Picolinamide derivatives useful as agricultural fungicides

Abstract

The present invention relates to picolinic acid derivatives that are useful for treating fungal diseases, especially in plants.

Description

Technical Field

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

Background Art

[0002] In view of the increasing global food demand, new treatments for reducing losses of food crops due to diseases, insects, and weeds are internationally needed. Worldwide, over 40% of crops are lost before harvest and 10% are lost after harvest. The losses have actually been increasing since the mid-1990s.

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

[0004] Recent research also suggests that, probably as a result of global warming, the geographical spread of many crop diseases and pests is increasing.

[0005] Certain picolinic acid derivatives have been shown to be useful for treating fungal diseases in PCT / GB2019 / 050111 (published as WO2019 / 141980).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of a specific embodiment of the present invention is to provide a pesticide (for example, a fungicide) that is non-selectively active, that is, has broad-spectrum activity, or is specifically active against a selected target organism.

[0009] An object of a specific embodiment of the present invention is to provide a compound that has lower persistence in the environment after use than the compounds of the prior art. Alternatively or additionally, the compounds of the present invention may be less likely to bioaccumulate than the compounds of the prior art once they enter the food chain.

[0010] Another object of a specific embodiment of the present invention is to provide a compound that is less harmful to humans than the compounds of the prior art. Alternatively or additionally, the compounds of the present invention may be less harmful than the compounds of the prior art to one or more of the following groups: amphibians, fish, mammals (including domestic animals such as dogs, cats, cows, sheep, pigs, goats, etc.), reptiles, birds, and beneficial invertebrates (for example, bees and other insects, or worms), beneficial nematodes, beneficial fungi, and nitrogen-fixing bacteria.

[0011] The compounds of the present invention can be as active as the compounds of the prior art or more active than the compounds of the prior art. They can be active against organisms that have developed resistance to the compounds of the prior art. However, the present invention can also relate to compounds having low or equivalent levels of activity compared to the activity of the compounds of the prior art. These low-activity compounds are still effective as fungicides but can have other advantages compared to existing compounds, such as reduced environmental impact.

[0012] The compounds of the present invention can be more selective than the compounds of the prior art, i.e., they can have better, equivalent or slightly lower activity against the target species than the compounds of the prior art, but significantly lower activity against non-target species (e.g., protected crops).

[0013] 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 be metabolized or react in an aqueous medium to give rise to an active compound.

Means for Solving the Problems

[0014] In a first aspect of the present invention, a compound of formula I, or an agriculturally acceptable salt or N-oxide thereof:

[0015]

Chemical Formula

[0016] [wherein, Y 1 is independently selected from O or S; R 1 , R 5a and R 15 are each independently, in each occurrence, C1-C6-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 selected from; R 2 and R 3 are each independently H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 , C(O)OR 14 , CH2OC(O)R 14 and CH2OC(O)OR 14 selected from; R 4 is independently selected from H, C3-C6-cycloalkyl, C1-C6-alkyl, and benzyl at each occurrence; or R 3 and R 4 together form a group independently selected from C1-C2-alkylene, -C(O)-, and -C(S)-; R 5 is a 10-membered heteroaryl group selected from quinoline, isoquinoline, and quinazoline; where R 5 is 1 to 5 R 5a groups and / or 1 Z 1 -Z 2 -R 6 group substituted; Z 1 is independently absent or CR 8 R 9 ; Z 2 is independently absent or 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 , NR7 S(O), CR 8 R 9 , C(O), C(S), C=NOR 10 , and NR 7 is selected from; R 6 is, independently at each occurrence, C3-C8-alkyl and C0-C3-alkylene-R 6a is selected from; where R 6a is, independently at each occurrence, selected from phenyl, 5- or 6-membered heteroaryl, 5-, 6-, 7- or 8-membered heterocycloalkyl and C5-C8-cycloalkyl; said heterocycloalkyl or cycloalkyl group is monocyclic or bicyclic; said heteroaryl or phenyl group is optionally substituted with 1-5 R 15 groups, or said heterocycloalkyl or cycloalkyl group is optionally substituted with 1-4 R 16 groups; R 16 is, independently at each occurrence, =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 is selected from, R 7 and R 12 are, independently at each occurrence, each selected from H, C3-C6-cycloalkyl, C1-C6-alkyl and benzyl; or when two R 12 groups are attached to the same nitrogen atom, said R 12 groups together with said nitrogen atom form a 4-, 5-, 6- or 7-membered heterocycloalkyl ring; R 8is, independently at each occurrence, selected from H, C3-C6-cycloalkyl, C1-C6-alkyl, phenyl and 5- or 6-membered heteroaryl; R 9 is, independently at each occurrence, selected from H, halo and OR 10 and; alternatively R 8 and R 9 may, together with the carbon atom to which they are attached, form a C3-C6-cycloalkyl ring or a 3-, 4-, 5- or 6-membered heterocycloalkyl ring; R 10 is, independently at each occurrence, selected from H, C3-C6-cycloalkyl, C1-C6-alkyl and C1-C3-alkylene-R 10a wherein R 10a is, independently at each occurrence, selected from phenyl and 5- or 6-membered heteroaryl; R 11 is, independently at each occurrence, selected from H, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)-C1-C6-alkyl and C1-C6-haloalkyl; R 13 is, independently at each occurrence, selected from H, C1-C6-alkyl, C(O)-C1-C6-alkyl and S(O)2-C1-C6-alkyl; or 12 groups and R 13 groups are attached to the same nitrogen atom, said R 12 and R 13 groups, together with said nitrogen atom, form a 4-, 5-, 6- or 7-membered heterocycloalkyl ring; R 14 is, independently at each occurrence, C1-C6-alkyl, phenyl, benzyl and C3-C6-cycloalkyl; n is an integer independently selected from 0, 1 and 2; m is an integer independently selected from 0, 1, 2 and 3; p is an integer independently selected from 0, 1, 2, 3 and 4; q is an integer independently selected from 0 and 1; Here, any of the aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including the case where two R 12 groups, or R 12 groups and R 13 groups together with the nitrogen to which they are attached form a heterocycloalkyl ring), alkynyl, C(O)-alkyl, S(O)2-alkyl, and benzyl, when chemically possible, are =O; =NR a , =NOR a , C1-C4-alkyl, halo, 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 are each independently optionally substituted by 1 to 4 substituents selected from the group consisting of; Here, R a is independently selected from H and C1-C4-alkyl; R b is independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl, and S(O)2-C1-C4-alkyl] is provided.

[0017] In certain embodiments, the compound of formula I is a compound of formula II:

[0018]

Chemical Formula

[0019] [wherein, R 1 , R 2 , R 3 , R4 , R 5a , n, Z 1 , Z 2 and R 6 are as described above for formula I; X 1 and X 2 one of which is nitrogen, 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; q is independently an integer selected from 0 and 1] is as follows.

[0020] In certain embodiments, the compound of formula I is a compound of formula III:

[0021]

Chemical formula

[0022] [wherein, R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 2 and R 6 are as described above for formula I; X 1 and X 2 one of which is nitrogen, X 1 and X 2 one of which is 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] is as follows.

[0023] In certain embodiments, the compound of formula I is a compound of formula IV:

[0024]

Chemical formula

[0025] [wherein, R 1 , R 2 , R5 and n is as described above for formula I; R 3a is 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 selected from] is.

[0026] In certain embodiments, the compound of formula I is a compound of formula V:

[0027]

Chemical formula

[0028] [wherein R 1 , R 2 , R 5 and n are as described above for formula I; Y 2 is independently selected from O and S] is.

[0029] In certain embodiments, the compound of formula I is a compound of formula VI:

[0030]

Chemical formula

[0031] [wherein R 1 , R 2 , R 5a , n, Z 1 , Z 2 and R 6 are as described above for formula I; X 1 and X 2 one of is nitrogen, X 1 and X 2 one of is carbon; m is an integer independently selected from 0, 1, 2 and 3; p is an integer independently selected from 0, 1, 2, 3 and 4; q is an integer independently selected from 0 and 1; R3a is 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 and is selected from] is.

[0032] In certain embodiments, the compound of formula I is a compound of formula VI:

[0033]

Chemical formula

[0034] [wherein R 1 , R 2 , R 5a , n, Z 1 , Z 2 and R 6 are as described above for formula I; one of X 1 and X 2 is nitrogen and one of X 1 and X 2 is carbon; m is an integer independently selected from 0, 1, 2, and 3; p is an integer independently selected from 0, 1, 2, 3, and 4; q is an integer independently selected from 0 and 1; Y 2 is independently selected from O and S] is.

[0035] In certain embodiments, the compound of formula I is a compound of formula VII:

[0036]

Chemical formula

[0037] [wherein R 1 , R 2 , R 5a , n, Z 2 and R 6 are as described above for formula I; X 1and X 2 One of which is nitrogen, X 1 and X 2 One of which is carbon; m is an integer independently selected from 0, 1, 2, and 3; p1 is an integer independently selected from 0, 1, 2, and 3; R 3a is independently H, C1-C4-alkyl, C3-C6-cycloalkyl, C(O)R 14 C(O)OR 14 CH2OC(O)R 14 and CH2OC(O)OR 14 selected from] is.

[0038] In certain embodiments, the compound of formula I is a compound of formula VIII:

[0039]

Chemical formula

[0040] [wherein R 1 R 2 R 5a n, Z 2 and R 6 are as described above for formula I; X 1 and X 2 One of which is nitrogen, X 1 and X 2 One of which is carbon; m is an integer independently selected from 0, 1, 2, and 3; p1 is an integer independently selected from 0, 1, 2, and 3; Y 2 is independently selected from O and S] is.

[0041] In certain embodiments, the compound of formula I is a compound of formula IX:

[0042]

Chemical formula

[0043] [wherein R 1 R2 , R 3 , R 4 , R 5a , n, Z 2 and R 6 is as described above for formula I; m is independently an integer selected from 0, 1, 2, and 3; p2 is independently an integer selected from 0, 1, and 2] is.

[0044] In certain embodiments, the compound of formula I is a compound of formula X:

[0045] [Chemical formula]

[0046] [Wherein, R 1 , R 2 , R 3 , R 4 , R 5a , n, Z 2 and R 6 is as described above for formula I; m1 is independently an integer selected from 0, 1, and 2; p1 is independently an integer selected from 0, 1, 2, and 3] is.

[0047] The following embodiments apply to any of the compounds of formulas (I)-(X). These embodiments are independent and interchangeable. Any one embodiment can be combined with any other embodiment if chemically acceptable. In other words, any of the features described in the following embodiments can be combined with the features described in one or more other embodiments (if chemically acceptable). In particular, when a compound is exemplified or described herein, any two or more of the embodiments listed below, represented at any level of generality and encompassing that compound, can be combined to provide further embodiments that form part of the present disclosure.

[0048] R 1 is independently, in each occurrence, C1-C4-alkyl, halo, and OR11 may also be selected from

[0049] n may be 1 or 2. However, preferably, n may be 0.

[0050] R 2 may independently be selected from H, C1-C4-alkyl and C3-C6-cycloalkyl. R 2 may independently be selected from C1-C4-alkyl and C3-C6-cycloalkyl. R 2 may be methyl or ethyl. R 2 may be methyl.

[0051] R 3 may independently be 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 from which R 3 may independently be selected from H, C(O)R 14 C(O)OR 14 CH2OC(O)R 14 and CH2OC(O)OR 14 from which R 3 may independently be selected from H and C(O)R 14 from which R 3 may be H. R 3 may be C(O)R 14 for example, C(O)Me.

[0052] R 4 may be selected from C3-C6-cycloalkyl, C1-C6-alkyl and benzyl. R 4 may be C1-C4-alkyl, for example, methyl. R 4 may be H.

[0053] R 3 and R 4may together form a group independently selected from C1-C2-alkylene, -C(O)- and -C(S)-. R 3 and R 4 may together form a -C(=Y 2 )- group; where Y 2 is independently selected from O and S.

[0054] Y 2 may be S. Y 2 may be O.

[0055] R 3 and R 4 may together form C1-C2-alkylene. R 3 and R 4 may together form C1 alkylene, such as CH2 or CMe2. R 3 and R 4 may together form C2 alkylene, such as CH2CMe2, CMe2CH2 or CH2CH2.

[0056] Y 1 may be S. Y 1 may be O.

[0057] R 5 may be quinoline. R 5 may be isoquinoline. R 5 may be quinazoline.

[0058] R 5 may be attached to the remainder of the molecule via a ring of a heteroaromatic group containing a nitrogen atom. R 5 may be attached to the remainder of the molecule via a ring of a heteroaromatic group not containing a nitrogen atom. R 5 may be attached to the remainder of the molecule via a carbon of a heteroaromatic group not adjacent to a carbon that is part of both rings of the heteroaromatic group. When present, Z 1 -Z 2 -R 6It may be bonded to R through a carbon atom of a heteroaromatic group that is not adjacent to a carbon atom that is part of both rings of the heteroaromatic group. 5 It may be bonded to

[0059] R 5 has the structure:

[0060]

Chemical formula

[0061] [wherein, one of X 1 , X 2 , X 3 and X 4 is nitrogen, and the other three of X 1 , X 2 , X 3 and X 4 are carbon; m is an integer independently selected from 0, 1, 2 and 3; p is an integer independently selected from 0, 1, 2, 3 and 4; q is an integer independently selected from 0 and 1] and may have

[0062] R 5 has the structure:

[0063]

Chemical formula

[0064] [wherein, one of X 1 and X 2 is nitrogen, one of X 1 and X 2 is carbon; m is an integer independently selected from 0, 1, 2 and 3; p is an integer independently selected from 0, 1, 2, 3 and 4; q is an integer independently selected from 0 and 1] and may have

[0065] R 5 has the structure:

[0066] [Chemical formula]

[0067] [In the formula, m is independently an integer selected from 0, 1, 2, and 3; p3 is independently an integer selected from 0, 1, 2, and 3; q is independently an integer selected from 0 and 1] may have.

[0068] R 5 has the structure:

[0069] [Chemical formula]

[0070] [In the formula, 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; R 5b is OR 11 and a C1-C6 alkyl group. may have. R 5b may be C1-C6 alkyl.

[0071] R 5 has the structure:

[0072] [Chemical formula]

[0073] [In the formula, m1 is independently an integer selected from 0, 1, and 2; p is independently an integer selected from 0, 1, 2, 3, and 4; q is independently an integer selected from 0 and 1] may have.

[0074] R 5 has the structure:

[0075] [Chemical formula]

[0076] [wherein, one of X 3 and X 4 is nitrogen, and one of X 3 and X 4 is carbon; m is an integer independently selected from 0, 1, 2, and 3; p is an integer independently selected from 0, 1, 2, 3, and 4; q is an integer independently selected from 0 and 1] may have.

[0077] R 5 has the structure:

[0078] [Chemical formula]

[0079] [wherein, m1 is an integer independently selected from 0, 1, and 2; p is an integer independently selected from 0, 1, 2, 3, and 4; q is an integer independently selected from 0 and 1] may have.

[0080] R 5 has the structure:

[0081] [Chemical formula]

[0082] [wherein, m is an integer independently selected from 0, 1, 2, and 3; p3 is an integer independently selected from 0, 1, 2, and 3; q is an integer independently selected from 0 and 1] may have.

[0083] R 5 has the structure:

[0084] [Chemical formula]

[0085] [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; q is independently an integer selected from 0 and 1] may have.

[0086] R 5 has the structure:

[0087]

Chemical formula

[0088] [wherein, m2 is independently an integer selected from 0 and 1; p is independently an integer selected from 0, 1, 2, 3 and 4; q is independently an integer selected from 0 and 1] may have.

[0089] R 5 has the structure:

[0090]

Chemical formula

[0091] [wherein, m is independently an integer selected from 0, 1, 2 and 3; p4 is independently an integer selected from 0, 1 and 2; q is independently an integer selected from 0 and 1] may have.

[0092] R 5 has the structure:

[0093]

Chemical formula

[0094] [wherein, m is independently an integer selected from 0, 1, 2, and 3; p4 is independently an integer selected from 0, 1, and 2; q is independently an integer selected from 0 and 1] may have.

[0095] q may be 0. However, preferably, q is 1.

[0096] When q is 1, Z 1 -Z 2 -R 6 group is preferably para to the point of attachment of R to the rest of the molecule. 5

[0097] R 5 has the structure:

[0098]

Chemical formula

[0099] [wherein, one of X 1 , X 2 , X 3 and X 4 is nitrogen, and the other three of X 1 , X 2 , X 3 and X 4 are 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] may have.

[0100] R 5 has the structure:

[0101]

Chemical formula

[0102] [wherein, one of X 1 and X 2 is nitrogen, and X 1 and X 2 ​One of them is 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. It may have.

[0103] R 5 has the structure:

[0104]

Chemical formula

[0105] [In the formula, X 3 and X 4 One of them is nitrogen, X 3 and X 4 One of them is 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. It may have. X 3 may be N. Alternatively, X 4 may be N.

[0106] R 5 has the structure:

[0107]

Chemical formula

[0108] [In the formula, m is, independently, an integer selected from 0, 1, 2, and 3; p2 is, independently, an integer selected from 0, 1, and 2. It may have.

[0109] R 5 has the structure:

[0110]

Chemical formula

[0111] [wherein, m1 is independently an integer selected from 0, 1 and 2; p1 is independently an integer selected from 0, 1, 2 and 3] may have.

[0112] m may be 0.

[0113] m1 may be 0.

[0114] m2 may be 0.

[0115] p may be 0. However, when q is 0, p is preferably at least 1.

[0116] p1 may be 0.

[0117] p2 may be 0.

[0118] p3 may be 0. However, when q is 0, p3 is preferably at least 1.

[0119] p4 may be 0. However, when q is 0, p4 is preferably at least 1.

[0120] p5 may be 0. However, when q is 0, p5 is preferably at least 1.

[0121] When present, R 5a is independently, in each occurrence, selected from cyano, nitro, C1-C4-alkyl, halo and OR 11 may be selected.

[0122] Z 1 may be CR 8 R 9 However, preferably, Z 1 does not exist. Z 1 -Z 2 -R 6 is Z 2 -R 6It may also be.

[0123] Z 2 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 may be selected from them. 2 Z may not exist, or be selected from C(O)O, OC(O), O, S, CR 8 R 9 and NR 7 Z may be selected from them. 2 Z may be selected from CR 8 R 9 S, NR 7 and O. Z may be selected from them. 2 Z may not exist, or be selected from NR 7 S, and O. Z may be selected from them. 2 Z may be selected from NR 7 S, and O. Z may be selected from them. 2 Z may be selected from O and S. 2 Z may be O. 2 Z may be S. 2 Z may be NR 7 Z may be it. 2 Z may be CR 8 R 9 Z may be it.

[0124] R 7 R may be H. However, preferably, R 7 is C1-C4-alkyl, for example, methyl.

[0125] Z 2 Z may not exist. 1 -Z 2 -R 6 may be R 6 Z may be it.

[0126] R 6 R may be CH2R 6a Z may be it. Alternatively, R 6 R may be R 6a Z may be it.

[0127] Z 1 -Z 2 -R 6 may be Z 1 -Z 2 -R 6a or may be Z 1 -Z 2 -R 6 may be Z 2 -R 6a or may be Z 1 -Z 2 -R 6 may be R 6a or may be

[0128] R 6a may be phenyl which is optionally substituted, for example unsubstituted phenyl. R 6 may be phenyl which is optionally substituted, for example unsubstituted phenyl.

[0129] R 6a has the structure:

[0130] [wherein, x is an integer selected from 0, 1, 2, 3, 4 and 5]

[0131] and may have

[0132] 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.

[0133] R 15 in one occurrence, may be located para to Z 2

[0134] R 6a has the structure:

[0135] [Chemical formula] ​​

[0136] [wherein, y is an integer selected from 0, 1, 2, 3 and 4] may have.

[0137] y may be at least 1. y may be 1 or 2. y may be 1. y may be 0.

[0138] R 6a has the structure:

[0139]

Chemical formula

[0140] may have.

[0141] R 15 is, in each occurrence, independently selected from cyano, nitro, C1-C4-alkyl, C1-C4-haloalkyl, halo, S-R 12 and O-R 11 and may be selected. R 15 is, in each occurrence, independently selected from C1-C4-alkyl, C1-C4-haloalkyl and halo.

[0142] R 6a may be 6-membered heteroaryl, for example pyridine.

[0143] R 6a is

[0144]

Chemical formula

[0145] and may have a structure selected from.

[0146] R 6may be C3-C8-alkyl, such as C3-C6-alkyl. This is when Z 2 is O, S and NR 7 is particularly preferred when selected from.

[0147] The compound of formula (I) is

[0148]

Chemical formula

[0149] may be selected from.

Mode for carrying out the invention

[0150] C m ~C n The term refers to a group having m to n carbon atoms.

[0151] The term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon chain. For example, C1-C6-alkyl may refer to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group may independently be fluorine, OR a or NHR a and may be.

[0152] The term "alkylene" refers to a straight-chain saturated divalent hydrocarbon chain. The alkylene group may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkylene group may independently be C1-C4-alkyl, fluorine, OR a or NHR a and may be.

[0153] The term "haloalkyl" refers to a hydrocarbon group substituted with at least one halogen atom independently selected in 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, such as 1-chloroethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoroethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. The haloalkyl group may be a fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom. Thus, the haloalkyl group may have any amount of halogen substituents. This group may contain a single halogen substituent, which may have two or three halogen substituents, or it may be saturated with halogen substituents.

[0154] 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 at any possible position in the hydrocarbon chain. For example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl group may be unsubstituted or substituted with one or more substituents. The specific substituents for any saturated carbon atom in each alkenyl group may independently be fluorine, OR a or NHR a and may be.

[0155] The term "alkynyl" refers to a branched or straight-chain hydrocarbon chain containing at least one triple bond. The triple bond can be at any possible position in the hydrocarbon chain. For example, "C2-C6-alkynyl" can refer to ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The alkynyl group may be unsubstituted or substituted by one or more substituents. The specific substituents for any saturated carbon atom in each alkynyl group are independently fluorine, OR a or NHR a and can be.

[0156] 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" can refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl group may be unsubstituted or substituted by one or more substituents. The specific substituents for each cycloalkyl group are independently fluorine, OR a or NHR a and can be.

[0157] The term heterocycloalkyl refers to a monocyclic or bicyclic saturated or partially saturated group having the number of atoms shown in the ring system and containing one or two heteroatoms independently selected from O, S, and N (in other words, one or two of the atoms forming the ring system are selected from O, S, and N). Partially saturated means that the ring may contain one or two double bonds. This particularly applies to 5- to 6-membered monocyclic rings. The double bond is typically between two carbon atoms, but may 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, azepine. The heterocycloalkyl group may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each heterocycloalkyl group are independently fluorine, OR a or NHR a and may be.

[0158] An aryl group can be any aromatic carbocyclic ring system (i.e., a ring system containing 2(2n + 1) π electrons). The aryl group can have 6 to 12 carbon atoms in the ring system. The aryl group is typically a phenyl group. The aryl group may be a naphthyl group or a biphenyl group.

[0159] In any of the above aspects and embodiments, the heteroaryl group may be a 5- to 10-membered ring system of any aromatic (i.e., a ring system containing 2(2n + 1) π electrons), containing 1 to 4 heteroatoms independently selected from O, S, and N (in other words, 1 to 4 of the atoms forming the ring system are selected from O, S, and N). Thus, any heteroaryl group may be a 5-membered heteroaryl group in which the heteroaromatic ring is substituted with 1 to 4 heteroatoms (14 heteroatoms) independently selected from O, S, and N; and a 6-membered heteroaryl group in which the heteroaromatic ring is substituted with 1 to 3 (e.g., 1 to 2) nitrogen atoms; a 9-membered bicyclic heteroaryl group in which the heteroaromatic system is substituted with 1 to 4 heteroatoms independently selected from O, S, and N; and a 10-membered bicyclic heteroaryl group in which the heteroaromatic system is substituted with 1 to 4 nitrogen atoms. Specifically, the heteroaryl group 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, benzoisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.

[0160] In any group that is an aryl or heteroaryl group, the aryl or heteroaryl group may be unsubstituted or, where chemically possible, halo, nitro, cyano, NR a R a 、NR a S(O)2R a 、NR a C(O)R a 、NR a CONR a R a 、NR a CO2R a 、OR a 、SR a 、S(O)Ra 、 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 may each independently be optionally substituted by 1 to 5 substituents selected in each occurrence; wherein R a and R b are as defined above for formula I.

[0161] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When the compounds of the invention contain a double bond such as a C=C or C=N group, geometric cis / trans (or Z / E) isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism, for example, in compounds of the invention containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. As a result, a single compound can exhibit more than one type of isomerism.

[0162] Within the scope of the invention are included all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, compounds exhibiting more than one type of isomerism, and one or more mixtures thereof.

[0163] The compounds of the present invention can be obtained, stored, and / or used in the form of agriculturally acceptable salts. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of agriculturally acceptable organic acids 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, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Suitable salts also include salts of inorganic bases and organic bases, for example, salts of counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium, etc. The compounds can also be obtained, stored, and / or used in the form of N-oxides. Acid addition salts or base salts in which the counterion is optically active; for example, d-lactate or l-lysine, or racemates; for example, dl-tartrate or dl-arginine are also included.

[0164] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0165] Conventional techniques for preparing / isolating individual enantiomers as needed 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 (and their chiral precursors) of the present invention can be obtained in an enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume, typically 2% to 20% isopropanol, and as a specific example, 0 to 5% by volume of an alkylamine, for example 0.1% diethylamine. By concentrating the eluate, an enriched mixture is obtained.

[0166] Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of the invention contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers may be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers may be converted to the corresponding pure enantiomers by means well known to those skilled in the art.

[0167] When any racemate crystallizes, two different types of crystals are possible. The first type is the above-mentioned racemic compound (true racemate) in which one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate in which two forms of crystals each containing a single enantiomer are produced in equimolar amounts.

[0168] Both crystal forms present in the racemic mixture have the same physical properties, but they may have different physical properties compared to the true racemate. The racemic mixture can 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).

[0169] The activity of the compounds of the invention can be evaluated by various in silico, in vitro and in vivo assays. In silico analysis of various compounds has been demonstrated to predict final in vitro activity and further in vivo activity.

[0170] The invention also includes all environmentally acceptable isotope-labeled compounds of Formulas I - X in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number typically found in nature, and their synthesis.

[0171] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H and 3 H, isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, isotopes of phosphorus, such as 32 P, and isotopes of sulfur, such as 35 S.

[0172] Isotopically labeled compounds can generally be prepared by processes similar to the described processes by conventional techniques known to those skilled in the art or by using appropriate isotopically labeled reagents in place of the unlabeled reagents previously used.

[0173] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of those words, such as "comprising" and "comprises", mean "include but are not limited to", and are not intended to (and do not) exclude other parts, additives, components, integers or steps.

[0174] Throughout the description and claims of this specification, unless the context requires otherwise, the singular form includes the plural. In particular, when an indefinite article is used, the specification should be understood to contemplate not only the singular form but also the plural form, unless the context requires otherwise.

[0175] Features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular embodiment, embodiment or example of the invention are to be understood as applicable to any other embodiment, embodiment or example described herein, unless incompatible.

[0176] Where appropriate, the compounds of the invention can be used as fungicides at a particular concentration or application rate.

[0177] According to another aspect of the invention, there is provided a method for controlling a fungal disease, comprising applying an agriculturally effective and substantially non-phytotoxic (to crop plants) amount of a compound of the invention to a plant seed, to the plant itself, or to the area in which the plant is intended to grow.

[0178] The agrochemical can be applied as a seed treatment, foliar spray, stem spray, perfusion or drip irrigation (chemical solution irrigation) to seeds, plants or plant fruits, or to soil or an inert substrate (e.g., inorganic substrates such as sand, rock wool, glass wool; expanded minerals such as perlite, vermiculite, zeolite or expanded clay), pumbe, frangible materials or substances, synthetic organic substrates (e.g., polyurethane), organic substrates (e.g., peat, compost, coir, wood waste such as wood fibers or chips, bark), or liquid substrates (e.g., floating hydroponic systems, nutrient film technique, aeroponics).

[0179] In a further aspect, the 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.

[0180] The term "effective and non-phytotoxic amount" means an amount of the pesticidal agent according to the invention which is sufficient to control or destroy any of the target diseases present in or likely to appear in the crop and which does not exert a significant harmful effect on the crop or, in the absence of the target organisms, actually has a beneficial effect on the plant vigour and yield. This amount will vary depending on the disease to be controlled, the type of crop, the climatic conditions and the compounds contained in the pesticidal composition. This amount can be determined by systematic field trials which are within the capabilities of the person skilled in the art.

[0181] Depending on their particular physical and / or chemical properties, the active compounds of the invention can be formulated as solutions, emulsions, suspension concentrates, powders, foams, pastes, granules, aerosols, microcapsules in polymeric substances and coating materials for seeds, and also as ULV cold and warm spray formulations.

[0182] The active compounds can be used as such or in the form of formulations, for example as directly utilisable solutions, emulsions, aqueous or oily suspension concentrates, powders, wettable powders, pastes, soluble powders, dusts, soluble granules, spreading granules, suspoemulsion concentrates, natural substances impregnated with the active compound, synthetic substances impregnated with the active compound, fertilisers, and also in the form of microcapsules in polymeric substances. Application can be effected, for example, by watering, spraying, atomising, scattering, dusting, foaming, diffusion, etc. It is also possible to apply the active compounds by the ultra-low volume method or to inject preparations of the active compound or the active compound itself into the soil. It is also possible to treat the seeds of plants.

[0183] The formulations containing the compounds of the invention are prepared in a known manner, for example by mixing the compounds with extenders (for example liquid solvents and / or solid carriers), optionally using surface-active agents (for example emulsifiers and / or dispersants and / or foam formers). The formulations are prepared either in a factory / manufacturing plant or else immediately before or during application.

[0184] An adjuvant is a substance suitable for imparting specific properties such as certain technical properties and / or even more specific biological properties to the composition itself and / or preparations derived therefrom (e.g., spray liquid, seed coating). Typical suitable adjuvants are extenders, solvents and carriers.

[0185] Suitable extenders are, for example, water, polar and non-polar organic chemical liquids such as aromatic and non-aromatic hydrocarbons (e.g., paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), alcohols and polyols (which may be substituted, etherified and / or esterified where appropriate), ketones (e.g., acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, unsubstituted and substituted amines, amides, lactams (e.g., N-alkylpyrrolidone) and lactones, sulfones, and sulfoxides (e.g., dimethyl sulfoxide) from the class.

[0186] When the extender used is water, it is also possible, for example, to use an organic solvent as a co-solvent. Essentially, suitable liquid solvents are aromatic compounds such as xylene, toluene or alkylnaphthalene; chlorinated aromatic compounds and chlorinated aliphatic hydrocarbons such as chlorobenzene, chloroethylene or methylene chloride; aliphatic hydrocarbons such as cyclohexane or paraffins such as 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.

[0187] 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 micronized silica, alumina and silicates; suitable solid carriers for granules are, for example, ground and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, and also synthetic granules of inorganic and organic powders, and granules of organic materials such as paper, sawdust, coconut shells, corn cobs and tobacco stalks; suitable emulsifiers and / or foam formers are, for example, nonionic and anionic emulsifiers such as polyoxyethylene fatty acid esters, polyoxyethylene aliphatic alcohol ethers such as alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and furthermore protein hydrolyzates; suitable dispersants are nonionic and / or ionic substances such as alcohol-POE and / or -POP ethers, acids and / or POP-POE esters, alkylaryl and / or POP-POE ethers, fatty- 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 those from the class of the corresponding PO-ether adducts. Furthermore, suitable oligomers or polymers are, for example, those derived from vinyl monomers, from acrylic acid, from EO and / or PO, alone or in combination, for example, with (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.

[0188] Adhesion promoters such as carboxymethyl cellulose, and natural and synthetic polymers in the form of powders, granules or latexes such as gum arabic, polyvinyl alcohol and polyvinyl acetate, and natural phospholipids such as cephalin and lecithin, and synthetic phospholipids can be used in the formulation.

[0189] Further additives can be mineral and vegetable oils. It is also possible to add colorants such as inorganic pigments such as iron oxide, titanium oxide and Prussian blue, and organic dyes such as alizarin dyes, azo dyes and metal phthalocyanine dyes, and micronutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc. Other possible additives are fragrances, minerals or plants, optionally modified oils and waxes.

[0190] The formulations can also include stabilizers such as cryo-stabilizers, preservatives, antioxidants, light stabilizers or other agents that improve chemical and / or physical stability.

[0191] The formulations generally contain 0.01 to 98% by weight, preferably 0.1 to 95% by weight, particularly preferably 0.5 to 90% by weight of the active compound.

[0192] The active compounds according to the invention can also be used as mixtures with other known fungicides, for example to improve the active spectrum or to reduce or delay the development of resistance. Mixtures with other known active compounds such as nematicides, herbicides, insecticides, acaricides or fungicides, or mixtures with fertilizers and growth regulators, phytotoxicity reducers or semiochemicals are also possible.

[0193] Exemplary application rates of the active compounds according to the invention are: when treating leaves: 0.1 to 10000 g / ha, preferably 10 to 1000 g / ha, particularly preferably 50 to 300 g / ha (when the application is carried out by spraying or dripping, particularly when an inert substrate such as rock wool or perlite is used, it is also possible to reduce the application rate); when treating seeds: 2 to 200 g per 100 kg of seeds, preferably 2.5 to 150 g per 100 kg of seeds, particularly preferably 2.5 to 25 g per 100 kg of seeds, very particularly preferably 2.5 to 12.5 g per 100 kg of seeds; when treating soil: 0.1 to 10000 g / ha, preferably 1 to 5000 g / ha.

[0194] The compositions according to the invention are suitable for protecting any plant variety used in agriculture, greenhouses, forests or horticulture, in particular cereals (such as wheat, barley, rye, millet and oats), maize, cotton, soybeans, rice, potatoes, sunflowers, legumes, coffee, beet (such as sugar beet and fodder beet), peanuts, vegetables (such as tomatoes, cucumbers, onions and lettuce), lawns, fruit and nut trees (such as apples, pears, peaches, nectarines, apricots, hazelnuts, pecans, macadamias, pistachios), soft fruits (such as strawberries, raspberries, blackberries, redcurrants), grapes, bananas, cocoa, as well as ornamental plants.

[0195] The active compounds of the invention, in combination with good plant tolerance, favorable toxicity to warm-blooded animals and better environmental tolerance, are suitable for protecting plants and plant organs, increasing yields, improving the quality of harvested products, and controlling diseases encountered in agriculture, horticulture, animal husbandry, forests, gardens and leisure facilities, in the protection of stored products and materials, and also in the health sector, in particular fungal diseases. They can preferably be used as crop protection agents.

[0196] Use as a fungicide The compounds of the invention have activity as fungicides.

[0197] The following are examples of agricultural diseases that can be controlled by the fungicidal compounds: Powdery mildew diseases, for example: diseases caused by Blumeria, for example Blumeria graminis; diseases caused by Podosphaera, for example Podosphaera leucotheca; diseases caused by Sphaerotheca, for example Sphaerotheca fuliginea; diseases caused by Uncinula, for example Uncinula necator; rust diseases, for example: diseases caused by Gymnosporangium, for example Gymnosporangium sabinae; diseases caused by Hemileia, for example Hemileia vastatix; diseases caused by Phakopsora, for example Phakopsora pachyrhizi or Phakopsora meibomiae; diseases caused by Puccinia, for example Puccinia recondita; diseases caused by Uromyces, for example Uromyces appendiculatus; oomycete diseases, for example: diseases caused by Albugo, for example Albugo Candida; Diseases caused by Bremia, such as those caused by Bremia lactucae; diseases caused by Peronospora, such as those caused by Peronospora pisi or Peronospora brassicae; diseases caused by Phytophthora, such as those caused by Phytophthora infestans; diseases caused by Plasmopara, such as those caused by Plasmopara viticola; diseases caused by Pseudoperonospora, such as those caused by Pseudoperonospora humuli or Pseudoperonospora cubensis; diseases caused by Pythium, such as those caused by Pythium ultimum; Leaf spot diseases, leaf blotch diseases and leaf blight diseases, for example: those caused by Alternaria diseases, for example Alternaria solani; Cercospora diseases, for example Cercospora beticola; Cladiosporum diseases, for example Cladiosporium cucumerinum; Cochliobolus diseases, for example Cochliobolus sativus; Colletotrichum diseases, for example Colletotrichum lindemuthanium; Cycloconium diseases, for example Cycloconium oleaginum; Diaporthe diseases, for example Diaporthe citri; Drechslera, synonym: Helminthosporium or Cochliobolus miyabeanus; Elsinoe diseases, for example those caused by Elsinoe fawcettii; Gloeosporium diseases, for example Gloeosporium laeticolor; Glomerella diseases, for example Glomerella cingulata; Guignardia diseases, for example Guignardia bidwelli; Leptosphaeria diseases, for example Leptosphaeria maculans; those caused by Leptosphaeria nodorum;Diseases caused by Magnaporthe, such as those caused by Magnaporthe grisea; diseases caused by Mycosphaerella, such as Mycosphaerella graminicola; Mycosphaerella arachidtola; those caused by Mycosphaerella fibensis; diseases caused by Phaeosphaeria, such as those caused by Phaeosphaeria nodorum; diseases caused by Pyrenophora, such as those caused by Pyrenophora teres; diseases caused by Ramularia, such as those caused by Ramularia collo-cygni; diseases caused by Rhynchosporium, such as those caused by Rhynchosporium secalis; diseases caused by Septoria, such as those caused by Septoria apii or Septoria lycopercisi; diseases caused by Typhula, such as those caused by Typhula incarnata; diseases caused by Venturia, such as those caused by Venturia inaequalis; Root and stem diseases, such as: Corticium diseases, such as those caused by Corticium graminearum; Fusarium diseases, such as those caused by Fusarium oxysporum; Gaeumannomyces diseases, such as those caused by Gaeumannomyces graminis; Rhizoctonia diseases, such as those caused by Rhizoctonia solani; Sarocladium diseases, such as those caused by Sarocladium oryzae; Sclerotium diseases, such as those caused by Sclerotium oryzae; Tapesia diseases, such as those caused by Tapesia acuformis; Thielaviopsis diseases, such as those caused by Thielaviopsis basicola; Ear and panicle diseases including maize ear axes, such as: diseases caused by Alternaria, such as those caused by Alternaria spp.; diseases caused by Aspergillus, such as those caused by Aspergillus flavus; diseases caused by Cladosporium, such as those caused by Cladosporium spp.; diseases caused by Claviceps, such as those caused by Claviceps purpurea; diseases caused by Fusarium, such as those caused by Fusarium culmorum; diseases caused by Gibberella, such as those caused by Gibberella zeae; diseases caused by Monographella, such as those caused by Monographella nivalis; Smut and bunt diseases, such as: diseases caused by Sphacelotheca, such as those caused by Sphacelotheca reiliana; diseases caused by Tilletia, such as those caused by Tilletia caries; diseases caused by Urocystis, such as those caused by Urocystis occulta; diseases caused by Ustilago, such as those caused by Ustilago nuda; Fruit rot and mold diseases, such as: those caused by Aspergillus diseases, such as Aspergillus flavus; Botrytis diseases, such as Botrytis cinerea; Penicillium diseases, such as Penicillium expansum; Rhizopus diseases, such as Rhizopus stolonifer; Sclerotinia diseases, such as Sclerotinia sclerotiorum; Verticilium diseases, such as those caused by Verticilium alboatrum; Decay, mold, withering, rot, and damping-off of seeds and soil, for example: those caused by Alternaria diseases, such as Alternaria brassicicola; Aphanomyces diseases, such as Aphanomyces euteiches; Ascochyta diseases, such as Ascochyta lentis; Aspergillus diseases, such as Aspergillus flavus; Cladosporium diseases, such as Cladosporium herbarum; Cochliobolus diseases, such as Cochliobolus sativus (conidial form: Drechslera, Bipolaris, synonym: Helminthosporium); Colletotrichum diseases, such as Colletotrichum coccodes; Fusarium diseases, such as Fusarium culmorum; Gibberella diseases, such as Gibberella zeae; Macrophomina diseases, such as Macrophomina phaseolina; Monographella diseases, such as Monographella nivalis; Penicillium diseases, such as Penicillium expansum; Phoma diseases, such as Phoma lingam; Phomopsis diseases, such as Phomopsis sojae; Phytophthora diseases, such as Phytophthora cactorum; Pyrenophora diseases, such as Pyrenophora graminea; Pyricularia diseases, such as Pyricularia oryzae; Pythium diseases, such as Pythium ultimum; Rhizoctonia diseases, such as Rhizoctonia solani; Rhizopus diseases, such as Rhizopus oryzae;Diseases caused by Sclerotium, such as those caused by Sclerotium rolfsii; Septoria diseases, such as those caused by Septoria nodorum; Tifula diseases, such as those caused by Tifula incarnata; Verticillium diseases, such as those caused by Verticillium dahliae; Canker diseases, witches' broom diseases and dieback diseases, such as: Nectria diseases, such as those caused by Nectria galligena; Sheath blight diseases, such as: Monilinia diseases, such as those caused by Monilinia laxa; Leaf blister diseases or leaf curl diseases, such as: Exobasidium diseases, such as those caused by Exobasidium vexans; Taphrina diseases, such as those caused by Taphrina deformans; Decline diseases of woody plants, such as: Esca diseases, such as those caused by Phaeomoniella clamydospora, Phaeomoniella chlamydospora, Phaeoacremonium aleophilum and Fomitiporia mediterranea; Eutypa dieback, such as those caused by Eutypa lata; Dutch elm disease, such as those caused by Ceratocystis ulmi; Ganoderma diseases, such as those caused by Ganoderma boninense; Diseases of flowers and seeds, such as: Botrytis diseases, such as those caused by Botrytis cinerea; Tuber diseases, such as: Rhizoctonia diseases, such as those caused by Rhizoctonia solani; Helminthosporium diseases, such as those caused by Helminthospohum solani. Tuber diseases, such as: Rhizoctonia diseases, such as those caused by Rhizoctonia solani; Helminthosporium diseases, such as those caused by Helminthospohum solani; Clubroot diseases, such as: Plasmodiophora diseases, such as those caused by Plamodiophora brassicae.

[0198] The compounds of the present invention can be active against a wide range of fungal diseases of plants. Alternatively, they can be specifically active against certain specific fungal diseases.

[0199] Specific fungal diseases for which the compounds of the present invention may be useful include Septoria tritici, Puccinia triticina, Puccinia striiformis, Venturia inaequalis, Uncinula necator, Rhynchosporium secalis, Magnaporthe grisea, Phakopsora pachyrhizi, Leptosphaeria nodorum, Blumeria graminis f. sp. tritici, Blumeria graminis f. sp. hordei, Erysiphe dehor acearum, Glomerella lagenarium, Cercospora beticola, Alternaria solani, and Cochliobolus sativus.

[0200] In addition to their fungicidal activity, the compounds of the present invention may also be active against other microorganisms, such as bacteria.

[0201] The fungicidal compounds of the present invention may also be used in the treatment of fungal diseases in humans and animals (e.g., mammals). Similarly, the bactericidal compounds of the present invention may be used in the treatment of bacterial diseases in humans and animals. Accordingly, the present invention includes a method of treating a fungal or bacterial disease, the method comprising administering a therapeutically effective amount of an antifungal agent of the present invention to a subject in need thereof (e.g., a human subject). The compound may be formulated for topical administration to the infected area of the body, or may be formulated for oral or parenteral administration.

[0202] Synthesis Those skilled in the art will understand that the application of methods known in the art can be applied in the production of the compounds of the present invention.

[0203] For example, those skilled in the art will immediately be familiar with standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (since the 1999 edition); "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (since the 5th edition); "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic / Plenum Publications, (since the 2001 edition); "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (since the 1982 edition); "Designing Organic Syntheses" S Warren (Wley) (since the 1983 edition); "Heterocyclic Chemistry", J. Joule (Wley 2010 edition and later); ("Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (since the 1982 edition), etc., as well as the references therein.

[0204] Those skilled in the art are familiar with a series of strategies for synthesizing organic and especially heterocyclic molecules, which are common general knowledge as described 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".

[0205] Those skilled in the art exercise their judgment and skills regarding the most efficient sequence of reactions for synthesizing a given target compound and use 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 affects the choice of reagents used in the synthesis process, the necessity and type of protecting groups employed, and the sequence for achieving the protection / deprotection steps. These and other reaction parameters will be apparent to those skilled in the art by reference to standard textbooks and the examples provided herein.

[0206] Sensitive functional groups may need to be protected and deprotected during the synthesis of the compounds of the present invention. This can be achieved by conventional methods as described, for example, in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc. (1999), and the references therein.

[0207] Throughout this specification, these abbreviations have the following meanings:

[0208] Throughout this specification, these abbreviations have the following meanings: PyBOP - benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate HATU - (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DIPEA - N,N-Diisopropylethylamine DMSO - Dimethyl sulfoxide aq. - Aqueous conc. - Concentrated DCM - Dichloromethane DMF - N,N-Dimethylformamide h - Hour min - Minute LCMS - Liquid chromatography mass spectrometry rt - Room temperature PE - Petroleum ether THF - Tetrahydrofuran XPHos - 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0209] Certain compounds of the present invention can be accessed according to or similar to the following general synthetic schemes. Certain compounds of the present invention can be accessed via the synthetic intermediates described in Examples 1 to 46 below.

[0210] General synthetic scheme The compounds of formula I can be prepared according to Schemes A to D. The quinoline of formula A is commercially available. Using the activating group X on quinoline A as a means, Z 1 -Z 2 -R 6 groups can be introduced to obtain quinoline B. Z 1 -Z 2 -R 6 can be introduced using a coupling reaction (e.g., Buchwald-Hartwig, Suzuki) with a suitable coupling partner (e.g., boronic acid ester), in which case X may be a halogen, e.g., bromide, or a boronic acid ester. Alternatively, Z 1 -Z 2 -R 6can be introduced using an addition - elimination reaction, in which case X may be a leaving group such as a halogen, such as chloro, or a sulfonate, such as methyl sulfonate. The addition / elimination reaction is particularly suitable when Z 1 -Z 2 -R 6 is Z 2 R 6 and Z 2 is O, S or NR 7 In these reactions, quinoline A is usually treated with R 6 -Z 2 -H in the presence of a base (e.g., NaH or Na2CO3). Then, amine C is obtained, for example, by reduction of the nitro group using Fe and NH4CI and using Pd / C and H2. When R 4 is not H, R 4 can be introduced at this stage, for example, using an alkyl halide. Compounds of formula F, which are a subset of the compounds of the present invention, are formed by amide formation with picolinic acid derivatives D (e.g., using LiHMDS) or E (e.g., using HATU).

[0211]

Chemical formula

[0212] Alternatively, the compounds of the present invention can be accessed via quinoline G. For example, amine H can be obtained by amine formation by heating with acetamide and K2CO3 at 200 °C. Compounds of formula J can be obtained by a palladium - coupling reaction (e.g., Suzuki) with a suitable halide or boronic acid ester. When R 4 is not H, R 4 can be introduced at this stage, for example, using an alkyl halide. Compounds of formula K, which are a subset of the compounds of the present invention, are formed by amide formation with picolinic acid derivatives D (e.g., using LiHMDS) or E (e.g., using HATU).

[0213] [Chemistry]

[0214] In a further alternative, the compounds of the invention can be accessed via quinoline L. By means of a palladium coupling reaction (e.g., Suzuki) with a suitable halide or boronic acid ester, compounds of formula M, which are a subset of the compounds of the invention, can be obtained. By Boc deprotection, the corresponding amine N is obtained. When R 4 is not H, R 4 can be introduced at this stage, for example using an alkyl halide. By amide formation with a picolinic acid derivative D (e.g., using LiHMDS) or E (e.g., using HATU), compounds of formula O, which are a subset of the compounds of the invention, are formed.

[0215] [Chemistry]

[0216] Compounds of formula F, K and O (generalized hereinafter as formula P) are two further subsets of the compounds of the invention, compounds of formula Q (e.g., using Ac2O) or R (e.g., when Y 2 is S, using thiophosgene, or when Y 2 is O, using triphosgene).

[0217] [Chemistry] [Examples]

[0218] General method Flash chromatography was carried out on 500m 2Biotage (registered trademark) SNAP KP-Sil cartridges filled with 50 μm silica particles having a surface area of / g, or Biotage Isolera 4 using an alternative cartridge (e.g., Puriflash manufactured by Interchim) if described, or using silica gel (40 - 63 μm particles). Visualization was performed by staining with any of potassium permanganate, phosphomolybdic acid (PMA), or ninhydrin solution using UV light (254 nm).

[0219] All 1 1H NMR spectra were acquired on a Bruker AVIII 400 equipped with a 5 mm QNP, or a Bruker AVI 500 equipped with a 5 mm QNP. Chemical shifts are expressed in parts per million (δ) and referenced to the solvent. Coupling constants J are expressed in Hertz (Hz).

[0220] LCMS was performed on a Waters Alliance ZQ MS using a YMC-Triart C18 50×2 mm, 5 micron LC column, according to Method A (solvent: acetonitrile gradient of 5 - 90% in water (containing 1 volume % of 28 (mass) % aqueous ammonia solution)), or according to Method B (solvent: acetonitrile gradient of 5 - 90% in water (containing 1% formic acid)). Flow rate: 0.8 mL / min. Wavelengths were 254 and 210 nm.

[0221] Method A (basic pH for 5 minutes) Column: YMC-Triart C18 50×2 mm, 5 μm. Flow rate: 0.8 mL / min. Injection volume: 5 μL. Mobile phase A H2O B CH3CN C 50% H2O / 50% CH3CN + 1.0% ammonia (aqueous solution)

[0222]

Table 1

[0223] Method B (acidic pH for 5 minutes) Column: YMC-Triart C18 50×2 mm, 5 μm. Flow rate: 0.8 mL / min. Injection volume: 5 μL. Mobile phase A H2O B CH3CN C 50% H2O / 50% CH3CN + 1.0% formic acid

[0224]

Table 2

[0225] Alternatively, MS was performed on a Waters Acquity UPLC-QDA UV-MS system using Method C (high pH) or Method D (low pH):

[0226] Method C (3.5 minutes at basic pH)

[0227]

Table 3

[0228] Method D (3.5 minutes at acidic pH)

[0229]

Table 4

[0230] All reagents were obtained from commercial suppliers and used as received unless otherwise stated.

[0231] All compounds were named using ChemBioDraw Ultra 14.0.

[0232] Intermediate A: 2-(4-fluorophenoxy)-6-nitroquinoline

[0233]

Chemical Structure

[0234] 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, then 2-chloro-6-nitroquinoline (250 mg, 1.20 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 4 hours and then quenched by pouring into water (20 mL). A precipitate 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 give the title compound as a beige solid (260 mg, 76%). 1H NMR (DMSO-d 6 ): 9.04 (d, J = 2.6 Hz, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.36 (dd, J = 9.2, 2.7 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.47 - 7.15 (m, 4H).

[0235] Intermediates B - D: The following intermediates were prepared from commercially available starting materials using the general method described for Intermediate A.

[0236]

Table 5

[0237] Intermediate E: 2-Isopropoxy-6-nitroquinoline

[0238]

Chemical Structure

[0239] 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 all at once, and the reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (3 mL), and a precipitate formed. The resulting mixture was stirred for 30 minutes, then EtOAc (3 mL) was added. The aqueous layer was extracted with EtOAc (3 × 3 mL), and the combined organics were dried (MgSO4) and evaporated in vacuo to give the title compound as a brown solid (44 mg, 79%). LCMS (Method B): 3.64 min, (333.0, MH + ).

[0240] Intermediates F - I: The following intermediates were prepared from commercially available starting materials using the general method described for Intermediate E.

[0241]

Table 6

[0242] Intermediate J: N-(4-Fluorophenyl)-N-methyl-6-nitroquinolin-2-amine

[0243]

Chem.

[0244] 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%). LCMS (Method B): 3.60 min, (298.1, MH + ).

[0245] Intermediate K: 2-((4-Fluorophenyl)thio)-6-nitroquinoline

[0246]

Chemical formula

[0247] 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 h. 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 (MgSO4) and concentrated under reduced pressure to give the title compound as a yellow solid (58 mg, 81%). LCMS (Method B): 3.62 min, (301.0, MH + )

[0248] Intermediate L: 2-(4-Fluorophenoxy)quinolin-6-amine

[0249]

Chemical formula

[0250] 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 h. After cooling to room temperature, the mixture was filtered through Dicalite® and washed with EtOAc. The filtrate was washed with water, dried (MgSO4) and concentrated under reduced pressure to give the title compound as an off-white solid (185 mg, 80%). LCMS (Method D): 1.62 min, (255.1, MH + )

[0251] Intermediates M to W: The following intermediates were prepared from the appropriate intermediates using the general methods described for Intermediate L.

[0252]

Table 7A

[0253]

Table 7B

[0254] Intermediate X: tert-Butyl (3-benzylquinolin-6-yl) carbamate

[0255]

Chemical formula

[0256] 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 (3-bromoquinolin-6-yl) 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 filtered through Dicalite® and washed with EtOAc (30 mL). The filtrate was dried (MgSO4) and concentrated under reduced pressure to give the crude residue of the title compound (estimated quantitative yield), which was used in the next step without further purification. LCMS (Method D): 3.02 min, (335.1, MH + )

[0257] Intermediate Y: 3-Benzylquinolin-6-amine

[0258]

Chemical formula

[0259] 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 h. The reaction mixture was neutralized with 1 M aqueous NaOH 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 (estimated quantitative yield), which was used in the next step without further purification. LCMS (Method B): 1.77 min, (235.0, MH + ).

[0260] Intermediate Z: 6-Bromoquinolin-2-amine

[0261]

Chemical Structure

[0262] A mixture of 6-bromo-2-chloroquinoline (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 h. The reaction mixture was cooled to room temperature where 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 (MgSO4) and concentrated in vacuo to give the title compound as a beige solid (780 mg, 34%). 1 H NMR δ 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 + ).

[0263] Intermediate AA: 6-Phenylquinolin-2-amine

[0264]

Chem.

[0265] 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 mixture was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (MgSO4) 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%). 1 H NMR δ H (400 MHz, 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 + ).

[0266] Intermediate AB: 6-Benzylquinolin-2-amine

[0267]

Chem.

[0268] 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), dichloromethane complex (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 (MgSO4) 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%). 1 H NMR δ H (400 MHz, 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 + ).

[0269] Intermediate AC: 4-Pentylquinolin-2-ol

[0270]

Chemical Structure

[0271] 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-Butyllithium (11.8 mL, 18.9 mmol) was added and the reaction was warmed to room temperature and stirred for 2 h. 1-Chlorobutane (1.31 mL, 12.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. Water (20 mL) was added to the reaction mixture, stirred for 10 min and then extracted with EtOAc (3 × 10 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as an off-white solid (500 mg, 37% yield). LCMS (Method B): 2.65 min, (216.1, MH + ).

[0272] Intermediate AD: 6-Nitro-4-pentylquinolin-2-ol

[0273]

Chem.

[0274] 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 followed by dropwise addition of nitric acid (97 μL, 2.32 mmol). The reaction mixture was stirred for 2 h and then poured onto a water / ice mixture (50 mL). A precipitate formed which was filtered and dried in vacuo to give the title compound as a pale yellow solid (410 mg, 68% yield). LCMS (Method B): 2.80 min, (261.1, MH + ).

[0275] Intermediate AE: 2-Chloro-6-nitro-4-pentylquinoline

[0276]

Chem.

[0277] A mixture of intermediate AD (410 mg, 1.58 mmol) and phosphorus oxychloride (V) (7.34 mL, 7.88 mmol) was stirred at room temperature for 18 h. The reaction mixture was added dropwise to ice-water (10 mL) and the resulting mixture was neutralized with a saturated aqueous solution of NaOH. The mixture was extracted with EtOAc (3 × 5 mL), 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 + ).

[0278] Intermediates AF - AJ: The following intermediates were prepared from commercially available starting materials using the general method described for Intermediate A.

[0279]

Table 8

[0280] Intermediate AK: 2-Chloro-6-nitro-5-propoxyquinoline

[0281]

Chem.

[0282] 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 h. The reaction was cooled to room temperature and water was added. The resulting suspension was stirred for 15 min and then filtered. The residue was washed with water and dried under vacuum to give the title compound as a pale yellow solid (292 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 8.92 (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 + ).

[0283] Intermediates AL - AO: The following intermediates were prepared from appropriate intermediates or commercially available starting materials using the general methods described for Intermediate K.

[0284]

Table 9

[0285] Intermediates AP - AX: The following intermediates were prepared from appropriate intermediates using the general methods described for Intermediate L.

[0286]

Table 10A

[0287]

Table 10B

[0288] (Example 1) N-(2 - Ethoxyquinolin - 6 - yl)-3 - hydroxy - 4 - methoxypicolinamide

[0289]

Chemical Structure

[0290] 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 h. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography (SiO2, 0 - 100% EtOAc in PE) to afford the title compound as a pale yellow solid (24 mg, 34%). 1 1H NMR δ H (DMSO-d 6 ): 12.26 (s, 1H), 11.04 (s, 1H), 8.43 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.17 (d, J = 5.3 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 5.5 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.45 (q, J = 6.9 Hz, 2H), 3.94 (d, J = 9.4 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H); LCMS (method B): 2.00 min, (340.0, MH + ).

[0291] (Examples 2 - 14) The following examples were prepared from the appropriate intermediates using the general method described in Example 1.

[0292]

Table 11A

[0293]

Table 11B

[0294]

Table 11C

[0295]

Table 11D

[0296] (Example 15) N-(6-Bromoquinolin-2-yl)-3-hydroxy-4-methoxypicolinamide

[0297]

Chem.

[0298] 6-Bromoquinolin-2-amine (69 mg, 0.30 mmol) was dissolved in DMF (4 mL), and 8-methoxy-2,2-dimethyl-4H-[1,3]dioxino[5,4-b]pyridin-4-one 2,2,2-trifluoroacetate (250 mg, 0.77 mmol) was added. A solution of sodium bis(trimethylsilyl)amide (0.8 mL, 1.5 mmol) was added, and the reaction mixture was stirred at 60 °C for 24 h. The reaction mixture was cooled to room temperature and then water (5 mL) was added. A precipitate formed, which was filtered, and the solid was slurried in ethanol, filtered, and dried under vacuum to give the title compound as a pale brown solid (14.3 mg, 16%). 1 H NMR δ H (400 MHz, DMSO-d 6 ) 15.80 (s, 1H), 8.66 (d, J = 9.7 Hz, 1H), 8.25 (d, J = 6.4 Hz, 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 visible); LCMS (Method B): 2.50 min, (374.0 / 375.9, MH + ).

[0299] (Example 16) 3-Hydroxy-4-methoxy-N-(6-phenylquinolin-2-yl)picolinamide

[0300]

Chem.

[0301] Following the procedure for Example 15, the title compound was obtained as a light brown solid (30 mg, 17%). 1 H NMR δ H (400 MHz, DMSO-d 6 ) 15.78 (s, 1H), 8.67 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.15 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 13.6, 8.0 Hz, 3H), 7.51 (t, J = 7.7 Hz, 2H), 7.44 (d, J = 4.6 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 6.61 (d, J = 4.7 Hz, 1H), 3.72 (s, 3H); LCMS (Method B): 2.82 min, (372.1, MH + ).

[0302] (Example 17) 2-((6-Bromoquinolin-2-yl)carbamoyl)-4-methoxypyridin-3-yl acetate

[0303]

Chem.

[0304] 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 co-evaporated successively with heptane, DCM and Et2O. The crude residue was purified by column chromatography (SiO2, 0 - 100% EtOAc in PE) to give the title compound as an orange solid (8 mg, 9%). 1 1H NMR δ H (400 MHz, DMSO-d 6 ) 10.85 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.49 - 8.38 (m, 2H), 8.27 (s, 1H), 7.92 - 7.78 (m, 1H), 7.54 (d, J = 5.5 Hz, 2H), 3.97 (s, 3H), 2.36 (s, 3H).

[0305] (Examples 18 - 19) The following examples were prepared from the appropriate intermediates using the general method described in Example 17.

[0306] [Table 12]

[0307] (Examples 20 - 28) The following examples were prepared from the appropriate intermediates using the general method described in Example 1.

[0308] [Table 13A]

[0309] [Table 13B]

[0310] [Table 13C]

[0311] (Examples 29 - 36) The following examples were prepared from the appropriate intermediates using the general method described in Example 17.

[0312] [Table 14A]

[0313] [Table 14B]

[0314] [Table 14C]

[0315] (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

[0316] [Chemical Structure]

[0317] 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), followed by 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 pale yellow solid (5.9 mg, 18%). 1 1H NMR δ H (DMSO-d 6): 8.61 (d, J = 5.4 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.61 (d, J = 5.5 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.18 (d, J = 8.7 Hz, 1H), 4.10 (s, 3H); LCMS (Method B): 3.19 min, (464.1, MH + ).

[0318] (Examples 38 - 46) The following examples were prepared from the appropriate intermediates using the general method described in Example 37.

[0319]

Table 15A

[0320]

Table 15B

[0321]

Table 15C

[0322] (Example 47) 2 - ((2 - Isopropoxyquinolin - 6 - yl)carbamoyl)-4 - methoxypyridin - 3 - ylacetate

[0323]

Chemical formula

[0324] Following the procedure for Example 17, the title compound was obtained as a pale yellow solid (24.5 mg, 94%). 1H NMR δ H(400 MHz, DMSO-d6) 10.72 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.40 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 11.2 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 5.5Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 5.52 - 5.39 (m, 1H), 3.94 (s, 3H), 2.31 (s, 3H), 1.36 (d, J = 6.2 Hz, 6H). LCMS (Method B): 3.98 min, (396.2, MH + ).

[0325] (Example 48) Test the fungicidal activity of the compounds of the present invention The compounds were screened in 96-well plates using 10 compounds per plate. Each compound was screened using agar amended with test substances at 20, 2, 0.2 and 0.02 ppm. 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 the plate.

[0326] The compounds were screened against Zymoseptoria tritici. The agar used in the test was 1% potato dextrose agar. Sufficient spores were added to the appropriate agar to obtain agar with 10,000 spores / mL.

[0327] ×10 stock solutions in 2% DMSO were generated for each dose, i.e., 200, 20, 2 and 0.2 ppm, and 10 μl of this was added to the appropriate wells on the plate. Equal volumes of 2% DMSO and 500 and 100 ppm proline stocks were added for controls. 90 μl of the appropriate agar spore suspension was added to each well to obtain the final well concentrations outlined in the first paragraph.

[0328] The plate was incubated at room temperature (18 °C) and evaluated after 7 days.

[0329] The amount of fungal growth in each well was compared to the DMSO control and scored according to the following legend: A - EC50 < 2 ppm B - 2 ≤ EC50 < 20 C - EC50 ≥ 20 D - No activity detected at the maximum dose tested NT - Not tested

[0330] The ranking in the table is as follows:

[0331]

Table 16A

[0332]

Table 16B

Claims

1. A compound of formula I, or an agriculturally acceptable salt or N-oxide thereof: 【Chemical 1】 [Wherein, Y 1 is independently selected from O or S; R 2 and R 3 are each independently H, C 1 ~C 4 -alkyl, and C(O)R 14 selected from; R 4 is H; or R 3 and R 4 together form -C(S)-; R 5 is quinoline substituted with 1 to 5 R 5a groups and / or 1 Z 1 -Z 2 -R 6 groups; R 5a and R 15 are each independently, in each occurrence, C 1 ~C 6 -alkyl, halo, and OR 11 selected from; Z 1 is independently absent or CR 8 R 9 ; Z 2 is independently absent or selected from O, S, and NR 7 ; R 6 is independently, in each occurrence, C 3 ~C 8 -alkyl, CH 2 R 6a and R 6a selected from; where R 6a is independently, in each occurrence, selected from phenyl and 5- or 6-membered heteroaryl; said heteroaryl or phenyl group is optionally substituted with 1 to 5 R 15 groups; R 7 is independently selected from H and C 1 ~C 6 -alkyl; R 8 and R 9 are each H; R 11 is independently, in each occurrence, C 1 ~C 6 -alkyl; R 14 is independently, in each occurrence, C 1 ~C 6 -alkyl; wherein any of the foregoing alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl, alkynyl, C(O)-alkyl, S(O) 2 -alkyl and benzyl are optionally substituted, in each occurrence, independently, with from 1 to 4 substituents selected from the group consisting of =O; =NR a , =NOR a , C 1 ~C 4 -alkyl, halo, nitro, cyano, C 1 ~C 4 -haloalkyl, C 2 ~C 4 -alkenyl, C 2 ~C 4 -alkynyl, NR a R b , S(O) 2 R a , S(O)R a , S(O)(NR a )R a , S(O) 2 NR a R a , CO 2 R a , C(O)R a , CONR a R a , OR a and SR a and is optionally substituted with from 1 to 4 substituents independently selected, in each occurrence, from the group consisting of; wherein R a is independently H and C 1 ~C 4-selected from -alkyl; R b is independently H, C 1 to C 4 -alkyl, C(O)-C 1 to C 4 -alkyl and S(O) 2 -C 1 to C 4 -alkyl].

2. R 2 is independently selected from C 1 to C 4 -alkyl, the compound according to claim 1.

3. R 3 is independently selected from H and C(O)R 14 the compound according to claim 1 or 2.

4. R 3 and R 4 together form -C(S)-, the compound according to claim 1 or 2.

5. Y 1 is O, the compound according to any one of claims 1 to 4.

6. R 5 has the structure 【Chemical Formula 2】 [wherein, one of X 1 , X 2 , X 3 and X 4 is nitrogen, and the other three of X 1 , X 2 , X 3 and X 4 are carbon; m is an integer independently selected from 0, 1, 2 and 3; p is an integer independently selected from 0, 1, 2, 3 and 4; q is 1] the compound according to any one of claims 1 to 5.

7. R 5 has the structure: 【Chemical Formula 3】 [wherein, one of X 1 , X 2 , X 3 and X 4 is nitrogen, and X 1 , X 2 , X 3 and X 4 are the other three carbon atoms; m is independently an integer selected from 0, 1, 2, and 3; p1 is independently an integer selected from 0, 1, 2, and 3] The compound according to claim 6, having

8. R 5 is of the structure: 【Chemical Formula 4】 [wherein, m is independently an integer selected from 0, 1, 2, and 3; p2 is independently an integer selected from 0, 1, and 2] The compound according to claim 6, having

9. R 5 is of the structure: 【Chemical Formula 5】 [wherein, m1 is independently an integer selected from 0, 1, and 2; p1 is independently an integer selected from 0, 1, 2, and 3] The compound according to claim 6, having

10. Z 1 is absent, the compound according to any one of claims 6 to 9.

11. Z 2 is independently selected from NR 7 , S, and O, the compound according to any one of claims 6 to 10.

12. Z 2 is independently absent, the compound according to any one of claims 6 to 10.

13. Z 2 is CR 8 R 9The compound according to any one of claims 6 to 10.

14. R 6 is R 6a The compound according to any one of claims 6 to 11.

15. R 6a is of the structure: 【Chemical Formula 6】 [wherein, x is an integer selected from 0, 1, 2, 3, 4 and 5] The compound according to claim 14, having

16. R 6 is C 3 ~C 8 -alkyl, the compound according to claim 15.

17. The compound of formula (I) is 【Chemical Formula 7A】 【Chemical Formula 7B】 【Chemical Formula 7C】 【Chemical Formula 7D】 【Chemical Formula 7E】 selected from, the compound according to claim 1.

18. A method for controlling mycosis, comprising applying an agriculturally effective and substantially non-phytotoxic amount of the compound according to any one of claims 1 to 17 to plant seeds, the plants themselves, or the area where the plants are intended to grow.

19. Use of the compound according to any one of claims 1 to 17 for controlling mycosis of plants.

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

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