Pyridineamide derivatives as agricultural fungicides

Abstract

The present invention relates to picolinic acid derivatives which can be used to treat fungal diseases, especially plant fungal diseases.

Description

Technical Field

[0001] The present invention relates to picolinic acid derivatives which are useful for treating fungal diseases. Background Art

[0002] Given the growing global demand for food, new treatments are needed internationally to reduce food crop losses due to disease, insects and weeds. Worldwide, more than 40% of crops are lost before harvest, while 10% are lost after harvest. Losses have actually increased since the mid-1990s.

[0003] An emerging threat to this situation is the emergence of chemically resistant organisms, such as glyphosate-resistant weeds and strobilurin-resistant strains of Septoria fungal species in the United States.

[0004] Recent studies also suggest that the geographic spread of many crop pests and diseases is increasing, possibly as a result of global warming.

[0005] In PCT / GB2019 / 050111 (published as WO2019 / 141980), certain picolinic acid derivatives were shown to be useful for treating fungal diseases.

[0006] It is an object of certain embodiments of the present invention to provide pesticides (eg, fungicides) that have either non-selective activity (ie, broad spectrum activity) or specific activity against selective target organisms.

[0007] It is an object of certain embodiments of the present invention to provide compounds which are less persistent in the environment after use than prior art compounds.Alternatively or additionally, the compounds of the present invention are less prone to bioaccumulation in the food chain than prior art compounds.

[0008] Another object of certain embodiments of the present invention is to provide compounds that are less harmful to humans than prior art compounds. Alternatively or additionally, the compounds of the present invention may be less harmful to one or more of the following groups than prior art compounds: amphibians, fish, mammals (including domestic animals such as dogs, cats, cattle, sheep, pigs, goats, etc.), reptiles, birds and beneficial invertebrates (such as bees and other insects or worms), beneficial nematodes, beneficial fungi and nitrogen-fixing bacteria.

[0009] The compounds of the present invention may be as active or more active than the compounds of the prior art. They may be active against organisms that have developed resistance to the compounds of the prior art. However, the present invention may also relate to compounds with lower or similar levels of activity relative to the compounds of the prior art. These less active compounds are still effective as fungicides, but may have other advantages relative to the existing compounds, such as reduced impact on the environment.

[0010] 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 significantly lower activity against non-target species (e.g. crops to be protected).

[0011] Certain embodiments of the present invention provide compounds that achieve one or more of the above objects. The compounds may be active per se, or may metabolize or react in an aqueous medium to produce an active compound. Summary of the invention

[0012] In a first aspect of the present invention, there is provided a compound of formula (I) or an agriculturally acceptable salt or N-oxide thereof:

[0013]

[0014] Y 1 Independently selected from O or S;

[0015] R 1 , R 5a and R 15 Each occurrence is independently selected from C 1 -C 6 -alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, halogen, nitro, OR 11 , SR 12 、OS(O)2R 12 、S(O)2R 12 、C(O)OR 12 、C(O)NR 12 R 12 、C(O)R 12 、S(O)2NR 12 R 12 、S(O)(NR 12 )R 12 、S(O)R 12 , cyano, C2-C6-alkenyl, C2-C6-alkynyl, and NR 12 R 13 ;

[0016] R 2 and R3 Each independently selected from H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 ;

[0017] R 4 Each occurrence is independently selected from: H, C3-C6-cycloalkyl, C1-C6-alkyl and benzyl;

[0018] or R 3 and R 4 together form a group independently selected from C1-C2-alkylene, -C(O)- and -C(S)-;

[0019] R 5 is a 10-membered heteroaryl group selected from quinoline, isoquinoline and quinazoline; wherein R 5 1 to 5 R 5a Groups and / or single Z 1 -Z 2 -R 6 group substitution;

[0020] Z 1 Independently absent or CR 8 R 9 ;

[0021] Z 2 independently absent or selected from C(O)O, OC(O), O, S, S(O), S(O)2, C(O)NR 7 NR 7 C(O), S(O)2NR 7 NR 7 S(O)2、S(O)NR 7 NR 7 S(O),CR 8 R 9 、C(O), C(S), C=NOR 10 and NR 7 ;

[0022] R 6 is independently selected at each occurrence from C3-C8-alkyl and C0-C3-alkylene-R 6a ; where R 6a is independently selected at each occurrence from phenyl, 5- or 6-membered heteroaryl, 5-, 6-, 7- or 8-membered heterocycloalkyl and C5-C8-cycloalkyl; the heterocycloalkyl or cycloalkyl is monocyclic or bicyclic; the heteroaryl or phenyl is optionally substituted by 1 to 5 R 15or the heterocycloalkyl or cycloalkyl group is optionally substituted by 1 to 4 R 16 Group substitution;

[0023] R 16 Each occurrence is independently selected from: =O, =S, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl; halogen, nitro, OR 11 , SR 12 、OS(O)2R 12 、S(O)2R 12 、S(O)2NR 12 R 12 、S(O)(NR 12 )R 12 、S(O)R 12 , cyano, C2-C6-alkenyl, C2-C6-alkynyl, and NR 12 R 13 ;

[0024] R 7 and R 12 Each occurrence is independently selected from: H, C3-C6-cycloalkyl, C1-C6-alkyl and benzyl;

[0025] Or two of the R 12 The groups are attached to the same nitrogen atom, the R 12 The group together with the nitrogen atom forms a 4-, 5-, 6- or 7-membered heterocycloalkyl ring;

[0026] R 8 is independently selected at each occurrence from: H, C3-C6-cycloalkyl, C1-C6-alkyl, phenyl and 5- or 6-membered heteroaryl;

[0027] R 9 Each occurrence is independently selected from: H, halogen, and OR 10 ;

[0028] or R 8 and R 9 Together with the carbon atoms to which they are attached they may form a C3-C6-cycloalkyl ring or a 3-, 4-, 5- or 6-membered heterocycloalkyl ring;

[0029] R 10 Each occurrence is independently selected from: H, C3-C6-cycloalkyl, C1-C6-alkyl and C1-C3-alkylene-R 10a ; where R 10a is independently selected at each occurrence from phenyl and 5- or 6-membered heteroaryl;

[0030] R 11Each occurrence is independently selected from: H, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)-C1-C6-alkyl and C1-C6-haloalkyl;

[0031] R 13 Each occurrence is independently selected from: H, C1-C6-alkyl, C(O)-C1-C6-alkyl, and S(O)2-C1-C6-alkyl;

[0032] or where R 12 Group and R 13 The groups are attached to the same nitrogen atom, the R 12 and R 13 The group together with the nitrogen atom forms a 4-, 5-, 6- or 7-membered heterocycloalkyl ring;

[0033] R 14 Each occurrence is independently: C1-C6-alkyl, phenyl, benzyl and C3-C6-cycloalkyl;

[0034] n is independently an integer selected from 0, 1 and 2;

[0035] m is independently an integer selected from 0, 1, 2 and 3;

[0036] p is independently an integer selected from 0, 1, 2, 3 and 4;

[0037] q is independently an integer selected from 0 and 1; and

[0038] Any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including two R 12 Group or R 12 Group and R 13 The groups, taken together with the nitrogen to which they are attached, form a heterocycloalkyl ring), alkynyl, C(O)-alkyl, S(O)2-alkyl and benzyl are optionally substituted (where chemically possible) with 1 to 4 substituents which are independently selected at each occurrence from the group consisting of: =O; =NR a , =NOR a , C1-C4-alkyl, halogen, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NR a R b 、S(O)2R a 、S(O)R a 、S(O)(NR a )R a 、S(O)2NR a R a 、CO2R a 、C(O)R a ,CONRa R a , OR a and SR a ;

[0039] Where R a are independently selected from H and C1-C4-alkyl; and R b Independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0040] In certain embodiments, the compound of Formula I is a compound of Formula II:

[0041]

[0042] Where R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 1 , Z 2 and R 6 As described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 one of which is carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; and q is independently an integer selected from 0 and 1.

[0043] In certain embodiments, the compound of Formula I is a compound of Formula III:

[0044]

[0045] Where R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 2 and R6 are as described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 one of which is carbon; m is independently an integer selected from 0, 1, 2, and 3; and p1 is independently an integer selected from 0, 1, 2, and 3.

[0046] In certain embodiments, the compound of Formula I is a compound of Formula IV:

[0047]

[0048] Where R 1 , R 2 , R 5 and n are as described above for Formula I; and R 3a are independently selected from: H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 .

[0049] In certain embodiments, the compound of Formula I is a compound of Formula V:

[0050]

[0051] Where R 1 , R 2 , R 5 and n is as described above for Formula I; and Y 2 Independently selected from O and S.

[0052] In certain embodiments, the compound of Formula I is a compound of Formula VI:

[0053]

[0054] Where R 1 , R 2 , R 5a , n, Z 1 , Z 2 and R 6 As described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 is a carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; q is independently an integer selected from 0 and 1; and R 3a are independently selected from: H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 .

[0055] In certain embodiments, the compound of Formula I is a compound of Formula VI:

[0056]

[0057] Where R 1 , R 2, R 5a , n, Z 1 , Z 2 and R 6 As described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 is a carbon; m is independently an integer selected from 0, 1, 2 and 3; p is independently an integer selected from 0, 1, 2, 3 and 4; q is independently an integer selected from 0 and 1; and Y 2 Independently selected from O and S.

[0058] In certain embodiments, the compound of Formula I is a compound of Formula VII:

[0059]

[0060] Where R 1 , R 2 , R 5a , n, Z 2 and R 6 As described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 is a carbon; m is independently an integer selected from 0, 1, 2 and 3; p1 is independently an integer selected from 0, 1, 2 and 3; and R 3a are independently selected from: H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 .

[0061] In certain embodiments, the compound of Formula I is a compound of Formula VIII:

[0062]

[0063] Where R 1 , R 2 , R 5a , n, Z 2 and R 6 As described above for Formula I; X 1 and X 2 One of them is nitrogen, and X 1 and X 2 is a carbon; m is independently an integer selected from 0, 1, 2 and 3; p1 is independently an integer selected from 0, 1, 2 and 3; and Y 2Independently selected from O and S.

[0064] In certain embodiments, the compound of Formula I is a compound of Formula IX:

[0065]

[0066] Where R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 2 and R 6 As described above for Formula I; m is independently an integer selected from 0, 1, 2 and 3; and p2 is independently an integer selected from 0, 1 and 2.

[0067] In certain embodiments, the compound of Formula I is a compound of Formula X:

[0068]

[0069] Where R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 2 and R 6 As described above for Formula I; m1 is independently an integer selected from 0, 1 and 2; and p1 is independently an integer selected from 0, 1, 2 and 3.

[0070] The following embodiments are applicable to any one of the compounds of formula (I)-(X). These embodiments are independent and interchangeable. Where chemically permitted, any one embodiment may be combined with any other embodiment. In other words, any feature described in the following embodiments may be combined (where chemically permitted) with the features described in one or more other embodiments. Specifically, for the compounds exemplified or illustrated in this specification, any two or more of the embodiments listed below comprising the compound may be combined to provide another embodiment forming a part of the present disclosure.

[0071] R 1 Each occurrence may be independently selected from C1-C4-alkyl, halogen and OR 11 .

[0072] n may be 1 or 2. However, preferably, n may be 0.

[0073] R 2 R may be independently selected from H, C1-C4-alkyl and C3-C6-cycloalkyl. 2R may be independently selected from C1-C4-alkyl and C3-C6-cycloalkyl. 2 May be methyl or ethyl. 2 Probably methyl.

[0074] R 3 may be independently selected from H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 . R 3 may be independently selected from H, C(O)R 14 、C(O)OR 14 、CH2OC(O)R 14 and CH2OC(O)OR 14 . R 3 may be independently selected from H and C(O)R 14 . R 3 Probably H. R. 3 Maybe C(O)R 14 , for example C(O)Me.

[0075] R 4 R may be selected from C3-C6-cycloalkyl, C1-C6-alkyl and phenyl. 4 It may be C1-C4-alkyl, for example methyl. 4 Maybe H.

[0076] R 3 and R 4 can together form a group independently selected from C1-C2-alkylene, -C(O)- and -C(S)-; R 3 and R 4 can form -C(=Y 2 )-group; wherein Y 2 Independently selected from O and S.

[0077] Y 2 It can be S.Y 2 It can be O.

[0078] R 3 and R 4 Together they can form C1-C2-alkylene. 3 and R 4 They may be combined to form a C1 alkylene group, such as CH2 or CMe2. 3 and R 4 Together they can form a C2 alkylene group, for example CH2CMe2, CMe2CH2 or CH2CH2.

[0079] Y 1 It can be S.Y 1 It can be O.

[0080] R 5 Probably quinoline. 5 Probably isoquinoline. 5 It could be quinazoline.

[0081] R 5 It may be attached to the rest of the molecule via a ring of a heteroaromatic group containing a nitrogen atom. 5 It may be attached to the rest of the molecule via a heteroaromatic ring that does not contain a nitrogen atom. 5 It may be attached to the rest of the molecule through a carbon of the heteroaromatic group that is not adjacent to a carbon that is part of either ring of the heteroaromatic group. 1 -Z 2 -R 6 can be bonded to R 5 connected, the carbon is not adjacent to carbon atoms that are part of two rings of the heteroaromatic group.

[0082] R 5 Can have the following structure:

[0083] Where X 1 , X 2 , X 3 and X 4 One of them is nitrogen, and X 1 , X 2 , X 3 and X 4 The other three of are carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; and q is independently an integer selected from 0 and 1.

[0084] R 5 Can have the following structure:

[0085] Where X 1 and X 2 One of them is nitrogen, and X 1 and X 2 one of which is carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; and q is independently an integer selected from 0 and 1.

[0086] R 5 Can have the following structure:

[0087] wherein m is independently an integer selected from 0, 1, 2 and 3; p3 is independently an integer selected from 0, 1, 2 and 3; and q is independently an integer selected from 0 and 1.

[0088] R 5 Can have the following structure:

[0089] wherein m is independently an integer selected from 0, 1, 2 and 3; p5 is independently an integer selected from 0, 1 and 2; q is independently an integer selected from 0 and 1; and R 5b Selected from OR 11 and C1-C6-alkyl. 5b Possibly C1-C6-alkyl.

[0090] R5 can have the following structure:

[0091] wherein m1 is independently an integer selected from 0, 1 and 2; p is independently an integer selected from 0, 1, 2, 3 and 4; and q is independently an integer selected from 0 and 1.

[0092] R 5 Can have the following structure:

[0093] Where X 3 and X 4 One of them is nitrogen, and X 3 and X 4 one of which is carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; and q is independently an integer selected from 0 and 1.

[0094] R 5 Can have the following structure:

[0095] wherein m1 is independently an integer selected from 0, 1 and 2; p is independently an integer selected from 0, 1, 2, 3 and 4; and q is independently an integer selected from 0 and 1.

[0096] R 5 Can have the following structure:

[0097] wherein m is independently an integer selected from 0, 1, 2 and 3; p3 is independently an integer selected from 0, 1, 2 and 3; and q is independently an integer selected from 0 and 1.

[0098] R 5 Can have the following structure:

[0099] wherein m is independently an integer selected from 0, 1, 2 and 3; p3 is independently an integer selected from 0, 1, 2 and 3; and q is independently an integer selected from 0 and 1.

[0100] R 5 Can have the following structure:

[0101] wherein m2 is independently an integer selected from 0 and 1; p is independently an integer selected from 0, 1, 2, 3 and 4; and q is independently an integer selected from 0 and 1.

[0102] R 5 Can have the following structure:

[0103] wherein m is independently an integer selected from 0, 1, 2 and 3; p4 is independently an integer selected from 0, 1 and 2; and q is independently an integer selected from 0 and 1.

[0104] R 5 Can have the following structure:

[0105] wherein m is independently an integer selected from 0, 1, 2 and 3; p4 is independently an integer selected from 0, 1 and 2; and q is independently an integer selected from 0 and 1.

[0106] q may be 0. However, preferably, q is 1.

[0107] When q is 1, Z 1 -Z 2 -R 6 The group is preferably located in R 5 Parallel position of the point of attachment to the rest of the molecule.

[0108] R 5 Can have the following structure:

[0109] Where X 1 , X 2 , X 3 and X 4 One of them is nitrogen, and X 1 , X 2 , X 3 and X 4 The other three of are carbon; m is independently an integer selected from 0, 1, 2 and 3; and p1 is independently an integer selected from 0, 1, 2 and 3.

[0110] R5 can have the following structure:

[0111] Where X 1 and X 2One of them is nitrogen, and X 1 and X 2 one of which is carbon; m is independently an integer selected from 0, 1, 2, and 3; and p1 is independently an integer selected from 0, 1, 2, and 3.

[0112] R 5 Can have the following structure:

[0113] Where X 3 and X 4 One of them is nitrogen, and X 3 and X 4 one of which is carbon; m is independently an integer selected from 0, 1, 2 and 3; and p1 is independently an integer selected from 0, 1, 2 and 3. 3 Can be N. Or, X 4 It can be N.

[0114] R 5 Can have the following structure:

[0115] wherein m is independently an integer selected from 0, 1, 2 and 3; and p2 is independently an integer selected from 0, 1 and 2.

[0116] R 5 Can have the following structure:

[0117] wherein m1 is independently an integer selected from 0, 1 and 2; and p1 is independently an integer selected from 0, 1, 2 and 3.

[0118] m can be 0.

[0119] m1 can be 0.

[0120] m2 can be 0.

[0121] p may be 0. However, when q is 0, p is preferably at least 1.

[0122] p1 can be 0.

[0123] p2 can be 0.

[0124] p3 may be 0. However, when q is 0, p3 is preferably at least 1.

[0125] p4 may be 0. However, when q is 0, p4 is preferably at least 1.

[0126] p5 may be 0. However, when q is 0, p5 is preferably at least 1.

[0127] When present, R 5acan be independently selected at each occurrence from: cyano, nitro, C1-C4-alkyl, halogen and OR 11 .

[0128] Z 1 Can be CR 8 R 9 However, it is preferred that Z 1 Does not exist. 1 -Z 2 -R 6 Can be Z 2 -R 6 .

[0129] Z 2 It may not exist or be selected from C(O)O, OC(O), O, S, S(O), S(O)2, CR 8 R 9 and NR 7 . Z 2 It may not exist or be selected from C(O)O, OC(O), O, S, CR 8 R 9 and NR 7 . Z 2 Can be selected from CR 8 R 9 , S, NR 7 and O.Z. 2 Can be absent or selected from NR 7 , S and O. Z 2 Can be selected from NR 7 , S and O. Z 2 Can be selected from O and S. Z 2 It can be O. Z 2 It can be S. Z 2 It can be NR 7 . Z 2 Can be CR 8 R 9 .

[0130] R 7 It may be H. However, preferably, R 7 is C1-C4-alkyl, for example methyl.

[0131] Z 2 It may not exist. 1 -Z 2 -R 6 It can be R 6 .

[0132] R 6 Can be CH2R 6a . Optionally, R 6 It can be R 6a.

[0133] Z 1 -Z 2 -R 6 Can be Z 1 -Z 2 -R 6a . Z 1 -Z 2 -R 6 Can be Z 2 -R 6a . Z 1 -Z 2 -R 6 It can be R 6a .

[0134] R 6a It may be an optionally substituted phenyl group, for example an unsubstituted phenyl group. 6a The phenyl group may be optionally substituted, for example, unsubstituted phenyl.

[0135] R 6a Can have the following structure:

[0136] wherein x is an integer selected from 0, 1, 2, 3, 4 and 5.

[0137] x may be at least 1. x may be 1, 2, or 3. x may be 1 or 2. x may be 1. x may be 0.

[0138] R 15 In one case it can be located at Z 2 The counterpoint.

[0139] R 6a Can have the following structure:

[0140] wherein y is an integer selected from 0, 1, 2, 3 and 4.

[0141] y may be at least 1. y may be 1 or 2. y may be 1. y may be 0.

[0142] R 6a Can have the following structure:

[0143]

[0144] R 15 can be independently selected at each occurrence from: cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, halogen, SR 12 OR 11 . R 15can be independently selected at each occurrence from: C1-C4-alkyl, C1-C4-haloalkyl and halogen.

[0145] R 6a It may be a 6-membered heteroaryl group, such as pyridine.

[0146] R 6a Can have a structure selected from the following:

[0147] R 6 It can be C3-C8-alkyl, for example C3-C6-alkyl. 2 Selected from O, S and NR 7 This is particularly preferred.

[0148] The compound of formula (I) may be selected from:

[0149]

[0150]

[0151]

[0152]

[0153] DETAILED DESCRIPTION

[0154] Terminology C m -C n It refers to a group having m to n carbon atoms.

[0155] The term "branched alkyl" refers to a straight or branched saturated monovalent hydrocarbon chain. 1- C6-alkyl may refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl group may be unsubstituted or substituted with one or more substituents. The specific substituents of each alkyl group may independently be fluorine, OR a or NHR a .

[0156] The term "alkylene" refers to a linear saturated divalent hydrocarbon chain. The alkylene group may be unsubstituted or substituted with one or more substituents. The specific substituents of each alkylene group may independently be C1-C4-alkyl, fluorine, OR a or NHR a .

[0157] The term "haloalkyl" refers to a hydrocarbon group substituted by at least one halogen atom, each occurrence of which is independently selected from: fluorine, chlorine, bromine and iodine. The halogen atom may be present in any position of 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-fluoroethyl 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 by at least one fluorine atom. Therefore, a haloalkyl group may have any number 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.

[0158] The term "alkenyl" refers to a branched or straight chain hydrocarbon group containing at least one double bond. The double bond may exist as an E or Z isomer. The double bond may be in any possible position of the hydrocarbon chain; for example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. Alkenyl may be unsubstituted or substituted with one or more substituents. The specific substituents on any saturated carbon atom in each alkenyl group may independently be fluorine, OR a or NHR a .

[0159] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. The triple bond may be in any possible position of the hydrocarbon chain. For example, "C2-C6-alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl may be unsubstituted or substituted with one or more substituents. The specific substituents for any saturated carbon atom in each alkynyl group may independently be fluorine, OR a or NHR a .

[0160] 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 group may be unsubstituted or substituted with one or more substituents. The specific substituents for each cycloalkyl group may independently be fluorine, OR a or NHR a .

[0161] The term heterocycloalkyl may refer to a monocyclic or bicyclic saturated or partially saturated group having a specified number of atoms in the ring system and containing 1 or 2 heteroatoms independently selected from O, S and N in the ring system (in other words, 1 or 2 atoms forming the ring system are selected from O, S and N). Partial saturation refers to a ring that may contain one or two double bonds. This is particularly applicable to monocyclic rings with 5 to 6 members. The double bond is usually between two carbon atoms, but it can also 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, aza. Heterocycloalkyl groups may be unsubstituted or substituted with one or more substituents. The specific substituents for any saturated carbon atom in each heterocycloalkyl group may independently be fluorine, OR a or NHR a .

[0162] Aryl can be any aromatic carbocyclic ring system (i.e. a ring system containing 2 (2n+1) π electrons). Aryl can have 6 to 12 carbon atoms in the ring system. Aryl is typically phenyl. Aryl can be naphthyl or biphenyl.

[0163] In any of the above aspects and embodiments, the heteroaryl group may be any aromatic (i.e., a ring system containing 2 (2n+1) π electrons) 5-10 membered ring system containing 1 to 4 heteroatoms independently selected from O, S and N (in other words, 1 to 4 atoms forming the ring system are selected from O, S and N). Thus, any heteroaryl group may be independently selected from: a 5-membered heteroaryl group, wherein the heteroaromatic ring is substituted with 14 heteroatoms independently selected from O, S and N; and a 6-membered heteroaryl group, wherein the heteroaromatic ring is substituted with 1-3 (e.g., 1-2) nitrogen atoms; a 9-membered bicyclic heteroaryl group, wherein the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from O, S and N; and a 10-membered bicyclic heteroaryl group, wherein the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, the heteroaryl group can 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.

[0164] It can be that in any aryl or heteroaryl group, the aryl or heteroaryl group is unsubstituted or, where chemically possible, optionally substituted with 1 to 5 substituents, each substituent being independently selected at each occurrence from: halogen, nitro, cyano, NR a R a NR a S(O)2Ra NR a C(O)R a NR a CONR a R a NR a CO2R a , OR a , SR a 、S(O)R a 、S(O)2OR a 、S(O)2R a 、S(O)2NR a R a 、CO2R a C(O)R a ,CONR a R a , CR b R b NR a R a , CR b R b OR a , C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl and C1-C4-haloalkyl; wherein R a and R b As described above for Formula I.

[0165] Compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When compounds of the invention contain double bonds (e.g., C=C or C=N groups), geometric cis / trans (or Z / E) isomers are possible. Tautomerism ("tautomerism") occurs when structural isomers interconvert across a low energy barrier. This can take the form of proton tautomerism in compounds of the invention containing, for example, imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. It can be seen that a single compound can exhibit more than one isomerism.

[0166] Included within the scope of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds of the present invention, including compounds exhibiting more than one type of isomer, and mixtures of one or more isomers.

[0167] Compound of the present invention can be obtained, stored and / or used in the form of agronomically acceptable salt. Suitable salt includes but is not limited to the salt of acceptable inorganic acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid), or the salt of agronomically acceptable organic acid (such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, parasulfamic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid and valeric acid). Suitable salt also comprises the salt of inorganic and organic base, such as counterion (such as Na, Ca, K, Li, Mg, ammonium, trimethyl sulfonium). These compounds can also be obtained, stored and / or used in the form of N-oxide. Also included are acid addition salts or base salts in which the counterion is optically active, such as d-lactate or l-lysine, or racemic salts; such as dl-tartrate or dl-arginine.

[0168] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0169] Conventional techniques for preparing / isolating individual enantiomers, if desired, include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography (HPLC). Thus, the chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form on an asymmetric resin using chromatography, typically HPLC, with a mobile phase consisting of heptane or hexane containing 0-50% by volume of isopropanol (typically 2%-20%), and for specific embodiments, 0-5% by volume of an alkylamine (e.g., 0.1% diethylamine). Concentration of the eluate provides an enriched mixture.

[0170] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol), or, in the case where the compounds of the invention contain an acidic or basic moiety, with a base or acid (e.g., 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding pure enantiomers by methods well known to those skilled in the art.

[0171] When any racemic crystal is crystallized, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which one uniform form of crystal is produced, containing equimolar amounts of both enantiomers. The second type is a racemic mixture or aggregate, in which two forms of crystals are produced in equimolar amounts, each containing a single enantiomer.

[0172] Although the two crystalline forms present in a racemic mixture have the same physical properties, they may have different physical properties compared to true racemates. A racemic mixture may be separated by conventional techniques known to those skilled in the art, for example, see "Stereochemistry of Organic Compounds" by EL Elel and SH Wilen (Wiley, 1994).

[0173] The activity of the compounds of the invention can be evaluated by various computer, in vitro and in vivo assays. Computer analysis of a variety of compounds has been shown to predict eventual in vitro and even in vivo activity.

[0174] The present invention also includes all environmentally acceptable isotopically labeled compounds of formula I to X and their syntheses wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0175] Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen (e.g. 2 H and 3 H), carbon (e.g. 11 C. 13 C and 14 C), chlorine (e.g. 36 Cl), fluorine (e.g. 18 F), iodine (e.g. 123 I and 125 I), nitrogen (e.g. 13 N and 15 N), oxygen (e.g. 15 O. 17 O and 18 O), phosphorus (e.g. 32 P) and sulfur (e.g. 35 S) isotopes.

[0176] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0177] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, such as "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other parts, additives, components, integers or steps.

[0178] 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 otherwise requires.

[0179] 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.

[0180] If appropriate, the compounds according to the invention can act as fungicides at certain concentrations or application rates.

[0181] According to another aspect of the present invention, there is provided a method of controlling fungal diseases, the method comprising applying to plant seeds, the plant itself or the area where the plant is to grow an agronomically effective and substantially non-phytotoxic (to crop plants) amount of a compound of the present invention.

[0182] The pesticide can be applied as a seed treatment, foliar application, stem application, drench or drip application (chemical application) to seeds, plants or plant fruits or soil or inert matrix (for example, inorganic matrix (such as sand, rock wool, glass wool); expanded minerals (such as perlite, vermiculite, zeolite or expanded clay)), pumice, volcanic debris material or substance, synthetic organic matrix (such as polyurethane), organic matrix (such as peat, compost, tree waste (such as coconut shell fiber, wood fiber or fragments, bark)) or liquid matrix (such as floating hydroponic system, nutrient film technology, aeroponics).

[0183] In another aspect, the present invention also relates to a fungicidal composition comprising an effective and non-phytotoxic amount of the active compound of the present invention. The composition may further comprise one or more additional fungicides.

[0184] The term "effective and non-phytotoxic amount" refers to an amount of the pesticide according to the invention which is sufficient to control or destroy any target pest present or susceptible to appearing in the crop, and which, in the absence of the target organism, does not have any significant detrimental effect on the crop, or does have a positive effect on plant vigor and yield. 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. The amount can be determined by systematic field trials, which is within the capabilities of those skilled in the art.

[0185] Depending on their specific physical and / or chemical properties, the active compounds of the present invention can be formulated as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, microcapsules in polymers, and can also be formulated into ULV cold mist and warm mist formulations.

[0186] The active compound can be used in pure form or in the form of a preparation (e.g., ready-to-use solution, emulsion, water-based or oil-based suspension, powder, wettable powder, paste, soluble powder, dust, soluble granules, granules for broadcasting, suspended emulsion concentrates, natural substances impregnated with active compounds, synthetic substances impregnated with active compounds, fertilizers, and microcapsules in polymers). Application can be carried out by, for example, watering, spraying, atomizing, broadcasting, dusting, foaming, diffusion, etc. The active compound can also be applied by ultra-low volume methods, or the active compound preparation or the active compound itself can be injected into the soil. The seeds of the plants can also be treated.

[0187] The preparations containing the compounds of the invention are produced in a known manner, for example by mixing the compound with an extender (e.g., a liquid solvent and / or a solid carrier), optionally using a surfactant (e.g., an emulsifier and / or a dispersant and / or a foaming agent). The preparations can be prepared in a factory / production workshop, or before or during application. The preparations are prepared in a factory / production workshop or before or during application.

[0188] Adjuvants are substances suitable for imparting specific properties (such as certain technological properties and / or specific biological properties) to the composition itself and / or to preparations derived therefrom (eg spray liquors, seed dressings). Typical suitable adjuvants are: extenders, solvents and carriers.

[0189] Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the group of aromatic and nonaromatic hydrocarbons (for example alkanes, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), alcohols and polyols (if appropriate also substituted, etherified and / or esterified), ketones (for example acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, unsubstituted and substituted amines, amides, lactams (for example N-alkylpyrrolidones) and lactones, sulfones and sulfoxides (for example dimethyl sulfoxide).

[0190] If the extender used is water, it is also possible to use, for example, organic solvents as auxiliary solvents. Basically, suitable liquid solvents are: aromatic hydrocarbons (such as xylene, toluene or alkylnaphthalene), chlorinated aromatic hydrocarbons and chlorinated aliphatic hydrocarbons (such as chlorobenzene, vinyl chloride or methylene chloride), aliphatic hydrocarbons (such as cyclohexane) or paraffins (such as petroleum fractions), alcohols (such as butanol or ethylene glycol, and their ethers and esters), ketones (such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone), strong polar solvents (such as dimethylformamide and dimethyl sulfoxide).

[0191] Suitable solid carriers are: for example, ammonium salts and ground natural minerals (such as kaolin, clay, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth), and ground synthetic minerals (such as finely divided silicon dioxide, aluminum oxide and silicates); suitable solid carriers for particles are: for example, crushed and classified natural rocks (such as calcite, marble, pumice, sepiolite and dolomite), and inorganic and organic powders, synthetic particles, and organic materials (such as paper, sawdust, coconut shells, corn cobs and tobacco rods) particles; suitable emulsifiers and / or foaming agents are: for example, nonionic and anionic emulsifiers (such as polyoxyethylene fatty acid esters), Polyoxyethylene fatty alcohol ethers (e.g. alkylaryl polyglycol ethers), alkyl sulfonates, alkyl sulfates, aryl sulfonates and protein hydrolysates; Suitable dispersants are nonionic and / or ionic substances (e.g. selected from 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 aryl sulfonates and alkyl or aryl phosphates or corresponding PO-ether adducts). In addition, suitable oligomers or polymers, for example derived from vinyl monomers, derived from acrylic acid, derived from EO and / or PO alone or derived from EO and / or PO in combination with, for example, (poly) alcohols or (poly) amines. It is also possible to use lignin and its sulfonic acid derivatives, unmodified and modified cellulose, aromatic and / or aliphatic sulfonic acids and their adducts with formaldehyde.

[0192] Viscosity enhancers such as carboxymethylcellulose and natural and synthetic polymers in powder, granule or latex form such as gum arabic, polyvinyl alcohol and polyvinyl acetate, and natural phospholipids such as cephalin and lecithin, and synthetic phospholipids may be used in the formulation.

[0193] Other additives may be mineral oils and vegetable oils. Colorants may also be added, such as inorganic dyes (e.g. iron oxides, titanium oxides and Prussian blue), and organic dyes (e.g. alizarin dyes, azo dyes and metal phthalocyanine dyes), and trace nutrients (e.g. salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc). Other possible additives are perfumes, mineral or vegetable, optionally modified oils and waxes.

[0194] The formulation may also contain stabilizers, such as low-temperature stabilizers, preservatives, antioxidants, light stabilizers or other agents that improve chemical and / or physical stability.

[0195] The preparations generally comprise from 0.01% to 98% by weight, preferably from 0.1% to 95% by weight, particularly preferably from 0.5% to 90% by weight, of active compound.

[0196] The active compounds of the invention can also be used as mixtures with other known fungicides, for example, to improve the activity spectrum or to reduce or slow down the development of resistance. Mixtures with other known active compounds (such as nematicides, herbicides, insecticides, acaricides, or bactericides), or with fertilizers and growth regulators, safeners or chemical messengers are also possible.

[0197] Exemplary application rates of the active compounds according to the invention are: when treating leaves: 0.1 to 10 000 g / ha, preferably 10 to 1000 g / ha, particularly preferably 50 to 300 g / ha (when applying by watering or drip irrigation, it is even possible to reduce the application rate, in particular when using inert substrates such as rock wool or perlite); when treating seeds: 2-200 g per 100 kg of seeds, preferably 2.5-150 g per 100 kg of seeds, particularly preferably 2.5-25 g per 100 kg of seeds, very particularly preferably 2.5-12.5 g per 100 kg of seeds; when treating the soil: 0.1 to 10 000 g / ha, preferably 1 to 5000 g / ha.

[0198] The compositions according to the invention are suitable for protecting any plant variety used in agriculture, greenhouses, forests or horticulture, in particular cereals (for example wheat, barley, rye, millet and oats), corn, cotton, soybeans, rice, potatoes, sunflowers, beans, coffee, beets (for example beets and fodder beets), peanuts, vegetables (for example tomatoes, cucumbers, onions and lettuce), lawns, fruit and nut trees (for example apples, pears, peaches, nectarines, apricots, hazelnuts, pecans, macadamia nuts, pistachios), soft fruits (such as strawberries, raspberries, black currants, red currants), grapevines, bananas, cocoa and ornamental plants.

[0199] The active compounds according to the invention, combined with good plant tolerance and favorable toxicity to warm-blooded animals, and well tolerated by the environment, are suitable for protecting plants and plant organs, for increasing harvest yields, for improving the quality of harvested materials, and for controlling pests (especially fungal diseases, which are encountered in agriculture, horticulture, animal husbandry, forests, gardens and leisure facilities), for protecting stored products and materials, and in the hygiene sector. They can preferably be used as crop protection agents.

[0200] Use as a fungicide

[0201] The compounds of the present invention are active as fungicides.

[0202] The following are illustrative examples of agricultural pests that can be controlled by fungicidal compounds:

[0203] Powdery mildew diseases, for example: Blumeria diseases, for example caused by Blumeria graminis; Podosphaera diseases, for example caused by Podosphaeraleucotheca; Sphaerotheca diseases, for example caused by Sphaerotheca fuliginea; Uncinula diseases, for example caused by Uncinula necator; Rust diseases, for example: Gymnosporangium diseases, for example caused by Gymnosporangium sabinae; Hemileia diseases, for example caused by Hemileia vastatix; Phakopsora pachyrhizi or Phakopsora sphaerotheca. meibomiae); Puccinia diseases, for example, caused by Puccinia recondita; Uromyces diseases, for example, caused by Uromyces appendiculatus; Oomycete diseases, for example, caused by Albugo Candida; Bremia diseases, for example, caused by Bremia lactucae; Peronospora pisi or P.brassicae); Phytophthora diseases, for example, caused by Phytophthora infestans; Plasmopara diseases, for example, caused by Plasmoparaviticola; Pseudoperonospora diseases, for example, caused by Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium diseases, for example, caused by Pythium ultimum;

[0204] Leaf spot diseases, leaf blisters and leaf blights, for example: Alternaria diseases, for example caused by Alternaria solani; Cercospora diseases, for example caused by Cercospora beticola; Cladiosporum diseases, for example caused by Cladiosporium cucumerinum; Cochliobolus diseases, for example caused by Cochliobolus sativus; Colletotrichum diseases, for example caused by Colletotrichum lindemuthanium; Cycloconium diseases, for example caused by Cycloconium oleaginum; Diaporthe citrifolia, for example caused by Diaporthe citrifolia; diseases); leaf spot (Drechslera, Syn): caused by Helminthosporium or Helminthosporium; for example, Elsinoe diseases caused by Elsinoe fawcettii; for example, Gloeosporium diseases caused by Gloeosporium laeticolor; for example, Glomerella diseases caused by Glomerella cingulata; for example, Guignardia diseases caused by Guignardia bidwelli; for example, Leptosphaeria diseases caused by Leptosphaeria maculans; wheat glume blight (Leptosphaeria nodorum; for example, rice blast disease (Magnaporthe diseases) caused by Magnaporthe grisea; for example, Mycosphaerella diseases (Mycosphaerella diseases) caused by Mycosphaerella graminicola;Mycosphaerella fibensis; Phaeosphaeria diseases, for example, caused by Phaeosphaera nodorum; Pyrenophora diseases, for example, caused by Pyrenophora teres; Ramularia diseases, for example, caused by Ramularia collo-cygni; Rhynchosporium diseases, for example, caused by Rhynchosporium secalis; Septoria diseases, for example, caused by Septoria apii or Septoria lycopercisi; Typhula diseases, for example, caused by Typhula incarnata; Venturia diseases, for example, caused by Venturia serrata inaequalis); root and stem diseases, such as:

[0205] For example, Corticium diseases caused by Corticium graminearum; Fusarium diseases caused by Fusarium oxysporum; Gaeumannomyces diseases caused by Gaeumannomyces graminis; Rhizoctonia diseases caused by Rhizoctonia solani; Sarocladium diseases caused by Sarocladium oryzae; Sclerotium diseases caused by Sclerotium oryzae; Tapesia diseases caused by Tapesia acuformis; Thielaviopsis diseases caused by basicola) caused by tobacco root black rot (Thielavbpsis diseases);

[0206] Ear diseases including corn cobs, for example: Alternaria diseases caused by Alternaria spp.; Aspergillus diseases caused by Aspergillus flavus; Cladosporium diseases caused by Cladosporium spp.; Claviceps diseases caused by Claviceps purpurea; Fusarium diseases caused by Fusarium culmorum; Gibberella diseases caused by Gibberella zeae; Monographella diseases caused by Monographella nivalis;

[0207] Smut and bunt, for example: Sphacelotheca diseases, for example caused by Sphacelotheca reiliana; Tilletia diseases, for example caused by Tilletia caries; Urocystis diseases, for example caused by Urocystis occulta; Ustilago diseases, for example caused by Ustilago nuda;

[0208] Fruit rot diseases, for example: Aspergillus diseases, for example caused by Aspergillus flavus; Botrytis diseases, for example caused by Botrytis cinerea; Penicillium diseases, for example caused by Penicillium expansum; Rhizopus diseases, for example caused by Rhizopus stolonifer; Sclerotinia diseases, for example caused by Sclerotinia sclerotiorum; Verticilium diseases, for example caused by Verticilium alboatrum;

[0209] Seed- or soil-borne rot, mildew, wilt, decay and moisture diseases, for example: Alternaria diseases, for example caused by Alternaria brassicicola; Aphanomyces diseases, for example caused by Aphanomyces euteiches; Ascochyta diseases, for example caused by Ascochyta lentis; Aspergillus diseases, for example caused by Aspergillus flavus; Cladosporium diseases, for example caused by Cladosporium herbarum; Cochliobolus sativus [Conidiaform: Drechslera; Bipolaris Syn): Cochliobolus diseases caused by Helminthosporium; Colletotrichum diseases, for example, caused by Colletotrichum coccodes; Fusarium diseases, for example, caused by Fusarium culmorum; Gibberella diseases, for example, caused by Gibberella zeae; Macrophomina diseases, for example, caused by Macrophomina phaseolina;

[0210] For example, Monographella diseases caused by Monographella nivalis; Penicillium diseases caused by Penicillium expansum; Phoma diseases caused by Phoma lingam; Phoma diseases caused by Phomopsis sojae; Phytophthora diseases caused by Phytophthora cactorum; Pyrenophora diseases caused by Pyrenophora graminea; Pyricularia diseases caused by Pyricularia oryzae; Pythium ultimum ultimum; Rhizoctonia diseases, for example, caused by Rhizoctonia solani; Rhizopus diseases, for example, caused by Rhizopus oryzae; Sclerotium diseases, for example, caused by Sclerotium rolfsii; Septoria diseases, for example, caused by Septoria nodorum; Typhula diseases, for example, caused by Typhula incarnata; Verticillium diseases, for example, caused by Verticillium dahliae;

[0211] Canker, cracking or scorch diseases, for example Nectria diseases caused by Nectria galligena;

[0212] Wilt diseases, such as:

[0213] For example, Monilinia diseases caused by Monilinia laxa; leaf blisters or leaf curl diseases, such as:

[0214] For example, tea cake disease (Exobasidiumdiseases) caused by Exobasidium vexans;

[0215] For example, Taphrina diseases caused by Taphrina deformans; woody plant decline diseases, such as:

[0216] For example, Esca diseases caused by Phaemoniella clamydospora, Phaeoacremonium aleophilum, and Fomitiporia mediterranea;

[0217] For example, Eutypa dyeback caused by Eutypa lata; Dutch elm disease caused by Ceratocystis ulmi; Ganoderma diseases caused by Ganoderma boninense;

[0218] Flower or seed diseases, such as:

[0219] For example, Botrytis diseases caused by Botrytis cinerea;

[0220] Tuber diseases, such as:

[0221] Examples include Rhizoctonia diseases caused by Rhizoctonia solani and Helminthosporium diseases caused by Helminthospohum solani. Tuber diseases, such as:

[0222] For example, Rhizoctonia diseases caused by Rhizoctonia solani; Helminthosporium diseases caused by Helminthospohum solani;

[0223] Club heel diseases, such as:

[0224] For example, Plasmophora parasites are caused by Plamodiophora brassicae.

[0225] The compounds of the invention may be active against a broad spectrum of fungal diseases of plants. Alternatively, they may be specifically active against certain specific fungal diseases.

[0226] Specific fungal diseases against which the compounds of the invention can be used include: wheat leaf spot (Septoria tritici), wheat brown rust (Puccinia triticina), wheat stripe rust (Puccinia striiformis), apple scab (Venturia inaequalis), grape powdery mildew (Uncinula necator), barley scald (Rhynchosporium secalis), rice blast (Magnaporthe grisea), soybean rust (Phakopsora pachyrhizi), wheat glume spot (Leptosphaerianodorum), wheat powdery mildew (Blumeria graminis f.sp. tritici), barley powdery mildew (Blumeria graminis f.sp. f.sp.hordei), powdery mildew of cucurbits (Erysiphe dehoracearum), anthracnose of cucurbits (Glomerella lagenarium), leaf spot of beet (Cercospora beticola), early blight of tomato (Alternaria solani), and spot of barley (Cochliobolus sativus).

[0227] In addition to their fungicidal activity, the compounds of the invention may also be active against other microorganisms, such as bacteria.

[0228] The antifungal compounds of the present invention can also be used to treat fungal diseases in humans and animals (e.g., mammals). Likewise, the antifungal compounds of the present invention can be used to treat bacterial diseases in humans and animals. Thus, the present invention includes methods for treating fungal or bacterial diseases, comprising administering to a subject (e.g., a human subject) a therapeutic amount of an antifungal agent of the present invention. The compound may be formulated for topical application to an infected area of ​​the body, or it may be formulated for oral or parenteral administration.

[0229] synthesis

[0230] Those skilled in the art will appreciate that adaptations of methods known in the art may be applied to the manufacture of the compounds of the present invention.

[0231] For example, the skilled person will immediately be familiar with standard textbooks such as "Comprehensive Organic Transformations-A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later edition); "March's Advanced Organic Chemistry-Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later edition); "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic / Plenum Publications, (2001 or later edition); "Organic Synthesis-The Disconnection Approach", S Warren (Wiley), (1982 or later edition); "Designing Organic Syntheses" S Warren (Wiley) (1983 or later edition); "Heterocyclic Chemistry", J. Joule (Wiley 2010 edition or later edition); "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), et al., and references therein, serve as a guide.

[0232] Those skilled in the art are familiar with a range of strategies for synthesizing organic molecules, particularly heterocyclic molecules, which represent common knowledge as set forth in textbooks such as Warren "Organic Synthesis: The Disconnection Approach"; Mackie and Smith "Guidebook to Organic Chemistry"; and Clayden, Greeves, Warren and Wothers "Organic Chemistry".

[0233] One skilled in the art will use his / her judgment and skill to determine the most effective reaction sequence for synthesizing a given target compound, and to use protecting groups when necessary. This will depend, inter alia, on factors such as the nature of other functional groups present in a particular substrate. Obviously, the type of chemistry involved will affect the selection of reagents used in the synthetic steps, the need and type of protecting groups employed, and the sequence for completing the protection / deprotection steps. These and other reaction parameters will be apparent to one skilled in the art by reference to standard textbooks and the examples provided herein.

[0234] During the synthesis of the compounds of the invention, it may be necessary to protect and deprotect sensitive functional groups. This can be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc. (1999) and references therein.

[0235] Throughout this specification, these abbreviations have the following meanings:

[0236] Throughout this specification, these abbreviations have the following meanings:

[0237] PyBOP – Benzotriazol-1-yl-oxytripyrrolidine hexafluorophosphate

[0238] HATU-(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0239] DIPEA – N,N-diisopropylethylamine DMSO-dimethyl sulfoxide

[0240] aq. – aqueous solution conc. – concentrated

[0241] DCM – dichloromethane DMF – N,N-dimethylformamide

[0242] h – hours min – minutes

[0243] LCMS – Liquid Chromatography Mass Spectrometry rt – Room Temperature

[0244] PE – Petroleum ether THF – Tetrahydrofuran

[0245] XPHos-2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0246] Certain compounds of the present invention can be obtained according to or in analogy to the following general synthetic schemes. Certain compounds of the present invention can be obtained via the synthetic intermediates described in Examples 1-46 below.

[0247] General synthetic scheme

[0248] Compounds of formula I can be prepared by Schemes A to D.

[0249] Quinoline of formula A is commercially available. The activated group X on quinoline A can be used to introduce Z 1 -Z 2 -R 6 The group provides a handle for quinoline B. 1 -Z 2 -R 6 It can be introduced using coupling reactions (e.g. Buchwald-Hartwig, Suzuki) with a suitable coupling partner (e.g. boronate), in which case X can be a halogen, such as bromide, or a boronate. Alternatively, Z 1 -Z 2 -R 6 It can be introduced using an addition elimination reaction, in which case X can be a leaving group, such as a halogen, such as chlorine, or a sulfonate, such as methanesulfonate. 1 -Z 2 -R 6 It's Z 2 R 6 And Z 2 O, S or NR 7 In these reactions, quinoline A is usually reacted with R in the presence of a base (e.g., NaH or Na2CO3). 6 -Z 2 -H treatment. Reduction of the nitro group, for example using Fe and NH4Cl, using Pd / C and H2, then provides the amine C. When R 4 If it is not H, R can be introduced at this stage 4 , for example using an alkyl halide. Amide formation with a picolinic acid derivative D (for example using LiHMDS) or E (for example using HATU) forms compounds of formula F, which are a subset of the compounds of the invention.

[0250]

[0251] Plan A

[0252] Alternatively, compounds of the invention can be obtained via quinoline G. Amine formation, for example by heating with acetamide and K2CO3 at 200°C, can provide amine H. Coupling reaction of palladium with a suitable halide or boronate (e.g. Suzuki) can provide compounds of formula J. When R 4 If it is not H, R can be introduced at this stage 4 , for example using an alkyl halide. Amide formation with a picolinic acid derivative D (for example using LiHMDS) or E (for example using HATU) forms compounds of formula K, which are a subset of the compounds of the invention.

[0253]

[0254] Plan B

[0255] In a further alternative, compounds of the invention may be obtained via quinoline L. Coupling reactions of palladium with suitable halides or boronates (e.g. Suzuki) can provide compounds of formula M, a subset of compounds of the invention. Boc deprotection provides the corresponding amine N. When R 4 If it is not H, R can be introduced at this stage 4 , for example using an alkyl halide. Amide formation with a picolinic acid derivative D (for example using LiHMDS) or E (for example using HATU) forms compounds of formula O, which are a subset of the compounds of the invention.

[0256]

[0257] Plan C

[0258] Compounds of formula F, K and O (hereinafter collectively referred to as formula P) can be converted to formula Q (eg, using Ac2O) or R (eg, using a compound wherein Y 2 is sulfur phosgene or wherein Y 2 are compounds of the invention which are triphosgene (O), which are two further subsets of the compounds of the invention.

[0259]

[0260] Plan D

[0261] Example

[0262] Conventional methods

[0263] Rapid chromatography was performed using Biotage Isolera 4 to Start with a SNAP KP-Sil cartridge (containing 50 μm silica particles with a surface area of ​​500 m2 / g) or other specified cartridges (such as Puriflash, manufactured by Interchim), or proceed with silica gel (40-63 μm particles). Visualization is performed with UV light (254 nm) and staining with potassium permanganate, phosphomolybdic acid (PMA) or ninhydrin solution.

[0264] all 1 H NMR spectra were acquired on a Bruker AVIII 400 with 5 mm QNP or a Bruker AVI 500 with 5 mm QNP. Chemical shifts are expressed in parts per million (δ) and are referenced to the solvent. Coupling constants, J, are expressed in Hertz (Hz).

[0265] LCMS was performed on a Waters Alliance ZQ MS using a YMC-Triart C18 50x2mm, 5 micron LC column by method A (solvent: gradient 5-90% acetonitrile in water (containing 1 vol% of a 28 wt% aqueous ammonia solution)) or by method B (solvent: gradient 5-90% acetonitrile in water (containing 1% formic acid). Flow rate: 0.8 mL / min. Wavelengths were 254 and 210 nm.

[0266] Method A (5 minutes alkaline pH)

[0267] Chromatographic column: YMC-Triart C18 50×2mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 5μL.

[0268] Mobile phase A H2O

[0269] B CH3CN

[0270] C 50%H2O / 50%CH3CN+1.0%Ammonia (aq.)

[0271]

[0272] Method B (5 minutes acidic pH)

[0273] Chromatographic column: YMC-Triart C18 50×2mm, 5μm. Flow rate: 0.8mL / min. Injection volume: 5μL.

[0274] Mobile phase A H2O

[0275] B CH3CN

[0276] C 50%H2O / 50%CH3CN+1.0%formic acid

[0277]

[0278] Alternatively, MS analysis was performed on a Waters Acquity UPLC-QDA UV-MS system using Method C (high pH) or Method D (low pH):

[0279] Method C (3.5 minutes alkaline pH)

[0280] Mobile phase: water (A) / acetonitrile (B), both containing 0.1% (v / v) ammonia

[0281] time ％A ％B Flow rate (mL / min) initial 98 2 1.0 0.2 98 2 1.0 2.5 2 98 1.0 3.0 2 98 1.0 3.1 98 2 1.0 3.5 98 2 1.0

[0282] Chromatographic column: BEH C18 2.1x50mm, 1.7μm@50℃

[0283] Method D (3.5 minutes acidic pH)

[0284] Mobile phase: water (A) / acetonitrile (B), both containing 0.1% (v / v) formic acid

[0285] time ％A ％B Flow rate (mL / min) initial 98 2 1.0 0.2 98 2 1.0 2.5 2 98 1.0 3.0 2 98 1.0 3.1 98 2 1.0 3.5 98 2 1.0

[0286] Chromatographic column: CSH C18 2.1x50mm, 1.7μm@50℃

[0287] Unless otherwise noted, all reagents were obtained from commercial suppliers and used as supplied.

[0288] All compounds were named using ChemBioDraw Ultra 14.0.

[0289] Intermediate A:2-(4-fluorophenoxy)-6-nitroquinoline

[0290]

[0291] A suspension of sodium hydride (60% in mineral oil) (67.1 mg, 1.68 mmol) in anhydrous DMF (2 mL) was treated with a solution of 4-fluorophenol (134 mg, 1.20 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 15 minutes, and then 2-chloro-6-nitroquinoline (250 mg, 1.20 mmol) was added in batches. The reaction mixture was stirred at room temperature for 4 hours, and then poured into water (20 mL) to quench. A precipitate was formed, and the resulting mixture was stirred for 30 minutes, and then filtered. The solid was washed with water (3 × 50 mL) and dried under vacuum to obtain the title compound as a beige solid (260 mg, 76%).

[0292] 1H NMR (DMSO-d 6):9.04(d,J=2.6Hz,1H),8.73(d,J=8.9Hz,1H),8.36(dd,J=9.2,2.7Hz,1H),7.79(d,J=9.2Hz,1H),7.50(d,J=8.9Hz,1H),7.47–7.15(m,4H).

[0293] Intermediate BD:

[0294] The following intermediates were prepared using the general procedure described in Intermediate A from commercial starting materials.

[0295]

[0296] Intermediate E:2-isopropoxy-6-nitroquinoline

[0297]

[0298] A suspension of potassium tert-butoxide (32 mg, 0.29 mmol) in DMF (0.5 mL) was treated with 2-propanol (20 μl, 0.26 mmol), and the mixture was stirred at room temperature for 30 minutes. Then 2-chloro-6-nitroquinoline (50 mg, 0.24 mmol) was added once, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (3 mL) to form a precipitate. The resulting mixture was stirred for 30 minutes, and then EtOAc (3 mL) was added. The aqueous layer was extracted with EtOAc (3 × 3 mL), the combined organic matter (MgSO4) was dried and evaporated in vacuo to give the title compound as a brown solid (44 mg, 79%).

[0299] LCMS (method B): 3.64 min, (333.0, MH + ).

[0300] Intermediate FI:

[0301] The following intermediates were prepared using the general procedure described in Intermediate E from commercial starting materials.

[0302]

[0303]

[0304] Stir the reaction at room temperature for 48 hours

[0305] Intermediate J: N-(4-fluorophenyl)-N-methyl-6-nitroquinolin-2-amine

[0306]

[0307] A mixture of 2-chloro-6-nitroquinoline (50 mg, 0.24 mmol), acetic acid (1.4 μl, 0.024 mmol) and 4-fluoro-N-methylaniline (29 μl, 0.24 mmol) in dioxane (2.4 mL) was heated at 150° C. for 3 hours under microwave irradiation. The reaction mixture was cooled to room temperature and then concentrated in vacuo to give the title compound as a light brown solid (50 mg, 70%).

[0308] LCMS (method B): 3.60 min, (298.1, MH + ).

[0309] Intermediate K: 2-((4-fluorophenyl)thio)-6-nitroquinoline

[0310]

[0311] A mixture of 2-chloro-6-nitroquinoline (50 mg, 0.24 mmol), potassium carbonate (16.6 mg, 0.12 mmol) and 4-fluorobenzenethiol (26 μl, 0.24 mmol) in DMF (0.5 mL) was stirred at room temperature for 18 hours. The reaction was diluted with water (4 mL) and EtOAc (4 mL), the two layers were separated, and the aqueous layer was further extracted with EtOAc (3×3 mL). The combined organics were dried (MgSO 4 ) and concentrated under reduced pressure to give the title compound as a yellow solid (58 mg, 81%).

[0312] LCMS (method B): 3.62 min, (301.0, MH + ).

[0313] Intermediate L: 2-(4-fluorophenoxy)quinolin-6-amine

[0314]

[0315] A solution of Intermediate A (260 mg, 0.915 mmol) in methanol (2.7 mL) / THF (5.4 mL) / water (1.1 mL) was treated with ammonium chloride (294 mg, 5.49 mmol) and iron (306 mg, 5.49 mmol). The reaction mixture was heated at 60 °C for 18 hours. After cooling to room temperature, the mixture was passed through Filter and wash with EtOAc. Wash the filtrate with water, dry (MgSO4) and concentrate under reduced pressure to give the title compound as a beige solid (185 mg, 80%).

[0316] LCMS (method D): 1.62 min, (255.1, MH + ).

[0317] Intermediate MW:

[0318] Using the general procedure described in Intermediate L, the following intermediates were prepared from the appropriate intermediates.

[0319]

[0320]

[0321]

[0322] Intermediate X: tert-butyl (3-benzylquinolin-6-yl)carbamate

[0323]

[0324] A mixture of benzylboronic acid pinacol ester (506 mg, 2.32 mmol), tripotassium phosphate (657 mg, 3.09 mmol), XPHOS (36.9 mg, 0.077 mmol), palladium (II) acetate (8.7 mg, 0.039 mmol) and tert-butyl carbamate (250 mg, 0.774 mmol) in THF (3 mL) / water (0.2 mL) was degassed and then heated at 90° C. for 18 h. The reaction was cooled to room temperature and then stirred by Filter and wash with EtOAc (30 mL).The filtrate was dried (MgSO4) and concentrated under reduced pressure to give a crude residue of the title compound (assumed quantitative yield) which was used in the next step without further purification.

[0325] LCMS (Method D): 3.02min, (335.1, MH + ).

[0326] Intermediate Y:3-Benzylquinolin-6-amine

[0327]

[0328] A solution of crude intermediate X (220 mg, 0.658 mmol) in HCl (4 M in dioxane) (4.11 mL, 16.5 mmol) was stirred at room temperature for 2 hours, the reaction mixture was neutralized with 1 M NaOH aqueous solution and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to give the crude residue of the title compound (assumed quantitative yield), which was used in the next step without further purification.

[0329] LCMS (method B): 1.77 min, (235.0, MH + ).

[0330] Intermediate Z: 6-bromoquinolin-2-amine

[0331]

[0332] A mixture of 6-bromo-2-chloro-quinoline (2.0 g, 8.3 mmol), acetamide (9.74 g, 165 mmol) and potassium carbonate (3.4 g, 25 mmol) was heated at 200 ° C for 2 hours. The reaction mixture was cooled to room temperature, at which point the mixture solidified. The residue was dissolved in DCM (15 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 15 mL), the combined organic extracts were washed with brine, dried (MgSO ) and concentrated under vacuum to give the title compound as a beige solid (780 mg, 34%).

[0333] 1 H NMRδ H (400 MHz, chloroform-d) 8.01 (d, J = 8.6 Hz, 1H), 7.83-7.78 (m, 1H), 7.78-7.73 (m, 1H), 7.61 (dd, J = 8.9, 2.2 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 4.94 (s, 2H); LCMS (method B): 1.10 min, (222.9 / 224.9, MH + ).

[0334] Intermediate AA:6-phenylquinolin-2-amine

[0335]

[0336] Intermediate Z (210 mg, 0.94 mmol), sodium carbonate (300 mg, 2.83 mmol) and phenylboronic acid (345 mg, 2.83 mmol) were dissolved in 1,4-dioxane (9 mL) / water (3 mL) and degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium (109 mg, 0.094 mmol) was added and the reaction was heated to 80°C overnight. The reaction was cooled to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organics were dried (magnesium sulfate) and concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0-60% EtOAc in PE) to give the title compound as a beige solid (180 mg, 87%).

[0337] 1 H NMRδ H (400MHz,DMSO-d 6)7.79–7.56 (m, 1H), 7.32 (d, J=4.6 Hz, 5H), 7.22 (dd, J=8.1, 4.9 Hz, 3H), 7.10 (t, J=4.2 Hz, 1H); LCMS (method B): 1.16 min, (221.0, MH + ).

[0338] Intermediate AB: 6-Benzylquinolin-2-amine

[0339]

[0340] Intermediate Z (900 mg, 4.03 mmol), cesium carbonate (3.94 g, 12.1 mmol) and benzylboronic acid pinacol ester (2.69 mL, 12.1 mmol) were dissolved in dioxane (20 mL) / water (7 mL) and degassed for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (659 mg, 0.807 mmol) was added and the reaction mixture was heated at 80°C for 18 hours. The reaction was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were dried (magnesium sulfate) and concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0-60% EtOAc in PE) to give the title compound as a pale yellow solid (492 mg, 52%).

[0341] 1 H NMRδ H (400MHz,DMSO-d 6 )7.79–7.50 (m, 1H), 7.42 (m, 5H), 7.22 (m, 3H), 7.10 (m, 1H), 4.50 (m, 2H) 3.57 (s, 2H); LCMS (method B): 1.82 min, (235.1, MH + ).

[0342] Intermediate AC: 4-pentylquinolin-2-ol

[0343]

[0344] A solution of 4-methylquinolin-2-ol (1.0 g, 6.3 mmol) in anhydrous THF (10.5 mL) was purged with nitrogen and cooled to -78 ° C. n-Butyl lithium (11.8 mL, 18.9 mmol) was added, the reaction was allowed to warm to room temperature and stirred for 2 hours. 1-Chlorobutane (1.31 mL, 12.6 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, stirred for 10 minutes, and then extracted with EtOAc (3×10 mL). The combined extracts were dried (magnesium sulfate) and concentrated under vacuum to give the title compound as an off-white solid (500 mg, 37% yield). LCMS (Method B): 2.65 min, (216.1, MH + ).

[0345] Intermediate AD: 6-nitro-4-pentylquinolin-2-ol

[0346]

[0347] A mixture of intermediate AC (500 mg, 2.32 mmol) and sulfuric acid (7.43 mL, 139 mmol) was cooled in an ice / methanol bath, water (0.5 mL) was added, and then nitric acid (97 μL, 2.32 mmol) was added dropwise. The reaction mixture was stirred for 2 hours and then poured into a water / ice mixture (50 mL). A precipitate formed, which was filtered and dried under vacuum to give the title compound as a light yellow solid (410 mg, 68%). LCMS (Method B): 2.80 min, (261.1, MH + ).

[0348] Intermediate AE: 2-Chloro-6-nitro-4-pentylquinoline

[0349]

[0350] A mixture of intermediate AD (410 mg, 1.58 mmol) and phosphorus (V) oxychloride (7.34 mL, 7.88 mmol) was stirred at room temperature for 18 hours. The reaction mixture was added dropwise to ice water (10 mL) and the resulting mixture was neutralized with saturated aqueous NaOH. The mixture was extracted with EtOAc (3×5 ml), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give the title compound as an off-white solid (350 mg, 80%). LCMS (Method B): 4.01 min (279.1, MH + ).

[0351] Intermediate AF-AJ:

[0352] The following intermediates were prepared using the general procedure described in Intermediate A from commercial starting materials.

[0353]

[0354]

[0355]

[0356] Intermediate AK: 2-Chloro-6-nitro-5-propoxyquinoline

[0357]

[0358] A mixture of 7-chloro-4-hydroxy-3-nitroquinoline (250 mg, 1.11 mmol), potassium carbonate (308 mg, 2.23 mmol) and 1-bromopropane (0.202 mL, 2.23 mmol) in DMF (3 mL) was stirred at 80 ° C for 18 hours. The reaction was cooled to room temperature and water was added. The resulting suspension was stirred for 15 minutes and then filtered. The residue was washed with water and dried under vacuum to obtain the title compound as a light yellow solid (292 mg, 98%).

[0359] 1H NMR (400 MHz, CDCl3) δ8.92 (s, 1H), 8.58 (dd, J = 8.3, 0.8 Hz, 1H), 7.56-7.49 (m, 2H), 4.28-4.20 (m, 2H), 2.10-1.97 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H); LCMS (method B): 2.40 min (267.0, MH + ).

[0360] Intermediate AL-AO:

[0361] The following intermediates were prepared using the general procedure described in Intermediate K from the appropriate intermediates or commercial starting materials.

[0362]

[0363]

[0364]

[0365] Intermediate AP-AX:

[0366] Using the general procedure described in Intermediate L, the following intermediates were prepared from the appropriate intermediates.

[0367]

[0368]

[0369]

[0370]

[0371]

[0372] Example 1: N-(2-ethoxyquinolin-6-yl)-3-hydroxy-4-methoxypicolinamide

[0373]

[0374] A mixture of intermediate M (42.8 mg, 0.23 mmol), 3-hydroxy-4-methoxypicolinic acid (35 mg, 0.21 mmol), PyBOP (118 mg, 0.228 mmol) and DIPEA (72 μl, 0.41 mmol) in anhydrous DCM (4.5 mL) was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc in PE) to give the title compound as a light yellow solid (24 mg, 34%).

[0375] 1 H NMRδ H (DMSO-d 6 ):12.26(s,1H),11.04(s,1H),8.43(s,1H),8.21(d,J=8.9Hz,1H),8.17(d,J=5.3Hz,1H),8.04(d,J=8.9Hz,1H),7.75(d,J=9.0Hz,1H),7.28 (d, J=5.5Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 4.45 (q, J=6.9Hz, 2H), 3.94 (d, J=9.4Hz, 3H), 1.38 (t, J=7.0Hz, 3H); LCMS (Method B): 2.00min, (340.0, MH + ).

[0376] Embodiment 2-14

[0377] Using the general procedure described in Example 1, the following examples were prepared from the appropriate intermediates.

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386] a The product was filtered from the reaction mixture without chromatography.

[0387] Example 15: N-(6-bromoquinolin-2-yl)-3-hydroxy-4-methoxypicolinamide

[0388]

[0389] 6-Bromoquinolin-2-amine (69 mg, 0.30 mmol) was dissolved in DMF (4 mL) and 8-methoxy-2,2-dimethyl-4H-[1,3]dioxo[5,4-b]pyridin-4-one 2,2,2-trifluoroacetate (250 mg, 0.77 mmol) was added. Sodium bis(trimethylsilyl)amide solution (0.8 mL, 1.5 mmol) was added and the reaction was stirred at 60°C for 24 hours. The reaction mixture was allowed to cool to room temperature and then water (5 mL) was added. The precipitate formed was filtered and the solid was slurried in ethanol, filtered and dried in vacuo to give the title compound as a light brown solid (14.3 mg, 16%).

[0390] 1 H NMRδ H (400MHz,DMSO-d 6 )15.80(s,1H),8.66(d,J=9.7Hz,1H),8.25(d,J=6.4Hz,1H),8.13(s,1H) ,7.81–7.68(m,2H),7.50–7.41(m,1H),6.66–6.52(m,1H),3.72(s,2H)(NH or OH not seen); LCMS (Method B): 2.50min, (374.0 / 375.9, MH + ).

[0391] Example 16: 3-Hydroxy-4-methoxy-N-(6-phenylquinolin-2-yl)picolinamide

[0392]

[0393] Following the procedure of Example 15, the title compound was obtained as a light brown solid (30 mg, 17%).

[0394] 1 H NMRδ H (400MHz,DMSO-d 6 )15.78(s,1H),8.67(d,J=9.0Hz,1H),8.33(d,J=9.0Hz,1H),8.15(s,1H),8.00(d,J=2.1Hz,1H),7.83(dd,J=13.6,8.0Hz,3H),7.51 (t,J=7.7Hz,2H),7.44(d,J=4.6Hz,1H),7.40(d,J=7.4Hz,1H),6.61(d,J=4.7Hz,1H),3.72(s,3H); LCMS (method B):2.82min,(372.1,MH + ).

[0395] Example 17: 2-((6-bromoquinolin-2-yl)carbamoyl)-4-methoxypyridin-3-yl acetate

[0396]

[0397] Example 15 (82 mg, 0.22 mmol) was dissolved in pyridine (1 mL) and acetic anhydride (0.4 mL, 4.4 mmol) and stirred for 1 hour. The solvent was evaporated in vacuo and the residue was azeotroped with heptane, DCM and Et2O in sequence. The crude residue was purified by column chromatography (SiO2, 0-100% EtOAc in PE) to give the title compound (8 mg, 9%) as an orange solid.

[0398] 1 H NMRδ H (400MHz,DMSO-d 6 )10.85(s,1H),8.56(d,J=5.5Hz,1H),8.49–8.38(m,2H),8.27(s,1H),7.92–7.78(m,1H),7.54(d,J=5.5Hz,2H),3.97(s,3H),2.36(s,3H).

[0399] Examples 18-19

[0400] Using the general procedure described in Example 17, the following examples were prepared from the appropriate intermediates.

[0401]

[0402]

[0403] Examples 20-28

[0404] Using the general procedure described in Example 1, the following examples were prepared from the appropriate intermediates.

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] Examples 29-36

[0412] Using the general procedure described in Example 17, the following examples were prepared from the appropriate intermediates.

[0413]

[0414]

[0415]

[0416]

[0417]

[0418] Example 37: 3-(2-((4-fluorophenyl)thio)quinolin-6-yl)-8-methoxy-2-thioxo-2,3-dihydro-4H-pyrido[2,3-e][1,3]oxazin-4-one

[0419]

[0420] A solution of Example 9 (30 mg, 0.071 mmol) in anhydrous DCM (1 mL) was treated with thiophosgene (10.9 μL, 0.142 mmol), then treated with pyridine (0.086 mL, 1.07 mmol), and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography (SiO2, 0-100% EtOAc in PE) to isolate the title compound as a light yellow solid (5.9 mg, 18%).

[0421] 1 H NMRδ H (DMSO-d 6):8.61(d,J=5.4Hz,1H),8.30(d,J=8.6Hz,1H),7.95(d,J=2.2Hz,1H),7.92(d,J=8.9Hz,1H),7.80–7.71(m,3H) ,7.61(d,J=5.5Hz,1H),7.45–7.37(m,2H),7.18(d,J=8.7Hz,1H),4.10(s,3H); LCMS (Method B):3.19min,(464.1,MH + ).

[0422] Examples 38-46

[0423] Using the general procedure described in Example 37, the following examples were prepared from the appropriate intermediates.

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] Example 47: 2-((2-isopropoxyquinolin-6-yl)carbamoyl)-4-methoxypyridin-3-yl acetate

[0431]

[0432] Following the procedure of Example 17, the title compound was obtained as a pale yellow solid (24.5 mg, 94%).

[0433] 1H NMRδ H (400MHz, DMSO-d6)10.72(s,1H),8.51(d,J=5.5Hz,1H),8.40(s,1H),8.18(d,J=8.9Hz,1H),7.95(d,J=11.2Hz,1H),7.71(d,J =8.9Hz,1H),7.46(d,J=5.5Hz,1H),6.92(d,J=8.9Hz,1H),5.52–5.39(m,1H),3.94(s,3H),2.31(s,3H),1.36(d,J=6.2Hz,6H).

[0434] LCMS (method B): 3.98 min, (396.2, MH + ).

[0435] Example 48: Testing the fungicidal activity of the compounds of the present invention

[0436] Compounds were screened in 96-well plates with 10 compounds per plate. Each compound was screened in agar adjusted to 20, 2, 0.2, and 0.02 ppm of the test material. 50 and 10 ppm of proline and 0.2% DMSO were used as positive and negative controls, respectively. Each test concentration and standard was tested twice on one plate.

[0437] Compounds were screened against wheat yeast (Zymoseptoria tritici). The agar used in the assay was 1% potato dextrose agar. Sufficient spores were added to the appropriate agar to give 10,000 spores / mL agar.

[0438] For each dose (i.e. 200, 20, 2 and 0.2 ppm), a x10 stock solution in 2% DMSO was prepared and 10 μl of the stock solution was added to the appropriate wells on the plate. Controls received an equal amount of 2% DMSO and 500 and 100 ppm of proline. 90 μl of the appropriate agar spore suspension was added to each well to give the final well concentrations listed in the first paragraph.

[0439] Plates were incubated at room temperature (18°C) and evaluated after 7 days.

[0440] The amount of fungal growth in each well was compared to the DMSO control and scored based on the following key factors:

[0441] A–EC50 < 2 ppm

[0442] B–2≤EC50<20

[0443] C–EC50 ≥ 20

[0444] D – No activity detected at the highest dose tested

[0445] NT – Not tested

[0446] The arrangement in the table is:

[0447]

[0448]

[0449]

Claims

1. A compound of formula I or an agriculturally acceptable salt thereof: in Y 1 Independently selected from O or S; R 2 and R 3 are each independently selected from H, C1-C4-alkyl and C(O)R 14 ; R 4 It is H; or R 3 and R 4 together to form -C(S)-; R 5 is quinoline, separated by 1 to 5 R 5a Groups and / or single Z 1 -Z 2 -R 6 Group substitution; R 5a and R 15 is independently selected at each occurrence from C1-C6-alkyl, halogen and OR 11 ; Z 1 Independently absent or CR 8 R 9 ; Z 2 Independently absent or selected from O, S and NR 7 ; R 6 is independently selected at each occurrence from C3-C8-alkyl, CH2R 6a and R 6a ; where R 6a is independently selected at each occurrence from phenyl and 5- or 6-membered heteroaryl, wherein said heteroaryl or phenyl is optionally substituted by 1 to 5 R 15 Group substitution; R 7 Independently selected from: H and C1-C6-alkyl; R 8 and R 9 independently H; R 11 is independently selected at each occurrence from C1-C6-alkyl; and R 14 is independently at each occurrence C1-C6-alkyl, wherein any of the aforementioned alkyl groups, where chemically possible, is optionally substituted with 1-4 substituents, said substituents being independently selected at each occurrence from the group consisting of: =O; =NR a , =NOR a , C1-C4-alkyl, halogen, nitro, cyano, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NR a R b 、S(O)2R a 、S(O)R a 、S(O)(NR a )R a 、S(O)2NR a R a 、CO2R a 、C(O)R a ,CONR a R a , OR a and SR a ; Where R a are independently selected from H and C1-C4-alkyl; and R b Independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

2. The compound according to claim 1, wherein R 2 Independently selected from C1-C4-alkyl.

3. The compound according to claim 1 or 2, wherein R 3 are independently selected from H and C(O)R 14 .

4. The compound according to claim 1 or 2, wherein R 3 and R 4 Together they form -C(S)-.

5. The compound according to claim 1 or 2, wherein Y 1 It's O.

6. The compound according to claim 1, wherein R 5 With structure Where X 1 , X 2 , X 3 and X 4 One of them is nitrogen, and X 1 , X 2 , X 3 and X 4 The other three of are carbon; m is independently an integer selected from 0, 1, 2, and 3; p is independently an integer selected from 0, 1, 2, 3, and 4; and q is independently an integer selected from 0 and 1.

7. The compound according to claim 6, wherein q is 1.

8. The compound according to claim 7, wherein R 5 Has the following structure: Where X 1 , X 2 , X 3 and X 4 One of them is nitrogen, and X 1 , X 2 , X 3 and X 4 The other three of are carbon; m is independently an integer selected from 0, 1, 2 and 3; and p1 is an integer independently selected from 0, 1, 2 and 3.

9. The compound according to claim 7, wherein R 5 Has the following structure: wherein m is independently an integer selected from 0, 1, 2 and 3; and p2 is independently an integer selected from 0, 1 and 2.

10. The compound according to claim 7, wherein R 5 Has the following structure: wherein m1 is independently an integer selected from 0, 1 and 2; and p1 is independently an integer selected from 0, 1, 2 and 3.

11. A compound according to any one of claims 7 to 10, wherein Z 1 Does not exist.

12. A compound according to any one of claims 7 to 10, wherein Z 2 Independently selected from NR 7 , S and O.

13. A compound according to any one of claims 7 to 10, wherein Z 2 Does not exist independently.

14. A compound according to any one of claims 7 to 10, wherein Z 2 Yes CR 8 R 9 .

15. A compound according to any one of claims 7 to 10, wherein R 6 YesR 6a .

16. The compound according to claim 15, wherein R 6a Has the following structure: wherein x is an integer selected from 0, 1, 2, 3, 4 and 5.

17. The compound according to claim 12, wherein R 6 It is C3-C8-alkyl.

18. The compound according to claim 1, wherein the compound of formula I is selected from:

19. A method for controlling fungal diseases, the method comprising applying an agronomically effective and substantially non-phytotoxic amount of a compound of claim 1 to the seeds of a plant, to the plant itself, or to the area where the plant will grow.

20. Use of a compound according to claim 1 for controlling fungal diseases of plants.

21. A fungicidal composition comprising an effective and non-phytotoxic amount of the active compound of claim 1.

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