WO2019141980A1

WO2019141980A1 - Agricultural chemicals

Info

Publication number: WO2019141980A1
Application number: PCT/GB2019/050111
Authority: WO
Inventors: Christopher John Urch; Victoria Elizabeth JACKSON; Linda Jordan; Ryan Neil BURGIN
Original assignee: Globachem Nv
Priority date: 2018-01-17
Filing date: 2019-01-16
Publication date: 2019-07-25

Abstract

The present invention relates to picolinic acid derivatives that are useful in treating fungal diseases ofplants.

Description

Agricultural Chemicals

The present invention relates to picolinic acid derivatives that are useful in treating fungal disease.

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 the USA and strobilurin-resistant strains of septoria fungal species.

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

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

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

An aim of certain embodiments of the present invention is to provide compounds which are less persistent in the environment after use than prior art compounds. Alternatively or additionally, the compounds of the present invention may be less prone to bioaccumulation once in the food chain than prior art compounds.

Another aim of certain embodiments of the invention is to provide compounds which are less harmful to humans than prior art compounds. Alternatively or additionally, the compounds of the invention may be less harmful than prior art compounds to one or more of the following groups: amphibians, fish, mammals (including domesticated animals such as dogs, cats, cows, sheep, pigs, goats, etc.), reptiles, birds, and beneficial invertebrates (e.g. bees and other insects, or worms), beneficial nematodes, beneficial fungi and nitrogen-fixing bacteria.

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 a lower or similar level of 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 compounds 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:

X¹ is independently selected from O, S and NH;

X², X³, X⁴ and X⁵ are each independently selected from carbon and nitrogen; provided that no more than two of X², X³, X⁴ and X⁵ are nitrogen;

Y¹ is independently selected from O and S;

Z¹ is independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, C(0)NR⁷, CR^7aR^7b, C(O), C(S), C=NOR7^c, NR⁷C(0), S(0)₂NR⁷, NR⁷S(0)₂, CrC₃- alkylene and NR⁷;

R¹ is a pyridine ring optionally substituted with a single OR² group and/or 1 , 2 or 3 R^1a groups;

R^1a, R⁴ and R¹² are each independently at each occurrence selected from CrC₆-alkyl, C1-C6- haloalkyl, C₃-C₆-cycloalkyl, halogen, nitro, OR⁸, SR⁹, 0S(0)₂R⁹, S(0)₂R⁹, C(0)0R⁹, C(0)NR⁹R⁹, C(0)R⁹, S(0)₂NR⁹R⁹, S(0)(NR⁹)R⁹, S(0)R⁹, cyano, C₂-C₆-alkenyl, C₂-C₆-alkynyl, and NR⁹R¹⁰;

R² is selected from H, CrC^alkyl, C(0)R¹¹ , C(0)0R¹¹ , CH₂0C(0)R¹¹ and CH₂0C(0)0R¹¹ ;

R³, R⁷ and R⁹ are each independently at each occurrence selected from: H, C₃-C₆-cycloalkyl and CrC₆-alkyl; or where two R⁹ groups are attached to the same nitrogen atom, said R⁹ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyl ring;

R⁵ is independently at each occurrence selected from C3-Cs-alkyl and Co-C3-alkylene-R^5a; wherein R^5a is independently at each occurrence selected from phenyl, 5- or 6- membered heteroaryl, 5-, 6-, 7- or 8- membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heterocycloalkyl or cycloalkyl group being monocyclic or bicyclic; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R¹² groups or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 4 R¹³ groups; said heterocycloalkyl or cycloalkyl group being optionally fused to phenyl or a 5- or 6- membered heteroaryl, said heteroaryl or phenyl group being optionally substituted with from 1 to 4 R¹² groups;

R^7a is independently at each occurrence selected from: H, C3-C6-cycloalkyl, CrC₆-alkyl, phenyl and 5- or 6- membered heteroaryl;

R^7b is independently at each occurrence selected from: H, halo and OR⁸;

R^7c is each independently at each occurrence selected from: H, C3-C6-cycloalkyl, CrC₆-alkyl and Ci-C3-alkylene-R^7d; wherein R^7d is independently at each occurrence selected from phenyl and 5- or 6-membered heteroaryl;

R⁸ is independently at each occurrence selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl, C(O)- CrC₆-alkyl and CrC₆-haloalkyl;

R¹⁰ is independently at each occurrence selected from; H, CrC₆-alkyl, C(0)-CrC₆-alkyl and S(0)₂-Ci-C₆-alkyl;

or where an R⁹ group and an R¹⁰ group are attached to the same nitrogen atom, said R⁹ and R¹⁰ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyl ring;

R¹¹ is CrC₆-alkyl, said alkyl group being optionally substituted with 1 to 4 R¹⁴ groups;

R¹³ is independently at each occurrence selected from: =0, =S, CrC₆-alkyl, CrC₆-haloalkyl, halogen, nitro, OR⁸, SR⁹, 0S(0)₂R⁹, S(0)₂R⁹, S(0)₂NR⁹R⁹, S(0)(NR⁹)R⁹, S(0)R⁹, cyano, C₂-C₆- alkenyl, C₂-C₆-alkynyl, and NR⁹R¹⁰;

R¹⁴ is independently selected from C3-C6-cycloalkyl, halogen, OR⁸, SR⁹, cyano, C₂-C₆-alkenyl, C₂-C₆-alkynyl and NR⁹R¹⁰;

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

p is independently an integer selected from 0, 1 and 2; wherein any aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including where two R⁹ groups or an R⁹ group and an R¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyl 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, CrC4-haloalkyl, C2-C₄-alkenyl, C2-C₄-alkynyl, NR^aR^b, S(0)₂R^a, S(0)R^a, S(0)(NR^a)R^a, S(0)₂NR^aR^a, C0₂R^a, C(0)R^a, CONR^aR^a and OR^a;

wherein R^a is independently selected from H and CrC₄-alkyl; and R^b is independently H, Cr C₄-alkyl, C(0)-CrC₄-alkyl, S(0)₂-Ci-C₄-alkyl. In certain embodiments, the compound of formula I is a compound of formula la:

wherein X¹, X², X³, X⁴, X⁵, Z\ R^1a, R², R³, R⁴, R⁵, m and p are as described above for formula I; and wherein n is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula II:

wherein Z\ R^1a, R², R⁴, R⁵, m and p are as described above for formula I; and wherein n is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula III:

wherein X¹ , X², X³, X⁵, R^1a, R², R³, R⁴ and R⁵ are as described above for formula I; wherein x is independently an integer selected from 0, 1 , 2 and 3; and wherein n is independently an integer selected from 0, 1 , 2 and 3. In certain embodiments, the compound of formula I is a compound of formula IV:

wherein X¹ , X², X³, X⁵, R^1a, R², R³, R⁴ and R⁵ are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, Ci-C₆-alkyl, C3-C6-cycloalkyl and Ci-C₆-haloalkyl.

In certain embodiments, the compound of formula I is a compound of formula V:

wherein R^1a, R², R⁴ and R⁵ are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, Ci-C₆-alkyl, C3-C6-cycloalkyl and Ci-C₆-haloalkyl.

In certain embodiments, the compound of formula I is a compound of formula VI:

wherein R^1a, R², R⁴, R⁵ and n are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula VII:

wherein X¹, X², X³, X⁴, X⁵, Z\ R^1a, R², R³, R⁴, R⁵, m and p are as described above for formula I; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and CrC₆-haloalkyl.

In certain embodiments, the compound of formula I is a compound of formula VIII:

wherein Z\ R^1a, R², R⁴, R⁵, m and p are as described above for formula I; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and CrC₆-haloalkyl.

In certain embodiments, the compound of formula I is a compound of formula IX:

wherein Z\ R¹ , R⁴, R⁵, m and p are as described above for formula I.

In certain embodiments, the compound of formula I is a compound of formula X:

wherein X¹ , X², X³, X⁵, R¹ , R³, R⁴ and R⁵ are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula XI:

wherein R¹ , R⁴ and R⁵ are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula XII:

wherein X¹ , X², X³, X⁴, X⁵, Y¹ , Z\ R¹ , R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; and x1 is an integer selected from 0, 1 , 2, 3, 4 and 5.

In certain embodiments, the compound of formula I is a compound of formula XIII:

wherein X¹ , X², X³, X⁵, Y¹ , Z\ R¹ , R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; and x1 is an integer selected from 0, 1 , 2, 3, 4 and 5.

In certain embodiments, the compound of formula I is a compound of formula XIV:

wherein X¹ , X², X³, X⁵, Z\ R^1a, R², R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; x1 is an integer selected from 0, 1 , 2, 3, 4 and 5; and wherein n is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula XV:

wherein X¹ , X², X³, X⁴, X⁵, Z\ R^1a, R², R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; x1 is an integer selected from 0, 1 , 2, 3, 4 and 5; and wherein n is independently an integer selected from 0, 1 , 2 and 3.

In certain embodiments, the compound of formula I is a compound of formula XVI:

wherein X¹ , X², X³, X⁵, Z\ R^1a, R², R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; x1 is an integer selected from 0, 1 , 2, 3, 4 and 5; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and CrC₆-haloalkyl.

In certain embodiments, the compound of formula I is a compound of formula XVII:

wherein X¹, X², X³, X⁴, X⁵, Z\ R^1a, R², R³, R⁴ and R¹² are as described above for formula I; and wherein x is independently an integer selected from 0, 1 , 2 and 3; x1 is an integer selected from 0, 1 , 2, 3, 4 and 5; y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and CrC₆-haloalkyl.

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

R¹ may be a 2-pyridyl group. R¹ may have the structure:

wherein n1 is an integer selected from 0 and 1 ; and wherein n is independently an integer selected from 0, 1 , 2 and 3. R¹ may be substituted with an OR² group (i.e. n1 may be 1). Where an OR² group is present, said OR² group may be situated ortho to the point of connection of R¹ to the rest of the molecule. R¹ may have the structure:

wherein n is independently an integer selected from 0, 1 , 2 and 3. It may be that R^1a is independently at each occurrence selected from Ci-C₄-alkyl, halo and OR⁸. It may be that R^1a is at least one occurrence OR^8a, wherein R^8a is independently selected from: H, Ci-C₆-alkyl, C3-C6-cycloalkyl and Ci-C₆-haloalkyl.

n may be an integer selected from 1 , 2 and 3. Where n is 1 or more, it may be that the R^1a group or at least one R^1a group (where there is more than 1 R^1a group) is situated ortho to the OR² group. The R^1a group situated ortho to the OR² group may be an OR^8a group

Thus, R¹ may have the structure

wherein y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, Ci-C₆-alkyl, C3-C6- cycloalkyl and Ci-C₆-haloalkyl.

R^8a may be independently selected from Ci-C₆-alkyl, C3-C6-cycloalkyl and Ci-C₆-haloalkyl. R^8a may be independently selected from Ci-C₆-alkyl and C3-C6-cycloalkyl. R^8a may be methyl or ethyl. R^8a may be methyl. n may be 0. Where n is 1 or more, it may be that the R^1a group or at least one R^1a group (where there is more than one R^1a group) is not situated ortho to the OR² group. Thus, R¹

may have the structure

wherein y is independently an integer selected from 0, 1 and 2. y may be 0.

R² may be H.

R² may be selected from C(0)R¹¹ , C(0)0R¹¹ , CH₂OC(0)R¹¹ and CH₂OC(0)OR¹¹.

R² may be selected from C(0)R¹¹ and CH₂OC(0)R¹¹. R² may be C(0)R¹¹ , e.g. C(0)Me. R² may be CH₂0C(0)R¹¹ , e.g. CH₂OC(0)Me.

R¹ may be a 4-pyridyl group.

R¹¹ may be unsubstituted alkyl. R¹¹ may be substituted with a single group selected from O-C1- C₄-alkyl and NH-Ci-C4-alkyl.

Y¹ may be S. Y¹ may be O.

R³ may be CrC4-alkyl. Preferably, however, R³ is H. X¹ may be NH. X¹ may be selected from O and S. X¹ may be S.

It may be that X², X³, X⁴ and X⁵ are each carbon. It may be that at least one of X², X³, X⁴ and X⁵ is nitrogen. It may be that a single one of X², X³, X⁴ and X⁵ is nitrogen. It may be that X⁵ is nitrogen. It may be that X⁵ is nitrogen and X², X³ and X⁴ are each carbon. It may be that X², X³ and X⁴ are each carbon and X⁵ is independently selected from carbon and nitrogen. It may be that R⁴, m, Z\ R⁵ and p are selected such that at least one R⁴or Z¹-R⁵ substituent has a molecular mass greater than 50. It may be that R⁴, m, Z\ R⁵ and p are selected such that at least one R⁴ or Z¹-R⁵ substituent has a molecular mass greater than 70. It may be that R⁴, m, Z\ R⁵ and p are selected such that at least one R⁴ or Z¹-R⁵ substituent has a molecular mass greater than 85. p may be 0. Where p is 0, m may be 0. It may be, however, that where p is 0, m is an integer selected from 1 , 2, 3 and 4. It may be that m is an integer selected from 1 , 2 and 3.

Preferably, p is not 0. p is preferably selected from 1 and 2. Most preferably, p is 1. Where p is 1 , the Z¹-R⁵ group may be situated para to the nitrogen of the ring comprising X¹. Alternatively, the Z¹-R⁵ group may be situated para to X¹.

, wherein x is independently an integer selected from 0, 1 , 2 and 3. In these embodiments, Z¹ may be O. In these embodiments, Z¹ may be absent.

Where p is 1 , the Z¹-R⁵ group may be situated para to X¹.

, wherein x is independently an integer selected from 0, 1 , 2 and 3. In these embodiments, Z¹ may be O. In these embodiments, Z¹ may be absent. p may be 2. Where p is 2, the Z¹-R⁵ groups may be situated para to the nitrogen of the ring comprising X¹ and para to X¹ , respectively. In these embodiments, Z¹ may at each occurrence be O. In these embodiments, Z¹ may at each occurrence be absent. x may be 0. x may be 1.

R⁴ may be independently at each occurrence selected from: cyano, nitro, Ci-C₄-alkyl, Ci-C₄- haloalkyl, halo and O-R⁸. R⁴ may be independently at each occurrence selected from: cyano, nitro, Ci-C₄-alkyl, halo and O-R⁸.

Z¹ may be at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, C(0)NR⁷, CR^7aR^7b, C(O), C(S), C=NOR^c, NR⁷C(0), S(0)₂NR⁷, NR⁷S(0)₂, CrCs-alkylene and NR⁷.

Z¹ may be independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, C(0)NR⁷, NR⁷C(0), S(0)₂NR⁷, NR⁷S(0)₂, CrCs-alkylene and NR⁷.

Z¹ may be independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, CrC3-alkylene and N(Ci-C₄-alkyl). Z¹ may be independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, CrC3-alkylene and N(Ci-C₄-alkyl). Z¹ may independently at each occurrence be selected from CrC3-alkylene, S, N(CrC₄-alkyl) and O. Z¹ may independently at each occurrence be selected from Ci-alkylene, S, N(CrC₄-alkyl) and O. Z¹ may independently at each occurrence be selected from Ci-alkylene, S, and O. Z¹ may independently at each occurrence be absent or selected from CrC3-alkylene and O. Z¹ may independently at each occurrence be absent or it may be O. Z¹ may, in at least one occurrence, be O. Z¹ may, at each occurrence, be O. Z¹ may, at each occurrence, be a group selected from Ci-alkylene, S, and O. Z¹ may, at each occurrence, be a group selected from S and O. Z¹ may, in at least one occurrence, be absent. Z¹ may, at each occurrence, be absent. Z¹ may, in at least one occurrence, be C(0)0. Z¹ may, at each occurrence, be C(0)0. Z¹ may, in at least one occurrence, be S. Z¹ may, at each occurrence, be S. Z¹ may, in at least one occurrence, be CrC3-alkylene. Z¹ may, at each occurrence, be CrC3-alkylene. Z¹ may, in at least one occurrence, be Ci-alkylene. Z¹ may, at each occurrence, be Ci-alkylene. Z¹ may, in at least one occurrence, be N(CrC4-alkyl). Z¹ may, at each occurrence, be N(CrC4-alkyl). Illustrative, Ci-alkylene groups that Zi may be include CH2, CH(OH), C(NHOR^a) and C(0).Z¹ may be CR^7aR^7b.

R^7a may, in at least one occurrence be phenyl. R^7a may at each occurrence be phenyl.

R^7b may, in at least one occurrence be H. R^7b may at each occurrence be H. R^7b may, in at least one occurrence be OR⁸, wherein OR⁸ is H. R^7b may at each occurrence be be OR⁸, wherein OR⁸ is H.

Z¹ may be C=NOR^c.

R^7c may, in at least one occurrence be Ci-C₆-cycloalkyl e.g. methyl. R^7c may at each occurrence be Ci-C₆-cycloalkyl e.g. methyl. R^7c may, in at least one occurrence be Ci-alkylene-R^7d, wherein R^7d is phenyl. R^7c may at each occurrence be Ci-alkylene-R^7d, wherein R^7d is phenyl.

R⁵ is independently at each occurrence selected from Cs-Cs-alkyl and Co-C3-alkylene-R^5a; wherein R^5a is independently at each occurrence selected from phenyl, 5- or 6- membered heteroaryl, 5-, 6-, 7- or 8- membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heterocycloalkyl or cycloalkyl group being monocyclic or bicyclic; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R¹² groups or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 4 R¹³ groups.

R⁵ may be ChhR⁵³. R⁵ may be R^5a.

R^5a may, in at least one occurrence, be optionally substituted phenyl, e.g. unsubstituted phenyl. R^5a may at each occurrence be optionally substituted phenyl, e.g. unsubstituted phenyl. R⁵ may, in at least one occurrence, be optionally substituted phenyl, e.g. unsubstituted phenyl. R⁵ may at each occurrence be optionally substituted phenyl, e.g. unsubstituted phenyl.

R⁵ may have the structure: herein x1 is an integer selected from 0, 1 , 2, 3, 4 and 5. t one occurrence, have the structure:

wherein x1 is an integer selected from 0, 1 , 2, 3, 4 and 5. x1 may be at least 1. x1 may be 0. R¹² may be independently at each occurrence selected from: cyano, nitro, Ci-C₄-alkyl, Ci-C₄- haloalkyl, halo and S-R⁹, O-R⁸. R¹² may be independently at each occurrence selected from: cyano, nitro, Ci-C₄-alkyl, halo and S-R⁹, O-R⁸. R¹² may be independently at each occurrence selected from: CrC₄-alkyl, CrC₄-haloalkyl and halo. R¹² may be independently at each occurrence halo e.g. fluro or chloro. R¹² may in one occurrence be situated para to Z¹. R⁵ may be optionally substituted heteroaryl, e.g. optionally substituted 6-membered heteroaryl. R⁵ may be optionally substituted pyridine. R⁵ may be independently selected from optionally substituted phenyl and optionally substituted pyridine.

R⁵ may be optionally substituted 5-, 6- 7, or 8 membered heterocycloalkyl. R⁵ may be optionally substituted 6-membered heterocycloalkyl, e.g. piperidine or piperazine. R⁵ may be optionally substituted Cs-Cs-cycloalkyl, e.g. bicyclic cycloalkyl.

R⁵ may have a structure selected from:

In certain illustrative embodiments, Z¹-R⁵ is O-Ph. In other illustrative embodiments, Z¹-R⁵ is Ph.

The compound of formula (I) may be selected from:

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

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

X¹ is independently selected from O, S and NR⁶;

Z¹ is independently at each occurrence absent or is selected from O, S, CrC3-alkylene and NR⁷;

R² is selected from H, C(0)R¹¹, C(0)0R¹¹, CH₂0C(0)R¹¹ and CH₂0C(0)0R¹¹;

R³, R⁶, R⁷ and R⁹ are each independently at each occurrence selected from: H, C3-C6-cycloalkyl and CrC₆-alkyl;

or where two R⁹ groups are attached to the same nitrogen atom, said R⁹ groups, together with said nitrogen atom form a 4-, 5-, 6- or 7- membered heterocycloalkyl ring;

R⁵ is independently at each occurrence Co-C3-alkylene-R^5a; wherein R^5a is independently at each occurrence selected from phenyl, 5- or 6- membered heteroaryl, 5-, 6- or 7- membered heterocycloalkyl ring and Cs-Cycycloalkyl; said heteroaryl or phenyl ring being optionally substituted with from 1 to 5 R¹² groups or said heterocycloalkyl or cycloalkyl ring being optionally substituted with from 1 to 4 R¹³ groups;

R¹¹ is Ci-C₆-alkyl, said alkyl group being optionally substituted with 1 to 4 R¹⁴ groups;

R¹⁴ is independently selected from C3-C6-cycloalkyl, halogen, OR⁸, SR⁹, cyano, C₂-C₆-alkenyl, C₂-C₆-alkynyl and NR⁹R¹⁰.

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

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

p is independently an integer selected from 0, 1 and 2;

wherein any aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including where two R⁹ groups or an R⁹ group and an R¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyl 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, CrC4-haloalkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, NR^aR^b, S(0)₂R^a, S(0)R^a, S(0)(NR^a)R^a, S(0)₂NR^aR^a, C0₂R^a, C(0)R^a, CONR^aR^a and OR^a;

wherein R^a is independently selected from H and CrC₄-alkyl; and R^b is independently H, Cr C₄-alkyl, C(0)-CrC₄-alkyl, S(0)₂-Ci-C₄-alkyl.

2. A compound of paragraph 1 , wherein n is 0. 3. A compound of paragraph 1 , wherein

has the structure

wherein y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and C1-C6- haloalkyl.

4. A compound of paragraph 3, wherein R^8a is independently selected from CrC₆-alkyl and C3-C6-cycloalkyl.

5. A compound of paragraph 1 , wherein

has the structure

wherein y is independently an integer selected from 0, 1 and 2;

6. A compound of any one of paragraphs 3 to 5, wherein y is 0. 7. A compound of any one of paragraphs 1 to 6, wherein R² is H.

8. A compound of one of paragraphs 1 to 6, wherein R² is selected from C(0)R¹¹, C(0)0R¹¹, CH₂OC(0)R¹¹ and CH₂OC(0)OR¹¹.

9. A compound of any one of paragraphs 1 to 7, wherein R³ is H.

10. A compound of any one of paragraphs 1 to 9, wherein X¹ is S. 11. A compound of any one of paragraphs 1 to 10, wherein each of X², X³, X⁴ and X⁵ is carbon.

12. A compound of any one of paragraphs 1 to 11 , wherein p is 0.

13. A compound of any one of paragraphs 1 to 11 , wherein p is 1. 14. A compound of paragraph 13, wherein the Z¹-R⁵ group is situated para to the nitrogen of the ring comprising X¹.

15. A compound of paragraph 13 or paragraph 14, wherein Z¹ is O.

16. A compound of paragraph 13 or paragraph 14, wherein Z¹ is absent. 17. A compound of any one of paragraphs 13 to 16, wherein R^5a is phenyl which is

optionally substituted with from 1 to 5 R¹² groups.

18. A compound of any one of paragraphs 13 to 16, wherein R⁵ is phenyl which is

optionally substituted with from 1 to 5 R¹² groups.

19. A compound of any one of paragraphs 13 to 18, wherein m is 0. 20. A compound of any one of paragraphs 1 to 18, wherein m is an integer selected from

1 , 2 and 3.

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

X¹ is independently selected from O, S and NH;

Y¹ is independently selected from O and S;

Z¹ is independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, C(0)NR⁷, NR⁷C(0), S(0)₂NR⁷, NR⁷S(0)₂, CrCs-alkylene and NR⁷;

R^1a, R⁴ and R¹² are each independently at each occurrence selected from CrC₆-alkyl, C Ce- haloalkyl, C₃-C₆-cycloalkyl, halogen, nitro, OR⁸, SR⁹, 0S(0)₂R⁹, S(0)₂R⁹, C(0)OR⁹, C(0)NR⁹R⁹, C(0)R⁹, S(0)₂NR⁹R⁹, S(0)(NR⁹)R⁹, S(0)R⁹, cyano, C₂-C₆-alkenyl, C₂-C₆-alkynyl, and NR⁹R¹⁰;

R² is selected from H, Ci-C₄-alkyl, C(0)R¹¹ , C(0)OR¹¹ , CH₂OC(0)R¹¹ and CH₂OC(0)OR¹¹ ; R³, R⁷ and R⁹ are each independently at each occurrence selected from: H, C3-C6-cycloalkyl and CrC₆-alkyl;

R⁵ is independently at each occurrence selected from C3-Cs-alkyl and Co-C3-alkylene-R^5a; wherein R^5a is independently at each occurrence selected from phenyl, 5- or 6- membered heteroaryl, 5-, 6-, 7- or 8- membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heterocycloalkyl or cycloalkyl group being monocylic or bicyclic; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R¹² groups or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 4 R¹³ groups;

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

p is independently an integer selected from 0, 1 and 2;

wherein any aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including where two R⁹ groups or an R⁹ group and an R¹⁰ group together with a nitrogen to which they are attached form a heterocycloalkyl 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, CrC4-haloalkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, NR^aR^b, S(0)₂R^a, S(0)R^a, S(0)(NR^a)R^a, S(0)₂NR^aR^a, C0₂R^a, C(0)R^a, CONR^aR^a and OR^a; wherein R^a is independently selected from H and Ci-C₄-alkyl; and R^b is independently H, Cr C₄-alkyl, C(0)-CrC₄-alkyl, S(0)₂-Ci-C₄-alkyl.

22. A compound of paragraph 1 , wherein R¹ has the structure

wherein n is independently an integer selected from 0, 1 , 2 and 3.

23. A compound of paragraph 2, wherein R¹ has the structure

wherein y is independently an integer selected from 0, 1 and 2; and R^8a is independently selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl and CrC₆-haloalkyl.

24. A compound of paragraph 3, wherein R^8a is independently selected from CrC₆-alkyl and C3-C6-cycloalkyl.

25. A compound of paragraph 3 or paragraph 4, wherein y is 0.

26. A compound of any one of paragraphs 1 to 5, wherein R² is H.

27. A compound of any one of paragraphs 1 to 5, wherein R² is selected from C(0)R¹¹, C(0)0R¹¹, CH₂OC(0)R¹¹ and CH₂OC(0)OR¹¹. 28. A compound of any one of paragraphs 1 to 5, wherein Y¹ is O.

29. A compound of any one of paragraphs 1 to 7, wherein R³ is H.

30. A compound of any one of paragraphs 1 to 9, wherein X¹ is selected from O and S.

31. A compound of any one of paragraphs 1 to 10, wherein each of X², X³ and X⁴ is carbon.

32. A compound of paragraph 11 , wherein X⁵ is carbon. 33. A compound of paragraph 11 , wherein X⁵ is nitrogen.

34. A compound of any one of paragraphs 1 to 13, wherein R⁴, m, Z\ R⁵ and p are selected such that the ring to which R⁴ and/or Z¹-R⁵ are attached is substituted with at least one group having a molecular mass greater than 50. 35. A compound of any one of paragraphs 1 to 14, wherein p is 1.

36. A compound of paragraph 15, wherein the Z¹-R⁵ group is situated para to the nitrogen of the ring comprising X¹.

37. A compound of any one of paragraphs 1 to 16, wherein Z¹ is selected from O, S and Cr alkylene.

38. A compound of paragraph 17, wherein Z¹ is O.

39. A compound of any one of paragraph 1 to 18, wherein R⁵ is R^5a.

40. A compound of any one of paragraph 1 to 18, wherein R⁵ is CFhR⁵³.

41. A compound of paragraph 19 or paragraphs 20, wherein R^5a is selected from optionally substituted phenyl and optionally substituted 6 membered heteroaryl.

42. 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 41 to seeds of plants, to plants themselves or to an area where it is intended that plants will grow.

43. A use of a compound of any one of paragraphs 1 to 41 to control fungal diseases of plants.

44. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of paragraphs 1 to 41.

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, tert- 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“alkylene” refers to a linear saturated divalent hydrocarbon chain. The alkylene groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkylene group independently may be Ci-C₄-alkyl, fluorine, OR^a or NHR^a. The term“haloalkyl” 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-chloroethyl 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 haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one fluorine atom. Thus, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen substituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.

The term“alkenyl” refers to a branched or linear hydrocarbon 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)p 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)p 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, benzothiazole, 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^aR^a, NR^aS(0)₂R^a, NR^aC(0)R^a, NR^aCONR^aR^a, NR^aC0₂R^a, OR^a, SR^a, S(0)R^a, S(0)₂OR^a, S(0)₂R^a, S(0)₂NR^aR^a _, C0₂R^a C(0)R^a, CONR^aR^a, CR^bR^bNR^aR^a, CR^bR^bOR^a, CrOalkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and CrC₄-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. 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. The compounds may also be obtained, stored and/or used in the form of an N-oxide. Also included are acid addition salts or base salts wherein the counter ion is optically active; for example, d-lactate or l-lysine, or racemic; for example, dl-tartrate or dl-arginine.

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

Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallisation 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 XVII and their syntheses, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

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

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

Throughout 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 the application of 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, atomising, 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 lattices, 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 colourants 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 for example by Rhizopus stolonifer; Sclerotinia diseases, caused for example by Sclerotinia sclerotiorum;

Verticilium diseases, caused for example by Verticilium alboatrum; Seed and soil borne decay, mould, wilt, rot and damping-off diseases such as: Alternaria diseases, caused for example by Alternaria brassicicola; Aphanomyces diseases, caused for example by Aphanomyces euteiches; Ascochyta diseases, caused for example by Ascochyta lentis; Aspergillus diseases, caused for example by Aspergillus flavus; Cladosporium diseases, caused for example by Cladosporium herbarum; Cochliobolus diseases, caused for example by Cochliobolus sativus (Conidiaform: Drechslera, Bipolaris Syn: Helminthosporium); Colletotrichum diseases, caused for example by Colletotrichum coccodes; Fusarium diseases, caused for example by Fusarium culmorum; Gibberella diseases, caused for example by Gibberella zeae; Macrophomina diseases, caused for example by Macrophomina phaseolina; Monographella diseases, caused for example by Monographella nivalis; Penicillium diseases, caused for example by Penicillium expansum; Phoma diseases, caused for example by Phoma lingam; Phomopsis diseases, caused for example by Phomopsis sojae; Phytophthora diseases, caused for example by Phytophthora cactorum; Pyrenophora diseases, caused for example by Pyrenophora graminea; Pyricularia diseases, caused for example by Pyricularia oryzae; Pythium diseases, caused for example by Pythium ultimum; Rhizoctonia diseases, caused for example by Rhizoctonia solani; Rhizopus diseases, caused for example by

Rhizopus oryzae; Sclerotium diseases, caused for example by Sclerotium rolfsii; Septoria diseases, caused for example by Septoria nodorum; Typhula diseases, caused for example by Typhula incarnata; Verticillium diseases, caused for example by Verticillium dahliae;

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

Blight diseases such as:

Monilinia diseases, caused for example by Monilinia laxa;

Leaf blister or leaf curl diseases such as: Exobasidium diseases caused for example by Exobasidium vexans; Taphrina diseases, caused for example by Taphrina deformans;

Decline diseases of wooden plants such as:

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

Eutypa dyeback, caused for example by Eutypa lata; Dutch elm disease, caused for example by Ceratocystsc ulmi; Ganoderma diseases caused for 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 certain specific fungal diseases.

Particular fungal diseases against which the compounds of the invention may be useful include: wheat leaf blotch (Septoria tritici), wheat brown rust (Puccinia triticina), wheat stripe rust (Puccinia striiformis), scab of apple (Venturia inaequalis), powdery mildew of grapevine (Uncinula necator), barley scald (Rhynchosporium secalis), blast of rice (Magnaporthe grisea), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminis f. sp. tritici), powdery mildew of barley (Blumeria graminis f. sp. hordei), powdery mildew of cucurbits (Erysiphe dehor acearum), anthracnose of cucurbits (Glomerella lagenarium), leaf spot of beet (Cercospora beticola), early blight of tomato (Alternaria solani), and spot blotch of barley (Cochliobolus sativus).

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 of administering a therapeutic amount of an antifungal agent of the invention to a subject (e.g. a human subject) in need thereof. The compound may be formulated for topical administration to the infected area of the body or it may be formulated for oral or parenteral administration.

The 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 editions);“Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions);“Organic Synthesis - The Disconnection Approach”, S Warren (Wiley), (1982 or later editions);“Designing Organic Syntheses” S Warren (Wley) (1983 or later editions);“Heterocyclic Chemistry”, J. Joule (Wley 2010 edition or later editions); (“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/her judgement and skill as to the most efficient sequence of reactions for the 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:

PyBOP - (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)

DIPEA - A/,A/-diisopropylethylamine TFAA - trifluoroacetic anhydride

NaHMDS - Sodium bis(trimethylsilyl)amide

aq. - aqueous cone. - concentrated

DCM - dichloromethane DMF - A/,/\/-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 74 below.

General Synthetic Schemes

Compounds of formula I can be made according to scheme A or scheme B. A carboxylic acid derivative A can be coupled with an amine B using traditional coupling agents to provide compounds of formula C (a subset of compounds of formula I). An illustrative coupling agent suitable for this reaction is PyBOP in the presence of a base (e.g. DIPEA) in a suitable solvent (e.g. DCM at room temperature).

Scheme A Carboxylic acid D can be reacted with a ketone, e.g. acetone or benzophenone (shown), (e.g. in the presence of TFA and TFAA at 60 °C) to provide ketal E. Reaction with an anion of amine B (e.g. the anion formed where B has been deprotonated with NaHMDS) under suitable conditions (e.g. THF at -40 °C to 0 °C) can provide compounds of formula F (a subset of compounds of formula I).

Scheme B

A number of routes to amine B can be envisaged. Certain of these are shown in Schemes C to G. Amino bromide G can be converted to thiourea H (e.g. using benzoylchloride, NhUSCN, Br₂, in acetone at reflux followed by 10% aqueous NaOH solution at reflux) which can be converted to amine J (a subset of amines of formula B), e.g. using Cul, CS2CO3, 1 ,10- phenanthroline in dioxane at reflux.

Scheme C Thiourea K can be converted to amine J, e.g. using either B¾ in CHC at 0 °C to reflux or Br2, AcOH and LiBr.

Scheme D Thiocyanate L can be converted to amine J, e.g. using either H2, Pd/C in acetic acid at room temperature or Fe/AcOH at room temperature.

Scheme E

Bicycle M can be aminated to form amine J, e.g. using tBu2Zn(TMP)Li, THF at room temperature followed by copper cyanide and BnONFh at room temperature.

Scheme F

Aminothiol N can react with compound O to form amine J, e.g. in THF at reflux.

Scheme G

A further subset of amine B, amines of formula S (in which x1 is an integer from 0 to 5) can be formed according to scheme H. Reaction of nitrofluoro compound P with phenol Q in the presence of a base (e.g. K2CO3 or NaH in DMF) can provide ether R. Reduction (e.g. with Pd/C and H2 in ethanol at room temperature or Fe, NH4CI in THF/methanol at 60 °C) followed by reaction with KSCN or NaSCN (e.g. in the presence of

in AcOH or methanol at 0 °C to room temperature) can provide amines S (a subset of amines B).

Scheme H

EXAMPLES

General Methods

Flash chromatography was carried out using a Biotage Isolera 4, with Biotage® SNAP KP-Sil cartridges, packed with 50 pm silica particles with a surface area of 500 m²/g, or alternative cartridges (e.g. Puriflash, produced by Interchim) where stated, or using silica gel (40-63 pm particles). Visualisation was carried out with UV light (254 nm) and by staining with either potassium permanganate, phosphomolybdic acid (PMA) or ninhydrin solutions.

All ¹H NMR spectra were obtained on a Bruker AVIII 400 with 5mm QNP or Bruker AVI 500 with 5mm QNP. Chemical shifts are expressed in parts per million (d) and are referenced to the solvent. Coupling constants 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 , 5 pm. Flow rate: 0.8 mL/min. Injection volume: 5 mI_.

Mobile Phase A H₂0

B CHsCN

C 50% H₂0 / 50% CHsCN + 1.0% ammonia (aq.)

Method B (15 minute basic pH)

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

Mobile Phase A H₂0

B CHsCN

C 50% H₂0 / 50% CHsCN + 1.0% ammonia (aq.)

Method C (5 minute acidic pH)

Column: YMC-Triart C18 50 x 2 mm, 5 pm. Flow rate: 0.8 mL/min. Injection volume: 5 pL. Mobile Phase A H₂0

B CHsCN

C 50% H₂0 / 50% CHsCN + 1.0% formic acid

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 7pm @ 50°C

Method F (3.5 minute acidic pH)

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

Column: CSH C 8 2.1 x 50mm, 1.7pm @ 50°C

All reagents were obtained from commercial suppliers and used as supplied unless otherwise stated. All compounds are named using ChemBioDraw Ultra 14.0.

3-Methoxy-2-methylaniline (0.33 mL, 2.5 mmol) and potassium thiocyanate (241 mg, 2.47 mmol) were dissolved in acetic acid (4.54 mL) and cooled to 0 °C. Bromine (0.190 mL, 3.69 mmol) was dissolved in acetic acid (1 5mL) and added to the mixture. The reaction was allowed to warm to r.t. and stirred for 1 h. A solution of 10% aq. NaS₂C>3 (5 mL) was added to the reaction and the precipitate formed was filtered, washed with water and dried in vacuo to obtain the title compound as a white solid (264 mg, 30 %). ¹H NMR d_H (500 MHz, DMSO-d⁶) 7.57 (s, 1 H), 5.73 (s, 2H), 3.74 (s, 3H), 2.10 (s, 3H). LCMS (Method C): 2.97 min, (275.1 , MH⁺).

Intermediate B: 4-Bromo-6-phenoxybenzo[d]thiazol-2-amine

4-Phenoxyaniline (1 0g, 5.4 mmol) and sodium thiocyanate (0.525 g, 6.48 mmol) were dissolved in MeOH (20 mL) and cooled to 0°C. Bromine (0.278 mL, 5.40 mmol) was added slowly dropwise and the reaction stirred at 0°C for 2h, then allowed to warm to r.t. and stirred for 18h. The solution was taken in NaOH (aq., 1 M) and extracted with DCM. The organics were extracted and dried over MgSC and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-70% EtOAc in PE) to yield the title compound as a cream solid (150 mg, 8.6 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 7.81 (s, 2H), 7.46 (d, J = 2.4 Hz, 1 H), 7.40 - 7.34 (m, 2H), 7.14 (d, J = 2.4 Hz, 1 H), 7.13 - 7.09 (m, 1 H), 7.00 - 6.96 (m, 2H). LCMS: (Method A) 1 .89 min, (322.9, MH⁺).

Intermediate C: 6-Phenylbenzo[d]thiazol-2-amine

Sodium thiocyanate (0.479 g, 5.91 mmol) and 4-aminobiphenyl (0.50 g, 3.0 mmol) were dissolved in acetic acid (5 mL) and bromine (0.190 mL, 3.69 mmol) was added slowly dropwise to the reaction mixture. The reaction was stirred at r.t. for 20 mins. The reaction was treated with a solution of 10% NaS₂C>3 (10 mL) and extracted with DCM. The organics were extracted and dried over MgSC and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE) and the title compound was isolated as a cream solid (40 mg, 6 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 7.99 (d, J = 1 .8 Hz, 1 H), 7.66 (dd, J = 8.3, 1 .1 Hz, 2H), 7.58 (s, 2H), 7.52 (dd, J = 8.3, 1 .9 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1 H), 7.34 - 7.29 (m, 1 H). LCMS: (Method A) 3.19 min, (227.2, MH⁺).

Intermediate D: 2,2-Diphenyl-4H-[1,3]dioxino[5,4-b]pyridin-4-one 2,2,2-trifluoroacetate

Benzophenone (262 mg, 1 .44 mmol) was added to a solution of 3-hydroxypyridine-2-carboxylic acid (100 mg, 0.72 mmol) in trifluoroacetic acid (0.6 ml_, 8 mmol)/trifluoroacetic acid anhydride (0.3 ml_, 2.3 mmol). After stirring for 18h at 60 °C, the reaction mixture was concentrated in vacuo. The resultant solid was slurried in Et20, filtered and dried under vacuum to yield the title compound as a black solid (185 mg, 62 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.28 (d, J = 5.3 Hz, 1 H), 7.80 - 7.73 (m, 2H), 7.63 - 7.52 (m, 7H), 7.45 - 7.39 (m, 3H). LCMS: (Method A) 2.50 min, (304.2, MH⁺).

Intermediate E: 8-Methoxy-2,2-dimethyl-4H-[ 1 ,3]dioxino[5,4-b]pyridin-4-one 2,2,2-trifluoroacetate

Acetone (4.4 mL, 59 mmol) was added slowly to a solution of 3-hydroxy-4-methoxy-2-pyridinecarboxylic acid (2.0 g, 12 mmol) in trifluoroacetic acid (10.0 mL, 130 mmol)/trifluoroacetic acid anhydride (5.3 mL, 38 mmol). After stirring for 1 h at r.t, further acetone (4.4 mL, 59 mmol) was added, and stirring continued for 3h. The reaction mixture was concentrated in vacuo. The resultant solid was slurried in Et₂0, filtered and dried under vacuum to yield the title compound as a pale yellow solid (4.0 g, quant.). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.57 (d, J = 6.3 Hz, 1 H), 7.50 (d, J = 6.4 Hz, 1 H), 4.04 (s, 3H), 1 .91 (s, 6H). LCMS: (Method A) 1 .32 min, (210.1 , MH⁺).

Intermediates F-G:

The following Intermediates were prepared using the general method described in

Intermediate E from the appropriate commercial pyridine.

Intermediate H: 1-(Benzy!oxy)-4-nitrobenzene

Sodium hydride (60 % in mineral oil) (0.198 g, 4.96 mmol) was suspended in DMF (5 mL) under nitrogen and cooled to 0 °C. Benzyl alcohol (0.42 mL, 4.1 mmol) was added, followed by 4- fluoronitrobenzene (0.50 g, 3.5 mmol) in DMF (2 mL). The reaction mixture was warmed to r.t. and stirred for 2h. After addition of the reaction mixture to water (~10 mL), the suspension was stirred for 15 min and filtered. The solid was washed with water, and dried under vacuum to yield the title compound as a yellow solid (808 mg, 99%). Ή NMR d_H (500 MHz, CDCb) 8.27 - 8.21 (m, 2H), 7.48 - 7.36 (m, 5H), 7.09 - 7.02 (m, 2H), 5.19 (s, 2H). LCMS: (Method A) 4.24 min, (mass not observed).

Intermediates l-K:

The following Intermediates were prepared using the general method described in Intermediate H from commercial materials.

1 ,3-Dichloro-2-fluoro-5-nitrobenzene (0.50 g, 2.4 mmol) and phenol (0.25 g, 2.6 mmol) were dissolved in DMF (5 mL). Potassium carbonate (0.66 g, 4.7 mmol) was added, and the reaction heated to 100 °C for 2h. After addition of the reaction mixture to water (~20 mL), the suspension was stirred for 15 min, and filtered. The solid was washed with water, and dried under vacuum to yield the title compound as a pale orange solid (695 mg, quant.). Ή NMR d_H (500 MHz, CDCb) 8.34 (s, 2H), 7.39 - 7.31 (m, 2H), 7.18 - 7.12 (m, 1 H), 6.88 - 6.82 (m, 2H).

LCMS: (Method A) 4.33 min, (mass not observed).

Intermediates M-T:

The following Intermediates were prepared using the general method described in Intermediate L from commercial materials.

Intermediate J (787 mg, 2.95 mmol) was dissolved in THF (8 mL) under nitrogen. The solution was cooled to 0 °C and sodium hydride (60 % in mineral oil) (142 mg, 3.54 mmol) was added. After stirring for 15 mins, iodomethane (0.28 mL, 4.4 mmol) was added. After stirring for 2h the reaction was quenched with water and extracted with EtOAc. The combined organics were washed (brine), dried (MgSC ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-40% EtOAc in PE) to yield the title compound as an orange oil (605 mg, 73 %). ¹H NMR 6H (500 MHz, CDCI3) 8.25 - 8.17 (m, 2H), 7.44 - 7.29 (m, 2H), 7.23 - 7.1 1 (m, 1 H), 7.14 - 7.08 (m, 2H), 3.34 (s, 3H); LCMS: (Method A) 4.09 min, (281 .0, MH⁺).

10% Palladium on carbon (0.185 g) was suspended in EtOH (10 mL). A solution of Intermediate I (0.979 g, 3.48 mmol) in EtOH (10 mL) was added, and the system put under a hydrogen balloon for 3h. The suspension was filtered through Dicalite®, washing with EtOAc. The combined filtrates were concentrated in vacuo to yield the title compound as a brown solid (861 mg, 98%). ¹H NMR 6H (500 MHz, DMSO-d⁶) 7.62 (dd, J = 8.6, 6.3 Hz, 1 H), 7.51 (dd, J = 8.9, 2.6 Hz, 1 H), 7.26 (td, J = 8.5, 2.6 Hz,

1 H), 6.83 - 6.76 (m, 2H), 6.68 - 6.62 (m, 2H), 5.96 (br s, 2H), 5.00 (s, 2H); LCMS: (Method A) 3.63 min, (252.1 , MH⁺).

Intermediate H (808 mg, 3.52 mmol) was dissolved in a mixture of THF (10 ml_) and MeOH (5 ml_). Ammonium chloride (566 mg, 10.6 mmol) was dissolved in water (2 ml_) and added to the reaction mixture along with iron (591 mg, 10.6 mmol). The reaction mixture was heated to 50 °C for 18h. After cooling to r.t., the mixture was filtered through Dicalite®, washing with EtOAc. The filtrate was washed with water, and the aqueous layer extracted with EtOAc. The combined organics were washed (brine), dried (MgS0₄) and concentrated in vacuo to yield the title compound as a yellow solid (609 mg, 87%). Ή NMR d_H (500 MHz, DMSO-d⁶) 7.45 - 7.35 (m, 4H), 7.34 - 7.27 (m, 1 H), 6.75 - 6.69 (m, 2H), 6.53 - 6.47 (m, 2H), 4.94 (s, 2H), 4.62 (br s, 2H); LCMS: (Method A) 3.32 min, (200.2, MH⁺).

Intermediates X-AH:

The following Intermediates were prepared using the general method described in Intermediate W from the appropriate intermediate.

4-(3-Chlorophenoxy)aniline (0.50 g, 2.3 mmol) and sodium thiocyanate (0.37 g, 4.5 mmol) were dissolved in MeOH (5 ml_) and cooled to 0°C. Bromine (190 mI_, 3.69 mmol) was added slowly dropwise and the reaction allowed to warm to r.t. and stirred for 18h. The solution was concentrated in vacuo, and the residue partitioned between DCM and sat. aq. NaHCC>3. The aqueous layer was extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-50% EtOAc in PE) to yield the title compound as a cream solid (234 mg, 37 %). Ή NMR d_H (500 MHz, CDCI3) 7.56 (d, J = 8.7 Hz, 1 H), 7.30 - 7.25 (m, 2H), 7.12 - 7.07 (m, 2H), 7.01 - 6.97 (m, 1 H), 6.92 - 6.88 (m, 1 H), 3.37 - 2.85 (br s, 2H); LCMS: (Method A) 3.56 min, (277.0, MH⁺).

Sodium thiocyanate (0.37 g, 4.5 mmol) was dissolved in MeOH (5 ml_) and cooled to 0 °C. Bromine 190 mI_, 3.69 mmol) was added slowly dropwise and the reaction stirred for 5 mins. 4-(2- fluorophenoxy)aniline (0.50 g, 2.45 mmol) was added, and reaction mixture allowed to warm to r.t. and stirred for 18h. The solution was concentrated in vacuo, and the residue partitioned between DCM and sat. aq. NaHC03. The aqueous layer was extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0- 50% EtOAc in PE) to yield the title compound as a yellow solid (441 mg, 69 %). ¹H NMR 6H (500 MHz, CDCI3) 7.51 (d, J = 8.8 Hz, 1 H), 7.23 (d, J = 2.5 Hz, 1 H), 7.22 - 7.18 (m, 1 H), 7.14 - 7.09 (m, 2H), 7.07 - 7.00 (m, 2H), 5.89 - 5.17 (br s, 2H); LCMS: (Method A) 3.28 min, (261 .3, MH⁺).

Intermediate AK: (2-Aminobenzo[d]thiazol-6-yl)(phenyl)methanone

4-Aminobenzophenone (1 .0 g, 5.1 mmol) and potassium thiocyanate (1 .72 g, 17.8 mmol) were dissolved in glacial acetic acid (10 mL). The solution was cooled to 0 °C. Bromine liquid (0.26 ml_, 5.6 mmol) was dissolved in glacial acetic acid (4 mL) and added dropwise to the solution, maintaining a reaction temperature below 25 °C. After addition was completed, the reaction mixture was stirred overnight at r.t. The reaction mixture was neutralised with ammonium hydroxide (~20 mL) under cooling. The product was collected on the filter, washed with water (~10 mL) and cold EtOAc (~20 mL), and dried in vacuo to give the title compound as a yellow solid (956 mg, 74%). ¹H NMR 6H (500 MHz, DMSO-d⁶) 8.13 (s, 1 H), 7.71 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1 H),

6.61 (br s, 2H); LCMS (Method C): 2.76 min, (255.0, MH⁺).

Intermediate AL: 4-Bromo-6-(2-chlorophenoxy)benzo[d]thiazol-2-amine

Sodium thiocyanate (249 mg, 3.07 mmol) was dissolved in MeOH (5 mL) and cooled to 0 °C. Bromine 0.56 mL, 2.6 mmol) was added slowly dropwise and the reaction stirred for 5 min. 4-(2- Chlorophenoxy)aniline (562 mg, 2.56 mmol) was added, and reaction mixture allowed to warm to r.t. and stirred for 18h. The solution was concentrated in vacuo and the residue partitioned between DCM and sat. aq. NaHCC>3. The aqueous layer was extracted with DCM. The combined organics were dried (MgSC ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-40% EtOAc in PE) to yield the title compound as a dark yellow solid (230 mg, 25%). LCMS (Method C) 2.86 min, (357.0, MH⁺).

Intermediate AM: 6-(2-Chlorophenoxy)benzo[d]thiazol-2-amine

Intermediate AL (230 mg, 0.65 mmol) was dissolved in EtOH (15 mL) and H2O (5 mL). Zinc dust (85 mg, 3.9 mmol) was added along with KOH (36.3 mg, 1 .94 mmol). The reaction was stirred at r.t for 60h. After this time the reaction was filtered through Dicalite® and washed through with EtOH. The filtrate was concentrated in vacuo and the residue was purified by chromatography (S1O2 0-40% EtOAc in PE) which yielded the title product as a yellow oil (51 mg, 29%).

Ή NMR d_H (500 MHz, CDCI3) 7.50 (d, J = 8.8 Hz, 1 H), 7.48 (dd, J = 8.0, 1 .5 Hz, 1 H), 7.24 - 7.19 (m, 2H), 7.08 (td, J = 8.0, 1 .5 Hz, 1 H), 7.02 (dd, J = 8.8, 2.5 Hz, 1 H), 6.96 (dd, J = 8.0, 1 .5 Hz, 1 H), 5.57 (br s, 2H); LCMS (Method C): 2.86 min, (277.6, MH⁺).

Intermediate AN: (2-Aminobenzo[d]thiazol-6-yl)(phenyl)methanol

Intermediate AK (688.0 mg, 2.7 mmol) was taken up in MeOH (15 mL) and cooled to 0 °C and NaBH₄ (0.409 g, 10.8 mmol) added. The suspension was allowed to warm to r.t. and stirred for 16 h. Aqueous NH4CI sat. (10 mL) was added slowly and the mixture concentrated to 10% volume. The reaction mixture was taken up in EtOAc (~10 mL) and H2O (~10 mL) and extracted into EtOAc (3 x 10 mL). The organic layer was dried (MgS0₄), and concentrated in vacuo to yield the title compound as a yellow solid (410.1 mg, 59%).

Ή NMR d_H (500 MHz, CDCI3) 7.66 (s, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.38 (m, 7H), 5.94 (s, 1 H), 5.53 (br s, 2H); LCMS (Method C): 1 .85 min, (257.5, MH⁺).

Intermediate AO: (2-Aminobenzo[d]thiazol-6-yl)(phenyl)methanone oxime

A solution of Intermediate AK (200 mg, 0.79 mmol) in EtOH (10 ml_) was treated with hydroxylamine (0.39 ml_, 6.3 mmol) and 1 M aq. hydrochloric Acid (1 .42 ml_, 2.84 mmol) and heated to 75 °C for 16h. The mixture was allowed to cool to r.t and diluted with H2O (~20 ml_) and saturated aq. NaHCOs solution (~ 20 mL, to pH 8), then extracted with EtOAc (3 x 20 ml_). The organics were washed with water (2 x 30 ml_) and brine (1 x 10 mL), dried (MgS0₄) and concentrated to afford crude product as a gum. The residue was purified by chromatography (S1O2, eluting with 0-40% EtOAc in PE) which yielded the title compound as a yellow solid (70 mg, 33%). Ή NMR d_H (500 MHz, Methanol-c ) 6.08 (m, 1 H), 5.96 - 5.83 (m, 4H), 5.83 - 5.71 (m, 3H). LCMS (Method C): 2.38 min, (270.2, MH⁺). Intermediates AP-BK:

The following intermediates were prepared using the general method described in Intermediate A/ from commercial anilines or appropriate Intermediates.

Benzyl bromide (129 mI_, 1 .08 mmol) was added dropwise to a solution of 2-amino-benzothiazole-6- carboxylic acid (200 mg, 1 .03 mmol) in acetonitrile (10 ml_) and the mixture was stirred at r.t. for 18h. The reaction mixture was diluted with water and stirred for 15 mins. The yellow precipitate was filtered, washed (water) and triturated in minimal Et₂0. After drying under vacuum the title compound was isolated as a yellow solid (178 mg, 61 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.34 (t, J = 7.7 Hz, 1 H), 7.93 (s, 2H), 7.88 - 7.81 (m, 1 H), 7.54 - 7.46 (m, 2H), 7.45 - 7.32 (m, 4H), 5.33 (s, 2H).

LCMS (Method C): 2.99 min (285.2, MH⁺).

Intermediate BM: Isopropyl 2-aminobenzo[d]thiazole-6-carboxylate

To a solution of 2-amino-benzothiazole-6-carboxylic acid (200 mg, 1 .03 mmol) in 2-propanol (5 ml_) at 0 °C was added a few drops of cone sulfuric acid. The reaction mixture was heated to reflux for 24h, then cooled to r.t.. The reaction mixture was basified with 1 M NaOH and extracted with EtOAc. The combined organics were washed (brine), dried (MgSC ) and concentrated in vacuo to afford the title compound as a white solid (172 mg, 71 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.32 - 8.08 (m, 1 H), 7.90 (s, 2H), 7.81 (dd, J = 8.4, 1 .8 Hz, 1 H), 7.42 - 7.26 (m, 1 H), 5.21 - 5.01 (m, 1 H), 1 .32 (d, J = 6.3 Hz, 6H); LCMS (Method C): 2.61 min, (237.1 , MH⁺).

Intermediate BN: Methyl (5-phenoxy-1H-benzo[d]imidazol-2-yl)carbamate

To a solution of Intermediate AC (395 mg, 1 .97 mmol) in EtOH (10 mL) was added 1 ,3- bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (427 mg, 2.07 mmol), and the mixture was heated to reflux for 18h. After cooling to r.t., Et_å0 was added and the resultant solid collected by filtration (washing with EtOH/Et₂0) to afford the title compound as an off-white solid (436 mg, 78%). ¹H NMR 6H (500 MHz, DMSO-d⁶) 1 1 .61 (br s, 2H), 7.40 (d, J = 8.5 Hz, 1 H), 7.38 - 7.32 (m, 2H), 7.09 - 7.03 (m, 2H), 6.97 - 6.92 (m, 2H), 6.81 (dd, J = 8.5, 2.4 Hz, 1 H), 3.75 (s, 3H); LCMS (Method A): 3.24 min, (284.2, MH⁺). Intermediate BO: 5-Phenoxy-1H-benzo[d]imidazol-2-amine

To a suspension of Intermediate BN (435 mg, 1 .54 mmol) in MeOH (10 mL) was added sodium hydroxide (2M aq) (10 mL, 20 mmol), and the mixture heated to reflux for 6h. After cooling to r.t., the mixture was concentrated in vacuo to remove MeOH. The residue was partitioned between EtOAc and brine, and the aqueous layer extracted with EtOAc. The combined organics were washed (brine), dried (MgS0₄) and concentrated in vacuo to afford the title compound as a pale brown solid (317 mg, 92%). Ή NMR d_H (500 MHz, CDCb) 7.26 - 7.20 (m, 2H), 7.06 (d, J = 8.5 Hz, 1 H), 7.02 - 6.98 (m, 1 H), 6.91 - 6.85 (m, 3H), 6.68 (dd, J = 8.5, 2.2 Hz, 1 H), 6.19 (br s, 3H); LCMS (Method A): 2.78 min, (226.2, MH⁺).

Intermediate BP: 2-(Benzyloxy)-4-fluoro-1-nitrobenzene

5-Fluoro-2-nitrophenol (5.00 g, 31 .8 mmol) was dissolved in DMF (50 mL) and benzyl bromide (4.16 mL, 35.0 mmol) and potassium carbonate (5.28 g, 38.2 mmol) were added. The reaction was heated to 60 °C for 3h. The reaction was cooled and partitioned between water and EtOAc, and the organics extracted and washed with brine. The organics were dried (MgSC ) and concentrated in vacuo to give the title compound in quantitative yield. ¹H NMR 6H (500 MHz, CDCI3) 7.92 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.43 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.31 (q, J = 7.1 Hz, 1 H), 6.81 (dd, J = 10.2, 2.5 Hz,

1 H), 6.70 (ddd, J = 9.8, 7.3, 2.5 Hz, 1 H), 5.18 (s, 2H). LCMS (Method A): 1 .93 min.

Intermediate BQ: 2-(Benzyioxy)-1-nitro-4-phenoxybenzene

Intermediate BP (3.00 g, 12.13 mmol) was dissolved in DMF (100 mL) and potassium carbonate (1 .68 g, 12.1 mmol) and phenol (1 .14 g, 12.1 mmol) added. The reaction was heated to 100 °C for 18h. The reaction was cooled and diluted with water. The product precipitated out of solution and was filtered off and washed with water and dried in vacuo to give the title compound (2.37g, 61 %). ¹H NMR 6H (500 MHz, CDCI3) 7.97 (d, J = 9.1 Hz, 1 H), 7.47 - 7.32 (m, 5H), 7.31 - 7.25 (m, 2H), 7.05 (dd, J = 8.6, 1 .0 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1 H), 6.54 (dd, J = 9.1 , 2.4 Hz, 1 H), 5.17 (s, 3H); LCMS (Method A): 2.20 min, (320.2, MH ). Intermediate BR: 2-Amino-5-phenoxyphenoi

Intermediate BQ (2.37 g, 7.38 mmol) was dissolved in ethanol (10 ml_) and the reaction was degassed. 10% Palladium on carbon (400 mg) was added and the reaction degassed and placed under a balloon of hydrogen. The reaction was stirred at r.t. for 18h. The reaction was filtered through Dicalite® and concentrated in vacuo to give the title compound as a brown solid (1 .40 g, 94 %). ¹H NMR 6H (500 MHz, CDCI₃) 7.25 (dd, J = 7.1 , 1 .5 Hz, 2H), 7.04 - 6.98 (m, 1 H), 6.95 - 6.89 (m, 2H), 6.69 (d, J = 8.3 Hz, 1 H), 6.49 - 6.39 (m, 2H), 3.83 (s, 2H). LCMS (Method A): 2.83 min, (202.9, MH⁺).

Intermediate BS: 6-Phenoxybenzo[d]oxazol-2-amine

A solution of Intermediate BR (500 mg, 2.48 mmol) in MeOH (10 ml_) was cooled to 0 °C and cyanogen bromide (263 mg, 2.48 mmol) was added. The reaction was stirred for 18h at r.t.. The reaction was quenched with sodium thiosulfate (10% solution) and extracted with DCM. The organics were dried (MgSC ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-50% EtOAc in PE) and the title compound isolated as a brown solid (270mg, 48 %). ¹H NMR 6H (500 MHz, CDCI3) 7.35 - 7.31 (m, 1 H), 7.31 - 7.27 (m, 2H), 7.07 (tt, J = 7.6, 1 .1 Hz, 1 H), 7.00 (d, J = 2.3 Hz, 1 H), 6.98 (dd, J = 8.2, 1 .5 Hz, 2H), 6.91 (dd, J = 8.5, 2.3 Hz, 1 H), 5.40 (s, 2H); LCMS (Method A): 3.12 min, (227.6, MH⁺).

Intermediate BT: 4-Bromo-6-(o-tolyloxy)benzo[d]thiazol-2-amine

A solution of sodium thiocyanate (0.479 g, 5.91 mmol) in MeOH (1 OmL) was cooled to 0 °C and bromine (0.19 mL, 3.7 mmol) added slowly dropwise and the reaction stirred for 5 mins before adding 4- (2-methylphenoxy)aniline (1 .00 g, 5.02 mmol). The reaction was stirred at r.t. for 6h. A solution of 10% sodium thiosulfate was added and a precipitate formed. This precipitate was filtered off and dried in vacuo and dissolved in DCM, and washed with NaHC03 (sat. aq). The organics were extracted and dried over MgSCU and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0- 50% EtOAc in PE) and the title compound isolated as a cream solid. ¹H NMR 6H (500 MHz, DMSO-d⁶) 7.75 (s, 2H), 7.32 (d, J = 2.4 Hz, 1 H), 7.32 - 7.29 (m, 1 H), 7.19 (td, J = 7.9, 2.1 Hz, 1 H), 7.07 (td, J =

7.4, 1 .1 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 2.20 (s, 3H); LCMS (Method A): 3.89 min, (337.0, MH⁺).

3-Hydroxy-4-methoxy-2-pyridinecarboxylic acid (50 mg, 0.3 mmol) was added to a solution of Intermediate A (121 mg, 0.443 mmol), DIPEA (0.26 ml_, 1 .5 mmol) in DCM (3 ml_). (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (169 mg, 0.35 mmol) was added and the mixture stirred at r.t. for 18h. The reaction was treated with water (5 ml_) and partitioned with DCM (5 ml_). The organics were extracted and dried over MgSC and concentrated in vacuo. The residue was purified by flash column chromatography (S1O2, 0-15% MeOH in DCM) to afford the title compound as a beige solid (25 mg, 18%). Ή NMR d_H (500 MHz, CDCI3) d 1 1 .73 (s, 1 H), 9.72 (s, 1 H), 8.09 (d, J = 5.2 Hz, 1 H), 7.74

(s, 1 H), 6.96 (d, J = 5.2 Hz, 1 H), 3.99 (s, 3H), 3.86 (s, 3H), 2.32 (s, 3H); LCMS (Method C): 3.94 min (424.1 /426.1 , MH⁺).

Examples 2-28:

The following Examples were prepared using the general method described for Example 1 from the corresponding prepared or commercially available aminobenzothiazole, with the appropriately substituted pyridinecarboxylic acid.

Example 29: 3-Hydroxy-N-(6-phenoxy-1H-benzo[d]imidazol-2-yl)picolinamide

3-Hydroxypyridine-2-carboxylic acid (74 mg, 0.53 mmol) was added to a solution of Intermediate BO (100 mg, 0.44 mmol) and DIPEA (0.16 mL, 0.89 mmol) in DCM (5 mL). (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (231 mg, 0.444 mmol) was added and the mixture stirred at r.t. for 1 week. The reaction mixture (suspension) was treated with water (5 mL) and filtered. The solid was washed (DCM) and dried under vacuum to afford the title compound as a pale yellow solid (42 mg, 27%). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.21 (br s, 1 H), 7.54 - 7.47 (m, 2H), 7.46 - 7.35 (m, 3H), 7.16 (d, J = 2.3 Hz, 1 H), 7.14 - 7.09 (m, 1 H), 7.00 (d, J = 7.7 Hz, 2H), 6.95 (dd, J = 8.6, 2.3 Hz, 1 H). LCMS (Method A): 2.24 min, (347.2 MH⁺).

Example 30: Isopropyl 2-(3-hydroxypicolinamido)benzo[d]thiazole-6-carboxylate

To a mixture of Intermediate BM (70 mg, 0.30 mmol) and Intermediate D (155 mg, 0.370 mmol) in THF (2.5 mL) at -40 °C was added sodium bis(trimethylsilyl)amide solution (2M in THF) (0.37 mL, 0.74 mmol). The mixture was allowed to warm to r.t. over 3h, then quenched with aq. NH4CI. The resultant suspension was filtered, and the solid washed (water), slurried (EtOH) and dried under vacuum to afford the title compound as a grey solid (1 1 mg, 10 %). ¹H NMR 6H (500 MHz, DMSO-d⁶) 12.59 (br s,

1 H), 10.95 (br s, 1 H), 8.70 (d, J = 1 .4 Hz, 1 H), 8.23 (br s, 1 H), 8.04 (dd, J = 8.5, 1 .8 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.63 (dd, J = 8.5, 4.4 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 5.27 - 5.1 1 (m, 1 H), 1 .36 (d, J = 6.3 Hz, 6H). LCMS (Method A): 2.34 min, (358.1 MH⁺). Example 31: N-(6-(Benzyloxy)benzo[d]thiazol-2-yl)-3-hydroxypicolinamide

To a mixture of Intermediate BL (50 mg, 0.20 mmol) and Intermediate F (86 mg, 0.29 mmol) in THF (2 mL) at r.t. was added sodium bis(trimethylsilyl)amide solution (2M in THF) (0.39 ml_, 0.78 mmol). The mixture stirred for 3h, then quenched with water. The resultant suspension was filtered, and the solid washed (water), slurried (EtOH) and dried under vacuum to afford the title compound as an orange solid (21 mg, 28 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 12.21 (br s, 1 H), 1 1 .03 (br s, 1 H), 8.24 (s, 1 H), 7.73 (d, J = 2.5 Hz, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.61 (dd, J = 8.5, 4.4 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.50 - 7.45 (m, 2H), 7.44 - 7.37 (m, 2H), 7.37 - 7.30 (m, 1 H), 7.15 (dd, J = 8.8, 2.6 Hz, 1 H), 5.16 (s,

2H); LCMS (Method A): 2.60 min, (378.1 MH⁺).

Examples 32-67:

The following Examples were prepared using the general method (using either DMF or THF as solvent) described in Example 31 from the appropriate intermediates.

To a solution of Example 52 (40 mg, 97 pmol) in DMF (1 mL) at r.t. was added potassium carbonate (20.1 mg, 146 pmol) and bromomethyl acetate (14 pL, 15 pmol). The mixture was stirred for 2h, then further bromomethyl acetate (10 pl_, 97 pmol) and catalytic sodium iodide (1 .5 mg, 10 pmol) were added. The mixture was stirred for 1 h, and then concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE then 0-20% MeOH in EtOAc) to afford the title compound as a yellow solid (14 mg, 30 %). Ή NMR d_H (500 MHz, DMSO-d⁶) 8.31 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 2.5 Hz, 1 H), 7.29 (d, J = 6.8 Hz, 1 H), 7.27 - 7.20 (m, 2H), 7.14 (dd, J = 8.7, 2.5

Hz, 1 H), 7.09 (dd, J = 9.2, 4.5 Hz, 2H), 6.70 (s, 2H), 4.05 (s, 3H), 2.08 (s, 3H). NH not observed; LCMS (Method A): 2.89 min, (484.0 MH⁺).

Acetic anhydride (0.63 mL, 6.7 mmol) was added to a solution of Example 50 (150 mg, 0.336 mmol) in pyridine (1 mL) and stirred at r.t. for 1 h. The reaction was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography (S1O2, 10-100% EtOAc in PE) and the title compound was isolated as a cream solid (60 mg, 37%). ¹H NMR 6H (500 MHz, DMSO-d⁶) 12.36 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 9.0, 2.7 Hz, 2H), 7.51 (d, J = 5.6 Hz, 1 H), 7.31 - 7.19 (m, 2H), 7.13 (dd, J = 8.8, 2.6 Hz, 1 H), 3.95 (s, 3H), 2.33 (s, 3H); LCMS (Method A): 3.89 min, (488.0, MH⁺). Example 70: ((4-Methoxy-2-((6-phenoxybenzo[d]thiazol-2-yl)carbamoyl)pyridin-3-yl)oxy)methyl acetate

Bromomethyl acetate (29.2 mg, 0.191 mmol) was added to a solution of Example 4 (50.0 mg, 0.13 mmol) and potassium carbonate (17.56 mg, 0.127) in DMF (1 ml_). The reaction mixture was stirred at r.t. for 2h and the solids filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography (S1O2, 0-20% MeOH in EtOAc) which yielded the title product as a beige solid (7.2 mg, 12%). Ή NMR d_H (500 MHz, DMSO-d⁶) 15.63 (s, 1 H), 7.77 - 7.69 (m, 3H), 7.43 - 7.34 (m, 2H), 7.14 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 6.48 (s, 2H), 3.34 (s, 3H - under the water peak), 2.03 (s, 3H); LCMS (Method C): 3.24 min, (466.2, MH⁺).

Example 71:

The following Example was prepared using the general method described in Example 69 from Example 4.

Example 72: 3-Methoxy-N-(6-phenoxybenzo[d]thiazol-2-yl)picolinamide

/V,/V-Diisopropylethylamine (72 mI, 0.41 mmol) and HATU (1 18 mg, 0.310 mmol) were added to a solution of 6-phenoxybenzo[d]thiazol-2-amine (50 mg, 0.21 mmol) and 3-methoxypyridine-2-carboxylic acid (32 mg, 0.21 mmol) in acetonitrile (1 ml_). The mixture was stirred at r.t. for 3h, then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were dried (MgSC ) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-100% EtOAc in PE) to yield the title compound as a pale yellow solid (42 mg, 54%).) ¹H NMR 6H (500 MHz, DMSO-d⁶) 12.52 (s, 1 H), 8.27 (dd, J = 4.5, 1 .1 Hz, 1 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.75 - 7.69 (m, 2H), 7.62 (dd, J = 8.6, 4.5 Hz, 1 H), 7.44 - 7.36 (m, 2H), 7.20 - 7.1 1 (m, 2H), 7.07 - 7.01 (m, 2H), 3.91 (s, 3H); LCMS (Method A): 3.39 min, (378.1 MH⁺).

Examples 73-74: The following Examples were prepared using the general method described in Example 72 from commercial materials.

Intermediates BU-CH:

Intermediates CI-DE:

Intermediate DF: 2'-Chloro-2-(2-chloro-4-fluorophenoxy)-5-nitro-1,1 '-biphenyl

Intermediate CQ (300 mg, 0.866 mmol) and 2-chlorobenzeneboronic acid (162 mg, 1.04 mmol) were dissolved in dioxane (3 ml). Sodium carbonate (2 M aq) (1.73 ml, 3.46 mmol) was added and the mixture degassed by nitrogen bubbling for 5 min.

Tetrakis(triphenylphosphine)palladium (100 mg, 87 mhioI) was added, and the reaction was heated to 120 °C under microwave conditions for 30 min. The reaction was filtered through decalite®, eluting with EtOAc, and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-20% EtOAc in PE) and the title compound was isolated as a yellow oil (327 mg, quant.)

¹ H NMR d_H (500 MHz, CDC ) 8.28 (d, J = 2.8 Hz, 1 H), 8.21 (dd, = 9.1 , 2.8 Hz, 1 H), 7.56 - 7.50 (m, 1 H), 7.48 - 7.44 (m, 1 H), 7.42 - 7.38 (m, 2H), 7.23 (dd, J = 7.9, 3.0 Hz, 1 H), 7.18 - 7.13 (m, 1 H), 7.08 - 7.01 (m, 1 H), 6.72 (d, J = 9.1 Hz, 1 H); LCMS (Method E): 2.35 min (mass not observed).

Intermediates DG-DI:

The following Intermediates were prepared using the general method described in

Intermediate DF from the appropriate intermediate.

Intermediate DJ: 2-chloro-4-fluoro-1-(2-(4-fluorophenoxy)-4-nitrophenoxy)benzene

Intermediate CQ (500 mg, 1.44 mmol) and 4-fluorophenol (194 mg, 1.73 mmol) were dissolved in DMF (5 ml). Potassium carbonate (399 mg, 2.89 mmol) was added, and mixture degassed by nitrogen bubbling for 5min, before Copper(l) chloride (28.6 mg, 0.289 mmol) was added. The reaction was heated to 200 °C under microwave conditions for 1 h. After cooling to r.t., the reaction mixture was partitioned between Et₂0 and water. The aqueous layer was extracted with Et₂0. The combined organics were washed (water, 1 N NaOH, water), dried (MgSCU) and concentrated in vacuo. The residue was purified by chromatography (Si0₂, 0- 20% EtOAc in PE) and the title compound was isolated (still impure) as a brown oil (281 mg, <

52%). Used without further purification.

¹H NMR d_H (500 MHz, CDCh) 8.26 - 8.20 (m, 2H), 7.18 - 7.03 (m, 6H), 7.03 - 6.98 (m, 2H); LCMS (Method E): 1.96 min (no mass observed). Intermediate DK:

The following Intermediate was prepared using the general method described in Intermediate DJ from the appropriate intermediate.

Intermediate DL: 4,4'-((4-Nitro-1,2-phenylene)bis(oxy))bis(fluorobenzene)

Sodium methoxide (30% in MeOH) (0.62 ml, 3.3 mmol) was added to a suspension of 4- fluorophenol (0.25 g, 2.2 mmol) in toluene (2.5 ml). After stirring at r.t. for 1 h, the mixture was concentrated in vacuo. Copper(l) chloride (221 mg, 2.23 mmol), Intermediate CS (1.04 g, 3.35 mmol) and pyridine (5 ml) were added, and the mixture was heated to 115 °C for 18 h. After cooling to r.t., the reaction mixture was diluted with EtOAc, washed (1 N HCI, water, brine), dried (MgSCU) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-20% EtOAc in PE) and the title compound was isolated (still impure) as a brown oil (327 mg,

< 42%). Used without further purification.

LCMS (Method A): 3.44 min (344.1 , MH⁺).

Intermediate DM: 2-Chioro-N-phenyibenzamide

2-Chlorobenzoyl chloride (3.95 g, 23 mmol) was added to a solution of aniline (2.1 g, 23 mmol), pyridine (1.4 ml_, 1.78 g, 23 mmol) and DMAP (3.0 g, 25 mmol) in DCM (30 ml_) at O °C under nitrogen. The reaction was warmed to 40 °C and allowed to run for 15 h. At the end of the reaction, DCM and aq. NaHCC>3 were added. The phases were separated and the organic layer extracted with DCM. The organic layers were washed with brine, dried (MgSCL), filtered then concentrated to afford the title compound as a white solid. Used without further purification (4.1 g , 78%).

¹ H NMR d_H (500 MHz, CDCh) 7.89 (s, 1 H), 7.77 (dd, J = 7.4, 1.8 Hz, 1 H), 7.65 (d, J = 7.4 Hz, 2H), 7.50 - 7.34 (m, 5H), 7.18 (t, J = 7.4 Hz, 1 H); LCMS (Method C): 3.39 min, (232.0 MH⁺).

Intermediate DN: (4-Aminophenyl)(2-chlorophenyl)methanone

A mixture of phosphorus pentoxide (5.0 g, 35 mmol), methanesulfonic acid (20 ml_) and Intermediate DM (4.1 g, 18 mmol) were heated at 1 15 °C for 48 h. The reaction mixture was allowed to cool to r.t. then quenched by adding water, neutralised with NaOH solution (1 M) and extracted with DCM. The reaction mixture was washed with HCI (30 ml_, 1 M). The aqueous phase was neutralised with NaOH (1 M) and extracted into ethyl acetate, dried (MgSCL), filtered and evaporated to yield a crude brown oil. The residue was purified by chromatography (SiCh, 0-60% EtOAc in PE) to yield the title compound as a yellow oil (510 mg, 12%).

¹ H NMR d_H (500 MHz, CDCh) 7.65 (d, J = 8.8 Hz, 2H), 7.45 - 7.42 (m, 1 H), 7.40 - 7.37 (m, 1 H), 7.35 - 7.31 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H); LCMS (Method C): 3.15 min, (232.2, MH⁺).

Intermediate DO: 1-Chloro-2-(4-nitrobenzyl)benzene

Step 1 :

Zinc powder (0.788 g, 12.0 mmol) was suspended in THF (1 ml) under nitrogen. 1 ,2- Dibromoethane (0.042 ml, 0.48 mmol) was added, and the mixture heated to reflux for 5 min. After cooling to 0 °C, chlorotrimethylsilane (0.122 ml, 0.964 mmol) was added and the mixture stirred for 5 min. A solution of 1-chloro-2-chloromethyl-benzene (0.761 ml, 6.02 mmol) in THF (5 ml) was added dropwise (still at 0 °C), and after complete addition, the mixture was warmed to r.t. for 1 h.

Step 2:

Tris(dibenzylideneacetone)dipalladium(0) (0.074 g, 0.080 mmol) and tri(2-furyl)phosphine (0.037 g, 0.16 mmol) were dissolved in THF (4 ml) under nitrogen. After cooling to 0 °C, the solution prepared in step 1 was added dropwise, followed by a solution of 1-iodo-4- nitrobenzene (1 g, 4 mmol) in THF (10 ml). The mixture was warmed to r.t., and stirred for 18 h. The reaction was quenched with sat. aq. NhUCI and filtered through dicalite®, eluting with EtOAc. The filtrate was concentrated in vacuo , and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were dried (MgS0₄) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-

30% EtOAc in PE) and the title compound was isolated as a yellow solid (754 mg, 76%).

¹ H NMR d_H (500 MHz, CDC ) 7.96 (d, J = 8.5 Hz, 2H), 7.25 - 7.19 (m, 1 H), 7.15 (d, J = 8.5 Hz, 2H), 7.07 - 7.03 (m, 2H), 7.02 - 6.97 (m, 1 H), 4.02 (s, 2H); LCMS (Method E): 2.1 1 min (mass not observed).

Intermediate DP:

The following Intermediate was prepared using the general method described in Intermediate DO from the appropriate intermediate.

Intermediates DQ-FH:

The following Intermediates were prepared using the general method described in

Intermediate W from the appropriate intermediate.

Intermediates FI-HA:

The following intermediates were prepared using the general method described in Intermediate A J from commercial anilines or appropriate Intermediates.

Intermediate HB: 6-(2-Chloro-4-fluorobenzyl)benzo[ d]thiazol-2-amine

Zinc powder (273 mg, 4.17 mmol) and potassium hydroxide (1 M aq) (2 ml, 2 mmol) were added to a suspension of Intermediate GG in ethanol (10 ml), and the mixture was heated to reflux for 18 h. After cooling to r.t., the mixture was filtered through dicalite®, eluting with EtOAc. The filtrate was concentrated in vacuo, and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were dried (MgS0₄) and concentrated in vacuo to yield the title compound as a yellow oil (262 mg, quant.).

LCMS (Method A): 3.21 min (293.0, MH⁺).

Intermediate HC: 5-(2-Chloro-4-fluorophenoxy)thiazolo[5,4-d]pyrimidin-2-amine

A/-(5-Chlorothiazolo[5,4-d]pyrimidin-2-yl)acetamide (350 mg, 1.53 mmol), 2-chloro-4- fluorophenol (0.184 ml, 1.68 mmol) and potassium carbonate (423 mg, 3.06 mmol) were combined in NMP (2.5 ml), and stirred at 150 °C under microwave conditions for 30 min. The mixture was then heated to 200 °C under microwave conditions for 2 h. The reaction was quenched by adding to water. The resultant suspension was filtered, and the solid washed (water) and dried under vacuum to yield a black solid (318 mg, 46 %) which was a 2: 1 mixture of the title compound and the /V-acetylated compound. Used directly without purification.

LCMS: (Method E) 1.69 min, (296.9, MH⁺).

Intermediate HD: 2-Aminobenzo[d]thiazol-6-yl)(phenyl)methanone O-methyl oxime

A solution of Intermediate AK (200.1 mg, 0.79 mmol) in ethanol (10 ml) was treated with methoxyamine hydrochloride (65.7 mg, 0.79 mmol) and hydrochloric acid (0.03 ml, 0.8 mmol) and heated to 90 °C for 3 h. The mixture was diluted with H2O and saturated NaHCC>3 solution, then extracted with EtOAc. The organics were washed with water and brine, dried (MgSCU) and concentrated to give crude product as a yellow gum. The material was taken onto the next step without purification.

LCMS (Method C): 3.60 min (284.3, MH⁺). Intermediate HE: (2-Aminobenzo[d]thiazol-6-yl)(phenyl)methanone O-benzyl oxime

A solution of Intermediate AK (233 mg, 0.91 mmol) in ethanol (10 ml) was treated with O- benzylhydroxylamine hydrochloride (146 mg, 0.91 mmol) and hydrochloric acid (0.03 ml, 0.9 mmol) then heated to 90 °C for 24 h. The mixture was diluted with water and saturated NaHCC>3 solution (to pH 8) then extracted with EtOAc. The organics were washed with water and brine, dried (MgSCU) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-60% EtOAc in PE) to yield the title compound as a light yellow solid (141 mg, 43 %).

LCMS (Method C): 4.17 min (360.3, MH⁺).

Intermediate HF: 2-Amino-N-benzylbenzo[d]thiazole-6-carboxamide

2-Amino-benzothiazole-6-carboxylic acid (229 mg, 1.18 mmol) taken up in DMF (5 ml_) and triethylamine (359 mg, 3.55 mmol) added. (Benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (676 mg, 1.30 mmol) was added and stirred for 2 min. Benzylamine (0.14 ml, 1.3 mmol) was added and the reaction stirred at r.t. for 18h. The suspension was concentrated and then taken up in DCM and washed with water. The DCM layer was washed with brine, dried (MgS0₄) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-85% EtOAc in PE) to yield the title compound as a white solid (293 mg, 88%).

¹ H NMR d_H (500 MHz, DMSO-d⁶) d 8.90 (d, J = 6.0 Hz, 1 H), 8.21 (d, J = 1.6 Hz, 1 H), 7.96 (s, 1 H), 7.79 (dd, J = 8.4, 1.9 Hz, 1 H), 7.76 (s, 2H), 7.36 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 4.5 Hz, 4H), 4.48 (d, J = 6.0 Hz, 2H); LCMS (Method C): 2.42 min (284.2, MH⁺). Intermediate HG: 2-Amino-N-benzyl-N-methylbenzo[ dJthiazole-6-carboxamide

The title compound was prepared using the procedure provided for Intermediate HF with /V-benzylmethylamine. ¹ H NMR d_H (500 MHz, DMSO-d⁶) d 7.81 (s, 1 H), 7.66 (s, 2H), 7.38 (t, J

= 7.4 Hz, 2H), 7.32 (dd, J = 16.7, 7.5 Hz, 5H), 4.64 (s, 2H), 2.89 (s, 3H); LCMS (Method C): 2.51 min (298.2, MH⁺).

Intermediate HH: 1 -(2-Aminobenzo[d]thiazol-6-yl)-1-phenylpropan-1-ol

mg, 1.84 mmol) was taken up in THF (15 ml_) and cooled to 0 °C. Ethylmagnesium bromide (3.0 ml_, 9.2 mmol) was added over 5 min and the solution stirred at r.t. for 1 h. Aq. NH₄CI (10 ml_) was added and the mixture extracted into EtOAc. The combined organics were dried (MgSCU), filtered and concentrated in vacuo to an orange oil. The residue was purified by chromatography (S1O2, 0-80% EtOAc in PE) to yield the title compound as a yellow solid (280 mg, 53%). ¹ H NMR d_H (500 MHz, DMSO-d⁶) d 7.70 (d, J = 1.6 Hz, 1 H), 7.42 (dd, J = 8.4, 1.2 Hz, 2H), 7.36 (br s, 2H), 7.27 - 7.22 (m, 3H), 7.20 (d, J = 8.3 Hz, 1 H), 7.15 - 7.09 (m, 1 H), 5.35 (br s, 1 H), 2.24 (q, J = 7.2 Hz, 2H), 0.75 (t, J = 7.2 Hz, 3H); LCMS (Method C): 2.33 min (285.2, MH⁺).

Intermediate HI: (2-Aminobenzo[d]thiazol-6-yl)(4-fluorophenyl)(phenyl)methanol

Intermediate AK (199 mg, 0.79 mmol) was dissolved in THF (10 ml_) and cooled to 0 °C. 4- Fluorophenylmagnesium bromide (14.7 ml_, 1 1.8 mmol) was added and the solution stirred at r.t. for 24 h. Aq. NH₄CI (10 ml_) was added and reaction mass extracted into EtOAc. The combined organics were dried (MgSCL), filtered and concentrated to an orange oil. The residue was purified by chromatography (S1O2, 0-40% EtOAc in PE) to yield the title compound as a pale yellow solid (79.2 mg, 29%).

¹ H NMR d_H (500 MHz, CDC ) d 7.52 (d, J = 1.8 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.37 - 7.30 (m, 5H), 7.28 - 7.25 (m, 3H), 7.21 (dd, J = 8.5, 1.8 Hz, 1 H), 7.03 (dt, J = 17.4, 8.5 Hz, 3H), 4.75 (br s, 1 H); LCMS (Method C): 2.99 min, (350.3, MH⁺).

Intermediate HJ: 6-((4-Fluorophenyl)(phenyl)methyl)benzo[ d]thiazol-2-amine

Intermediate HI (100.1 mg, 0.22 mmol) taken up in DCM (6 ml_) and triethylsilane (0.18 ml_, 1.1 mmol) and trifluoroacetic acid (0.08 ml_, 1 mmol) added. The mixture was stirred for 24 h. The reaction was quenched by careful addition of aq. NaHCC>3 and extracted into DCM. The combined organic layers were dried (MgSCL) and concentrated in vacuo. The residue was purified by chromatography (S1O2, 0-20% EtOAc in PE) to yield the title compound as a pale yellow solid.

LCMS (Method C): 3.94 min (335.3, MH⁺).

Intermediate HK: 3-Acetoxy-4-methoxypicoiinic acid

Acetic anhydride (7.5 mL, 79 mmol) was added to a suspension of 3-hydroxy-4- methoxypicolinic acid (1.0 g, 5.9 mmol) in pyridine (7.5 mL), and the reaction stirred at r.t. for 18 h. The reaction mixture was concentrated in vacuo to yield the title compound as a yellow- orange solid (1.25 g, quant.).

¹ H NMR d_H (500 MHz, DMSO-d⁶)^^ (v br s, 1 H), 8.42 (d, J = 5.5 Hz, 1 H), 7.40 (d, J = 5.6 Hz, 1 H), 3.91 (s, 3H), 2.27 (s, 3H); LCMS (Method A): 0.81 min (212.0, MH⁺). Intermediate HL:

The following Intermediate was prepared using the general method described in Intermediate BT from 4-amino-4'-methyldiphenyl ether.

Intermediate HM-HN:

The following Intermediates were prepared using the general method described in

Intermediate HB from the appropriate Intermediates.

Intermediate HO:

The following Intermediate was prepared using the general method described in Intermediate W from the appropriate intermediate.

Intermediates HP-HQ:

The following Intermediates were prepared using the general method described in

Intermediate AJ from the appropriate Intermediate.

Example 75:

The following Example was prepared using the general method described in Example 70 from Example 50.

Examples 76-92:

The following Examples were prepared using the general method described in Example 72 from commercial materials or appropriate intermediates.

Examples 93-140:

Example 141: 3-Hydroxy-4-methoxy-N-(6-phenoxybenzo[d]thiazol-2-yl)pyridine-2- carbothioamide

Example 4 (73.5 mg, 0.19 mmol) was taken up in acetonitrile (3 ml_) and hexamethyldisiloxane (0.20 ml, 0.93 mmol) and phosphorus pentasulfide (249.0 mg, 0.560 mmol) added. The suspension was heated to 60 °C and the reaction continued for 5 h. The reaction was allowed to cool to r.t. and water and EtOAc added. The layers were separated and aqueous layer extracted into EtOAc. The combined organics were dried (MgS0₄), filtered and concentrated to yield a light brown solid. This was slurried several times in ethanol and the cake dried under high vacuum (no heat) to yield the title compound as a yellow solid (8.2 mg, 9.8%).

¹H NMR d_H (500 MHz, DMSO-d⁶) 13.51 (s, 1 H), 8.04 (d, J = 6.0 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 2.4 Hz, 1 H), 7.46 - 7.34 (m, 2H), 7.26 - 7.09 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 4.01 (s, 3H) No NH observed; LCMS (Method C): 3.72 min (410.1 , MH⁺).

Example 142: N-(6-(2-Chlorophenoxy)benzo[ d]thiazol-2-yl)-3-hydroxy-4- methoxypyridine-2-carbothioamide

Example 63 (119 mg, 0.29 mmol) was taken up in acetonitrile (3 mL) and hexamethyldisiloxane (0.3 mL, 1.4 mmol) and phosphorus pentasulfide (371 mg, 0.83 mmol) added. The suspension was heated to 60 °C and continued for 3 h. The reaction was allowed to cool to r.t. and water and EtOAc added. The layers were separated and aqueous layer extracted into EtOAc. The combined organics were dried (MgSCU), filtered and concentrated to yield a light brown solid. This was slurried several times in ethanol and the cake dried under high vacuum (no heat) to yield the title compound as a light yellow solid (45.2 mg, 36%).

1H NMR d_H (500 MHz, DMSO-d⁶) 13.60 (s, 1H), 8.08 (d, J = 6.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1 H), 7.69 (d, J= 2.6 Hz, 1H), 7.62 (dd, J= 8.2, 1.6 Hz, 1H), 7.36 (td, J= 8.2, 1.6 Hz, 1H), 7.29 (d, J= 6.4 Hz, 1H), 7.25-7.20 (m, 1H), 7.17 (dd, J= 8.8, 2.6 Hz, 1H), 7.10 (dd, J= 8.2, 1.5 Hz, 1 H), 4.05 (s, 3H) No NH observed; LCMS (Method C): 3.19 min (444.0, MH⁺). Examples 143-161:

The following Examples were prepared using the general method described in Example 69 from the appropriate Examples.

Example 162:

The following Example was prepared using the general method described in Example 68 from the relevant Example.

Example 163-164:

Example 165: Testing the fungicidal activity of the 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 three fungal pathogens - Botrytis cinerea, Alternaria alternata 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 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 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 pi 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 mI 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 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:

A - EC50 <2 ppm

B - 2£EC50<20

C - EC50³20

D - No activity detected at the highest dose tested

NT - Not tested

The ranking in the table is:

Claims

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

X¹ is independently selected from O, S and NH;

Y¹ is independently selected from O and S;

Z¹ is independently at each occurrence absent or is selected from C(0)0, OC(O), O, S, S(O), S(0)₂, C(0)NR⁷, CR⁷R⁸, CR⁷OR⁸, C=NOR⁷, NR⁷C(0), S(0)₂NR⁷, NR⁷S(0)₂, CrCs-alkylene and NR⁷;

R³ and R⁹ are each independently at each occurrence selected from: H, C3-C6-cycloalkyl and CrCe-alkyl;

R⁵ is independently at each occurrence selected from C3-Cs-alkyl and Co-C3-alkylene-R^5a; wherein R^5a is independently at each occurrence selected from phenyl, 5- or 6- membered heteroaryl, 5-, 6-, 7- or 8- membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heterocycloalkyl or cycloalkyl group being monocyclic or bicyclic; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R¹² groups or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 4 R¹³ groups; said heterocycloalkyl or cycloalkyl group being optionally fused to phenyl or a 5- or 6- membered heteroaryl; R⁷ is each independently at each occurrence selected from: H, C3-C6-cycloalkyl, CrC₆-alkyl and Co-C3-alkylene-R^7a; wherein R^7a is independently at each occurrence selected from phenyl and 5- or 6- membered heteroaryl;

R⁸ is independently at each occurrence selected from: H, CrC₆-alkyl, C3-C6-cycloalkyl, C(O)- Ci-C₆-alkyl and CrC₆-haloalkyl;

R¹³ is independently at each occurrence selected from: =0, =S, Ci-C₆-alkyl, Ci-C₆-haloalkyl, halogen, nitro, OR⁸, SR⁹, 0S(0)₂R⁹, S(0)₂R⁹, S(0)₂NR⁹R⁹, S(0)(NR⁹)R⁹, S(0)R⁹, cyano, C₂-C₆- alkenyl, C₂-C₆-alkynyl, and NR⁹R¹⁰;

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

p is independently an integer selected from 0, 1 and 2;

2. A compound of claim 1 , wherein R¹ has the structure

; wherein n is independently an integer selected from 0, 1 , 2 and 3.

3. A compound of claim 2, wherein R¹ has the structure

4. A compound of claim 3, wherein R^8a is independently selected from CrC₆-alkyl and C3-

C₆-cycloalkyl.

5. A compound of claim 3 or claim 4, wherein y is 0.

6. A compound of any one of claims 1 to 5, wherein R² is H.

7. A compound of any one of claims 1 to 5, wherein R² is selected from C(0)R¹¹ , C(0)0R¹¹ , CH₂OC(0)R¹¹ and CH₂OC(0)OR¹¹.

8. A compound of any one of claims 1 to 5, wherein Y¹ is O.

9. A compound of any one of claims 1 to 7, wherein R³ is H.

10. A compound of any one of claims 1 to 9, wherein X¹ is selected from O and S.

1 1. A compound of any one of claims 1 to 10, wherein each of X², X³ and X⁴ is carbon.

12. A compound of claim 1 1 , wherein X⁵ is carbon.

13. A compound of claim 1 1 , wherein X⁵ is nitrogen.

14. A compound of any one of claims 1 to 13, wherein R⁴, m, Z\ R⁵ and p are selected such that at least one R⁴ or Z¹-R⁵ substituent has a molecular mass greater than 50.

15. A compound of any one of claims 1 to 14, wherein p is 1.

16. A compound of claim 15, wherein the Z¹-R⁵ group is situated para to the nitrogen of the ring comprising X¹.

17. A compound of any one of claims 1 to 16, wherein Z¹ is selected from O, S and Cr alkylene.

18. A compound of claim 17, wherein Z¹ is O.

19. A compound of any one of claims 1 to 18, wherein R⁵ is R^5a.

20. A compound of any one of claims 1 to 18, wherein R⁵ is CH2R^5a.

21. A compound of claim 19 or claim 20, wherein R^5a is selected from optionally substituted phenyl and optionally substituted 6 membered heteroaryl.

22. A compound of claim 1 , wherein the compound of formula (I) is selected from:

23. 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 claims 1 to 22 to seeds of plants, to plants themselves or to an area where it is intended that plants will grow.

24. A use of a compound of any one of claims 1 to 22 to control fungal diseases of plants.

25. A fungicidal composition comprising an effective and non-phytotoxic amount of an active compound of any one of claims 1 to 22.