MICROBIOCIDAL PICOLINAMIDE DERIVATIVES

The present invention relates to microbiocidal picolinamide derivatives, e.g., as active ingredients, which have microbiocidal activity, in particular fungicidal activity. The invention also relates to the preparation of these picolinamide derivatives, to agrochemical compositions which comprise at least one of the picolinamide derivatives and to uses of the picolinamide derivatives or compositions thereof in agriculture or horticulture for controlling or preventing the infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, preferably fungi.

Picolinamide compounds as fungicidal agents are described in WO 2016/109257, WO 2016/109288, WO 2016/109289, WO 2016/109300, WO 2016/109301, WO 2016/109302, WO 2016/109303, WO 2019/068809, WO 2019/068812 and WO2019/121149.

According to the present invention, there is provided a compound of formula (I):

wherein,

R1 is hydrogen, formyl, C1-C12alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6haloalkylcarbonyl, C1-C6alkoxyC1-C6alkylcarbonyl, or C1-C6haloalkoxycarbonyl;

R2 is hydroxyl, C2-C6acyloxy, C2-C6haloacyloxy, C1-C6alkoxyC1-C6alkoxy, C1-C6haloalkoxyC1-C6alkoxy, C1-C6alkoxy C1-C6haloalkoxy, C2-C6acyloxyC1-C6alkoxy, C2-C6haloacyloxyC1-C6alkoxy, or C2-C6acyloxyC1-C6haloalkoxy;

R3 is hydrogen, C1-C6alkyl, C1-C6alkoxy or C3-C8cycloalkyl;

R4 and R5 are each independently C1-C12alkyl, C3-C8cycloalkyl, C1-C6haloalkyl, or C1-C6alkoxyC1-C6alkyl, wherein each C3-C8cycloalkyl moiety is optionally substituted with 1, 2 or 3 halogen atoms which may be the same or different;

R6 is C1-C12alkyl, C3-C8cycloalkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8;

or

R5 and R6 together with the carbon atoms to which they are attached may form a 3-, 4-, 5- or 6-membered cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a stable 3-, 4-, 5- or 6-membered non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S;

R7 is phenyl, phenoxy, heteroaryl or heteroaryloxy, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8;

R8 is hydroxyl, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C4haloalkyl, cyanoC1-C6alkyl, hydroxyC1-C6alkyl, or C1-C4alkoxyC1-C6alkyl;

or a salt or an N-oxide thereof.

Surprisingly, it has been found that the novel compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.

According to a second aspect of the invention, there is provided an agrochemical composition comprising a fungicidally effective amount of a compound of formula (I) according to the present invention. Such an agricultural composition may further comprise at least one additional active ingredient and/or an agrochemically-acceptable diluent or carrier.

According to a third aspect of the invention, there is provided a method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms, wherein a fungicidally effective amount of a compound of formula (I), or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.

According to a fourth aspect of the invention, there is provided the use of a compound of formula (I) as a fungicide. According to this particular aspect of the invention, the use may exclude methods for the treatment of the human or animal body by surgery or therapy.

Where substituents are indicated as being“optionally substituted”, this means that they may or may not carry one or more identical or different substituents, e.g., one, two or three R8 substituents. For example, C1-C6alkyl substituted by 1, 2 or 3 halogens, may include, but not be limited to, -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -CH2CF3 or -CF2CH3 groups. As another example, C1-C6alkoxy substituted by 1, 2 or 3 halogens, may include, but not be limited to, CH2ClO-, CHCl2O-, CCl3O-, CH2FO-, CHF2O-, CF3O-, CF3CH2O- or CH3CF2O- groups.

As used herein, the term“hydroxyl” or“hydroxy” means a -OH group.

As used herein, the term“cyano” means a -CN group.

As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

As used herein, the term“formyl” means a -C(=O)H group.

As used herein, the term "C1-C6alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. The terms "C1-C12alkyl" and "C1-C4alkyl" are to be construed accordingly. Examples of C1-C6alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the isomers thereof, for example, iso-propyl, iso-butyl, sec-butyl, tert-butyl or iso-amyl. A“C1-C6alkylene” group refers to the corresponding definition of C1-C6alkyl, except that such radical is attached to the rest of the molecule by two single bonds. The term “C1-C2alkylene” is to be construed accordingly. Examples of C1-C6alkylene, include, but are not limited to, -CH2-, -CH2CH2- and -(CH2)3-.

As used herein, the term "C2-C6alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond that can be of either the (E)- or (Z)-configuration, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. Examples of C2-C6alkenyl include, but are not limited to, ethenyl (vinyl), prop-1-enyl, prop-2-enyl (allyl), and but-1-enyl.

As used herein, the term "C2-C6alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of C2-C6alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, and but-1-ynyl.

As used herein, the term " C3-C8cycloalkyl" refers to a radical which is a monocyclic saturated ring system and which contains 3 to 8 carbon atoms. The term“C3-C6cycloalkyl” is to be construed accordingly. Examples of C3-C8cycloalkyl include, but are not limited to, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the term "C1-C6alkoxy" refers to a radical of the formula -ORa where Ra is a C1-C6alkyl radical as generally defined above. The term "C1-C4alkoxy" is to be construed accordingly. Examples of C1-C6alkoxy include, but are not limited to, methoxy, ethoxy, 1-methylethoxy (iso-propoxy), propoxy, butoxy, 1-methylpropoxy and 2-methylpropoxy.

As used herein, the term "C1-C6alkoxyC1-C6alkoxy" refers to a radical of the formula RbO-RaO-where Rb is a C1-C6alkyl radical as generally defined above, and Ra is a C1-C6alkyl radical as generally defined above. Examples of C1-C6alkoxyC1-C6alkoxy include, but are not limited to, methoxymethoxy, ethoxymethoxy and methoxyethoxy.

As used herein, the term“C1-C6haloalkoxyC1-C6alkoxy” refers to a radical of the formula RbO-RaO-, where Ra is a C1-C6alkyl radical as generally defined above and Rb is a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C1-C6haloalkoxyC1-C6alkoxy groups include, but not limited to trifluoromethoxymethoxy.

As used herein, the term“C1-C6alkoxyC1-C6haloalkoxy” refers to a radical of the formula RaO-RbO-, where Ra is a C1-C6alkyl radical as generally defined above and Rb is a C1-C6alkyl radical as

generally defined above substituted by one or more of the same or different halogen atoms. Examples of C1-C6alkoxyC1-C6haloalkoxy groups include, but not limited to methoxydifluoromethoxy.

As used herein, the term“C2-C6acyl” refers to a radical RaC(=O)-, where Ra is a C1-C5alkyl or a C3-C5cycloalkyl radical as generally defined above. Acyl groups include, but are not limited to, acetyl, propanoyl and cyclopropanoyl.

As used herein, the term "C2-C6acyloxy" refers to a radical of the formula -ORb where Rb is a C2-C6acyl, or a C3-C5cycloalkyl radical as generally defined above. C2-C6acyloxy groups include, but are not limited to, acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, and cyclopropanoyloxy.

As used herein, the term“C2-C6haloacyloxy” refers to a radical of the formula RaC(=O)O-, where Ra is C1-C5alkyl or a C3-C5cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. C2-C6haloacyloxy groups include, but are not limited to trifluoroacetoxy.

As used herein, the term "C2-C6acyloxyC1-C6alkoxy" refers to a radical of the formula RaC(=O)ORbO- where Ra is a C1-C5alkyl or a C3-C5cycloalkyl radical as generally defined above and where Rb is a C1-C6alkyl radical as generally defined above.

As used herein, the term "C2-C6haloacyloxyC1-C6alkoxy" refers to a radical of the formula RaC(=O)ORbO- where Ra is a C1-C5alkyl or a C3-C5cycloalkyl radical as generally defined above substituted by one or more of the same or different halogen atoms, and Rb is a C1-C6alkyl radical as generally defined above.

As used herein, the term "C2-C6acyloxyC1-C6haloalkoxy" refers to a radical of the formula RaC(=O)ORbO- where Ra is a C1-C5alkyl or a C3-C5cycloalkyl radical as generally defined above, and Rb is a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.

As used herein, the term "C1-C6alkoxyC2-C6haloacyloxy" refers to a radical of the formula RaORbC(=O)O- where Ra is a C1-C6alkyl radical as generally defined above, and Rb is a C1-C5alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms.

As used herein, the term“cyanoC1-C6alkyl” refers to a C1-C6alkylene radical as generally defined above substituted by one or more cyano groups as defined above.

As used herein, the term“hydroxyC1-C6alkyl” refers to a C1-C6alkylene radical as generally defined above substituted by one or more hydroxyl groups as defined above.

As used herein, the term“C1-C6alkylcarbonyl” refers to a radical of the formula -C(O)Ra where Ra is a C1-6alkyl radical as generally defined above. The terms "C1-C12alkylcabonyl" and "C1-C4alkylcarbonyl" are to be construed accordingly. Examples of C1-C6alkylcarbonyl include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl and the isomers thereof, for example, iso-propylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl or iso-amylcarbonyl.

As used herein, the term“C1-C6alkoxycarbonyl” refers to a radical of the formula -C(O)ORa where Ra is a C1-C6alkyl radical as generally defined above. The term "C1-C4alkoxycarbonyl" is to be construed accordingly. Examples of C1-C6alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, 1-methylethoxycarbonyl (iso-propoxycarbonyl), propoxycarbonyl, butoxycarbonyl 1-methylpropoxycarbonyl and 2-methylpropoxycarbonyl.

As used herein, the term“C1-C6haloalkylcarbonyl” refers to a radical of the formula -C(O)Ra where Ra is a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C1-C6haloalkylcarbonyl include, but are not limited to trifluoromethylcarbonyl.

As used herein, the term“C1-C6alkoxyC1-C6alkylcarbonyl” refers to a radical of the formula– C(O)RbORa where Rb is a C1-C6alkyl radical as generally defined above, and Ra is a C1-C6alkyl radical as generally defined above. Examples of C1-C6alkoxyC1-C6alkylcarbonyl include, but are not limited to, methoxymethylcarbonyl.

As used herein, the term“C1-C6haloalkoxycarbonyl” refers to a radical of the formula -C(O)ORa where Ra is a C1-C6alkyl radical as generally defined above substituted by one or more of the same or different halogen atoms. Examples of C1-C6haloalkoxycarbonyl groups include, but are not limited to trifluoromethoxycarbonyl.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 3-, 4-, 5- or 6-membered non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S. The heterocyclyl radical may be bonded to the rest of the molecule via a carbon atom or heteroatom. Examples of heterocyclyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidnyl, piperidinyl, piperazinyl, morpholinyl, dioxolanyl, dithiolanyl and thiazolidinyl.

As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring radical which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S. Examples of heteroaryl include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl.

As used herein, the term "heteroaryloxy" refers to a radical of the formula -ORa where Ra is a heteroaryl radical as generally defined above. Examples of heteroaryloxy include, but are not limited to, pyridyloxy and thienyloxy.

As used herein, =O means an oxo group, e.g., as found in a carbonyl (-C(=O)-) group.

The presence of one or more possible stereogenic elements in a compound of formula (I) means that the compounds may occur in optically isomeric forms, i.e., enantiomeric or diastereomeric forms. Also, atropisomers may occur as a result of restricted rotation about a single bond. Formula (I) is intended to include all those possible isomeric forms and mixtures thereof. The present invention includes all those possible isomeric forms and mixtures thereof for a compound of formula (I). Likewise, formula (I) is intended to include all possible tautomers. The present invention includes all possible tautomeric forms for a compound of formula (I).

In each case, the compounds of formula (I) according to the invention are in free form, in oxidized form as an N-oxide, or in salt form, e.g., an agronomically usable salt form.

N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen-containing heteroaromatic compounds. They are described for instance in the book“Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton (1991).

The following list provides definitions, including preferred definitions, for substituents R1, R2, R3, R4, R5, R6, R7 and R8, with reference to compounds of formula (I). For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document.

R1 is hydrogen, formyl, C1-C12alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6haloalkylcarbonyl, C1-C6alkoxyC1-C6alkylcarbonyl, or C1-C6haloalkoxycarbonyl. Preferably, R1 is hydrogen, formyl, C1-C6alkylcarbonyl, C1-C6alkoxycarbonyl, or C1-C6alkoxyC1-C6alkylcarbonyl, more preferably, hydrogen, formyl, C1-C6alkylcarbonyl, or C1-C6alkoxycarbonyl, even more preferably hydrogen, formyl, C1-C4alkylcarbonyl, or C1-C4alkoxycarbonyl. More preferably still, R1 is hydrogen, formyl or C1-C4alkylcarbonyl, and most preferably R1 is hydrogen or formyl.

R2 is hydroxyl, C2-C6acyloxy, C2-C6haloacyloxy, C1-C6alkoxyC1-C6alkoxy, C1-C6haloalkoxyC1-C6alkoxy, C1-C6alkoxyC1-C6haloalkoxy, C2-C6acyloxyC1-C6alkoxy, C2-C6haloacyloxyC1-C6alkoxy, or C2-C6acyloxyC1-C6haloalkoxy. Preferably, R2 is hydroxyl, C2-C6acyloxy, C1-C6alkoxyC1-C6alkoxy or C2-C6acyloxyC1-C6alkoxy, more preferably hydroxyl, C2-C6acyloxy or C2-C6acyloxyC1-C6alkoxy, and even more preferably hydroxyl, acetoxy or isobutyryloxymethoxy. Most preferably, R2 is hydroxyl or isobutyryloxymethoxy.

R3 is hydrogen, C1-C6alkyl, C1-C6alkoxy or C3-C8cycloalkyl. Preferably R3 is hydrogen, C1-C6alkyl, C1-C6alkoxy or C3-C6cycloalkyl. More preferably R3 is, hydrogen, C1-C4alkyl, C1-C4alkoxy or C3-C6cycloalkyl. Even more preferably R3 is, hydrogen, methoxy or cyclopropyl, more preferably still hydrogen or methoxy, and most preferably, R3 is hydrogen.

R4 and R5 are each independently C1-C12alkyl, C3-C8cycloalkyl, C1-C6haloalkyl, C1-C6alkoxyC1-C6alkyl, wherein each C3-C8cycloalkyl moiety is optionally substituted with 1, 2 or 3 halogen atoms which may be the same or different. Preferably, R4 and R5 are each independently C1-C6alkyl, C3-C6cycloalkyl, C1-C6haloalkyl, or C1-C6alkoxyC1-C6alkyl. More preferably, R4 and R5 are each independently C1-C6alkyl, C3-C6cycloalkyl or C1-C6haloalkyl, even more preferably C1-C4alkyl, C3-C6cycloalkyl or C1-C4haloalkyl, more preferably still, C1-C4alkyl or C1-C4haloalkyl, even more preferably still, C1-C4alkyl, and most preferably R4 and R5 are each independently methyl or ethyl. In one set of embodiments, R4 and R5 are both methyl.

R6 is C1-C12alkyl, C3-C8cycloalkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8. Preferably, R6 is C1-C6alkyl, C3-C6cycloalkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R8.

More preferably, R6 is C1-C6alkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 heteroatoms individually selected from N, O and S (e.g. pyridyl), and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8. More preferably still, R6 is C1-C6alkyl or phenyl, wherein the phenyl moiety is optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8. Even more preferably, R6 is isopropyl, phenyl or 4-fluorophenyl. Most preferably, R6 is phenyl, or 4-fluorophenyl; or

R5 and R6 together with the carbon atoms to which they are attached may form a 3-, 4-, 5- or 6-membered cycloalkyl or heterocycloalkyl ring, wherein the heterocyclic moiety is a stable 3-, 4-, 5- or 6-membered non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S, preferably a 3-, 4-, 5- or 6-membered cycloalkyl ring, and more preferably cyclopropyl, cyclopentyl or cyclohexyl.

R7 is phenyl, phenoxy, heteroaryl or heteroaryloxy, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8. Preferably, R7 is phenyl, phenoxy, heteroaryl or heteroaryloxy, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R8. More preferably, R7 is phenyl, phenoxy or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 nitrogen atoms (e.g. pyridyl), and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8. Even more preferably, R7 is phenyl or phenoxy, wherein the phenyl moieties are optionally substituted by one R8. More preferably still, R7 is phenyl, 4-fluorophenyl, phenoxy or 4-fluorophenoxy. Most preferably, R7 is phenyl, or 4-fluorophenyl.

In one set of embodiments, R6 and R7 are both phenyl. In another set of embodiments, R6 and R7 are both 4-fluorophenyl.

R8 is hydroxyl, halogen, cyano, C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C1-C4haloalkyl, cyanoC1-C6alkyl, hydroxyC1-C6alkyl, or C1-C4alkoxyC1-C6alkyl. Preferably, R8 is hydroxyl, halogen, cyano, C1-C6alkyl or C1-C4haloalkyl, more preferably, hydroxyl, chloro, fluoro, methyl, cyano, difluoromethyl, or trifluoromethyl, even more preferably, chloro and fluoro, and most preferably, R8 is fluoro.

In a compound of formula (I) according to the present invention, preferably:

R1 is hydrogen, formyl, C1-C12alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6haloalkylcarbonyl, C1- C6alkoxyC1-C6alkylcarbonyl, or C1-C6haloalkoxycarbonyl;

R2 is hydroxyl, C2-C6acyloxy or C2-C6acyloxyC1-C6alkoxy;

R3 is hydrogen;

R4 is methyl;

R5 is methyl;

R6 is C1-C12alkyl, C3-C8cycloalkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8;

R7 is phenyl, phenoxy, heteroaryl or heteroaryloxy, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R8; and

R8 is hydroxyl, halogen, cyano, C1-6alkyl, or C1-4haloalkyl.

More preferably, R1 is hydrogen, formyl, C1-C12alkylcarbonyl, C1-C6alkoxycarbonyl, C1-C6haloalkylcarbonyl, C1-C6alkoxyC1-C6alkylcarbonyl, or C1-C6haloalkoxycarbonyl;

R2 is hydroxyl, C2-C6acyloxy or C2-C6acyloxyC1-C6alkoxy;

R3 is hydrogen;

R4 is methyl;

R5 is methyl;

R6 is C1-C6alkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8;

R7 is phenyl, phenoxy or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 nitrogen atoms (e.g. pyridyl), and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8; and

R8 is halogen.

Even more preferably, R1 is hydrogen or formyl;

R2 is hydroxyl or C2-C6acyloxy;

R3 is hydrogen;

R4 is methyl;

R5 is methyl;

R6 is C1-C6alkyl, phenyl or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 heteroatoms individually selected from N, O and S, and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8;

R7 is phenyl, phenoxy or heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 nitrogen atoms (e.g. pyridyl), and wherein the phenyl and heteroaryl moieties are optionally substituted by 1 or 2 substituents, which may be the same or different, selected from R8; and

R8 is halogen.

Still more preferably, R1 is hydrogen or formyl;

R2 is hydroxyl or C2-C6acyloxy;

R3 is hydrogen;

R4 is methyl;

R5 is methyl;

R6 is isopropyl, phenyl or 4-fluorophenyl; and

R7 is phenyl, phenoxy or 4-fluorophenyl.

In a further set of preferred embodiments, R1 is hydrogen or formyl;

R2 is hydroxyl or isobutyryloxymethoxy;

R3 is hydrogen;

R4 is methyl;

R5 is methyl;

R6 is phenyl or 4-fluorophenyl; and

R7 is phenyl or 4-fluorophenyl.

Preferably, the compound according to formula (I) is selected from:

[4-amino-2-[[(1S)-2-[2,2-bis(4-fluorophenyl)-1-methyl-ethoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate;

[2,2-bis(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[2-[[(1S)-2-[2,2-bis(4-fluorophenyl)-1-methyl-ethoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-4-formamido-3-pyridyl]oxymethyl 2-methylpropanoate;

[2,2-bis(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

(1-methyl-2,2-diphenyl-ethyl) (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[4-formamido-2-[[(1S)-1-methyl-2-(1-methyl-2,2-diphenyl-ethoxy)-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate;

(1-methyl-2,2-diphenyl-ethyl) (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

(1,3-dimethyl-2-phenoxy-butyl) (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[2-[[(1S)-2-(1,3-dimethyl-2-phenoxy-butoxy)-1-methyl-2-oxo-ethyl]carbamoyl]-4-formamido-3-pyridyl]oxymethyl 2-methylpropanoate;

(1,3-dimethyl-2-phenoxy-butyl) (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

[2-(4-fluorophenoxy)-1,3-dimethyl-butyl] (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[2-[[(1S)-2-[2-(4-fluorophenoxy)-1,3-dimethyl-butoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-4-formamido-3-pyridyl]oxymethyl 2-methylpropanoate;

[2-(4-fluorophenoxy)-1,3-dimethyl-butyl] (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

(1-methyl-2-phenoxy-2-phenyl-ethyl) (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[4-formamido-2-[[(1S)-1-methyl-2-(1-methyl-2-phenoxy-2-phenyl-ethoxy)-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate;

(1-methyl-2-phenoxy-2-phenyl-ethyl) (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

[2-(4-fluorophenoxy)-2-(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[2-[[(1S)-2-[2-(4-fluorophenoxy)-2-(4-fluorophenyl)-1-methyl-ethoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-4-formamido-3-pyridyl]oxymethyl 2-methylpropanoate;

[2-(4-fluorophenoxy)-2-(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(3-acetoxy-4-formamido-pyridine-2-carbonyl)amino]propanoate;

[2,2-bis(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(4-amino-3-hydroxy-pyridine-2-carbonyl) amino]propanoate; and

[4-amino-2-[[(1S)-1-methyl-2-(1-methyl-2,2-diphenyl-ethoxy)-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate.

More preferably, the compound according to formula (I) is selected from:

[2,2-bis(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(4-formamido-3-hydroxy-pyridine-2-carbonyl)amino]propanoate;

[2-[[(1S)-2-[2,2-bis(4-fluorophenyl)-1-methyl-ethoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-4-formamido-3-pyridyl]oxymethyl 2-methylpropanoate;

[4-amino-2-[[(1S)-2-[2,2-bis(4-fluorophenyl)-1-methyl-ethoxy]-1-methyl-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate;

[4-formamido-2-[[(1S)-1-methyl-2-(1-methyl-2,2-diphenyl-ethoxy)-2-oxo-ethyl]carbamoyl]-3-pyridyl]oxymethyl 2-methylpropanoate;

[2,2-bis(4-fluorophenyl)-1-methyl-ethyl] (2S)-2-[(4-amino-3-hydroxy-pyridine-2-carbonyl) amino]propanoate; and

[4-amino-2-[[(1S)-1-methyl-2-(1-methyl-2,2-diphenyl-ethoxy)-2-oxo-ethyl] carbamoyl]-3-pyridyl] oxymethyl 2-methylpropanoate.

Compounds of the present invention can be made as shown in the following schemes, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).

The compounds of formula (I) according to the invention, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined for formula (I), can be obtained by transformation of a compound of formula (II), wherein R1 and R2 are as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, with a compound of formula (III), wherein R3, R4, R5, R6 and R7 are as defined for formula (I), and a base or a peptide coupling reagent. This is shown in Scheme 1 below.

Scheme 1

(II) (III) (I)

Alternatively, the compounds of formula (I), wherein R1, R2, R3, R4, R5, R6 and R7 are as defined for formula (I), can be obtained by transformation of a compound of formula (IV), wherein R1, R2, R3, and R4 are as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, with a compound of formula (V), wherein R5, R6 and R7 are as defined for formula (I), and an acid or a base. This is shown in Scheme 2 below.

Scheme 2

(IV) (V) (I)

The compounds of formula (II), wherein R1 and R2 are as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, can be obtained by transformation of a compound of formula (VI), wherein R2 is as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, with a carboxylic acid and an acid anhydride or a carboxylic acid chloride. This is shown in Scheme 3 below.

Scheme 3

(VI) (II)

The compounds of formula (III), wherein R3, R4, R5, R6 and R7 are as defined for formula (I), can be obtained by transformation of a compound of formula (VII), wherein R3 and R4 are as defined for

formula (I), R9 is hydroxyl, halogen or C1-C6alkoxy and R10 is C1-C6alkylcarbonyl or C1-C6alkoxycarbonyl, with a compound of formula (V), wherein R5, R6 and R7 are as defined for formula (I), and an acid or a base. This is shown in Scheme 4 below.

Scheme 4

(VII) (V) (III)

The compounds of formula (IV), wherein R1, R2, R3, and R4 are as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, can be obtained by transformation of a compound of formula (VIII), wherein R2, R3, and R4 are as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, with a carboxylic acid and an acid anhydride or a carboxylic acid chloride. This is shown in Scheme 5 below.

Scheme 5

The compounds of formula (VI), wherein R2 is as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy can be obtained by transformation of a compound of formula (IX), wherein R2 is as defined for formula (I) and R9 is hydroxyl, halogen or C1-C6alkoxy, under reductive conditions, e.g. catalytic hydrogenation. This is shown in Scheme 6 below.

Scheme 6

METHODS OF MANUFACTURING A RESILIENT RAIL CLIP
The present invention relates to a method of manufacturing a resilient rail clip.
Various forms of resilient rail clips are known, for example as shown and described in GB1510224A and EP0619852B. A known method of manufacturing a resilient rail clip comprises bending a metal rod (usually made of steel) into a predetermined shape and then subjecting the bent rod to a cold setting process to achieve the final form of the clip.
Such rods have a common load-deflection characteristic with a common slope (clip stiffness) up to the elastic limit of the metal from which the bent rod is formed. Cold setting is intended to take the bent rod beyond that elastic limit, thereby inducing a permanent deflection (set) into the resulting clip, such that if it is then unloaded and taken up the load-deflection characteristic a second time, the load-deflection characteristic will be linear up to a much higher load, that is up to the load at which the new characteristic intercepts that for the original rod. One of the key problems in cold-setting is that the metal rods from which the clips are made themselves vary in hardness, typically between 44 and 48 Rockwell hardness. Since the elastic limit of rods made from softer metal is lower than that of rods made from harder metal, if all rods are taken to a fixed deflection, they will all unload down slightly different parallel lines and take on different and varying amounts of set. The softer rods will take on more set, the harder ones less set. This is illustrated in Figure 1A of the accompanying drawings, which shows the load-deflection characteristics of a soft clip and a hard clip and the difference in set As between them after cold setting. This difference in set results in clips that have different geometries (above and beyond the variation already inherent in manufacture), where the geometry depends on the hardness. Thus, although these cold-set clips will all have the same stiffness, regardless of hardness, driving these clips into a fixed assembly which deflects them all by the same amount will result in the clips generating slightly different loads at the portion (the "toe") of the clip which bears on the railway rail. It is impractical to measure the hardness of each clip to be cold set directly before the start of the cold-setting process. Moreover, as shown in Figures 1B and 1C of the accompanying drawings, the problem cannot be overcome simply by changing the fixed amount of deflection applied during cold-setting (Fig. 1B), or by applying a fixed force instead of a fixed deflection (Fig. 1C), as this

does not address the underlying problem. In the past, in an attempt to address this problem, the rod is repeatedly cold-set a number of times, but this is not fully effective.
According to an embodiment of a first aspect of the present invention there is provided a method of manufacturing a resilient rail clip comprising bending a rod, made of metal having a hardness value falling within a known hardness value range, into a predetermined shape and then subjecting the bent rod to a cold setting process in order to induce in the bent rod a predetermined amount of permanent set, wherein the cold setting process comprises: applying a first load to part of the bent rod so as to cause a first amount of deflection of that part of the bent rod, which first load is a predetermined load having a value equal to or greater than that required to reach the yield point of metal having the highest hardness value in the said hardness value range; measuring the first amount of deflection of the said part of the bent rod achieved by applying the predetermined first load; determining, on the basis of the measured deflection amount, either (i) a second load, which, when applied to the said part of the bent rod, will cause the bent rod to acquire the predetermined amount of permanent set, or (ii) a second amount of deflection of the said part of the bent rod required in order to bring about in the bent rod the predetermined amount of permanent set; and applying the determined second load to the said part of the bent rod or deflecting the said part of the bent rod by the determined second amount of deflection.
According to an embodiment of a second aspect of the present invention there is provided a method of manufacturing a resilient rail clip comprising bending a rod, made of metal having a hardness value falling within a known hardness value range, into a predetermined shape and then subjecting the bent rod to a cold setting process in order to induce in the bent rod a predetermined amount of permanent set, wherein the cold setting process comprises: deflecting part of the bent rod by a predetermined first amount by applying a first load having a value equal to or greater than that required to reach the yield point of metal having the highest hardness value in the said hardness value range; measuring the amount of the first load required to achieve the predetermined first amount of deflection; determining, on the basis of the measured first load, either (i) a second deflection amount required in order to bring about in the bent rod the predetermined amount of permanent set, or (ii) a second load, which, when applied to the said part of the bent rod, will cause the bent rod to acquire the predetermined amount of permanent set; and deflecting the said part of the bent rod by

the determined second deflection amount or applying the determined second load to the said part of the bent rod.
Reference will now be made, by way of example, to the accompanying drawings, in which:
Figures 1A to 1C (described above) show the load-deflection characteristics of two rail clips of different respective hardness which have been cold set according to a previously-proposed method;
Figures 2A and 2B show respective flow diagrams depicting two alternative cold setting processes used in embodiments of the present invention;
Figure 3A shows a rail clip undergoing part of a cold setting process used in an embodiment of the present invention and Figure 3B shows the same rail clip after cold setting with a set caused by that cold setting process; and
Figures 4A and 4B each show the load-deflection characteristics of two rail clips of different respective hardness, the thicker lines showing the characteristics after the clips have been cold set according to a method embodying the present invention and the thinner lines showing the characteristics of the clips before cold setting, in which Figures 4A and 4B correspond respectively to methods embodying the first aspect and the second aspect of the present invention.
According to an embodiment of the present invention a rod of metal, having a hardness value falling within a known hardness value range, is bent into a predetermined clip shape (see Figure 3A) and then subjected to a two-stage cold setting process, as shown in the flow diagrams of Figure 2A or 2B. Firstly, the rod is loaded to a level equal to or beyond the yield point of a rod having a hardness value at the top of the hardness value range (STEP 1). Then, depending on the method being used, either a measurement is taken of how much deflection dx has resulted in STEP 1 from a fixed applied force F0 (STEP 2, Figure 2A), or how much force Fx has been required in STEP 1 to reach a fixed deflection d0(STEP 2, Figure 2B). In the method of Figure 2A, which embodies the first aspect of the present invention, the measured deflection dx is then used to determine the amount of force F0 + AFxor second deflection amount dx + Adx (STEP 3, Figure 2A) required in order to induce in the bent rod a predetermined

amount of permanent set S in a second stage of the process, during which the larger force or deflection is applied to the rod. Similarly, in the method of Figure 2B, which embodies the second aspect of the present invention, the measured force Fx is then used to determine the deflection d0 + Adxor second load Fx + AFX (STEP 3, Figure 2B) required in order to induce in the bent rod a predetermined amount of permanent set S in a second stage of the process, during which the larger deflection or force is applied to the rod. In each case the measured values are used by equipment (and/or by a person) to find the additional force/deflection required, for example by reference to a predetermined look-up table or by calculation, In the second processing stage (STEP 4), the rod is subjected to the force or deflection determined in STEP 3 of the preceding stage, the amount of which will vary depending on the hardness of the rod, such that the resulting clip (see Figure 3B) is always set to a point that lies along a line that is parallel to the initial load-deflection characteristic of the original rod, as shown in Figures 4A and 4B. In other words, as shown in Figures 4A and 4B, each clip when unloaded will always fall back along an extension of this line, and thus all clips made using this method will have the same amount of set, and therefore the same finished geometry, as each other, regardless of the hardness of the rod. Thus, employing a method embodying the present invention allows the geometry of the clip after the cold-setting process to be closely defined, and in particular it may be more precisely defined than the geometry of the clip before the cold-setting process.
Figure 4A shows the load-deflection characteristics for clips of different respective hardness, before (thinner lines) and after (thicker lines) cold setting by a method embodying the first aspect of the present invention, in which a measurement is taken of how much deflection, dH (hard clip) or ds (soft clip), has resulted from application to the clip of a fixed applied force F0. and the measured deflection for that clip (dH/ds) is then used to determine the amount of force, F0 + AFH (hard clip) or F0 + AFS (soft clip), or the amount of deflection, dH + AdH (hard clip) or ds + Ads (soft clip), required in order to achieve a predetermined amount of permanent set S. All clips cold set in this manner, throughout the whole of the hardness range, will have the same set S. Similarly, Figure 4B shows the load-deflection characteristics for clips of different respective hardness, before (thinner lines) and after (thicker lines) cold setting by a method embodying the second aspect of the present invention, in which a measurement is taken of how much force, FH (hard clip) or Fs (soft clip), is required in order to achieve a fixed deflection d0 of the clip, and the measured force for that clip (FH/FS) is then used to determine the amount of deflection, d0 + AdH (hard clip) or d0 + Ads (soft ciip), or the

amount of force, FH + AFH (hard clip) or Fs + AFS (soft clip), required in order to achieve a predetermined amount of permanent set S. All clips cold set in this manner, throughout the whole of the hardness range, will have the same set S.
These methods are particularly advantageous when using hydraulic equipment of the type having force and deflection control, as this allows the determination to be made effectively instantaneously so that there is scarcely a pause in the cold-setting process,

1. A method of manufacturing a resilient rail clip comprising bending a
rod, made of metal having a hardness value falling within a known hardness value range, into a predetermined shape and then subjecting the bent rod to a cold setting process in order to induce in the bent rod a predetermined amount of permanent set (S), wherein the cold setting process consisting of:
deflecting part of the bent rod by a predetermined first amount (do) by applying a first load (Fx) having a value equal to or greater than that required to reach the yield point of metal having the highest hardness value in the said hardness value range;
measuring the amount of the first load (Fx) required to achieve the predetermined first amount of deflection (do);
determining, on the basis of the measured first load (Fx), either (i) a second deflection amount (d0+Adx) required in order to bring about in the bent rod the predetermined amount of permanent set, or (ii) a second load (FX+AFX), which, when applied to the said part of the bent rod, will cause the bent rod to acquire the predetermined amount of permanent set (S); and
deflecting the said part of the bent rod by the determined second deflection amount (do+Adx) or applying the determined second load (FX+AFX) to the said part of the bent rod.