PYRAZOLE, ISOTHIAZOLE AND ISOXAZOLE DERIVATIVES USEFUL AS

AGRICULTURAL FUNGICIDES

The present invention relates to pyrazole, isoxazole and isothiazole 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.

Certain pyrazole compounds have been shown to have antifungal activity against

agriculturally relevant fungal pathogens (see WO2012/031061 and WO2016/055801). An aim of certain embodiments 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 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 are 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.

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 may 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 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, or an agronomically acceptable salt or N-oxide thereof:

Z ¹ and Z ² are each independently selected from N, NR ² , O and S; wherein at least one of Z ¹ and Z ² is N;

R ¹ is independently a 5- or 6- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups;

R ² is independently selected from Ci-C6-alkyl, C3-C6-cycloalkyl, Ci-C6-haloalkyl and C(0)-Ci- Ce-alkyl;

R ³ is independently selected from H, halo, Ci-C6-alkyl, C3-C6-cycloalkyl and Ci-C6-haloalkyl;

R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are independently at each occurrence selected from H, Ci-C6-alkyl, Ci- Ce-haloalkyl, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ; or wherein R ^4b and R ^5b together with the carbon atoms to which they are attached together form a ring selected from: phenyl, 5- or 6- membered heteroaryl , 5-, 6- or 7- membered heterocycloalkyi ring and Cs-Cycycloalkyl; said heteroaryl or phenyl ring being optionally substituted with from 1 to 4 R ¹¹ groups or said heterocycloalkyi or cycloalkyl ring being optionally substituted with from 1 to 4 R ¹² groups;

with the proviso that either at least one of R ^4a and R ^4b is selected from Ci-C6-alkyl, C1 -C4- haloalkyl, halo, nitro, 0-Ci-C ₄ -alkyl, SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ; or R ^4b and R ^5b together form a ring;

R ⁷ is independently at each occurrence selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6- cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , 9R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, NR ⁹ R ¹⁰ and , wherein R is selected from H, Ci-C6-alkyl, C3-C6-alkenyl, C3-C6- alkynyl, C ₃ -C ₆ -cycloalkyl, Ci-C ₆ -haloalkyl CH ₂ Ph and CH ₂ C(0)OR ⁹ ;

R ⁸ is independently at each occurrence selected from: H, Ci-C6-alkyl, C3-C6-alkenyl, C3-C6- alkynyl, C3-C6-cycloalkyl and Ci-C6-haloalkyl;

R ⁹ is independently at each occurrence selected from: H, C3-C6-cycloalkyl and Ci-C6-alkyl; or where two R ⁹ groups are attached to the same nitrogen atom, said R ⁹ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹⁰ is independently at each occurrence selected from; H, Ci-C6-alkyl, C(0)-Ci-C6-alkyl and S(0) ₂ -Ci-C ₆ -alkyl;

or where an R ⁹ group and an R ¹⁰ group are attached to the same nitrogen atom, said R ⁹ and R ¹⁰ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹¹ are each independently at each occurrence selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, C3- Ce-cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ;

R ¹² is independently at each occurrence selected from: =0, =S, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, halogen, nitro, OR ⁹ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ;

wherein for any R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ or R ¹² group that is alkyl, alkenyl, cycloalkyl, heterocycloalkyi (including where two R ⁹ groups or an R ⁹ group and an R ¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyi ring), alkynyl, C(0)-alkyl or S(0)2-alkyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: =0; =NR ^a , =NOR ^a , Ci-C4-alkyl, halo, nitro, cyano, Ci-C4-haloalkyl, C2-C4-alkenyl, C ₂ -C ₄ -alkynyl, NR ^a R ^b , S(0) ₂ R ^a , S(0)R ^a , S(0)(NR ^a )R ^a , S(0) ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a and OR ^a ;

wherein R ^a is independently selected from H and Ci-C4-alkyl; and R ^b is independently H, Ci- C ₄ -alkyl, C(0)-Ci-C ₄ -alkyl, S(0) ₂ -Ci-C ₄ -alkyl.

For the absence of doubt, the ring comprising Z ¹ and Z ² is a heteroaryl ring, i.e. Z ¹ and Z ² are selected such that a ring selected from pyrazole, isoxazole and isothiazole. nd of formula I is a compound of formula la:

wherein R ¹ , R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are as described above for formula I. In an embodiment, the compound of formula I is a compound of formula II:

wherein R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ and R ⁷ are as described above for formula I; Ring A is a 5-membered heteroaryl ring; and x is an integer from 0 to 4.

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

wherein R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ and R ⁷ are as described above for formula I; and x is an integer from 0 to 4.

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

wherein R ¹ , R ² , R ³ , R ^4a and R ⁶ are as described above for formula I. mula I is a compound of formula V:

wherein R ² , R ³ , R ^4a , R ⁶ and R ⁷ are as described above for formula I; Ring A is a 5-membered heteroaryl ring; and x is an integer from 0 to 4. la I is a compound of formula VI:

wherein R ² , R ³ , R ^4a , R ⁶ and R ⁷ are as described above for formula I; and x is an integer from 0 to 4. la I is a compound of formula VII:

wherein R ² , R ³ , R ^4a , R ^4b , R ⁶ and R ⁷ are as described above for formula I; and x is an integer from 0 to 4. It may be that neither R ^4a nor R ^4b are H. The following embodiments apply to compounds of any of formulae (l)-(VII). 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.

The ring comprising Z ¹ and Z ² may be a pyrazole. The ring comprising Z ¹ and Z ² may be selected from isoxazole and isothiazole. The ring comprising Z ¹ and Z ² may be isoxazole. It may be that Z ¹ is NR ² . It may be that Z ² is N. It may be that Z ¹ is NR ² and Z ² is N.

It may be that Z ¹ is N. It may be that Z ² is selected from O and S. Z ² may be O. It may be that Z ¹ is N and Z ² is selected from O and S. It may be that Z ¹ is N and Z ² is O.

It may be that R ¹ is an independently a 5- or 6- membered heteroaryl ring. Thus, it may be that the heteroaryl ring of R ¹ is not fused to a further ring. It may be however that R ¹ is a 5- or 6- membered heteroaryl ring; said heteroaryl ring being fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl. It may be that R ¹ is a 5- or 6- membered heteroaryl ring; said heteroaryl ring being fused to a phenyl ring.

R ¹ may be a 5- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups. It may be that R ¹ is a 5- membered heteroaryl ring. Thus, it may be that the heteroaryl ring of R ¹ is not fused to a further ring. It may be however that R ¹ is a 5- membered heteroaryl ring; said heteroaryl ring being fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl. It may be that R ¹ is a 5-membered heteroaryl ring; said heteroaryl ring being fused to a phenyl ring.

R ¹ may be a 6-membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups. It may be that R ¹ is a 6- membered heteroaryl ring. Thus, it may be that the heteroaryl ring of R ¹ is not fused to a further ring. It may be however that R ¹ is a 6- membered heteroaryl ring; said heteroaryl ring being fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl. It may be that R ¹ is a 6-membered heteroaryl ring; said heteroaryl ring being fused to a phenyl ring. R ¹ may comprise at least one nitrogen atom in the ring system. Thus, R ¹ may be a 5- membered heteroaryl ring comprising at least one nitrogen atom in the ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups. It may be however, that R ¹ is a 5- membered heteroaryl ring comprising at least one nitrogen atom in the ring; said heteroaryl ring being fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl. It may be that R ¹ is a 5-membered heteroaryl ring comprising at least one nitrogen atom in the ring; said heteroaryl ring being fused to a phenyl ring.

R ¹ may comprise no more than two nitrogen atoms in the ring system. Thus, R ¹ may comprise 1 or 2 nitrogen atoms in the ring system. Where R ¹ is a heteroaryl ring comprising at least one nitrogen atom in the ring, it may be that R ¹ is attached to the rest of the molecule via the nitrogen atom in the ring or, where there are more than one nitrogen atoms in the ring, via one of those nitrogen atoms. 1 may have the structure: , wherein Ring A is a 5- or 6-membered heteroaryl ring and x is an integer from 0 to 4. It may be that Ring A is a 5-membered heteroaryl ring. Ring A may be a 6- membered heteroaryl ring.

Ring A may be a 5- or 6-membered heteroaryl ring, said heteroaryl ring comprising at least one nitrogen atom in the ring. Thus, it may be that Ring A is a 5-membered heteroaryl ring, said heteroaryl ring comprising at least one nitrogen atom in the ring. Where Ring A is a heteroaryl ring comprising at least one nitrogen atom in the ring, it may be that Ring A is attached to the rest of the molecule via the nitrogen atom in the ring or, where there are more than one nitrogen atoms in the ring, via one of those nitrogen atoms.

It may be that ring A is attached to the rest of the molecule at an attachment point (which may be a carbon atom or a nitrogen atom) that is next to one of the two carbon atoms that form part of both Ring A and the phenyl ring.

It may be that R ¹ has the structure:

, wherein ring B is either a benzene ring or a 6-membered heteroaryl ring;

X ¹ is either nitrogen or carbon and wherein X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; wherein if X ¹ is nitrogen, X ² and X ³ are independently selected from CR ^7a and N; and wherein if X ¹ is carbon, X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; provided that if X ¹ is carbon, X ² and X ³ are not both CR ^7a ; R ^7a is independently at each occurrence selected from: H, Ci-C ₄ -alkyl, Ci-C -haloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and NR ⁹ R ¹⁰ ; R ^7b is independently selected from H, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, C3-C ₄ -alkenyl and C3-C ₄ - alkynyl.

Ring B may be selected from a benzene ring and a pyridine ring. Ring B may be a benzene ring. Ring B may be a 6-membered heteroaryl ring. Ring B may be a pyridine ring.

It may be that R ¹ has the structure:

It may be that R ¹ has the structure:

, wherein X ¹ is either nitrogen or carbon and wherein X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; wherein if X ¹ is nitrogen, X ² and X ³ are independently selected from CR ^7a and N; and wherein if X ¹ is carbon, X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; provided that if X ¹ is carbon, X ² and X ³ are not both CR ^7a ; R ^7a is independently at each occurrence selected from: H, Ci-C4-alkyl, Ci- C ₄ -haloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C2-C ₄ -alkenyl, C2-C ₄ -alkynyl and NR ⁹ R ¹⁰ ; R ^7b is independently selected from H, Ci-C ₄ - alkyl, Ci-C ₄ -haloalkyl, C3-C ₄ -alkenyl and C3-C ₄ -alkynyl.

It may be that X ¹ is nitrogen. Where X ¹ is nitrogen, it may be that X ² is CR ^7a and X ³ is N. Where X ¹ is nitrogen, it may be that X ² is CH and X ³ is N. Where X ¹ is nitrogen, it may be that X ² and X ³ are each CR ^7a . In these embodiments, it may be that X ² is CH. Alternatively, it may be that X ³ is CH. Where X ¹ is nitrogen, it may be that X ² and X ³ are each N.

It may be that X ¹ is nitrogen and X ³ is N. It may be that X ² is selected from N and CR ^7a , wherein R ^7a is selected from methyl, halogen (e.g. CI, F), OH and H.

It may be that X ¹ is carbon. Where X ¹ is carbon, it may be that X ² is CR ^7a , e.g. CH. In these embodiments, X ³ may be O. Alternatively, X ³ may be S. Where X ¹ is carbon, it may be that X ² is N. In these embodiments, X ³ may be selected from O and S.

It may be that R ¹ has the structure:

In illustrative examples R ¹ may have a structure selected from:

It may be that R ¹ has the structure:

, wherein X ² is selected from N and CR ^7a , wherein R ^7a is selected from methyl, halogen (e.g. CI, F), OH and H. It may be that R ¹ has the structure:

In illustrative embodiments, R ¹ may have a structure selected from:

be that R ¹ has the structure:

It may be that R ^7a is selected from methyl, halogen (e.g. CI, F), OH and H. It may be that R ^7a is selected from halogen (e.g. CI, F), OH and H. It may be that R ^7a is selected from halogen (e.g. CI, F) and H. It may be that R ^7a is halogen, e.g. CI or F. It may be that R ^7a is H. Thus, it may be that R ¹ has the structure:

Thus, it may be that R ¹ has the structure:

. This structure is a tautomeric form of the structure above in which

R ^7a is OH.

In illustrative embodiments, R ¹ may have a structure:

It may be that R ^7b is Ci-C4-alkyl, e.g. methyl. Alternatively, it may be that R ^7b is H,

It may be that x is an integer selected from 1 and 2.

It may be that R ⁷ is independently at each occurrence selected from: Ci-C6-alkyl, Ci-Ce- haloalkyi, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ .

It may be that R ⁷ is independently at each occurrence selected from Ci-C4-alkyl, C1-C4- haloalkyl, halogen, nitro, S0 ₂ NR ⁹ R ⁹ , S(0) ₂ R ⁹ , NR ⁹ R ¹⁰ , OR ⁸ , SR ⁹ , C0 ₂ -Ci-C ₄ -alkyl and cyano. It may be that R ⁷ is independently at each occurrence selected from Ci-C4-alkyl, C1-C4- haloalkyi, halogen, nitro, S0 ₂ NH ₂ , S(0) ₂ C1-C4-alkyl, NH ₂ , 0-Ci-C ₄ -alkyl, 0-C ₃ -C ₄ -alkenyl, S- Ci-C4-alkyl, C0 ₂ -Ci-C4-alkyl and cyano. It may be that R ⁷ is independently at each

occurrence selected from Ci-C4-alkyl, Ci-C4-haloalkyl, halogen, nitro, SR ⁹ , OR ⁸ , and cyano. It may be that R ⁷ is independently at each occurrence selected from Ci-C4-alkyl, C1-C4- haloalkyl, halogen, nitro, OR ⁸ , and cyano. It may be that R ⁷ is independently at each occurrence selected from halogen, nitro, OR ⁸ , and cyano. It may be that R ⁷ is independently at each occurrence selected from halogen, nitro and cyano. It may be that R ⁷ is independently at each occurrence halo, e.g. fluoro.

It may be that R ¹ has the structure:

wherein y is an integer from 0 to 3; and wherein R ^7c is selected from H, halo and OH.

It may be that R ^7c is OH.

It may be that y is 0. It may be that y is 1.

In illustrative embodiments, R ¹ may have a structure selected from:

R ² may be independently selected from Ci-C4-alkyl and C(0)-Ci-C4-alkyl. R ² may be C1-C4- alkyl, e.g. methyl. R ² may be C(0)-Ci-C4-alkyl, e.g. acetyl. R ³ may be independently selected from halo (e.g. CI), Ci-C2-alkyl and Ci-C2-haloalkyl. R ³ may be independently selected from Ci-C2-alkyl and Ci-C2-haloalkyl. R ³ may be Ci-C2-alkyl, e.g. methyl or ethyl. R ³ may be Ci-C2-haloalkyl, e.g. CF3.

It may be that R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are each independently selected from H, cyano, halo, Ci-C4-alkyl, Ci-C4-haloalkyl, 0-Ci-C4-alkyl, O-cyclopropyl and 0-Ci-C4-haloalkyl. It may be that R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are each independently selected from H, halo, Ci-C ₄ -alkyl, C1-C4- haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

It may be that R ^4a is independently selected from halo, Ci-C4-alkyl, Ci-C4-haloalkyl, O-C1-C4- alkyl and 0-Ci-C4-haloalkyl.

It may be that R ^4b is H. Alternatively, it may be that R ^4b is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

It may be that R ^5a is H. Alternatively, it may be that R ^5a is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. It may be that R ^5a is selected from halogen and H.

It may be that neither R ^4a nor R ^4b are H. It may be that both R ^4a and R ^4b are each independently selected from halo, Ci-C4-alkyl, C1-C4- haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. It may be that R ^5b is H. Alternatively, it may be that R ^5b is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. It may be that R ^5b is selected from halogen and H.

It may be that R ⁶ is H. Alternatively, it may be that R ⁶ is independently selected from halo, Ci- C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. It may be that R ⁶ is independently selected from halo, cyano, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl, O- cyclopropyl and 0-Ci-C ₄ -haloalkyl. It may be that R ⁶ is independently selected from halo, Ci- C ₄ -alkyl, Ci-C ₄ -haloalkyl, OH, 0-Ci-C ₄ -alkyl and O-cyclopropyl. It may be that R ⁶ is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, OH and 0-Ci-C ₄ -alkyl. It may be that R ^5a and R ^5b are each H. It may be that R ^4b and R ^5b are each H. It may be that R ^4b , R ^5a and R ^5b are each H.

It may be that none of R ^4a , R ^4b and R ⁶ are H.

It may be that R ^4a , R ^4b and R ⁶ are each independently selected from halo, cyano, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl, O-cyclopropyl and 0-Ci-C ₄ -haloalkyl. It may be that R ^4a , R ^4b and R ⁶ are each independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

It may be that at least one of R ^4a and R ^4b is selected from Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, chloro, bromo, iodo, nitro, 0-Ci-C ₄ -alkyl, cyano, C2-C ₄ -alkenyl and C2-C ₄ -alkynyl. It may be that at least one of R ^4a and R ^4b is selected from Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, chloro, bromo, iodo, O- Ci-C -alkyl, C ₂ -C -alkenyl and C ₂ -C -alkynyl.

The group may have a structure selected from



20

22

The compounds of the invention may also be as described in the following numbered paragraphs:

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

R ¹ is independently a 5- or 6- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups;

R ² is independently selected from Ci-C6-alkyl, C3-C6-cycloalkyl, Ci-C6-haloalkyl and C(O)- d-Ce-alkyl;

R ³ is independently selected from H, halo, Ci-C6-alkyl, C3-C6-cycloalkyl and Ci-C6-haloalkyl; R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are independently at each occurrence selected from H , Ci-C6-alkyl, d-Ce-haloalkyl, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)N R ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ N R ⁹ R ⁹ , S(0)(N R ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, and N R ⁹ R ¹⁰ ; or wherein R ^4b and R ^5b together with the carbon atoms to which they are attached together form a ring selected from: phenyl, 5- or 6- membered heteroaryl, 5-, 6- or 7- membered heterocycloalkyi ring and Cs-Cycycloalkyl; said heteroaryl or phenyl ring being optionally substituted with from 1 to 4 R ^{1 1} groups or said heterocycloalkyi or cycloalkyl ring being optionally substituted with from 1 to 4 R ¹² groups;

with the proviso that either at least one of R ^4a and R ^4b is selected from Ci-C6-alkyl, C1-C6- haloalkyl, halo, nitro, 0-Ci-C ₄ -alkyl, SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ N R ⁹ R ⁹ , S(0)(N R ⁹ )R ⁹ ,

S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and N R ⁹ R ¹⁰ ; or R ^4b and R ^5b together form a ring;

R ⁷ and R ^{1 1} are each independently at each occurrence selected from: Ci-C6-alkyl, C1-C6- haloalkyl, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)N R ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ N R ⁹ R ⁹ , S(0)(N R ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkynyl, and N R ⁹ R ¹⁰ ;

R ⁸ is independently at each occurrence selected from: H , Ci-C6-alkyl, C3-C6-cycloalkyl and Ci-Ce-haloalkyl;

R ⁹ is independently at each occurrence selected from: H , C3-C6-cycloalkyl and C1-C6 alkyl; or where two R ⁹ groups are attached to the same nitrogen atom, said R ⁹ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹⁰ is independently at each occurrence selected from; H , Ci-C6-alkyl, C(0)-Ci-C6-alkyl and S(0) ₂ -Ci-C ₆ -alkyl;

or where an R ⁹ group and an R ¹⁰ group are attached to the same nitrogen atom, said R ⁹ and R ¹⁰ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹² is independently at each occurrence selected from: =0, =S, Ci-C6-alkyl, Ci-C6-haloalkyl, halogen, nitro, OR ⁹ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ N R ⁹ R ⁹ , S(0)(N R ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and N R ⁹ R ¹⁰ ;

wherein for any R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{1 1} or R ¹² group that is alkyl, alkenyl, cycloalkyl, heterocycloalkyi (including where two R ⁹ groups or an R ⁹ group and an R ¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyi ring), alkynyl, C(O)- alkyl or S(0)2- alkyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: =0; =NR ^a , =NOR ^a , Ci-C4-alkyl, halo, nitro, cyano, Ci-C4-haloalkyl, C ₂ - C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, NR ^a R ^b , S(0) ₂ R ^a , S(0)R ^a , S(0)(NR ^a )R ^a , S(0) ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a and OR ^a ;

wherein R ^a is independently selected from H and Ci-C ₄ -alkyl; and R ^b is independently H, CrC ₄ -alkyl, C(0)-Ci-C ₄ -alkyl, S(0) ₂ -Ci-C ₄ -alkyl;

A compound of paragraph 1 , wherein R ¹ is a 5- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups. aragraph 2, wherein R ¹ has the structure:

, wherein X ¹ is either nitrogen or carbon and wherein X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; wherein if X ¹ is nitrogen, X ² and X ³ are independently selected from CR ^7a and N; and wherein if X ¹ is carbon, X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; provided that if X ¹ is carbon, X ² and X ³ are not both CR ^7a ; R ^7a is independently at each occurrence selected from: H, Ci-C ₄ -alkyl, Ci- C ₄ -haloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and NR ⁹ R ¹⁰ ; R ^7b is independently at each occurrence selected from H, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, C3-C ₄ -alkenyl and C3-C ₄ -alkynyl.

4. A compound of paragraph 3, wherein X ¹ is nitrogen. 5. A compound of paragraph 4, wherein X ² is CH and X ³ is N. 6. A compound of paragraph 3, wherein X ¹ is carbon.

7. A compound of any one of paragraphs 3 to 6, wherein x is an integer selected from 1 and 2 and R ⁷ is independently at each occurrence selected from Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, halogen, nitro, OR ⁸ , and cyano.

8. A compound of any one of paragraphs 1 to 7, wherein R ² is Ci-C ₄ -alkyl. 9. A compound of any one of paragraphs 1 to 8, wherein R ³ is independently selected from Ci- C2-alkyl and Ci-C2-haloalkyl. 10. A compound of any one of paragraphs 1 to 9, wherein R ^4a is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

1 1. A compound of any one of paragraphs 1 to 10, wherein R ^4b is H. 12. A compound of any one of paragraphs 1 to 10, wherein R ^4b is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

13. A compound of any one of paragraphs 1 to 12, wherein R ^5a is H. 14. A compound of any one of paragraphs 1 to 13, wherein R ^5b is H.

15. A compound of any one of paragraphs 1 to 14, wherein R ⁶ is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

16. A compound of formula lb, or an agronomically acceptable salt or N-oxide thereof:

Z ¹ and Z ² are each independently selected from N, NR ² , O and S; wherein at least one of Z ¹ and Z ² is N;

R ¹ is independently a 5- or 6- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups;

R ² is independently selected from Ci-C6-alkyl, C3-C6-cycloalkyl, Ci-C6-haloalkyl and C(0)-Ci- Ce-alkyl;

R ³ is independently selected from H, halo, Ci-C6-alkyl, C3-C6-cycloalkyl and Ci-C6-haloalkyl; R ^4a , R ^4b , R ^5a , R ^5b and R ⁶ are independently at each occurrence selected from H, Ci-C6-alkyl, Ci- Ce-haloalkyl, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ; or wherein R ^4b and R ^5b together with the carbon atoms to which they are attached together form a ring selected from: phenyl, 5- or 6- membered heteroaryl , 5-, 6- or 7- membered heterocycloalkyi ring and Cs-Cycycloalkyl; said heteroaryl or phenyl ring being optionally substituted with from 1 to 4 R ¹¹ groups or said heterocycloalkyi or cycloalkyl ring being optionally substituted with from 1 to 4 R ¹² groups;

with the proviso that either at least one of R ^4a and R ^4b is selected from Ci-C6-alkyl, Ci-C ₄ - haloalkyl, halo, nitro, 0-Ci-C ₄ -alkyl, SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ; or R ^4b and R ^5b together form a ring;

R ⁷ and R ¹¹ are each independently at each occurrence selected from: Ci-C6-alkyl, C1-C6- haloalkyl, C ₃ -C ₆ -cycloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , C(0)OR ⁹ , C(0)NR ⁹ R ⁹ , C(0)R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ; R ⁸ is independently at each occurrence selected from: H, Ci-C6-alkyl, C3-C6-alkenyl, C3-C6- alkynyl, C3-C6-cycloalkyl and Ci-C6-haloalkyl;

R ⁹ is independently at each occurrence selected from: H, C3-C6-cycloalkyl and Ci-C6-alkyl; or where two R ⁹ groups are attached to the same nitrogen atom, said R ⁹ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹⁰ is independently at each occurrence selected from; H, Ci-C6-alkyl, C(0)-Ci-C6-alkyl and S(0) ₂ -Ci-C ₆ -alkyl;

or where an R ⁹ group and an R ¹⁰ group are attached to the same nitrogen atom, said R ⁹ and R ¹⁰ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyi ring;

R ¹² is independently at each occurrence selected from: =0, =S, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, halogen, nitro, OR ⁹ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ -alkynyl, and NR ⁹ R ¹⁰ ;

wherein for any R ² , R ³ , R ^4a , R ^4b , R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ or R ¹² group that is alkyl, alkenyl, cycloalkyl, heterocycloalkyi (including where two R ⁹ groups or an R ⁹ group and an R ¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyi ring), alkynyl, C(0)-alkyl or S(0) ₂ -alkyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: =0; =NR ^a , =NOR ^a , Ci-C4-alkyl, halo, nitro, cyano, Ci-C4-haloalkyl, C2-C4-alkenyl, C ₂ -C ₄ -alkynyl, NR ^a R ^b , S(0) ₂ R ^a , S(0)R ^a , S(0)(NR ^a )R ^a , S(0) ₂ NR ^a R ^a , C0 ₂ R ^a , C(0)R ^a , CONR ^a R ^a and OR ^a ;

wherein R ^a is independently selected from H and Ci-C ₄ -alkyl; and R ^b is independently H, Ci- C ₄ -alkyl, C(0)-Ci-C ₄ -alkyl, S(0) ₂ -Ci-C ₄ -alkyl.

17. A compound of paragraph 16, wherein Z ¹ is NR ² and Z ² is N.

18. A compound of paragraph 16 or paragraph 17, wherein R ¹ is a 5- membered heteroaryl ring; said heteroaryl ring being optionally fused to a further ring selected from phenyl, and 5- or 6-membered heteroaryl; wherein R ¹ is optionally substituted with from 1 to 6 R ⁷ groups. aragraph 18, wherein R ¹ has the structure:

, wherein ring B is either a benzene ring or a 6-membered heteroaryl ring; X ¹ is either nitrogen or carbon and wherein X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; wherein if X ¹ is nitrogen, X ² and X ³ are independently selected from CR ^7a and N; and wherein if X ¹ is carbon, X ² and X ³ are independently selected from CR ^7a , NR ^7b , N, O and S; provided that if X ¹ is carbon, X ² and X ³ are not both CR ^7a ; R ^7a is independently at each occurrence selected from: H, Ci-C -alkyl, Ci-C -haloalkyl, halogen, nitro, OR ⁸ , SR ⁹ , OS(0) ₂ R ⁹ , S(0) ₂ R ⁹ , S(0) ₂ NR ⁹ R ⁹ , S(0)(NR ⁹ )R ⁹ , S(0)R ⁹ , cyano, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and NR ⁹ R ¹⁰ ; R ^7b is independently selected from H, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, C3-C ₄ -alkenyl and C3-C ₄ - alkynyl and x is an integer from 0 to 4.

20. A compound of paragraph 19, wherein X ¹ is nitrogen.

21. A compound of paragraph 20, wherein X ² is CR ^7a and X ³ is N.

22. A compound of paragraph 21 , wherein R ^7a is selected from halogen and H. 23. A compound of paragraph 22, wherein X ¹ is carbon.

24. A compound of any one of paragraphs 19 to 23, wherein x is an integer selected from 1 and 2 and R ⁷ is independently at each occurrence selected from Ci-C ₄ -alkyl, Ci-C ₄ - haloalkyl, halogen, nitro, S0 ₂ NH ₂ , S(0) ₂ Ci-C ₄ -alkyl, NH ₂ , 0-Ci-C ₄ -alkyl, 0-Ci-C ₄ -alkenyl, S-Ci-C ₄ -alkyl, C0 ₂ -Ci-C ₄ -alkyl and cyano..

25. A compound of any one of paragraphs 16 to 24, wherein R ² is Ci-C ₄ -alkyl.

26. A compound of any one of paragraphs 16 to 25, wherein R ³ is independently selected from halogen, Ci-C ₂ -alkyl and Ci-C ₂ -haloalkyl.

27. A compound of any one of paragraphs 16 to 26, wherein R ^4a is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl.

28. A compound of any one of paragraphs 16 to 27, wherein R ^4b is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. 29. A compound of any one of paragraphs 16 to 28, wherein neither R ^4a nor R ^4b are H.

30. A compound of any one of paragraphs 16 to 27, wherein R ^4b is H.

31. A compound of any one of paragraphs 16 to 30, wherein R ^5a is H.

32. A compound of any one of paragraphs 16 to 30, wherein R ^5b is H.

33. A compound of any one of paragraphs 16 to 32, wherein R ⁶ is independently selected from halo, Ci-C ₄ -alkyl, Ci-C ₄ -haloalkyl, 0-Ci-C ₄ -alkyl and 0-Ci-C ₄ -haloalkyl. 34. A method for controlling fungal diseases, the method comprising applying an

agronomically effective and substantially non-phytotoxic quantity of a compound of any one of paragraphs 1 to 33 to seeds of plants, to plants themselves or to an area where it is intended that plants will grow.

35. A use of a compound of any one of paragraphs 1 to 33 to control fungal diseases of

plants.

36. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of paragraphs 1 to 33. Detailed Description

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 monovalent 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 group 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 fluorine 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 group 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, for example, 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 .

The term heterocycloalkyl may refer to a monocyclic or bicyclic saturated or partially saturated group having the indicated number of atoms in the ring system and comprising 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words 1 or 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 monocyclic rings with from 5 to 6 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine. A heterocycloalkyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, OR ^a or NHR ^a .

Aryl groups may be any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1)π electrons). Aryl groups may have from 6 to 12 carbon atoms in the ring system. Aryl groups will typically be phenyl groups. Aryl groups may be naphthyl groups or biphenyl groups.

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 group which is an aryl or heteroaryl group, that aryl or heteroaryl group is unsubstituted or is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently selected at each occurrence from: halo, nitro, cyano, NR ^a R ^a , NR ^a S(0) ₂ R ^a , NR ^a C(0)R ^a , NR ^a CONR ^a R ^a , NR ^a C0 ₂ R ^a , OR ^a , SR ^a , S(0)R ^a , S(0) ₂ OR ^a , S(0) ₂ R ^a , S(0) ₂ NR ^a R ^a , C0 ₂ R ^a C(0)R ^a , CONR ^a R ^a , CR ^b R ^b NR ^a R ^a , CR ^b R ^b OR ^a , Ci-C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl and Ci-C ₄ -haloalkyl; wherein R ^a and R ^b are as described above for formula I.

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. Example 111 is an illustrative example of a compound that can exist in two tautomeric forms, said forms being the hydroxy-imidazole and the imidazolone. 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.

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. 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. The compounds of formula (I) may also be obtained, stored and/or used in the form of an N- oxide. Examples 121 and 123 are illustrative examples of N-oxides of compounds of formula (I).

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 VII 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 ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ l and ¹²⁵ l, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ 0, ¹⁷ 0 and ¹⁸ 0, phosphorus, such as ³² P, and sulfur, such as ³⁵ S.

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 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. 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 of plants. 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:

Plasmopara 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. Detailed Description - Synthesis

The skilled person 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 (Wley), (1982 or later editions); "Designing Organic Syntheses" S Warren (Wley) (1983 or later editions); "Heterocyclic Chemistry", J. Joule (Wley 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 person 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 Wley & Sons Inc. (1999), and references therein.

Throughout this specification these abbreviations have the following meanings:

aq. - aqueous cone. - concentrated

DCM - dichloromethane DMF - N,N-dimethylformamide

dppf - 1 ,1 '-bis(diphenylphosphino)ferrocene h - hour

HPLC - high performance liquid chromatography min - minute

NBS - N-bromosuccinimide PE - petroleum ether

R.T. - room temperature sat. - saturated

TFA - trifluoroacetic acid THF - tetrahydrofuran

Certain compounds of the invention can be accessed according to or analogously to the general synthetic schemes below. Certain compounds of the invention can be accessed via the synthetic intermediates described in Examples 1 to 104 below.

General Synthetic Schemes

Certain compounds of formula (I) can be made according to Scheme A. Amino pyrazole A can be brominated (e.g. using NBS, perhaps in MeCN at room temperature) to provide bromopyrazole B. Deprotonation (e.g. using NaH in DMF) followed by reaction with a fluorobenzene of formula C can provide a compound of formula D. Reduction of the nitro group (e.g. using Fe/NhUCI in THF/MeOH/water at 65°C) followed by cyclisation using an orthoformate under acidic conditions (e.g. CH(OMe)3 and HCI at 100 °C) can provide benzimidazole E. Suzuki coupling (e.g. using Pd(PP i3) ₄ in a microwave at 120 °C in 1 ,4-dioxane) between benzimidazole E and boronic acid F can provide compounds of formula G (a subset of

Scheme A

Certain compounds of formula (I) can be made according to Scheme B. Benzyl nitrile H can be reacted with ester J in the presence of a base (e.g. NaOEt at 80 °C) and the product reacted with hydrazine K in the presence of an acid (e.g. AcOH in ethanol at 80 °C) to provide aminopyrazole L. Deprotonation (e.g. using NaH in DMF) followed by reaction with a fluorobenzene of formula C can provide a compound of formula M. Reduction of the nitro group (e.g. using Fe/NH ₄ CI in THF/MeOH/water at 65°C) followed by cyclisation using an orthoformate under acidic conditions (e.g. CH(OMe)3 and HCI at 100 °C) can provide compounds of formula N (a subset of compounds of formula (I)).

Scheme B

Certain compounds of formula (I) can be made according to Scheme C. Following either Scheme A or Scheme B with the R ² group being te/f-butyl can provide a compound of formula O. Removal of the tert-butyl group using an acid (e.g. TFA at 65°C) can provide pyrazole P which upon treatment with (Ci-C4-alkylCO)20 in the presence of a base (e.g. pyridine in DMF at room temperature) can provide acetyl pyrazole Q (a subset of compounds of formula (I)). Alternatively, treatment with an alkyl halide in the presence of a base (e.g. K2CO3 in DM F at room temperature) can provide alkyl pyrazole R (where R ² is other than tert- butyl; a subset of compounds of formula (I)).

Scheme C

Certain compounds of formula (I) can be made according to Scheme D. Amino pyrazole L can be converted to bromopyrazole S (e.g. using tBuONO and CuBr2 in acetonitrile at room temperature). Bromopyrazole S can be converted to boronate T (e.g. using bis(pinacoloto)diboron, KOAc, Pd(dppf)Cl2 in DMF at 80 °C). Boronate T can be coupled with an appropriate coupling agent (e.g. in the presence of Na2CC>3 and Pd(dppf)Cl2 in dioxane at 120 °C) to provide a compounds of formula U (where R ¹ is a heteroaryl group linked to the central pyrazole via a carbon atom; a subset of compounds of formula (I)). Compounds of formula U can alternatively be accessed by coupling bromopyrazole S with an appropriate boronate ester (e.g. in the presence of Na2C03 and Pd(dppf)Cl2 in dioxane at 120 °C). Coupling of compounds of formula S with a nitrogen heteroaryl group having an NH group in the ring (e.g. in the presence of Cul, MeNHCI-bCI-bNHMe, K3PO4 and toluene at reflux) can provide compounds of formula W (where R ¹ is a heteroaryl group linked to the central pyrazole via a nitrogen atom; a subset of compounds of the formula (I))

Scheme D

Certain compounds of formula (I) can be made according to Scheme E. Ketone Y can be deprotonated (e.g. using NaH in THF at room temperature) and the resultant anion reacted with ester Z to provide 1 ,3-dicarbonyl AA. Treatment with hydrazine K (R2NHNH2; e.g. in DMF at 80 °C) can provide compounds of formula AB (a subset of compounds of the formula (I))

Scheme E EXAMPLES

General Methods

Flash chromatography was carried out using a Biotage Isolera 4, with Biotage® SNAP KP-Sil cartridges, packed with 50 μηι silica particles with a surface area of 500 m ² /g, or alternative cartridges (e.g. Puriflash, produced by Interchim) where stated, or using silica gel (40-63 μηι particles). Visualisation was carried out with UV light (254 nm) and by staining with either potassium permanganate, phosphomolybdic acid (PMA) or ninhydrin solutions.

All ¹ H NMR spectra were obtained on a Bruker AVI 11 400 with 5mm QNP or Bruker AVI 500 with 5mm QNP. Chemical shifts are expressed in parts per million (δ) and are referenced to the solvent. Coupling constants J are expressed in Hertz (Hz).

MS was carried out on a Waters Alliance ZQ MS, using a YMC-Triart C18 50 x 2 mm, 5 micron LC column (solvent: 5-90% gradient of acetonitrile in water (with 1 % by volume of 28% (by weight) aqueous ammonia solution)) by Method A or B, or (solvent: 5-90% gradient of acetonitrile in water (with 1 % formic acid) by Method C or D. Flow rate 0.8 mL/min.

Wavelengths were 254 and 210 nM.

Method A (5 minute basic pH)

Column: YMC-Triart C18 50 x 2 mm, 5 μηι. Flow rate: 0.8 mL/min. Injection volume: 5 μί. Mobile Phase A H ₂ 0

B CHsCN

C 50% H ₂ 0 / 50% CHsCN + 1.0% ammonia (aq.)

Method C (5 minute acidic pH)

Column: YMC-Triart C18 50 x 2 mm, 5 μηι. Flow rate: 0.8 mL/min. Injection volume: 5 μί. Mobile Phase A H ₂ 0

B CHsCN

C 50% H ₂ 0 / 50% CHsCN + 1.0% formic acid Time (min) A (%) B (%) C (%)

0 95 0 5

4 0 95 5

4.4 0 95 5

4.5 95 5 0

4.5 STOP

Method D (15 minute acidic pH)

Column YMC Triart-C18 50 x 2 mm, 5 μηι Flow rate: 0.8 mL/min. Injection volume: 10 μΙ_

Mobile Phase H ₂ 0

CHsCN

50% H ₂ 0 / 50% CHsCN + 1.0% formic acid

Alternatively MS was carried on a Waters Acquity UPLC-QDA UV-MS system using Method E (high pH) or Method F (low pH):

Method E (3.5 minute basic pH)

Mobile phases: Water (A)/Acetonitrile (B) both with 0.1 % (v/v) Ammonia

Column: BEH C 8 2.1 x 50mm, 1.7μηι @ 50°C Method F (3.5 minute acidic pH)

Mobile phases: Water (A)/Acetonitrile (B) both with 0.1 % (v/v) Formic Acid

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

All compounds are named using ChemBioDraw Ultra 14.0. 6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-amine

Stage 1 : Sodium ethoxide (21 % in ethanol, 24.5 mL, 65.5 mmol) was added to a solution of 2,6- difluoro-4-methoxyphenylacetonitrile (10.0 g, 54.6 mmol) in toluene (200 mL) at room temperature. The mixture was heated to reflux, and after 15 min, EtOAc (7.5 mL, 76 mmol) was added. The solution was refluxed for 2 h. After cooling to room temperature, the mixture was partitioned between water and PE. The aqueous layer was washed with PE. The pH of the aqueous layer was adjusted to ~ pH 4 by addition of 2 M aq. HCI, and then extracted with EtOAc (x3). The combined EtOAc layers were washed (brine), dried (MgS0 ₄ ) and concentrated in vacuo.

Stage 2: The intermediate from Stage 1 was dissolved in ethanol (200 mL), then acetic acid (3.0 mL, 54 mmol) and methylhydrazine (2.9 mL, 54 mmol) were added. The resulting solution was heated at reflux for 2 h. The reaction was cooled to room temperature and concentrated in vacuo to yield the title compound as an off-white solid (5.63 g, 41 %). ¹ H NMR δ _Η (500 MHz, CDC ) 6.62 - 6.53 (m, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 3.44 (s, 2H), 2.13 (s, 3H).

LCMS (Method A): 2.28 min (254.1 , MH ⁺ ). Intermediates B-E:

The following Intermediates were prepared using the general method described for Intermediate A from the appropriate benzonitrile and substituted hydrazine.

Intermediate F: 4-(2, 6-Difluoro-4-methoxyphenyl)-N-(2,4-difluoro-6-nitrophenyl)-1 ,3- dimethyl-1H-pyrazol-5-amine

/V-Bromosuccinimide (3.20 g, 18.0 mmol) was added to a solution of 5-amino-1 ,3- dimethylpyrazole (2.00 g, 18.0 mmol) in acetonitrile (25 ml_), and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between aq. NaHCC>3 and EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed (aq. Na2S203), dried (MgS0 ₄ ) and concentrated in vacuo to yield the title compound as a red oil (2.85 g, 83%). ¹ H NMR δ _Η (500 MHz, CDCb) 3.66 (s, 3H), 3.58 (br s, 2H), 2.16 (s, 3H). LCMS (Method A): 1.73 min (192.0, MH ⁺ ).

Intermediate G: 4-(2, 6-Difluoro-4-methoxyphenyl)-N-(2,4-difluoro-6-nitrophenyl)-1 ,3- e

Sodium hydride (60%, 95 mg, 2.4 mmol) was added to a solution of Intermediate A (200 mg, 0.79 mmol) in DMF (5 ml_). After stirring at room temperature for 25 min, 1 ,2,5-trifluoro-3- nitrobenzene (90 μΙ_, 0.79 mmol) was added, and stirring continued for 3 h. The reaction mixture was quenched cautiously with water and extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE) and the title compound was isolated as a red solid (1 19 mg, 37 %). ¹ H NMR δ _Η (500 MHz, CDCb) 8.40 (d, J = 2.6 Hz, 1 H), 7.67 - 7.57 (m, 1 H), 6.99 - 6.88 (m, 1 H), 6.37 (d, J = 9.5 Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H). LCMS (Method A): 3.24 min (411.3, MH ⁺ ).

Intermediates H-O:

The following Intermediates were prepared using the general method described for Intermediate G from the appropriate Intermediate (B-F) and nitro-arene.

Intermediate P: N ¹ -(4-(2,6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyr azol-5-yl)-4,6- e

A solution of ammonium chloride (45 mg, 0.84 mmol) in water (0.4 ml_) was added to a solution of Intermediate G (1 15 mg, 0.280 mmol) in THF (2 ml_) and methanol (1 ml_). Iron powder (47 mg, 0.84 mmol) was added, and the mixture was heated to 65 °C for 18 h. After cooling to room temperature, the mixture was filtered through decalite®, eluting with EtOAc. The filtrate was washed (water, brine), dried (MgSCU) and concentrated in vacuo to yield the title compound as a brown solid (104 mg, 98 %). ¹ H NMR δ _Η (500 MHz, CDC ) 6.34 - 6.25 (m, 2H), 6.06 - 5.98 (m, 1 H), 5.96 - 5.89 (m, 1 H), 4.98 (br s, 1 H), 3.87 (br s, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 2.02 (s, 3H). LCMS (Method A): 2.88 min (381.3, MKT).

Intermediates Q-X:

The following Intermediates were prepared using the general method described for Intermediate from the appropriate Intermediate (H-O).

LCMS (Method A): 2.60 min (367.0, MH ⁺ ).

s N ¹ -(4-(2-Chloro-4- (500 MHz, CDCb) δ 7.1 1 (m, 2H), 6.90 - fluorophenyl)-3-ethyl-1 - 6.83 (m, 1 H), 6.73 (td, J = 7.5, 1.3 Hz, 1 H), methyl-1 H-pyrazol-5- 6.67 - 6.57 (m, 2H), 6.38 (dd, J = 7.8, 1.2 yl)benzene-1 ,2-diamine Hz, 1 H), 4.85 (br s, 1 H), 3.50 (s, 3H), 2.55

- 2.38 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H). LCMS (Method A): 3.15 min (345.2, MH ⁺ ).

T N ¹ -(4-(2-Chloro-4- (500 MHz, CDCb) δ 7.25 - 7.19 (m, 2H),

fluorophenyl)-1 -methyl-3- 7.03 - 6.96 (m, 1 H), 6.90 - 6.84 (m, 1 H), (trifluoromethyl)-l H-pyrazol- 6.77 (ddd, J = 7.8, 5.4, 1.3 Hz, 1 H), 6.74 - 5-yl)benzene-1 ,2-diamine 6.69 (m, 1 H), 6.52 - 6.46 (m, 1 H), 4.97 (s,

1 H), 3.67 (s, 3H), 3.55 (br s, 2H).

LCMS (Method A): 3.38 min (385.1 , MH ⁺ ).

u N ¹ -(1-(tert-Butyl)-4-(2-chloro- LCMS (Method A): 3.55 min (373.2, MH ⁺ ).

4-fluorophenyl)-3-methyl- 1 H-pyrazol-5-yl)benzene-1 ,2- diamine

V N ¹ -(4-Bromo-1 ,3-dimethyl- (500 MHz, CDCb) δ 6.96 - 6.88 (m, 1 H),

1 H-pyrazol-5-yl)benzene-1 ,2- 6.84 (d, J = 7.6 Hz, 1 H), 6.80 - 6.70 (m, diamine 1 H), 6.45 (d, J = 7.9 Hz, 1 H), 5.06 (br s, 1 H), 3.55 (s, 3H), 2.27 (s, 3H) [NH2 not seen - very broad].

LCMS (Method A): 2.59 min (283.1 , MKT).

w N ¹ -(4-Bromo-1 ,3-dimethyl- (500 MHz, CDC ) δ 6.32 - 6.21 (m, 2H),

1 H-pyrazol-5-yl)-4, 6- 4.90 (br s, 1 H), 3.57 (s, 3H), 2.21 (s, 3H). difluorobenzene-1 ,2-diamine [NH2 not seen - very broad].

LCMS (Method A): 2.69 min (319.1 , MKT).

X N ¹ -(4-(2-Chloro-4- (500 MHz, CDCb) δ 8.75 (s, 1 H), 8.25 (dd,

fluorophenyl)-1 ,3-dimethyl- J = 9.0, 2.1 Hz, 1 H), 8.00 (s, 1 H), 7.12 - 1 H-pyrazol-5-yl)-4- 7.06 (m, 2H), 6.89 - 6.85 (m, 1 H), 3.68 (s, nitrobenzene-1 ,2-diamine 3H), 2.25 (s, 3H).

LCMS (Method C): 2.94 min (376.1 , MH ⁺ ).

Intermediates Y-AB:

The following Intermediates were prepared using a 2-step procedure without purification from the general method described for Intermediate G followed by the general method described for Intermediate P from Intermediate B and the appropriate fluoro-nitro-arene.

ntermediate AC: 1-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol e

Cone. HCI (37 μΙ_, 0.45 mmol) was added to a solution of Intermediate V (2.50 g, 8.89 mmol) in trimethylorthoformate (14.6 mL, 133 mmol), and the mixture was stirred at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgS04) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE) and the title compound was isolated as a tan solid (1.31 g, 51 %). ¹ H NMR 5 _H (500 MHz, CDC ) 8.18 (s, 1 H), 8.02 - 7.97 (m, 1 H), 7.51 - 7.42 (m, 2H), 7.28 - 7.23 (m, 1 H), 3.68 (s, 3H), 2.37 (s, 3H). LCMS (Method A): 2.64 min (293.0, MH ⁺ ).

Intermediate AD: 1-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-5,7-difluoro-1H-

Intermediate AD was prepared using the general method described for Intermediate AC from Intermediate d. ¹ H NMR δ _Η (500 MHz, CDCb) 7.98 (s, 1 H), 7.45 (dd, J = 8.5, 1.9 Hz, 1 H), 6.98 - 6.91 (m, 1 H), 3.70 (s, 3H), 2.35 (s, 3H). LCMS (Method A): 2.86 min (329.1 , MH ⁺ ).

Intermediate AE: 1 -(4-(2-Chloro-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)-1H-

A solution of Example 6 (295 mg, 0.771 mmol) in trifluoroacetic acid (3.0 mL, 39 mmol) was heated to 65 °C for 90 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with aq. NaHCOs. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgS0 ₄ ) and concentrated in vacuo to yield the title compound as an orange solid (172 mg, 68 %). ¹ H NMR 5H (500 MHz, CD3OD) 8.07 (s, 1 H), 7.72 - 7.64 (m, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.35 (dd, J = 8.6, 6.1 Hz, 1 H), 7.32 - 7.21 (m, 3H), 7.08 (td, J = 8.4, 2.7 Hz, 1 H), 2.34 (s, 3H). LCMS (Method A): 2.80 min (327.1 , MH ⁺ ). romo-4-(2-chloro-4-fluorophenyl)-1 ,3-dimethyl-1 H-pyrazole

Copper(ll) bromide (1.715 g, 7.68 mmol) was added to a solution of Intermediate B (1.84 g, 7.68 mmol) in dry acetonitrile (77 ml_). Subsequently te/f-butyl nitrite (1.83 ml_, 15.4 mmol) was added dropwise to the ice cooled solution. The reaction was stirred at 50 °C for 90 min.

Water, sat. NH4CI (aq) and EtOAc were added (1 : 1 : 1). The aqueous phases were extracted with EtOAc (x3). The organic phases were washed with brine, dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-40 % EtOAc in PE) to give the title compound (2.71 g,34 %). ¹ H NMR (500 MHz, CDC ) δ 7.24 (dd, J = 8.6, 2.6 Hz, 1 H), 7.20 (dd, J = 8.5, 6.1 Hz, 1 H), 7.04 (ddd, J = 8.5, 8.1 , 2.6 Hz, 1 H), 3.89 (s, 3H), 2.14 (s, 3H); LCMS (Method A): 3.34 min (303.0, MH ⁺ ).

Intermediate A G: 4-(2-Chloro-4-fluorophenyl)-1 , 3-dimethyl-5-(4,4, 5, 5-tetramethyl-1 ,3, 2- -1 H-pyrazole

Bis(pinacolato)diboron (0.837 g, 3.29 mmol), potassium acetate (0.259 g, 2.64 mmol) and Intermediate AF (0.200 g, 0.659 mmol) were dissolved in DMF (30 ml_) and mixture was purged with nitrogen for half an hour. Pd(dppf)2Cl2 (0.096 g, 0.13 mmol) was added under N2 and the closed vessel was heated to 130 °C for 2 h in the microwave. Water was added and the aqueous phase was extracted with EtOAc (x3). The combined organic layers were washed with brine (x3), dried (MgS0 ₄ ), concentrated and the residue was purified using column chromatography (Si0 ₂ , 0-50 % EtOAc in PE) to obtain the title compound (131 mg, 57 %). ¹ H NMR (500 MHz, CDCb) δ 7.21-7.15 (m, 2H), 6.98 (td, J = 8.3, 2.6 Hz, 1 H), 4.1 1 (s, 3H), 2.16 (s, 3H), 1.20 (s, 12H). LCMS (Method A): 2.78 min (351.2, MH ⁺ ). Intermediate AH:

The following Intermediate was prepared using the general method described for Intermediate A from the appropriate benzonitrile and substituted hydrazine.

Intermediates AI-AL:

The following Intermediates were prepared using the general method described for Intermediate G from the appropriate Intermediates (B or AH) and nitro-arene.

Intermediates AM-AP:

The following Intermediates were prepared using the general method described for Intermediate from the appropriate Intermediates (AI-AL).

Intermediate AQ: 4-(2-Chloro-4-fluorophenyl)-N-(2-fluoro-4,6-dinitrophenyl)-1 ,3- dimethyl-1 H-pyrazol-5-amine

2-Bromo-1-fluoro-3,5-dinitrobenzene (248 mg, 0.935 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (108 mg, 0.187 mmol), caesium carbonate (426 mg, 1.31 mmol) and Intermediate B (224 mg, 0.935 mmol) were dissolved in 1 ,4-dioxane (5 mL) at R.T. The solution was treated with N2 for 30 min and tris(dibenzylideneacetone)dipalladium(0) (84 mg, 0.19 mmol) was added. The solution was heated to 120 °C overnight.

After cooling to R.T., the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgSCU) and concentrated in vacuo. The residue was purified using chromatography (S1O2, 0-70 % EtOAc in PE) and the title compound was isolated as a yellow solid (265 mg, 67 %).

¹ H NMR δ _Η (500 MHz, CDC ) 9.25 (s, 1 H), 8.86 (s, 1 H), 7.96 (dd, J = 1 1.7, 2.1 Hz, 1 H), 7.12 (dd, J = 8.6, 6.0 Hz, 1 H), 7.08 (dd, J = 8.4, 2.6 Hz, 1 H), 6.97 - 6.91 (m, 1 H), 3.84 (s, 3H), 2.17 (s, 3H). LCMS (Method A): 3.18 min (424.2, MH ⁺ ).

Intermediates AR-BE:

The following Intermediates were prepared using the general method described in Intermediate G from the appropriate Intermediate (A-B) and nitro-arene.

amine LCMS (Method C): 3.30 min (375.3, MH ⁺ ).

dimethyl-1 H-pyrazol-5-amine

BC 4-(2-Chloro-4-fluorophenyl)- LCMS (Method C): 3.40 min (391.3, MH ⁺ ).

N-(4-methoxy-2-nitrophenyl)- 1 ,3-dimethyl-1 H-pyrazol-5- amine

BD 4-((4-(2-Chloro-4- LCMS (Method C): 2.74 min (405.2, MH ⁺ ).

fluorophenyl)-1 ,3-dimethyl- 1 H-pyrazol-5-yl)amino)-3- nitrobenzoic acid

F

BE 4-Bromo-N-(2,4-difluoro-6- (500 MHz, CDC ) δ 7.81 - 7.75 (br s, 1 H),

nitrophenyl)-5- 7.74 - 7.69 (m, 1 H), 7.25 - 7.21 (m, 1 H), 2.40 methylisoxazol-3-amine (s, 3H).

N0 _{2 |} _ _| Br LCMS (Method A): 3.44 min (336.0, MH ⁺ ) Intermediates BF-BS:

The following Intermediates were prepared using the general method described in Intermediate from the appropriate Intermediate (AQ-BE).

Bl 6-Chloro-N ¹ -(4-(2, 6-difluoro- LCMS (Method A): 3.22 min (379.2, MKT).

4-methoxyphenyl)-1 ,3- dimethyl-1 H-pyrazol-5- yl)benzene-1 ,2-diamine

BJ 6-Chloro-N ¹ -(4-(2, 6-difluoro- LCMS (Method A): 3.61 min (447.2, MKT).

4-methoxyphenyl)-1 ,3- dimethyl-1 H-pyrazol-5-yl)-4- (trifluoromethyl)benzene-l ,2- diamine

BK 6-Chloro-N ¹ -(4-(2, 6-difluoro- LCMS (Method A): 3.20 min (397.2, MH ⁺ ).

4-methoxyphenyl)-1 ,3- dimethyl-1 H-pyrazol-5-yl)-5- fluorobenzene-1 ,2-diamine

BL 3-Amino-4-((4-(2-chloro-4- LCMS (Method C): 2.80 min (356.3, MH ⁺ ).

fluorophenyl)-1 ,3-dimethyl- 1 H-pyrazol-5- yl)amino)benzonitrile

BM N ¹ -(4-(2-Chloro-4- LCMS (Method C): 2.55 min (344.9, MH ⁺ ).

fluorophenyl)-1 ,3-dimethyl- 1 H-pyrazol-5-yl)-6- methylbenzene-1 ,2-diamine

F

BN 3-Amino-2-((4-(2-chloro-4- LCMS (Method C): 2.88 min (356.2, M).

fluorophenyl)-1 ,3-dimethyl- 1 H-pyrazol-5- yl)amino)benzonitrile

nitrobenzene-1 ,2-diamine

BR 3-Amino-4-((4-(2-chloro-4- LCMS (Method C): 2.29 min (375.1 , MH ⁺ ).

fluorophenyl)-1 ,3-dimethyl- 1 H-pyrazol-5- yl)amino)benzoic acid

BS N ¹ -(4-Bromo-5- LCMS (Method A): 2.86 min (304.3, MH ⁺ ).

methylisoxazol-3-yl)-4, 6- difluorobenzene-1 ,2-diamine

Intermediate BT: N ¹ -(4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol- 5-yl)-4- methoxybenzene-1 ,2-diamine

A stirred suspension of Intermediate BC (400 mg, 1.02 mmol) in EtOH (20 mL) under N ₂ was treated with 10 % palladium on activated charcoal (100 mg, 1.02 mmol) then ammonium formate (194 mg, 3.07 mmol) was added and the mixture was heated under reflux for 2.5 h. The reaction was cooled to R.T., filtered through dicalite® under N ₂ and washed with MeOH then EtOAc. Then the combined filtrates were concentrated in vacuo. The crude was purified using column chromatography (S1O2, 0-20 % MeOH in DCM) to obtain the title compound (200 mg, 16 %). LCMS (Method C): 2.73 min (361.3, MH ⁺ ).

Intermediate BU:

The following Intermediate was prepared using the general method described in Intermediate

AC from Intermediate BS.

Intermediate BV: (4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)(2 - methoxyphenyl)methanol

To a cooled solution of Intermediate AF (377 mg, 1.24 mmol) in dry THF (10 ml_) was added isopropylmagnesium chloride lithium chloride (1.35 ml_, 1.76 mmol) dropwise and the solution was stirred for 20 min at 0 °C. 2-Methoxybenzaldehyde (141 mg, 1.03 mmol) was added and the reaction was stirred 4 h at 0 °C. Water was added and the crude product was extracted with EtOAc. Combined organics were dried (MgS0 ₄ ) and cone, in vacuo. The crude was purified using flash chromatography (S1O2, 0-10 % MeOH in DCM) to obtain Intermediate BV {307 mg, 82 %). ¹ H NMR 5 _H (500 M HZ, CDCb) 7.21 (ddd, J = 11.9, 9.8, 1.6 Hz, 1 H), 7.12 - 7.08 (m, 1 H), 7.08 - 7.04 (m, 0.5H), 7.00 (dd, J = 7.6, 0.9 Hz, 0.5H), 6.95 (dd, J = 8.5, 6.3 Hz, 1 H), 6.91 (td, J = 8.3, 2.6 Hz, 0.5H), 6.86 - 6.81 (m, 1.5H), 6.78 (dd, J = 10.7, 8.3 Hz, 1 H), 5.94 (s, 0.5H), 5.92 (s, 0.5H), 3.92 (s, 1.5H), 3.91 (s, 1.5H), 3.77 (s, 1.5H), 3.73 (s, 1.5H), 2.10 (s, 1.5H), 2.08 (s, 1.5H). Rotameric compound, hence signal splitting/broadening. Intermediate BW:

The following Intermediate was prepared using the general method described in Intermediate S\/ from the appropriate aldehyde and Intermediate AF.

Intermediate BX: (4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)(2 - none

In a dry flask Intermediate BV (307 mg, 0.851 mmol) was dissolved in dry DCM (8 ml_) and cooled to 0 °C when Dess-Martin periodinane (650 mg, 1.53 mmol) was added. The resulting mixture was stirred overnight. Sat. aq. NaHCC>3 was carefully added to quench the reaction and it was diluted with DCM. The organic layer was subsequently washed sequentially with sat. aq. Na2S203 then water, dried (MgSCU) and concentrated in vacuo. The crude material was purified using flash chromatography (S1O2, 0-20 % EtOAc in PE) to obtain Intermediate BX (252 mg, 0.702 mmol, 83 % yield). ¹ H NMR (500 MHz, CDC ) δ 7.20 (dd, J = 7.5, 1.7 Hz, 1 H), 7.16 (ddd, J = 8.4, 7.5, 1.8 Hz, 1 H), 6.89 - 6.82 (m, 2H), 6.73 (td, J = 7.5, 0.8 Hz, 1 H), 6.66 (td, J = 8.3, 2.6 Hz, 1 H), 6.51 (d, J = 8.3 Hz, 1 H), 4.18 (s, 3H), 3.65 (s, 3H), 2.09 (s, 3H); LCMS (Method A): 3.28 min (359.3 m/z, MH ⁺ ). Intermediate BY:

The following Intermediate was prepared using the general method described in Intermediate B from Intermediate BW.

Intermediate BZ: (4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)(2 - hydroxyphenyl)methanone

In dry DCM (5 ml_) Intermediate BX (252 mg, 0.702 mmol) was stirred at 0 °C under a nitrogen atmosphere when boron tribromide (1 M, 0.702 ml_, 0.702 mmol) in DCM was added dropwise to be stirred for 1.5 h at 0 °C. The reaction mixture was quenched by addition of H2O, the mixture was then extracted with DCM. The combined organic layer was dried over anhydrous MgS0 ₄ . The solvents were evaporated under reduced pressure. The crude was purified using column chromatography (Si0 ₂ , 0-10 % MeOH in DCM) to obtain Intermediate BZ (179 mg, 0.519 mmol, 73.9 % yield). ¹ H NMR δ _Η (500 MHz, CDCI3) 1 1.53 (s, 1 H), 7.32 (m, 2H), 7.09 - 7.01 (m, 2H), 6.89 (d, J = 8.3 Hz, 1 H), 6.84 (td, J = 8.3, 2.6 Hz, 1 H), 6.60 - 6.52 (m, 1 H), 3.99 (s, 3H), 2.22 (s, 3H); LCMS (Method C): 3.36 min (345.2 m/z, MH ⁺ ). Intermediate CA: (4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)(2 ,4-difluoro- -hydroxyphenyl)methanone

A solution of Intermediate BY (100 mg, 0.238 mmol) in THF (5 mL) was stirred under an atmosphere of nitrogen and was treated with 2,2-dimethyl-1 ,3-dioxane-4,6-dione (69 mg, 0.48 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 60 μηιοΙ), to be then stirred at R.T. for 2 days. The reaction was diluted with Et20 and water was added. The aqueous phase was extracted with EtOAc and subsequently washed with brine, dried (MgSCU) and the solvents were removed. The crude was purified using column chromatography (S1O2, 0-20 % EA in PE) to obtain Intermediate CA (40 mg, 0.1 1 mmol, 44.2 % yield). ¹ H NMR δ _Η (500 MHz, CDC ) 10.78 (d, J = 1.1 Hz, 1 H), 7.27 (dd, J = 8.9, 2.6 Hz, 1 H), 7.10 (dd, J = 8.6, 6.3 Hz, 1 H), 7.02 (td, J = 8.5, 2.7 Hz, 1 H), 6.40 (td, J = 9.8, 2.1 Hz, 1 H), 6.12 (d, J = 10.7 Hz, 1 H), 4.09 (s, 3H), 1.95 (s, 3H); LCMS (Method C): 3.06 min (381.1 m/z, MH ⁺ ).

Intermediate CB: 4-(2-Chloro-4-fluorophenyl)-1-methyl-1H-pyrazol-5-amine

In a vial 3-amino-4-bromo-2-methylpyrazole (0.20 g, 1.1 mmol), 2-chloro-4-fluorophenylboronic acid (0.30 g, 1.7 mmol) and sodium carbonate (2 M) (2.3 mL, 4.6 mmol) were dissolved in dioxane (2.5 mL). After degassing the resulting mixture for 10 min, tetrakis(triphenylphosphine)palladium (66 mg, 60 μηιοΙ) was added and it was stirred at 120 °C for 1 h under microwave conditions. Solvents were removed and the crude material was purified by column chromatography (S1O2, 0-100 % EtOAc in PE) to obtain the title compound (97 mg, 38 %). ¹ H NMR δ _Η (500 MHz, CDCb) 7.44 (s, 1 H), 7.31 (dd, J = 8.6, 6.1 Hz, 1 H), 7.24 (dd, J = 8.5, 2.6 Hz, 1 H), 7.05 (ddd, J = 8.6, 7.9, 2.7 Hz, 1 H), 3.80 (s, 3H), 3.73 (br s, 2H). LCMS (Method A): 2.70 min (226.2 m/z, MH ⁺ ).

Intermediate CC:

The following Intermediate was prepared using the general method described in Intermediate AQ from Intermediate A and 3-bromo-4-nitro-pyridine. Intermediate Compound ¹ H NMR/LCMS

No

CC N-(4-(2,6-Difluoro-4- LCMS (Method C): 3.14 min (376.2 m/z,

methoxyphenyl)-1 ,3-dimethyl- MH ⁺ ).

1H-pyrazol-5-yl)-4-nitropyridin- -amine

Intermediates CD-CU:

The following Intermediates were prepared using the general method described in Intermediate G from the appropriate aminopyrazole and fluoro-nitro-arene.

Intermediate Compound ¹ H NMR/LCMS

No

CD 2-((4-(2-Chloro-4-fluorophenyl)- LCMS (Method C): 1.52 min (423.2 m/z,

1 ,3-dimethyl-1 H-pyrazol-5- MH ⁺ ).

yl)amino)-5-fluoro-3- nitrobenzoic acid

CE 4-((4-(2-Chloro-4-fluorophenyl)- LCMS (Method C): 3.22 min (404.2 m/z,

1 ,3-dimethyl-1 H-pyrazol-5- MH ⁺ ).

yl)amino)-3-fluoro-5- nitrobenzonitrile

nitrobenzene-1 ,4-diamine

1 H-pyrazol-5-amine

1 H-pyrazol-5-amine

Intermediate CT:

The following Intermediate was prepared using the general method described in Intermediate G from Intermediate CB and 1 ,2,5-trifluoro-3-nitro-benzene.

Intermediate CU: 3-Chloro-4-(2-chloro-4-fluorophenyl)-N-(2,4-difluoro-6-nitro phenyl)-1- methyl-1H-pyrazol-5-amine

Intermediate CT (45 mg, 0.12 mmol) was dissolved in DMF (1 ml_). /V-Chlorosuccinimide (24 mg, 0.18 mmol) was added, then the reaction mixture was stirred at room temperature for 18 h. A further amount of /V-chlorosuccinimide (24 mg, 0.18 mmol) was added and the solution heated to 50 °C for 2 h. EtOAc and water were added and the aqueous phase extracted with EtOAc.The combined organics were washed with water, dried over MgSCU and concentrated in vacuo. The crude material was purified by column chromatography (S1O2, 0-50 % EtOAc in PE) to obtain the title compound (35 mg, 72 %). ¹ H NMR δ _Η (500 MHz, CDCI3) 7.44 (m, 2H), 7.08 (dd, J = 8.0, 2.6 Hz, 1 H), 7.98 (m, 1 H), 6.79 (br m, 1 H), 6.68 (br m, 1 H), 3.50 (s, 3H). LCMS (Method A): 3.95 min (417.0 m/z, MH ⁺ ).

Intermediates CV-DO:

The following Intermediates were prepared using the general method described in Intermediate from the appropriate Intermediate (CC-CU).

Intermediate DP: 1-(4-(2,6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol- 5-yl)-5- H-benzo[d]imidazol-2-one

Λ/,Λ/'-Carbonyl diimidazole (0.15 g, 0.90 mmol) was added in 3 portions to a stirred solution of Intermediate CY (0.27 g, 0.75 mmol) in THF (3 ml_). The solution was then at room temperature for 48 h. Water was added and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried, concentrated in vacuo and the crude title compound (0.24 g, 65 %) was used wthout further purification in the subsequent step (Example 102). LCMS (Method C): 3.09 min (389.3 m/z, MH ⁺ ).

Intermediates DQ-DV:

The following Intermediates were prepared using the general method described in Intermediate G from the appropriate aminopyrazole and fluoro-nitro-arene.

amine

DU N-(4-Bromo-2-fluoro-6- LCMS (Method C): 3.96 min

nitrophenyl)-4-(2,6-difluoro-4- (473.0 m/z, MH+).

methoxyphenyl)-1 ,3-dimethyl-1 H- pyrazol-5-amine

DV 4-Bromo-N-(4-fluoro-2- LCMS (Method C): 3.64 min

nitrophenyl)-1 ,3-dimethyl-1 H- (331.0 m/z, MH+).

pyrazol-5-amine

Intermediates DW-EB

The following Intermediates were prepared using the general method described in Intermediate P from the appropriate Intermediate (DQ-DV).

Intermediate Compound ¹ H NMR/LCMS

No

DW N ¹ -(4-(2,6-Difluoro-4- LCMS (Method A): 3.83 min

methoxyphenyl)-1 ,3-dimethyl-1 H- (413.2 m/z, MKT).

pyrazol-5-yl)-4- (trifluoromethyl)benzene-l ,2- diamine

DX N ¹ -(4-(2,6-Difluoro-4- LCMS (Method C): 3.30 min

methoxyphenyl)-1 ,3-dimethyl-1 H- (359.5 m/z, MH+).

pyrazol-5-yl)-4-methylbenzene-1,2- diamine

DY N ¹ -(4-(2-Chloro-4-fluorophenyl)- LCMS (Method C): 2.86 min

1,3-dimethyl-1H-pyrazol-5-yl)-4- (345.3 m/z, MH+).

methylbenzene-1 ,2-diamine

DZ 5-Chloro-N ² -(4-(2,6-difluoro-4- LCMS (Method C): 3.30 min

methoxyphenyl)-1 ,3-dimethyl-1 H- (380.1 m/z, MH+).

pyrazol-5-yl)pyridine-2,3-diamine

EA 4-Bromo-N ¹ -(4-(2, 6-difluoro-4- LCMS (Method C): 3.68 min

methoxyphenyl)-1 ,3-dimethyl-1 H- (443.0 m/z, MH+).

pyrazol-5-yl)-6-fluorobenzene-1,2- diamine

EB N ¹ -(4-Bromo-1,3-dimethyl-1H- LCMS (Method C): 3.10 min

pyrazol-5-yl)-4-fluorobenzene-1,2- (299.2 m/z, MH+).

diamine

Intermediate EC: N ¹ -(4-(4-Fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)-4- e-1 ,2-diamine

Intermediate EC was prepared using the general method described for Intermediate BT from Intermediate BC. LCMS (Method C): 2.57 min (327.4 m/z, MKT).

Intermediate ED: 1 -(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-5-fluoro-1 H-

Intermediate ED was prepared using the general method described for Intermediate AC from Intermediate EB.

LCMS (Method C): 3.09 min (31 1.0 m/z, MKT). Examples 1-11:

The following Examples were prepared using the general method described in Intermediate AC from Intermediates P-AB.

- =

-

fluoro- 1 H-benzo[ d] imidazole (m, 2H), 3.65 (s, 3H), 2.23 (s, 3H). Example 12: 1-(4-(2-Chloro-4-fluorophenyl)-1-ethyl-3-methyl-1H-pyrazol-5 -yl)-1H-

Potassium carbonate (42 mg, 0.31 mmol) and iodoethane (14 μΙ_, 0.17 mmol) were added to a solution of Intermediate AE (50 mg, 0.15 mmol) in DMF (1 mL), and the reaction was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-60% EtOAc in PE) and the title compound was isolated as a brown gum (21 mg, 39 %). ¹ H NMR 5 _H (500 MHz, CDC ) 7.90 - 7.80 (m, 2H), 7.63 - 7.57 (m, 1 H), 7.35 - 7.29 (m, 2H), 7.20 (dd, J = 8.4, 2.6 Hz, 1 H), 7.12 (dd, J = 8.6, 6.0 Hz, 1 H), 7.00 - 6.92 (m, 1 H), 4.26 (q, J = 7.3 Hz, 2H), 2.28 (s, 3H), 1.60 (t, J = 7.3 Hz, 3H). LCMS (Method A): 3.31 min (355.2, MH ⁺ ). Example 13: 1-(5-(1H-Benzo[d]imidazol-1-yl)-4-(2-chloro-4-fluorophenyl)- 3-methyl-1H- one

Pyridine (19 μΙ_, 0.23 mmol) and acetic anhydride (22 μΙ_, 0.23 mmol) were added to a solution of Intermediate AE (50 mg, 0.15 mmol) in DCM (1 mL). After stirring at room temperature for 18 h DMF (1 mL), pyridine (19 μΐ, 0.23 mmol) and acetic anhydride (22 μΐ, 0.23 mmol) were added. After stirring at room temperature for 24 h, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgS0 ₄ ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-60% EtOAc in PE) and the title compound was isolated as a brown gum (28 mg, 50 %). ¹ H NMR δ _Η (500 MHz, CDCb) 7.94 - 7.84 (m, 2H), 7.80 (br s, 1 H), 7.45 - 7.37 (m, 2H), 7.31 - 7.29 (m, 1 H), 7.25 (dd, J = 8.6, 5.9 Hz, 1 H), 7.15 - 7.06 (m, 1 H), 2.87 (s, 3H), 2.57 (s, 3H). LCMS (Method A): 3.53 min (369.2, MH ⁺ ). -Chlorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)-1H-benzo[d]imid azole

Intermediate AC (50 mg, 0.17 mmol) and 2-chlorobenzeneboronic acid (30 mg, 0.19 mmol) were dissolved in dioxane (1 ml_). Sodium carbonate (2 M aq) (0.34 ml_, 0.69 mmol) was added and the mixture degassed by nitrogen bubbling for 5 min. [1 , T-

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (14 mg, 0.02 mmol) was added, and the reaction was heated to 120 °C under microwave conditions for 20 min. The reaction was filtered through dicalite®, eluting with EtOAc, and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE) and the title compound was isolated as a yellow solid (22 mg, 40 %). ¹ H NMR δ _Η (500 MHz, CDC ) 8.08 - 7.63 (br m, 3H), 7.56 - 7.31 (br m, 3H), 7.25 - 6.91 br (m, 3H), 3.68 (br s, 3H), 2.28 (s, 3H). LCMS (Method A): 2.93 min (323.2, MH ⁺ ).

Examples 15-25

The following Examples were prepared using the general method described for Example 14 from Intermediates AC or AD with the appropriate boronic acid.

Example 25: 1 -(4-(2-Chloro-4-fluorophenyl)-1 ,3-dimethyl-1 H-pyrazol-5-yl)-5,7-difluoro-2- azole

A suspension of Intermediate R (64 mg, 0.17 mmol) in trimethyl orthoacetate (439 μΙ_, 3.49 mmol) was treated with cone, hydrochloric acid (0.727 μΙ_, 8.72 μηιοΙ) and heated to 130 °C for 2 h. The cooled down solution was diluted with water and extracted with EtOAc (x3). The organic phases were washed with brine, dried (MgSCU) and evaporated in vacuo. The crude product was purified via column chromatography (preparative HPLC, basic mode) to obtain the title compound (15.2 mg, 0.039 mmol, 22 %). ¹ H NMR (500 MHz, CDCb) δ 7.20 (dd, J = 8.7, 2.0 Hz, 1 H), 7.17 (s, 1 H), 6.91 (s, 1 H), 6.87 - 6.74 (m, 2H), 3.61 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); LCMS (Method A): 3.25 min (391.2, MH ⁺ ).

Example 26:

The following Example was prepared using the general method described in for Example 25 from Intermediate Q.

hloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)isoquinol ine

Intermediate AG (50.0 mg, 0.143 mmol), 4-bromoisoquinoline (29.7 mg, 0.143 mmol) and potassium phosphate tribasic (91.0 mg, 0.428 mmol) were dissolved in 1 ,4-dioxane (4 ml_). The heterogeneous mixture was purged with N2 for 20 minutes before Pd(PP i3) ₄ (33.0 mg, 0.029 mmol) was added, subsequently the mixture was heated to 100 °C over 90 min in the microwave. Water was added and the aqueous phase was extracted with EtOAc (x3). The organic phase was washed (brine), dried (MgS0 ₄ ) and concentrated to be purified using preparative HPLC to obtain the title compound (4.8 mg,10 %). ¹ H NMR (500 MHz, CDC ) δ 9.27 (s, 1 H), 8.39 (m, 1 H), 8.02 (dd, J = 24.4, 8.1 Hz, 1 H), 7.68 (m, 3H), 7.15 - 6.60 (m, 3H), 3.63 (m, 3H), 2.25 (m, 3H); LCMS (Method A): 3.27 min (352.2, MH ⁺ ).

Examples 28-32:

The following Examples were prepared using the general method described for Example 27 from Intermediate AG with the appropriate bromo-heterocycle.

30 3-(4-(2-Chloro-4-fluorophenyl)- (500 MHz, CDCb) δ 7.73 - 7.68 (m, 2H), 1 ,3-dimethyl-1 H-pyrazol-5- 7.63 (d, J= 9.0 Hz, 1H), 7.25-7.16 (m, yl)imidazo[ 1,2-a]pyridine 1H), 7.11 (dd, J= 8.5, 2.5 Hz, 1H), 6.98

(dd, J = 8.5, 6.1 Hz, 1H), 6.82-6.77 (m, 1H), 6.73 (t, J = 6.8 Hz, 1H), 3.77 (s, 3H), 3.49 (s, 3H), 2.24 (s, 3H).

— N I, LCMS (Method C): 2.27 min (341.2,

MH ⁺ ).

31 3-(4-(2-Chloro-4-fluorophenyl)- (500 MHz, CDCb) δ 7.76 (d, J= 9.3 Hz,

1 ,3-dimethyl-1 H-pyrazol-5-yl)- 1H), 7.54 (d, J= 7.0 Hz, 1H), 7.22 (ddd,

[ 1 ,2,4]triazolo[4, 3-a] pyridine J = 9.3, 6.6, 1.0 Hz, 1H), 7.16 (dd, J =

8.4, 2.6 Hz, 1H), 6.97 (dd, J = 8.6, 6.1

P0 Hz, 1H), 6.81-6.74 (m, 1H), 6.65 (td, J

= 6.9, 0.9 Hz, 1H), 4.00 (s, 3H), 2.28 (s, 3H).

LCMS (Method A): 2.47 min (342.2, MH ⁺ ).

32 4-(4-(2-Chloro-4-fluorophenyl)- (500 MHz, CDCb) δ 8.72 (d, J= 5.0 Hz,

1,3-dimethyl-1H-pyrazol-5-yl)-2- 1H), 7.49 (s, 1H), 7.26 (d, J = 3.8 Hz,

(trifluoromethyl)pyridine 1H), 7.21 (dd, J= 8.4, 2.6 Hz, 1H), 7.10

F (dd, J = 8.5, 6.1 Hz, 1H), 6.98 (td, J =

8.3, 2.6 Hz, 1H), 3.92 (s, 3H), 2.19 (s, 3H).

LCMS (Method A): 3.41 min (370.1, MH ⁺ ).

^FsC N-N

/ loro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl)-1H-indole

Copper(l) iodide (8.13 mg, 0.043 mmol), 1H-indole (100 mg, 0.854 mmol) and potassium phosphate tribasic (380 mg, 1.79 mmol) were flushed with nitrogen, then dissolved in toluene (2 mL). Intermediate AF (311 mg, 1.02 mmol) in toluene and Λ/,Λ/'-dimethylethylenediamine (0.018 μΙ_, 0.17 mmol) was added. The mixture was heated to 110 °C for 18h. After filtering through dicalite® (washed with EtOAc and water) the phases were separated. The aqueous phase was extracted with EtOAc (x3), washed with brine and concentrated. The crude was purified by preparative HPLC to obtain the title compound (2.5 mg, 1 %) as an orange gum. ¹ H NMR (500 MHz, CDCb) δ 7.61 (m, 1 H), 7.24 - 6.86 (m, 6H), 6.79 (m, 1 H), 6.60 (m, 1 H), 3.60 - 3.55 (s, 3H), 2.24 (s, 3H); LCMS (Method C): 4.18 min (340.05, MH ⁺ ).

Example 34:

The following Example was prepared using the general method described for Example 33 from Intermediate AF with the appropriate heterocycle.

Examples 36-39:

The following Examples were prepared using the general method described in Intermediate AC from Intermediates (AM-AP).

m, 3H), 3.71 (s, 3H), 2.26 (s, 3H).

Rotameric compound, hence signal splitting/broadening.

LCMS (Method A): 2.51 min (342.2,

MH ⁺ ).

Examples 40-44

The following Examples were prepared using the general method described in Example 27 from Intermediate AG with the appropriate bromo-heterocycle.

Examples 45-49

The following Examples were prepared using the general method described in Example 14 from Intermediate AD with the appropriate boronic acid.

Example No Compound ¹ H NMR/LCMS

45 1-(4-(2-Chloro-4- (500 MHz, CDCb) δ 7.79 (br m, 1 H),

(trifluoromethoxy)phenyl)-1 ,3- 7.36 - 7.31 (m, 1 H), 7.28 (br m, 2H), dimethyl-1H-pyrazol-5-yl)-5, 7- 7.01 (br m, 1 H), 6.93 - 6.84 (m, 1 H), difluoro- 1 H-benzo[ d] imidazole 3.68 (s, 3H), 2.23 (s, 3H).

splitting/broadening. LCMS (Method A): 3.22 min (393.2,

MH ⁺ ).

49 5,7-Difluoro-1-(4-(4-methoxy-2- (699 MHz, CDCb) δ 7.76 (s, 0.8H),

(trifluoromethyl)phenyl)-1 ,3- 7.64 (s, 0.5H), 7.31 - 7.27 (m, 0.4H), dimethyl-1 H-pyrazol-5-yl)-1 H- 7.18 (d, J = 2.6 Hz, 0.7H), 7.11 - 7.06 benzo[ d] imidazole (m, 0.9H), 7.04 (d, J = 8.5 Hz, 0.7H),

OMe 6.92 - 6.82 (m, 2H), 3.83 (s, 1.2H),

3.79 (s, 1.8H), 3.68 (s, 1.2H), 3.61 (s, 1.8H), 2.12 (2 x s, 3H).Rotameric compound, hence signal

_F ix _F splitting/broadening.

LCMS (Method A): 3.28 min (423.4, MH ⁺ ).

Examples 50-63:

The following Examples were prepared using the general method described in Intermediate AC from Intermediates BF-BS.

- (s,

Hz, = 1

Example 64: Ethyl 1-(4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl) -1H-

Example 63 (28 mg, 0.073 mmol) was dissolved in ethanol (10 mL), treated with cone, sulfuric acid (4.0 μί, 80 μηιοΙ) and heated to 90 °C in a closed vial over two days. After cooling to R.T., the pH of the mixture was adjusted to >7 (1 M aqueous NaOH) and extracted with EtOAc. The combined organic layers were washed with NaHCC>3 solution and brine, dried over MgSCU, then the solvents were removed. The crude was purified using column chromatography (S1O2, 0- 100 % EtOAc in PE) to yield the title compound (18 mg, 60 %).

¹ H NMR δ _Η (500 MHz, CDC ) 8.59 (s, 1 H), 8.09 (d, J = 7.5 Hz, 1 H), 8.04 (s, 1 H), 7.09 (m, 2H), 6.94 (m, 1 H), 6.83 (m, 1 H), 4.41 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 2.25 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H): LCMS (Method C): 3.10 min (413.2, MH ⁺ ). Example 65: 1-(4-(2,6-Difluoro-4-hydroxyphenyl)-1,3-dimethyl-1H-pyrazol- 5-yl)-1H-

A solution of Example 50 (50 mg, 0.13 mmol) in DCM (2 mL) was cooled to 0 °C under a nitrogen atmosphere. Boron tribromide (1 M in DCM, 0.26 mL, 0.26 mmol) was added dropwise and the reaction was stirred for an hour at 0 °C. After stirring at R.T. for 18 h, boron tribromide (1 M in DCM, 1.0 mL, 1.0 mmol) was added. A further 2 portions of boron tribromide (1 M in DCM, 1.0 ml_, 1.0 mmol) were added at 24 h intervals. The mixture was carefully quenched with water, and layers separated. The aqueous layer was neutralised with NaHCC>3 to ~ pH 7 and extracted with EtOAc. The combined organic layers were dried (MgSCU) and concentrated in vacuo to yield the title compound as a yellow solid (22 mg, 48 %). ¹ H NMR 5H (500 MHz, CDsOD) 7.81 (s, 1H), 7.08 (dd, J= 8.1, 0.9 Hz, 1H), 7.02 (t, J= 8.0 Hz, 1H), 6.60 (dd, J = 7.8, 0.7 Hz, 1 H), 6.21 (br m, 2H), 3.57 (s, 3H). LCMS (Method A): 1.67 min (357.2, MH ⁺ ).

Example 66: 1-(4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl) -1H- l

Following the procedure for Example 65, Example 52 (60 mg, 0.16 mmol) was reacted to afford the title compound (29 mg, 51 %) as a yellow oil.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.51 (br m, 1H), 7.33 (brm, 2H), 7.13 (d, J= 7.6 Hz, 1H), 6.94 (brm, 3H), 6.76 (d, J= 7.8 Hz, 1H), 3.60 (brs, 3H), 2.10 (s, 3H).

LCMS (Method A): 2.85 min (357.1, MH ⁺ ).

Example 67: 1-(4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl) -7-(prop-2-yn-1- idazole

To a solution of Example 66 (20 mg, 0.06 mmol) in DMF (1 ml_) was added potassium carbonate (15.5 mg, 0.112 mmol) and propargyl bromide (80% in toluene, 7.0 μΙ_, 0.07 mmol). After stirring at R.T. for 72 h, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgSCU) and concentrated in vacuo to yield the title compound as a brown gum (10 mg, 47 %). ¹ H NMR5 _H (500 MHz, CDC ) 7.69-7.60 (m, 1H), 7.48-7.41 (m, 1H), 7.26 (m, 1H), 7.18-7.11 (m, 1H), 7.05-6.84 (m, 2H), 6.81 -6.70 (m, 1H), 4.81-4.63 (m, 2H), 3.73 - 3.52 (m, 3H), 2.57 - 2.43 (m, 1 H), 2.22 (s, 3H). LCMS (Method A): 3.25 min (395.3, MH ⁺ ).

Example 68: 3-(4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-

Stage 1 :

Intermediate BZ (86 mg, 0.25 mmol) was dissolved in ammonia in methanol (3.5 mL). Under a nitrogen atmosphere, titanium(IV) isopropoxide (0.22 mL, 0.75 mmol) was added and the solution was stirred overnight at R.T. The solvents were removed and the crude material was purified using column chromatography (Si0 ₂ , 0-40 % EtOAc in PE, then 0-80 % MeOH in DCM) to obtain the yellow intermediate.

Stage 2: The imine intermediate (35 mg, 0.10 mmol), /V-chlorosuccinimide (20.39 mg, 0.153 mmol) and potassium carbonate (28.1 mg, 0.204 mmol) were dissolved in THF (5 mL). The solution was stirred at R.T. overnight. Water was added to the reaction and the mixture was extracted with EtOAc, dried (MgSCU) and concentrated. The crude material was purified using column chromatography (S1O2, 0-15 % EtOAc in PE) to obtain the title compound (1.8 mg, 5.2 %).

¹ H NMR (500 MHz, CDC ) δ 7.58 (d, J = 8.5 Hz, 1 H), 7.51 - 7.46 (m, 1 H), 7.13 (m, 3H), 7.03 (d, J = 8.0 Hz, 1 H), 6.84 (td, J = 8.3, 2.6 Hz, 1 H), 4.03 (s, 3H), 2.27 (s, 3H); LCMS (Method A): 3.06 min (344.2 m/z, M(lmide)H ⁺ ); LCMS (Method A): 3.58 min (342.2 m/z, MH ⁺ ).

Example 69:

The following example was prepared using the general method described in Example 68 from Intermediate CA.

Example 70:

The following Example was prepared using the general method described in Example 14 from Intermediate SI/ with the appropriate boronic acid.

Examples 71-90:

The following Examples were prepared using the general method described in Intermediate AC from Intermediates CV-DO.

76 1-(4-(2-Chloro-4- (500 MHz, CDC ) 57.77 (s, 1H), 7.18-6.73

fluorophenyl)-1 ,3-dimethyl- (m, 6H), 3.64 (s 3H), 3.02 (s, 6H), 2.23 (s, 1H-pyrazol-5-yl)-N,N- 3H).

dimethyl-1H- LCMS (Method C): 2.53 min (384.2 m/z, benzo[ d]imidazol-5-amine MH ⁺ ).

77 1-(4-(2,6-Difluoro-4- (500 MHz, CDCb) δ 7.83 (s, 1H), 7.28 (d,

methoxyphenyl)-1 ,3-dimethyl- J=2.3Hz, 1H), 7.03 (d, J=8.8Hz, 1H), 1 H-pyrazol-5-yl)-5-methoxy- 6.92 (dd, J= 8.8, 2.3 Hz, 1H), 6.36 (m, 2H), 1 H-benzo[ d] imidazole 3.85 (s, 3H), 3.71 (s, 3H), 3.62 (s, 3H), 2.24

(s, 3H).

LCMS (Method C): 3.06 min (385.2 m/z, MH ⁺ ).

78 1-(4-(2,6-Difluoro-4- (500 MHz, CDCb) δ 8.76 (s, 1H), 8.24 (dd,

methoxyphenyl)-1 ,3-dimethyl- J= 8.9, 1.8 Hz, 1H), 8.07 (m, 1H), 7.23 (m, 1 H-pyrazol-5-yl)-5-nitro-1H- 1H), 6.37 (m, 2H), 3.72 (s, 3H), 3.66 (s, 3H), benzo[ d] imidazole 2.27 (s, 3H).

LCMS (Method C): 3.24 min (400.2 m/z, MH ⁺ ).

79 1-(4-(2-Chloro-4- (500 MHz, CDCb) δ 8.03 (s, 1H), 7.12 (m,

fluorophenyl)-1 ,3-dimethyl- 4H), 7.03 (m, 1H), 6.92 (m, 1H), 6.84 (m, 2H), 1H-pyrazol-5-yl)-1H- 3.66 (s, 3H), 2.22 (s, 3H). LCMS (Method E): benzo[ d]imidazol-5-amine 1.34 min (356.1 m/z, MH ⁺ ). Example 91:

The following example was prepared using the general method described in Intermediate BZ from Example 3.

Example 92: 1-(4-(2-Chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-yl) -7-fluoro-N,N- dimethyl-1H-benzo[d]imidazol-5-amine

Example 75 (60 mg, 0.16 mmol) was dissolved in MeCN (3 ml_). Formaldehyde (37 % in water) (0.54 ml, 6.6 mmol) was added, followed by sodium cyanoborohydride (54 mg, 0.86 mmol) and glacial acetic acid (40 μΙ, 0.70 mmol). The reaction mixture was stirred for 5 h at R.T. Saturated sodium bicarbonate solution was added and the aqueous phase was extracted with diethyl ether. The organic layer was washed with brine, dried (MgSCU) and concentrated in vacuo. The crude was purified by column chromatography (S1O2, 0-100 % EtOAc in PE) to obtain the title compound (9 mg, 14 %). ¹ H NMR δ _Η (500 MHz, CDC ) 7.75 (m, 2H), 7.15 (m, 1 H), 7.05 (m, 1 H), 6.99 (m, 1 H), 6.84 (m, 1 H), 3.68 (s, 3H), 3.09 (s, 6H), 2.21 (s, 3H). LCMS (Method C): 3.28 min (402.3 m/z, MH ⁺ ).

Example 93:

The following example was prepared using the general method described in Example 64 from Example 63 and methanol.

Example 94: 1-(4-(3-Chloro-2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H -pyrazol-5-yl)- -fluoro- 1 H-benzo[ d] imidazole

Example 74 (69 mg, 0.19 mmol) was dissolved in acetonitrile (3 ml_) and cooled to 0 °C and N- chlorosuccinimide (25 mg, 0.19 mmol) was added. The reaction was then stirred at room temperature for 18h. Water was added to the reaction mixture and extracted with EtOAc. The combined organics were then washed with aq. NaHCC and brine, dried (MgSCU), the solvents removed and the crude residue was purified using preparative HPLC (acidic conditions) to obtain the title compound (31 mg, 41 % yield). ¹ H NMR δ _Η (500 MHz, CDCb) 8.01 (m, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.10 (m, 2H), 6.44 (m, 1 H), 3.84 (s, 3H), 3.63 (s, 3H), 2.26 (s, 3H). LCMS (Method C): 3.22 min (407.3 m/z, MH ⁺ ).

Example 95-96

The following example was prepared using the general method described in Example 94 from Example 8 or Example 74 and the appropriate succinimide.

Example 97: 1-(4-(2,6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol- 5-yl)-7-fluoro- -nitro- 1 H-benzo[ d] imidazole

Sodium perborate tetrahydrate (45 mg, 0.56 mmol) was added to glacial acetic acid (4.0 mL, 71 mmol) and a solution of Example 75 (43 mg, 0.1 1 mmol) in glacial acetic acid (1.0 mL, 17 mmol) was added slowly. The mixture was heated to 65 °C for 18h. After cooling to room temperature, water and EtOAc were added and the phases separated. The aqueous phase was extracted with EtOAc, then the combined organics washed with brine, dried (MgS0 ₄ ), and concentrated in vacuo. The crude residue was purified by chromatography (S1O2, 0-100 % EtOAc in PE) to obtain the title compound (10 mg, 21 %). ¹ H NMR δ _Η (500 MHz, CDCb) 8.59 (d, J = 1.9 Hz, 1 H), 8.00 (dd, J = 10.3, 1.8 Hz, 1 H), 7.95 (s, 1 H), 6.39 (m, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 2.26 (s, 3H). LCMS (Method C): 3.30 min (418.1 m/z, MH ⁺ ). Example 98: 2-Chloro-1-(4-(2, 6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl)- 5-fluoro- 1 H-benzo[ d] imidazole

To thoroughly dried Intermediate DP (0.10 g, 0.26 mmol), phosphorus(V) oxychloride (0.13 ml_, 1.4 mmol) was added. The reaction was heated to reflux for 3 h and then cooled to room temperature. The solution was poured onto crushed ice/water and was neutralized to pH = 7.0 with 1 M aq. NaOH. The aqueous solution was extracted with DCM and the combined organic layers washed with 1 M aq. HCI, sat. NaHCC>3, then brine, dried (MgSCU), and concentrated in vacuo. The crude residue was purified using column chromatography (S1O2, 0-100 % EtOAc in PE) to obtain the title compound (8.4 mg, 6 %). ¹ H NMR δ _Η (500 MHz, CDC ) 7.38 (m, 1 H), 7.01 (m, 1 H), 6.97 (m, 1 H), 6.36 (m, 2H), 3.72 (s, 3H), 3.65 (s, 3H), 2.27 (s, 3H). LCMS (Method C): 3.68 min (407.1 m/z, MH ⁺ ).

Example 99: 1-(4-(2, 6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl)-N, N- -5-sulfonamide

To a suspension of potassium carbonate (0.041 g, 0.30 mmol) and caesium carbonate (12 mg, 36 μηιοΙ) in DMF (10 ml_) was added Example 83 (52 mg, 0.12 mmol). After stirring for 30 min, iodomethane (16 μΙ_, 0.26 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was poured into water, stirred for half an hour and subsequently extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSCU), the solvent was removed in vacuo and the crude residue was purified by column chromatography (Si0 ₂ , 0-100 % EtOAc in PE) to obtain the title compound (26 mg, 37 %). ¹ H NMR δ _Η (500 MHz, CDCb) 8.29 (d, J = 1.3 Hz, 1 H), 8.04 (s, 1 H), 7.73 (dd, J = 8.5, 1.4 Hz, 1 H), 7.28 (s, 1 H), 6.38 (m, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 2.74 (s, 6H), 2.27 (s, 3H). LCMS (Method C): 3.10 min (462.1 m/z, MH ⁺ ). Example 100: 1 -(4-(2, 6-Difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl)-5- idazole

Sodium methanethiolate (0.18 g, 0.25 mmol) was added to a solution of Example 84 (0.10 g, 0.23 mmol) in ethanol (8 mL) and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified using column chromatography (Si0 ₂ , 0-100 % EtOAc in PE) to obtain the title compound (0.2 mg, 2 %). ¹ H NMR δ _Η (500 MHz, CDCb) 7.28 (d, J = 8.3 Hz, 1 H), 6.62 (dd, = 8.3, 1.7 Hz, 1 H), 6.48 (m, 2H), 6.17 (d, J = 1.6 Hz, 1 H), 5.90 (s, 1 H), 3.78 (s, 3H), 3.71 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H). LCMS (Method C): 3.52 min (401.1 m/z, MH ⁺ ).

Examples 101 - 106:

The following Examples were prepared using the general method described in Intermediate AC from Intermediates DW-EA or Intermediate EC.

Example 106: 5-Chloro-1-(4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H -pyrazol-5- -7-fluoro-1H-benzo[d][1,2,3]triazole

Hydrochloric acid (3 M, 1 mL) was added to Intermediate CS (0.027 g, 0.068 mmol) and sonicated until a suspension. A solution of sodium nitrite (7 mg, 0.1 mmol) in water (0.25 mL) was then added dropwise and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was then diluted with EtOAc and water, the organics were extracted, dried (MgS0 ₄ ) and concentrated in vacuo to give the title compound (21 mg, 77 %). ¹ H NMR (500 MHz, CDC ) δ 7.95 - 7.90 (m, 1H), 7.18 (dd, J= 9.4, 1.5 Hz, 1H), 6.33 (d, J= 10.0 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.30 (s, 3H).

LCMS (Method E): 2.13 min (408.2 m/z, MH ⁺ ). Examples 107-109:

The following Examples were prepared using the general method described in Example 107 from Intermediates P, CYorDF.

Example 110: 5-Chloro-1-(4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H -pyrazol-5- yl)-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

Triphosgene (0.017 g, 0.059 mmol) was added to a solution of Intermediate CS (0.023 g, 0.059 mmol) in hydrochloric acid (2.5 ml, 5.00 mmol) and Toluene (1.5 ml_) and stirred at room temperature for 48 h. The reaction mixture was then neutralised with 1 M NaOH and extracted into EtOAc before being dried (MgSCU) and concentrated in vacuo. Chromatography (S1O2, 0-100 % EtOAc in PE) of the residue gave the title compound as a brown oil (0.0145 g, 58 %). ¹ H NMR (500 MHz, CDC ) δ 9.77 (s, 1 H), 6.94 (s, 1 H), 6.78 (d, J = 10.2 Hz, 1 H), 6.42 (s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.30 (s, 3H). LCMS (Method A): 3.25 min (423.1 m/z, MH ⁺ ).

Example 111: Methyl 2-(4-(((1-(4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H- oxy)methyl)-1H-1,2,3-triazol-1-yl)acetate

Example 82 (43 mg, 0.105 mmol) was dissolved in dry THF (5 ml_). Triethylamine (0.029 ml_, 0.21 1 mmol), copper (I) iodide (10.0 mg, 0.053 mmol) and methylazidoacetate (10.3 μΙ_, 0.105 mmol) was added and the mixture was then stirred at room temperature for 20 min. The reaction was quenched by adding 5 drops of 26 % NH4OH solution and stirring for 5 min. Water and EtOAc were added and the aqueous phase was extracted with EtOAc (3x). Combined organic layeres were washed with sat. NH4CI solution, then brine, dried (MgS04) and the solvent removed in vacuo. The resulting residue was purified using column chromatography (S1O2, 0-100% EtOAc in PE) to obtain the title compound (32 mg, 58 % yield). ¹ H NMR (500 MHz, CDCb) δ 7.85 (s, 1 H), 7.79 (s, 1 H), 7.40 (d, J = 1.9 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 1 H), 7.00 (dd, J = 8.9, 2.2 Hz, 1 H), 6.37 (s, 2H), 5.27 (s, 2H), 5.19 (s, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H), 2.25 (s, 3H). LCMS (Method C): 2.98 min (524.2 m/z, MH ⁺ ). Example 112: 5-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(4-(2,6-difluo ro-4- l-5-yl)-1 H-benzo[ d] imidazole

The following Example was prepared using the general method described in Example 111 from Example 82 and the appropriate azide.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.40 (s, 1 H), 8.30 (s, 1 H), 7.45 (s, 1 H), 7.40 - 7.26 (m, 5H), 7.01 (d, J = 8.4 Hz, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 6.70 (d, J = 10.3 Hz, 2H), 5.62 (s, 2H), 5.15 (s, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 2.15 (s, 3H). LCMS (Method E): 1.91 min (542.2 m/z, MH ⁺ ).

Examples 113 - 114:

The following Examples were prepared using the general method described for Example 14 from Intermediate ED with the appropriate boronic acid.

Examples 115 - 116

The following Examples were prepared using the general method described for Example 65 from Example 61 or Example 81.

118 1-(4-(2-Chloro-4-fluorophenyl)- (500 MHz, CDCb) δ 7.66 (s, 1 H), 7.40 1,3-dimethyl-1H-pyrazol-5-yl)-7- (m, 1 H), 7.16 (m, 1 H), 6.99 (m, 1 H), ethoxy-1 H-benzo[d]imidazole 6.86 (m, 1 H), 6.76 (m, 2H), 4.10 (q,

J = 7.1 Hz, 2H), 3.59 (s, 3H), 2.21 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H).

r ⁰ - - LCMS (Method A): 3.72 min

(385.2 m/z, MH ⁺ ).

Example 119: 5-Chloro-1-(4-(4-cyclopropoxy-2,6-difluorophenyl)-1,3-dimeth yl-1H- ole

To a solution of Example 116 (72 mg, 0.19 mmol) in DMF (5 mL) was added potassium carbonate (53 mg, 0.38 mmol) and bromocyclopropane (18.0 μΙ_, 0.231 mmol). After stirring at 150 °C for 72 h, more bromocyclopropane (31.0 μΙ_, 0.384 mmol) was added and the reaction was stirred 12 h at 150 °C. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (MgSCU) and concentrated in vacuo. The crude was purified using column chromatography (preparative HPLC, acidic mode) to obtain the title compound (15 mg, 15 %). ¹ H NMR (500 MHz, CDCb) δ 7.89 (s, 1 H), 7.81 (d, J = 1.9 Hz, 1 H), 7.27 (dd, J = 8.6, 1.9 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 6.52 (m, 2H), 3.64 (m, 1 H), 3.61 (s, 3H), 2.26 (s, 3H), 0.76 (m, 2H), 0.73 (m, 2H). LCMS (Method C): 3.95 min (415.2 m/z, MH ⁺ ).

Example 120:

The following Example was prepared using the general method described in Example 119 from Example 66.

Example No Compound ¹ H NMR/LCMS 120 1-(4-(2-Chloro-4-fluorophenyl)- (500 MHz, CDCb) δ 7.64 (s, 1 H), 7.42

1,3-dimethyl-1H-pyrazol-5-yl)-7- (m, 1 H), 7.05 (m, 5H), 3.79 (m, 1 H), cyclopropoxy- 1 H- 3.54 (s, 3H), 2.20 (s, 3H), 0.79 (m, 2H), benzo[ d] imidazole 0.58 (m, 2H).

LCMS (Method F): 2.00 min

(397.2 m/z, MKT).

Example 121: 5-Chloro-1-(4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H -pyrazol-5- -1 H-benzo[d]imidazole 3-oxide

Example 81 (80 mg, 0.20 mmol) was dissolved in DCM (5 mL) and the reaction mixture was cooled to 0 °C. 3-Chloroperbenzoic acid (71 mg, 0.41 mmol) was added and the mixture was stirred at R.T overnight. The solvents were removed and the remaining crude was purified by preparative HPLC (acidic method) to afford the title compound (6 mg, 7 % yield).

1 H NMR δ _Η (500 MHz, CDCb) 10.01 (s, 1 H), 7.08 (d, J = 1.8 Hz, 1 H), 6.91 (dd, J = 8.4, 2.0 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 1 H), 6.37 (d, J = 17.1 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.25 (s, 3H). LCMS (Method C): 3.54 min (405.1 m/z, MH ⁺ ).

Example 122:

The following Example was prepared using the general method described in Example 121 from Example 88.

Example 123: 4-(2,6-Difluoro-4-methoxyphenyl)-5-(4,5-dimethyl-1H-imidazol -1-yl)-1,3-

Intermediate A (56.5 mg, 0.223 mmol) was dissolved in chloroform (2 rtiL), then 2,3- butanedione (0.016 mL, 0.18 mmol), ammonium acetate (14.3 mg, 0.186 mmol), acetic acid (0.053 mL, 0.93 mmol) and formaldehyde (37 % in water, 0.015 ml, 0.18 mmol) were added. The mixture was heated overnight at 120 °C. The solvents were removed and the resulting crude was purified using preparative HPLC (basic method) to obtain the title compound (6 mg, 10 % yield). ¹ H NMR δ _Η (500 MHz, CDC ) 7.41 (s, 1 H), 6.45 (dd, J = 3.9, 3.2 Hz, 1 H), 6.43 (t, J = 3.5 Hz, 1 H), 3.87+3.77 (2 x s, 3H), 3.58+3.78 (2 x s, 3H), 2.20 (2 x s, 3H), 2.14 (2 x s, 3H), 1.89 (2 x s, 3H) (Rotameric compound, hence signal splitting). LCMS (Method A): 3.44 min (333.2 m/z, MH ⁺ ).

Example 124 - Testing the fungicidal activity of compounds of the invention

Compounds were screened in 96 well plates with 10 compounds per plate. Each compound was screened using agar amended to 20, 2, 0.2 and 0.02 ppm of the test material. Proline at 50 and 10 ppm and 0.2% DMSO were used respectively as positive and negative controls. Each test concentration and standard were tested twice on a plate.

Compounds were screened against the following four fungal pathogens - Botrytis cinerea, Alternaria alternata, Rhizoctonia cerealis and Zymoseptoria tritici. The agar used in the test varied depending on the pathogen with Medium N used for B. cinerea and A. alternata and 1 % potato dextrose agar for R. cerealis and Z. tritici. For each pathogen sufficient spores were added to the appropriate agar to give 1 ,000 spores/ml agar of A. alternata, 5,000 spores/ml agar of B. cinerea and R. cerealis and 10,000 spores/ml agar of Z. tritici.

A x10 stock solution in 2% DMSO was produced for each dose i.e. 200, 20, 2 and 0.2 ppm, and 10 μΙ of this added to the appropriate wells on the plate. An equivalent amount of 2% DMSO and Proline stock at 500 and 100 ppm were added for the controls. To each well 90 μΙ of the appropriate agar spore suspension was added to give the final well concentrations outlined in the first paragraph.

Plates were incubated at room temperature (18°C) and assessed after

a) 3 to 4 days A. alternata, R. cerealis and B. cinerea

b) 7 days for Z tritici

The amount of fungal growth in each well was compared to the DMSO controls and scored according to the following key

0 - no growth (100% control)

1 - growth reduced by 75% compared to DMSO control (25% growth)

2 - growth reduced by 50% compared to DMSO control (50% growth)

3 - growth reduced by 25% compared to DMSO control growth (75% growth)

4 - no reduction in growth compared to DMSO control growth (100% growth)

Those numbers were then used to give an EC50. The ranking in the table is:

A) EC50<20 ppm

B) EC50>20 ppm but with activity detected at 20ppm

C) No activity detected at the highest dose tested (20ppm)

D) Not tested

Example Botrytis Rhizoctonia Alternaria Zymoseptoria

1 A A A A

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