selected from: H, Ci-C4-alkyl, and C1-C4- haloalkyl;

R⁷ is independently selected from: H, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl; R⁹ is independently selected from: H, Ci-C4-alkyl, C(0)-Ci-C4-alkyl and Ci-C4-haloalkyl; n is an integer independently selected from 0, 1 and 2; p is an integer independently selected from 0, 1 , 2, 3 and 4; q and r are each an integer selected from 0, 1 , 2 and 3; wherein in any R¹-R⁹ group is an alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group, that alkyl, haloalkyi, cycloalkyi, heterocycloalkyi, aryl or heteroaryl group is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: oxo, =NR^a, =NOR^a, halo, nitro, cyano, NR^aR^a, NR^aS(0)2R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a; SR^a, S(0)R^a, S(0)²OR^a, S(0)₂R^a, S(0)₂NR^aR^a, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, Ci-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and Ci-C₄-haloalkyl; wherein R^a is independently at each occurrence selected from H, Ci-C₄ alkyl and Ci-C₄-haloalkyl; and R^b is independently at each occurrence selected from H, halogen, Ci-C₄-alkyl and Ci-C₄-haloalkyl; 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 CH.

4. A compound of any one of claims 1 to 3, wherein Y is O.

5. A compound of any one of claims 1 to 3, wherein Y is NH.

6. A compound of any one of claims 1 to 5, wherein R¹-B- is

7. A compound of any one of claims 1 to 6, wherein R¹ may be Ci-C₄-alkyl; optionally wherein R¹ is methyl.

8. A compound of any one of claims 1 to 7, wherein -(CR²R²)_n- is -CH₂-.

9. A compound of any one of claims 1 to 8, wherein A is pyridine.

10. A compound of any one of claims 1 to 8, wherein A is thiazole.

11. A compound of any one of claims 1 to 10, wherein R³ is -(CR⁶R⁶)_q-Z-(CR⁶R⁶)_r-R⁷.

12. A compound of claim 1 1 , wherein Z is O.

13. A compound of claim 12, wherein q is 1 and r is selected from 0, 1 and 2.

14. A compound of any one of claims 1 1 to 13, wherein R⁷ is selected from C3-C7-cycloalkyl, C3-C7-heterocycloalkyl, phenyl and 5- or 6- membered heteroaryl.

15. A compound of any one of claims 11 to 14, wherein R⁶ is at each occurrence F.

16. A compound of any one of claims 1 to 10, wherein R³ is CF20Ph.

17. A compound of any one of claims 1 to 16, wherein p is 0.

18. A method for controlling the fungal diseases of plants, crops or seeds, the method comprising applying an agronomically effective and substantially non-phytotoxic quantity of a compound of any one of claims 1 to 17 to the seeds of the plants, to the plants themselves or to the area where it is intended that the plants will grow.

19. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of claims 1 to 17.