WO2016055801A2

WO2016055801A2 - Agricultural chemicals

Info

Publication number: WO2016055801A2
Application number: PCT/GB2015/052957
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: WO2016055801A3; GB201417962D0

Abstract

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

Description

Agricultural Chemicals

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.

Certain pyrazole and imidazole compounds have been shown to have antifungal activity against agriculturally relevant fungal pathogens (see WO2012/031061 and WO2012/044650).

An aim of certain embdiments 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 certain embdiments 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 certain embdiments 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 as 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 may also concern compounds which have only a low level activity relative to that of the 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.

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 compound sagainst 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 or formula II, or an agronomically acceptable salt or N-oxide thereof:

Y¹ is selected from C and N; and Y² is selected from CR⁴ and NR⁵; wherein when is Y¹ is C, Y² is NR⁵ and the bond between the carbon labelled 'a' and Y¹ is a double bond; and when Y¹ is N, Y² is CR⁴ and the bond between the carbon labelled 'a' and Y² is a double bond;

X is independently selected from: a bond, O, NR⁶, CR⁷R⁷;

R¹ and R² are each independently an aryl group or a heteroaryl group;

R³ and R⁴ are each independently selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro, OR⁸, SR⁸, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-cycloalkyl and NR⁹R⁹; R⁵ and R⁹ are each independently at each occurrence selected from; H, C1-C4 alkyl, C(0)-Ci- C₄-alkyl and Ci-C₄-haloalkyl;

R⁶ is independently selected from: H, S(O)₂R^10a, S(O)₂OR^10a, S(O)₂NR^10aR^10b, CO₂R^10a, CONR^10aR^10b and COR^10a;

R⁷ is independently at each occurrence selected from: H, halo; Ci-C₄-alkyl and Ci-C₄-haloalkyl;

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

R^10a is independently selected from: Ci-C₄-alkyl, aryl, Ci-C₄-haloalkyl;

R^10b is independently selected from: H, Ci-C₄-alkyl, aryl, Ci-C₄-haloalkyl; wherein any R¹-R^10b group which is an alkyl, haloalkyi, cycloalkyi, aryl or heteroaryl group, that alkyl, haloalkyi, cycloalkyi, 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 and R^b are each independently at each occurrence selected from H, Ci-C₄-alkyl and Ci-C₄-.

For the absence of doubt, where X is a bond it is intended to mean that there is a carbon carbon double bond between the two carbon atoms to which the group X is attached.

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

wherein X, R¹ , R², R³ and R⁴ are as described for formula I above. In an embodiment, the compound of formula I is a compound of formula IV:

wherein X, R¹ , R², R³ and R⁵ are as described for formula I above.

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

wherein Y¹ , Y², R¹ , R² and R³ are as described for formula I above.

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

wherein Y¹ , Y², R¹ , R², R³ and R⁶ are as described for formula I above. Preferably, R⁶ is H.

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

wherein Y¹ , Y², R¹ , R², R³ and R⁷ are as described for formula I above.

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

wherein Y¹ , Y², R¹ , R² and R³ are as described for formula I above. , the compound of formula I is a compound of formula IX:

wherein R¹ , R², R³ and R⁵ are as described for formula I above.

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

wherein R¹ , R², R³, R⁵ and R⁶ are as described for formula I above. Preferably, R⁶ is H. In an embodiment, the compound is a compound of formula II.

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

It is preferred that Y¹ is C, Y² is NR⁵ and the bond between the carbon labelled 'a' and Y¹ is a double bond. The ring which contains Y¹ , Y² and the carbon labelled 'a' is thus preferably a pyrazole. Alternatively, it may be that Y ¹ is N, Y² is CR⁴ and the bond between the carbon labelled 'a' and Y² is a double bond. The ring which contains Y¹ , Y² and the carbon labelled 'a' may thus be an imidazole.

R⁴ is independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl (e.g. Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl). Preferably, R⁴ is selected from Ci-C4-alkyl and Cs-Cs-cycloalkyl. Thus, R⁴ may be Me. R³ is independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl (e.g. Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl). R³ may be halogen. Preferably, R³ is CI. These embodiments are particularly preferred when the ring which contains Y¹ , Y² and the carbon labelled 'a' is an imidazole, e.g. compounds of formula II and III.

R³ may be independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6- cycloalkyl (e.g. Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl). Thus, R³ may be selected from Ci-C4-alkyl and C3-C6-cycloalkyl. It may be that R³ is Me. In an embodiment, R⁵ is independently selected from Ci-C4-alkyl, C3-C6-cycloalkyl and Ci-C4-haloalkyl. Thus, R⁵ may be selected from Ci-C4-alkyl and C3-C6-cycloalkyl. It may be that R⁵ is Me. These embodiments are particularly preferred when the ring which contains Y¹ , Y² and the carbon labelled 'a' is a pyrazole, e.g. compounds of formula IV.

X may be O.

Alternatively, X may be CR⁷R⁷. R⁷ may be independently at each occurrence selected from H and halogen, e.g. F. Thus, X may be CH2. Alternatively, X may be selected from CHF and CF₂.

In another alternative, X may be NR⁶. R⁶ may be selected from H, S(O)₂R^10a and COR^10a. R⁶ may be H. Alternatively, R⁶ may be selected from: S(O)₂R^10a, S(O)₂OR^10a, S(O)₂NR^10aR^10b, CO₂R^10a, CONR^10aR^10b and COR^10a. Thus, R⁶ may be selected from S(O)₂R^10a and COR^10a. R⁶ may be S(O)₂R^10a. Alternatively, R⁶ may be C(O)R^10a. R^10a may be Me. Thus, X may be selected from NH , NC(0)Me and NS(0)₂Me. Preferably, X is N H.

In yet another alternative, X may be a bond.

X may be selected from NR⁶ (e.g. N H), O and a bond. R¹ may be heteroaryl, e.g. pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be unsubstituted or may be substituted with from 1 to 4 substituents selected from Ci-C4-alkyl, Ci- C₄-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl and NR^aR^a. The substituents may be selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro and cyano.

R¹ may be unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C2-C₄-alkenyl, C2-C₄-alkynyl and NR^aR^a. The substituents may be selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro and cyano. R¹ may be substituted with from 1 to 5 substituents selected from Ci-C₄-alkyl, Ci- C₄-haloalkyl and halogen. Preferably, R¹ is substituted with from 1 to 5 (e.g. 2 or 3) halogen substituents. Said halogen substituents may be the same or different. If, for example, the phenyl has two halogen substituents, they may both be F. As another example, if the phenyl has three halogen substituents, it may be that two are F and the third may be I.

In certain specific examples, particularly preferred for compounds of formulae II and III, R¹ is

In certain other specific examples, particularly preferred for compounds of

R² may be heteroaryl, e.g. pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be unsubstituted or may be substituted with from 1 to 4 substituents selected from Ci-C₄-alkyl, Ci- C₄-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl and NR^aR^a. The substituents may be selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro and cyano.

Preferably, R² is aryl, e.g. phenyl. R² may be unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C2-C₄-alkenyl, C2-C₄-alkynyl and NR^aR^a. The substituents may be selected from Ci-C₄- alkyl, Ci-C₄-haloalkyl, OR^a, halogen, nitro and cyano. R² may be substituted with from 1 to 5 substituents selected from OR^a, Ci-C₄-alkyl, Ci-C₄-haloalkyl and halogen. Preferably, R² is substituted with from 1 to 5 (e.g. 2 or 3) halogen substituents. Said halogen substituents may be the same or different. If, for example, the phenyl has two halogen substituents, one may be F and the other may be CI. As another example, if the phenyl has three halogen substituents, it may be that two are F and the third may be CI.

Where R² is a phenyl group comprising more than one electron withdrawing substituent (e.g. more than one substituent selected from halogen, cyano and nitro), it will preferably be that the phenyl group is 2,6- disubstituted (i.e, the two positions ortho to the point of connectivity to the imidazole or pyrazole ring are preferably substituted). Compounds, and particularly pyrazole compounds, in which R² is aryl having this 2,6-disubstitution pattern on the R² aryl group, can be easier to produce than equivalent compounds not having the 2,6-disubstitution pattern.

It may be that R² is substituted by at least one OR^a, e.g. OMe group. There may be other substituents on R², e.g. substituents selected from the group Ci-C4-alkyl, Ci-C4-haloalkyl and halogen. It may be that R² is substituted by at least one OR^a, e.g. OMe group, and from 1 to 3 (e.g. 2) halogen substituents. The inventors have found that an alkoxy substituent on R² can facilitate the preparation of the compounds of the invention. examples, particularly preferred for compounds of formulae II, III and IV R² is

pecific examples, particularly preferred for compounds of

in yet further specific embodiments, R² is

It may be that at each occurrence R^a is selected from H and Ci-C4-alkyl. Likewise, it may be that R^b is independently at each occurrence selected from H and Ci-C4-alkyl.

In an embodiment, the compound of formula (I) is a compound selected from compounds 1 to 19 and 26 to 30 as shown in the General Synthetic Schemes and Examples below. It may be that the compound of formula (I) is a compound selected from compounds 26 to 30 as shown in the Examples below.

Further embodiments of the invention are described in the following numbered paragraphs: 1. A compound of formula I or formula II:

Y¹ is selected from C and N; and Y² is selected from CR⁴ and NR⁵; wherein when is Y¹ is C, Y² is NR⁵ and the bond between the carbon labelled 'a' and Y¹ is a double bond; and when Y ¹ is N, Y² is CR⁴ and the bond between the carbon labelled 'a' and Y² is a double bond; X is independently selected from O, NR⁶, CR⁷R⁷; R¹ and R² are each independently an aryl group or a heteroaryl group; R³ and R⁴ are each independently selected from: H, Ci-C4-alkyl, C1-C4- haloalkyl, halogen, nitro, OR⁸, SR⁸, cyano, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl and NR⁹R⁹; R⁵ and R⁹ are each independently at each occurrence selected from; H, Ci-C4-alkyl, C(0)-Ci-C₄-alkyl and Ci-C₄-haloalkyl; R⁶ is independently selected from: H, SO2R¹⁰ and COR¹⁰; R⁷ is independently at each occurrence selected from: H, halo; Ci-C4-alkyl and Ci-C4-haloalkyl; R⁸ is independently at each occurrence selected from; H, Ci-C4-alkyl and Ci-C4-haloalkyl;

R¹⁰ is independently selected from: Ci-C4-alkyl, aryl, Ci-C4-haloalkyl; wherein any R¹-R¹⁰ group which is an alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl group, that alkyl, haloalkyl, cycloalkyl, 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, SOR^a, S0₃R^a, S0₂R^a, S0₂NR^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 paragraph 1 , wherein the compound of formula I is a compound of formula IV:

3. A compound of paragraph 2, wherein each of R³ and R⁵ are Me.

4. A compound of paragraph 1 , wherein the compound of formula I is a compound of formula III:

5. A compound of paragraph 1 , wherein the compound is a compound of formula II.

6. A compound of paragraph 4 or paragraph 5, wherein R³ is CI and R⁴ is Me.

7. A compound of any one of paragraphs 1 to 6, wherein X is O.

8. A compound of any one of paragraphs 1 to 6, wherein X is CR⁷R⁷ optionally wherein X is selected CH₂, CHF and CF₂.

9. A compound of any one of paragraphs 1 to 6, wherein X is NR⁶ optionally wherein X is selected from NH, NHC(0)Me and NS(0)₂Me.

10. A compound of any one of paragraphs 1 to 9, wherein R¹ is unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from C1-C4 alkyl, Ci-C4-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl and NR^aR^a.

d of paragraph 10, wherein R¹ is selected from

12. A compound of any one of paragraphs 1 to 1 1 , wherein R² is unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄.alkenyl, C₂-C₄-alkynyl and NR^aR^a.

13. A compound of paragraph 12, wherein R² is selected from

14. 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 one of paragraphs 1 to 13 to the seeds of the plants, to the plants themselves or to the area where it is intended that the plants will grow.

15. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of paragraphs 1 to 13.

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 "haloalkyl" 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 halo alkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one halogen atom. Thus, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen substituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.

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.

It may be that, in any R¹-R^10b group which 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 and R^b are each independently at each occurrence selected from H, Ci-C₄-alkyl and Ci-C₄-haloalkyl. It may be that, in any R¹-R^10b group which is an alkyl, haloalkyl, or cycloalkyl 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 and R^b are each independently at each occurrence selected from H, 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.

Many of the compounds of the invention contain a chiral centre at the carbon of the cyclopropane, epoxide or aziridine ring which is directly attached to the carbon labelled 'a' of the imidazole or pyrazole ring. The invention thus comprises the (S)-enantiomer of any such compound, the (R)- enantiomer of any such compound and any mixture thereof. Likewise, were the compound is a cyclopropane, that cyclopropane may include a further chiral centre (e.g. where X is CHF). The invention thus encompasses compounds in which this carbon has the (S)-configuration, the (R)- configuration and any mixture thereof.

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, sulfuric, 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, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, 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. Also included are acid addition salts 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.

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 X 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 sulfur, 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:

DCM - dichloromethane

DMAP - A/,A/-dimethyl-4-aminopyridine

Selectfluor™ - 1-Chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) THF - tetrahydrofuran

TMS - trimethylsilyl

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

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

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

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

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

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

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

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

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

The active compounds can be used neat, or in the form of a formulation, e.g. ready-to-use solutions, emulsions, water- or oil-based suspensions, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, granules for broadcasting, suspoemulsion

concentrates, natural substances impregnated with active compound, synthetic substances impregnated with active compound, fertilizers and also microencapsulations in polymeric substances. Application may be carried out, for example, by watering, spraying, atomizing, broadcasting, dusting, foaming, spreading, etc. It is also possible to apply the active

compounds by the ultra-low volume method or to inject the preparation of active compound or the active compound itself into the soil. It is also possible to treat the seed of the plants.

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

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

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

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 sulfoxide. 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, alkylsulfonates, alkyl sulfates, arylsulfonates and also protein hydrolysates; suitable dispersants are nonionic and/or ionic substances, for example from the classes of the alcohol-POE and/or -POP ethers, acid and/or POP-POE esters, alkylaryl and/or POP-POE ethers, fat- and/or POP-POE adducts, POE- and/or POP- polyol derivatives, POE- and/or POP-sorbitan- or -sugar adducts, alkyl or aryl sulfates, alkyl- or arylsulfonates and alkyl or aryl phosphates or the corresponding PO-ether adducts.

Furthermore, suitable oligo- or polymers, for example those derived from vinylic monomers, from acrylic acid, from EO and/or PO alone or in combination with, for example, (poly)alcohols or (poly)amines. It is also possible to employ lignin and its sulfonic acid derivatives, unmodified and modified celluloses, aromatic and/or aliphatic sulfonic acids and their adducts with formaldehyde.

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

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

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

The formulations generally comprise between 0.01 and 98% by weight of active compound, preferably between 0.1 and 95% and particularly preferably between 0.5 and 90%. The active compounds of the invention can also be used as a mixture with other known fungicides, for example, to improve the activity spectrum or to reduce or slow the development of resistance. A mixture with other known active compounds such as nematicides, herbicides, insecticides, acaricides, or bactericides, or with fertilizers and growth regulators, safeners or semiochemicals is also possible.

Exemplary application rates of the active compounds according to the invention are: when treating leaves: from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used); when treating seed: from 2 to 200 g per 100 kg of seed, preferably from 2.5 to 150 g per 100 kg of seed, and particularly preferably from 2.5 to 25 g per 100 kg of seed, very particularly preferably from 2.5 to 12.5 g per 100 kg of seed; when treating the soil: from 0.1 to 10000 g/ha, preferably from 1 to 5000 g/ha.

A very basic formulation which could be used to administer the compounds, paricularly 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 or oil formation 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 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 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 pathogens are: Erisyphe graminis (now Blumeria)

Septoria nodorum

Septoria tritici

Fusarium oxysporum

Rhychosporium secalis

Pyrenophora teres

It may be that the compounds of the invention are for use in treating a fungal disease caused by a pathogen selected from Botrytis cinerea, an Alternaria species, Septoria tritici and

Rhizoctonia cerealis.

Notable oomycete fungal pathogens 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 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 are exemplary methodologies for testing the fungicidal activities of compounds of the invention:

In vivo test on Leptosphaeria nodorum in wheat

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

Illustrative routes to the compounds of the invention are set out in the general synthetic schemes below.

General Synthetic Schemes

Compounds of formula II can be made according to Scheme A:

Scheme A

A typical synthesis according to Scheme A starts from an imidazole A, which can be converted to the fluoride B (e.g. using Selectfluor™ optionally in MeCN at room temperature). Reaction of fluoride B with alcohol C (e.g. in the presence of triethylamine optionally in MeCN at room temperature) can provide compounds of formula D. An exemplary compound which can be made using these methods is compound 1 :

Compounds of formulae III and IV in which X is O and compounds of formula V can be made according to Scheme B:

Scheme B

Scheme B starts with alcohol E or ketone F. Alcohol E and/or ketone F can be made according to the methods described in WO2012/044650 (see in particular Schemes 1 , 2, 1 1 and 12 and the Examples) and WO2012/03106 (see in particular Scheme 12 and the

Examples). If alcohol E is used as the starting material, it can be oxidised to ketone F (e.g. using Na2Cr20₇ in acetic acid and water at room temperature). Reaction between ketone F and an appropriate sulfur ylid (e.g. that formed from MesSI and KOH, with the reaction optionally taking place in ¾uOH between 30 °C and 50 °C). Exemplary compounds which can be made using these methods are compounds 2, 3 and 4:

Compounds of formulae III and IV in which X is a bond or CR⁷R⁷, and compounds of formulae VII, VIII and IX can be made according to Scheme C:

In the above scheme Hal = halogen. In a specific example Hal = F.

Scheme C

The route depicted in Scheme C starts with ketone F which undergoes a Wittig reaction (e.g. using PhsPMel, BuLi, THF optionally at -78 °C initially and then warming to room temperature). The reaction may then be treated with NH₄CI solution optionally at room temperature) to generate alkene H (corresponding to formula VIII). Alkene H can then undergo a Simmons- Smith reaction (e.g. using a reagent derived from CH2I2 and Et2Zn, optionally in DCM and hexane at reflux) to provide the unsubstituted cyclopropane ring J. Alternative

cyclopropanation conditions provide mono-fluorinated (e.g. in a three step sequence: BrsCF, BuLi, THF, -1 16 °C to room temperature; Me₃SnCI, UAIH4, reflux; HN0₃, H₂0, 0 °C) or difluorinated (e.g. using TMSCF3, Nal, THF, 65 °C) cyclopropane rings K and L. Exemplary compounds which can be made using these methods include compounds 5 to 13:

Compounds of formulae III and IV in which X is NR⁶, and compounds of formula VI can be made according to Scheme D:

Scheme D

Alkene H can be converted into aziridines (e.g. using R⁶S02NCINa and PhNMe3Br3 optionally in MeCN at room temperature to provide a sulfonyl aziridine or alternatively using I2, NH3 optionally in water and a detergent, e.g. Brij™ 35, at room temperature to provide the NH aziridine). An NH aziridine can be converted into an amide (i.e. a compound in which R⁶ is C(O)R^10a) by reacting with an acid chloride (e.g. by carrying out the reaction in pyridine or by using catalytic DMAP and EUN in DCM). Exemplary compounds which can be made using

Example 1 - Synthetic Procedures

2-(2,6-Difluoro-4-methoxyphenyl)acetoacetonitrile 20

A solution of 2,6-difluoro-4-methoxyphenylacetonitrile (10.00 g, 54.6 mmol) in ethyl acetate (10 mL) was added dropwise over 10 minutes to a stirred suspension of sodium ethoxide (8.92 g, 131.0 mmol) in toluene (100 mL) at room temperature under nitrogen. The mixture was heated to reflux under nitrogen for 3 hours and then cooled to room temperature. Petroleum ether (100 mL) and water (200 mL) were added to the mixture. The separated aqueous phase was washed with petrol (100 mL) and then the pH of the aqueous phase was adjusted to pH 4 by dropwise addition of 2M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate (3 x 100 mL) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave 12.29 g (assume 100% yield) of 2-(2,6-difluoro-4- methoxyphenyl) acetoacetonitrile as a brown oil. The product was used in the next step without further purification: ¹ H NMR (300 MHz, CDC ): 6.60-6.52 (m, 2H), 4.86 (s, 1 H), 3.83 (s, 3H), 2.40 (s, 3H); MS (ESI+) m/z calculated for C11 H10F2NO2, [M + H⁺] 226.07; found 226.0.

4- 2,6-Difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazol-3-ylamine 21

Methyl hydrazine (2.51 g, 2.87 mL, 54.6 mmol) was added dropwise over 10 minutes to a stirred solution of 2-(2,6-difluoro-4-methoxyphenyl) acetoacetonitrile 20 (12.29 g, 54.6 mmol) in acetic acid (10 mL) and ethanol (100 mL) at room temperature under nitrogen. The mixture was heated to reflux under nitrogen for 14 hours and then cooled to room temperature. The mixture was concentrated in vacuo to leave a brown oil. The residue was dissolved in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (2 x 150 mL). The separated aqueous phases were combined and extracted with ethyl acetate (2 x 75 mL). The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo to leave a light brown solid. The solid was recrystallized from diethyl ether. The precipitated solid was collected by filtration, washed with diethyl ether (2 x 10 mL) and dried under vacuum to leave 10.28 g (74% yield over 2 steps) of 4-(2,6-difluoro-4-methoxyphenyl)-2- methyl-5-methyl-2H-pyrazol-3-ylamine as a colourless solid: ¹ H NMR (300 MHz, CDCI3): 6.60- 6.51 (m, 2H), 3.83 (s, 3H), 3.69 (s, 3H), 3.39 (br. s, 2H), 2.10 (s, 3H); MS (ESI+) m/z calculated for C12H14F2N3O, [M + H⁺] 254.1 1 ; found 254.2.

3-Bromo-4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazole 22

te/f-Butyl nitrite (5.57 g, 4.83 mL, 40.6 mmol) was added dropwise over 30 minutes to a stirred solution of 4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-ylamine 21 (5.14 g, 20.3 mmol) and copper(ll) bromide (4.53 g, 20.3 mmol) in acetonitrile (100 mL) at 0°C under nitrogen. The mixture was stirred at 0°C under nitrogen for 90 minutes and then warmed to room temperature. The mixture was stirred at room temperature under nitrogen for 30 minutes. Water (100 mL), saturated aqueous sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL) were added to the mixture. The separated organic phase was washed with saturated aqueous sodium hydrogen carbonate (100 mL). The aqueous phases were combined and extracted with ethyl acetate (2 x 100 mL). The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo to leave a light brown oil. The residue was purified by chromatography on silica, eluting with a gradient of 5%, 10% to 15% ethyl acetate in petroleum ether, to leave 3.54 g (55% yield) of 3-bromo-4-(2,6-difluoro-4-methoxyphenyl)-2- methyl-5-methyl-2/-/-pyrazole as a light yellow solid: ¹ H NMR (300 MHz, CDC ): 6.60-6.51 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z calculated for Ci2Hi₂Br⁸¹ F2N₂0, [M + H⁺] 319.01 ; found 318.9.

[4-(2,6-Difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazol-3-yl](2,4- difluorophenyl)methanol 23

n-Butyllithium (3.78 mL, 9.46 mmol, 2.5M in hexanes) was added dropwise over 15 minutes to a stirred solution of 3-bromo-4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazole 22 (1.00 g, 3.15 mmol) and 2,4-difluorobenzaldehyde (896 mg, 0.69 mL, 6.31 mmol) in

tetrahydrofuran (40 mL) at -78 °C under nitrogen. The mixture was stirred at -78 °C under nitrogen for 1 hour and then warmed to room temperature under nitrogen. The mixture was stirred at room temperature under nitrogen for 1 hour. Saturated aqueous ammonium chloride (50 mL) and ethyl acetate (20 mL) were added to the mixture. The separated aqueous phase was extracted with ethyl acetate (2 x 20 mL) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a brown oil. The residue was purified by chromatography on silica, eluting with a gradient of 10%, 20%, 30%, 40% to 50% ethyl acetate in petroleum ether, to leave an orange solid. The solid was recrystallised in petroleum ether. The solid was collected by filtration, washed with petroleum ether (2 x 20 mL) and dried under vacuum to leave 496 mg (41 % yield) of [4-(2,6-difluoro-4-methoxyphenyl)-2- methyl-5-methyl-2/-/-pyrazol-3-yl](2,4-difluorophenyl)methanol as a pale yellow solid ¹ H NMR (300 MHz, CDC ): 7.41 (dt, J = 8.6 and 6.3 Hz, 1 H), 6.77 (ddt, J = 8.6, 2.5 and 1.1 Hz, 1 H), 6.67 (ddd, J = 10.6, 8.6 and 2.5 Hz, 1 H), 6.51-6.39 (m, 2H), 5.98 (d, J = 3.7 Hz, 1 H), 3.82 (s, 3H), 3.80 (s, 3H), 2.55 (d, J = 2,1 Hz, 1 H), 2.09 (s, 3H); MS (ESI+) m/z calculated for C19H17F4N2O2, [M + H⁺] 381.12; found, 380.9.

[4-(2,6-Difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazol-3-yl](2,4- difluorophenyl)formaldehyde 24

A suspension of [4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl](2,4- difluorophenyl)methanol 23 (3.31 g, 8.71 mmol), Dess-Martin periodinane (5.54 g, 13.1 mmol) and sodium hydrogen carbonate (2.20 g, 26.1 mmol) in dichloromethane (60 mL) was stirred at room temperature under nitrogen for 30 minutes. Saturated aqueous sodium thiosulfate (100 mL), saturated aqueous sodium hydrogen carbonate (50 mL), water (50 mL) and

dichloromethane (150 mL) were added to the mixture. The separated aqueous phase was extracted with dichloromethane (100 ml_) and then the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a brown oil. The residue was dissolved in ethyl acetate (150 ml_) and the precipitated solid was filtered. The filtrate was concentrated in vacuo to leave a brown oil. The residue was purified by chromatography on silica, eluting with a gradient of 10%, 15% to 20% ethyl acetate in petroleum ether, to leave 3.11 g (94% yield) of [4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl](2,4- difluorophenyl)formaldehyde as an orange oil, which solidified on standing: ¹ H NMR (300 MHz, CDCIs): 7.45 (dt, J = 8.4 and 6.4 Hz, 1 H), 6.73 (ddt, J = 8.4, 2.3 and 0.8 Hz, 1 H), 6.50 (ddd, J = 10.2, 8.9 and 2.3 Hz, 1 H), 6.29-6.19 (m, 2H), 4.18 (s, 3H), 3.72 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z calculated for C19H15F4N2O2, [M + H⁺] 379.1 1 ; found, 379.1.

1-[4-(2,6-Difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazol-3-yl]-1 -(2,4- difluorophenyl)-1 -ethanol 25

Methyllithium (0.41 ml_, 0.66 mmol, 1.6M in diethyl ether) was added dropwise over 10 minutes to a stirred solution of [4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3- yl](2,4-difluorophenyl)formaldehyde 24 (500 mg, 1.32 mmol) in tetrahydrofuran (50 ml_) at 0 °C under nitrogen. The mixture was stirred at 0 °C under nitrogen for 30 minutes. Additional methyllithium (1.03 ml_, 1.65 mmol, 1.6M in diethyl ether) was added dropwise over 30 minutes to the mixture at 0 °C under nitrogen. The mixture was stirred at 0 °C under nitrogen for 30 minutes. Saturated aqueous ammonium chloride (50 ml_) and ethyl acetate (20 ml_) were added to the mixture. The separated aqueous phase was extracted with ethyl acetate (2 x 25 ml_) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave an orange solid. The residue was purified by chromatography on silica, eluting with a gradient of 30%, 40% to 50% ethyl acetate in petroleum ether, to leave 520 mg (100% yield) of 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl]-1- (2,4-difluorophenyl)-1-ethanol as a colourless solid: ¹ H NMR (300 MHz, CDC ): 7.31 (dt, J = 8.8 and 6.6 Hz, 1 H), 6.80-6.65 (m, 2H), 6.46-6.36 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 2.78 (s, 0.5H), 2.76 (s, 0.5H), 2.00 (s, 3H), 1.76 (s, 3H); MS (ESI+) m/z calculated for C20H19F4N2O2, + H⁺] 395.14; found, 395.0.

1-[4-(2,6-Difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2H-pyrazol-3-yl]-1 -(2,4- difluorophenyl)ethene 26

A solution of 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl]-1-(2,4- difluorophenyl)-1-ethanol 25 (290 mg, 0.74 mmol) in concentrated sulfuric acid (2 ml_) and tetrahydrofuran (10 ml_) was stirred at 50 °C under nitrogen for 1 week. The mixture was poured into saturated aqueous sodium hydrogen carbonate (75 ml_). The separated aqueous phase was extracted with ethyl acetate (3 x 40 ml_) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a brown oil. The residue was purified by chromatography on silica, eluting with 20% ethyl acetate in petroleum ether, to leave 189 mg (68% yield) of 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-

3- yl]-1-(2,4-difluorophenyl)ethene as a light yellow oil, which solidified on standing: ¹ H NMR (300 MHz, CDC ): 7.04 (dt, J = 8.9 and 6.7 Hz, 1 H), 6.84-6.72 (m, 2H), 6.47-6.37 (m, 2H), 5.80 (s, 1 H), 5.48 (s, 1 H), 3.78 (s, 3H), 3.60 (s, 3H), 2.16 (s, 3H); MS (ESI+) m/z calculated for C20H17F4N2O, [M + H⁺] 377.13; found, 377.0.

4- (2,6-Difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-2-oxiranyl]-1 -methyl-3-methyl- 1H-pyrazole 27

A solution 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl]-1-(2,4- difluorophenyl)ethene 26 (250 mg, 0.66 mmol) and m-chloroperbenzoic acid (1.64 g, 6.64 mmol) in dichloromethane (10 mL) was stirred at room temperature under nitrogen for 14 hours. Saturated aqueous sodium hydrogen carbonate (100 mL) and dichloromethane (100 mL) were added to the mixture. The separated aqueous phase was extracted with

dichloromethane (50 mL) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a yellow solid. The residue was purified by chromatography on silica, eluting with a gradient of 20%, 25% to 30% diethyl ether in petroleum ether, to leave a light yellow oil. The residue was purified again by chromatography on silica, eluting with a gradient of 20% to 25% ethyl acetate in petroleum ether, to leave 61 mg (23% yield) of 4-(2,6-difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-2-oxiranyl]-1-methyl-3- methyM H-pyrazole as a colourless oil: ¹ H NMR (300 MHz, CDC ): 7.12 (dt, J = 8.8 and 6.3 Hz, 1 H), 6.82-6.70 (m, 2H), 6.51 (dt, J = 10.7 and 1.8 Hz, 1 H), 6.46 (dt, J = 10.7 and 1.8 Hz, 1 H), 3.89 (s, 3H), 3.82 (s, 3H), 3.24 (d, J = 6.2 Hz, 1 H), 3.22 (d, J = 6.2 Hz, 1 H), 2.08 (s, 3H); MS (ESI+) m/z calculated for C20H17F4N2O2, [M + H⁺] 393.12; found, 393.0.

4-(2,6-Difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-2-aziridinyl]-1-methyl-3- methyl-1H-pyrazole 28

Sodium hypochlorite (0.50 ml_, 13% active chlorine) was added dropwise over 20 minutes to a stirred solution of 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/-pyrazol-3-yl]-1- (2,4-difluorophenyl)ethene 26 (300 mg, 0.80 mmol), ammonium iodide (1 16 mg, 0.80 mmol) and brij 35 (287 mg, 0.24 mmol) in ammonium hydroxide (10 ml_, 28% ammonia in water) and tetrahydrofuran (1 ml_) at room temperature under nitrogen. The mixture was stirred at room temperature under nitrogen for 14 hours. Sodium hypochlorite (4 x 1.00 ml_, 13% active chlorine) was added dropwise over 15 minutes per portion, to the mixture at room temperature under nitrogen, over an 8 hour period. The mixture was stirred at room temperature under nitrogen for 14 hours. Ethyl acetate (100 ml_), water (20 ml_) and brine (80 ml_) were added to the mixture. The separated aqueous phase was extracted with ethyl acetate (2 x 50 ml_) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a brown oil. The residue was purified by chromatography on silica, eluting with a gradient of 30%, 60% to 90% ethyl acetate in petroleum ether, to leave a yellow oil. The residue was dissolved in a mixture of 50% diethyl ether in petroleum ether. The mixture was filtered and the filtrate was concentrated in vacuo to leave 235 mg (75% yield) of 4-(2,6-difluoro-4- methoxyphenyl)-5-[2-(2,4-difluorophenyl)-2-aziridinyl]-1-methyl-3-methyl-1 /-/-pyrazole as a yellow oil: ¹ H NMR (300 MHz, CDC ): 7.14 (br. s, 1 H), 6.78-6.67 (m, 2H), 6.61-6.43 (m, 2H), 3.95 (br. s, 3H), 3.84 (s, 3H), 3.47 (br. s, 1 H), 2.59 (br. s, 1 H), 2.04 (s, 3H), 2.02 (br. s, 1 H); MS (ESI+) m/z calculated for C20H18F4N3O, [M + H⁺] 392.14; found, 392.0.

4-(2,6-Difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-1-(methylsulfonyl)-2- aziridinyl]-1-methyl-3-methyl-1H-pyrazole 29

Methanesulfonyl chloride (41 mg, 0.028 mL, 0.37 mmol) was added dropwise over 5 minutes to a stirred solution of 4-(2,6-difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-2-aziridinyl]-1- methyl-3-methyl-1/-/-pyrazole 28 (130 mg, 0.33 mmol) and triethylamine (101 mg, 0.14 mL, 1.00 mmol) in dichloromethane (3 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C under nitrogen for 1 hour. Methanol (0.50 mL) was added to the mixture and the mixture was then stirred at room temperature under nitrogen for 15 minutes. Ethyl acetate (150 mL) was added to the mixture and the organic phase was then washed with 0.5M aqueous hydrochloric acid (2 x 25 mL), saturated aqueous sodium hydrogen carbonate (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo to leave a light yellow oil. The residue was purified by chromatography on silica, eluting with 70% ethyl acetate in petroleum ether, to leave a colourless oil. The residue was dissolved in diethyl ether (10 mL). The precipitated solid was collected by filtration and dried under vacuum to leave 103 mg (66% yield) of 4-(2,6-difluoro-4-methoxyphenyl)-5-[2-(2,4-difluorophenyl)-1-(methylsulfonyl)-2- aziridinyl]-1-methyl-3-methyl-1 /-/-pyrazole as a colourless solid: ¹ H NMR (300 MHz, CDC ): 7.33-7.23 (m, 1 H), 6.82-6.70 (m, 2H), 6.57 (dt, J = 10.7 and 2.0 Hz, 1 H), 6.41 (dt, J = 10.7 and 2.0 Hz, 1 H), 3.98 (s, 3H), 3.84 (s, 3H), 3.40 (s, 1 H), 2.94 (s, 3H), 2.84 (s, 1 H), 2.03 (s, 3H); MS (ESI+) m/z calculated for C21 H20F4N3O3S, [M + H⁺] 470.12; found, 470.0.

4-(2,6-Difluoro-4-methoxyphenyl)-5-[1 -(2,4-difluorophenyl)-2,2-difluorocyclopropyl]-1- methyl-3-methyl-1H-pyrazole 30

Trifluoromethyltrimethylsilane (141 mg, 0.15 ml_, 1.00 mmol) was added dropwise over 2 minutes to a stirred solution of 1-[4-(2,6-difluoro-4-methoxyphenyl)-2-methyl-5-methyl-2/-/- pyrazol-3-yl]-1-(2,4-difluorophenyl)ethene 26 (150 mg, 0.40 mmol) and sodium iodide (60 mg, 0.40 mmol) in tetrahydrofuran (3 ml_) at room temperature under nitrogen. The mixture was heated to 65 °C, in a sealed tube, under nitrogen for 14 hours. Sodium iodide (60 mg, 0.40 mmol) and trifluoromethyltrimethylsilane (141 mg, 0.15 ml_, 1.00 mmol) were added

sequentially to the mixture. The mixture was heated to 65 °C, in a sealed tube, under nitrogen for 3 days. Ethyl acetate (100 ml_), water (50 ml_) and brine (50 ml_) were added to the mixture. The separated aqueous phase was extracted with ethyl acetate (50 ml_) and the combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to leave a brown oil. The residue was purified by chromatography on silica, eluting with a gradient of 20% to 25% ethyl acetate in petroleum ether, to leave 147 mg (87% yield) of 4-(2,6-difluoro-4- methoxyphenyl)-5-[1-(2,4-difluorophenyl)-2,2-difluorocyclopropyl]-1-methyl-3-methyl-1 /-/- pyrazole as a yellow oil, which solidified on standing: ¹ H NMR (300 MHz, CDC ): 7.01 (dt, J = 8.2 and 6.6, 1 H), 6.83-6.73 (m, 2H), 6.63-6.51 (m, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 2.13 (ddd, J = 12.8, 8.0 and 5.4 Hz, 1 H), 1.99 (s, 3H), 1.87 (ddd, J = 12.1 , 8.0 and 5.4 Hz, 1 H); MS (ESI+) m/z calculated for C21 H17F6N2O, [M + H⁺] 427.12; found, 427.0.

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 50% at said dosage; ** represents an average control of 50% 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-

Alternaria Botrytis Rhizoctonia Septoria

Pathogen

Dose 0.8 4 20 0.8 4 20 0.8 4 20 1 10 100

23 * * -* * * * * * * 26 \¾ *** * * * *** ***

27 ** * * * * * * * ** * * * *

28 *** *** * * * *_· * *** *** *** ***

29 * * * * * *

30 *** ** **.

Compound 23 was included in the testing for comparative purposes (see WO2012031061). All compounds tested showed antifungal activity, with compounds 26, 27 and 28 showing excellent acitivity against certain pathogens. Against certain pathogens (e.g. botrytis) compounds 26, 27 and 28 showed higher activity than the comparative compound 23.

Claims

1. A compound of formula I or formula II, or an agronomically acceptable salt or N-oxide thereof:

Y¹ is selected from C and N; and Y² is selected from CR⁴ and NR⁵; wherein when is Y¹ is C, Y² is NR⁵ and the bond between the carbon labelled 'a' and Y¹ is a double bond; and when Y¹ is N , Y² is CR⁴ and the bond between the carbon labelled 'a' and Y² is a double bond;

X is independently selected from: a bond, O, NR⁶, CR⁷R⁷;

R¹ and R² are each independently an aryl group or a heteroaryl group;

R³ and R⁴ are each independently selected from: H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro, OR⁸, SR⁸, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-cycloalkyl and NR⁹R⁹;

R⁵ and R⁹ are each independently at each occurrence selected from; H, C1-C4 alkyl, C(0)-Ci- C4-alkyl and C1-C4 haloalkyl;

R⁷ is independently at each occurrence selected from: H, halo; Ci-C4-alkyl and Ci-C4-haloalkyl;

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

R^10a is independently selected from: Ci-C4-alkyl, aryl, Ci-C4-haloalkyl;

R^10b is independently selected from: H, Ci-C4-alkyl, aryl, Ci-C4-haloalkyl; wherein any R¹-R^10b group which is an alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl group, that alkyl, haloalkyl, cycloalkyl, 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 and R^b are each independently at each occurrence selected from H, Ci-C₄-alkyl and Ci-C₄- haloalkyl.

2. A compound of claim 1 , wherein the compound of formula I is a compound of formula IV:

3. A compound of claim 2, wherein R⁵ is selected from Ci-C₄-alkyl and C3-C6-cycloalkyl.

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

5. A compound of any one of claims 1 to 4, wherein X is O.

6. A compound of any one of claims 1 to 4, wherein X is CR⁷R⁷.

7. A compound of claim 6, wherein X is selected CH₂, CHF and CF₂.

8. A compound of any one of claims 1 to 4, wherein X is NR⁶.

9. A compound of claim 8, wherein R⁶ is H.

10. A compound of any one of claims 1 to 4, wherein X is a bond.

11. A compound of any one of claims 1 to 10, wherein R¹ is unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from Ci-C₄-alkyl, Ci-C₄-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl and NR^aR^a.

13. A compound of any one of claims 1 to 12, wherein R² is unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents selected from C1-C4 alkyl, Ci-C4-haloalkyl, halogen, nitro, OR^a, SR^a, cyano, C₂-C₄ alkenyl, C₂-C₄ alkynyl and NR^aR^a.

A compound of claim 13, wherein R² is selected from

15. A compound of any one of claims 1 to 14, wherein R³ is independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl (e.g. Ci-C4-alkyl, Ci-C4-haloalkyl, halogen and C3-C6-cycloalkyl).

16. A compound of claim 15, wherein R³ is Me.

17. 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 one of claims 1 to 16 to the seeds of the plants, to the plants themselves or to the area where it is intended that the plants will grow.

18. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of claims 1 to 16.