Antiparasitic Aaents
Background of the Invention
The present invention relates to pentafluorothiobenzamidoacetonitnle derivatives The invention also relates to pharmaceutical compositions containing such compounds and their use in treating parasitic infestations
There is a continuing need to provide new agents for the control of parasitic infestations that present a threat to human and animal health In particular, new agents are needed to manage endoparasitic infestations in livestock animals due to the increasing prevalence of parasites, and in particular nematodes, that are resistant to many of the agents currently approved for this indication
European patent application EP-0953565-A2 (Nihon Nohyaku Co Ltd ) describes a genus of amidoacetonitnle denvatives and reports that these compounds have insecticidal properties International patent application WO-2002/060257-A1 (Novartis AG) records that the same genus is active against endoparasites such as helminths Related genera and subgenera are discussed in WO-2002/049641-A2 (Novartis), WO-2002/050052-A1 (Syngenta), WO-2005AM4784-A1 (Novartis), WO-2005/121075-A1 (Novartis) and WO-2006/043654 (Nihon) The mechanism by which these agents act has not yet been fully elucidated
There remains a need for further compounds as alternative or improved therapeutic agents Preferred compounds should be potent parasiticidal agents while presenting little or no toxicity to the host animal, and should exist in a physical form that is stable, non-hygroscopic and easily formulated They should have high bioavailability, be metabolically stable and possess favourable pharmacokinetic properties When intended for use in livestock animals, the compounds should be cleared in such a manner as to minimise withholding times without presenting a nsk to the food chain
Summary of the Invention
In a first aspect, the present invention provides a compound of the formula
(Formula Removed)
or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tairtomer or
prodrug, wherein
R', R2, R3, R4 and R5 are each independently selected from H, halo, CNhQf^and CONH2

(Formula Removed)
In a further aspect, the present invention provides a compound of the formula (I) or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tautomer or prodrug, for use as a medicament
In a further aspect, the present invention provides for the use of a compound of the formula (I) or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tautomer or prodrug, for the preparation of a medicament for the treatment of a parasitic infestation in a host animal
In a further aspect, the present invention provides for a method of treatment of a parasitic infestation in a host animal, comprising treating the host animal with an effective amount of a compound of the formula (I) or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tautomer or prodrug
In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tautomer or prodrug, and a pharmaceutically acceptable carrier
Detailed Descnphon of the invention
For the purposes of the present document, the following definitions apply
"Halo" includes fluoro, chloro, bromo or lodo
The term "pharmaceutically acceptable" as used in this specification, for example with reference to salts and solvates, includes "vetennanly acceptable" and "agriculturally acceptable*
The compounds of formula (I) have an asymmetric carbon atom (chiral centre), labelled 7* in the structural formula below Accordingly, the compounds of formula (I) may exist as optical isomers The present invention includes individual enantiomers of the compounds of formula (I) and mixtures thereof, including racemates
(Formula Removed)
Certain compounds of formula (I) may exist as geometric isomers The present invention encompasses such compounds in the as (Z-) or trans (E-) configuration, as well as mixtures of these geometric isomers
Certain compounds of formula (I) may exist in more than one tautomenc form The present invention encompasses all such tautomers, as well as mixtures thereof
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as MCI, fluonne, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150,170 and 180 and sulphur, such as ^S
Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies The radioactive isotopes tntjum, i e 3H, and carbon-14, i e 14C, are particularly useful for this purpose m view of their ease of incorporation and ready means of detection
Substitution with heavier isotopes such as deuterium, i e 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy
Isotoptcally-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed
Certain compounds of formula (I) which have a basic functional group are able to form addition salts with acids Certain compounds of formula (I) which have an acidic functional group are able to form salts with suitable bases Such salts are included within the scope of the preseTtftrfftention to the extent that they are acceptable for veterinary or pharmaceutical use
Suitable acid addition salts are formed from acids which form non-toxic salts Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cydamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochlonde/chloride, hydrobromide/bromide, hydroiodide/iod/de, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, paimitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, (annate, tartrate, tosylate, trrfluoroacetate and xinafoate salts
Suitable base salts are formed from bases which form non-toxic salts Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamme, potassium, sodium, tromethamine and zinc salts
Hemisaits of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts
For a review on suitable salts, see Handbook of Pharmaceutical Salts Properties Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002)
Pharmaceutical^ acceptable salts of compounds of formula (I) may be prepared by one or more of three methods
(i) by reacting the compound of formula (I) with the desired acid or base,
(II) by removing an acid- or base-labile protecting group from a suitable precursor of the
compound of formula (I) or by nng-openlng a suitable cyclic precursor, for example, a lactone
or lactam, using the desired acid or base, or (ill) by converting one salt of the compound of formula (I) to another by reaction with an
appropnate acid or base or by means of a suitable ion exchange column
All three reactions are typically earned out in solution The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent
The compounds of formula (I) and their salts may exist in a continuum of solid states ranging from fully amorphous to fully crystalline The term 'amorphous' refers to a state in which the matenal lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid Typically such matenals do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally desenbed as a liquid Upon heating, a change from solid to liquid properties occurs which is charactensed by a change of state, typically second order ("glass transition') The term 'crystalline' refers to a solid phase in which the matenal has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks Such matenals when heated sufficiently will also exhibit the
properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point')
The compounds of formula (I) and their salts may also exist In unsolvated and solvated forms The term 'solvate' Is used herein to descnbe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol The term 'hydrate' is employed when said solvent is water
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K R Morris (Ed H G Bnttain, Marcel Dekker, 1995) Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion
When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity When, however, the solvent or water Is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions In such cases, non-stoichiometry will be the norm
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e g DjO, ds-acetone, ds-DMSO
Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt Co-crystals may be prepared by melt crystallisation, by recrystaliisation from solvents, or by physically gnnding the components together - see Chem Commun, .17,1889-1896, by O Almarsson and M J Zaworotko (2004) For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Halebhan (August 1975)
The compounds of formula (I) and their salts may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is descnbed as 'lyotropic' Compounds that have the potential to form lyotropic mesophases are descnbed as 'amphiphilic' and consist of molecules which possess an ionic (such as -COOTJa*, -COOK*, or -SCVNa*) or non-ionic (such as -
N"N*(CH3)3) polar head group For more information, see Crystals and the Polanzina Microscope by N H HartshorneandA Stuart, 4th Edition (Edward Arnold, 1970)
Hereinafter all references to compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof
In a preferred embodiment of the compounds of formula (I), R1, R2, R3, R4 and R5 are each independently selected from H, F, CI, Br, CN and CF3 More preferably, at least one of R1, R2, R3, R4 and R6 is CN and at least two of R1, R2, R3, R4 and R5 are H More preferably still, R1 and R4 are H, one of R2 and R3 is H and the other is CN, and R5 is selected from F, CI, Br and CF3
In a further preferred embodiment of the compounds of formula (I), R1, R4 and R5 are each independently selected from H, halo and CF3 and one of R2 and R3 is CN and the other is selected from H and CN
In a further preferred embodiment of the compounds of formula (I), R1 and R4 are each H, and R5 is selected from CI, Br and CF3
In a further preferred embodiment of the compounds of formula (I), R1, R2, R3, R4 and R5 are each independently selected from H, CN and CF3
In a further preferred embodiment of the compounds of formula (I), R1, R2 and R4 are each H
In a further preferred embodiment of the compounds of formula (I), R3 is CN
In a further preferred embodiment of the compounds of formula (I), Rs is CF3
Particularly preferred compounds according to formula (I) include /^1-cyancK2-{5-cyanc-2-(tnfluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothiobenzamide,
/vH(1RH-cyanc-2-[5-cyanc-2-(trtfluoromethyl)phenoxyM-m
rV-{(1 S)-1 -cyano-2-[5-cyano-2-(tnfluoromethyl)phenoxy]-1 -methyiethylM-pentafluorothiobenzamide,
AK2-(2-chloro-5-cyanophenoxy)-1-cyanc-1-methylethyl]-4-pentafluorothiobenzamide,
rv^[2-(2-chlorc-5-cyanophenoxyH1RV1-cyanc-1-memylemyll-4-pentafluorothiobenzamide,
AH2-(2-chlon)o^(^anophenoxyH1S)-1-cyanc-lHTiethylethyl)-4-pentafiuorothiobenzamide,
AK1-cyanc--2-[4-cyano-2-(mfluoromemyl)prienoxy]-1-methylethyl)-4-pentafluoromloben2amide,
N-{(1R)1-cyarK)-244-cyano-2-(tnfluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothioben2amide,
fV-{(1S)1-cyano-2-[4-cyano-2-(tnfluoromethyl)phenoxy]-1-meto
/V-{2-[2-chloro-5-cyano-3-(tnfluoromethyl)pherroxyH-cy^^
benzamide,
N-{2-[2-chloro-5-cyano-3-(t^fluo^omethyl)phenoxy^(1R)-1-cyano-1-methylethyl}-4-
pentafluorothiobenzamide,
A/^2-[2-chloro-5-cyano-3-(tnf)uoromethyl)phenoxyH1S)-1-cyano-1-methylethyl}-4-pentafluorothio-
benzamide,
/\/-{2-(2-chloro-4,5-dicyanophenoxy)-1-cyano-1-methylethyl]-4-pentafiuorothiobenzamide,
N-[2-(2-chloro-4,5-dicyanophenoxy)-(1R)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide,
N-[2-(2-chloro-4,5-dicyanophenoxy)-(1S)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide,
N-{ 1 -cyano-2-[4-cyano-2-(trifluoromethyl)phenoxy]-1 -methylethyl}-4-pentafluorothiobenzamide,
/V-{(1 R)-1 -cyano-2-{4-cyano-2-(tnfluoromethyl)phenoxy]-1 -methylethyl}-4-pentafluorothiobenzamide,
and
/V-{(1S)-1-cyano-2-t4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothiobenzamide,
and pharmaceutical^ acceptable salts thereof
A further preferred compound according to formula (I) is
W^(1S)-lH^arK)-2-f4Kyano-2^tnfluoromethyl)phenoxy]-1-memylethyl)-4-pentafluorothrobenzamide and pharmaceutically acceptable salts thereof
In a further aspect, the present invention provides processes for the preparation of a compound of formula (I), or a pharmaceutically, vetennanly or agriculturally acceptable salt thereof, or a pharmaceutically, vetennanly or agriculturally acceptable solvate (including hydrate) of either entity, as illustrated below
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein
The following processes are Illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention
When one or more of R1, R2, R3, R\ and R5 contain reactive functional groups then additional protection may be provided according to standard procedures during the synthesis of compounds of formula (I) In the processes described below, for all synthetic precursors used in the synthesis of compounds of formula (I), the definitions of R', R2, R3, R4, and R5 wherein R1, R2, R3, R4, and R5 are as defined for formula (I), are intended to optionally include suitably protected vanants, P1, P2 P3, P4 and P5 Such suitable protecting groups for these functionalities are described in the references listed herein and the use of these protecting groups where needed is specifically intended to fall within the scope of the processes described in the present Invention for producing compounds of formula (I) and its precursors When suitable protecting groups are used, then these will need to be removed to yield compounds of formula (I) Deprotecuon can be effected according to standard procedures including those described in the references listed herein
Synthesis of compounds of formula (I)
(Formula Removed)
II Amide bond formation
Compounds of formula (I) wherein R1, R2, R3, R4, and R5, are as defined for formula (I) may be synfhesised by the coupling of amino-nrtnles of formula (II), wherein R1, R2, R3, R4, and R5 are as defined for formula (I) with the acid of formula (III), or suitably activated acid derivatives such as acyl halides, esters or anhydrides
(Formula Removed)
Those skilled in the art will recognise that many standard literature reaction conditions may be used to effect such amide formation, some of these are reviewed in "Amide bond formation and peptide coupling" C A G N Montalbetb and V Falque, Tetrahedron, 2005, 61, 10827-10852
(Formula Removed)
For example, amino-nitnles of formula (II) may be reacted with the acid chloride of formula (IV) in a dipolar aprotic solvent, such as tetrahydrofuran, in the presence of a base, such as dnsopropylethylamme, at reduced temperature, typically 0*C for 2 to 24 hours Alternatively, the acid of formula (III) may be reacted with ammo-nitrites of formula (II), in a polar solvent, such as N, N-dimethylformamide in the presence of 0-(ethoxycarbonyl)cyanomethyleneamino)-A/,fV,A/'N-tetramethyluronium tetrafluoroborate, and in the presence of a base, such as dnsopropylethylamme, at reduced temperature, typically 0°C for 2 to 24 hours, in an inert atmosphere
1 2 Nucieoohilic displacement of aryl halides
Compounds of formula (I) wherein R1, R2, R3, R*, and Rs are as defined for formula (I), may also be synthesised by the reaction of the alcohol of formula (V) with aryl halides of formula (VI) wherein R1, R2, R3, R4 and R5 are as defined for formula (I) and Hal = fluoro or chloro, preferably fluoro
(Formula Removed)
For example, potassium fert-butoxide is added at reduced temperature, typically 0°C, to a solution of the compound of formula (V) and compounds of formula (VI) in a dipolar aprotic solvent, such as tetrahydrofuran, followed by reaction at room temperature for an extended penod of time, typically 16 - 24 hours, optionally under nitrogen Alternatively, potassium terf-butoxide is added at room temperature to a solution of compounds of formula (V) and compounds of formula (VI) in a dipolar aprotic solvent, such as tetrahydrofuran, followed by reaction at temperatures ranging from 55°C -75"C, typically 65°C for an extended penod of time, typically 16-24 hours, optionally under nitrogen Other bases, such as sodium hydride may be used in suitable solvents, typically N,N-dimethylformamide, optionally in an inert atmosphere Alternatively, potassium tert-butoxide in tetrahydrofuran is added to a solution of the compound of formula (V) and compounds of formula (VI) in dimethyl sulphoxide followed by reaction at room temperature for an extended penod of time, typically 16 - 24 hours, optionally under nitrogen When using some aryl fluondes of formula (VI), wherein Hal = fluorine, anhydrous dimethyl sulphoxide Is required for this reaction
The individual enantiomers of the alcohol of formula (V) may be obtained from the racemate by chiral hplc using standard literature chromatographic conditions For example, using methanol/ethanol/hexane mixtures as eluants on a 500mm x 50mm ID Chiralcel AO-H 50m with a flow rate of 50ml/mm These enantiomers of formula (V) may also be used in the nucleophilic displacement reaction to yield individual enantiomers of the compounds of formula (I)
For this reaction, when using compounds of formula (VI), wherein Hal = fluorine and one or more of R1, R2, R3, R4 or Rs is also fluonne, then each individual fluonne atom is susceptible to substitution yielding mixtures of regioisomers
1 3 Synthesis of amino-nitnles of formula III)
Scheme A
(Scheme Removed)
mpounds of formula (II) wherein R1, R2, R3, R4, and R5 are as defined for formula (I) may be synthesised as shown in Scheme A
Hydroxyacetone of formula (VII) may be protected as the ethylene ketal of formula (IX) by reaction with 1,2-bis(tnmethylsilyloxy)ethane, the compound of formula (VIII), and trimethytsilyl tnfluoromethanesulphonate in an anhydrous dipolar aprotic solvent, such as tetrahydrofuran at room temperature for 10 - 30 hours, typically 18 hours Compounds of formula (X), wherein R1, R2, R3, R4, and R5 are as defined for formula (I), may be synthesised by the reaction of the ethylene ketal of formula (IX) with the aryl fluondes of formula (VI) For example, potassium tert-butoxide is added at reduced temperature, typically 0°C, to a solution of compounds of formula (IX) and compounds of formula (VI) in a dipolar aprotic solvent, such as tetrahydrofuran, followed by reaction at room temperature for an extended period of time, typically 16-24 hours, optionally under nitrogen The ketals of formula (X) may be deprotected to afford the phenoxyketones of formula (XI) by re fluxing in acetone in the presence of an acid catalyst, such as 2M hydrochlonc acid, for periods ranging from 15 - 30 hours, typically 20 hours The ammo-nitnles of formula (II) may be prepared from the ketones of formula (XI) using standard literature Strecker synthesis conditions For example, the ketones of formula (XI) may be reacted with ammonium chloride in methanols ammonia at room temperature for 15-45 minutes followed by the addition of sodium cyanide and continuing the reaction at room temperature for 15 - 70 hours
Amino-nrtnles of formula (II) wherein R1, R2, R3, R4, and R5 are as defined for formula (I) have a single
stereocentre alpha to the nitnle, provided R1, R2, R3, R4, and Rs lack stereocentres Such compounds may be prepared stereochemically pure using a variety of literature asymmetric Strecker syntheses Some of these procedures are described in Org Letters, 2000, 2, 6, 867-870, Tetrahedron -Asymmetry 2001, 12, 1147-1150, JAmer Chem Soc 2003,125,5634-5635, JAmer Chem Soc, 1998, 120, 5315-5316, Tetrahedron Leters, 1996, 37, 33, 5839-5840, and Org Letters, 2004, 5, 26, 5027-5029
1 4 Acid chloride of formula (IV)
4-Pentaf)uorothiobenzoyl chlonde may be prepared according to Scheme B
Scheme B
(Scheme Removed)
Iodo-4-(pentafiuorothio)benzene, the compound of formula (XIII), may be prepared by the reaction of the diazonium salt formed by the reaction of 4-{pentafluorothio)aniline with sodium nitrite in aqueous hydrochloric aad, with potassium iodide The diazonium salt is preferably formed at 0°C, the subsequent lodination may take place at room temperature over a period of 18 - 60 hours The alkene of formula (XIV) may be prepared by reaction of the lodo compound of formula (XIII) with tnbutyl(vmyl)Un using a tetrakis(tnphenylphosphine)palladium(0) catalyst in a polar solvent, such as A/,/v-dimethyt formamide at 100°C, under nitrogen, for 1 - 5 hours, typically 1 5 hours The acid of formula (XV) may be prepared by oxidation of the alkene, of formula (XIV) using, for example, sodium penodate in an acetonitnle/carbon tetrachlonde/water solvent mix in the presence of a ruthenium (III) chlonde hydrate catalyst, under an inert atmosphere, at room temperature for 1 - 20 hours The acid chlonde of formula (IV) may be prepared from the acid of formula (XV) using literature procedures well know to those skilled in the art Typically heating with excess thionyl chloride at 65*C for 2 - 4 hours
The acid of formula (XV) may be prepared directly from the compound of formula (XIII) by reaction of carbon dioxide with an organometallic species generated from (XIII), for example using isopropyl magnesium chlonde in an anhydrous aprotic solvent such as tetrahydrofuran
Compounds of formula (XV) and (IV) may also be obtained commercially
1.5 Synthesis of the amido-alcohol of formula (V)
(Scheme Removed)
e amido-alcohol of formula (V) may be prepared as shown in Scheme C The amino-nrtrile of formula (XVI) may be prepared from hydroxylacetone of formula (VII) using standard literature Strecker synthesis conditions For example, the hydroxyacetone may be reacted with ammonium chloride in methanols ammonia at room temperature for 15 - 45 minutes followed by the addition of sodium cyanide and continuing the reaction at room temperature for 15 - 25 hours The amide of formula (V) may be prepared by the reaction of the acid chlonde of formula (IV), with the amino-nrtnle of formula (XVI) For example, the amino-nitnle of formula (XVI) may be reacted with acid chlorides of formula (IV), wherein R7, Rs, R9, R10 and R11 in a dipolar aprotic solvent, such as tetrahydrofuran, in the presence of a base, such as diisopropylethylamine, at reduced temperature, typically 0°C for 2 to 24 hours
1 6 Arvi halides of formula (VI)
Most of the aryl halides of formula (VI) are commercially available or may be prepared by standard literature procedures well known to those skilled in the art The following examples illustrate some successful synthetic conversions and does not represent an all Inclusive list
4-cyano-2-fluorobenzamide may be prepared by the ammonorysis of 4-cyanc-2-fluorobenzoic acid using aqueous ammonium hydroxide (35%) In a suitable solvent, such as acetomtnle, in the presence of 1, 1'-dicarbonyldiimidazole 2-Fluoroterephthalonitnle may be prepared from 4-cyano-2-fluorobenzamide by reaction with palladium (II) chlonde in a suitable solvent, such as acetomtnle, at temperatures ranging from 30*-60*C, typically 50°C, for 15 - 30 hours, typically 24 hours 4-Fluoroisophthalonitnle may be prepared from 2-fluoro-5-formylbenzonitnle by reaction with hydroxylamine-O-sulphonic acid in aqueous solution at 50*C for several hours, normally 5 hours
(Scheme Removed)
heme D shows the preparation of 4-chloro-3-fluoro-5-(trifluoromethyl)benzonrtnle, compound (XX) Compound (XVIII) may be prepared by brominabon of 2-amino-3-fluorobenzotnfluonde using N-bromosuccinimide in a suitable solvent, such as acetonitnle, in the presence of iron (111) chlonde The nitrite (XIX) may be prepared from compound (XVIII) by reaction with sodium cyanide in a suitable solvent, such as 1-methyl-2-pyrrolidinone, in the presence of nickel (II) bromide, by heating in a microwave oven (typical model CEM 300W) at 160°C for several hours, normally 6 hours Compound (XIX) may be converted to compound (XX) by standard Sandmeyer conditions using lerf-butyl nitrite and copper (I) chlonde
Methyl 5-cyano-2-fluorobenzoate may be prepared from 3-bromo-4-fluorobenzonitnle by heating in methanol at 60*C, under a carbon monoxide atmosphere in the presence of a base, such as tnethytamine, and a suitable catalyst, typically [1,1'-bis(diphenylpbcsphino)ferrocene]dichloropalladium (II)
2 Functional qroup Interconversions.
The substrtuents, R1, R2, R3, R4 and R5, wherein as defined for compounds of formula (I), in compounds of formula (I) or compounds of formula (V), may be converted, where chemically feasible, to other substrtuents, R\ R2, R3, R* and R5 as defined for compounds of formula (I)
(Scheme Removed)
mpounds of formula (I), wherein one of R1, R2, R3, R* and R5 = -C(0)NH2 may be prepared from the corresponding compounds of formula (XXI), wherein one of R1, R2, R3, R* and R5 = -C(0)OH using standard literature methods Those skilled in the art will recognise that many standard literature reaction conditions may be used to effect such amide formation, some of these are reviewed in "Amide
bond formation and peptide coupling" C AG N Montalbetti and V Falque, Tetrahedron, 2005, 61, 10827-10852
Acids of formula (XXI) wherein one of R1, R2, R3, R4, R5 = C(0)OH and the others of R1, R2, R3, R4, and Rs are as defined for compounds of formula (I) may be prepared from the corresponding alkyl esters by reaction with lithium hydroxide monohydrate in tetrahydrofuran water (11) at room temperature overnight Acids may be converted to methyl esters by reaction with diazomethane or (tnmethylsiiyl)diazomethane
The alkyl esters of formula (XXI), wherein one of R1, R2, R3, R4 and Rs = -C(0)0alkyl may be obtained from the corresponding bromo compounds by the Pd-catalysed carbonylation using carbon monoxide in the presence of alcohols in a solvent such as N, N-dimethyl formamide These esters may be directly converted to amides using literature procedures well known to those skilled in the art
These bromo compounds may also undergo a variety of organometallic coupling reactions For these reactions, other sensitive functional groups elsewhere In the molecule may require appropriate protection For example, lithiation using butyl lithium in aprotic solvents, such as tetrahydrofuran, in an inert atmosphere, gives intermediate aryl lithium species which may be reacted with chloroformate esters to give compounds of formula (I) or compounds of formula (V), wherein one of R1, R2, R3, R4 and R5 = -COOMe
It wilt also be appreciated by persons skilled In the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps
The skilled person will appreciate that the compounds of the Invention could be made by methods other than those herein descnbed, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions)
It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be earned out in various different sequences in order that the desired compounds can be efficiently assembled The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound
The compounds of formula (I) have antiparasitic activity and so are useful in the control of parasitic infestations in host animals
The parasite may be an endoparasite, such as a helminth, or an ectoparasite, such as an arthropod
Examples of helminths include parasites of the phylum Platyhelminthes (such as cestodes and trematodes, e g Fasaola spp , Fasctolotdes spp , Paramphistomum spp , Dicrocoelium spp , Eurytrema spp , Ophisthorchis spp , Fasciolopsis spp , Echinostoma spp , Paragonimus spp) and the phylum Nematoda (such as filarial, intestinal and tissue nematodes, e g Haemonchus spp , Ostertagia spp , Coopena spp , Oesphagastomum spp , Nematodirus spp , Dictyocaulus spp , Tnchuns spp , Toxocara spp , Toxascans spp , Tnchinella spp , Dirofilaria spp , Ancyclostoma spp , Necator spp , Strongyloides spp, Captllana spp, Ascans spp , Enterobius spp, andTrichostrongylus spp )
Examples of arthropods include Acanna, including ticks (e g Ixodes spp, Boophilus spp e g Boophiius microplus, Amblyomma spp , Hyalomma spp , Rhipicephalus spp e g Rhipicephalus appendicular, Haemaphysalis spp , Dermacentor spp , Omithodorus spp (e g Omithodorus moubata)), mites (e g Damalima spp , Dermanyssus gallmae, Sarcoptes spp e g Sarcoptes scabiei, Psoroptes spp, Chonoptes spp, Demodex spp, Eutrombicula spp ), Diptera (e g Aedes spp , Anopheles spp , Musadae spp e g Stomoxys calcitrans and Haematobia imtans, Hypoderma spp , Gastrophilus spp , Sltnulium spp), Hemiptara (e g Tnatoma spp ), Phthiraptera (e g Damalima spp , Unognathus spp), Siphonaptera (e g Ctenocephalides spp), Oictyoptera (e g Penplaneta spp, Blatella spp) and Hymenoptera (e g Monomonum pharaoms)
The compounds of formula (I) are partjcularty useful for the control of helminth infestations
The host animal may be a mammal or a non-mammal, such as a bird or a fish Where the host animal is a mammal, it may be a human or non-human mammal Non-human mammals include livestock animals and companion animals, such as cattle, sheep, goats, equines, swine, dogs and cats
The compounds of formula (I) may be administered by any suitable route Examples of suitable routes of administration include oral, topical and parenteral administration The choice of the route will depend on the species of the host animal and the nature of the parasitic infestation For example, oral administration might be preferred In the case of a human or companion animal host, or for the treatment of endoparasites, while topical administration might be more convenient for treating large numbers of livestock animals such as a herd of cattle
The compounds of formula (I) may be administered alone or in a formulation appropnate to the specific use envisaged Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients The term "excipient" is used herein to describe any ingredient other than the active components The choice of exapient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form
The compounds of formula (I) may be administered as crystalline or amorphous products, for example, spray-dned dispersions or as produced by melt-extrusion or nano-millmg They may be obtained, for example, as solid plugs, powders, or films (for example, rapid dissolving or mucoadhesrve films) by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying Microwave or radio frequency drying may be used for this purpose
The methods by which the compounds of formula (I) may be administered include oral administration by capsule, bolus, tablet, powders, lozenges, chews, multi and nanoparticulates, gels, solid solution, films, sprays, or liquid formulation Liquid forms include suspensions, solutions, syrups, drenches and elixirs Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents Liquid formulations may also be prepared by the reconshtution of a solid, for example, from a sachet Oral drenches are commonly prepared by dissolving or suspending the active ingredient in a suitable medium
Thus compositions useful for oral administration may be prepared by mixing the active ingredient with a suitable finery divided diluent and/or disintegrating agent and/or binder, and/or lubricant etc Other possible ingredients include antioxidants, colourants, flavouring agents, preservatives and taste-masking agents
For oral dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form Examples of suitable dismtegrants for use herein include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, lower alkyl-substrtuted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form
Binders are generally used to impart cohesive qualities to a tablet formulation Examples of suitable binders for use herein include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose Examples of diluents include lactose (monohydrate, spray-dned monohydrate, anhydrous and the like), mannrtol, xyirtol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate
Oral formulations may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glldants such as silicon dioxide and talc When present, surface active agents may comprise from 0 2 wt% to 5 wt% of the tablet, and glldants may compnse from 0 2 wt% to 1 wt% of the tablet
Lubncants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and
mixtures of magnesium stearate with sodium lauryl sulphate Lubricants generally compnse from 0 25 wt% to 10 wt%, preferably from 0 5 wt% to 3 wt% of the tablet
Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% dismtegrant, and from about 0 25 wt% to about 10 wt% lubricant
The formulation of tablets is discussed in "Pharmaceutical Dosage Forms Tablets, Vol 1", by H Lieberman and L Lachman, Marcel Dekker, N Y , N Y, 1980 (ISBN 0-8247-6918-X)
The compounds of formula (I) may be administered topically to the skin, that is dermaliy or transdermally The compounds may also be administered via the mucosa or mucous membranes Typical formulations for this purpose include pour-on, spot-on, dip, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions Liposomes may also be used Typical earners include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycenn, polyethylene glycol and propylene glycol Penetration enhancers may be incorporated - see, for example, J Pharm So, 88 (10), 955-958 by Fmnin and Morgan (October 1999) Pour-on or spot-on formulations may be prepared by dissolving the active ingredient in an acceptable liquid earner vehicle such as butyl digol, liquid paraffin or a non-votaSe ester, optionally with the addition of a volatile component such as propan-2-ol Alternatively, pour-on, spot-on or spray formulations can be prepared by encapsulation, to leave a residue of active agent on the surface of the animal
Injectable formulations may be prepared in the form of a stenle solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood Acceptable liquid earners include vegetable oils such as sesame oil, glycerides such as tnacetin, esters such as benzyl benzoate, isopropyl mynstate and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrohdin-2-one and glycerol formal The formulations are prepared by dissolving or suspending the active ingredient in the liquid earner such that the final formulation contains from 0 01 to 10% by weight of the active ingredient These formulations may be self-preserving, setf-stenhsing or may be non-sterile to which preservatives may be optionally added
Equally suitably the compounds of formula (I) can be administered parenteral^, or by injection directly into the blood stream, muscle or into an internal organ Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, mtraurethral, intrasternal, intracranial, intramuscular and subcutaneous Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as powdered a dned form to be used in conjunction with a suitable vehicle such as stenle, pyrogen-free water The preparation of
parenteral formulations under sterile conditions, for example, by lyophihsation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents
Such formulations are prepared in a conventional manner in accordance with standard medicinal or veterinary practice
These formulations will vary with regard to the weight of active compound contained therein, depending on the species of host animal to be treated, the seventy and type of infection and the body weight of the host For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0 01 to 100 mg per kg of body weight of the animal Preferably the range is 0 1 to 10mgperkg
Formulations may be immediate release or be designed to have a controlled or modified release profile Modified release formulations include those formulations which have a delayed-, sustained-, pulsed-, targeted, or programmed release Suitable modified release formulations for the purposes of the invention are described in US Patent No 6,106,864 Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001) The use of chewing gum to achieve controlled release is described m WO 00/35298 Alternatively, compounds of the invention may be formulated as a solid, serm-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound Examples of such formulations include drug-coated stents and PGLA microspheres
As an alternative the compounds of formula (I) may be administered to a non-human animal with the feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed
The compounds of formula (I) may advantageously be used in combination with one or more further therapeutic agents, including, but not limited to, further antiparasitic agents
Examples of antiparasitic agents that may be used in combination with the compounds of formula (I) include anthelmintic agents, fasciollcides and ectoparasiticides
In one embodiment of the invention, the compounds of formula (I) are used in combination with a second anthelmintic agent Such a combination may reduce the likelihood of resistance developing Suitable further anthelmintic agents include
• the macrocyclic lactone class of compounds (such as ivermectin, avermectin, abamectin, emamectin, epnnomectin, doramectin, selamectin, moxidectin, nemadectin, milbemycin and
milbemycm derivatives such as those described in EP-357460, EP-444964 and EP-594291, and semisynthetic and biosynthetic avermectin/milbemycin derivatives such as those descnbed in US-5015630, WO-9415944 and WO-9522552),
• benzimidazoles (such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole and parbendazole),
• imidazothiazoles and tetrahydropynmidines (such as tetramisole, levamisole, pyrantel pamoate, oxante) or morantel),
• derivatives and analogues of the paraberquamide/marcfortine class of anthelmintic agents, particularly 2-desoxoparaherquamide,
• nitroscanate,
• antiparasitic oxazolmes (such as those disclosed in US-5478855, US-4639771 and DE-19520936),
• derivatives and analogues of the general class of dioxomorpholine antiparasitic agents as descnbed mWO-9615121, and
. cyclic depsipeptides (such as those descnbed in WO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334, EP-382173, and EP-503538, and particularly emodepside)
In a preferred embodiment, the compounds of formula (I) are used in combination with a macrocychc lactone anthelmintic agent selected from ivermectin, avermectm, abamectw, emamectin, epnnomectin, doramectin, selamectin, moxidectin, nemadecbn and milbemycin oxune
In another preferred embodiment, the compounds of formula (I) are used in combination with a benzimidazole anthelmintic agent selected from albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole and parbendazole
In another preferred embodiment, the compounds of formula (I) are used in combination with an anthelmintic agent selected from tetramisole, levamisole, pyrantel pamoate, oxantel and morantel
In another preferred embodiment, the compounds of formula (I) are used in combination with denvatrves and analogues of the paraherquamide/marcfortine class of anthelmintic agents, particularly 2-desoxoparaherquamide
In another embodiment of the invention, the compounds of formula (I) are used In combination with a flukictde, for example a fasciolicide Suitable agents include closantei, tnclabendazole, clorsulon, rafoxanide, niclosamide, praziquantel and epsiprantel
In another embodiment of the invention, the compounds of formula (I) are used in combination with an ectoparasjfcctdal agent Suitable agents include
• aryl pyrazotes (such as Mpronil, pynproie, pyrafluprole and the like),
• pyrethroids,
• organophosphates,
• insect growth regulators (such as lufenuron and the like),
• spiroketoenol insecticides (such as spiromesifen and the like),
• ecdysone agonists (such as tebufenozide and the like),
• spinosyns (such as spinosad, spinetoram and the like, especially spinetoram),
• neonicotinoids (such as imidaclopnd, dinotefuran and the like) and
• other insecticides (such as metaflumizone, flubendiamide, chlorantraniliprole, indoxacarb, pyndalyl, pynmidifen and pynfluquinazon, especially metaflumizone, indoxacarb and flubendiamide)
In another preferred embodiment, the compounds of formula (I) are used In combination with an ectoparasrticidal agent selected from fipronil, pyriprole, pyrafluprole, lufenuron, spiromesifen, tebufenozide, tebufenozide, spinosad, spinetoram, imidacloprid, dinotefuran, metaflumizone, flubendiamide, chlorantraniliprole, indoxacarb, pyndalyl, pynmidifen and pynfluquinazon
When the compounds of formula (I) are used to treat a parasitic infestation in a livestock animal then they may be used m combination with any of the agents commonly known in the art to be useful as feed additives for such livestock animals, and which are described in such manuals as "2006 Feed Additive Companion" and "Handbook of Feed Additives 2006" Suitable agents include
• poryether tonophores (such as lasaload, monensin, salinomyan, narasm and laidlornycin),
• antibiotics (such as the tetracyclines, bacitracin, tylosin, bamulin, lincomyan, virgmiamyctn, quinolone antibactenals and carbadox),
• steroid derivatives (such as melengesterol acetate),
• agents for the prevention or treatment of sub-acute rumen acidosis (such as sodium bicarbonate, acarbose and other amylase or glucosidase inhibitors),
• carcass quality / anabolic agents (such as beta adrenergic ligands, including ractopamme, salbutamol and almeterol), and
• other supplements (such as enzymes, minerals and vitamins)
The two components may be administered simultaneously, sequentially or separately Where the two components are administered sequentially or separately then they may both be given by the same route, or they may be administered by different routes
As used herein, simultaneous administration means the administration of both components to the host animal in a single action, which requires the two components to be incorporated into a single dosage unit, such as a single tablet or a single pour-on solution
Sequential administration means the administration of each component is a separate action, but the two actions are linked For example, administering a tablet compnsing one component and a second tablet compnsing the second component is considered to be sequential administration, even if the two tablets are given to the host animal at the same time
Separate administration refers to the administration of each component independently of the other
For convenience, simultaneous administration may be preferable
The two components may be presented in kit form Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) and one contains a further antiparasitic agent, and means for separately retaining said compositions, such as a container, divided bottte, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like
The kit is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administenng the separate compositions at different dosage intervals, or for titrating the separate compositions against one another To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid
EXAMPLES
The following Examples illustrate the preparation of compounds of the formula (I)
In the following experimental details, nuclear magnetic resonance (N m r) spectral data were obtained using Vanan Inova 300, Vanan Inova 400, Vanan Mercury 400, Vanan Unrtyplus 400, Bruker AC 300MHz, Bruker AM 250MHz or Vanan T60 MHz spectrometers, the observed chemical shifts being consistent with the proposed structures Nmr chemical shifts are quoted in ppm downfield from tetramethylsilane In the following Examples, where an Example is indicated as being a mixture of diastereoisomers, then the n m r integrals shown refer to the relative ratio of integrals for the quoted chemical shift Mass spectral data were obtained on a Finnigan ThermoQuest Aqa, a Waters micromass ZQ, or a Hewlett Packard GCMS System Model 5971 spectrometer The calculated and observed ions quoted refer to the isotopic composition of lowest mass HPLC means high performance liquid chromatography Room temperature means 20 to 25°C Where an Example Is indicated as being a mixture of regioisomers, the biological data refers to a mixture of compounds with the quoted ratios
When the source of a simple precursor is unspecified these compounds may be obtained from commercial suppliers or according to literature procedures The following is a list of commercial suppliers for such compounds
Sigma-AWnch, P O Box 14508, St Louis, MO, 63178, USA
Fluorochem Ltd . Wesley Street Old Glossop, Derbyshire, SK13 7RY, UK
Alfa Aesar, 26 Parkridge Road, Ward HHI, MA, 01835, USA
Apollo Scientific Ltd , WhitefiekJ Rd , Bredbury, Stockport, Cheshire, SK6 2QR, UK
Fluka Chemie GmbH, Industriestrasse 25, P O Box 260, CH-9471 Buchs, Switzerland
ChemPur GmbH, Rueppurrer Str 92, Karlsruhe, D-76137, Germany
Biological assay
The Haemonchus contortus L3 (HcL3) test is used to measure the biological activities of the compounds claimed The assay involves in vitro testing against H contortus conducted according to the following general procedure
HcL3 larvae were collected from infected sheep and, after cleaning, stored in water at 12°C for up to one month Viable infective larvae were exsheathed using 10% hypochlorite in Glucose Tyrodes balanced salt solution containing antibiotics and resuspended in basal medium (20 g/l bacto-tryptone, 5 g/l yeast extract, 57 g/l glucose, 0 8 g/l di-Potassium hydrogen orthophosphate, 0 8 g/l potassium dfhydrogen orthophosphate and 2 uM Hepes with antibiotics) 95 (J worm suspension was added to each well of a 96 well plate
Test compounds were dissolved in dimethylsulfoxide to give a working stock solution of 20mg/ml The stock concentration was diluted 1 10 in Basal media to give 2 0 mg/ml (10% DMSO) 5 ui of the stock compound solution was added to the worm suspension to give a final concentration of 100 ^ml Plates were sealed with-pressure sensitive film and incubated at 37°C Observations were made 2 hrs, 24 hrs, 48 hrs, 72 hrs and 4 days post-treatment using an inverted microscope Activity was recorded if a significant proportion of the worms were dead or adversely affected by the compound when compared to the control well containing 1% DMSO Compounds were initially tested at 100 ng/ml, wherefrom relevant dose responses (100, 30, 10, 3, 1, 0 3, 0 1 ug/ml) were conducted in duplicate experiments to generate n=2 Data was recorded as minimum effective dose
Example 1
N-T1 -Cyano-2-[5-Cyano-2-(trifluoromethyl)Dherioxyl-1 -methyiethylV-4-
(Dentaftuorothio)benzamide
(Formula Removed)
Example 1a (Racemate)
To a solution of the compound of Preparation 1 (2 2 g, 8 2 mmol) and fV,/V-diisopropylethyiamme (1 7 ml, 9 9 mmol) in tetrahydrofuran (10 ml), at O'C, was added the compound of Preparation 2 (2 7 g, 8 2 mmol) in tetrahydrofuran (10 ml) The reaction mixture was allowed to warm to room temperature over 2 h, before addition of water (10 ml) To the mixture was added ethyl acetate (25 ml) and the two layers were separated The organic phase was washed with aqueous potassium carbonate solution (10%, 20 ml), saturated aqueous ammonium chloride solution (20 ml) and bnne, dned (MgSO() and concentrated in vacuo The residue was triturated with tert-butyl methyl ether and the resulting precipitate was collected by filtration and dned in vacuo to give the compound of Example 1a (2 0 g) Expenmental MH* 500 0, expected 500 1
1H-NMR (CDCI3) 1 99 - 2 01 (3H), 4 45 - 4 48 (1H). 4 70 - 4 74 (1H), 6 47 - 6 50 (1H), 7 28 - 7 30 (1H), 7 42 - 7 45 (1H), 7 71 - 7 75 (1H), 7 84 - 7 88 (4H) in vitro H c (L3) MED = 3 ug/ml
Alternative Synthesis
To a solution of the compound of Preparation 1 (228 mg, 0 8 mmol) and Preparation 3 (210 mg, 0 8
mmol) in N,/V-dimethylformamide (5 ml), at 0°C, was added O-
((ethoxycarbonyl)cyanomethyleneamino)-rv,rV,/v',W4etramethyluronium tetrafluoroborate (TOTU, 278
mg, 0 8 mmol) The reaction vessel was purged with nitrogen, before the dropwise addition of N,N-
diisopropylethylamine (0 3 ml, 1 7 mmol), and the reaction mixture was allowed to warm to room
temperature and stirred for 18 h The mixture was poured into water (50 ml) and extracted with ethyl
acetate (40 ml) The combined extracts were washed successively with water (20 ml), saturated
aqueous sodium hydrogen carbonate solution (20 ml), water (20 ml), aqueous citric acid solution (5%,
1 20 ml) and bnne (20 ml) The solution was dned (MgSCu) and concentrated in vacuo to give the
compound of Example 1 a (395 mg)
Expenmental (M-H*) 498 1, expected 498 1
Example 1b (Flrst-eiutinq enanbomer) and Example 1c fSecond-elutina enantiomer)
The compound of Example 1a (240 mg, 0 5 mmol) was dissolved in ethanol (8 ml) and the enanhomers were separated by automated preparative liquid chromatography (Gilson system, 250 x 20 mm ID ChiralceJ AD-H, 5 um column, 12 ml/mm) using methanol ethanol hexane [10 10 80] as the mobile phase The appropriate fractions were combined and concentrated to give two enantiomencally pure products, the compound of Example 1b and the compound of Example 1c Example 1b Retention time =14 50 mm (250 x 4 6 mm Chiralcel AD-H, 5 um column, methanol ethanol hexane [10 10 80], 1ml/min) Expenmental MH* 500 1, expected 500 1
1H-NMR (CDCl3) 2 00 - 2 02 (3H). 4 41 - 4 44 (1H), 4 70 - 4 73 (1H), 6 42 - 6 45 (1H), 7 27 - 7 28 (1H), 7 40 - 7 42 (1H), 7 72 -7 74 (1H), 7 81 - 7 84 (4H) in vitro H c (L3) MED =1 µg/ml
Example 1c Retention time = 19 51 mm (250 x 4 6 mm Chiralcel AD-H, 5 um column, methanol
ethanol hexane [10 10 80], 1ml/min)
Experimental MH* 500 1, expected 500 1
1H-NMR (CDCb) 1 99 - 2 01 (3H), 4 42 - 4 45 (1H), 4 70 - 4 73 (1H), 6 41 - 6 44 (1H), 7 25 - 7 26
(1H), 7 40 - 7 42 (1H), 7 72 - 7 74 (1H), 7 81 - 7 84 (4H)
in vitro H c (L3) MED ) 30 µg/ml
(Formula Removed)
Example 1c - absolute stereochemistry as determined by single crystal X-ray analysis
Example 2 N-[2-(2-Chloro-5-CyanoBrienoxy)-1-Cyano-1-methylethyn-4-(pentafluorothio)ben2amide
(Formula Removed)
To a mixture of the compound of Preparation 9 (150 mg, 0 5 mmol) and 4-chloro-3-fluorobenzonrtnle (71 mg, 0 5 mmol), under nitrogen, was added tetrahydrofuran (2 ml) The mixture was cooled to 0°C, before the dropwise addition of potassium fort-butoxide (1M in tetrahydrofuran, 0 8 ml, 0 8 mmol) The reaction mixture was allowed to warm to room temperature and stirred for 19 h The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution (x2), water and brine, dned (MgSO4) and concentrated In vacuo The residue was dissolved in acetonitnle (2 ml) and purified by automated preparative liquid chromatography (Gifson system, 150 mm x 50 mm LUNA C18(2) 10um column, 120 ml/mm) using an acetonitnle water gradient [60 40 (for 15 mm) to 98 2 (for 3 mm) to 60 40 (for 1 mm)] The appropriate fractions were concentrated in vacuo to give the trtte compound (72 mg) as a racemic mixture Experimental MH* 466 0, expected 466 O
1H-NMR (oVAcetone) 2 00 - 2 03 (3H), 4 65 - 4 69 (1H), 4 78 - 4 82 (1H), 7 40 - 7 43 (1H), 7 63 - 7 67 (2H), 8 00 - 8 03 (2H), 8 10 - 8 14 (2H), 8 56 - 8 60 (1H) m vitro H c (L3) MED = 1 ug/ml
Example 3
AM 1 -Cyano-2-f4-Cyano-2-(trtfluorornethyl)Dhenoxyl-1 -methylethylM-
(pentafluorothio)benzamlde
(Formula Removed)
Example 3a (Racemate)
To a mixture of the compound of Preparation 9 (150 mg, 0 5 mmol) and 4-fluoro-3-(tnfluoromethyl)benzonrtnle (86 mg, 0 5 mmol), under nitrogen, was added tetrahydrofuran (2 ml) The mixture was cooled to 0°C, before the dropwise addition of potassium te/t-butoxide (1M in tetrahydrofuran, 0 8 ml, 0 8 mmol) The reaction mixture was allowed to warm to room temperature and stirred for 19 h The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chlonde solution (x2), water and bnne, dned (MgSO4) and concentrated in vacuo The residue was dissolved in methanol (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 50 mm LUNA C18(2) 10um column, 120 ml/mm) using an acetonitnle water gradient [55 45 (for 15 mm) to 98.2 (for 3 mm) to 55 45 (for 1 mm)] The appropriate fractions
were concentrated in vacuo to give the compound of Example 3a (73 mg) as a racemic mixture
Expenmental MH* 499 9, expected 500 1
1H-NMR (dg-Acetone) 1 98 - 2 00 (3H), 4 78 - 4 80 (1H), 4 84 - 4 86 (1H), 7 58 - 7 60 (1H), 8 00 - 8 03
(2H), 8 08 - 8 12 (4H)
in vitro H c (L3) MED = 1 ug/ml
Example 3b (Sinqle enantiomer)
To a solution of the compound of Preparation 20 (2 5 g, 7 6 mmol) and 4-fluoro-3-(tnfluoromethyl)-benzonrtnle (2 2 g, 11 4 mmol) in tetrahydrofuran (25 ml), at -10°C, was added dropwise potassium terf-butoxide (1M in tetrahydrofuran, 15 1 ml, 15 1 mmol) The reaction mixture was stirred at -10°C for 2 h and then quenched by addition of saturated aqueous ammonium chloride solution (80 ml) The mixture was extracted with ethyl acetate (2 x 40 ml) and the combined extracts were washed with water (50 ml) and brine (40 ml), dried (MgSO4) and concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™, 65i silica cartridge) with gradient elution, ethyl acetate cyclohexane [0 100 to 50 50] The appropnate fractions were combined and concentrated and to the residue was added ethyl acetate (50 ml) The solution was washed with water (40 ml), dned (MgSO4) and concentrated in vacuo The residue was re-dissolved in diethyl ether and re-concentrated in vacuo to give the compound of Example 3b (1 6 g) as a single enanbomer Expenmental MH* 499 9, expected 500 1
1H-NMR (CDCIj) 1 98 - 2 00 (3H), 4 46 - 4 48 (1H), 4 79 - 4 81 (1H), 7 12 - 7 14 (1H), 7 81 - 7 86 (5H),7 89-7 90(1H) in vitro H c (L3) MED = 1 ug/ml
Example 3c (Slnale enantiomer)
To a solution of the compound of Preparation 21 (2 5 g, 7 6 mmol) and 4-fluoro-3-(tnfluoromethyl)-benzonrtnle (2 2 g, 114 mmol) in tetrahydrofuran (25 ml), at -10°C, was added dropwise potassium fert-butoxide (1M in tetrahydrofuran, 151 ml, 151 mmol) The reaction mixture was stirred at -10°C for 2 h and then quenched by addition of saturated aqueous ammonium chloride solution (80 ml) The mixture was extracted with ethyl acetate (2 x 40 ml) and the combined extracts were washed with water (50 ml) and bnne (40 ml), dried (MgSO4) and concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™, 65M silica cartridge) with gradient elution, ethyl acetate cyclohexane [0 100 to 50 50] The appropriate fractions were combined and concentrated to give the title compound (3 1 g) as a single enantiomer Expenmental MH* 499 9, expected 500 1
1H-NMR (CDCI3) 1 98 - 2 00 (3H), 4 48 - 4 50 (1H), 4 79 - 4 81 (1H), 7 13-715 (1H), 7 82 - 7 87 (5H),7 88-7 90(1H) in vitro He (L3) MED ) 30 ug/ml
Example 4
AH 1 -Cyano-2-{4-Cyano-2-fluoro-6-(tnfluoromethyl)DhenoxyM -fliethytetbvl)-4-(pentafluorothK))-
benzamlde
(Formula Removed)
To a solution of the compound of Preparation 9 (500 mg, 1 5 mmol) and 3,4-difluoro-5-
(tnfluoromethyl)benzonitnle (376 mg. 1 8 mmol) in tetrahydrofuran (10 ml), at 0°C, was added
dropwise potassium terf-butoxide (1M in tetrahydrofuran, 1 8 ml, 1 8 mmol) The reaction mixture was
allowed to warm to room temperature and stirred for 18 h under nitrogen The mixture was diluted
with ethyl acetate (50 ml) and washed with saturated aqueous ammonium chloride solution (20 ml),
water (20 ml) and brine (20 ml), dried (MgSO4) and concentrated in vacuo The residue was dissolved
in acetomtnle (2 ml) and purified by automated preparative liquid chromatography (Gllson system, 150
mm x 50 mm LUNA C18(2) 10um column, 120 ml/mm) using an acetomtnle water gradient [60 40 (for
13 mm) to 98 2 (for 3 min) to 60 40 (for 1 mm)] The appropriate fractions were combined and
concentrated to give the title compound (123 mg) as a racemic mixture
Expenmental MH* 517 9, expected 518 1
1H-NMR (oV-Acetone) 1 99 - 2 01 (3H), 4 90 - 4 92 (1H), 5 01 - 5 03 (1H), 7 99 - 8 03 (3H), 8 09 - 8 12
(3H)
in vitro H c (L3) MED = 3 pg/ml
Similarly prepared were
(Formula Removed)
Example 5 N-[2-(2-Chioro-4-Cyanophenoxy)-1-Cyano-1-methylethyri-4-(pentafluorothio)benzamide
1H-NMR (cfe-Acetone) 2 00 - 2 06 (3H), 4 72 - 4 76 (1H), 4 80 - 4 84 (1H), 7 40 - 7 42 (1H), 7 78 - 7 80 (1H), 7 B7 - 7 89 (1H), 8 00 - 8 05 (2H), 8 08 - 8 12 (2H), 8 56 - 8 59 (1H)
Example 6 N-[2-(3-Chloro-4-cyanophenoxy)-1-Cyano-1-methylethyll-4-(pentafluorothio)benzamide
1H-NMR (ofe-Acetone) 1 97 - 1 99 (3H), 4 60 - 4 63 (1H), 4 76 - 4 79 (1H), 7 20 - 7 22 (1H), 7 38 - 7 39 (1H), 7 80 - 7 82 (1H), 8 00 - 8 03 (2H), 8 08 - 8 11 (2H)
Example 7
N-11 -Cyano-2-r3-c vano-5-(tnfluoromethyl)phenoxyl-1 -methylethyD-4-
(pantafluorothio)benzamide
1H-NMR (cfe-Acetone) 1 99 - 2 01 (3H), 4 65 - 4 68 (1H), 4 80 - 4 83 (1H), 7 75 - 7 77 (1H), 7 79 - 7 82 (2H), 7 99 - 8 02 (2H), 8 10-813 (2H)
Example 8 N-ri-Cyano-2-(2-Cyano-4,6-difIuorophenoxyV-1-rnethylethyri-4-{pentafluorothlo)benzamide
1H-NMR (cfe-Acetone) 2 01 - 2 04 (3H), 4 82 - 4 84 (2H), 7 47 - 7 50 (1H), 7 57 - 7 60 (1H), 7 99 - 8 03 (2H), 8 09 - 8 12 (2H)
Example 9 N-T1-Cyano-2-(3,5-diCyanophenoxy)-1-methylethyn-4-(pentafluorothk))ben2amide
1H-NMR (cfe-Acetone) 1 98 - 2 00 (3H), 4 63 - 4 65 (1H), 4 78 - 4 81 (1H), 7 82 - 7 84 (2H), 7 89 - 7 90 (1H), 8 00 - 8 03 (2H), 8 09 - 8 12 (2H)
Example 10
N-f2-f4-Bromo-2-(trifluoromethyl)phenoxy1-1 -Cyano-1 -methylethyD-4-
(pentafluorothio)benzamide
1H-NMR (cfe-Acetone) 1 98 - 2 01 (3H), 4 61 - 4 63 (1H). 4 74 - 4 77 (1H), 7 35 - 7 38 (1H), 7 78 - 7 82 (2H), 8 00 - 8 03 (2H), 8 06 - 8 09 (2H)
Example 11 N-[2-(2-Bromo-4-Cyanophenoxy)-1-Cyano-1-methylettivl1-4-(pentafluorothio)benzamide
1H-NMR (CDjOD) 1 95 - 1 98 (3H), 4 57 - 4 60 (1H), 4 65 - 4 68 (1H), 7 21 - 7 23 (1H), 7 70 - 7 72 (1H), 7 94-8 01 (5H)
Example 12
N-T1 -Cyano-2-(2,4-dichloroDhenoxy)-1 -methylethyl]-4-(pentafluorothio)benzamide
(Formula Removed)
To a solution of the compound of Preparation 9 (120 mg, 0 4 mmol) in dimethyl sulphoxide (0 8 ml) was added 2,4-dichloro-1-fluorobenzene (90 mg, 0 5 mmol), followed by potassium terf-butoxide (1M in tetrahydrofuran, 0 5 ml, 0 5 mmol) The reaction mixture was then stirred at room temperature for 18 h The reaction mixture was purified by automated preparative liquid chromatography (Gilson system, 150 mm x 22 4 mm Gemini C18(2) 5^m column, 20 ml/min) using an acetomtnle water gradient [50 50 (for 2 mm) to 98 2 (for 13 mm) to 50 50 (for 2 mm)] The appropriate fractions were combined and concentrated in vacuo to give the trtle compound (55 mg) Expenmental MH* 474 9, expected 475 0
1H-NMR (cfe-Acetone) 2 00 - 2 02 (3H), 4 59 - 4 61 (1H), 4 68 - 4 70 (1H), 7 20 - 7 22 (1H), 7 34 - 7 36 (1H). 8 00 - 8 02 (2H), 8 09 - 8 11 (2H) in vitro H c (L3) MED = 3
Similarly prepared were

(Scheme Removed)
'Mixtures of regioisomers were obtained from these starting materials
Example 13
Example 13a
N-f2-(2-Chloro-4-f luorophenoxyM -Cyano-1 -methylethyl1-4-(pentafluorotriio)benzamide
and Example 13b N-f2-(3-Chloro-4-fluorophenoxy)-1-Cyano-1-methylethyn-iMDentafluoroHiio)ben2amide
1H-NMR (da-Acetone) 1 97-201 (3H),458-461 (1H), 462 -465 (1H), 7 09 - 7 12 (1H), 7 22 -7 28 (2H), 7 99 - 8 02 (2H), 8 07 - 8 10 (2H) (for major component) 3 1 mixture of regioisomers
Example 14 M-[2-(3-Chloro-5-CyanoDhenoxy)-1-Cyano-1-methylethyl]-4-(pentafluorothio)benzamide
'H-NMR (dg-Acetone) 1 99 - 2 02 (3H), 4 58 - 4 61 (1H), 4 69 - 4 72 (1H), 7 43 - 7 47 (3H), 7 99 - 8 02 (2H),8 08-8 11(2H)
Example 15 Af-[2-(4-Chlorophenoxy)-1-Cyano-1-methylethyn-4-(pentafluorothio)benzamide
1 H-NMR (de-Acetone) 1 97 - 1 99 (3H), 4 42 - 4 44 (1H). 4 59 - 4 61 (1H), 7 02 - 7 05 (2H), 7 30 - 7 33 (2H), 7 99 - 8 01 (2H), 8 09 - 8 11 (2H)
Example 16
Jv-f 2-(5-Bromo-2-Cyanophenoxy)-1 -cyano-1 -methylethyll-4-(pentafluorothio)benzamide
'H-NMR (CDjOD) 1 90 - 1 93 (3H), 4 61 - 4 63 (2H), 7 30 - 7 33 (1H), 7 50 - 7 59 (2H), 7 95 - 7 98 (2H), 7 98 - 8 01 (2H)
Example 17
AM2-(4-Chloro-2-Cyanophenoxy)-1 -Cyano-1 -methylethyl1-4-lpentafliiorQthio)benzamide
'H-NMR (de-Acetone) 2 00 - 2 02 (3H), 4 76 - 4 79 (2H), 7 38 - 7 41 (1H), 7 67 - 7 70 (1H), 7 74 - 7 77 (1H), 7 99 - 8 02 (2H), 8 09 - 8 11 (2H)
Example 18 Af-f1-Cyano-2-(2-cyano-3-fluorophenoxy)-1-methylethyn-4-{pentafluorothio)benzamide
1H-NMR (de-Acetone) 1 50 - 1 51 and 1 79 - 1 80 (3H), 4 79 - 4 80 (2H). 7 00 - 7 03 (1H), 7 19 - 7 21 (1H), 7 70 - 7 76 (1H), 8 00 - 8 04 (2H), 8 08 - 8 10 (1H), 817-819 (1H)
Example 19 N-f1-Cyano-2-(2-cyanophenoxy)-1-methylethyn-4-(pentafluorothio)benzamide
1H-NMR (de-Acetone) 2 00 - 2 02 (3H), 4 76 - 4 78 (2H), 7 15-717 (1H), 7 36 - 7 38 (1H), 7 63 - 7 66 (2H), 7 99 - 8 01 (2H), 810-812 (2H)
Example 20
Af-f1 -Cyano-2-(4-iodODhenoxy)-1 -methylethyf|-4-(pentafluorothio)benzamide
'H-NMR (CDCI3) 1 98 - 2 00 (3H), 4 26 - 4 28 (1H), 4 40 - 4 42 (1H), 6 71 - 6 73 (2H), 7 59 - 7 61 (2H), 7 81 - 7 83 (4H)
Example 21 /V-H-Cyano-1-methyl-2-f2-(tnfluoromethyl)phenoxy1ethylV4-{pentafluorothio)benzamide
1H-NMR (CDCl3) 1 98 - 2 00 (3H). 4 30 - 4 32 (1H), 4 63 - 4 65 (1H). 7 00 - 7 02 (1H), 711 - 7 13
(1H), 7 55 - 7 58 (1H), 7 60 - 7 62 (1H), 7 81 - 7 83 (4H)
Example 22
N-[1-Cyano-2-(4-Cyanophenoxy)-1-methylethyl]-4-(pentafluorothio)benzamide
1H-NMR (da-Acetone) 1 97 - 2 00 (3H), 4 56 - 4 60 (1H), 4 68 - 4 72 (1H), 7 20 - 7 24 (2H), 7 75 - 7 79
(2H), 8 00 - 8 04 (2H), 8 07 - 8 11 (2H)
Example 23 N-[2-(3-Chloro-5-fluorophenoxy)-1-Cyano-1-methylethyll-4-{pentafluorothio)benzamide
1H-NMR (dg-Acetone) 1 97 - 1 99 (3H), 4 50 - 4 52 (1H), 4 62 - 4 64 (1H), 6 82 - 6 85 (2H), 6 98 - 6 99 (1H), 8 00 - 8 02 (2H), 8 08 - 8 10 (2H)
Example 24 N-[2-(5-Chloro-2-Cyanonhenoxy)-1-Cyano-1-niethylethyn-4-(Rentafluorothio)benzamide
'H-NMR (dg-Acetone) 1 45 - 1 49 (3H), 4 79 - 4 82 (2H), 7 20 - 7 23 (1H), 7 45 - 7 47 (1H), 7 70 - 7 73 (1H), 8 00 - 8 03 (2H), 8 10-813 (2H)
Example 25
N-[2-(2-Chlorophenoxy)-1 -Cyano-1 -methylethyll-4-(pentafluorothio)benzamide
1H-NMR (de-Acetone) 2.00 - 2 02 (3H), 4 59 - 4 61 (1H), 4 63 - 4 65 (1H), 7 00 - 7 02 (1H), 7 20 - 7 22
(1H), 7 30 - 7 32 (1H), 7 41 - 7 43 (1H), 8 00 - 8 02 (2H), 8 10-813 (2H)
Example 26 M-T2-(3-Chloro-2-CyanophenoxyM-Cyano-1-methylethyn-4-(pentafluorothio)benzamide
'H-NMR (dg-Acetone) 2 00 - 2 02 (3H), 4 79 - 4 82 (2H), 7 24 - 7 29 (2H), 7 65 - 7 68 (1H), 8 00 - 8 03 (2H),8 08-810(2H)
Example 27
Example 27a ,
N-[1-Cyano-2-(2-Cyano-4-fluorophenoxy)-1-methylethyn-4-(D€ntafIuorothio)benzamide
and Example 27b N-[1-Cyano-2-(3-Gvano-4-fluorophenoxy)-1-methylethyll-4-(pentafluorothio)benzamide
1H-NMR (dg-Acetone) 2 00 - 2 02 (3H), 4 70 - 4 74 (2H), 7 39 - 7 42 (1H), 7 49 - 7 55 (1H), 7 57 - 7 60 (1H), 7 99 - 8 03 (2H), 8 10 - 8 14 (2H) (for major component) 4 1 mixture of regioisomers
Example 28
N--[2-(4-Chloro-2-fluorophenoxy)-1 -cyano-1 -meth ylethyll-4-(pentafluorothio)benzarnide
1H-NMR (dg-Acetone) 1 97 - 1 99 (3H), 4 60 - 4 62 (1H), 4 69 - 4 71 (1H), 7 01 - 7 03 (1H), 7 19 - 7 22 (1H), 7 35 - 7 37 (1H), 7 99 - 8 01 (2H). 8 08 - 8 11 (2H)
Example 29
Example 29a
N-f1-Cyano-2-(4-Cyano-2-fluorophenoxy)-1-methylethyn-4-(pentafluorothio)benzamide
and Example 29b N-[1-Cyano-2-(5-Cyano-2-fluorDphenoxy)-1-methylethyll-4-(pentafluorothio)benzamide
1H-NMR (CDCt) 2 00 - 2 03 (3H), 4 45 - 4 48 (1H), 4 51 - 4 53 (1H), 7 07 - 7 11 (1H), 7 39 - 7 45 (2H), 7 80 - 7 84 (2H), 8 02 - 8 06 (2H) 1 1 mixture of regioisomers
Example 30
N-{1 -Cyano-242-fluoro-4-(tnfluorornethyl)Dhenoxyl-1 -methylethylV4-
(pentafluorothk))benzamide
1H-NMR (dff-Acetone) 1 99 - 2 02 (3H), 4 70 - 4 73 (1H), 4 77 - 4 80 (1H), 7 45 - 7 49 (1H), 7 52 - 7 57
(2H), 7 99 - 8 03 (2H), 8 03 - 8 06 (2H)
Example 31 N-[2-(3-Chlorophenoxy)-1-Cyano-1-methYlethyn-4-(pentafluorothlo)benzamide
1H-NMR (flfe-Acetone) 1 96 - 1 99 (3H). 4 45 - 4 48 (1H), 4 60 - 4 63 (1H), 7 00 - 7 03 (2H), 7 09 - 7 11 (1H), 7 30 - 7 33 (1H), 8 00 - 8 03 (2H), 8 05 - 8 08 (2H)
Example 32
N-F2-(2-Bromo-5-CyanoDhenoxy)-1 -Cyano-1 -methylethyll-4-(oentafluorothio)benzamide 1H-NMR (CD3OD) 1 96 - 2 00 (3H), 4 54 - 4 57 (1H), 4 60 - 4 63 (1H), 7 25 - 7 28 (1H), 7 44 - 7 46 (1H), 7 77 - 7 80 (1H), 7 95 - 8 05 (4H)
Example 33
Example 33a
N-[2-(2-Bromo-4-fluorophenoxy)-1-Cyano-1-mothylethyH-4-{pentafluorothiolben2amide
and Example 33b N-[2-(3-Bromo-4-fluorophenoxy)-1-Cyano-1-methylethyl]-4-(pentafluorothio)ben2amide
1H-NMR (CD3OD) 1 96 - 1 98 (3H), 4 46 - 4 48 (1H), 4 53 - 4 55 (1H). 7 09 - 7 13 (2H), 7 38 - 7 40 (1H), 7 92 - 8 00 (4H) (for major component) 31 mixture of regioisomers
Example 34
N-[2-(4-Bromo-2-fluorophenoxy)-1-Cyano-1-methylethyll-44pentaf1uorothio)benzamide 1H-NMR (CDjOD) 1 90 - 1 92 (3H), 4 50 - 4 52 (1H), 4 52 - 4 54 (1H), 7 07 - 7 10 (1H), 7 11 - 7 13 (1H), 7 36 - 7 38 (1H), 7 95 - 7 98 (4H)
Example 35 N-[2-(3-6romo-5-CyanoDhenoxy)-1-Cyano-1-niethylethyn-4-(pentafluorothio)benzamide
'H-NMR (CDjOD) 1 95 - 1 97 (3H), 4 40 - 4 42 (1H), 4 58 - 4 60 (1H), 7 40 - 7 41 (1H), 7 56 - 7 58 (2H), 7 95 - 8 00 (4H)
Example 36
N-(1 -Cyano-2-r3-Cyano-2-(tnfluoromethyllphenoxyl-1 -methylethy}-4-
(pentafluorothio)benzamide
1H-NMR (CD3OD) 1 90 - 1 95 (3H), 4 57 - 4 61 (1H), 4 67 - 4 71 (1H), 7 55 - 7 58 (1H), 7 58 - 7 61 (1H), 7 72 - 7 76 (1H). 7 92 - 8 00 (4H)
Example 37 N-f2-^2-Bromo-3-CyanoDhenoxyM-Cyano-1-methylethyll-4-{pentafluorothlo)benzamide
1H-NMR (rig-Acetone) 2 01 - 2 03 (3H), 4 73 - 4 75 (1H), 4 77 - 4 79 (1H). 7 45 - 7 47 (1H), 7 53 - 7 60 (2H). 8 00 - 8 02 (2H), 8 09 - 8 11 (2H)
Example 38
N-T1-Cyano-2-{2.5-dichlorophenoxyM-methylethyn-4-(pentafluorothio)benzamide
1H-NMR (CP,OD) 1 96 - 1 97 (3H), 4 50 - 4 52 (1H), 4 57 - 4 59 (1H), 6 99 - 7 01 (1H), 7 19 - 7 20
(1H), 7 37 - 7 39 (1H), 7 92 - 8 00 (4H)
Example 39 N-[2-(2-Chloro-3-fluoroDhenoxy)-1-Cyano-1-niethylethyn-4-(pentafluorothlo)benzamlde
1H-NMR (CD3OD) 1 95 - 1 99 (3H), 4 50 - 4 54 (1H), 4 59 - 4 63 (1H), 6 85 - 6 89 (1H), 6 95 - 6 98 (1H), 7 22 - 7 27 (1H), 7 92 - 8 00 (4H)
Example 40 N-[2-/3-Bromo-2-CyanoDbenoxy)-1-Cyano-1-methylethyl]-4-(pentafluorothio)benzamide
1H-NMR (drAcetone) 2 00 - 2 02 (3H), 4 78 - 4 80 (2H), 7 38 - 7 41 (1H), 7 41 - 7 43 (1H), 7 60 - 7 63 (1H), 8 00 - 8 02 (2H), 8 10 - 8 12 (2H)
Example 41
N-[2-(4-Bromo-2-CyanoDhenoxy)-1-Cyano-1-methylethyn-4-(Dentafluorothio)benzamide 1H-NMR (CDjOD) 1 96 - 1 98 (3H), 4 61 - 4 63 (2H), 7 20 - 7 22 (1H), 7 75 - 7 78 (1H), 7 81 - 7 82 (1H), 7 90 - 7 93 (2H), 7 98 - 8 00 (2H)
Example 42
N-[1-Cyano-2-(2,3-dichlorophenoxy)-1 -methylethyll-4-(pentafIuorothio)benzamide
1H-NMR (CO3OD) 1 96 - 1 99 (3H), 4 50 - 4 53 (1H), 4 56 - 4 59 (1H), 7 08 - 7 10 (1H), 715-717 (1H), 7 20 - 7 23 (1H), 7 90 - 8 00 (4H)
Example 43 (M2-Cyano-24r4-(pentafluorothio)benzovllamino)DroDoxy)-3-(tnfluoromethyl)benzamide
(Formula Removed)
To a solution of the compound of Preparation 9 (200 mg, 0 6 mmol) in anhydrous dimethyl sulphoxide
(3 ml) was added dropwise potassium tert-butoxide (1M in tetrahydrofuran, 1 2 ml, 12 mmol) After
stimng for 15 mln, 4-fluoro-3-(tnfluoromethyl)ben2amide (251 mg, 12 mmol) was added and the
reaction mixture was stirred at room temperature for 4 h Additional potassium terf-butoxide (1M in
tetrahydrofuran, 1 2 ml, 1 2 mmol) was added and the reaction mixture was stirred for a further 16 h
The mixture was quenched by addition of aqueous ammonium chloride solution and extracted with
ethyl acetate The combined extracts were washed with water and bnne, dned (MgSO4) and
concentrated in vacuo The residue was purified by automated flash chromatography (Biotage™,
25+S silica cartridge) with gradient eluton, ethyl acetate cyclohexane [12 88 to 100 0] The
appropriate fractxxis were combined and concentrated give the title compound (290 mg) as a racemic
mixture
Expenmental MH* 518 0; expected 518 1
1H-NMR (CD3OD): 1 95 - 1 98 (3H), 4 59 - 4 62 (1H), 4 69 - 4 72 (1H). 7 30 - 7 32 (1H), 7 92 - 8 00
(4H), 8 10 - 8 12 (1H), 812-813 (1H)
in vitro H c (L3) MED = 1
Example 44
N^42^hloro-5^vano^^tnfluoromethynohenoxyl-1-CyarK)-1-methylethylV4-(Rentafluorothio)-
Benzamide
(Formula Removed)
To a solution of the compound of Preparation 9 (110 mg, 0 3 mmol) and the compound of Preparation 14 (112 mg, 0 5 mmol) in anhydrous dimethyl sulphoxide (4 ml) was added dropwise potassium tert-butoxide (1M in tetrahydrofuran, 0 7 ml, 0 7 mmol) The reaction mixture was stirred at room temperature for 3 h and then quenched by addition of saturated aqueous ammonium chloride solution (15 ml) The mixture was extracted with ethyl acetate (2x5 ml) and the combined extracts were washed with water (5 ml) and bnne (5 ml), dned (MgSO4) and concentrated in vacuo The residue was dissolved in acetonitnle water (9 1,2 ml) and purified by automated preparative liquid chromatography (Gilson system, 250 mm x 50 mm LUNA C18(2) 10fim column, 120 ml/mm) using an acetonitnle water gradient [65 35 (for 12 mm) to 95 5 (for 3 mm) to 65 35 (for 1 min)J The
appropriate fractions were combined and concentrated to give the title compound (28 mg) as a
racemic mixture
Expenmental (M-H*)" 532 0, expected 532 0
1H-NMR (CD3OD) 1 96 - 1 98 (3H), 4 60 - 4 62 (1H), 4 72 - 4 74 (1H), 7 80 - 7 81 (1H), 7 87 - 7 88
(1H), 7 92-8 00 (4H)
invitmHc (L3)MED=10
Similarly prepared were
(Scheme Removed)
Example 45 4-Cyano-2-(2-Cyano-2-[[4-(Dentafluorothio)benzovl]amino)Dropoxy)benzamide
1H-NMR (d6-Acetone) 1 99 - 2 01 (3H), 4 78 - 4 81 (2H), 7 54 - 7 55 (1H), 7 69 - 7 70 (1H), 7 98 - 8 01 (3H), 8 12-8 14 (2H)
Example 46 N-[1-Cyano-2-(2,5-diCyanqphenoxy)-1-methylethyll-4-lDeritafluorothio)ben2amlda
1H-NMR (CD3OD) 1 96 - 1 98 (3H), 4 65 - 4 67 (1H), 4 70 - 4 72 (1H), 7 48 - 7 50 (1H), 7 69 - 7 70 (1H), 7 82 - 7 84 (1H), 7 95 - 7 97 (2H), 8 00 - 8 02 (2H)
Example 47 N-T1-Cyano-2-(2,4-dicyanoDhenoxy)-1-methylethyll-4-{pentafluorothio)benzamlde
'H-NMR (CDCI3) 1 60 -1 61 (3H), 4 50-4 52 (1H), 4 86 - 4 88 (1H), 7 15 - 7 17 (1H), 7 82 - 7 91 (6H)
Example 48
N-f1-Cyano-2-(3-Cyano-5-fluoroDhenoxy)-1-methylethYn-4-(pentafluorot1iiq)benzamide 1H-NMR (CDCI3) 1 97 - 1 99 (3H), 4 40 - 4 42 (1H), 4 44 - 4 46 (1H), 6 92 - 6 94 (1H), 7 00 - 7 02 (2H), 7 92 - 7 94 (4H)
Example 49 3-Chloro-4-(2-Cyano-2-fr4-(pentafluorothio)benzovllamino)proDoxy)benzamide
1H-NMR (CDCI3) 2 00 - 2 02 (3H), 4 39 - 4 41 (1H), 4 62 - 4 64 (1H), 7 00 - 7 02 (1H), 7 66 - 7 68 (1H),7 83-7 88(5H)
Example 50 N-f1-CYano-2-(3-CyanoDhenoxy)-1-methylethyll-4-(pentafluorothio)benzamide
(Scheme Removed)
To a solution of the compound of Preparation 9 (200 mg, 0 6 mmol) in N,N-dimethytformamide (2 ml) was added sodium hydride (60% in oil, 32 mg, 1 3 mmol) and the mixture was stirred for 15 mm To the mixture was added 3-fluorobenzonrtnle (81 mg, 0 7 mmol) in N,N-dimethylformamide (1 ml) and the reaction mixture was stirred at room temperature for 24 h Additional sodium hydride (60% in oil 64 mg, 2 7 mmol) was added and the mixture was stirred for a further 4 days The mixture was quenched by addition of water and extracted with ethyl acetate The combined extracts were washed
with water and brine, dried (MgSO4) and concentrated in vacuo The residue was dissolved in dimethyl sulphoxide (2 8 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 50 mm LUNA C18(2) 10µm column, 120 ml/mm) using an acetonitnle water gradient [55 45 (for 15 mm) to 98 2 (for 3 min) to 55 45 (for 1 mm)] The appropnate fractions were combined and concentrated to give the title compound (46 mg) as a racemic mixture Experimental MH+ 431 9, expected 432 1
1H-NMR (d6-Acetone) 1 98 - 2 00 (3H), 4 56 - 4 58 (1H), 4 67 - 4 69 (1H), 7 39 - 7 41 (2H), 7 43 - 7 44 (1H), 7 54 - 7 56 (1H), 8 00 - 8 02 (2H), 8 09 - 8 11 (2H) in vitro H c (L3) MED = 3
Similarly prepared were
(Formula Removed)
Example 51 N-ri-Cyano-2-/4-Cyano-2,6-difluoroDhenoxy)-1-metrivlethyi1-4-Derttafluorothio)benzamide
1H-NMR (Os-Acetone) 1 98 - 2 00 (3H), 4 81 - 4 83 (1H), 4 85 - 4 87 (1H), 7 61 - 7 63 (2H), 8 00 - 8 03 (2H), 8 06 - 8 09 (2H)
Example 52
N-l2-f3-Chloro-2-(rrifluoromethyl)Dhenoxy1-1 -Cyano-1 -methylethylV-4-
(pentafluorothio)benzamide
1H-NMR (CD3OD) 1 90 - 1 92 (3H), 4 50 - 4 52 (1H), 4 61 - 4 63 (1H), 7 18 - 7 20 (2H), 7 49 - 7 52 (1H),7 95-8 00(4H)
Example 53 3-Cyano-5-(2-Cyano-2-[f4-(Dentaf1uorothio)benzovllamino)propoxy)benzamide

(Formula Removed)
To a solution of the compound of Preparation 17 (194 mg, 0 4 mmol) in acetonitnle (4 ml) was added 1,1'-carbonyldnmidazole (99 mg, 0 6 mmol) and the reaction mixture was stirred at room temperature, under nitrogen, for 1 5 h Additional 1,T-carbonyldumidazole (99 mg, 0 6 mmol) was added and the reaction mixture was stirred for a further 1 h To the mixture was added aqueous ammonium hydroxide solution (35%, 5 ml) and the reaction mixture was stirred for 1 h The mixture was quenched with water and diluted with ethyl acetate The two layers were separated and the aqueous phase was extracted with ethyl acetate The combined organic phases were washed with water and bnne, dried (MgSO4) and concentrated in vacuo The residue was dissolved in methanol (1 5 ml), containing a few drops of dimethyl sulphoxide, and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm LUNA C18(2) 10um column, 40 ml/min) using an acetonitnle water gradient [45 55 (for 14 min) to 98 2 (for 3 mm) to 45 55 (for 1 min)] The appropnate fractions were combined and concentrated to give the title compound (71 mg) as a racemic mixture
Experimental (M-H*)" 473 0, expected 473 1
1H-NMR (CDjOD) 1 89 - 1 93 (3H), 4 45 - 4 48 (1H), 4 60 - 4 63 (1H), 7 56 - 7 58 (1H), 7 79 - 7 84 (2H), 790-800 (4H) inwfroHc (L3)MED = 30
PREPARATIONS
The following Preparations illustrate the synthesis of certain intermediates used in the preparation of the preceding Examples
Preoaration 1 3-(2-Amlno-2-CyanoDroDoxy)-4^trifluoromethyl)benzonitnle
A mixture of the compound of Preparation 6 (3 5 g, 14 4 mmol), ammonium chloride (1 2 g, 22 3 mmol) and ammonia (7N in methanol, 41 1 mi, 288 0 mmol) was stirred at room temperature for 20 mm, before addition of sodium cyanide (921 mg, 18 4 mmol) The reaction mixture was stirred at room temperature for 65 h and then quenched by addition of aqueous sodium hydroxide solution (2M, 100 ml) The mixture was extracted with toluene (3 x 75 ml) and the combined extracts were washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo To the residue was added dichloromethane (380 ml) and Amberiyst® 15 ion-exchange resin (prepared according to J Org Chem, 1998, 63, 3471) The solution was shaken gentry for 17 b and the resin was removed and washed with cydohexane, followed by tetrahydrofuran and methanol To the resin was added ammonia (2M in methanol, 380 ml) and the solution was shaken for 1 h To the solution was added tetrahydrofuran (380 ml) and the resin was removed The solution was then concentrated in vacuo to give the title
compound (3 2 g)
1H-NMR (CDCI3) 1 61 - 1 62 (3H), 3 97 - 4 00 (1H), 4 18 - 4 20 (1H), 7 20 - 7 22 (1H), 7 40 - 7 42
(1H),7 73-7 75(1H)
Preparation 2 4-fPentafliiorothio)benzovl chloride
A solution of the compound of Preparation 3 (8 5 g, 34 3 mmol) in thionyl chloride (50 ml) was heated
at 65°C for 4 h The mixture was concentrated in vacuo and the residue was triturated with toluene to
give the title compound (7 6 g)
1H-NMR (CDCI3) 7 95 - 8 00 (2H), 8 21 - 8 26 (2H)
Preparation 3
4-(Pentafluorothlo)benzolc acid
A mixture of the compound of Preparabon 4 (8 0 g, 34 8 mmol) and sodium penodate (30 5 g, 142 0
mmol) in acetonrtrile (60 ml), carbon tetrachlonde (60 ml) and water (60 ml) was de-gassed and
treated with ruthenium (III) chlonde hydrate (157 mg, 0 7 mmol) The reaction mixture was stirred at
room temperature for 1 h and then partitioned between diethyl ether and water The two layers were
separated and the organic phase was washed with aqueous sodium hydroxide solution (1N) The
aqueous phase was adjusted to pH 1 by addition of hydrochloric acid and then extracted with diethyl
ether The combined extracts were washed with brine, dried (MgSQ() and concentrated in vacuo to
give the title compound (2 8 g)
Expenmental (M-H*)" 247 1, expected 247 0
Preparation 4
1 -(Pentafluorothio)-4-vinvlbenzene
A mixture of the compound of Preparation 5 (16 6 g, 50 4 mmol), tnbutyt(viny1)tin (221 ml, 24 0 g, 75 6 mmol) and tetrakis(tnphenylphosphine)palladium(0) (2 1 g, 1 8 mmol) in A/.N-dimethylformamide (170 ml) was purged with nitrogen and heated at 100°C for 1 5 h The mixture was partitioned between diethyl ether and water and the organic phase was separated, washed with aqueous potassium fluoride solution (2 x 50 ml) and bnne, dried (MgSO4) and concentrated in vacuo The residue was purified by column chromatography (silica, 800 g), eluting with pentane The residue was further purified by distillation to give the title compound (18 0 g) 1H-NMR (CDCIj) 5 39 - 5 43 (1H), 5 80 - 5 84 (1H), 6 65 - 6 70 (1H), 7 41 - 7 44 (2H), 7 68 - 7 72 (2H)
Preparation 5
1 -iodo-4-f oentafluorothioibenzene
To a solution of 4-(pentafluorothlo)aniline (15 0 g, 68 4 mmol) and ice (40 0 g) in hydrochloric acid (12M, 30 ml) was added a solution of sodium nitrite (5 0 g, 72 5 mmol) in water (120 ml) at 0°C After stirring for 2 mm, the mixture was added to potassium iodide (13 0 g, 78 3 mmol) in water (120 ml), ensuring the temperature did not nse above 10*C The reaction mixture was stirred at 0°C for 10 mm and then at room temperature for 60 n The mixture was extracted with diethyl ether (2x100 ml) and the combined extracts were washed with bnne, dried (MgSO*) and concentrated in vacuo The
residue was purified by column chromatography (silica, 300 g), eluting with diethyl ether cyclohexane [1 10] The appropriate fractions were combined and concentrated to give the title compound (16 6 g) 1H-NMR (CDCI3) 7 90 - 7 95 (2H), 8 20 - 8 25 (2H)
Preparation 6 3-{2-OxoproDoxy)-4-(trifluoromethyl)benzonitnle
A solution of the compound of Preparation 7 (7 0 g, 24 5 mmol) in acetone (122 ml) and hydrochloric acid (2M, 61 1 ml) was heated at reflux for 19 h After cooling to room temperature, the mixture was concentrated in vacuo and to the residue was added ethyl acetate (150 ml) The solution was washed with saturated aqueous sodium carbonate solution and water, dried (MgSO*) and concentrated in vacuo The residue was re-crystallised from cyclohexane ferf-butyl ether [95 5] to give the title compound (3 5 g) 1H-NMR (CDCI3) 2 37 - 2 39 (3H), 4 60 - 4 62 (2H), 7 07 - 7 09 (1H), 7 39 - 7 41 (1H), 7 75 - 7 78 (1H)
Preparation 7 3-f(2-MeUivl-1.3-dioxolan-2-vl)methoxyl-4-(tnfluoromethynbenzonrtrile
To a mixture of 3-fluoro-4-(tnfluoromethy!)benronitnle (12 1 g, 63 9 mmol) and the compound of Preparation 8 (21 0 g, 160 0 mmol) in tetrahydrofuran (345 ml), at 0°C and under nitrogen, was added dropwise potassium fert-butoxide (1M in tetrahydrofuran, 70 3 mi, 70 3 mmol) The reaction mixture was stirred at 0"C for 1 h and then allowed to warm to room temperature To the mixture was added ethyl acetate (200 mi) and saturated aqueous ammonium chloride solution (250 ml) and the two layers were separated The organic phase was washed with saturated aqueous ammonium chloride solution, water and bnne, dried (MgSO4) and concentrated in vacuo To the residue was added cyclohexane (100 ml) and the mixture was allowed to stand for 1 h The solid residue was collected by filtration and dried to give the title compound (16 3 g) 1H-NMR (CDCI3) 1 45 - 1 47 (3H), 4 00 - 4 06 (6H), 7 20 - 7 21 (1H), 7 32 - 7 34 (1H), 7 63 - 7 65 (1H)
Preparation 8
(2-Methyt-1,3-dioxolan-2-vl)methanol
To a solution of 1,2-bis(tnmethylsUyloxy)ethane (41 2 g, 200 0 mmol) and 1-hydroxyacetone (15 2 ml, 200 0 mmol) in anhydrous tetrahydrofuran (35 ml) was added dropwise trimethylsilyl trifluoromethanesulphonate (2 0 ml, 11 1 mmol) The reaction mixture was stirred at room temperature for 18 h, before addition of pyridine (32 3 ml) The mixture was poured into aqueous sodium hydrogen carbonate solution (100 ml) and extracted with ethyl acetate (3 x 150 ml) The combined extracts were washed with brine, dned (MgSO4) and concentrated in vacuo The residue was azeotroped with toluene (x 2) to give the title compound (16 6 g) 1H-NMR (CDC13) 1 35 - 1 37 (3H), 3 51 - 3 53 (2H), 3 98 - 4 00 (4H)
Preparation 9
N-(1-Cyano-2-hvdroxy-1-methylethyl)-4-(Dentafluorothio)benzamide
To a solution of the compound of Preparation 10 (563 mg, 5 6 mmol) and A/,N-dusopropylethylamine
(1 1 ml, 6 4 mmol) in tetrahydrofuran (9 ml), at -10*C, was added dropwise the compound of Preparation 2 (1 5 g, 5 6 mmol) in tetrahydrofuran (10 ml) After stirring for 1 h, the reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate (200 ml) This solution was washed with hydrochloric acid (0 1M, 80 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1 6 g) Expenmental (M-H*)' 329 1, expected 329 0
Preparation 10 2-Amino-3-hvdroxy-2-methylDroDanenitnle
A mixture of sodium cyanide (13 0 g, 259 0 mmol), ammonium chlonde (16 8 g, 314 0 mmol) and ammonia (7M in methanol, 579 ml, 41 mol) was stirred at room temperature for 10 mm, before addition of 1-hydroxyacetone (14 ml, 202 0 mmol) The reaction mixture was stirred at room temperature, under nitrogen, for 23 h and then concentrated in vacuo To the residue was added ethyl acetate (200 ml) and the mixture was filtered The filtrate was concentrated in vacuo and to the residue was added dichloromethane The solution was cooled to -20*C and allowed to stand for 60 h The resulting precipitate was collected by filtration, washed with cold dichloromethane and dried in vacuo to give the title compound (8 3 g) 1H-NMR (CD3OD) 1 40 - 1 43 (3H), 3 45 - 3 55 (2H)
Preparation 11 4-Cyano-2-fluorobenzamide
To a solution of 4-cyanc~2-fluorobenzoic acid (500 mg, 3 0 mmol) in acetonitrtle (20 ml) was added 1,1'-carbonyldlimidazole (736 mg, 4 5 mmol) The mixture was stirred at room temperature for 45 mm, before addition of aqueous ammonium hydroxide solution (35%, 10 ml) The reaction mixture was stirred for 45 mm and ice cold water (15 ml) was added The precipitate was collected by filtration and dried in a vacuum oven at 60°C for 18 h to give the title compound (292 mg) 1H-NMR (d6-Acetone) 7 70 - 7 78 (2H), 7 98 - 8 02 (1H)
Preparation 12 2-Fluoroterephthalonitrile
To a solution of the compound of Preparation 11 (138 mg, 0 8 mmol) in acetomtrile (6 ml) and water (2
ml) was added palladium (II) chloride (15 mg) and the reaction mixture was heated at 50°C for 24 h
The mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2 x 10 ml)
The combined extracts were dned (MgSO4) and concentrated in vacuo to give the title compound (113
mg)
1H-NMR (CD3OD) 7 80 - 7 84 (2H), 7 84 - 7 87 (1H)
Preparation 13 4-Fluoroisophthalomtrile
To a solution of 2-fluoro-5-formyfbenzonitnle (51 g, 33 9 mmol) in water (75 ml) was added hydroxylamine-O-sulphomc acid (4 6 g, 40 7 mmol) and the reaction mixture was heated at 50°C for 5
h The mixture was filtered and the solid material was washed with water and dried in vacuo for 18 h
to give the title compound (4 3 g)
1H-NMR (CDCI3) 7 38 - 7 41 (1H), 7 91 - 7 94 (1H), 7 94 - 7 97 (1H)
Preparation 14 4-Chloro-3-fluoro-5-ftnfluoromethynbenzonitnle
A mixture of the compound of Preparation 15 (200 mg, 1 0 mmol), ferf-butyl nitrite (0 2 ml, 1 5 mmol) and copper (II) chlonde (209 mg, 1 2 mmol) in acetonrtnle (10 ml) was heated at 70°C for 2 h The mixture was cooled and added to hydrochloric acid (20%, 10 ml), before addition of water (10 ml) The mixture was extracted with dtchloromethane (2x10 ml) and the combined organic phases were dned (MgSO4) and concentrated In vacuo to give the title compound (180 mg) 1H-NMR (CDCI3) 7 63 - 7 67 (1H), 7 80 - 7 82 (1H)
Preparation 15 4-Amino-3-fluoro-5-(tnfluoromethyl)Denzonitnle
A mixture of the compound of Preparation 16 (1 1 g, 4 3 mmol), sodium cyanide (418 mg, 8 5 mmol) and nickel (II) bromide (932 mg, 4 3 mmol) in 1-methyl-2-pyrrolidinone (12 ml) was heated at 160°C in a microwave oven (CEM 300W) for 6 h To the mixture was added water (60 ml) and dichloromethane (50 ml) and the solution was filtered through Arbocel®, washing through with dichloromethane (50 ml) The two layers were separated and the organic phase was dned (MgSO4) and concentrated in vacuo The residue was combined with other crude batches (approximately 4 g in total) and purified by automated flash chromatography (Biotage™ 60si cartridge) with gradient elution, ethyl acetate cyclohexane [01 to 2 3] The appropnate fractions were combined and concentrated to give the title compound (1 7 g) 1H-NMR (CDCI3) 4 75 - 4 90 (2H). 7 39 - 7 43 (1H), 7 56 - 7 58 (1H)
Preparation 16 4-Bromo-2-fluoro-6-(tnfluoromethyl)aniline
To a solution of 2-amino-3-fluorobenzotnfluonde (0 7 ml, 5 6 mmol) in acetonrtnle (2 ml) was added N-bromosuccmimide (994 mg, 5 6 mmol), followed by iron (III) chlonde (90 1 mg, 0 6 mmol) The reaction mixture was stirred at room temperature for 90 mm, before addition of water (20 ml) The mixture was extracted with tert-butyl methyl ether (2x15 ml) and the combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1 4 g), which was used directly
Preparation 17 3-Cyano-5-(2-Cyano-2-[[4-(DentafIuorothlo)benzovnamino)propoxy)benzoicacid
To a solution of the compound of Preparation 18 (257 mg, 0 5 mmol) in tetrahydrofuran and water (11,6 ml) was added lithium hydroxide monohydrate (44 mg, 1 0 mmol) and the reaction mixture was stirred at room temperature for 2 h The mixture was adjusted to pH 4 by addition of hydrochlonc acid (2M) and extracted with ethyl acetate The combined organic phases were washed with bnne, dned
(MgSO4) and concentrated in vacuo to give the title compound (202 mg) Experimental MH+ 475 8, expected 476 1
Preparation 18 Methyl-3-Cyano-S-(2-Cyano-24r4-(Dentaf1uorothio)benzovnamino)DroDoxy)benzoate
To a solution of the compound of Preparation 9 (200 mg, 0 6 mmol) in anhydrous N,N-dimethylformamide (3 ml), at 0°C and under nitrogen, was added sodium hydride (60% in oil, 48 mg, 1 2 mmol) After stimng for 15 mm, a solution of the compound of Preparation 19 (217 mg, 1 2 mmol) in anhydrous A/./V-dimethyrformamide (1 ml) was added and the reaction mixture was stirred at room temperature for 2 5 h The mixture was quenched by addition of water (10 ml) and additional water (10 ml) and ethyl acetate (20 ml) were added The two layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml) The combined extracts were washed with water and bnne, dried (MgSO() and concentrated in vacuo The residue was dissolved in dichloromethane and purified by automated flash chromatography (Biotage™ 25+M cartridge) with gradient eiution, ethyl acetate cyclohexane [6 94 to 50 50] The appropriate fractions were combined and concentrated to give the title compound (61 mg)
1H-NMR (CD3OD) 1 96 - 1 98 (3H), 3 92 - 3 94 (3H), 4 50 - 4 52 (1H). 4 61 - 4 63 (1H), 7 63 - 7 64 (1H), 7 89 - 7 90 (1H), 7 94 - 7 97 (3H), 7 97 - 8 00 (2H)
Preparation 19
Methyt 3-Cyano-5-ftuorobenzoate
To a solution of 3-cyano-5-ftuorobenzoic acid (1 0 g, 6 1 mmol) in dichloromethane (5 ml) and methanol (0 5 ml), at 0*C, was added dropwise (tnmethylsilyi)diazomethane (2M in hexanes, 3 6 ml, 7 3 mmol) The reaction mixture was stirred at room temperature, under nitrogen, for 18 h and then concentrated in vacuo to give the title compound (1 1 g) 1H-NMR (CDCIj) 3 98 - 4 00 (3H). 7 56 - 7 58 (1H), 7 97 - 7 99 (1H), 8 15 - 8 17 (1H)
Preparation 20 N-(1-Cyano-2-hvdroxy-1-methylethyl)-4-(Dentafluorothlo)benzamWe(First-elutinaenantiomer)
The compound of Preparation 9 (12 1 g, 36 8 mmol) was dissolved in ethanol (4 5 ml) in batches of
605 mg and the enantiomers were separated by automated preparative liquid chromatography (Gilson
system, 500 x 50 mm ID Chiralcel AD-H, 5 um column, 50 ml/mm) using methanol ethanol hexane
[10 10 80] as the mobile phase The fractions containing the first eiuting enantiomer were combined
and concentrated to give the title compound (5 9 g)
Retention time = 7 55 mm 250 x 4 6 mm Chiralpak AD-H, 5 um column, methanol ethanol hexane
f1010 80],1ml/min
Experimental MH* 331 0, expected 331 1
Preparation 21
N41-Cyano-2-hvdroxy-1-methylethyl)-4-(pentafluorothto)benzamide (Second-elutinq
enantiomer)
The compound of Preparation 9 (12 1 g, 36 8 mmol) was dissolved in ethanol (4 5 ml) in batches of
605 mg and the enanbomers were separated by automated preparative liquid chromatography (Gilson
system, 500 x 50 mm ID Chiralcel AD-H, 5 urn column, 50 ml/mm) using methanol ethanol hexane
[1010 80] as the mobile phase The fractions containing the second eluting enantiomer were
combined and concentrated to give the title compound (5 7 g)
Retention time = 10 40 mm 250 x 4 6 mm Chiralpak AD-H, 5 urn column, methanol ethanol hexane
[1010 80], 1ml/rmn
Experimental MH* 331 0, expected 331 1

WE CLAIMS
1. A compound of the formula
(Formula Removed)
or a tautomer or prodrug thereof, or a pharmaceutical^ acceptable salt of said compound,
tautomer or prodrug, wherein:
R1, R2, R3, R4 and Rs are each independently selected from H, halo, CN, CF3 and CONH2.
2. A compound according to claim 1 wherein R1, R2, R3, R4 and Rs are each independently selected from H, F, CI, Br, CN and CF3.
3. A compound according to claim 1 or claim 2 wherein at least one of R1, R2, R3, R4 and R5 is CN and at least two of R1, R2, R3, R4 and R5 are H.
4. A compound according to any preceding claim wherein R1 and R4 are H, one of R2 and R3 is H and the other is CN, and R5 is selected from F, CI, Br and CF3.
5. A compound according to any preceding claim wherein R3 is CN and R5 is CF3.
6. A compound according to any preceding claim selected from: N-{1-cyano-2-[5-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-pentafluorothiobenzamide,
N-(1R)-1-cyano)-2-[5-cyanc-2-{trifluc>romethyl)pherK3xy]-1-methylethyl}-4-pentafluorothio-benzamide,
N-(1S)-1-cyano-2-[5-cyano-2-(trifluorornethyl)phenoxy]-1-methylethyl}-4-pentafiuorothio-benzamide,
N-[2-(2-chloro-5-cyanophenoxy)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamidel N-[2-(2-chloro-5-cyanophenoxy)-(1R)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide, /V-[2-(2-chloro-5-cyanophenoxy-(1S)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide, N-{1-cyano-2-[4-cyano-2--2^4-cyano-2-(trifluoromemyl)phenoxyJ-1-methylethylH-pentafluorothio-benzamide,
N-(((1S)1-cyano2-[4-cyano-2-(trifluoromethyl)phenoxy]-1-meth^ethyl)-4-pentafluorothio-
benzamide,
N-{2-[2-chloro-5-cyatro-3-{trifluoromethyl)phenoxyJ-1-cyanc-1-methylethyl}-4-pentaf!uorDttiio-
benzamide,
N-{2-{2-chloro-5-cyano-3-(triflluoromethyl)phenoxy]-( 1R )-1 -cyano-1 -methylethyl}-4-
pentafluorothiobenzamide,
N-{2-[2-chbro-5-cyano-3-(trifluoromethyl)phenoxy-(1S)-1-cyano-1-methylethyl)-4-
pentafluorothiobenzamide,
N-f2-(2-chloro-4,5-dicyanophenoxy}-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide,
N-[2-(2-chloro-4,5-dicyanophenoxy)-(1R)-1-cyano-1-methylethyi]-4-penlafluorothiobenzamideI
N-[2-{2-chloro-4,5-dicyanophenoxy)-(1S)-1-cyano-1-methylethyl]-4-pentafluorothiobenzamide,
N-{1-cyano-2-[4-cyano-2-(trifluoromelhy!)phenoxy]-1-methylethyl}-4-
pentafluorothiobenzamide,
N-{(1R)-1-cyano-2-I4-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl}-4-pentaf(uorQthio-
benzamide, and
or a pharmaceutical^ acceptable salt thereof.
7. A pharmaceutical composition including a compound of formula (I) as defined in any one of
claims 1 to 6, or a pharmaceutical^ acceptable salt thereof, and a pharmaceuticafly
acceptable carrier.
8. The pharmaceutical composition according to claim 7 further including a second therapeutic
agent
9. The pharmaceutical composition according to claim 8 wherein the second therapeutic agent is selected from ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin, milbemycin oxime, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazoie, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, closantet, triciabendazole, clorsulon, rafoxanide, niclosamide, praziquantel, epsiprantel, 2-desoxoparaherquamide, fipronil, pyriprole, pyrafluprole, lufenuron, spiromesifen, tebufenozide, tebufenozide, spinosad, spinetoram, imidacloprid, dinotefuran, metaflumizone, flubendiamide, chlorantraniliprole, indoxacarb, pyridalyl, pyrimidifen and pyrifluquinazon.
10. A compound of formula (I), or a pharmaceutical^ acceptable salt thereof, as defined in any one of claims 1 to 6, for use as a medicament