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WO2019141957A1 - N-pyrimidinyl hydroxy pyrazole derivatives and uses thereof - Google Patents

N-pyrimidinyl hydroxy pyrazole derivatives and uses thereof Download PDF

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Publication number
WO2019141957A1
WO2019141957A1 PCT/GB2018/050171 GB2018050171W WO2019141957A1 WO 2019141957 A1 WO2019141957 A1 WO 2019141957A1 GB 2018050171 W GB2018050171 W GB 2018050171W WO 2019141957 A1 WO2019141957 A1 WO 2019141957A1
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compound
spp
optionally substituted
group
het
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French (fr)
Inventor
Simon Ross Crumpler
William DALBY-BROWN
Thomas David Pallin
John Bondo Hansen
Anne-Marie Lund WINTHER
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Cado Biotechnology Ivs
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Cado Biotechnology Ivs
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to uses of certain /V-pyrimidinyl hydroxy pyrazoles, and pharmaceutically acceptable salts and/or prodrugs thereof, which compounds have been found to be potent inhibitors of fungal growth. As such, these compounds are of use in the treatment or prevention of fungal infections and associated diseases, and in other applications requiring the inhibition of fungal growth. Such compounds have also been found to have antibacterial properties, redering them of use in the treatment or prevention of bacterial infections.
  • the present invention relates to the use of such compounds as medicaments and agrochemicals, to pharmaceutical and agrochemical compositions containing such compounds, and to processes for the production of such compositions. Further, the present invention relates to certain novel compounds and synthetic processes for their production.
  • Severe systemic fungal infection in hospitals (such as candidiasis, aspergillosis, fusariosis, histoplasmosis, blastomycosis, coccidioidomycosis and scedosporiosis; see, for example, Chapman et ai, Trans Am Clin Climatol Assoc., 119, 197-215 (2008)) is commonly seen in neutropenic patients following chemotherapy, in other oncology patients with immune suppression, and in patients who are immune-compromised due to, for example, Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, as well as in patients in intensive care. Serious fungal infections may cause 5-10% of deaths in patients undergoing lung, pancreas or liver transplantation (Ribaud et al., Clin Infect Dis., 28, 322- 30 (1999)).
  • AIDS Acquired Immune Deficiency Syndrome
  • invasive aspergillosis remains a major cause of morbidity and death in neutropenic patients with hematologic malignancies, especially in patients undergoing induction chemotherapy and hematopoietic stem cell transplantation. Indeed, despite recent advances in antifungal therapy, the overall mortality rate in patients with invasive pulmonary aspergillosis remains very high, approaching 90%.
  • Mucormycosis is a highly lethal infection caused by fungi belonging to the order Mucorales of the class Zygomycetes (Spellberg B et al. , Clin Microbiol Rev, 18(3), 556-569 (2005)). Recent data have demonstrated a striking increase in the frequency of mucormycosis cases. Unfortunately, despite aggressive surgical debridement and antifungal therapy, mortality from mucormycosis remains at least 50% (Ibrahim, A. S. et al., Journal of Clinical Investigation, 117(9), 2649-2657 (2007)).
  • Risk factors associated with candidemia and/or systemic candidiasis include granu locytopenia, bone marrow transplantation, solid organ transplantation (e.g. liver, kidney), parenteral hyperalimentation, solid neoplasms, corticosteroids, broad-spectrum antibiotics, burns, prolonged ICU (intensive care units) stay (i.e.
  • antifungal drug e.g. amphotericin B
  • the azoles e.g. voriconazole, fluconazole, posaconazole, ketoconazole or itraconazole
  • the echinocandins e.g. caspofungin, micafungin or anidulafungin
  • flucytosine e.g. flucytosine
  • polyenes are the oldest class of antifungal agents, having been first introduced in the 1950s. The exact mode of action remains unclear, but polyenes are only effective against fungal organisms that contain ergosterols in their outer membranes. It has been proposed that amphotericin B interacts with fungal membrane ergosterols, leading to pore formation, which in turn results in leakage of cytoplasmic components and subsequent cell death. Azoles inhibit fungal growth by inhibition of CYP51A1 (lanosterol C14a-demethylase) . This leads to a depletion of the membrane ergosterol and the accumulation of ergosterol precursors resulting in a plasma membrane with altered fluidity and structure.
  • CYP51A1 lanosterol C14a-demethylase
  • Echinocandins work by inhibition of the enzyme 1 ,3 ⁇ -glucan synthase, responsible for synthesis of b-glucans in the fungal cell wall. This leads to abnormal cell wall formation, osmotic sensitivity and cell lysis.
  • Flucytosine is a pyrimidine analogue interfering with the cellular pyrimidine metabolism as well DNA, RNA and protein synthesis.
  • widespread resistance to flucytosine limits its therapeutic use.
  • the present invention relates to compounds that are /V-pyrimidinyl substituted hydroxy pyrazoles, and pharmaceutically acceptable salts thereof. Although certain such compounds have been previously described, there is no disclosure of the use of such compounds as anti-fungal agents.
  • R 1 and R 2 each independently represent H or a substituent selected from the group consisting of
  • each of R 1a to R 1 k independently represent H, Ar 3 , Het 3 , C1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A 3 ; each of R 1a to R 1 k independently represent H, Ar 3 , Het 3 , C1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A 3 , or any pair of R 1c and R 1d , R 1e and R 1f , R 19 and R 1 h , and R 1j and R 1 k may, together with the atom(s) to which they are attached, form a 4- to -14- membered heterocycloalky
  • each of A 1 to A 6 independently represent a substituent selected from the group consisting of
  • each of Ar 1 to Ar 5 independently represents a Ce-io carbocyclic aromatic group optionally substituted with one or more substituents selected from B 1 ; each of Het 1 to Het 5 independently represents:
  • each of D 1 to D 3 independently represents a group selected from halo, oxy, -NO2, -CN, - OR 6a , -N(R 6b )(R 6c ), -C(0)0R 6d , -C(0)NR 6e R 6f , Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C5-6 cycloalkenyl and phenyl, wherein the latter six groups are optionally substituted, where possible, by one or more fluoro; or wherein D 1 represents Het 10 ;
  • Het 10 represents:
  • each X 5 individually represents a group selected from oxy or a Ci-e alkyl, wherein the Ci-e alkyl is optionally substituted by OH; each of R 5a to R 5f and R 6a to R 6f independently represents a group selected from Ci-e alkyl, H and phenyl, wherein the latter two groups are optionally substituted by one or more group selected from halo, -NH 2 and -OH, Ci-e alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 cycloalkyl and C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more group selected from halo, oxy, -NH 2 and -OH; and each p, q and r independently represents 0, 1 or 2, which compounds may be
  • a method for the treatment or prevention of a fungal and/or bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt and/or prodrug thereof.
  • references herein to particular aspects of the invention will include references to all embodiments and particular features thereof. Further, any one or more embodiments and/or particular features of any aspect of the invention may be combined with any one or more other such embodiments in order to form more particular embodiments and/or features of that aspect of the invention, without departing from the disclosure of the invention as provided herein.
  • pharmaceutically acceptable salt includes references to pharmaceutically acceptable salts formed with either acids or bases (i.e. acid-formed proton addition salts or base-formed proton removal salts).
  • Particular pharmaceutically acceptable salts include acid addition salts, such as carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippur
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts.
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate,
  • TFA trifluoroacetate
  • HCI hydrochloride salts
  • mono- or di- salts i.e. formed using one or two equivalents of the acid, respectively
  • base addition salts include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo , by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Compounds of the invention may contain double bonds and may thus exist as E (entussi) and Z ( Milton ) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Enantiomers and diastereoisomers may be isolated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a‘chiral pool’ method by reaction of the appropriate starting material with a‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • the present invention also embraces isotopically-labelled compounds of the first aspect of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • the compounds described herein also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
  • Ci -Z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain.
  • a C 3-z -cycloalkyl group (where z is the upper limit of the range) may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such cycloalkyl groups may also be part cyclic. Where the number of carbon atoms permits, cycloalkyl groups may also be spiro- groups (i.e. two cycloalkyl rings linked together by a single common carbon atom).
  • Ci -Z alkenyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain.
  • a Cs- z -cycloalkenyl group (where z is the upper limit of the range) may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of six) of carbon atoms, such groups may also be part cyclic.
  • Ci -Z alkynyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain.
  • halo refers to a halogen group, such as fluoro, chloro, bromo and iodo (e.g. fluoro and chloro and bromo).
  • the term“halo” may refer to a fluoro or chloro group (e.g. F).
  • the term“oxy”, when used herein, refers to a carbonyl (i.e. 0) group. The skilled person will understand that such oxy groups, where present, will only be present at suitable positions on the group to which they are attached, i.e. on suitable, saturated carbon atoms (e.g. forming ketone or aldehyde moieties).
  • such oxy substituents may be present, in particular, on alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups (i.e. on saturated carbon atoms present therein) or on alkyl moieties forming part of aryl, heteroaryl or heterocycloaryl groups as described herein (in which case, references to other instances of such substitution may be removed).
  • alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups i.e. on saturated carbon atoms present therein
  • alkyl moieties forming part of aryl, heteroaryl or heterocycloaryl groups as described herein (in which case, references to other instances of such substitution may be removed).
  • refereneces to oxy substituents may be deleted throughout.
  • Heterocycloalkyl groups (e.g. where representing a Het group, such as Het 1 , as defined herein) group that may be mentioned include saturated monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as boron, nitrogen, oxygen or sulphur), and in which the total number of atoms in the ring system is as defined (e.g. from four to fourteen).
  • a heteroatom such as boron, nitrogen, oxygen or sulphur
  • heterocycloalkyl groups that may be mentioned include those in which the total number of atoms in the ring system is from four to twelve, such as from five to twelve (e.g. from five to ten and, most particularly, from five to six, so forming a 5- or 6- membered heterocycloalkyl group). More particular heterocycloalkyl groups that may be mentioned include those containing one, two or three heteroatoms (e.g. one or two heteroatoms, such as one heteroatom), such as boron and two oxygens (i.e. as a boronate ester), one or two nitrogens, one or two sulphurs, one or two oxygens, or one oxygen and one nitrogen, such as those in which the total number of atoms in the ring system is five or six.
  • heteroatoms e.g. one or two heteroatoms, such as one heteroatom
  • boron and two oxygens i.e. as a boronate ester
  • heterocycloalkenyl groups e.g. where representing a Het group, such as Het 1 , as defined herein
  • group that may be mentioned include unsaturated (but non-aromatic) monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as boron, nitrogen, oxygen or sulphur), and in which the total number of atoms in the ring system is as defined (e.g. from four to fourteen).
  • unsaturated (but non-aromatic) monocyclic and bicyclic heterocycloalkyl groups which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as boron, nitrogen, oxygen or sulphur), and in which the total number of atoms in
  • heterocycloalkenyl groups that may be mentioned include those in which the total number of atoms in the ring system is from five to twelve, such as from five to twelve (e.g. from five to ten and, most particularly, from five to six, so forming a 5- or 6- membered heterocycloalkenyl group). More particular heterocycloalkenyl groups that may be mentioned include those containing one, two or three heteroatoms (e.g. one or two heteroatoms, such as one heteroatom), such as one or two nitrogens, one or two (e.g. one) sulphur(s), one or two (e.g. one) oxygen(s), or one oxygen and one nitrogen, such as those in which the total number of atoms in the ring system is five or six.
  • heteroatoms e.g. one or two heteroatoms, such as one heteroatom
  • Heterocycloalkyl and heterocycloalkenyl groups (e.g. where representing a Het group as defined herein) that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6- azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1 ]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5- dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl,
  • Substituents on heterocycloalkyl and heterocycloalkenyl groups may, where appropriate, be located on any atom in the ring system including, where possible, a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called“spiro”-compound.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen or boron atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • heteroatom(s) as used herein shall include references to boron, oxygen, nitrogen and sulphur (e.g. oxygen, nitrogen and sulphur).
  • a heterocycloalkyl group is preferably a 5- or 6-membered heterocycloalkyl group.
  • a heterocycloalkenyl group is preferably a 5- or 6-membered heterocycloalkyl group.
  • bicyclic refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring.
  • bridged refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Carbocyclic aromatic groups (which may also be referred to as aryl groups; e.g. where representing an Ar group, such as Ar 1 , as defined herein) that may be mentioned include those containing from six to fourteen atoms (i.e. carbon atoms) in the ring (which may be referred to as Ce- M groups).
  • Particular carbocyclic aromatic groups that may be mentioned include Ce-io (e.g. Ce) groups.
  • Such groups may be monocyclic or bicyclic, in which at least one ring is aromatic.
  • aryl groups that may be mentioned include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl.
  • the point of attachment of aryl groups may be via any atom of the ring system.
  • aryl groups are bicyclic or tricyclic, they are preferably linked to the rest of the molecule via an aromatic ring.
  • Particular carbocyclic aromatic groups i.e. aryl groups; e.g. where representing an Ar group as defined herein
  • aryl groups e.g. where representing an Ar group as defined herein
  • Particular carbocyclic aromatic groups include phenyl and naphthyl.
  • carbocyclic aromatic groups i.e. aryl groups; e.g. where representing an Ar group as defined herein
  • aryl groups e.g. where representing an Ar group as defined herein
  • Heteroaryl groups include those having from 5 to 14 (e.g. from 5 to 10, or 5 or 6) ring members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to three) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as nitrogen, oxygen or sulphur).
  • a heteroaryl group as described herein contains more than one ring (e.g. is bicyclic) and one or more (e.g.
  • Heteroaryl groups include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl and, in particular, oxazolo[4,5-c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5-b]pyridyl, thiazolo[5,4-b]pyridyl and, in particular, thiazolo[4,5- c]pyridyl and thiazolo[5,4-c]pyridyl), benzothiadiazolyl (including 2, 1 ,3-benzothiadiazolyl), iso
  • heteroaryl groups that may be mentioned include furanyl, pyridinyl, triazolyl (including 1 ,2,4-triazolyl), pyrimidinyl and oxadiazolyl (including 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl).
  • heteroaryl groups that may be mentioned include those bound (to the remainder of the compound) via a heteroatom (e.g. bound via a nitrogen atom, as comprised in the heteroaryl group).
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including, where possible, a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • heteroaryl groups when heteroaryl groups are polycyclic, they are preferably linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • the aryl or heteroaryl group is partly aromatic, i.e. the aryl or heteroaryl group consists of at least two rings where at least one ring is not aromatic.
  • the identity of two or more substituents in a compound of the first aspect of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.
  • the identity of those groups is in no way interdependent.
  • the identities of those individual substituents are not to be regarded as being interdependent.
  • the identities of the two R 1a groups are not to be regarded as being in any way interdependent.
  • R 1a to R 1k this will be understood by the skilled person to mean R 1a , R 1 b , R 1c , R 1d , R 1 e , R 1f , R 19 , R 1 h , R 1 i , R 1j and R 1 k , inclusively.
  • R 1 is not H (i.e. R 1 is a group other than H).
  • R 1 represents Ar 1 , Het 1 , C 1-6 alkyl, C 2-6 alkenyl, C ⁇ alkynyl, C 3-6 cycloalkyl or C 5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A 1 .
  • R 1 represents Ar 1 , Het 1 , C 1-6 alkyl or C 1-6 cycloalkyl, wherein the latter two groups are optionally substituted by one or more A 1 .
  • the Ar 1 group represents phenyl optionally substituted with one or more B 1 .
  • the Ar 1 group represents phenyl optionally substituted with one or more (e.g. one or two) groups selected from halo (e.g. F and Cl) and -CN.
  • the Het 1 group represents:
  • a 5- to 6- membered heteroaryl group optionally substituted with one or more substitutent selected from B 2 (e.g. wherein B 2 represents C1-3 alkyl, such as methyl or ethyl) or
  • a 5- to 6- membered heterocycloalkyl or heterocycloalkenyl group e.g. a 5- to 6- membered heterocycloalkyl group
  • a 5- to 6- membered heterocycloalkyl group optionally substituted with one or more substitutent selected from B 3 .
  • R 1 represents Ci-e alkyl
  • the C alkyl group is optionally substituted with one or more group selected from halo and, in particular, Ar 5 (e.g. wherein Ar 5 represents phenyl optionally substituted with one or more B 1 ), Het 5 , and -OR 3a (e.g. wherein R 3a represents methyl).
  • Ar 5 e.g. wherein Ar 5 represents phenyl optionally substituted with one or more B 1
  • Het 5 e.g. wherein R 3a represents methyl
  • -OR 3a e.g. wherein R 3a represents methyl
  • such Ci-e alkyl groups may represent, in particular, corresponding C1-3 alkyl groups (e.g. methyl).
  • R 1 represents Ci-e cycloalkyl
  • the Ci-e cycloalkyl group is optionally substituted with one or more halo (e.g. one or more F) or, more particularly, is unsubstituted.
  • R 1 represents alkyl
  • the substituents on R 1 groups do not include fluoro
  • R 1 represents alkyl
  • the substituents on R 1 groups do not include halo.
  • R 1 represents alkyl
  • the R 1 group is unsubstituted.
  • R 1 represents a 5- to 6- membered heteroaryl group optionally substituted with one or more substitutent selected from B 2 (e.g. wherein B 2 represents Ci- 3 alkyl, such as methyl or ethyl).
  • B 2 represents Ci- 3 alkyl, such as methyl or ethyl
  • the heteroaryl group may be optionally substituted with two C1-3 alkyl groups.
  • R 2 represents H, halo (e.g. F, Cl or Br, such as Cl or Br), C1-3 alkyl optionally substituted with one or more A 1 (e.g. wherein A 1 represents -CN) or -N(R 1g )R 1 h (e.g. wherein R 1 9 represents H and R 1 h represents C1-2 alkyl optionally substituted with one or more oxy, such as to form a -NHC(0)CH3 group).
  • halo e.g. F, Cl or Br, such as Cl or Br
  • a 1 represents e.g. wherein A 1 represents -CN
  • -N(R 1g )R 1 h e.g. wherein R 1 9 represents H and R 1 h represents C1-2 alkyl optionally substituted with one or more oxy, such as to form a -NHC(0)CH3 group.
  • R 2 does not represent Ar 1 or Het 1 .
  • R 2 represents H
  • R 3 represents H or fluoro.ln a more particular embodiment, R 3 represents H.
  • R 5 represents H or fluoro. In a more particular embodiment, R 5 represents H.
  • R 3 and R 5 are each H or fluoro. In more particular embodiments of the first aspect of the invention, R 3 and R 5 are each H.
  • R 2 , R 3 and R 5 are each H or fluoro. In further embodiments of the first aspect of the invention, R 2 , R 3 and R 5 are each H.
  • R 1 and R 4 are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
  • R 4 represents H or, particularly, a substituent selected from the group consisting of Het 2 , halo, -N0 2 , -OR 2a , -S(0) P R 2b , -S(0) q N(R 2c )(R 2d ), -N(R 2e )S(0) r R 2f and -N(R 29 )(R 2h ).
  • R 4 is a group bound to the remainder of the compound (i.e. bound to the core pyrazole moiety) via a heteroatom (e.g. via a nitrogen atom).
  • R 4 represents H or, particularly, a substituent selected from the group consisting of Het 2 (e.g. wherein Het 2 is bound via a nitrogen atom), -OR 2a (e.g. -OH) and -N(R 29 )(R 2h ).
  • the -N(R 29 )(R 2h ) group is a -NHR 2h group (i.e. R 29 represents H) , such as wherein R 2h represents C 1-3 alkyl (e.g. C 1-2 alkyl) optionally substituted with one or more A 5 (such as wherein A 5 represents Ar 5 , Het 5 , halo, -OR 3a , -N(R 39 )R 3h , -C(0)0R 3i or -C(0)NR 3 iR 3k .
  • the Het 2 group may in particular represent a 5- to 14- membered heteroaryl group (e.g. a 5- to 6- membered heteroaryl group) optionally substituted by one or more substituents selected from B 2 .
  • B 2 groups that may be mentioned include halo (e.g. fluoro), -OR 4a (e.g. -OCH 3 ) and C 1-6 alkyl (e.g. C 1-3 alkyl, such as C 1 alkyl) optionally substituted by one or more fluoro.
  • halo e.g. fluoro
  • -OR 4a e.g. -OCH 3
  • C 1-6 alkyl e.g. C 1-3 alkyl, such as C 1 alkyl
  • R 4 represents H or, particularly, a substituent selected from the group consisting of -OR 2a and -N(R 29 )(R 2h ).
  • R 4 represents -N(R 29 )(R 2h ).
  • the pair of R 29 and R 2h together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A 6 .
  • R 4 represents -N(R 29 )(R 2h ) wherein R 29 and R 2h together with the atom(s) to which they are attached do not form a ring.
  • R 4 represents Het 2 (e.g. wherein Het 2 is bound via a nitrogen atom), -OR 2a (e.g. -OH) or -N(R 29 )(R 2h ), wherein each of R 2a , R 29 and R 2h independently represent H or C alkyl optionally substituted by one or more A 5 , or alternatively the pair of R 29 and R 2h , together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A 6 .
  • -OR 2a e.g. -OH
  • -N(R 29 )(R 2h ) independently represent H or C alkyl optionally substituted by one or more A 5
  • R 29 and R 2h together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloal
  • the 5- membered heterocycloalkyl group formed by R 29 and R 2h is a pyrrolidine group.
  • a 6 represents fluoro or, particularly, -OR 3a .
  • R 3a represents Het 8 .
  • Het 7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D 2 .
  • Het 7 represents pyrimidinyl optionally substituted by one or more substituents selected from fluoro and, particularly, -CN.
  • R 29 and R 2h both represent C1 -3 alkyl (e.g. C1 alkyl) optionally substituted by one or more fluoro, such as wherein R 29 and R 2h both represent methyl.
  • R 1 , R 29 and R 2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
  • R 1 may not represent H.
  • the compound of formula III is not a compound selected from the list consisting of:
  • that ring may not be a pyrrole.
  • R 29 and R 2h may not be joined together to form a ring (e.g. R 29 represents H).
  • R 29 and R 2h both represent methyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 groups that may be mentioned include those present in the example compounds as described hereinafter.
  • R 1 and R 2 together form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more (e.g. one) Y 1 .
  • R 1 and R 2 may form a 5 to 7 membered heterocycloalkyl comprising a single heteroatom, for example oxygen, nitrogen and sulphur, such as nitrogen.
  • R 1 and R 2 may form a 5 to 7 membered heterocycloalkyl comprising a single heteroatom, wherein the hetero atom of the heterocycloalkyl is substituted by Y 1 .
  • R 1 and R 2 form a 6 membered heterocycloalkyl comprising a nitrogen atom. More particularly, R 1 and R 2 form a piperidinyl ring, which is thus fused to the essential pyrazolyl ring of the compounds of formula I.
  • R 1 and R 2 form a piperidinyl ring which is substituted at the nitrogen atom by Y 1 .
  • Y 1 represents -S(0) 2 R 4b or a Ci-e alkyl optionally substituted by one or more C 1 . In further embodiments, Y 1 represents a C1- 6 alkyl optionally substituted by a phenyl group.
  • Y 1 is a benzyl group.
  • R 3 represents H
  • R 5 represents H or fluoro
  • R 5 represents H
  • R 1 and R 2 form a 5 to 7 membered heterocycloalkyl
  • R 3 and R 5 are each H or fluoro.
  • R 1 and R 2 form a 5 to 7 membered heterocycloalkyl
  • R 3 and R 5 are each H.
  • R 1 and R 2 form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y 1 ;
  • R 4 is as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
  • R 4 represents H or, particularly, a substituent selected from the group consisting of Het 2 , halo, -NO2, -OR 2a , -S(0) p R 2b , -S(0) q N(R 2c )(R 2d ), -N(R 2e )S(0) r R 2f and -N(R 29 )(R 2h ).
  • R 4 is a group bound to the remainder of the compound (i.e. bound to the core pyrazole moiety) via a heteroatom (e.g. via a nitrogen atom).
  • R 4 represents H or, particularly, a substituent selected from the group consisting of Het 2 (e.g. wherein Het 2 is bound via a nitrogen atom), -OR 2a (e.g. -OH) and -N(R 29 )(R 2h ).
  • the -N(R 29 )(R 2h ) group is a -NHR 2h group (i.e. R 29 represents H) , such as wherein R 2h represents C1-3 alkyl (e.g. C1-2 alkyl) optionally substituted with one or more A 5 (such as wherein A 5 represents Ar 5 , Het 5 , halo, -OR 3a , -N(R 39 )R 3h , -C(0)0R 3i or -C(0)NR 3j R 3k .
  • the Het 2 group may in particular represent a 5- to 14- membered heteroaryl group (e.g. a 5- to 6- membered heteroaryl group) optionally substituted by one or more substituents selected from B 2 .
  • R 4 represents H or, particularly, a substituent selected from the group consisting of -OR 2a and -N(R 29 )(R 2h ).
  • R 4 represents -N(R 29 )(R 2h ).
  • the pair of R 29 and R 2h together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A 6 .
  • R 4 represents -N(R 29 )(R 2h ) wherein R 29 and R 2h together with the atom(s) to which they are attached do not form a ring.
  • R 4 represents Het 2 (e.g. wherein Het 2 is bound via a nitrogen atom), -OR 2a (e.g. -OH) or -N(R 29 )(R 2h ), wherein each of R 2a , R 29 and R 2h independently represent H or Ci-e alkyl optionally substituted by one or more A 5 , or alternatively the pair of R 29 and R 2h , together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A 6 .
  • a 4- to 6- membered e.g. 5-membered
  • the 5- membered heterocycloalkyl group formed by R 29 and R 2h is a pyrrolidine group.
  • a 6 represents fluoro or, particularly, -OR 3a .
  • R 3a represents Het 8 .
  • Het 7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D 2 .
  • Het 7 represents pyrimidinyl optionally substituted by one or more substituents selected from fluoro and, particularly, -CN.
  • R 29 and R 2h both represent C 1-3 alkyl (e.g. C 1 alkyl) optionally substituted by one or more fluoro, such as wherein R 29 and R 2h both represent methyl.
  • R 1 and R 2 form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y 1 ;
  • R 29 and R 2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
  • R 29 and R 2h are joined together to form a ring, that ring may not be a pyrrole.
  • that ring may not be a heteroaryl group.
  • R 29 and R 2h may not be joined together to form a ring (e.g. R 29 represents H).
  • R 29 and R 2h both represent methyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 groups that may be mentioned include those present in the example compounds as described hereinafter.
  • Particular compounds of the first aspect of the invention include those described in the examples provided herein, and pharmaceutically acceptable salts and/or prodrugs (e.g. pharmaceutically acceptable salts) thereof.
  • references to such compounds also include references to the free (i.e. non-salt) form of said compound (e.g. the free base) and all possible pharmaceutically acceptable salts thereof.
  • references to such compounds also include references to the free (i.e. non-salt) form of said compound (e.g. the free base) and all possible pharmaceutically acceptable salts thereof.
  • more particular forms of the compounds as described in the examples provided herein are those in the salt or non-salt form as described.
  • the term“patient” will be understood to refer to the subject being treated or, similarly, the subject benefiting from the preventative measure.
  • the term “patient” includes mammalian patients (such as equines, cattle, swine, sheep, goats, horses, primates, mice, rats, and pets in general including dogs, cats, guinea pigs, ferrets, and rabbits).
  • the term“patient” refers to humans.
  • compounds of the first aspect of the invention may possess pharmacological activity as such, there may be certain compounds which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolized in the body to form active compounds.
  • compounds mentioned in respect of the first aspect of the invention are useful because they possess pharmacological activity, and/or are metabolized in the body following oral or parenteral administration to form compounds, which possess pharmacological activity.
  • the present invention encompasses the use of prodrugs of compounds as described herein (e.g. compounds of the first aspect of the invention).
  • esters of such compounds include esters of such compounds (i.e. esters formed by reaction of the compound of invention to form an ester comprising that compound).
  • the references to esters of compounds of the invention may refer to pharmaceutically-acceptable esters as known to those skilled in the art, such as Ci -4 alkyl esters.
  • such esters may include those formed by reaction of the essential hydroxyl moiety present on the core pyrazole group of compounds of the invention to form an ester thereof (e.g. so forming a -OWi group, wherein Wi may represent Ci -4 alkyl optionally substituted by one or more fluoro).
  • Particular esters that may be mentioned include methyl, ethyl and t-butyl (i.e. pivaloyl) esters.
  • prodrugs of compounds of the invention include carbonate esters of such compounds (i.e. carbonate esters formed by reaction of the compound of invention to form a carbonate ester comprising that compound).
  • carbonate esters of compounds of the invention may refer to pharmaceutically-acceptable carbonate esters as known to those skilled in the art, such as C 1-4 alkyl esters.
  • Particular esters that may be mentioned include methyl, ethyl and t- butyl (i.e. pivaloyl) esters.
  • therapeutically effective amount refers to an amount of a compound which confers a therapeutic effect (e.g. the relevant treatment or prevention, such as the relevant treatment) on the treated patient (i.e. the patient (e.g. the mammal) to which the compound is administered).
  • the effect may be objective (i.e. measurable by some test or marker, such as the measurable treatment of the condition or the identifiable prophylaxis of the condition) or subjective (i.e. the subject gives an indication of or feels an effect).
  • a therapeutically effective amount of a compound according to the present invention is an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease or disorder and its complications.
  • suitable daily doses may be in the range of about 10 to 2000 mg per patient, administered in single or multiple doses (for example, administered as three daily doses of 200 to 500 mg/kg, such as three daily doses of around 400 mg/kg).
  • the compounds of the invention may be administered in doses of 10 to 3000 mg, such as 50 to 2500 mg, or such as 10 mg to 2000 mg per day (for example, until such time as said treatment is no longer required).
  • Compounds of the first aspect of the invention may provide systemic and/or local (e.g. topical) therapeutic effects.
  • the treatment may involve systemic or local (e.g. topical) administration of a compound of the first aspect of the invention (including all embodiments thereof).
  • Particular forms of local administration include topical administration, for example to an area of the skin or a mucous membrane of the body (including internal and external mucous membranes).
  • Compounds of the first aspect of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • compounds of the first aspects of the invention may be administered topically (i.e. applied directly to the area to be treated, as defined herein, or where prevention, as defined herein, is required).
  • the skilled person will be able to select the route of administration depending on the nature of the infection to be treated or prevented.
  • the compound may be administered by inhalation (and a suitable inhalable formulation used).
  • the compound may be administered topically to the relevant area (and a suitable topical formulation used, such as a pessary).
  • treatment or prevention as described herein may further comprise treatment or prevention with one or more active ingredient, wherein the term “administration” includes separate, sequential and/or simultaneous administration of the additional (i.e. other) active ingredient.
  • the treatment or prevention is of a fungal infection.
  • fungal infection refers to infection with one or more fungi, fungal-like species and/or parasite (e.g. one or more fungi).
  • fungi fungi, fungal-like species and/or parasite (e.g. one or more fungi).
  • parasite e.g. one or more fungi.
  • infections may be systemic and/or local.
  • bacterial infection refers to infection with one or more bacterial species.
  • the skilled person will understand that such infections may be systemic and/or local.
  • treatment takes its normal meaning in the field of medicine.
  • the term may refer to achieving a reduction in the severity of one or more clinical symptom associated with the disease or disorder (e.g. the fungal infection), as may be determined using techniques known to those skilled in the art (for example, by a medical physician).
  • the term may refer to killing and/or inhibiting or reducing growth of the fungi, fungal-like species and/or parasite (e.g. the fungal cells) associated with the infection.
  • treatment and “treating” may refer to achieving a reduction of colony forming units (CFUs) associated with the fungi, fungal-like species and/or parasite (e.g. the fungal cells), which may be determined through analysis of samples of bodily fluid (e.g. blood and/or urine) taken from the patient subjected to said treatment (e.g. comparison of samples taken before and after said treatment) using techniques known to those skilled in the art.
  • CFUs colony forming units
  • the treatment or prevention is of a bacterial infection.
  • the term may refer to killing and/or inhibiting or reducing growth of bacterial species associated with the infection.
  • prevention includes references to the prophylaxis of the disease or disorder (and vice- versa).
  • references to prevention may also be references to prophylaxis, and vice versa.
  • the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
  • references herein throughout to treating or preventing may refer in particular to treating (or, similarly, to treatment).
  • references herein to a fungal infection will refer to a (systemic or local, e.g. systemic) infection caused by one or more species of fungus as known to those skilled in the art.
  • the fungal infection is an infection caused by one or more (e.g. one) species of fungus selected from the group consisting of: Acremonium spp. (e.g. A. recifei or A. alabamense), Acrophialophora spp. (e.g. A. fusispora or A. levis), Alternaria spp. (e.g. A. infectoria, A. alternata), Aphanoascus fulvescens, Apophysomyces spp. (A. elegans or A. variabilis), Arthroderma spp. (e.g. A. insingulare or A.
  • Acremonium spp. e.g. A. recifei or A. alabamense
  • Acrophialophora spp. e.g. A. fusispora or A. levis
  • Alternaria spp. e.g. A. infectoria, A.
  • Aspergillus spp. e.g. A. clavatus, A. flavus, A. fumigatus, A. felis, A. nidulans, A. niger, A. terreus, A. lentulus or A. versicolor
  • Aureobasidium pullulans e.g. B. australiensis, B. hawaiiensis orB. spicifera
  • Blastomyces spp. e.g. B. dermatitidis
  • Blastoschizomyces e.g. B. capitatus
  • Botrytis cinerea Candida spp. (e.g. C. albicans, C.
  • C. oxysporum e.g. C. oxysporum
  • C. sphaerospermum e.g. C. devriesii
  • Cladophialophora spp. e.g. C. bantiana
  • Clavispora lusitaniae e.g. C. bantiana
  • Coccidioides e.g. C. immitis, C. posadasii
  • Cokeromyces recurvatus etotrichum spp.
  • Conidiobolus spp. e.g. C. coronatus, C. incongruus or C. lamprauges
  • Coniochaeta spp. e.g. C. C.
  • Cryptococcus spp. e.g. C. albidus, C. laurentii or C. neoformans (like var. neoformans or vargattii)
  • Cunninghamella spp. e.g. C. berthollethiae or C. elegans
  • Curvicularia lunata e.g. C. berthollethiae or C. elegans
  • Curvicularia lunata e.g. E. dermatitidis, E. jeanselmei, E. oligosperma, E. phaeomuriformis E. spinifera orE. xenobiotica
  • Fonsecaea spp. e.g. F. compacta, F. monophora, or F. pedrosi
  • Fusarium spp. e.g. F. oxysporum, F. solani, F. verticillioides, F. chlamydosporum, F. dime rum, F. fujikuroi, or F. incarnatum
  • Geotrichum spp. e.g. G. candiddum, G. capitatum or G.
  • M. globosa or M. furfur Malassezia spp.
  • Microsphaeropsis arundinis Microsporum spp.
  • M. audouinii M. canis
  • M. ferrugineum M. cookei
  • M. gallinae M. vanbreuseghemii
  • Mortierella wolfii Monilinia spp.
  • Mucor e.g. M. amphibiorum, M. circinelloides, M. indicus, M. irregularis or M.
  • ramosissimus Myrmecridium schulzeri Nannizzia spp. (e.g. N. fulva, N. gypsea, N. nana or N. persicolor), Neosartorya fischeri, Neoscytalidium dimidiatum, Onychocola canadensis, Paecilomyces spp. (e.g. P. marquandii, P. variotii or P. lilacinus), Paracoccidioides (e.g. P. brasiliensis), Penicillium (e.g. P. marneffei), Phaeoacremonium spp. (e.g. P. P.
  • Pseudallescheria spp. e.g. P. boydii, Puccinia arachidis
  • Pyricularia spp. Pythium spp.
  • P. insidiosum P. aphanidermatum and P. ultimum
  • Quambalaria spp. e.g. Q. cyanescens, Q. pitereka, Q. eucalypti, Q. coyrecup or Q. simpsonii
  • Rhinocladiella spp. e.g. R. atrovirens or R.
  • Rhizoctonia solani Rhizomucor spp.
  • Rhizomucor spp. e.g. R. miehei or R. pusillus
  • Rizopus spp. e.g. R. micropsorus, R. oryzae, R. pusillus
  • Rhodotorula spp. e.g. R. glutinis orR. mucilaginosa
  • Saccharomyces e.g. S. cerevisiae
  • Saksenaea vasiformis Scedosporium spp. (e.g. S. apiospermum, S. auraticum, S. boydii or S.
  • Trichosporon spp. e.g. T. asahii, T. asteroids, T. beigelii, T. cuaneum, T. inkin, T. ovoides, T. roseum or T. terrestre
  • Uncinula necator syn. Erysiphe necator
  • Venturia spp. Veronaea botryose
  • Verruconis spp. e.g. V. gallopava
  • Wickerhamomyces anomalus e.g. V. gallopava
  • fungus particularly species include C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, A. fumigatus, A. flavus, A. terms, F. solani, F. verticillioides, F. Oxysporum, Mucor spp. and Cryptococcus spp.
  • references to particular species of fungi may also include references to naturally-ocurring mutant forms thereof, as known to those skilled in the art.
  • compounds of the first aspect of the invention may be useful for the treatment and/or prevention of a variety of superficial, cutaneous, subcutaneous fungal infections, such as systemic mycotic infections in skin, eye, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal portion, oral cavity, ophthalmus, systemic, kidney, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, blood and so on.
  • superficial, cutaneous, subcutaneous fungal infections such as systemic mycotic infections in skin, eye, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal portion, oral cavity, ophthalmus, systemic, kidney, heart, external auditory canal, bone, nasal cavity
  • the treatment or prevention of a fungal infection may comprise (or consist of) the treatment or prevention of one or more condition selected from the group consisting of: dermatophytosis (e.g. trichophytosis, ringworm or tinea infections), athletes foot, paronychia, pityriasis versicolor, erytrasma, intertrigo, fungal diaper rash, Candida vulvitis, Candida balanitis, otitis externa, candidiasis (cutaneous and mucocutaneous), chronic mucocandidiasis (e.g.
  • dermatophytosis e.g. trichophytosis, ringworm or tinea infections
  • athletes foot paronychia
  • pityriasis versicolor erytrasma
  • intertrigo fungal diaper rash
  • Candida vulvitis Candida balanitis
  • otitis externa candidiasis (cutaneous and mucocutaneous)
  • chronic mucocandidiasis e.
  • thrush and vaginal candidiasis cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, pneumocystosis, rhinocerebral mucomycosis, lobomycosis, phaeohyphomycosis, and fugemia.
  • compounds of formula I may also be used as prophylactic agents to prevent fungal or bacterial infections (e.g. systemic and topical fungal or bacterial infections).
  • Use as prophylactic agents may, for example, be appropriate as part of a selective gut decontamination regimen in the prevention of infection in immune-compromised patients (e.g. AIDS patients, patients receiving cancer therapy or transplant patients). Further, prevention of fungal overgrowth during antibiotic treatment may also be desirable in some disease syndromes or iatrogenic states.
  • compounds of formula I, or pharmaceutically acceptable salts thereof may prevent fungal infections by hindering fungal biofilm formation.
  • compounds of formula I (as defined in the first aspect of the invention, including any one or more embodiment thereof), or pharmaceutically acceptable salts thereof, may also be used for the prevention or treatment of a bacterial infection.
  • the bacterial infection may be an infection with one or more (e.g. one) Gram-positive bacterial species. [Is this correct?]
  • the bacterial infection may be an infection with one or more (e.g. one) bacterial species selected from the following: [Please provide a list of relevant species]
  • the treatment or prevention comprises administering a therapeutically effective amount of a pharmaceutical formulation comprising a compound as defined in the first aspect of the invention (including all embodiments thereof), and optionally one or more pharmaceutically acceptable excipients.
  • Suitable pharmaceutically acceptable excipients will be well-known to those skilled in the art, and may include suitable adjuvants, diluents and carriers as known to those skilled in the art, such as those described herein.
  • pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
  • compositions may be formulated to deliver the active ingredient (i.e. the compound of formula I, or pharmaceutically acceptable salt thereof) in a manner designed to provide systemic and/or local therapeutic effects.
  • compositions may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • pharmaceutical compositions according to the first aspect of the invention may be specifically formulated for administration by the oral route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release, according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also regarded as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • a typical oral dosage may be in the range from about 0.01 to about 500 mg/kg body weight per day, particularly from about 0.1 to about 200 mg/kg body weight per day, and more particularly from about 10 to about 100 mg/kg body weight per day, administered in one or more doses such as 1-3 doses.
  • doses such as 1-3 doses.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated, and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day, such as 1-3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg of a compound of the invention.
  • typical dosages are in the order of about half the dosage employed for oral administration.
  • solutions of compounds may be administered in sterile aqueous solution, in aqueous propylene glycol or in sesame or peanut oil.
  • Aqueous solutions should be suitably buffered where appropriate, and the liquid diluent rendered isotonic with, e.g., sufficient saline or glucose.
  • Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media to be employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • compositions suitable for oral administration may be presented as discrete units, such as capsules or tablets, which each contain a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more additional components selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may, for example, be: inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356, 108; 4, 166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
  • a typical tablet is prepared by conventional tabletting techniques and contains the following.
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the pharmaceutical composition comprising a compound according to the first aspect of the invention may additionally comprise further active substances.
  • the treatment or prevention as described in the first aspect of the invention may also comprise (i.e. as part of the same medical intervention) administration of one or more (e.g. one) additional (i.e. other) active substances.
  • such further active substances may include one or more agent selected from the group consisting of fungicidal and/or fungistatic agents, antibacterial agents, antiviral agents, antiseptics, analgesics and anaesthetics (e.g. local anaesthetics), as known to those skilled in the art.
  • such further active substances may include one or more (additional) anti-fungal agent, as known to those skilled in the art.
  • amphotericin B and any suitable formulations of amphotericin, such as amphotericin deoxycholate, amphotericin B lipid complex, amphotericin B cholesteryl sulfate complexes, amphotericin B colloidal dispersions, and liposomal amphotericin B formulations, as well as echinocandins such as caspofungin, micafungin, and anidulafungin.
  • amphotericin B and any suitable formulations of amphotericin such as amphotericin deoxycholate, amphotericin B lipid complex, amphotericin B cholesteryl sulfate complexes, amphotericin B colloidal dispersions, and liposomal amphotericin B formulations, as well as echinocandins such as caspofungin, micafungin, and anidulafungin.
  • Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the compound as described in the first aspect of the invention (including all embodiments thereof) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients may include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids
  • oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil, for example arachis oil, olive oil, sesame oil, corn oil, or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol
  • compositions comprising a compound of the first aspect of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • compositions may also be provided in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • compositions for buccal and sublingual use include mouth washes and gargles.
  • compounds of the first aspect of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • compounds of the first aspect of the invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form, or may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • pharmaceutical formulations comprising compounds of the first aspect of the invention (including all embodiments thereof) may also be formulated for topical administration.
  • the pharmaceutical formulation as described herein is a topical pharmaceutical composition.
  • the term“topica includes references to formulations that are adapted for application to body surfaces (e.g. the skin or mucous membranes).
  • Mucous membranes that may be mentioned in this respect include the mucosa of the vagina, the penis, the urethra, the bladder, the anus, the mouth (including the mucosa of the cheek, the soft palate, the under surface of tongue and the floor of the mouth), the nose, the throat (including the mucosa of the pharynx, the larynx, the trachea and the esophagus), the bronchi, the lungs, the eye and the ear.
  • Topical compositions which are useful for treating disorders of the skin or of membranes (e.g. membranes accessible by digitation, such as membranes of the mouth, vagina, cervix, anus and rectum), include creams, ointments, lotions, sprays, gels and sterile aqueous solutions or suspensions.
  • topical compositions include those in which the active ingredient(s) is (are) dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or non-aqueous gels, ointments, water-in-oil or oil-in-water emulsions).
  • Constituents of such vehicles may comprise water, aqueous buffer solutions, non-aqueous solvents (such as ethanol, isopropanol, benzyl alcohol, 2-(2- ethoxyethoxy)ethanol, propylene glycol, propylene glycol monolaurate, glycofurol or glycerol), oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides, or silicone oils such as dimethicone).
  • non-aqueous solvents such as ethanol, isopropanol, benzyl alcohol, 2-(2- ethoxyethoxy)ethanol, propylene glycol, propylene glycol monolaurate, glycofurol or glycerol
  • oils e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides, or silicone oils such as dimethicone.
  • the amount of the active compound used in topical compositions or combination products will depend, inter alia, upon the particular nature of the composition or combination product, as well as its intended use. In any event, those skilled in the art will be able to determine, by routine and non-inventive methods, amount that can be employed. Typically, however, the compound of formula I, or pharmaceutically acceptable salt thereof, will be present in the topical composition or combination product at from 0.01 to 25% by weight (e.g. from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or, particularly, from 0.5 to 3% (e.g. 2% or 1 %) by weight) of the composition or product.
  • 0.01 to 25% by weight e.g. from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or, particularly, from 0.5 to 3% (e.g. 2% or 1 %) by weight
  • topical pharmaceutical compositions such as creams, ointments, lotions, sprays and sterile aqueous solutions or suspensions are well known in the art. Suitable methods of preparing topical pharmaceutical compositions are described, for example in WO 95/10999, US 6,974,585, WO 2006/048747, as well as in documents cited in any of these references.
  • compounds of the invention may be utilized in reducing or preventing the growth of fungal or bacterial cells both in vivo and in vitro (i.e. ex vivo).
  • a method of killing and/or inhibiting or reducing growth of one or more fungal or bacterial cell comprising applying to said fungal or bacterial cell an effective amount of a compound as defined in the first aspect of the invention (including all embodiments thereof).
  • the method or use is an ex vivo (or in vitro) method or use.
  • a compound as defined in the first aspect of the invention (including all embodiments thereof) as an anti-fungal agent.
  • the use is an ex vivo use.
  • the compounds as defined in the first aspect of the invention are used to prevent or hinder fungal and/or bacterial biofilm formation.
  • compounds of the first aspect of the invention also have activity as agricultural agents, in particular in treating or preventing fungal infections in plants.
  • a method of treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising applying to the plant, plant material or plant propagation material or the locus thereof an effective amount of a compound of formula I as defined in the first aspect of the invention, or a salt thereof.
  • composition for use in treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising:
  • composition in treating or preventing a fungal infection in plants, plant material and/or plant propagation material, wherein the composition comprises:
  • a method of treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising applying to the plant, plant material or plant propagation material or the locus thereof an effective amount of:
  • fungal cell and “fungal cells” may refer to the cell of a fungi, fungal-like species and/or parasite (e.g. a fungi) as described in the first aspect of the invention (including any one or more embodiment thereof).
  • references to agents that kill fungal cells or inhibit or reduce growth of fungal cells include references to agents that are fungicidal and/or fungistatic.
  • the terms“killing” and“kill” when used in respect of fungal cells includes references to rendering said fungal cells inactive, for example such that the fungal cells are irreversibly rendered incapable of metabolism, growth and/or reproduction. Such an effect may also be described as fungicidal.
  • fungal cells may be killed by preventing, or disrupting, fungal biofilm formation.
  • the terms“killing” and“kill” when used in respect of bacteria cells includes references to rendering said bacteria cells inactive, for example such that the bacteria cells are irreversibly rendered incapable of metabolism, growth and/or reproduction. Such an effect may also be described as bactericidal.
  • bacetria cells may be killed by preventing, or disrupting, bacteria biofilm formation.
  • the terms“inhibiting or reducing growth” and “inhibit or reduce growth” includes references to reducing the rate at which one or more fungal cell (such as a colony consisting of multiple fungal cells) increases in size and/or number.
  • Such an effect may be determined by observing the size of individual fungal cells and/or the number of fungal cells forming a colony before and after treatment with a compound of the invention, using techniques known to those skilled in the art. Such an effect may also be described as fungistatic.
  • the fungal infection, fungus or fungal cell is of one or more (e.g. one) species as defined in the first aspect of the invention.
  • the fungal infection in plants, plant material and/or plant propagation material may be an infection caused by one or more (e.g. one) of the following plant pathogens: Blumeria graminis; Colletotrichium trifolii; Fusarium graminearium; Fusarium solani; Fusarium sporotriezes; Leptospharia nodorum; Magnaporthe grisea; Mycosphaerella graminicola; Neurospora crassa; Phytophthora capsid; Pyricularia oryzae; Pythium ultimum; Rhizoctonia solani; Trichophyton rubrum; and Ustilago maydis.
  • plant pathogens Blumeria graminis
  • Colletotrichium trifolii Fusarium graminearium; Fusarium solani; Fusarium sporotriezes
  • Leptospharia nodorum Magnaporthe grisea; Mycosphaer
  • Compounds may be assessed in respect of their activity in killing and/or inhibiting or reducing growth of one or more fungal or bacterial cell using techniques known to those skilled in the art, such as those described herein. For example, the ability of compounds to reduce or inhibit growth may be determined using the techniques described in the biological examples provided herein below. In this context, compounds may be considered to be effective in inhibiting or reducing growth of a given fungal strain if they are found to have a MIC50 (i.e. concentration delivering 50% growth inhibition) of less than or equal to 100 pg/mL (such as less than or equal to 50 pg/mL).
  • MIC50 i.e. concentration delivering 50% growth inhibition
  • compounds as described herein may be applied to control fungi in areas such as in the prevention of fungal infection in agriculture (e.g. in crop plants, such as those discussed herein, in wood and wood related technical products, in food storage and/or in hygiene management.
  • the present invention therefore specifically contemplates anti-fungal use, such as that described in respect of the third aspect of the invention, in these areas.
  • compounds of the invention may be characterised by being inhibitory or fungicidal at low rates of application, by being well tolerated by plants and by being environmentally safe. Therefore, compounds described herein may be used agrochemically to protect important crop plants against diseases that are caused by plant pathogenic fungi.
  • the term“treating” takes its normal meaning in the field of agriculture.
  • the term may refer to killing and/or inhibiting or reducing growth of the fungi, fungal-like species and/or parasite (e.g. the fungal cells) associated with the infection.
  • prevention includes references to the prophylaxis of the infection (and vice-versa).
  • the term may refer to achieving a reduction in the likelihood of the infection arising (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
  • the term“salt thereof” refers to any salt form suitable for use in the relevant method (i.e. suitable for use in agriculture) and may include those salts referred to herein as being“pharmaceutically acceptable” (as referred to in the first aspect of the invention).
  • the methods and compositions of the fourth and fifth aspects of the invention may utilise compounds of the first aspect of the invention (including all embodiments thereof).
  • the term“effective amount” refers to an amount of a compound which confers the desired (anti-fungal) effect on the recipient plant, plant material and/or plant propagation material (i.e. an amount that is capable of treating or preventing the fungal infection present in the plant, plant material and/or plant propagation material).
  • plants that may be mentioned include crop plants, such as: cereals (such as wheat, barley, rye, oat, rice, maize, and sorghum), beets (such as sugar beet and fodder beet), pomes, drupes, citrus and soft fruits (such as apples, pears, plums, peaches, almonds, cherries, oranges, lemons, grapefruits, mandarins, bananas, strawberries, raspberries, and blackberries), leguminous plants (such as beans, lentils, peas and soybeans), oil plants (such as rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans and groundnuts), cucumber plants (such as pumpkins, cucumbers and melons), fibre plants (such as cotton, flax, hemp and jute), vegetables (such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, garlic, potatoes, eggplants and
  • plant material includes references to any material obtained and/or derived from a plant source (such as those plants mentioned herein), including food substances and structural materials (e.g. wood)
  • plant propagation material includes references to any material capable of being germinated and/or cultivated to produce a growing plant such as those plants mentioned herein), such as material in the form of seeds, tubers, bulbs, rhizomes and plant cuttings.
  • Compounds as described herein may also be applied to control fungi in related areas, including protection of technical materials, such as wood and wood related technical products, in food storage or in hygiene management.
  • compositions comprising compounds as described herein (e.g. compounds of the first aspect of the invention) can be applied to different plant parts such as fruits, blossoms, leaves, stems, tubers and roots.
  • Plant propagation material such as seeds, tubers, bulbs, rhizomes and plant cuttings may be coated by a liquid or solid formulation of the fungicide for protection against fungal infections, in particular against root pathogens, such as Pythium spp. and Phytophtora spp.
  • formulations containing compounds as described herein may be sprayed on growing plants to obtain a surface protection of leaves or by acquiring a systemic protection resulting in crop plants that are immune against plant pathogenic fungi at the whole plant level.
  • the systemic effect is obtained by plants through root uptake of the fungicide from the soil or by penetration through the cuticle layer and epidermis cells of leaves.
  • the present invention therefore specifically contemplates methods comprising all such forms of application (including any combination thereof).
  • compounds as described herein can be formulated to obtain a curative, preventive, or systemic effect on plants susceptible to various plant pathogenic fungi.
  • the preventive effect may be obtained by adding a formulation containing compounds described herein (e.g.
  • the soil prior to sowing e.g. the field where the crop plants will be cultivated or soil used for greenhouse production of vegetables or ornamentals. Young plants may be protected prior to transplantation by a total or partial treatment by immersion.
  • the present invention therefore specifically contemplates methods comprising these steps (optionally combined with the methods of application as known to those skilled in the art, such as discussed herein).
  • compounds as described herein When used in the treatment or prevention of infections, as anti-fungal agents or in killing or inhibiting the growth of fungal cells in plants, plant material and/or plant propagation material (e.g. as described herein), compounds as described herein may be administered as formulations or compositions suitable for such uses, such as those comprising one or more agriculturally acceptable carrier or diluent
  • compositions e.g. for treating a fungal infection in plants, plant material and/or plant propagation material as described in the fifth aspect of the invention
  • an agrochemical composition may be referred to as an agrochemical composition.
  • compounds as described herein may be formulated with an inert carrier in emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, as well as in encapsulations in e.g. polymeric substances.
  • the formulations may be further modified by addition of adjuvants such as stabilisers, antifoams, viscosity regulators, thickeners, binders, or tackifiers, depending on the desired properties.
  • the compound or the formulation of the compound may be added to fertilizers.
  • the composition may comprise at least one additional fungicidal and/or fungistatic compound in addition to the compound of formula I as described in the first aspect of the invention, or salt thereof.
  • compositions for treating a fungal infection in plants, plant material and/or plant propagation material comprising compounds of the invention may be applied by spraying, atomizing, dusting, scattering, coating or pouring, depending on the intended objectives and the prevailing circumstances.
  • the application to plants, plant material and/or plant propagation material may occur simultaneously or in succession with other compounds, such as fertilizers or micronutrients, or other substances influencing plant growth, as well as herbicides, insecticides, fungicides, bactericides, nematicides, molluscicides, or mixtures of several of these preparations.
  • the combination of several different active ingredients can be accompanied by further addition of carriers, surfactants or other adjuvants generally used in the art of formulation.
  • compositions are typically done, according to known protocols, by mixing or grinding of the compounds with adjuvants and extenders like solvents, solid carriers and optionally surface-active compounds (surfactants).
  • adjuvants and extenders like solvents, solid carriers and optionally surface-active compounds (surfactants).
  • compositions containing compounds as described herein may contain from 0.1 to 99% by weight, preferably from 0.1 to 95%, of the compound of formula I as defined in respect of the first aspect of the invention, or a salt thereof. Such compositions may also contain from 99.9 to 1 % by weight, preferably 99.9 to 5%, of a solid or liquid adjuvant, and from 0 to 25% by weight of a surfactant.
  • compositions of the fifth aspect of the invention may be formulated as concentrates (i.e. for dilution by an end user to provide a dilute formulation for application).
  • the amount to apply can be experimentally determined and may depend on type of action, the developmental stage of the crop plant as well as on the application location, timing, application method and amount of disease causing fungi and the severity of the fungal attack.
  • the rate of application may constitute from 5 g to 2 kg of active ingredient (a.i.) (i.e. the compound of formula I, or salt thereof) per hectare (ha), preferably from 10 g to 1 kg a.i. /ha or most preferably from 20 to 600 g a.i. /ha.
  • convenient application rates are from 10 mg to 1 g of active ingredient per kg of seeds.
  • compositions as described in respect of the fifth aspect of the invention may be used in methods and uses as described in the second, third and fourth aspects of the invention.
  • R 1 , R 29 and R 2h are as defined in the first aspect of the invention (including all embodiments thereof).
  • the compound of formula III is not a compound selected from the list consisting of:
  • compounds of formula III, or pharmaceutically acceptable salts thereof have uses in medicine, such as in the treating or prevention of fungal and/or bacterial infections.
  • compounds of the invention may be utilized in medicine (i.e. as pharmaceuticals), such compounds may be incorporated in pharmaceutical compositions.
  • a pharmaceutical formulation comprising a compound of formula III as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carrier or excipient.
  • R 1 and R 2 taken together, form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y 1 (as defined herein);
  • R 29 and R 2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
  • compounds of formula Ilia, or pharmaceutically acceptable salts thereof have uses in medicine, such as in the treating or prevention of fungal and/or bacterial infections.
  • a compound of formula Ilia as described in the first aspect of the invention or a pharmaceutically acceptable salt thereof, for use in medicine (or as a pharmaceutical).
  • compounds of the invention may be utilized in medicine (i.e. as pharmaceuticals), such compounds may be incorporated in pharmaceutical compositions.
  • a pharmaceutical formulation comprising a compound of formula Ilia as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carrier or excipient.
  • compounds of the first aspect of the invention may be commercially available and/or described in the literature, and may be prepared in accordance with techniques known to those skilled in the art.
  • compounds described herein are not previously disclosed (i.e. are novel), such as compounds of formula III and pharmaceutically acceptable salts thereof (as described in the first and sixth aspects of the invention, including all embodiments thereof).
  • novel compounds may be prepared in accordance with techniques known to those skilled in the art, such as those described herein after (e.g. in the examples).
  • LG 1 represents a suitable leaving group (e.g. a group of formula -OR za wherein R za represents C 1-3 alkyl optionally substituted by one or more fluoro, or halo), under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. a suitable alcohol, such as /so-propanol) and optionally at elevated temperature (i.e. at above room temperature, such as the reflux temperature of the solvent);
  • a suitable solvent e.g. a suitable alcohol, such as /so-propanol
  • elevated temperature i.e. at above room temperature, such as the reflux temperature of the solvent
  • LG 2 represents a suitable leaving group (e.g. a halo group, such as chloro), with a compound of formula VII
  • LG 4 represents a suitable leaving group, for example wherein one of LG 3 and LG 4 represents halo (such as iodo, chloro or, particularly, bromo) and the other represents - B(OH)2 or -B(OR zb )2, in which each R zb independently represents a C1-6 alkyl group or the respective R zb groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), under conditions known to those skilled in the art, such as in the presence of a suitable catalyst (such as a palladium catalyst, for example a palladium (0) catalyst, e.g.
  • a suitable catalyst such as a palladium catalyst, for example a palladium (0) catalyst, e.g.
  • Pd(PPh3)4 and in the presence of a suitable base (such as a suitable carbonate, e.g. sodium carbonate or potassium carbonate), optionally as an aqueous solution, and optionally in the presence of a suitable solvent (such as 1 ,4-dioxane, toluene and/or ethanol);
  • a suitable base such as a suitable carbonate, e.g. sodium carbonate or potassium carbonate
  • a suitable solvent such as 1 ,4-dioxane, toluene and/or ethanol
  • phenyl optionally substituted by one or more fluoro, under conditions known to those skilled in the art, for example in the presence of a suitable aqueous base (such as an aqueous hydroxide salt, for example aqueous sodium hydroxide) and in the presence of a suitable solvent (such as a polar solvent, for example methanol);
  • a suitable aqueous base such as an aqueous hydroxide salt, for example aqueous sodium hydroxide
  • a suitable solvent such as a polar solvent, for example methanol
  • compounds of formula I may be prepared by reaction of a compound of formula IVa
  • LG 1a represents a suitable leaving group (e.g. a group as defined as LG 1 for compounds of formula V as hereinbefore defined), under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. a suitable alcohol, such as /so-propanol) and optionally at elevated temperature (i.e. at above room temperature, such as the reflux temperature of the solvent).
  • a suitable solvent e.g. a suitable alcohol, such as /so-propanol
  • elevated temperature i.e. at above room temperature, such as the reflux temperature of the solvent.
  • compounds of formula IV may be prepared by reaction of a compound of formula XI or a suitable salt and/or protected derivative thereof (e.g. a compound of formula XI wherein the hydrazine group is protected with a f-butylcarbonyl (Boc) group), wherein LG 5 represents a suitable leaving group (e.g. a halo group, such as chloro), with a compound of formula VII
  • R 29 and R 2h are as hereinbefore defined, under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. where R 29 and R 2h are both methyl, using the compound of formula VII as a solvent).
  • a suitable solvent e.g. where R 29 and R 2h are both methyl, using the compound of formula VII as a solvent.
  • compounds of formula IVa may be prepared by analogy with the processes used for the preparation of compounds of formula IV.
  • Substituents on alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic groups in compounds of formula I may be introduced and/or intercon verted using techniques well known to those skilled in the art by way of standard functional groups interconversions, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. For example, benzyloxy may be converted to hydroxy, etc.
  • Compounds of formula III (and, similarly, compounds of formula I and other compounds the preparation of which is described herein) may be isolated from their reaction mixtures using conventional techniques. For example, compounds of formula III may be isolated by conversion to an acid (e.g. hydrochloric acid) salt (e.g.
  • the salt can simply be washed with or slurried in the presence such a suitable solvent in order to isolate the pure acid salt of the compound of formula III.
  • compounds of formula III may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers and enantiomers may be isolated using conventional techniques, e.g. chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. HPLC techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation (for example with a homochiral acid), followed by separation of the diastereomeric derivatives by conventional means (e.g. fractional crystallisation, HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • Functional groups that it may be desirable to protect include hydroxy, amino and carboxylic acid group.
  • suitable protecting groups for hydroxy groups include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert- butyl), trialkylsilyl or diarylalkylsilyl groups (e.g.
  • suitable protecting groups for carboxylic acid include Ci-e alkyl or benzyl esters
  • suitable protecting groups for amino include te/f-butyloxycarbonyl and benzyloxycarbonyl.
  • protection and deprotection of functional groups may take place before or after coupling, or before or after any other reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter.
  • Protected derivatives of compounds of formula III may be converted chemically to compounds of the invention using standard deprotection techniques (e.g. hydrogenation).
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of formula II I, or a pharmaceutically acceptable salt thereof, as described in respect of the first aspect of the invention (including any one or more embodiment thereof), with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compounds as described herein may have the advantage that they may be more convenient for the physician, patient or agrochemical user than, be more efficacious than, have less unwanted toxicity (e.g. mammalian, such as human, toxicity) than, have a broader range of activity than, be more potent than, produce fewer unwanted effects than, or may have other useful (e.g. pharmacological) properties over compounds known in the prior art as being useful in such methods and uses.
  • unwanted toxicity e.g. mammalian, such as human, toxicity
  • All microbial cells need zinc for growth, although the concentrations required may be very low.
  • Beside ZIP family uptake transporters some fungal species possess additional mechanisms to sequester zinc from host cells and tissues in a process analogous to iron chelation by secreted siderophores.
  • C. albicans secretes the antigenic protein Pra1 , a zinc-binding protein that is able to scavenge zinc from tissues invaded by the fungus.
  • othologs of the gene encoding Pra1 are found in diverse fungal pathogens including A. fumigatus (the zinc-regulated aspf2 gene).
  • These zinc- sequestering genes are generally clustered with Zrt1 orthologs in these fungi in a highly syntenic fashion, representing a conserved mechanism for zinc acquisition during host- fungal interactions (see, for example, Pope et ai, Mini Review Article “Fungal zinc metabolism and its connections to virulence” (2013), and Citiulo et ai, PLoS Pathogens, (2012)).
  • SOD Cu/Zn superoxide dismutase
  • alcohol dehydrogenase ribosomes.
  • SODs are the central enzymes in fungi associated with the detoxification of ROS generated by host cells during host-pathogen interactions. In this view, specific SODs from pathogenic fungi are assumed to be virulence determinants.
  • compounds as described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological and/or agricultural, physical, or chemical properties over, compounds known in the prior art (whether such compounds are known in the prior art for use in the above-stated indications or otherwise).
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • STKED20 buffer Sucrose-Tris-HCI-KCI-EDTA-glucose buffer 200 g/L sucrose, 40 g/L glucose, 50 mM Tris-HCI pH 7.25, 50mM KCI, 1 mM EDTA pH 8.0, 1 mM DTT, 0.2 mM PMSF, 2 pg/ml Pepstatin A)
  • YPD medium Yeast-peptone-glucose medium (10 g/L yeast extract, 20 g/L bacto-peptone, 20 g/L glucose, 20 g/L agar)
  • Purification by chromatography refers to purification using either the CombiFlash® Companion purification system or the Biotage Isolera® purification systems.
  • Isolute SPE Si cartridge refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 pm and nominal 60A porosity.
  • thin layer chromatography TLC
  • it refers to silica gel TLC using plates, typically silica gel on aluminium foil plates with a fluorescent indicator (254 nm, e.g. Fluka 60778).
  • Microwave reactions were carried out using a Biotage Initiator 60TM which uses a single mode resonator and dynamic field tuning. Temperature from 40-250 °C can be achieved, and pressures of up to 30 bar can be reached.
  • Mass Directed Auto-Purification was used to purify compounds where indicated. Separation using Agilent 1260 Infinity Purifications System, XSelect CSH Prep C18 5 pm, 21 x 250 mm (acidic modifier) or XBridge Prep C18 5 pm, 21 c 250 mm as the stationary phase, maintained at RT and a 19 mL/min flow.
  • the initial solvent system was 90% water and 10% acetonitrile followed by a gradient up to 5% water and 95% acetonitrile (containing either 0.1 % formic acid or ammonium hydroxide modifiers), centred around a specific focused gradient, over 22 min.
  • Product collection was triggered by an Agilent 6100 series single Quadrupole LC/MS. The desired fractions were concentrated in vacuo at 40 °C.
  • Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
  • reaction may vary in relation to reaction temperature, reagent/solvent amount, reaction time, work-up conditions and/or chromatographic purification conditions.
  • Impure material was repurified by column chromatography eluting with EtOAc/cHexane (0:100 to 50:50, each eluent containing 0.5% AcOH). Pure fractions from both columns were combined and evaporated to give a white solid (400 mg). This was recrystallised from 7 mL EtOAc to give the title compound as a white solid (112 mg, 5%).
  • Trifluoroacetic acid (32.3 ml_, 422 mmol) was added slowly to a solution of tert- butyl (3S)- 3-[(4-cyano-3-pyridyl)oxy]pyrrolidine-1-carboxylate (8.14 g, 28.1 mmol) in DCM (80 ml_) .
  • the reaction mixture was stirred at room temperature for 1 h then diluted with toluene and concentrated in vacuo.
  • the crude was loaded onto an SCX-2 cartridge (50 g) washing first with methanol then eluting with 2 M NH 3 in MeOH.
  • the reaction mixture was stirred at 100 °C for 3 h, and then concentrated in vacuo , diluted with DCM and the organic layer washed with water using a phase separator. The organic layer was concentrated in vacuo. The crude was then purified using MDAP to give the title compound as a red solid (13 mg, 9%).
  • reaction mixture was concentrated in vacuo and the oily residue was diluted with DCM and the organic layer washed with water using a phase separator. The organic layer was concentrated in vacuo then purified using MDAP to give the title compound as a colourless solid (8.0 mg, 14%).
  • 6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine 150 mg, 0.98 mmol was added to a solution of ethyl 3-(4-cyanophenyl)-3-oxo-propanoate (276 mg, 1.27 mmol) in iPrOH (2.0 ml_).
  • the reaction mixture was stirred at 83°C for 1 h.
  • the precipitate formed during the reaction was collected by filtration then purified by column chromatography eluting with DCM/NH 3 2 M in MeOH (100:0 to 90: 10) to give the title compound as a yellow solid (52 mg, 17%).
  • 6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.40 g, 2.61 mmol) and methyl -3- methoxyprop-2-enoate (606 mg, 5.22 mmol) in MeOH (4 ml_) was heated to 130°C in the microwave for 1 h. Further methyl-3-methoxyprop-2-enoate (303 mg, 2.61 mmol) was added and reaction was heated at 130°C for a further 1 h. The reaction mixture was evaporated and purified by column chromatography eluting with DCM/NH3 2 M in MeOH (100:0 to 95:5).
  • 6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.10 g, 0.650 mmol) and ethyl 2-methyl-3- oxo-propanoate (102 mg, 0.780 mmol) in iPrOH (1.0 ml_) was heated to 120°C in the microwave for 3 h. The reaction was evaporated to 200 mg yellow gum, and purified by acidic MDAP to give the title material as an off white solid (68 mg, 47%).
  • 6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.10 g, 0.650 mmol) and ethyl 2-methyl-3- oxo-butanoate (122 mg, 0.850 mmol) in iPrOH (2.0 ml_) was heated to reflux under argon for 2.5 h.
  • the mixture was evaporated and purified by column chromatography eluting with DCM/MeOH (100:0 to 95:5), to give a sharp first peak and a larger broad second peak. The fractions of the second peak containing uncyclised intermediate were combined and evaporated. The residue was dissolved in iPrOH (2.0 ml_) and refluxed overnight.
  • Step 2 tert-butyl N-[[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4- yl]amino]carbamate
  • Step 4 Compound 225 (6-benzyl-2-[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4- yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-ol dihydrochloride)
  • Step 3 Common intermediate 228-A (ethyl 3-(2,4-dimethylthiazol-5-yl)-3-oxo-propanoate)
  • Tetrahydrofuran (500 ml_) and potassium t-butoxide 57.8g; 0.52 mol) were added to a reactor and cooled to -5°C.
  • 1-(2,4-dimethylthiazol-5-yl)ethanone (40g, 258 mmol) and diethyl carbonate (30.4g, 258mmol) in 25 ml_ of tetrahydrofuran was dropwise added to the reactor for 30 minutes and stirred at a temperature of 20 to 25 C overnight.
  • the organic layer was concentrated to a volume of 100 ml_ and this was poured into 500 ml_ of water and AcOH (2.5 equiv) was added thereto.
  • the mixture was finally extracted with 2x200 ml of EtOAc.
  • the resultant extract was dried and evaporated yielding the title compound.
  • Step 4 5-(2,4-dimethylthiazol-5-yl)-2-[6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4- yl]pyrazol-3-ol
  • Step 1 ethyl 3-(2,4-dimethylthiazol-5-yl)-3-hydroxy-2-methyl-propanoate
  • Step 2 ethyl 3-(2,4-dimethylthiazol-5-yl)-2-methyl-3-oxo-propanoate was obtained
  • Step 1 (4,6-dichloropyrimidin-2-yl)methyl acetate
  • Kd dissociation constant
  • the minimum inhibitory concentration is here defined as the compound concentration that results in 50% growth reduction of a fungal isolate when exposed to an antifungal agent.
  • MICs are determined according to the reference procedure of the Antifungal Susceptibility Testing Subcommittee, EUCAST E.DEF 7.1 (Anon, EUCAST definitive document EDef 7.1 : method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 14(4), 398-405 (2008); available at: http://www.ncbi.nlm.nih.gov/pubmed/18190574).
  • MICs are determined according to the reference procedure of the Antifungal Susceptibility Testing Subcommittee, EUCAST E.DEF 9.1 (Arendrup, M.C. et ai, EUCAST DEFINITIVE DOCUMENT E . DEF 9 . 1 : Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. (July), .1-13 (2008)) for spore-forming moulds.
  • the fungal inocula are prepared from the species Candida albicans SC5314; Candida krusei ATCC6258, Candida parapsilosis ATCC22019, Candida glabrata ATCC90030, Candida glabrata Bra03, Candida tropicalis E1 -7276125B, Aspergillus fumigatus ATCC46645, Aspergillus terreus At070, Aspergillus flavus ATCC15547, Fusarium solani DSMZ10696, Fusarium verticillioides MYA-3629 and Cryptococcus neoformans DSM11959.
  • the fungal inoculum size is between 1x10 5 cfu/mL and 2.5x10 5 cfu/mL and the inoculum is prepared directly from subcultures of the various fungal strains grown on YPD or SD media at 35°C. .
  • Fungus, compound and growth medium are incubated in microtiter plates without agitation at 35 ⁇ 2°C 24hrs for yeast and 72hrs for moulds.
  • the endpoint is spectrophotometric recordings at OD 490nm.
  • a cell survival XTT assay This is a colorimetric assay that detects the cellular metabolic activity of the mammalian Hep G2 cell line after pre-incubation with a dilution series of NCE for either 24 or 72 hrs. Subsequent incubation of the exposed cells with the yellow tetrazolium salt XTT for 2-3 hrs allows enough time for metabolically active cells to reduce XTT to a highly colored dye. This conversion occurs only in viable cells so the amount of color produced is proportional to cell viability in the sample and endpoint is measured spectrophotometrically at OD450 nm for IC50 determination. Tamoxifen is used as a positive control compound and DMSO as negative control.
  • Balb/c mice are infected with 0.1 ml_ of inoculum of Candida albicans SC5314 by intravenous route on day 0. NCE are tested in 2 doses; low and high dose. Administration of NCE is initiated 24 hr prior (day -1) to infection (day 0) by intraperitoneal route, b.i.d. treatment for 4 days (day -1 to day 2). Inoculum: 1-5 x 10 5 CFU per animal. Control compound: Fluconazole. Sample collection and processing: 12 hours post last dose all treated and untreated animals are sacrificed by cervical dislocation and kidneys are collected in 3ml of sterile normal saline. The samples are homogenized, diluted serially and plated on SDA.
  • the cell survival window measured as 50% growth inhibition of C. albicans and 50% growth inhibition HepG2 cells, in the presence of compound 4 was found to be 40-fold

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Abstract

There is provided herein a compound of formula (I) or a pharmaceutically acceptable salt and/or prodrug thereof, for use in the treatment or prevention of a fungal or bacterial infection wherein R1 to R5 have meanings provided in the description. There is also provided certain compounds and methods for preparating the same.

Description

N-PYRIMIDINYL HYDROXY PYRAZOLE DERIVATIVES AND USES THEREOF
Field of the Invention
The present invention relates to uses of certain /V-pyrimidinyl hydroxy pyrazoles, and pharmaceutically acceptable salts and/or prodrugs thereof, which compounds have been found to be potent inhibitors of fungal growth. As such, these compounds are of use in the treatment or prevention of fungal infections and associated diseases, and in other applications requiring the inhibition of fungal growth. Such compounds have also been found to have antibacterial properties, redering them of use in the treatment or prevention of bacterial infections.
In particular, the present invention relates to the use of such compounds as medicaments and agrochemicals, to pharmaceutical and agrochemical compositions containing such compounds, and to processes for the production of such compositions. Further, the present invention relates to certain novel compounds and synthetic processes for their production.
Background of the Invention
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Fungal infections are a major healthcare problem, and the incidence of hospital acquired fungal diseases continues to rise (see, for example, Yapar N., Therapeutics and Clinical Risk Management, 10, 95-105 (2014)). This is due to a number of factors including new and aggressive immunosuppressive therapies, increased survival in intensive care, increased number of transplant procedures and the increased use of antibiotics worldwide. Severe systemic fungal infection in hospitals (such as candidiasis, aspergillosis, fusariosis, histoplasmosis, blastomycosis, coccidioidomycosis and scedosporiosis; see, for example, Chapman et ai, Trans Am Clin Climatol Assoc., 119, 197-215 (2008)) is commonly seen in neutropenic patients following chemotherapy, in other oncology patients with immune suppression, and in patients who are immune-compromised due to, for example, Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, as well as in patients in intensive care. Serious fungal infections may cause 5-10% of deaths in patients undergoing lung, pancreas or liver transplantation (Ribaud et al., Clin Infect Dis., 28, 322- 30 (1999)).
For example, invasive aspergillosis remains a major cause of morbidity and death in neutropenic patients with hematologic malignancies, especially in patients undergoing induction chemotherapy and hematopoietic stem cell transplantation. Indeed, despite recent advances in antifungal therapy, the overall mortality rate in patients with invasive pulmonary aspergillosis remains very high, approaching 90%.
Mucormycosis is a highly lethal infection caused by fungi belonging to the order Mucorales of the class Zygomycetes (Spellberg B et al. , Clin Microbiol Rev, 18(3), 556-569 (2005)). Recent data have demonstrated a striking increase in the frequency of mucormycosis cases. Unfortunately, despite aggressive surgical debridement and antifungal therapy, mortality from mucormycosis remains at least 50% (Ibrahim, A. S. et al., Journal of Clinical Investigation, 117(9), 2649-2657 (2007)).
Risk factors associated with candidemia and/or systemic candidiasis include granu locytopenia, bone marrow transplantation, solid organ transplantation (e.g. liver, kidney), parenteral hyperalimentation, solid neoplasms, corticosteroids, broad-spectrum antibiotics, burns, prolonged ICU (intensive care units) stay (i.e. for greater than 3 days), prolonged hospitalization, mechanical ventilation for greater than 3 days, pancreatitis, severe trauma, recent surgery (especially of the gastrointestinal tract), central venous catheters, premature birth weights, and hemodialysis (see, for example, Yapar N., Therapeutics and Clinical Risk Management, 10, 95-105 (2014) and Kriengkauykiat et al., Clinical Epidemiology, 3, 175-191 (2011)).
Currently only four classes of antifungal drug are available to treat systemic fungal infections. These are the polyenes (e.g. amphotericin B), the azoles (e.g. voriconazole, fluconazole, posaconazole, ketoconazole or itraconazole), the echinocandins (e.g. caspofungin, micafungin or anidulafungin) and flucytosine.
The polyenes are the oldest class of antifungal agents, having been first introduced in the 1950s. The exact mode of action remains unclear, but polyenes are only effective against fungal organisms that contain ergosterols in their outer membranes. It has been proposed that amphotericin B interacts with fungal membrane ergosterols, leading to pore formation, which in turn results in leakage of cytoplasmic components and subsequent cell death. Azoles inhibit fungal growth by inhibition of CYP51A1 (lanosterol C14a-demethylase) . This leads to a depletion of the membrane ergosterol and the accumulation of ergosterol precursors resulting in a plasma membrane with altered fluidity and structure.
Echinocandins work by inhibition of the enzyme 1 ,3^-glucan synthase, responsible for synthesis of b-glucans in the fungal cell wall. This leads to abnormal cell wall formation, osmotic sensitivity and cell lysis.
Flucytosine is a pyrimidine analogue interfering with the cellular pyrimidine metabolism as well DNA, RNA and protein synthesis. However, widespread resistance to flucytosine limits its therapeutic use.
Despite the plurality of known anti-fungal agents, it is notable that currently available treatments act primarily against only two cellular targets: membrane sterols (polyenes and azoles) and b-glucan synthase (echinocandins).
Moreover, treatment failures are still very common with all systemic mycoses, and widespread and prolonged use of azoles has led to the rapid development of multidrug resistance, which poses a major hurdle in antifungal therapy (see, for example: Snelders et al., Future Microbiology, 6, 335-347 (2011); Sanguinetti et al., Antimicrob Agents Chemother, 49, 668-679 (2005)). Thus, there is an increasing need for new and effective therapies to target mycotic infections.
As described herein, the present invention relates to compounds that are /V-pyrimidinyl substituted hydroxy pyrazoles, and pharmaceutically acceptable salts thereof. Although certain such compounds have been previously described, there is no disclosure of the use of such compounds as anti-fungal agents.
Disclosure of the Invention
We have now found that certain /V-pyrimidinyl substituted hydroxy pyrazoles, and pharmaceutically acceptable salts thereof, are surprisingly active as inhibitors of fungal growth, and are therefore useful in the treatment or prevention of fungal infections, and as agrochemical agents. Several such compounds are thought to be novel.
Medical uses and methods In a first aspect of the invention, there is provided a compound of formula I
Figure imgf000005_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, for use in the treatment or prevention of a fungal or bacterial infection wherein:
R1 and R2 each independently represent H or a substituent selected from the group consisting of
(a) Ar1 ,
(b) Het\
(c) halo,
(d) oxy,
(e) -N02,
(f) -CN,
(g) -OR1a,
(h) -S(0)pR1 b,
(i) -S(0)qN(R1c)(R1d),
G) -N(R1e)S(0)rR1f,
(k) -N(R1a)(R1 h),
(L) -C(0)0R1 i,
(m) -C(0)NR1jR1 k, and
(n) Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A1; or R1 and R2 may, taken together, form a 5 to 7 membered heterocycloalkyl optionally substituted, where possible, by one or more Y1; R3, R4 and R5 each independently represent H or a substituent selected from the group consisting of
(A) Ar2,
(B) Het2,
(C) halo,
(D) oxy,
(E) -N02,
(F) -CN,
(G) -OR2a,
(H) -S(0)pR2b,
(I) -S(0)qN(R2c)(R2d),
(J) -N(R2e)S(0)rR2f,
(K) -N(R29)(R2h),
(L) -C(0)0R2i,
(M) -C(0)NR2jR2k, and
(N) C1 -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A2; each of R1a to R1 k independently represent H, Ar3, Het3, C1 -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A3, or any pair of R1c and R1d, R1e and R1f, R19 and R1 h, and R1j and R1 k may, together with the atom(s) to which they are attached, form a 4- to -14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A4; each of R2a to R2k independently represent H, Ar4, Het4, C1 -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A5, or any pair of R2c and R2d, R2e and R2f, R29 and R2h, and R2j and R2k may, together with the atom(s) to which they are attached, form a 4- to -14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from
A6; each of A1 to A6 independently represent a substituent selected from the group consisting of
(i) Ar5,
(ii) Het5,
(iii) halo,
(iv) oxy,
(v) -N02,
(vi) -CN,
(vii) -OR3a,
(viii) -S(0)PR3b,
(ix) -S(0)qN(R3c)(R3d),
(x) -N(R3e)S(0)rR3f,
(xi) -N(R39)(R3h),
(xii) -C(0)0R3i, and
(xiii) -C(0)NR3jR3k; each of Ar1 to Ar5 independently represents a Ce-io carbocyclic aromatic group optionally substituted with one or more substituents selected from B1 ; each of Het1 to Het5 independently represents:
(a) a 5- to 14- membered heteroaryl group optionally substituted by one or more substituents selected from B2, or
(b) a 4- to 14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from B3; each of B1 B2, B3 and Y1 independently represent a substituent group selected from the group consisting of
(I) Ar6,
(II) Het6,
(III) halo,
(IV) oxy,
(V) -N02,
(VI) -CN,
(VII) -OR4a,
(VIII) -S(0)PR4b,
(IX) -S(0)qN(R4c)(R4d),
(X) -N(R4e)S(0)rR4f, (XI) -N(R49)(R4h),
(XII) -C(0)0R4i,
(XIII) -C(0)NR4jR4k, and
(XIV) C1 -6 alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C1 ; each of R3a to R3k independently represent H, Ar7, Het7, Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C2, or any pair of R3c and R3d, R3e and R3f, R39 and R3h, and R3j and R3k may, together with the atom(s) to which they are attached, form a 4- to 7- membered heterocycloalkyl or heterocycloalkenyl group optionally containing one or more additional heteroatoms, comprising one ring, and optionally substituted by one or more substituents selected from and C3; each of R4a to R4k independently represent H, Ar8, Het8, Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C4, or any pair of R4c and R4d, R4e and R4f, R49 and R4h, and R4j and R4k may, together with the atom(s) to which they are attached, form a 4- to 7- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from
C5; each of C1 to C5 independently represents a group selected from halo, oxy, -NO2, -CN, - OR5a, -N(R5b)(R5c), =NH, Het9, -C(0)0R5d, -C(0)NR5eR5f and phenyl, wherein the group is optionally substituted by one or more fluoro; each of Ar6 to Ar8 independently represents phenyl optionally substituted with one or more substituents selected from D1 ; each of Het6 to Het9 independently represents:
(a) a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2, or (b) a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from
D3; each of D1 to D3 independently represents a group selected from halo, oxy, -NO2, -CN, - OR6a, -N(R6b)(R6c), -C(0)0R6d, -C(0)NR6eR6f, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl and phenyl, wherein the latter six groups are optionally substituted, where possible, by one or more fluoro; or wherein D1 represents Het10;
Het10 represents:
(a) a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from X5; each X5 individually represents a group selected from oxy or a Ci-e alkyl, wherein the Ci-e alkyl is optionally substituted by OH; each of R5a to R5f and R6a to R6f independently represents a group selected from Ci-e alkyl, H and phenyl, wherein the latter two groups are optionally substituted by one or more group selected from halo, -NH2 and -OH, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more group selected from halo, oxy, -NH2 and -OH; and each p, q and r independently represents 0, 1 or 2, which compounds may be referred to herein as compounds of the first aspect of the invention.
In an alternative first aspect of the invention, there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt and/or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of a fungal and/or bacterial infection.
In a further alternative first aspect of the invention, there is provided a method for the treatment or prevention of a fungal and/or bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt and/or prodrug thereof. Unless indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
The skilled person will understand that references herein to particular aspects of the invention will include references to all embodiments and particular features thereof. Further, any one or more embodiments and/or particular features of any aspect of the invention may be combined with any one or more other such embodiments in order to form more particular embodiments and/or features of that aspect of the invention, without departing from the disclosure of the invention as provided herein.
When used herein, the term “pharmaceutically acceptable salt” includes references to pharmaceutically acceptable salts formed with either acids or bases (i.e. acid-formed proton addition salts or base-formed proton removal salts).
Particular pharmaceutically acceptable salts that may be mentioned include acid addition salts, such as carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts (e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts.
More particular acid addition salts that may be mentioned include trifluoroacetate (TFA) salts (i.e. salts formed with trifluoroacetic acid), acetate, citrate and maleate salts, and hydrochloride salts (i.e. formed with HCI), such as the corresponding mono- or di- salts (i.e. formed using one or two equivalents of the acid, respectively), e.g. the corresponding mono-salts. Particular base addition salts that may be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo , by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z ( zusammen ) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Enantiomers and diastereoisomers may be isolated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a‘chiral pool’ method), by reaction of the appropriate starting material with a‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention. The present invention also embraces isotopically-labelled compounds of the first aspect of the invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds described herein also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.
Unless otherwise specified, Ci-Z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain.
Similarly, a C3-z-cycloalkyl group (where z is the upper limit of the range) may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such cycloalkyl groups may also be part cyclic. Where the number of carbon atoms permits, cycloalkyl groups may also be spiro- groups (i.e. two cycloalkyl rings linked together by a single common carbon atom).
Unless otherwise specified, Ci-Z alkenyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain.
Similarly, a Cs-z-cycloalkenyl group (where z is the upper limit of the range) may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of six) of carbon atoms, such groups may also be part cyclic.
Unless otherwise specified, Ci-Z alkynyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain.
The term“halo”, when used herein, refers to a halogen group, such as fluoro, chloro, bromo and iodo (e.g. fluoro and chloro and bromo). In particular, the term“halo” may refer to a fluoro or chloro group (e.g. F). The term“oxy”, when used herein, refers to a carbonyl (i.e. =0) group. The skilled person will understand that such oxy groups, where present, will only be present at suitable positions on the group to which they are attached, i.e. on suitable, saturated carbon atoms (e.g. forming ketone or aldehyde moieties). Thus, such oxy substituents may be present, in particular, on alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl groups (i.e. on saturated carbon atoms present therein) or on alkyl moieties forming part of aryl, heteroaryl or heterocycloaryl groups as described herein (in which case, references to other instances of such substitution may be removed). Alternatively, refereneces to oxy substituents may be deleted throughout.
Heterocycloalkyl groups (e.g. where representing a Het group, such as Het1 , as defined herein) group that may be mentioned include saturated monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as boron, nitrogen, oxygen or sulphur), and in which the total number of atoms in the ring system is as defined (e.g. from four to fourteen).
Particular heterocycloalkyl groups that may be mentioned include those in which the total number of atoms in the ring system is from four to twelve, such as from five to twelve (e.g. from five to ten and, most particularly, from five to six, so forming a 5- or 6- membered heterocycloalkyl group). More particular heterocycloalkyl groups that may be mentioned include those containing one, two or three heteroatoms (e.g. one or two heteroatoms, such as one heteroatom), such as boron and two oxygens (i.e. as a boronate ester), one or two nitrogens, one or two sulphurs, one or two oxygens, or one oxygen and one nitrogen, such as those in which the total number of atoms in the ring system is five or six.
Similarly, heterocycloalkenyl groups (e.g. where representing a Het group, such as Het1 , as defined herein) group that may be mentioned include unsaturated (but non-aromatic) monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as boron, nitrogen, oxygen or sulphur), and in which the total number of atoms in the ring system is as defined (e.g. from four to fourteen).
Particular heterocycloalkenyl groups that may be mentioned include those in which the total number of atoms in the ring system is from five to twelve, such as from five to twelve (e.g. from five to ten and, most particularly, from five to six, so forming a 5- or 6- membered heterocycloalkenyl group). More particular heterocycloalkenyl groups that may be mentioned include those containing one, two or three heteroatoms (e.g. one or two heteroatoms, such as one heteroatom), such as one or two nitrogens, one or two (e.g. one) sulphur(s), one or two (e.g. one) oxygen(s), or one oxygen and one nitrogen, such as those in which the total number of atoms in the ring system is five or six.
Heterocycloalkyl and heterocycloalkenyl groups (e.g. where representing a Het group as defined herein) that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6- azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1 ]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5- dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]- octanyl, dihydrooxazolyl (including 4,5-dihydrooxazolyl), dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1 ,2,3,4-tetrahydropyridyl and 1 ,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Other heterocycloalkyl groups that may be mentioned include boronic acid esters, such as ethylene diol and pinacol esters, for example wherein the point of attachment is via the boron atom.
Substituents on heterocycloalkyl and heterocycloalkenyl groups may, where appropriate, be located on any atom in the ring system including, where possible, a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called“spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen or boron atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form.
Unless otherwise specified, the term "heteroatom(s)" as used herein shall include references to boron, oxygen, nitrogen and sulphur (e.g. oxygen, nitrogen and sulphur).
At each occurrence when mentioned herein, a heterocycloalkyl group is preferably a 5- or 6-membered heterocycloalkyl group. At each occurrence when mentioned herein, a heterocycloalkenyl group is preferably a 5- or 6-membered heterocycloalkyl group.
For the avoidance of doubt, the term“bicyclic” (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term “bridged” (e.g. when employed in the context of heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
Carbocyclic aromatic groups (which may also be referred to as aryl groups; e.g. where representing an Ar group, such as Ar1 , as defined herein) that may be mentioned include those containing from six to fourteen atoms (i.e. carbon atoms) in the ring (which may be referred to as Ce-M groups). Particular carbocyclic aromatic groups that may be mentioned include Ce-io (e.g. Ce) groups. Such groups may be monocyclic or bicyclic, in which at least one ring is aromatic. Particular aryl groups that may be mentioned include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are preferably linked to the rest of the molecule via an aromatic ring.
Particular carbocyclic aromatic groups (i.e. aryl groups; e.g. where representing an Ar group as defined herein) that may be mentioned include phenyl and naphthyl.
More particular carbocyclic aromatic groups (i.e. aryl groups; e.g. where representing an Ar group as defined herein) that may be mentioned include phenyl.
Heteroaryl groups (e.g. where representing a Het group, such as Het1 , as defined herein) that may be mentioned include those having from 5 to 14 (e.g. from 5 to 10, or 5 or 6) ring members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to three) of the atoms in the ring system is other than carbon (i.e. a heteroatom, such as nitrogen, oxygen or sulphur). For the avoidance of doubt, where a heteroaryl group as described herein contains more than one ring (e.g. is bicyclic) and one or more (e.g. one) of the rings is non-aromatic, the heteroatom(s) present may form part of the aromatic or non-aromatic ring(s). Heteroaryl groups (e.g. where representing a Het group as defined herein) that may be mentioned include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl and, in particular, oxazolo[4,5-c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5-b]pyridyl, thiazolo[5,4-b]pyridyl and, in particular, thiazolo[4,5- c]pyridyl and thiazolo[5,4-c]pyridyl), benzothiadiazolyl (including 2, 1 ,3-benzothiadiazolyl), isothiochromanyl, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2, 1 , 3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/-/-1 ,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2, 1 ,3-benzoselena-diazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, imidazo[5,4-b]pyridyl and, preferably, imidazo[1 ,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyl), oxadiazolyl (including 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5, 6,7,8- tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1 ,2,3-thiadiazolyl, 1 ,2,4- thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1 ,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl) and the like. Particular heteroaryl groups that may be mentioned include furanyl, pyridinyl, triazolyl (including 1 ,2,4-triazolyl), pyrimidinyl and oxadiazolyl (including 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl).
Particular heteroaryl groups that may be mentioned include those bound (to the remainder of the compound) via a heteroatom (e.g. bound via a nitrogen atom, as comprised in the heteroaryl group).
Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including, where possible, a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. However, when heteroaryl groups are polycyclic, they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups may also be in the N- or S- oxidised form. For the avoidance of doubt, when an aryl or an heteroaryl group is substituted with a group via a double bond, such as oxy (i.e. =0), it is understood that the aryl or heteroaryl group is partly aromatic, i.e. the aryl or heteroaryl group consists of at least two rings where at least one ring is not aromatic.
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the first aspect of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which two Ar1 groups are present, the identity of those groups is in no way interdependent. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent. For example, when there are two -OR1a substituents present, the identities of the two R1a groups are not to be regarded as being in any way interdependent.
For the avoidance of doubt, when a term such as“R1a to R1k" is employed herein, this will be understood by the skilled person to mean R1a, R1 b, R1c, R1d, R1 e, R1f, R19, R1 h, R1 i, R1j and R1 k, inclusively.
In certain embodiments of the first aspect of the invention, R1 is not H (i.e. R1 is a group other than H).
In a particular embodiment of the first aspect of the invention, R1 represents Ar1 , Het1 , C1-6 alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A1.
For the avoidance of doubt, where groups defined herein are referred to as being optionally substituted, in each instance there is provided an embodiment wherein that group is unsubstituted (i.e. wherein the reference to optional substitution is removed).
In a more particular embodiment, R1 represents Ar1 , Het1 , C1-6 alkyl or C1-6 cycloalkyl, wherein the latter two groups are optionally substituted by one or more A1.
In a yet more particular embodiment, when R1 represents Ar1 , the Ar1 group represents phenyl optionally substituted with one or more B1. For example, in certain embodiments of the first aspect of the invention, when R1 represents Ar1 , the Ar1 group represents phenyl optionally substituted with one or more (e.g. one or two) groups selected from halo (e.g. F and Cl) and -CN.
Further, in certain embodiments of the first aspect of the invention, when R1 represents Het1 , the Het1 group represents:
(a) a 5- to 6- membered heteroaryl group optionally substituted with one or more substitutent selected from B2 (e.g. wherein B2 represents C1-3 alkyl, such as methyl or ethyl) or
(b) a 5- to 6- membered heterocycloalkyl or heterocycloalkenyl group (e.g. a 5- to 6- membered heterocycloalkyl group) optionally substituted with one or more substitutent selected from B3.
In yet more embodiments of the first aspect of the invention, when R1 represents Ci-e alkyl, the C alkyl group is optionally substituted with one or more group selected from halo and, in particular, Ar5 (e.g. wherein Ar5 represents phenyl optionally substituted with one or more B1), Het5, and -OR3a (e.g. wherein R3a represents methyl). Further, such Ci-e alkyl groups may represent, in particular, corresponding C1-3 alkyl groups (e.g. methyl).
In yet more embodiments of the first aspect of the invention, when R1 represents Ci-e cycloalkyl, the Ci-e cycloalkyl group is optionally substituted with one or more halo (e.g. one or more F) or, more particularly, is unsubstituted.
In certain embodiments, in particular where R1 represents alkyl, the substituents on R1 groups (and, in certain embodiments, any substitutents present thereon) do not include fluoro.
In further embodiments, in particular where R1 represents alkyl, the substituents on R1 groups (and, in certain embodiments, any substitutents present thereon) do not include halo.
In yet further embodiments, in particular where R1 represents alkyl, the R1 group is unsubstituted.
In certain embodiments, R1 represents a 5- to 6- membered heteroaryl group optionally substituted with one or more substitutent selected from B2 (e.g. wherein B2 represents Ci-3 alkyl, such as methyl or ethyl). For example, the heteroaryl group may be optionally substituted with two C1-3 alkyl groups.
In a particular embodiment of the first aspect of the invention (including all embodiments thereof), R2 represents H, halo (e.g. F, Cl or Br, such as Cl or Br), C1-3 alkyl optionally substituted with one or more A1 (e.g. wherein A1 represents -CN) or -N(R1g)R1 h (e.g. wherein R1 9 represents H and R1 h represents C1-2 alkyl optionally substituted with one or more oxy, such as to form a -NHC(0)CH3 group).
In certain embodiments of the first aspect of the invention, R2 does not represent Ar1 or Het1.
In certain embodiments of the first aspect of the invention, R2 represents H.
In a particular embodiment of the first aspect of the invention (including all embodiments thereof), R3 represents H or fluoro.ln a more particular embodiment, R3 represents H.
In a further embodiment of the first aspect of the invention (including all embodiments thereof), R5 represents H or fluoro. In a more particular embodiment, R5 represents H.
Thus, in particular embodiments of the first aspect of the invention, R3 and R5 are each H or fluoro. In more particular embodiments of the first aspect of the invention, R3 and R5 are each H.
In certain embodiments of the first aspect of the invention, R2, R3 and R5 are each H or fluoro. In further embodiments of the first aspect of the invention, R2, R3 and R5 are each H.
Thus, particular compounds of the first aspect of the invention (including all embodiments thereof) that may be mentioned include compounds of formula II
Figure imgf000020_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein: R1 and R4 are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
In a further embodiment of the first aspect of the invention (including all embodiments thereof), R4 represents H or, particularly, a substituent selected from the group consisting of Het2, halo, -N02, -OR2a, -S(0)PR2b, -S(0)qN(R2c)(R2d), -N(R2e)S(0)rR2f and -N(R29)(R2h).
In particular embodiments of the first aspect of the invention (including all embodiments thereof), p, q and r each represent 2. In certain embodiments, R4 is a group bound to the remainder of the compound (i.e. bound to the core pyrazole moiety) via a heteroatom (e.g. via a nitrogen atom).
In a further embodiment of the first aspect of the invention (including all embodiments thereof), R4 represents H or, particularly, a substituent selected from the group consisting of Het2 (e.g. wherein Het2 is bound via a nitrogen atom), -OR2a (e.g. -OH) and -N(R29)(R2h).
In certain embodiments, where R4 represents -N(R29)(R2h), the -N(R29)(R2h) group is a -NHR2h group (i.e. R29 represents H) , such as wherein R2h represents C1-3 alkyl (e.g. C1-2 alkyl) optionally substituted with one or more A5 (such as wherein A5 represents Ar5, Het5, halo, -OR3a, -N(R39)R3h, -C(0)0R3i or -C(0)NR3iR3k. In certain embodiments, where R4 represents Het2, the Het2 group may in particular represent a 5- to 14- membered heteroaryl group (e.g. a 5- to 6- membered heteroaryl group) optionally substituted by one or more substituents selected from B2.
Particular B2 groups that may be mentioned include halo (e.g. fluoro), -OR4a (e.g. -OCH3) and C1-6 alkyl (e.g. C1-3 alkyl, such as C1 alkyl) optionally substituted by one or more fluoro.
In a particular embodiment of the first aspect of the invention (including all embodiments thereof), R4 represents H or, particularly, a substituent selected from the group consisting of -OR2a and -N(R29)(R2h).
In a more particular embodiment of the first aspect of the invention (including all embodiments thereof), R4 represents -N(R29)(R2h).
In other embodiments of the first aspect of the invention (including all embodiments thereof), the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A6.
In other particular embodiments of the first aspect of the invention (including all embodiments thereof), R4 represents -N(R29)(R2h) wherein R29 and R2h together with the atom(s) to which they are attached do not form a ring.
Thus, in particular embodiments, R4 represents Het2 (e.g. wherein Het2 is bound via a nitrogen atom), -OR2a (e.g. -OH) or -N(R29)(R2h), wherein each of R2a, R29 and R2h independently represent H or C alkyl optionally substituted by one or more A5, or alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
In particular embodiments, the 5- membered heterocycloalkyl group formed by R29 and R2h is a pyrrolidine group.
In a particular embodiment of the first aspect of the invention (including all embodiments thereof), A6 represents fluoro or, particularly, -OR3a.
For example, in particular embodiments R3a represents Het8. Further, in more particular embodiments Het7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2.
Moroever, in yet more particular embodiments Het7 represents pyrimidinyl optionally substituted by one or more substituents selected from fluoro and, particularly, -CN.
In particular embodiments, R29 and R2h both represent C1 -3 alkyl (e.g. C1 alkyl) optionally substituted by one or more fluoro, such as wherein R29 and R2h both represent methyl.
Particular compounds of the invention that may be mentioned include compounds of formula III
Figure imgf000022_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R1, R29 and R2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
For the avoidance of doubt, in particular embodiments, R1 may not represent H.
In particular embodiments, the compound of formula III is not a compound selected from the list consisting of:
1 ,2-dihydro-5-methyl-2-[6-(methylamino)-4-pyrimidinyl] 3H-pyrazol-3-one;
N-[3-(1 ,1-dimethylethyl)-1-[6-[3-(1 ,1-dimethylethyl)-5-hydroxy-1 H-pyrazol-1-yl]-4- pyrimidinyl]- 1 H-pyrazol-5-yl] acetamide; and 1-[6-[5-amino-3-(1 ,1-dimethylethyl)-1 H-pyrazol-1-yl]-4-pyrimidinyl]-3-(1 , 1-dimethylethyl)
1 H-pyrazol-5-ol.
In certain embodiments (particularly in relation to compounds of formula III, and all embodiments thereof), where R29 and R2h are joined together to form a ring, that ring may not be a pyrrole.
In further embodiments (particularly in relation to compounds of formula III, and all embodiments thereof), where R29 and R2h are joined together to form a ring, that ring may not be a heteroaryl group.
For the avoidance of doubt, in yet further embodiments (particularly in relation to compounds of formula III, and all embodiments thereof), R29 and R2h may not be joined together to form a ring (e.g. R29 represents H).
For the avoidance of doubt, in certain embodiments (particularly in relation to compounds of formula III, and all embodiments thereof), R29 and R2h both represent methyl.
Particular R1 , R2, R3, R4 and R5 groups that may be mentioned include those present in the example compounds as described hereinafter.
In certain embodiments, R1 and R2 together form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more (e.g. one) Y1. For example, R1 and R2 may form a 5 to 7 membered heterocycloalkyl comprising a single heteroatom, for example oxygen, nitrogen and sulphur, such as nitrogen. For example, R1 and R2 may form a 5 to 7 membered heterocycloalkyl comprising a single heteroatom, wherein the hetero atom of the heterocycloalkyl is substituted by Y1.
In a particular embodiment, R1 and R2 form a 6 membered heterocycloalkyl comprising a nitrogen atom. More particularly, R1 and R2 form a piperidinyl ring, which is thus fused to the essential pyrazolyl ring of the compounds of formula I.
In a more particular embodiment, R1 and R2 form a piperidinyl ring which is substituted at the nitrogen atom by Y1.
In certain embodiments, Y1 represents -S(0)2R4b or a Ci-e alkyl optionally substituted by one or more C1. In further embodiments, Y1 represents a C1-6 alkyl optionally substituted by a phenyl group.
Thus, in certain embodiments, Y1 is a benzyl group.
In a more particular embodiment, where R1 and R2 form a 5 to 7 membered heterocycloalkyl, R3 represents H.
In a further embodiment of the first aspect of the invention (including all embodiments thereof), where R1 and R2 form a 5 to 7 membered heterocycloalkyl, R5 represents H or fluoro.
In a more particular embodiment, where R1 and R2 form a 5 to 7 membered heterocycloalkyl, R5 represents H.
Thus, in particular embodiments of the first aspect of the invention, where R1 and R2 form a 5 to 7 membered heterocycloalkyl, R3 and R5 are each H or fluoro.
In more particular embodiments of the first aspect of the invention, where R1 and R2 form a 5 to 7 membered heterocycloalkyl, R3 and R5 are each H.
Thus, particular compounds of the first aspect of the invention (including all embodiments thereof) that may be mentioned include compounds of formula lla
Figure imgf000024_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein: R1 and R2 form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y1 ; and
R4 is as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
In a further embodiment of the first aspect of the invention (including all embodiments thereof), for compounds of formula I la, R4 represents H or, particularly, a substituent selected from the group consisting of Het2, halo, -NO2, -OR2a, -S(0)pR2b, -S(0)qN(R2c)(R2d), -N(R2e)S(0)rR2f and -N(R29)(R2h).
In particular embodiments of the first aspect of the invention (including all embodiments thereof), for compounds of formula I la, p, q and r each represent 2.
In certain embodiments, for compounds of formula I la, R4 is a group bound to the remainder of the compound (i.e. bound to the core pyrazole moiety) via a heteroatom (e.g. via a nitrogen atom).
In a further embodiment of the first aspect of the invention (including all embodiments thereof), for compounds of formula I la, R4 represents H or, particularly, a substituent selected from the group consisting of Het2 (e.g. wherein Het2 is bound via a nitrogen atom), -OR2a (e.g. -OH) and -N(R29)(R2h).
In certain embodiments, for compounds of formula lla, where R4 represents -N(R29)(R2h), the -N(R29)(R2h) group is a -NHR2h group (i.e. R29 represents H) , such as wherein R2h represents C1-3 alkyl (e.g. C1-2 alkyl) optionally substituted with one or more A5 (such as wherein A5 represents Ar5, Het5, halo, -OR3a, -N(R39)R3h, -C(0)0R3i or -C(0)NR3jR3k.
In certain embodiments, for compounds of formula lla, where R4 represents Het2, the Het2 group may in particular represent a 5- to 14- membered heteroaryl group (e.g. a 5- to 6- membered heteroaryl group) optionally substituted by one or more substituents selected from B2.
Particular B2 groups that may be mentioned for compounds of formula lla include halo (e.g. fluoro), -OR4a (e.g. -OCH3) and Ci-e alkyl (e.g. C1-3 alkyl, such as C1 alkyl) optionally substituted by one or more fluoro. In a particular embodiment of the first aspect of the invention (including all embodiments thereof), for compounds of formula I la, R4 represents H or, particularly, a substituent selected from the group consisting of -OR2a and -N(R29)(R2h).
In a more particular embodiment of the first aspect of the invention (including all embodiments thereof), for compounds of formula lla, R4 represents -N(R29)(R2h).
In other embodiments of the first aspect of the invention (including all embodiments thereof), for compounds of formula lla, the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A6.
In other particular embodiments of the first aspect of the invention (including all embodiments thereof), for compounds of formula lla, R4 represents -N(R29)(R2h) wherein R29 and R2h together with the atom(s) to which they are attached do not form a ring.
Thus, in particular embodiments, for compounds of formula l la, R4 represents Het2 (e.g. wherein Het2 is bound via a nitrogen atom), -OR2a (e.g. -OH) or -N(R29)(R2h), wherein each of R2a, R29 and R2h independently represent H or Ci-e alkyl optionally substituted by one or more A5, or alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
In particular embodiments, for compounds of formula lla, the 5- membered heterocycloalkyl group formed by R29 and R2h is a pyrrolidine group.
In a particular embodiment of the first aspect of the invention (including all embodiments thereof), for compounds of formula lla, A6 represents fluoro or, particularly, -OR3a.
For example, in particular embodiments for compounds of formula lla, R3a represents Het8.
Further, in more particular embodiments for compounds of formula lla, Het7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2. Moroever, in yet more particular embodiments for compounds of formula lla, Het7 represents pyrimidinyl optionally substituted by one or more substituents selected from fluoro and, particularly, -CN. In particular embodiments, for compounds of formula lla, R29 and R2h both represent C1-3 alkyl (e.g. C1 alkyl) optionally substituted by one or more fluoro, such as wherein R29 and R2h both represent methyl.
Particular compounds of the invention that may be mentioned include compounds of formula Ilia
Figure imgf000027_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R1 and R2 form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y1; and
R29 and R2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof).
In certain embodiments in relation to compounds of formula Ilia, and all embodiments thereof), where R29 and R2h are joined together to form a ring, that ring may not be a pyrrole. In further embodiments (in relation to compounds of formula Ilia, and all embodiments thereof), where R29 and R2h are joined together to form a ring, that ring may not be a heteroaryl group.
For the avoidance of doubt, in yet further embodiments (in relation to compounds of formula Ilia, and all embodiments thereof), R29 and R2h may not be joined together to form a ring (e.g. R29 represents H).
For the avoidance of doubt, in certain embodiments (in relation to compounds of formula Ilia, and all embodiments thereof), R29 and R2h both represent methyl.
Particular R1, R2, R3, R4 and R5 groups that may be mentioned include those present in the example compounds as described hereinafter.
Particular compounds of the first aspect of the invention that may be mentioned include those described in the examples provided herein, and pharmaceutically acceptable salts and/or prodrugs (e.g. pharmaceutically acceptable salts) thereof.
For the avoidance of doubt, where compounds as described in the examples provided herein are indicated to be in the form of a salt (e.g. a pharmaceutically acceptable salt), references to such compounds also include references to the free (i.e. non-salt) form of said compound (e.g. the free base) and all possible pharmaceutically acceptable salts thereof. However, for the avoidance of doubt, more particular forms of the compounds as described in the examples provided herein are those in the salt or non-salt form as described.
For the avoidance of doubt, all individual (e.g. particular) features and embodiments mentioned herein may be taken in isolation or in combination with any one or more other feature and/or embodiment mentioned herein. In other words, particular features and/or embodiments may be taken in conjunction with other particular features and/or embodiments, or independently of them.
As used herein, the term“patient” will be understood to refer to the subject being treated or, similarly, the subject benefiting from the preventative measure.
Unless otherwise specified, as used herein, the term “patient” includes mammalian patients (such as equines, cattle, swine, sheep, goats, horses, primates, mice, rats, and pets in general including dogs, cats, guinea pigs, ferrets, and rabbits). In particular, the term“patient” refers to humans.
Although compounds of the first aspect of the invention may possess pharmacological activity as such, there may be certain compounds which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolized in the body to form active compounds. Thus, compounds mentioned in respect of the first aspect of the invention are useful because they possess pharmacological activity, and/or are metabolized in the body following oral or parenteral administration to form compounds, which possess pharmacological activity.
Compounds that do not possess pharmacological activity as such, but may be administered parenterally or orally and thereafter be metabolized in the body to form active compounds (or which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the “active” compounds to which they are metabolized) may be described as“prodrugs”.
For the avoidance of doubt, the present invention encompasses the use of prodrugs of compounds as described herein (e.g. compounds of the first aspect of the invention).
Particular prodrugs of compounds of the invention that may be mentioned include esters of such compounds (i.e. esters formed by reaction of the compound of invention to form an ester comprising that compound). In particular, the references to esters of compounds of the invention may refer to pharmaceutically-acceptable esters as known to those skilled in the art, such as Ci-4 alkyl esters. For example, such esters may include those formed by reaction of the essential hydroxyl moiety present on the core pyrazole group of compounds of the invention to form an ester thereof (e.g. so forming a -OWi group, wherein Wi may represent Ci-4 alkyl optionally substituted by one or more fluoro). Particular esters that may be mentioned include methyl, ethyl and t-butyl (i.e. pivaloyl) esters.
Other prodrugs of compounds of the invention that may be mentioned include carbonate esters of such compounds (i.e. carbonate esters formed by reaction of the compound of invention to form a carbonate ester comprising that compound). In particular, the references to carbonate esters of compounds of the invention may refer to pharmaceutically-acceptable carbonate esters as known to those skilled in the art, such as C1-4 alkyl esters. Particular esters that may be mentioned include methyl, ethyl and t- butyl (i.e. pivaloyl) esters.
The term“therapeutically effective amount” refers to an amount of a compound which confers a therapeutic effect (e.g. the relevant treatment or prevention, such as the relevant treatment) on the treated patient (i.e. the patient (e.g. the mammal) to which the compound is administered). The effect may be objective (i.e. measurable by some test or marker, such as the measurable treatment of the condition or the identifiable prophylaxis of the condition) or subjective (i.e. the subject gives an indication of or feels an effect).
In particular, a therapeutically effective amount of a compound according to the present invention is an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease or disorder and its complications.
The skilled person will understand that such amounts may vary according to the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and or other treatments used by the individual, and may be determined by conventional techniques in the field. The amount that is effective for a particular therapeutic purpose will depend on the severity of the disease or injury as well as on the weight and general state of the subject. It will be understood that determination of an appropriate dosage may be achieved, using routine experimentation, by constructing a matrix of values and testing different points in the matrix, all of which is within the ordinary skills of a trained physician or veterinary.
For example, although doses will vary from patient to patient, suitable daily doses (e.g. for systemic adminstration, such as for oral adminstration) may be in the range of about 10 to 2000 mg per patient, administered in single or multiple doses (for example, administered as three daily doses of 200 to 500 mg/kg, such as three daily doses of around 400 mg/kg).
In particular embodiments, the compounds of the invention may be administered in doses of 10 to 3000 mg, such as 50 to 2500 mg, or such as 10 mg to 2000 mg per day (for example, until such time as said treatment is no longer required).
Compounds of the first aspect of the invention may provide systemic and/or local (e.g. topical) therapeutic effects. Thus, the treatment may involve systemic or local (e.g. topical) administration of a compound of the first aspect of the invention (including all embodiments thereof). Particular forms of local administration that may be mentioned include topical administration, for example to an area of the skin or a mucous membrane of the body (including internal and external mucous membranes).
Compounds of the first aspect of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. Alternatively, particularly where compounds are intended to act locally, compounds of the first aspects of the invention may be administered topically (i.e. applied directly to the area to be treated, as defined herein, or where prevention, as defined herein, is required).
For the avoidance of doubt, the skilled person will be able to select the route of administration depending on the nature of the infection to be treated or prevented. For example, for treatment or prevention in the lungs (e.g. of infection by aspergillius), the compound may be administered by inhalation (and a suitable inhalable formulation used). Similarly, for treatment or prevention in the vulva or vagina (e.g. of infection by candidiasis), the compound may be administered topically to the relevant area (and a suitable topical formulation used, such as a pessary).
For the avoidance of doubt, treatment or prevention as described herein may further comprise treatment or prevention with one or more active ingredient, wherein the term “administration” includes separate, sequential and/or simultaneous administration of the additional (i.e. other) active ingredient.
In particular embodiments of the invention, the treatment or prevention is of a fungal infection.
Unless otherwise specified, as used herein, the term“fungal infection” refers to infection with one or more fungi, fungal-like species and/or parasite (e.g. one or more fungi). The skilled person will understand that such infections may be systemic and/or local.
Unless otherwise specified, as used herein, the term“bacterial infection” refers to infection with one or more bacterial species. The skilled person will understand that such infections may be systemic and/or local.
Unless otherwise specified, as used herein, the term “treatment” (and, similarly, to “treating”) takes its normal meaning in the field of medicine. In particular, the term may refer to achieving a reduction in the severity of one or more clinical symptom associated with the disease or disorder (e.g. the fungal infection), as may be determined using techniques known to those skilled in the art (for example, by a medical physician).
For example, in relation to the treatment of a fungal infection, the term may refer to killing and/or inhibiting or reducing growth of the fungi, fungal-like species and/or parasite (e.g. the fungal cells) associated with the infection.
In particular, in relation to the treatment of a fungal infection, the terms "treatment” and “treating” may refer to achieving a reduction of colony forming units (CFUs) associated with the fungi, fungal-like species and/or parasite (e.g. the fungal cells), which may be determined through analysis of samples of bodily fluid (e.g. blood and/or urine) taken from the patient subjected to said treatment (e.g. comparison of samples taken before and after said treatment) using techniques known to those skilled in the art.
In other embodiments of the invention, the treatment or prevention is of a bacterial infection.
In relation to the treatment of a bacterial infection, the term may refer to killing and/or inhibiting or reducing growth of bacterial species associated with the infection.
Unless otherwise specified, as used herein, the term “prevention” (and, similarly, to “preventing”) includes references to the prophylaxis of the disease or disorder (and vice- versa). As such, references to prevention may also be references to prophylaxis, and vice versa. In particular, the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
In particular, references herein throughout to treating or preventing (and, similarly, to treatment and prevention), or the like, may refer in particular to treating (or, similarly, to treatment).
For the avoidance of doubt, the skilled person will understand that references herein to a fungal infection will refer to a (systemic or local, e.g. systemic) infection caused by one or more species of fungus as known to those skilled in the art.
In a particular embodiment of first aspect of the invention (including all embodiments thereof), the fungal infection is an infection caused by one or more (e.g. one) species of fungus selected from the group consisting of: Acremonium spp. (e.g. A. recifei or A. alabamense), Acrophialophora spp. (e.g. A. fusispora or A. levis), Alternaria spp. (e.g. A. infectoria, A. alternata), Aphanoascus fulvescens, Apophysomyces spp. (A. elegans or A. variabilis), Arthroderma spp. (e.g. A. insingulare or A. uncinatum) Aspergillus spp. (e.g. A. clavatus, A. flavus, A. fumigatus, A. felis, A. nidulans, A. niger, A. terreus, A. lentulus or A. versicolor), Aureobasidium pullulans, Bipolaris spp. (e.g. B. australiensis, B. hawaiiensis orB. spicifera), Blastomyces spp. (e.g. B. dermatitidis), Blastoschizomyces (e.g. B. capitatus), Botrytis cinerea, Candida spp. (e.g. C. albicans, C. dubliniensis, C. famata, C. glabrata (Torulopsis glabrata), C. guillermondii, C. nivariensis, C. haemulonii, C. kefyr, C. krusei, C. lipolytica, C. lusitaniae, C. norvegensis, C. parapsilosis, C. pseudotropicalis, C. rugosa, C. stellatoidea, C. tropicalis, C. utilis or C. viswanathii), Cercospora spp., Cladosporium (e.g. C. bantiana, C. carrionii, C. cladosporioides, C. herbarum, C. oxysporum, C. sphaerospermum or C. devriesii), Cladophialophora spp. (e.g. C. bantiana), Clavispora lusitaniae, Coccidioides (e.g. C. immitis, C. posadasii), Cokeromyces recurvatus, Colletotrichum spp. (e.g. C. coccodes, C. acutatum, C. gloeosporioides), Conidiobolus spp. (e.g. C. coronatus, C. incongruus or C. lamprauges), Coniochaeta spp. (e.g. C. hoffmannii or C. mutabilis), Cryptococcus spp. (e.g. C. albidus, C. laurentii or C. neoformans (like var. neoformans or vargattii)), Cunninghamella spp. (e.g. C. berthollethiae or C. elegans), Curvicularia lunata, Epidermophyton floccosum, Exophiala spp. (e.g. E. dermatitidis, E. jeanselmei, E. oligosperma, E. phaeomuriformis E. spinifera orE. xenobiotica), Exserohilum spp. (e.g. E. rostratum, E. mcginnisii or E. longirostratum), Fonsecaea spp. (e.g. F. compacta, F. monophora, or F. pedrosi), Fusarium spp. (e.g. F. oxysporum, F. solani, F. verticillioides, F. chlamydosporum, F. dime rum, F. fujikuroi, or F. incarnatum), Geotrichum spp. (e.g. G. candiddum, G. capitatum or G. clavatum), Graphium basitruncatum, Helminthosporium spp., Histoplasma capsulatum, Hortaea werneckii, Kluyveromyces marxianus, Lasiodiplodia theobromae, Lichtheimia corymbifera (formerly Absidia corymbifera), Lodderomyces elongisporus, Lomentospora prolificans, Lophophyton spp. (e.g. L. cookie or L. gallinae), Macrophomina phaseolina (syn. Sclerotium bataticola; Rhizoctonia bataticola), Madurella spp. (e.g. M. griseum or M. mycetomatis), Magnaporte grisea (Ana morph: Pyricularia oryzae), Malassezia spp. (e.g. M. globosa or M. furfur), Microsphaeropsis arundinis, Microsporum spp. (e.g. M. audouinii, M. canis, M. ferrugineum, M. cookei, M. gallinae or M. vanbreuseghemii), Mortierella wolfii, Monilinia spp., Mucor (e.g. M. amphibiorum, M. circinelloides, M. indicus, M. irregularis or M. ramosissimus), Myrmecridium schulzeri Nannizzia spp. (e.g. N. fulva, N. gypsea, N. nana or N. persicolor), Neosartorya fischeri, Neoscytalidium dimidiatum, Onychocola canadensis, Paecilomyces spp. (e.g. P. marquandii, P. variotii or P. lilacinus), Paracoccidioides (e.g. P. brasiliensis), Penicillium (e.g. P. marneffei), Phaeoacremonium spp. (e.g. P. alvesii, P. amstelodamense, P. griseorubrum, P. minimum, P. rubrigenum, P. tardicrescens, or P. venezuelense) , Phialophora verrucosa, Phoma spp., Phytophtora spp., Pichia spp., Pithomyces chartarum, Pityrosporum ovale, Plasmopara viticola (syn. Peronospora viticola), Pneumocystis (e.g. P. carinii, P. jirovecii), Podosphaera spp., Prototheca spp. (e.g. P. wickerhamii or P. zopfii), Pseudallescheria spp. (e.g. P. boydii, Puccinia arachidis), Pyricularia spp., Pythium spp. (e.g. P. insidiosum, P. aphanidermatum and P. ultimum), Quambalaria spp. (e.g. Q. cyanescens, Q. pitereka, Q. eucalypti, Q. coyrecup or Q. simpsonii), Rhinocladiella spp. (e.g. R. atrovirens or R. mackenziei, Rhizoctonia solani, Rhizomucor spp. (e.g. R. miehei or R. pusillus), Rizopus spp. (e.g. R. micropsorus, R. oryzae, R. pusillus), Rhodotorula spp. (e.g. R. glutinis orR. mucilaginosa), Saccharomyces (e.g. S. cerevisiae), Saksenaea vasiformis, Scedosporium spp. (e.g. S. apiospermum, S. auraticum, S. boydii or S. prolificans), Schizophyllum commune, Sclerotium rolfsii, Scopulariopsis, Sepedonium spp., Septoria spp., Sporothrix schenckii, Syncephalastrum racemosum, Talaromyces marneffei, Torulaspora delbrueckii, Trichoderma spp., Trichophyton spp. (e.g. T. concentricum, T. equinum, T. eritrephon, T. interdigitale, T. mentagrophytes, T. quinckeanum, T. rubrum, T. schoenleinii, T. soudanense, T. tonsurans, T. verrucosum or T. violaceum), Trichosporon spp. (e.g. T. asahii, T. asteroids, T. beigelii, T. cuaneum, T. inkin, T. ovoides, T. roseum or T. terrestre), Uncinula necator (syn. Erysiphe necator), Venturia spp., Veronaea botryose, Verruconis spp. (e.g. V. gallopava), and Wickerhamomyces anomalus.
Particular species of fungus that may be mentioned include C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, A. fumigatus, A. flavus, A. terms, F. solani, F. verticillioides, F. Oxysporum, Mucor spp. and Cryptococcus spp.
For the avoidance of doubt, references to particular species of fungi may also include references to naturally-ocurring mutant forms thereof, as known to those skilled in the art.
As described herein, in view of their antifungal activity, compounds of the first aspect of the invention (including all embodiments thereof) may be useful for the treatment and/or prevention of a variety of superficial, cutaneous, subcutaneous fungal infections, such as systemic mycotic infections in skin, eye, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal portion, oral cavity, ophthalmus, systemic, kidney, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, blood and so on. In a particular embodiment of the first aspect of the invention, the treatment or prevention of a fungal infection may comprise (or consist of) the treatment or prevention of one or more condition selected from the group consisting of: dermatophytosis (e.g. trichophytosis, ringworm or tinea infections), athletes foot, paronychia, pityriasis versicolor, erytrasma, intertrigo, fungal diaper rash, Candida vulvitis, Candida balanitis, otitis externa, candidiasis (cutaneous and mucocutaneous), chronic mucocandidiasis (e.g. thrush and vaginal candidiasis), cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, pneumocystosis, rhinocerebral mucomycosis, lobomycosis, phaeohyphomycosis, and fugemia.
As discussed herein, compounds of formula I (as defined in the first aspect of the invention, including any one or more embodiment thereof), or pharmaceutically acceptable salts thereof, may also be used as prophylactic agents to prevent fungal or bacterial infections (e.g. systemic and topical fungal or bacterial infections). Use as prophylactic agents may, for example, be appropriate as part of a selective gut decontamination regimen in the prevention of infection in immune-compromised patients (e.g. AIDS patients, patients receiving cancer therapy or transplant patients). Further, prevention of fungal overgrowth during antibiotic treatment may also be desirable in some disease syndromes or iatrogenic states.
In certain embodiments, compounds of formula I, or pharmaceutically acceptable salts thereof, may prevent fungal infections by hindering fungal biofilm formation.
Additionally, compounds of formula I (as defined in the first aspect of the invention, including any one or more embodiment thereof), or pharmaceutically acceptable salts thereof, may also be used for the prevention or treatment of a bacterial infection.
In particular embodiments, the bacterial infection may be an infection with one or more (e.g. one) Gram-positive bacterial species. [Is this correct?]
In more particular embodiments, the bacterial infection may be an infection with one or more (e.g. one) bacterial species selected from the following: [Please provide a list of relevant species]
The skilled person will understand that compounds as defined in the first aspect of the invention (including all embodiments thereof) may be administered in the form of pharmaceutical formulations.
Thus, in particular embodiments, the treatment or prevention comprises administering a therapeutically effective amount of a pharmaceutical formulation comprising a compound as defined in the first aspect of the invention (including all embodiments thereof), and optionally one or more pharmaceutically acceptable excipients.
Suitable pharmaceutically acceptable excipients will be well-known to those skilled in the art, and may include suitable adjuvants, diluents and carriers as known to those skilled in the art, such as those described herein.
Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1 :99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
Pharmaceutical formulations may be formulated to deliver the active ingredient (i.e. the compound of formula I, or pharmaceutically acceptable salt thereof) in a manner designed to provide systemic and/or local therapeutic effects.
Pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route. In particular, pharmaceutical compositions according to the first aspect of the invention may be specifically formulated for administration by the oral route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release, according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also regarded as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
As discussed herein, the skilled person will be able to select an appropriate dose of compounds of the invention based on the patient, the route of administration and the nature of the treatment or prevention required.
For example, a typical oral dosage may be in the range from about 0.01 to about 500 mg/kg body weight per day, particularly from about 0.1 to about 200 mg/kg body weight per day, and more particularly from about 10 to about 100 mg/kg body weight per day, administered in one or more doses such as 1-3 doses. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated, and other factors evident to those skilled in the art.
The formulations described herein may conveniently be prepared in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day, such as 1-3 times per day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg of a compound of the invention. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical dosages are in the order of about half the dosage employed for oral administration.
For parenteral administration, solutions of compounds may be administered in sterile aqueous solution, in aqueous propylene glycol or in sesame or peanut oil. Aqueous solutions should be suitably buffered where appropriate, and the liquid diluent rendered isotonic with, e.g., sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media to be employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers (i.e. excipients) include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Moreover, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of the first aspect of the invention and the optional pharmaceutically acceptable excipients are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Pharmaceutical formulations suitable for oral administration may be presented as discrete units, such as capsules or tablets, which each contain a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more additional components selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may, for example, be: inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356, 108; 4, 166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
A typical tablet is prepared by conventional tabletting techniques and contains the following.
Core:
Active compound (as free compound or salt thereof) 5.0 mg
Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite® IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg
* Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.
** Acylated monoglyceride used as plasticizer for film coating.
The skilled person will understand that, if desired, the pharmaceutical composition comprising a compound according to the first aspect of the invention may additionally comprise further active substances. Similarly, the treatment or prevention as described in the first aspect of the invention may also comprise (i.e. as part of the same medical intervention) administration of one or more (e.g. one) additional (i.e. other) active substances. As described herein, such further active substances may include one or more agent selected from the group consisting of fungicidal and/or fungistatic agents, antibacterial agents, antiviral agents, antiseptics, analgesics and anaesthetics (e.g. local anaesthetics), as known to those skilled in the art. In particular, such further active substances may include one or more (additional) anti-fungal agent, as known to those skilled in the art.
Particular such such further active substances that may be mentioned include amphotericin B and any suitable formulations of amphotericin, such as amphotericin deoxycholate, amphotericin B lipid complex, amphotericin B cholesteryl sulfate complexes, amphotericin B colloidal dispersions, and liposomal amphotericin B formulations, as well as echinocandins such as caspofungin, micafungin, and anidulafungin.
Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the compound as described in the first aspect of the invention (including all embodiments thereof) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Similarly, oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil, for example arachis oil, olive oil, sesame oil, corn oil, or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavouring and/or colouring agents, may also be present.
Pharmaceutical compositions comprising a compound of the first aspect of the invention (including all embodiments thereof) may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Similarly, syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Pharmaceutical formulations may also be provided in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.
For buccal and sublingual use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the first aspect of the invention may be employed. In particular, formulations for buccal and sublingual application include mouth washes and gargles.
Further, compounds of the first aspect of the invention (including all embodiments thereof) may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
In addition, compounds of the first aspect of the invention (including all embodiments thereof) may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form, or may be in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
As described herein, pharmaceutical formulations comprising compounds of the first aspect of the invention (including all embodiments thereof) may also be formulated for topical administration. Thus, in certain embodiment the pharmaceutical formulation as described herein is a topical pharmaceutical composition.
When used herein, the term“topica includes references to formulations that are adapted for application to body surfaces (e.g. the skin or mucous membranes). Mucous membranes that may be mentioned in this respect include the mucosa of the vagina, the penis, the urethra, the bladder, the anus, the mouth (including the mucosa of the cheek, the soft palate, the under surface of tongue and the floor of the mouth), the nose, the throat (including the mucosa of the pharynx, the larynx, the trachea and the esophagus), the bronchi, the lungs, the eye and the ear.
Topical compositions, which are useful for treating disorders of the skin or of membranes (e.g. membranes accessible by digitation, such as membranes of the mouth, vagina, cervix, anus and rectum), include creams, ointments, lotions, sprays, gels and sterile aqueous solutions or suspensions. As such, topical compositions include those in which the active ingredient(s) is (are) dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or non-aqueous gels, ointments, water-in-oil or oil-in-water emulsions). Constituents of such vehicles may comprise water, aqueous buffer solutions, non-aqueous solvents (such as ethanol, isopropanol, benzyl alcohol, 2-(2- ethoxyethoxy)ethanol, propylene glycol, propylene glycol monolaurate, glycofurol or glycerol), oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides, or silicone oils such as dimethicone).
Similarly, the amount of the active compound used in topical compositions or combination products will depend, inter alia, upon the particular nature of the composition or combination product, as well as its intended use. In any event, those skilled in the art will be able to determine, by routine and non-inventive methods, amount that can be employed. Typically, however, the compound of formula I, or pharmaceutically acceptable salt thereof, will be present in the topical composition or combination product at from 0.01 to 25% by weight (e.g. from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or, particularly, from 0.5 to 3% (e.g. 2% or 1 %) by weight) of the composition or product.
Methods of producing topical pharmaceutical compositions such as creams, ointments, lotions, sprays and sterile aqueous solutions or suspensions are well known in the art. Suitable methods of preparing topical pharmaceutical compositions are described, for example in WO 95/10999, US 6,974,585, WO 2006/048747, as well as in documents cited in any of these references.
Further uses and methods
As described herein, due to their biological activity in fungal and bacterial cells, compounds of the invention may be utilized in reducing or preventing the growth of fungal or bacterial cells both in vivo and in vitro (i.e. ex vivo). In a second aspect of the invention, there is provided a method of killing and/or inhibiting or reducing growth of one or more fungal or bacterial cell, comprising applying to said fungal or bacterial cell an effective amount of a compound as defined in the first aspect of the invention (including all embodiments thereof).
In an alternative second aspect of the invention, there is provided the use of a compound as defined in the first aspect of the invention (including all embodiments thereof) in killing and/or inhibiting or reducing growth of one or more fungal or bacterial cell.
In particular embodiments of the second aspect of the invention, the method or use is an ex vivo (or in vitro) method or use.
In a third embodiment of the invention, there is provided the use of a compound as defined in the first aspect of the invention (including all embodiments thereof) as an anti-fungal agent.
In a particular embodiment of the third aspect of the invention, the use is an ex vivo use.
In an embodiment of the third aspect of the invention, the compounds as defined in the first aspect of the invention are used to prevent or hinder fungal and/or bacterial biofilm formation.
As also described herein, compounds of the first aspect of the invention also have activity as agricultural agents, in particular in treating or preventing fungal infections in plants.
Thus, in a fourth aspect of the invention, there is provided a method of treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising applying to the plant, plant material or plant propagation material or the locus thereof an effective amount of a compound of formula I as defined in the first aspect of the invention, or a salt thereof.
In a fifth aspect of the invention, there is provided a composition for use in treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising:
(a) a compound of formula I as defined in the first aspect of the invention, or a salt thereof; and
(b) an agriculturally acceptable carrier or diluent. In an alternative fifth aspect of the invention, there is provided the use of a composition in treating or preventing a fungal infection in plants, plant material and/or plant propagation material, wherein the composition comprises:
(a) a compound of formula I as defined in the first aspect of the invention, or a salt thereof; and
(b) an agriculturally acceptable carrier or diluent.
In an alternative fifth aspect of the invention, there is provided a method of treating or preventing a fungal infection in plants, plant material and/or plant propagation material, wherein the method comprises applying to the plant, plant material or plant propagation material or the locus thereof an effective amount of:
(a) a compound of formula I as defined in the first aspect of the invention, or a salt thereof; and
(b) an agriculturally acceptable carrier or diluent.
Unless otherwise specified, as used herein, the terms "fungal cell" and "fungal cells" may refer to the cell of a fungi, fungal-like species and/or parasite (e.g. a fungi) as described in the first aspect of the invention (including any one or more embodiment thereof).
Unless otherwise specified, as used herein, the term“anti-fungal” includes references to agents that kill fungal cells or inhibit or reduce growth of fungal cells. As such, the skilled person will understand that references to an“anti-fungal” agent herein include references to agents that are fungicidal and/or fungistatic.
Unless otherwise specified, as used herein, the terms“killing” and“kill” when used in respect of fungal cells includes references to rendering said fungal cells inactive, for example such that the fungal cells are irreversibly rendered incapable of metabolism, growth and/or reproduction. Such an effect may also be described as fungicidal. For example, fungal cells may be killed by preventing, or disrupting, fungal biofilm formation.
Unless otherwise specified, as used herein, the terms“killing” and“kill” when used in respect of bacteria cells includes references to rendering said bacteria cells inactive, for example such that the bacteria cells are irreversibly rendered incapable of metabolism, growth and/or reproduction. Such an effect may also be described as bactericidal. For example, bacetria cells may be killed by preventing, or disrupting, bacteria biofilm formation. Unless otherwise specified, as used herein, the terms“inhibiting or reducing growth” and “inhibit or reduce growth” includes references to reducing the rate at which one or more fungal cell (such as a colony consisting of multiple fungal cells) increases in size and/or number. Such an effect may be determined by observing the size of individual fungal cells and/or the number of fungal cells forming a colony before and after treatment with a compound of the invention, using techniques known to those skilled in the art. Such an effect may also be described as fungistatic.
For the avoidance of doubt, in particular embodiments of the second to fifth aspects of the invention, the fungal infection, fungus or fungal cell, as appropriate, is of one or more (e.g. one) species as defined in the first aspect of the invention.
In particular, the fungal infection in plants, plant material and/or plant propagation material may be an infection caused by one or more (e.g. one) of the following plant pathogens: Blumeria graminis; Colletotrichium trifolii; Fusarium graminearium; Fusarium solani; Fusarium sporotrichides; Leptospharia nodorum; Magnaporthe grisea; Mycosphaerella graminicola; Neurospora crassa; Phytophthora capsid; Pyricularia oryzae; Pythium ultimum; Rhizoctonia solani; Trichophyton rubrum; and Ustilago maydis.
Compounds may be assessed in respect of their activity in killing and/or inhibiting or reducing growth of one or more fungal or bacterial cell using techniques known to those skilled in the art, such as those described herein. For example, the ability of compounds to reduce or inhibit growth may be determined using the techniques described in the biological examples provided herein below. In this context, compounds may be considered to be effective in inhibiting or reducing growth of a given fungal strain if they are found to have a MIC50 (i.e. concentration delivering 50% growth inhibition) of less than or equal to 100 pg/mL (such as less than or equal to 50 pg/mL).
The skilled person will understand that compounds as described herein (e.g. compounds as described in the first aspect of the invention) may be applied to control fungi in areas such as in the prevention of fungal infection in agriculture (e.g. in crop plants, such as those discussed herein, in wood and wood related technical products, in food storage and/or in hygiene management. The present invention therefore specifically contemplates anti-fungal use, such as that described in respect of the third aspect of the invention, in these areas. In particular, compounds of the invention may be characterised by being inhibitory or fungicidal at low rates of application, by being well tolerated by plants and by being environmentally safe. Therefore, compounds described herein may be used agrochemically to protect important crop plants against diseases that are caused by plant pathogenic fungi.
As used herein in respect of the fourth and fifth aspects of the invention, the term“treating” takes its normal meaning in the field of agriculture. In particular, the term may refer to killing and/or inhibiting or reducing growth of the fungi, fungal-like species and/or parasite (e.g. the fungal cells) associated with the infection.
As used herein in respect of the fourth and fifth aspects of the invention, the term “prevention” (and, similarly, to“preventing”) includes references to the prophylaxis of the infection (and vice-versa). In particular, the term may refer to achieving a reduction in the likelihood of the infection arising (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).
As used herein in respect of the fourth and fifth aspects of the invention, the term“salt thereof” refers to any salt form suitable for use in the relevant method (i.e. suitable for use in agriculture) and may include those salts referred to herein as being“pharmaceutically acceptable” (as referred to in the first aspect of the invention). Thus, for the avoidance of doubt, the methods and compositions of the fourth and fifth aspects of the invention may utilise compounds of the first aspect of the invention (including all embodiments thereof).
As used herein in respect of the fourth and fifth aspects of the invention, the term“effective amount” refers to an amount of a compound which confers the desired (anti-fungal) effect on the recipient plant, plant material and/or plant propagation material (i.e. an amount that is capable of treating or preventing the fungal infection present in the plant, plant material and/or plant propagation material).
As referred to herein (e.g. in respect of the fourth and fifth aspects of the invention), plants that may be mentioned include crop plants, such as: cereals (such as wheat, barley, rye, oat, rice, maize, and sorghum), beets (such as sugar beet and fodder beet), pomes, drupes, citrus and soft fruits (such as apples, pears, plums, peaches, almonds, cherries, oranges, lemons, grapefruits, mandarins, bananas, strawberries, raspberries, and blackberries), leguminous plants (such as beans, lentils, peas and soybeans), oil plants (such as rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans and groundnuts), cucumber plants (such as pumpkins, cucumbers and melons), fibre plants (such as cotton, flax, hemp and jute), vegetables (such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, garlic, potatoes, eggplants and paprika), lauraceae (avocado, cinnamon, camphor), or other plants such as tobacco, coffee, tea, sugar cane, pepper, vines, hops, nuts and natural rubber plants, as well as ornamentals (such as roses, ferns, gerberas, geraniums and chrysanthemum).
Unless otherwise specified, as used herein the term“plant material” includes references to any material obtained and/or derived from a plant source (such as those plants mentioned herein), including food substances and structural materials (e.g. wood)
Unless otherwise specified, as used herein the term“plant propagation material” includes references to any material capable of being germinated and/or cultivated to produce a growing plant such as those plants mentioned herein), such as material in the form of seeds, tubers, bulbs, rhizomes and plant cuttings.
Compounds as described herein (e.g. compounds of the first aspect of the invention) may also be applied to control fungi in related areas, including protection of technical materials, such as wood and wood related technical products, in food storage or in hygiene management.
The skilled person will understand that to obtain protection against plant pathogenic fungi, compositions comprising compounds as described herein (e.g. compounds of the first aspect of the invention) can be applied to different plant parts such as fruits, blossoms, leaves, stems, tubers and roots. Plant propagation material such as seeds, tubers, bulbs, rhizomes and plant cuttings may be coated by a liquid or solid formulation of the fungicide for protection against fungal infections, in particular against root pathogens, such as Pythium spp. and Phytophtora spp. Moreover, to control plant diseases, formulations containing compounds as described herein may be sprayed on growing plants to obtain a surface protection of leaves or by acquiring a systemic protection resulting in crop plants that are immune against plant pathogenic fungi at the whole plant level. The systemic effect is obtained by plants through root uptake of the fungicide from the soil or by penetration through the cuticle layer and epidermis cells of leaves. The present invention therefore specifically contemplates methods comprising all such forms of application (including any combination thereof). For the avoidance of doubt, compounds as described herein can be formulated to obtain a curative, preventive, or systemic effect on plants susceptible to various plant pathogenic fungi. The preventive effect may be obtained by adding a formulation containing compounds described herein (e.g. as described in the first aspect of the invention) to the soil prior to sowing, e.g. the field where the crop plants will be cultivated or soil used for greenhouse production of vegetables or ornamentals. Young plants may be protected prior to transplantation by a total or partial treatment by immersion. The present invention therefore specifically contemplates methods comprising these steps (optionally combined with the methods of application as known to those skilled in the art, such as discussed herein).
When used in the treatment or prevention of infections, as anti-fungal agents or in killing or inhibiting the growth of fungal cells in plants, plant material and/or plant propagation material (e.g. as described herein), compounds as described herein may be administered as formulations or compositions suitable for such uses, such as those comprising one or more agriculturally acceptable carrier or diluent
In particular, the skilled person will understand that such compositions (e.g. for treating a fungal infection in plants, plant material and/or plant propagation material as described in the fifth aspect of the invention) may be referred to as an agrochemical composition.
In particular, when required for such uses, compounds as described herein may be formulated with an inert carrier in emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, as well as in encapsulations in e.g. polymeric substances. The formulations may be further modified by addition of adjuvants such as stabilisers, antifoams, viscosity regulators, thickeners, binders, or tackifiers, depending on the desired properties. In addition, the compound or the formulation of the compound may be added to fertilizers.
In a particular embodiment of the fifth aspect of the invention, the composition may comprise at least one additional fungicidal and/or fungistatic compound in addition to the compound of formula I as described in the first aspect of the invention, or salt thereof.
Compositions for treating a fungal infection in plants, plant material and/or plant propagation material comprising compounds of the invention may be applied by spraying, atomizing, dusting, scattering, coating or pouring, depending on the intended objectives and the prevailing circumstances. The application to plants, plant material and/or plant propagation material may occur simultaneously or in succession with other compounds, such as fertilizers or micronutrients, or other substances influencing plant growth, as well as herbicides, insecticides, fungicides, bactericides, nematicides, molluscicides, or mixtures of several of these preparations. The combination of several different active ingredients can be accompanied by further addition of carriers, surfactants or other adjuvants generally used in the art of formulation.
The preparation of said compositions is typically done, according to known protocols, by mixing or grinding of the compounds with adjuvants and extenders like solvents, solid carriers and optionally surface-active compounds (surfactants).
Agrochecmical compositions containing compounds as described herein may contain from 0.1 to 99% by weight, preferably from 0.1 to 95%, of the compound of formula I as defined in respect of the first aspect of the invention, or a salt thereof. Such compositions may also contain from 99.9 to 1 % by weight, preferably 99.9 to 5%, of a solid or liquid adjuvant, and from 0 to 25% by weight of a surfactant.
In a particular embodiment, compositions of the fifth aspect of the invention may be formulated as concentrates (i.e. for dilution by an end user to provide a dilute formulation for application). In such cases, the amount to apply can be experimentally determined and may depend on type of action, the developmental stage of the crop plant as well as on the application location, timing, application method and amount of disease causing fungi and the severity of the fungal attack. In particular, the rate of application may constitute from 5 g to 2 kg of active ingredient (a.i.) (i.e. the compound of formula I, or salt thereof) per hectare (ha), preferably from 10 g to 1 kg a.i. /ha or most preferably from 20 to 600 g a.i. /ha. Alternatively, for use as seed coating agent, convenient application rates are from 10 mg to 1 g of active ingredient per kg of seeds.
For the avoidance of doubt, the skilled person will appreciate that compositions as described in respect of the fifth aspect of the invention may be used in methods and uses as described in the second, third and fourth aspects of the invention.
Novel compounds and formulations As described herein, certain compounds of formula I, or pharmaceutically acceptable salts thereof, as described in the first aspect of the invention (including all embodiments thereof) may be novel. Thus, in a sixth aspect of the invention there is provided a compound of formula III
Figure imgf000051_0001
as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, wherein:
R1 , R29 and R2h are as defined in the first aspect of the invention (including all embodiments thereof). In particular embodiments, the compound of formula III is not a compound selected from the list consisting of:
1 ,2-dihydro-5-methyl-2-[6-(methylamino)-4-pyrimidinyl] 3H-pyrazol-3-one;
N-[3-(1 , 1-dimethylethyl)-1-[6-[3-(1 , 1-dimethylethyl)-5-hydroxy-1 H-pyrazol-1-yl]-4- pyrimidinyl]-1 H-pyrazol-5-yl]acetamide; and
1-[6-[5-amino-3-(1 , 1-dimethylethyl)-1 H-pyrazol-1-yl]-4-pyrimidinyl]-3-(1 , 1-dimethylethyl)- 1 H-pyrazol-5-ol.
As described herein, compounds of formula III, or pharmaceutically acceptable salts thereof, have uses in medicine, such as in the treating or prevention of fungal and/or bacterial infections. Thus, in a seventh aspect of the invention, there is provided a compound of formula III as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for use in medicine (or as a pharmaceutical). As compounds of the invention may be utilized in medicine (i.e. as pharmaceuticals), such compounds may be incorporated in pharmaceutical compositions.
Thus in an eighth aspect of the invention, there is provided a pharmaceutical formulation comprising a compound of formula III as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carrier or excipient.
For the avoidance of doubt, particular pharmaceutical formulations that may be mentioned in respect of the eighth aspect of the invention include those as described in the first aspect of the invention.
In a ninth aspect of the invention there is provided a compound of formula Ilia
Figure imgf000052_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R1 and R2, taken together, form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y1 (as defined herein); and
R29 and R2h are as defined herein (i.e. in the first aspect of the invention, including all embodiments thereof). As described herein, compounds of formula Ilia, or pharmaceutically acceptable salts thereof, have uses in medicine, such as in the treating or prevention of fungal and/or bacterial infections.
Thus, in a tenth aspect of the invention, there is provided a compound of formula Ilia as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for use in medicine (or as a pharmaceutical).
As compounds of the invention may be utilized in medicine (i.e. as pharmaceuticals), such compounds may be incorporated in pharmaceutical compositions.
Thus in an eleventh aspect of the invention, there is provided a pharmaceutical formulation comprising a compound of formula Ilia as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carrier or excipient.
For the avoidance of doubt, particular pharmaceutical formulations that may be mentioned in respect of the ninth aspect of the invention include those as described in the first aspect of the invention.
Preparation of compounds
As described herein, compounds of the first aspect of the invention may be commercially available and/or described in the literature, and may be prepared in accordance with techniques known to those skilled in the art.
However, as also described herein, compounds described herein are not previously disclosed (i.e. are novel), such as compounds of formula III and pharmaceutically acceptable salts thereof (as described in the first and sixth aspects of the invention, including all embodiments thereof). Such novel compounds may be prepared in accordance with techniques known to those skilled in the art, such as those described herein after (e.g. in the examples).
Thus, according to a twelfth aspect of the invention, there is provided a process for the preparation of a compound of formula III (as defined in respect of the sixth aspect of the invention, including all embodiments thereof), or a pharmaceutically acceptable salt thereof, which process comprises:
(i) reaction of a compound of formula IV
Figure imgf000054_0001
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as hereinbefore defined (i.e. in the first aspect of the invention, including all embodiments thereof), with a compound of formula V
Figure imgf000054_0002
or a suitable salt and/or protected derivative thereof, wherein R1 is as hereinbefore defined and LG1 represents a suitable leaving group (e.g. a group of formula -ORza wherein Rza represents C1-3 alkyl optionally substituted by one or more fluoro, or halo), under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. a suitable alcohol, such as /so-propanol) and optionally at elevated temperature (i.e. at above room temperature, such as the reflux temperature of the solvent);
(ii) reaction of a compound of formula VI
Figure imgf000054_0003
or a suitable salt and/or protected derivative thereof, wherein R1 is as hereinbefore defined and LG2 represents a suitable leaving group (e.g. a halo group, such as chloro), with a compound of formula VII
Figure imgf000055_0001
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as hereinbefore defined, under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. where R29 and R2h are both methyl, using the compound of formula VII as a solvent); (iii) for compounds of formula III where R1 represents Ar1 or Het1 wherein Het1 represents heteroaryl, reaction of a compound of formula VIII
Figure imgf000055_0002
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as hereinbefore defined and LG3 represents a suitable leaving group, with a compound of formula IX
Figure imgf000055_0003
or a suitable salt and/or protected derivative thereof, wherein R1 is as hereinbefore defined and LG4 represents a suitable leaving group, for example wherein one of LG3 and LG4 represents halo (such as iodo, chloro or, particularly, bromo) and the other represents - B(OH)2 or -B(ORzb)2, in which each Rzb independently represents a C1-6 alkyl group or the respective Rzb groups may be linked together to form a 4- to 6- membered cyclic group (such as a 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl group), under conditions known to those skilled in the art, such as in the presence of a suitable catalyst (such as a palladium catalyst, for example a palladium (0) catalyst, e.g. Pd(PPh3)4) and in the presence of a suitable base (such as a suitable carbonate, e.g. sodium carbonate or potassium carbonate), optionally as an aqueous solution, and optionally in the presence of a suitable solvent (such as 1 ,4-dioxane, toluene and/or ethanol);
(iv) for compounds of formula III wherein any substituent represents -OH, reaction of a compound of formula III wherein the corresponding substituent represents -ORzc wherein Rzc represents C1-3 alkyl (e.g. methyl) under conditions known to those skilled in the art, such as in the presence of a suitable demethylating agent (such as boron tribromide) and in the presence of a suitable solvent (such as dichloromethane) and optionally at reduced temperature (such as at about 0° C) and/or under an inert atmosphere (such as under nitrogen);
(v) for compounds of formula I II wherein any substituent represents a -C(0)0H group, hydrolysis (i.e. reaction) of a compound of formula III wherein the corresponding substituent represents a -C(0)0Rzd group wherein Rzd represents Ci-e alkyl (e.g. methyl or ethyl), optionally substituted by one or more fluoro, or an aryl group (e.g. phenyl), optionally substituted by one or more fluoro, under conditions known to those skilled in the art, for example in the presence of a suitable aqueous base (such as an aqueous hydroxide salt, for example aqueous sodium hydroxide) and in the presence of a suitable solvent (such as a polar solvent, for example methanol);
(vi) for compounds of formula III wherein any substituent represents a group selected from -C(0)0R1 i to -C(0)0R4i, reaction of a compound of formula III wherein the corresponding substituent represents -C(0)0H with a compound of formula X
Figure imgf000056_0001
wherein Rze represents the required R1 i to R4i group, under conditions known to those skilled in the art, such as in the presence of a suitable acid (such as concentrated H2SO4) and in the presence of a suitable solvent (such as toluene) and optionally at elevated temperature (such as at the reflux temperature of the compound of formula X); or
(vii) for compounds of formula I II that contain only saturated alkyl groups, reduction of a corresponding compound of formula III that contains an unsaturation, such as a double or triple bond, under conditions known to those skilled in the art, such as under suitable reducing conditions (for example by catalytic (e.g. employing Pd) hydrogenation) and in the presence of a suitable solvent (such as methanol). For the avoidance of doubt, compounds of formula I which are not also compounds of formula III may nevertheless also be prepared by analogy with the processes described herein for the preparation of compounds of formula III, such as by following the procedures described in the examples provided herein.
For example, compounds of formula I may be prepared by reaction of a compound of formula IVa
Figure imgf000057_0001
or a suitable salt and/or protected derivative thereof, wherein R3 and X1 to X3 are as hereinbefore defined (i.e. in the first aspect of the invention, including all embodiments thereof), with a compound of formula Va
Figure imgf000057_0002
or a suitable salt and/or protected derivative thereof, wherein R1 and R2 are as hereinbefore defined and LG1a represents a suitable leaving group (e.g. a group as defined as LG1 for compounds of formula V as hereinbefore defined), under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. a suitable alcohol, such as /so-propanol) and optionally at elevated temperature (i.e. at above room temperature, such as the reflux temperature of the solvent). Compounds of formulae VI, Via, V, Va, VI, VII, VIII, IX and X are either commercially available, are known in the literature, or may be obtained by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
For example, compounds of formula IV may be prepared by reaction of a compound of formula XI
Figure imgf000058_0001
or a suitable salt and/or protected derivative thereof (e.g. a compound of formula XI wherein the hydrazine group is protected with a f-butylcarbonyl (Boc) group), wherein LG5 represents a suitable leaving group (e.g. a halo group, such as chloro), with a compound of formula VII
Figure imgf000058_0002
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as hereinbefore defined, under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. where R29 and R2h are both methyl, using the compound of formula VII as a solvent).
Similarly, compounds of formula IVa may be prepared by analogy with the processes used for the preparation of compounds of formula IV.
Compounds of formula XI are either commercially available, are known in the literature, or may be obtained by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
Substituents on alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic groups in compounds of formula I may be introduced and/or intercon verted using techniques well known to those skilled in the art by way of standard functional groups interconversions, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. For example, benzyloxy may be converted to hydroxy, etc. Compounds of formula III (and, similarly, compounds of formula I and other compounds the preparation of which is described herein) may be isolated from their reaction mixtures using conventional techniques. For example, compounds of formula III may be isolated by conversion to an acid (e.g. hydrochloric acid) salt (e.g. by way of addition of acid to the crude product) and then recrystallisation of the salt from a suitable solvent (e.g. methanol or, particularly, ethanol). Alternatively, the salt can simply be washed with or slurried in the presence such a suitable solvent in order to isolate the pure acid salt of the compound of formula III.
As discussed herein, compounds of formula III (and, similarly, compounds of formula I) may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers and enantiomers may be isolated using conventional techniques, e.g. chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. HPLC techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation (for example with a homochiral acid), followed by separation of the diastereomeric derivatives by conventional means (e.g. fractional crystallisation, HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
It will be appreciated by those skilled in the art that in the processes described above and hereinafter the functional groups of intermediate compounds used in the processes as described may need to be protected by protecting groups as known to those skilled in the art (which protected compounds may be referred to as protected derivatives of the compounds described).
Functional groups that it may be desirable to protect include hydroxy, amino and carboxylic acid group. For example, it will be known that: suitable protecting groups for hydroxy groups include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert- butyl), trialkylsilyl or diarylalkylsilyl groups (e.g. f-butyldimethylsilyl, t- butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl; suitable protecting groups for carboxylic acid include Ci-e alkyl or benzyl esters; and suitable protecting groups for amino include te/f-butyloxycarbonyl and benzyloxycarbonyl.
The protection and deprotection of functional groups may take place before or after coupling, or before or after any other reaction in the above-mentioned schemes. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter.
Persons skilled in the art will appreciate that, in order to obtain compounds of formula III (and, similarly, compounds of formula I) in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups. The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is described in“Protective Groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).
Protected derivatives of compounds of formula III (and, similarly, compounds of formula I) may be converted chemically to compounds of the invention using standard deprotection techniques (e.g. hydrogenation).
Those skilled in the art will also appreciate that certain compounds of formula III (and, similarly, compounds of formula I) will be useful as intermediates in the synthesis of certain other compounds of formula III (and, similarly, compounds of formula I).
The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of formula II I, or a pharmaceutically acceptable salt thereof, as described in respect of the first aspect of the invention (including any one or more embodiment thereof), with a pharmaceutically acceptable adjuvant, diluent or carrier.
Technical advantages
When used in the methods and uses described herein, compounds as described herein may have the advantage that they may be more convenient for the physician, patient or agrochemical user than, be more efficacious than, have less unwanted toxicity (e.g. mammalian, such as human, toxicity) than, have a broader range of activity than, be more potent than, produce fewer unwanted effects than, or may have other useful (e.g. pharmacological) properties over compounds known in the prior art as being useful in such methods and uses.
Without wishing to be bound by theory, is it thought that compounds as disclosed herein have in vitro and in vivo antifungal activities due to their ability to chelate zinc ions (specifically, Zn2+ ions), which are important for the growth and virulence of the fungal cell.
All microbial cells need zinc for growth, although the concentrations required may be very low. Beside ZIP family uptake transporters, some fungal species possess additional mechanisms to sequester zinc from host cells and tissues in a process analogous to iron chelation by secreted siderophores. For example, C. albicans secretes the antigenic protein Pra1 , a zinc-binding protein that is able to scavenge zinc from tissues invaded by the fungus. Further, othologs of the gene encoding Pra1 are found in diverse fungal pathogens including A. fumigatus (the zinc-regulated aspf2 gene). These zinc- sequestering genes are generally clustered with Zrt1 orthologs in these fungi in a highly syntenic fashion, representing a conserved mechanism for zinc acquisition during host- fungal interactions (see, for example, Staats et ai, Mini Review Article “Fungal zinc metabolism and its connections to virulence" (2013), and Citiulo et ai, PLoS Pathogens, (2012)).
In yeast, the major zinc binding proteins include Cu/Zn superoxide dismutase (SOD), alcohol dehydrogenase and ribosomes. SODs are the central enzymes in fungi associated with the detoxification of ROS generated by host cells during host-pathogen interactions. In this view, specific SODs from pathogenic fungi are assumed to be virulence determinants.
Competition for metal ions between the mammalian host and pathogenic microorganisms appears to be an important form of host defense. In macrophages both metal starvation and intoxication are part of the arsenal employed in host defenses; for instance, in macrophages infected with the fungus Histoplasma capsulatum, zinc is bound to metallothioneins to combat the infection (Vignesh et al., Immunity, 39(4), 697-710 2013).
Moreover, the opposite effect as also been observed, as zinc poisoning has been proposed as a mechanism deployed to macrophages to combat Mycobacterium tuberculosis (Botella et ai, Cell Host and Microbe, 10(3), 248-259 (201 1)). Further, in order to combat microbial infections, neutrophils will synthesize high amounts of calprotectin, which is an antimicrobial Zn/Fe/Mn-chelating protein. Calprotectin is also called S100A8, S100A9, MRP 8/14, L1 , Calgranulin A and B. It has been found in relatively high concentrations (1-20 mg/ml_) in abscess fluids and its effect is reversible by mM quantities of zinc (see, for example, Lulloff et al. , Journal of laboratory and Clinical Medicine, 144(4), 208-214 (2004), and Clark et ai, 2016).
Thus, the regulation of zinc homeostasis and zinc acquisition is thought to provide an effective anti-fungal target, as a zinc-chelating antifungal agent such as those described herein will boost the immune system of the host by utilizing the same defense mechanism as naturally occurring agents such as calprotectin.
In addition, compounds as described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological and/or agricultural, physical, or chemical properties over, compounds known in the prior art (whether such compounds are known in the prior art for use in the above-stated indications or otherwise).
Examples
The invention is illustrated by way of the following examples. In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).
Abbreviations
In respect of the examples provided herein, the following abbreviations may be employed.
AcOH Acetic acid
aq. Aqueous
Boc tert-Butyloxycarbonyl group
CDC Deuterated chloroform
cHexane cyclohexanes DCM Dichloromethane / methylene chloride
DIPEA Di-/so-propylethylamine
DMF A/./V-Dimethylformamide
DMSO Dimethyl sulfoxide
DTT Dithiothreitol
EDTA ethylenediaminetetraacetic acid
ES Electrospray
Et20 Diethyl ether
Et3N Triethylamine
EtOH Ethanol/Ethyl alcohol
EtOAc Ethyl acetate
GTEK20 buffer Glucose-Tris-HCI-EDTA-KCI (20% glycerol, 10 mM Tris-HCI pH 7.25, 25 mM KCI, 0.5 mM EDTA pH 8.0, 1 mM DTT, 0.2 mM PMSF, 2 pg/ml Pepstatin A)
h hour(s)
HPLC High pressure liquid chromatography
LDA Lithium diisopropylamide
iPrOH Isopropanol / isopropyl alcohol / propan-2-ol
LCMS Liquid Chromatograph / Mass Spectroscopy
MDAP Mass Directed Automated Purification
MeCN Acetontrile
MeOH Methanol / Methyl alcohol
milli-Q Ultrapure water, filtered and deionized
min minute(s)
MOPS 3-(N-morpholino)propanesulfonic acid
MW Microwaves
nmr nuclear magnetic resonance
OD Optical density
PMSF Phenylmethylsulfonyl fluoride
RT Room temperature
Rt Retention time
sat. Saturated
SCX-2 Pre-packed Isolute® silica-based sorbent with a chemically bonded propylsulfonic acid functional group
SGAH medium minimal galactose medium supplemented with adenine and histine (7.04 g/L yeast nitrogen base, 19.8 g/L galactose, 64 mg/L adenine, 64 mg/L histidine) STKED20 buffer Sucrose-Tris-HCI-KCI-EDTA-glucose buffer (200 g/L sucrose, 40 g/L glucose, 50 mM Tris-HCI pH 7.25, 50mM KCI, 1 mM EDTA pH 8.0, 1 mM DTT, 0.2 mM PMSF, 2 pg/ml Pepstatin A)
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
tic thin layer chromatography
Tris tris(hydroxymethyl)aminomethane
UPLC Ultra High performance Liquid Chromatography
YPD medium Yeast-peptone-glucose medium (10 g/L yeast extract, 20 g/L bacto-peptone, 20 g/L glucose, 20 g/L agar)
General experimental details
Reactions were not carried out under an inert atmosphere unless specified and all solvents and commercial reagents were used as received.
Purification by chromatography refers to purification using either the CombiFlash® Companion purification system or the Biotage Isolera® purification systems. Where products were purified using an Isolute® SPE Si II cartridge, ‘Isolute SPE Si cartridge’ refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 pm and nominal 60A porosity. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically silica gel on aluminium foil plates with a fluorescent indicator (254 nm, e.g. Fluka 60778). Microwave reactions were carried out using a Biotage Initiator 60™ which uses a single mode resonator and dynamic field tuning. Temperature from 40-250 °C can be achieved, and pressures of up to 30 bar can be reached.
Mass Directed Auto-Purification (MDAP) was used to purify compounds where indicated. Separation using Agilent 1260 Infinity Purifications System, XSelect CSH Prep C18 5 pm, 21 x 250 mm (acidic modifier) or XBridge Prep C18 5 pm, 21 c 250 mm as the stationary phase, maintained at RT and a 19 mL/min flow. The initial solvent system was 90% water and 10% acetonitrile followed by a gradient up to 5% water and 95% acetonitrile (containing either 0.1 % formic acid or ammonium hydroxide modifiers), centred around a specific focused gradient, over 22 min. Product collection was triggered by an Agilent 6100 series single Quadrupole LC/MS. The desired fractions were concentrated in vacuo at 40 °C.
Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
LS-MS measurements were performed using standard equipment and using techniques known to those skilled in the art.
Compound names were generated using the Autonom 2000 feature in MDL ISIS™/Draw 2.5 SP2 software.
NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300 MHz, using techniques known to those skilled in the art. Chemical shifts are expressed in ppm relative to an internal standard, tetramethylsilane (ppm = 0.00). The following abbreviations have been used: b = broad signal, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or any combination thereof.
General considerations
In the procedures that follow, when reference is made to the use of a “similar” or “analogous” procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variations; for example, the reaction may vary in relation to reaction temperature, reagent/solvent amount, reaction time, work-up conditions and/or chromatographic purification conditions.
Example compounds
In accordance with the present invention, the compounds described in the Table 1 (below) were prepared.
Table 1:
Figure imgf000066_0001
Figure imgf000067_0001
66
Figure imgf000068_0001

Figure imgf000069_0001

Figure imgf000070_0001

Figure imgf000071_0001
70
Figure imgf000072_0001
71
Figure imgf000073_0001
72
Figure imgf000074_0001
73
Figure imgf000075_0001
74
Figure imgf000076_0001
75
Figure imgf000077_0001
76
Figure imgf000078_0001
77
Figure imgf000079_0001

Figure imgf000080_0001

Figure imgf000081_0001
Figure imgf000082_0001
81
Figure imgf000083_0001
82
Figure imgf000084_0001
83
Figure imgf000085_0001
84
Figure imgf000086_0001
85
Figure imgf000087_0002
Preparation of compounds
The compounds as described in Table 1 herein above were prepared and characterized using proceedures as known to those skilled in the art. For example, the compounds identified below were prepared using the proceedures as described.
Compound 5: 2-(6-Dimethylamino-pyrimidin-4-yl)-5-phenyl-2H-pyrazol-3-ol
Figure imgf000087_0001
INTA:
I NT A: 5-Phenyl-2-(6-Chloro-pyrimidin-4-yl)-2H-pyrazol-3-ol -
Ethyl 3-oxo-3-phenyl-propanoate (1.73 g, 8.99 mmol) in MeOH (5.0 ml_) was treated with (6-chloropyrimidin-4-yl)hydrazine (1.00 g, 6.92 mmol) (PCT Int AppL 2008042639). The mixture was heated to reflux. After 1 h a yellow solid had crystallised out. The suspension was cooled and slurried in a further 5 ml_ MeOH, the solid was filtered off and washed with a little more MeOH to give, after drying under vacuum, the title compound as a yellow solid (1.04 g, 55%).
LCMS (LCMS method 1): Rt = 1.03 min; [MH]+ = 272.9/274.9 2-(6-Dimethylamino-pyrimidin-4-yl)-5-phenyl-2H-pyrazol-3-ol -
5-Phenyl-2-(6-Chloro-pyrimidin-4-yl)-2H-pyrazol-3-ol///\/T A (100 mg, 0.370 mmol) was dissolved in 40% aq. dimethylamine (5 ml_) at RT. After 3.5 h the reaction was transferred to a freezer overnight. The reaction was evaporated to lower volume. A purple solid crystallised out and was filtered off. The soluble material was purified by acid MDAP to give the title compound as a brown gum (11 mg, 11 %).
LCMS (QC LCMS method 1): Rt = 4.73 min; [MH]+ = 282.2; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 13.2 (1 H, bs), 8.49 (1 H, d), 7.89 (2H, bd), 7.43 (3H, m), 6.92 (1 H, bs), 6.13 (H, s) and 3.17 (6H, s) Compound 6: 5-Phenyl-2-pyrimidin-4-yl-2H-pyrazol-3-ol
Figure imgf000088_0001
To ethyl 3-oxo-3-phenyl-propanoate (2.27 g, 11.8 mmol) in MeOH (20 mL) was added pyrimidin-4-ylhydrazine (1.00 g, 9.08 mmol). The mixture was heated to reflux for 1 h then cooled and evaporated. The residue was redissolved in 50 mL MeOH and refluxed under argon for 5 h, then 1.0 mL of iPr2NEt was added and the solution refluxed for a further 14 h. The reaction mix was evaporated and purified by column chromatography eluting with MeOH/DCM (0:100 to 5:95, each eluent containing 0.5% AcOH). Impure material was repurified by column chromatography eluting with EtOAc/cHexane (0:100 to 50:50, each eluent containing 0.5% AcOH). Pure fractions from both columns were combined and evaporated to give a white solid (400 mg). This was recrystallised from 7 mL EtOAc to give the title compound as a white solid (112 mg, 5%).
LCMS (QC LCMS method 1): Rt = 3.58 min; [MH]+ = 238.9; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 12.2 (1 H, bs), 9.08 (1 H, d), 8.84 (1 H, d), 8.10 (1 H, b) 7.89 (2H, bd), 7.48 (3H, m) and 6.11 (H, bs)
Compound 1: 2-(6-Dimethylamino-pyrimidin-4-yl)-5-trifluoromethyl-2H-pyrazol-ol
Figure imgf000089_0001
INTB:
INT B: 6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine -
To 4,6-dichloropyrimidine (5.00 g, 33.6 mmol) and TEA (3.40 g, 33.6 mmol) in iPrOH (50 ml_) was added 2 M dimethylamine in THF (33.6 ml_, 67.1 mmol). The solution became warm and after a few minutes a solid started to crystallise out. After the reaction mix was concentrated to low volume, iPrOH (25 ml_), hydrazine hydrate (3.36 g, 67.1 mmol), and TEA (2.5 ml_) were added and the reaction heated to reflux under argon. After 2.5 h further hydrazine hydrate (3.36 g, 67.1 mmol) was added and the reflux continued for 17 h. The reaction was cooled and the precipitate filtered off and washed with cHexane. The solid was dried under vacuum at 50 °C to give the title compound as an off white solid (3.6 g, 70%). LCMS (LCMS method 2): Rt = 0.92 min; [MH]+ = 154.1
2-(6-Dimethylamino-pyrimidin-4-yl)-5-trifluoromethyl-2H-pyrazol-ol - Ethyl 4,4,4-trifluoro-3-oxo-butanoate (0.32 ml_, 2.6 mmol) in /PrOH (2.0 ml_) was treated with 6-hydrazino-N,N-dimethyl-pyrimidin-4-amine///\/TS (0.30 g, 1.96 mmol). The reaction was heated to reflux. After 1 h it was cooled and stirred at RT until a white solid crystallised out. The solid was filtered off.
The solution was heated to reflux under argon for 15 h. The reaction mixture was then diluted with iPrOH (2 ml_), reheated to reflux then allowed to cool with stirring. On cooling a pink solid formed which was filtered off and washed with iPrOH (166 mg, after drying at 50 °C under vacuum). The solid was recrystallised from 6 ml_ iPrOH with a hot filtration, to give the title compound as a pink solid (120 mg, 22%).
LCMS (QC LCMS method 1): Rt = 1.81 min; [MH]+ = 273.8; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 13.5 (1 H, bs), 8.50 (1 H, d), 6.78 (1 H, d), 5.97 (1 H, s) and 3.17 (6H, s)
Compound 8: 5-(3,4-Difluoro-phenyl)-2-(6-dimethylamino-pyrimidin-4-yl)-2H-pyrazol-3-ol
Figure imgf000089_0002
Ethyl 3-(3,4-difluorophenyl)-3-oxo-propanoate (387 mg, 1.70 mmol) in iPrOH (2.0 mL) was treated with 6-hydrazino-N,N-dimethyl-pyrimidin-4-amine///\/T B (0.20 g, 1.31 mmol). The reaction was heated to reflux under argon for 30 min then cooled and the resulting pale yellow precipitate filtered off and washed with iPrOH (240 mg). The solid was recrystallised from 20 mL iPrOH with a hot filtration to give the title compound as a white solid (168 mg, 40%).
LCMS (CC LCMS method 1): Rt = 5.19 min; [MH]+ = 317.9; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 13.2 (1 H, bs), 8.45 (1 H, d), 7.95 (1 H, ddd), 7.75 (1 H, bd), 7.52 (1 H, ddd), 6.91 (1 H, bs), 6.20 (1 H, s) and 3.17 (6H, s)
Compound 11: 2-(6-Methoxy-pyrimidin-4-yl)-5-methyl-2H-pyrazol-3-ol
Figure imgf000090_0001
INT C: 2-(6-Chloro-pyrimidin-4-yl)-5-methyl-2H-pyrazol-3-ol -
To methyl 3-oxobutanoate (0.225 mL, 2.07 mmol) in iPrOH (1.0 mL) was added (6- chloropyrimidin-4-yl)hydrazine (200 mg, 1.38 mmol). The reaction was heated to reflux for 1 h then cooled. On standing the solution deposited a white solid, which was collected by filtration, washed with iPrOH and dried to give the title compound as a white solid (40 mg, 13%). LCMS (LCMS method 1) Rt = 0.92 min; [MH]+ = 21 1.1/213.1 2-(6-Methoxy-pyrimidin-4-yl)-5-methyl-2H-pyrazol-3-ol -
To MeOH (3.0 mL) under argon was added 60% sodium hydride in oil (57 mg, 1.42mmol). After the gas evolution had ceased 2-(6-chloropyrimidin-4-yl)-5-methyl-pyrazol-3-ol///\/T C (75. mg, 0.360mmol) was added as a solid and the reaction stirred and heated to 50 °C under argon for 20 h. To the cooled reaction mix was added silica gel, the MeOH evaporated and the dry silica was purified by column chromatography eluting with MeOH/DCM (15:85). A broad peak eluted, the fractions of which were combined and evaporated to a pink solid. The solid was sonicated with 1 mL EtOAc, filtered off and dried to give the title compound as a pink solid (15 mg, 20%).
LCMS (QC LCMS method 1): Rt = 2.41 min; [MH]+ = 207.0; ca. 99.3% purity
1 H NMR (400 MHz; DMSO-cfe, d): 1 1.5 (1 H, bs), 8.67 (1 H, d), 7.64 (1 H, bs), 5.16 (1 H, s), 3.95 (3H, s) and 2.17 (3H, s) Compound 3-[(3S)-1 -[ 6- ( 5-hydroxy-3-methyl-pyrazol- 1 -yl) pyrimidin-4-yl]pyrrolidin-3- yl]oxypyridine-4-carbonitrile
Figure imgf000091_0001
INT H: INTI:
INT D: tert- Butyl (3S)-3-[(4-cyano-3-pyridyl)oxy]pyrrolidine-1-carboxylate -
Sodium hydride (60 wt% in oil; 1.35 g, 33.6 mmol) was added portionwise at 0°C to a solution of tert- butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (6.30 g, 33.6 mmol) in THF (35 ml_). The reaction mixture was stirred at 0°C for 3 h, then carefully quenched with water (50 ml_) and extracted with EtOAc (3 c 100 ml_). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The crude was purified by column chromatography eluting with cHexane: EtOAc (88: 12 to 0: 100) to give the title compound as a colourless solid (8.14 g, 75%). LCMS (LCMS method 1) Rt = 0.1.29 min; [MNa]+ = 312.1 INT E: 3-[(3S)-pyrrolidin-3-yl]oxypyridine-4-carbonitrile -
Trifluoroacetic acid (32.3 ml_, 422 mmol) was added slowly to a solution of tert- butyl (3S)- 3-[(4-cyano-3-pyridyl)oxy]pyrrolidine-1-carboxylate (8.14 g, 28.1 mmol) in DCM (80 ml_) . The reaction mixture was stirred at room temperature for 1 h then diluted with toluene and concentrated in vacuo. The crude was loaded onto an SCX-2 cartridge (50 g) washing first with methanol then eluting with 2 M NH3 in MeOH. The crude was purified by column chromatography eluting with DCM: 2 M NH3 solution in MeOH (100:0 to 92:8) to give the title compound as a yellow oil (2.0 g, 37%). 1 H NMR (400 MHz; CDCI3, d): 8.47 (s, 1 H), 8.36 (d, 1 H), 7.45 (d, 1 H), 5.05-5.08 (m, 1 H), 2.22-2.32 (m, 2H), 3.11-3.16 (m, 1 H), 2.94-3.01 9m, 1 H), 2.16-2.25 (m, 1 H), 2.01-2.08 ( , 1 H)
INT F: tert-Butyl N-[(6-chloropyrimidin-4-yl)amino]carbamate -
Diisopropylethylamine (6.49 g, 50.3 mmol) was added to a solution of 4,6- dichloropyrimidine (7.50 g, 50.3 mmol) in THF (100 ml_) followed by portionwise addition of tert- butyl N-aminocarbamate (6.65 g, 50.3 mmol). The reaction mixture was stirred at RT for 28 h, then at 45 °C for 16 h. Further dichloropyrimidine (1.50 g) was added and the reaction mixture was stirred at reflux for 24 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc:cHexane (1 : 1 ; 100 ml_) and washed with citric acid (10 wt% aqueous solution, 100 ml_) and brine (50 ml_), dried (Na2S04), filtered and concentrated in vacuo. The gelatinous solid was triturated with DCM and the solid collected by filtration. The mother liquor was then concentrated in vacuo and was purified by column chromatography eluting with cHexane:EtOAc (90: 10 to 40:60) to give the expected product which combined with the solid recovered from the filtration gave the title compound as a yellow solid (12.08 g, 98%). LCMS (LCMS method 1): Rt = 1.09 min; [MH]+ = 145.0/147.0
INT G: tert-Butyl N-[[6-[(3S)-3-[(4-cyano-3-pyridyl)oxy]pyrrolidin-1-yl]pyrimidin-4- yl]amino]carbamate -
A solution of tert- butyl N-[(6-chloropyrimidin-4-yl)amino]carbamate (1.70 g, 6.86 mmol) , 3-[(3S)-pyrrolidin-3-yl]oxypyridine-4-carbonitrile (1.20 g, 6.24 mmol) and DIPEA (1.60 mg, 12.5 mmol) in 1-methyl-2-pyrrolidinone (2.0 ml_) were stirred under argon at 110 °C for 2 h. The excess of diisopropylethylamine was removed in vacuo and the residue loaded onto a SCX-2 (20 g), washed first with methanol then eluted with 2 M NH3 in MeOH. The ammonia fractions were concentrated in vacuo then purified by column chromatography eluting with DCM: 2 M NH3 in MeOH (100:0 to 90:10) to give the title compound as a pink foam (1.99 g, 80%). LCMS (LCMS method 1): Rt = 0.91 min; [MH]+ = 398.3
INT H: 3-[(3S)-1-(6-Hydrazinopyrimidin-4-yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile dihydrochloride -
4 M HCI in dioxane (9.44 mL, 37.7 mmol) was added at 0°C to a solution of tert- butyl N- [[6-[(3S)-3-[(4-cyano-3-pyridyl)oxy]pyrrolidin-1-yl]pyrimidin-4-yl]amino]carbamate (500 mg, 1.26 mmol) in MeOH (4.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo to give the title compound as a white solid (450 mg, 87%). LCMS (LCMS method 1): Rt = 0.67 min; [MH]+ = 298.2 INT I: 3-[(3S)-1-(6-Hydrazinopyrimidin-4-yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile - The solid was dissolved in MeOH (2.0 mL) and DMSO (few drops), then loaded onto an SCX-2 cartridge (5g), eluting first with MeOH then with 2 M NH3 in MeOH to give the title compound as a white solid (353 mg, 97%). LCMS (LCMS method 1): Rt = 0.63min; [MH]+ = 298.1
3-[(3S)-1-[6-(5-hydroxy-3-methyl-pyrazol-1-yl)pyrimidin-4-yl]pyrrolidin-3-yl]oxypyridine-4- carbonitrile - AcOH (92.7 pL, 1.62 mmol) was added to a solution of ethyl 3-oxobutanoate (56.8 GL, 0.45 mmol), 3-[(3S)-1-(6-hydrazinopyrimidin-4-yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile dihydrochloride / INT H (150 mg, 0.41 mmol) and DI PEA (110 pL, 0.81 mmol) in 1-butanol (500 pL). The reaction mixture was stirred at 100 °C for 3 h, and then concentrated in vacuo , diluted with DCM and the organic layer washed with water using a phase separator. The organic layer was concentrated in vacuo. The crude was then purified using MDAP to give the title compound as a red solid (13 mg, 9%).
LCMS (QC LCMS method 1): Rt = 3.07 min; [MH]+ = 364.1 ; 98.3% purity
1 H NMR (400 MHz; DMSO-cfe, d): 8.84 (s, 1 H), 8.46 (d, 1 H), 8.42(d, 1 H), 7.77 (dd, 1 H), 7.08 (bs, 1 H), 5.59 (bs, 1 H), 5.24 (bs, 1 H), 3.95 (dd, 1 H), 3.81 (bs, 2H), 3.68 (dq, 1 H), 2.43-2.50 (m, 1 H), 2.35-2.40 (m, 1 H), 2.19 (s, 3H)
Compound 3: 3-[(3S)-1-[6-(5-hydroxy-3-phenyl-pyrazol- 1-yl)pyrimidin-4-yl]pyrrolidin-3- yl]oxypyridine-4-carbonitrile
Figure imgf000093_0001
AcOH (0.02 mL, 0.270 mmol) was added to a solution of 3-[(3S)-1-(6-hydrazinopyrimidin- 4-yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile///\/7 / (40 mg, 0.130 mmol) and ethyl 3-oxo-3- phenyl-propanoate (28.4 mg, 0.15 mmol) in EtOH (0.50 mL) and DMSO (0.10 mL). The reaction mixture was stirred at 80 °C for 18 h then at 100 °C for 5 h before concentrating in vacuo. The oily residue was diluted with DCM and the organic layer washed with water using a phase separator. The organic layer was concentrated in vacuo then purified using MDAP followed by subsequent column chromatography eluting with DCM: 2 M NH3 in MeOH (100:0 to 90: 10, 20 CV) to give the title compound as a colourless solid (9.0 mg, 15%).
LCMS (QC LCMS method 1): Rt = 4.75 min; [MH]+ = 426.2; 98.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 8.86 (s, 1 H), 8.50 (d, 1 H), 8.47 (dd, 1 H), 7.90-7.93 (m, 2H), 7.78 (dd, 1 H), 7.41-7.51 (m, 3H), 6.92 (bs, 1 H), 6.08 (bs, 1 H), 5.61 (bs, 1 H), 3.99- 4.03 (m, 1 H), 3.87-3.94 (2H), 3.72-3.79 (m, 1 H), 2.46-2.52 (m, 1 H), 2.37-2.43 (m, 1 H) Compound 2: 3-[(3S)-1-[6-[5-hydroxy-3-(trifluoromethyl)pyrazol-1-yl]pyrimidin-4- yl]pyrrolidin-3-yl]oxypyridine-4-carbonitrile
Figure imgf000094_0001
AcOH (0.02 mL, 0.27 mmol) was added to a solution of 3-[(3S)-1-(6-hydrazinopyrimidin-4- yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile///\/7 / (40 mg, 0.13 mmol) and ethyl 4,4,4- trifluoro-3-oxo-butanoate (27.2 mg, 0.15 mmol) in EtOH (0.50 mL) and DMSO (0.10 mL). The reaction mixture was stirred at 80 °C for 18 h then at 90 °C for 2 h and finally at 100 °C for 7 h. The reaction mixture was concentrated in vacuo and the oily residue was diluted with DCM and the organic layer washed with water using a phase separator. The organic layer was concentrated in vacuo then purified using MDAP to give the title compound as a colourless solid (8.0 mg, 14%).
LCMS (QC LCMS method 1): Rt = 4.68 min; [MH]+ = 418.1 ;
1 H NMR (400 MHz; DMSO-cfe, d): 8.85(s, 1 H), 8.53 (s, 1 H), 8.47 (d, 1 H), 7.78 (dd, 1 H), 6.88 (bs, 1 H), 5.88 (bs, 1 H), 5.59-5.62 (m, 1 H), 4.00 (dd, 1 H), 3.86-3.93 (m, 2H), 3.70-3.77 (m, 1 H), 2.45-2.51 (m, 1 H), 2.36-2.43 (m, 1 H)
Compound 1: 3-[(3S)-1 -[ 6- ( 5-hydroxy-3-isopropyl-pyrazol- 1 -yl) pyrimidin-4-yl]pyrrolidin-3- yl]oxypyridine-4-carbonitrile
Figure imgf000095_0001
AcOH (0.02 ml_, 0.27 mmol) was added to a solution of 3-[(3S)-1-(6-hydrazinopyrimidin-4- yl)pyrrolidin-3-yl]oxypyridine-4-carbonitrile///\/T / (40 mg, 0.13 mmol) and ethyl 4-methyl-3- oxo-pentanoate (23 mg, 0.15 mmol) in EtOH (0.50 ml_) and dimethyl sulfoxide (0.10 ml_). The reaction mixture was stirred at 80°C for 18 h. The reaction mixture was then concentrated in vacuo , diluted with DCM and washed with water using a phase separator. The organic layer was concentrated in vacuo then purified using MDAP to give the title compound as a red solid (21 mg, 38%)
LCMS (QC LCMS method 1): Rt = 3.87 min; [MH]+ = 392.2; 96.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 8.85 (s, 1 H), 8.47 (d, 1 H), 8.44 (d, 1 H), 7.78 (dd, 1 H),
6.98 (bs, 1 H), 5.58-5.61 (m, 1 H), 5.37 (bs, 1 H), 3.96 (dd, 1 H), 3.79-3.88 (m, 2H), 3.65-3.73 (m, 1 H), 2.90 (sept, 1 H), 2.44-2.52 (m, 1 H), 2.36-2.41 (m, 1 H), 1.26 (d, 6H)
Compound 37: 4-(1-(6-(dimethylamino)pyrimidin-4-yl)-5-hydroxy-1H-pyrazol-3- yl)benzonitrile (
Figure imgf000095_0002
6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (150 mg, 0.98 mmol) was added to a solution of ethyl 3-(4-cyanophenyl)-3-oxo-propanoate (276 mg, 1.27 mmol) in iPrOH (2.0 ml_). The reaction mixture was stirred at 83°C for 1 h. The precipitate formed during the reaction was collected by filtration then purified by column chromatography eluting with DCM/NH3 2 M in MeOH (100:0 to 90: 10) to give the title compound as a yellow solid (52 mg, 17%).
LCMS (QC Acidic method): Rt = 4.67 min; [MH]+ = 307.2; 99.7% purity
1 H NMR (400 MHz; DMSO-cfe, d): 8.5 (s, 1 H), 8.1 (d, 2H), 7.9 (d, 2H), 6.9 (s, 1 H), 6.3 (s, 1 H), 3.2 (s, 6H) Compound 17: 2-(6-Dimethylamino-pyrimidin-4-yl)-2H-pyrazol-3-ol
Figure imgf000096_0001
6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.40 g, 2.61 mmol) and methyl -3- methoxyprop-2-enoate (606 mg, 5.22 mmol) in MeOH (4 ml_) was heated to 130°C in the microwave for 1 h. Further methyl-3-methoxyprop-2-enoate (303 mg, 2.61 mmol) was added and reaction was heated at 130°C for a further 1 h. The reaction mixture was evaporated and purified by column chromatography eluting with DCM/NH3 2 M in MeOH (100:0 to 95:5). The recovered starting hydrazine, the uncyclised intermediate and methyl -3-methoxyprop-2-enoate (1.0 ml_) in MeOH (5.0 ml_) were heated in a microwave at 130°C for 2 h. The crude was evaporated to dryness and purified by column chromatography eluting with DCM/NH3 2 M in MeOH (100:0 to 97:3). The product from both columns was slurried in MeOH (2.0 ml_) and filtered to give after drying the title compound as a white solid (62 mg, 11%).
LCMS (QC Acidic method): Rt = 2.59 min; [MH]+ = 206.0; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 12.8 (1 H, bs), 8.4 (1 H, d), 7.6 (1 H, bs), 7.0 (1 H, bs), 5.5 (1 H, bs) and 3.1 (6H, s)
Compound 18: 2-(6-Dimethylamino-pyrimidin-4-yl)-4-methyl-2H-pyrazol-3-ol
Figure imgf000096_0002
6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.10 g, 0.650 mmol) and ethyl 2-methyl-3- oxo-propanoate (102 mg, 0.780 mmol) in iPrOH (1.0 ml_) was heated to 120°C in the microwave for 3 h. The reaction was evaporated to 200 mg yellow gum, and purified by acidic MDAP to give the title material as an off white solid (68 mg, 47%).
LCMS (QC Acidic method): Rt = 2.87 min; [MH]+ = 220.2; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 12.2 (1 H, bs), 8.4 (1 H, d), 7.5 (1 H, s), 7.2 (1 H, bs), 3.1 (6H, s) and 1.8 (3H, s) Compound 87: 2-(6-Dimethylamino-pyrimidin-4-yl)-4,5-dimethyl-2H-pyrazol-3-ol
Figure imgf000097_0001
6-Hydrazino-N,N-dimethyl-pyrimidin-4-amine (0.10 g, 0.650 mmol) and ethyl 2-methyl-3- oxo-butanoate (122 mg, 0.850 mmol) in iPrOH (2.0 ml_) was heated to reflux under argon for 2.5 h. The mixture was evaporated and purified by column chromatography eluting with DCM/MeOH (100:0 to 95:5), to give a sharp first peak and a larger broad second peak. The fractions of the second peak containing uncyclised intermediate were combined and evaporated. The residue was dissolved in iPrOH (2.0 ml_) and refluxed overnight. The mixture was evaporated and purified by column chromatography eluting with DCM/MeOH (100:0 to 95:5). The fractions of the first peak from both columns were combined and evaporated to a white solid, sonicated and triturated with cHexane and the solid filtered off. After drying in vacuo the title material is obtained as a white solid (68 mg, 44%). LCMS (QC Acidic method): Rt = 2.81 min; [MH]+ = 234.2; >99.5% purity
1 H NMR (400 MHz; DMSO-cfe, d): 11.5 (1 H, bs), 8.4 (1 H, d), 7.35 (1 H, bs), 3.1 (6H, s), 2.1 (3H, s) and 1.7 (3H, s)
Other compounds described in Table 1 were prepared by analogy with the above- mentioned synthetic methods.
Example compounds (continued)
In accordance with the present invention, the compounds described in the Table 2 (below) were prepared. For the avoidance of doubt, compounds are numbered 1-96 and 100 onwards. Table 2:
Figure imgf000097_0002
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Preparation of compounds (continued) The compounds as described in Table 1 herein above were prepared and characterized using procedures as known to those skilled in the art. For example, the compounds identified below were prepared using the procedures as described.
Compound 221: (6-benzyl-2-[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4-yl]-5, 1- dihydro-4H-pyrazolo[3, 4-c]pyridin-3-ol dihydrochloride)
Figure imgf000150_0001
Step 1 : Common Intermediate 225-A (tert-butyl N-[(6-fluoropyrimidin-4- yl)amino]carbamate)
Figure imgf000150_0002
To an ice-cooled stirred solution of 4,6-difluoropyrimidine (44.99 g, 0.3876 mol) and Hunig's base (74.26 ml_, 0.4264 mol) in anhydrous THF (250 ml_) was added dropwise a solution of te/f-butyloxycarbonyl-NHNFh (51.227 g, 0.3876 mol) in anhydrous THF (200 ml_) over a period of 2 h. The reaction mixture was allowed to warm to room temperature, and heated to reflux for 8 h. The volatile compounds were removed in vacuo (P = 25 mbar, t = 60°C). The yellow oily residue was treated with water (300 ml_) and allowed to stand for 36 h at rt. The precipitate was filtered and washed with water (5 x 300 ml_) affording tert-butyl A/-[(6-fluoropyrimidin-4-yl)amino]carbamate as colourless solid m = 67.58 g.
Step 2: tert-butyl N-[[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4- yl]amino]carbamate
Figure imgf000151_0001
To a stirred solution of tert- butyl N-[(6-fluoropyrimidin-4-yl)amino]carbamate (0.305 g, 1.323 mmol) in anhydrous acetonitrile (5 ml_) were successively added 5- oxabicyclo[4.2.0]octan-8-amine hydrochloride (0.217 g, 1.323 mmol) and sodium carbonate (0.222 g, 2.646 mmol). The mixture was heated 70 °C for 16 h. Gas evolution was observed for 5 h. The reaction mixture was allowed to warm to room temperature. The precipitate (mixture of sodium fluoride and sodium chloride) was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by HPLC (gradient mixture of CH3CN/water (20-55%) was used as eluent) affording tert- butyl L/-[[6-(5- oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4-yl]amino]carbamate as colourless solid m = 0.097 g
Step 3: 6-hydrazino-/\/-(5-oxabicyclo[4.2.0]octan-8-yl)pyrimidin-4-amine dihydrochloride
Figure imgf000151_0002
Tert- butyl A/-[[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4-yl]amino]carbamate
(0.097 g, 0.275 mmol) was dissolved in 1 ,4-dioxane/HCI (2 ml_). The mixture was allowed to stand at rt for 20 h. The volatile compounds were removed in vacuo (P = 0.01 mbar, t = 20°C) affording 6-hydrazino-/\/-(5-oxabicyclo[4.2.0]octan-8-yl)pyrimidin-4-amine dihydrochloride as colourless solid m = 0.080 g
Step 4: Compound 225 (6-benzyl-2-[6-(5-oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4- yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-ol dihydrochloride)
Figure imgf000152_0001
A vial was charged with ethyl 1-benzyl-3-oxo-piperidine-4-carboxylate hydrochloride (0.73 g, 0.247 mmol), anhydrous sodium acetate (0.061 g, 0.740 mmol), 6-hydrazino-N-(5- oxabicyclo[4.2.0]octan-8-yl)pyrimidin-4-amine dihydrochloride (0.080 g, 0.247 mmol) and 1-butanol (1 ml), purged with argon and sealed. Then, the mixture was stirred and heated 110°C for 12 h. Sodium chloride was filtered off and the filtrate was concentrated in vacuo (P = 0.01 mbar, t = 20°C). The crude product was purified by HPLC (gradient mixture of CH3CN / 0.1% hydrochloric acid (0-50%) was used as eluent) affording 6-benzyl-2-[6-(5- oxabicyclo[4.2.0]octan-8-ylamino)pyrimidin-4-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3- ol dihydrochloride as brown solid m = 0.018 g.
Compound 224: (5-(2,4-dimethylthiazol-5-yl)-2-[6-(3-oxa-9-azaspiro[5.5]undecan-9- yl)pyrimidin-4-yl]pyrazol-3-ol)
Figure imgf000152_0002
Preparation of hydrazine derivative [6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4- yl]hydrazine dihydrochloride in two steps
Figure imgf000153_0001
Then, [6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4-yl]hydrazine dihydrochloride was prepared in two steps as described in the synthesis of compound 225 from the common intermediate 225-A using commercially available 3-oxa-9-azaspiro[5.5]undecane (CAS 311-21-7)
Figure imgf000153_0002
Step 3: Common intermediate 228-A (ethyl 3-(2,4-dimethylthiazol-5-yl)-3-oxo-propanoate)
Figure imgf000153_0003
Tetrahydrofuran (500 ml_) and potassium t-butoxide 57.8g; 0.52 mol) were added to a reactor and cooled to -5°C. 1-(2,4-dimethylthiazol-5-yl)ethanone (40g, 258 mmol) and diethyl carbonate (30.4g, 258mmol) in 25 ml_ of tetrahydrofuran was dropwise added to the reactor for 30 minutes and stirred at a temperature of 20 to 25 C overnight. The organic layer was concentrated to a volume of 100 ml_ and this was poured into 500 ml_ of water and AcOH (2.5 equiv) was added thereto. The mixture was finally extracted with 2x200 ml of EtOAc. The resultant extract was dried and evaporated yielding the title compound.
Step 4: 5-(2,4-dimethylthiazol-5-yl)-2-[6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4- yl]pyrazol-3-ol
Figure imgf000154_0001
Ethyl 3-(2,4-dimethylthiazol-5-yl)-3-oxo-propanoate 150 mg, 0.66mmol), acetoxypotassium (129.5mg, 1.32 mmol), and [6-(3-oxa-9-azaspiro[5.5]undecan-9- yl)pyrimidin-4-yl]hydrazine dihydrochloride (221.9, 0.66 mmol) were mixed and heated in butanol-1 4 ml_) at 120°C for 12 h. Thereafter the mixture was evaporated and the residue was purified by HPLC (gradient mixture of MeOH/water was used as eluent) to yield 52mg title compound as a yellow solid.
Compound 287: 2-[6-(dimethylamino)-2-(hydroxymethyl)pyrimidin-4-yl]-5-(2, 4- dimethylthiazol-5-yl)-4-methyl-pyrazol-3-ol
Figure imgf000154_0002
Preparation of common intermediate 292-A ethyl 3-(2,4-dimethylthiazol-5-yl)-2-methyl-3- oxo-propanoate
Figure imgf000155_0001
Step 1 : ethyl 3-(2,4-dimethylthiazol-5-yl)-3-hydroxy-2-methyl-propanoate
Figure imgf000155_0002
To a stirred suspension of zinc powder 16.7g, 255 mmol) in dry THF (150 ml) under argon atmosphere, 1 ,2-dibromoethane (2.4g, 12.7 mmol) and TMS-CI (1.4g, 12.7 mmol) were added. The mixture was stirred for 15 min. A slight exotherm (ca. 2-3°C) was observed. Ethyl 2-bromopropanoate (17.3g, 95 mmol) was added dropwise, keeping the temperature between 40-50°C (significant exotherm was observed during the addition). The mixture was then slowly cooled to room temperature. A solution of 2,4-dimethylthiazole-5- carbaldehyde (18g, 127 mmol) and ethyl 2-bromopropanoate ((17.3g, 95 mmol) in dry THF (50 ml) was added dropwise, keeping the temperature again between 40-50°C. RM was stirred at room temperature overnight, then diluted with cone solution of citric acid in water (200 ml) and extracted with ethyl acetate (150 ml). Organic phase was washed with cone solution of citric acid (150 ml), cone solution of sodium bicarbonate (200 ml), brine, then dried (Na2S04) and evaporated in vacuo. The product was purified by flash-column chromatography on silica gel using EtOAc/Hexane=1/1 mixture as eluent. Yield 13g
Step 2: ethyl 3-(2,4-dimethylthiazol-5-yl)-2-methyl-3-oxo-propanoate was obtained
Figure imgf000156_0001
To an ice-cooled DCM solution of ethyl 3-(2,4-dimethylthiazol-5-yl)-3-hydroxy-2-methyl- propanoate (13g, 53 mmol) Dess-Martin periodinane (34g, 80 mmol) was added in portions. RM was stirred at room temperature for 1.5-2h. The following reaction was monitored by TLC (mixture EtOAc/Hex=1 : 1 was used as eluent). RM was treated with a 1 :1 mixture of saturated NaHCCh and Na2S2C>3 solutions (400 ml_) and stirred for 30 min. Organic phase was separated, washed additionally twice with a 1 : 1 mixture of saturated NaHCOs and Na2S203 solutions (2*300 ml_), dried (Na2S04) and evaporated to dryness. 12.8g of pure ethyl 3-(2,4-dimethylthiazol-5-yl)-2-methyl-3-oxo-propanoate was obtained.
Preparation of common intermediate 292-B [4-(dimethylamino)-6-hydrazino-pyrimidin-2- yl]methanol
Step 1 : (4,6-dichloropyrimidin-2-yl)methyl acetate
Figure imgf000156_0002
Sodium acetate 4.15g, 50.6 mmol) was added at r.t. to a stirred solution of 4,6-dichloro-2- (chloromethyl)pyrimidine 5g, 25 mmol) in dry DMF (50 ml_). Then reaction mixture was stirred at r.t. for 12 hand then diluted with water and chloroform, organic layer was washed with water twice and evaporated to give crude tittle compound. The crude product was purified by column chromatography (eluent - EtOAc : Hex - 1 :4) to give tittle compound as colorless oil. Yield 4.2g
Step 2: 6-chloro-2-(methoxymethyl)-N,N-dimethyl-pyrimidin-4-amine
Figure imgf000157_0001
To a solution of (4,6-dicbioropyrimidin-2-y!)methyi acetate 5g, 22.6 mmol) in methyl alcohol (20 ml_)were added 40% aqueous MbzNH 1 1 6g, 257 mmol) at r.t. The mixture was stirred at ambient temperature for 48 hours and after completion of reaction the product was extracted twice with MTBE and evaporated under reduced pressure to give crude product. The crude product was purified by column chromatography (eluent EtOAc : Hex - 1 :1) to give the tittle compound as a white solid. Yield 2.1 g
Step 3: Common intermediate 292-B ([4-(dimethylamino)-6-hydrazino-pyrimidin-2- yl]methanol)
Figure imgf000157_0002
6-chloro-2-(methoxymethyl)-N,N-dimethyl-pyrimidin-4-amine (5.9g, 31.4 mmol) was dissolved in methyl alcohol 50 ml_) and hydrazine hydrate 15.7g, 314 mmol) was added at r.t.. Then reaction mixture was refluxed for 24 h. After completion of reaction (confirmed by TLC, eluent - EtOAc : Hex - 1 : 1) solution was cooled to r.t. and product was crystallized as a white crystals. Yield 4.9g
Compound 287
Figure imgf000158_0001
To a solution of [4-(dimethylamino)-6-hydrazino-pyrimidin-2-yl]methanol (180mg, 0.98 mmol) in 2-propanol (40 ml_) ethyl 3-(2,4-dimethylthiazol-5-yl)-2-methyl-3-oxo-propanoate (284, 5mg, 1.18 mmol) was added. The reaction mixture was stirred at 175C in autoclave for 48h, then cooled down to room temperature. The precipitate was filtered, washed twice with 2-propanol (2 times 10 ml_) and dried. The product was additionally recrystallized from 20 ml of 2-propanol. Yield 100mg Other compounds described in Table 2 were prepared by analogy with the above- mentioned synthetic methods.
General biological procedures Dissociation constant determination
The determination of the dissociation constant (Kd) of zinc to compound is performed using FluoZin-3 (ThermoFisher Scientific, F24194), which has a Kd, Ruozin-3:zn2+ = 15 nM. Testing buffer consists of PBS pH 7.4 with 200 nM ZnCh and 500 nM FluoZin-3. In a microtiter plate 98 pl_ testing buffer is mixed with 2 mI_ compound at various concentrations for an IC50 determination. Testing plates are incubated for 2 min before the plate is read at Ex=485 and Em=516 with a Fluoroskan Ascent Microplate Fluorometer, ThermoScientific. Kd is calculated using the following equation: Kd(compound:Zn2+) = IC50 / (1 + [Fluozin-3]
/ Kd , Fluozin-3:Zn2+ ) Fungal growth inhibition
The minimum inhibitory concentration (MIC) is here defined as the compound concentration that results in 50% growth reduction of a fungal isolate when exposed to an antifungal agent. For Candida spp. and other fermentative yeasts, MICs are determined according to the reference procedure of the Antifungal Susceptibility Testing Subcommittee, EUCAST E.DEF 7.1 (Anon, EUCAST definitive document EDef 7.1 : method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 14(4), 398-405 (2008); available at: http://www.ncbi.nlm.nih.gov/pubmed/18190574). For spore-forming moulds, MICs are determined according to the reference procedure of the Antifungal Susceptibility Testing Subcommittee, EUCAST E.DEF 9.1 (Arendrup, M.C. et ai, EUCAST DEFINITIVE DOCUMENT E . DEF 9 . 1 : Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. (July), .1-13 (2008)) for spore-forming moulds. The fungal inocula are prepared from the species Candida albicans SC5314; Candida krusei ATCC6258, Candida parapsilosis ATCC22019, Candida glabrata ATCC90030, Candida glabrata Bra03, Candida tropicalis E1 -7276125B, Aspergillus fumigatus ATCC46645, Aspergillus terreus At070, Aspergillus flavus ATCC15547, Fusarium solani DSMZ10696, Fusarium verticillioides MYA-3629 and Cryptococcus neoformans DSM11959. The fungal inoculum size is between 1x105 cfu/mL and 2.5x105 cfu/mL and the inoculum is prepared directly from subcultures of the various fungal strains grown on YPD or SD media at 35°C. . Fungus, compound and growth medium are incubated in microtiter plates without agitation at 35 ± 2°C 24hrs for yeast and 72hrs for moulds. The endpoint is spectrophotometric recordings at OD 490nm.
Hep G2 cell survival assay
To address potential off-target effects these compounds are evaluated in a cell survival XTT assay. This is a colorimetric assay that detects the cellular metabolic activity of the mammalian Hep G2 cell line after pre-incubation with a dilution series of NCE for either 24 or 72 hrs. Subsequent incubation of the exposed cells with the yellow tetrazolium salt XTT for 2-3 hrs allows enough time for metabolically active cells to reduce XTT to a highly colored dye. This conversion occurs only in viable cells so the amount of color produced is proportional to cell viability in the sample and endpoint is measured spectrophotometrically at OD450 nm for IC50 determination. Tamoxifen is used as a positive control compound and DMSO as negative control.
In vivo model - Fungal kidney burden
Balb/c mice are infected with 0.1 ml_ of inoculum of Candida albicans SC5314 by intravenous route on day 0. NCE are tested in 2 doses; low and high dose. Administration of NCE is initiated 24 hr prior (day -1) to infection (day 0) by intraperitoneal route, b.i.d. treatment for 4 days (day -1 to day 2). Inoculum: 1-5 x 105 CFU per animal. Control compound: Fluconazole. Sample collection and processing: 12 hours post last dose all treated and untreated animals are sacrificed by cervical dislocation and kidneys are collected in 3ml of sterile normal saline. The samples are homogenized, diluted serially and plated on SDA. The plates are incubated for 24-48 hrs at 35±2° C, fungal counts are enumerated and reported as log CFU/kidney. Endpoint: Mean log CFU of fungi in kidneys of treated animals compared to that of untreated animals.
Biological Example 1
The antifungal activity of each compound as described in Table 1 herein above was assessed using a combination of the above-mentioned general methods. Results for the Kd(compound:Zn2+) correlated with antifungal activity (wherein MIC is defined as ³50% growth reduction) are shown in Table 3 below.
Table 3:
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Biological Example 2
The anti-fungal activity of compound 4 was screened against a variety of fungal strains. The results are presented in Table 4 below.
Table 4:
Figure imgf000163_0002
Biological Example 3
The cell survival window, measured as 50% growth inhibition of C. albicans and 50% growth inhibition HepG2 cells, in the presence of compound 4 was found to be 40-fold
Biological Example 4
A significant reduction in the fungal kidney burden was obtained in a systemic candidiasis mouse model with compound 4 at 60 mg/kg; IP, BID (i.e. twice daily). The dosing was given as a clear solution (vehicle: 0.9% w/v NaCI + 20% v/v 0.1 N NaOH + q.s. water + q.s. 0.1 N HCI sol.; pH adjustment to 9.0). The results are presented in Figure 1 and summarized in Table 5 below (wherein in Figure 1 Compound 4 is referred to as PCO309989). Table 5:
Figure imgf000164_0001
*P<0.05
Biological Example 5
The antifungal activity of each compound as described in Table 2 herein above was assessed using a combination of the above-mentioned general methods. Results for the Kd(compound:Zn2+) correlated with antifungal activity (wherein MIC is defined as ³50% growth reduction) are shown in Table 7 below.
Table 1:
Figure imgf000164_0002
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
A list of the fungal strains that compounds 100 onwards were tested against is provided below.
Figure imgf000216_0002
Figure imgf000217_0001

Claims

Claims
Figure imgf000218_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, for use in the treatment or prevention of a fungal or bacterial infection wherein:
R1 and R2 each independently represent H or a substituent selected from the group consisting of
(a) Ar\
(b) Het\
(c) halo,
(d) oxy,
(e) -N02,
(f) -CN,
(9) -OR1a,
(h) -S(0)PR1 b,
(i) -S(0)qN(R1c)(R1d),
(j) -N(R1e)S(0)rR1f,
(k) -N(R1a)(R1 h),
(L) -C(0)0R1 i,
(m) -C(0)NR1jR1 k, and
(n) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A1 ; or R1 and R2 may, taken together, form a 5 to 7 membered heterocycloalkyl optionally substituted, where possible, by one or more Y1 ;
R3, R4 and R5 each independently represent H or a substituent selected from the group consisting of
(A) Ar2,
(B) Het2,
(C) halo,
(D) oxy,
(E) -N02,
(F) -CN,
(G) -OR2a,
(H) -S(0)pR2b,
(I) -S(0)qN(R2c)(R2d),
(J) -N(R2e)S(0)rR2f,
(K) -N(R29)(R2h),
(L) -C(0)0R2i,
(M) -C(0)NR2jR2k, and
(N) C1 -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A2; each of R1a to R1 k independently represent H, Ar3, Het3, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A3, or any pair of R1c and R1d, R1e and R1f, R19 and R1 h, and R1j and R1 k may, together with the atom(s) to which they are attached, form a 4- to -14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from A4; each of R2a to R2k independently represent H, Ar4, Het4, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more A5, or any pair of R2c and R2d, R2e and R2f, R29 and R2h, and R2j and R2k may, together with the atom(s) to which they are attached, form a 4- to -14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from
A6; each of A1 to A6 independently represent a substituent selected from the group consisting of
(i) Ar5,
(ii) Het5,
(iii) halo,
(iv) oxy,
(v) -N02,
(vi) -CN,
(vii) -OR3a,
(viii) -S(0)PR3b,
(ix) -S(0)qN(R3c)(R3d),
(x) -N(R3e)S(0)rR3f,
(xi) -N(R39)(R3h),
(xii) -C(0)0R3i, and
(xiii) -C(0)NR3jR3k; each of Ar1 to Ar5 independently represents a Ce-io carbocyclic aromatic group optionally substituted with one or more substituents selected from B1 ; each of Het1 to Het5 independently represents:
(a) a 5- to 14- membered heteroaryl group optionally substituted by one or more substituents selected from B2, or
(b) a 4- to 14- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from B3; each of B1 B2, B3 and Y1 independently represent a substituent group selected from the group consisting of
(I) Ar6,
(II) Het6,
(III) halo,
(IV) oxy,
(V) -N02,
(VI) -CN,
(VII) -OR4a, (VI I I ) -S(0)pR4b,
(IX) -S(0)qN(R4c)(R4d),
(X) -N(R4e)S(0)rR4f,
(XI) -N(R49)(R4h),
(XII) -C(0)0R4i,
(XIII) -C(0)NR4jR4k, and
(XIV) Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C1 ; each of R3a to R3k independently represent H, Ar7, Het7, Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C2, or any pair of R3c and R3d, R3e and R3f, R39 and R3h, and R3j and R3k may, together with the atom(s) to which they are attached, form a 4- to 7- membered heterocycloalkyl or heterocycloalkenyl group optionally containing one or more additional heteroatoms, comprising one ring, and optionally substituted by one or more substituents selected from and C3; each of R4a to R4k independently represent H, Ar8, Het8, Ci-e alkyl, C2-6 alkenyl, C^ alkynyl, C3-6 cycloalkyl or C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more C4, or any pair of R4c and R4d, R4e and R4f, R49 and R4h, and R4j and R4k may, together with the atom(s) to which they are attached, form a 4- to 7- membered heterocycloalkyl or heterocycloalkenyl group optionally substituted by one or more substituents selected from
C5; each of C1 to C5 independently represents a group selected from halo, oxy, -NO2, -CN, - OR5a, -N(R5b)(R5c), =NH, Het9, -C(0)0R5d, -C(0)NR5eR5f and phenyl, wherein the group is optionally substituted by one or more fluoro; each of Ar6 to Ar8 independently represents phenyl optionally substituted with one or more substituents selected from D1 ; each of Het6 to Het9 independently represents: (a) a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2, or
(b) a 4- to 6- membered heterocycloalkyl or heterocycloalkenyl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from
D3; each of D1 to D3 independently represents a group selected from halo, oxy, -NO2, -CN, - OR6a, -N(R6b)(R6c), -C(0)0R6d, -C(0)NR6eR6f, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl and phenyl, wherein the latter six groups are optionally substituted, where possible, by one or more fluoro; or wherein D1 represents Het10;
Het10 represents:
(a) a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from X5; each X5 individually represents a group selected from oxy or a Ci-e alkyl, wherein the Ci-e alkyl is optionally substituted by OH; each of R5a to R5f and R6a to R6f independently represents a group selected from Ci-e alkyl, H and phenyl, wherein the latter two groups are optionally substituted by one or more group selected from halo, -NH2 and -OH, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and C5-6 cycloalkenyl, wherein the latter five groups are optionally substituted, where possible, by one or more group selected from halo, oxy, -NH2 and -OH; and each p, q and r independently represents 0, 1 or 2.
2. The compound for use of Claim 1 , wherein R1 represents Ar1 , Het1 , Ci-e alkyl or C1 -6 cycloalkyl, wherein the latter two groups are optionally substituted by one or more A1.
3. The compound for use of Claim 2, wherein Ar1 group represents phenyl optionally substituted with one or more B1.
4. The compound for use of any one of Claims 2 to 3, wherein Het1 group represents:
(a) a 5- to 6- membered heteroaryl group optionally substituted with one or more substitutent selected from B2 (e.g. wherein B2 represents C1-3 alkyl, such as methyl or ethyl) or (b) a 5- to 6- membered heterocycloalkyl or heterocycloalkenyl group (e.g. a 5- to
6- membered heterocycloalkyl group) optionally substituted with one or more substitutent selected from B3.
5. The compound for use of any one of Claims 2 to 4, wherein the Ci-e cycloalkyl group is optionally substituted with one or more halo.
6. The compound for use of any one of Claims 2 to 5, wherein the Ci-e alkyl group is optionally substituted with one or more group substituent selected from Ar5, Het5, halo and -OR3a.
7. The compound for use of any one of Claims 1 to 6, wherein R2 represents H, halo, C1 -3 alkyl optionally substituted with one or more A1, or -N(R1a)R1 h.
8. The compound for use of any one of Claims 1 to 7, wherein R3 represents H or fluoro.
9. The compound for use of any one of Claims 1 to 8, wherein R5 represents H or fluoro.
10. The compound for use of any one of Claims 1 to 9, wherein the compound is a compound of formula II
Figure imgf000223_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein: R1 and R4 are as defined in any one or more of the preceding claims.
1 1. The compound for use of any one of Claims 1 to 10, wherein R4 represents H or a substituent selected from the group consisting of Het2, halo, -NO2, -OR2a, -S(0)pR2b, -S(0)qN(R2c)(R2d), -N(R2e)S(0)rR2f and -N(R29)(R2h).
12. The compound for use of any one of Claims 1 to 11 , wherein at each instance p, q and r each represent 2.
13. The compound for use of any one of Claims 1 to 12, wherein R4 represents -OR2a or -N(R29)(R2h).
14. The compound for use of Claim 13, wherein: each of R2a, R29 and R2h independently represent H or Ci-e alkyl optionally substituted by one or more A5; or, alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
15. The compound for use of Claim 14, wherein: each of R2a, R29 and R2h independently represent Ci-e alkyl optionally substituted by one or more A5, or alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
16. The compound for use of Claim 15, wherein R2a represents C1 alkyl optionally substituted by one more fluoro.
17. The compound for use of Claim 16, wherein:
R29 and R2h, together with the atom(s) to which they are attached, form a 5- membered heterocycloalkyl group optionally substituted by one or more substituents selected from A6; or R29 and R2h, together with the atom(s) to which they are attached, do not form a ring.
18. The compound for use of Claim 17, wherein the 5- membered heterocycloalkyl group formed by R29 and R2h is a pyrrolidine group.
19. The compound for use of any one of Claims 13 to 18, wherein A6 represents fluoro or -OR3a.
20. The compound for use of Claim 19, wherein R3a represents Het7.
21. The compound for use of Claim 20, wherein Het7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2.
22. The compound for use of Claim 15, wherein R29 and R2h both represent methyl.
23. The compound for use of Claim 1 , wherein R1 and R2 form a 5 to 7 membered heterocycloalkyl optionally substituted, where possible, by one or more Y1.
24. The compound for use of any one of Claim 23, wherein R3 represents H or fluoro.
25. The compound for use of any one of Claim 23 or 24, wherein R5 represents H or fluoro.
26. The compound for use of any one of Claims 23 to 25, wherein the compound is a compound of formula I la
Figure imgf000225_0001
(I la) or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R1 and R2 form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y1 ; and
R4 is as defined in Claim 1.
27. The compound for use of any one of Claims 23 to 26, wherein R4 represents H or a substituent selected from the group consisting of Het2, halo, -NO2, -OR2a, -S(0)pR2b, -S(0)qN(R2c)(R2d), -N(R2e)S(0)rR2f and -N(R29)(R2h).
28. The compound for use of any one of Claims 23 to 27, wherein at each instance p, q and r each represent 2.
29. The compound for use of any one of Claims 23 to 28, wherein R4 represents -OR2a or -N(R29)(R2h).
30. The compound for use of Claim 29, wherein: each of R2a, R29 and R2h independently represent H or Ci-e alkyl optionally substituted by one or more A5; or, alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered (e.g. 5-membered) heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
31. The compound for use of Claim 30, wherein: each of R2a, R29 and R2h independently represent Ci-e alkyl optionally substituted by one or more A5, or alternatively the pair of R29 and R2h, together with the atom(s) to which they are attached, form a 4- to 6- membered heterocycloalkyl group optionally substituted by one or more substituents selected from A6.
32. The compound for use of Claim 31 , wherein R2a represents C1 alkyl optionally substituted by one more fluoro.
33. The compound for use of Claim 32, wherein:
R29 and R2h, together with the atom(s) to which they are attached, form a 5- membered heterocycloalkyl group optionally substituted by one or more substituents selected from A6; or
R29 and R2h, together with the atom(s) to which they are attached, do not form a ring.
34. The compound for use of Claim 33, wherein the 5- membered heterocycloalkyl group formed by R29 and R2h is a pyrrolidine group.
35. The compound for use of any one of Claims 29 to 34, wherein A6 represents fluoro or -OR3a.
36. The compound for use of Claim 35, wherein R3a represents Het7.
37. The compound for use of Claim 36, wherein Het7 represents a 5- to 6- membered heteroaryl group containing one or more heteroatoms and optionally substituted by one or more substituents selected from D2.
38. The compound for use of Claim 30, wherein R29 and R2h both represent methyl.
39. The use of a compound as defined in any one of Claims 1 to 38, or a pharmaceutically acceptable salt and/or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a fungal and/or bacterial infection.
40. A method of treating or preventing a fungal and/or bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of Claims 1 to 38, or a pharmaceutically acceptable salt and/or prodrug thereof.
41. A method of killing and/or inhibiting or reducing growth of one or more fungal and/or bacterial cell, comprising applying to said fungal or bacterial cell an effective amount of a compound as claimed in any one of Claims 1 to 38, or a pharmaceutically acceptable salt and/or prodrug thereof.
42. The method of Claim 41 , wherein the method is performed ex vivo.
43. A method of treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising applying to the plant, plant material or plant propagation material or the locus thereof an effective amount of a compound as defined in any one of Claims 1 to 38, or a salt thereof.
44. The use of a compound as defined in any one of Claims 1 to 38, or a pharmaceutically acceptable salt or prodrug thereof, in killing and/or inhibiting or reducing growth of one or more fungal and/or bacterial cell.
45. The use of a compound as defined in any one of Claims 1 to 38, or a pharmaceutically acceptable salt or prodrug thereof, as an anti-fungal and/or anti-bacterial agent.
46. The use of Claim 44 or Claim 45, wherein the use is ex vivo.
47. A composition for use in treating or preventing a fungal infection in plants, plant material and/or plant propagation material comprising:
(a) a compound as defined in any one of Claims 1 to 38, or a salt thereof; and
(b) an agriculturally acceptable carrier or diluent.
48. The compound for use, composition for use, use or method of any one of Claims 1 to 47, wherein the infection or cell, as appropriate, is of a fungus selected from the group consisting of:
Acremonium spp. (e.g. A. recifei or A. alabamense), Acrophialophora spp. (e.g. A. fusispora or A. levis), Alternaria spp. (e.g. A. infectoria, A. alternata), Aphanoascus fulvescens, Apophysomyces spp. (A. elegans or A. variabilis), Arthroderma spp. (e.g. A. insingulare or A. uncinatum) Aspergillus spp. (e.g. A. clavatus, A. flavus, A. fumigatus, A. felis, A. nidulans, A. niger, A. terreus, A. lentulus or A. versicolor), Aureobasidium pullulans, Bipolaris spp. (e.g. B. australiensis, B. hawaiiensis orB. spicifera), Blastomyces spp. (e.g. B. dermatitidis), Blastoschizomyces (e.g. B. capitatus), Botrytis cinerea, Candida spp. (e.g. C. albicans, C. dubliniensis, C. famata, C. glabrata (Torulopsis glabrata), C. guillermondii, C. nivariensis, C. haemulonii, C. kefyr, C. krusei, C. lipolytica, C. lusitaniae, C. norvegensis, C. parapsilosis, C. pseudotropicalis, C. rugosa, C. stellatoidea, C. tropicalis, C. utilis or C. viswanathii), Cercospora spp., Cladosporium (e.g. C. bantiana, C. carrionii, C. cladosporioides, C. herbarum, C. oxysporum, C. sphaerospermum or C. devriesii), Cladophialophora spp. (e.g. C. bantiana), Clavispora lusitaniae, Coccidioides (e.g. C. immitis, C. posadasii), Cokeromyces recurvatus, Colletotrichum spp. (e.g. C. coccodes, C. acutatum, C. gloeosporioides), Conidiobolus spp. (e.g. C. coronatus, C. incongruus or C. lamprauges), Coniochaeta spp. (e.g. C. hoffmannii or C. mutabilis), Cryptococcus spp. (e.g. C. albidus, C. laurentii or C. neoformans (like var. neoformans or vargattii)), Cunninghamella spp. (e.g. C. berthollethiae or C. elegans), Curvicularia lunata, Epidermophyton floccosum, Exophiala spp. (e.g. E. dermatitidis, E. jeanselmei, E. oligosperma, E. phaeomuriformis E. spinifera orE. xenobiotica), Exserohilum spp. (e.g. E. rostratum, E. mcginnisii or E. longirostratum), Fonsecaea spp. (e.g. F. compacta, F. monophora, or F. pedrosi), Fusarium spp. (e.g. F. oxysporum, F. solani, F. verticillioides, F. chlamydosporum, F. dime rum, F. fujikuroi, or F. incarnatum), Geotrichum spp. (e.g. G. candiddum, G. capitatum or G. clavatum), Graphium basitruncatum, Helminthosporium spp., Histoplasma capsulatum, Hortaea werneckii, Kluyveromyces marxianus, Lasiodiplodia theobromae, Lichtheimia corymbifera (formerly Absidia corymbifera), Lodderomyces elongisporus, Lomentospora prolificans, Lophophyton spp. (e.g. L. cookie or L. gallinae), Macrophomina phaseolina (syn. Sclerotium bataticola; Rhizoctonia bataticola), Madurella spp. (e.g. M. griseum or M. mycetomatis), Magnaporte grisea (Ana morph: Pyricularia oryzae), Malassezia spp. (e.g. M. globosa or M. furfur), Microsphaeropsis arundinis, Microsporum spp. (e.g. M. audouinii, M. canis, M. ferrugineum, M. cookei, M. gallinae or M. vanbreuseghemii), Mortierella wolfii, Monilinia spp., Mucor (e.g. M. amphibiorum, M. circinelloides, M. indicus, M. irregularis or M. ramosissimus), Myrmecridium schulzeri Nannizzia spp. (e.g. N. fulva, N. gypsea, N. nana or N. persicolor), Neosartorya fischeri, Neoscytalidium dimidiatum, Onychocola canadensis, Paecilomyces spp. (e.g. P. marquandii, P. variotii or P. lilacinus), Paracoccidioides (e.g. P. brasiliensis), Penicillium (e.g. P. marneffei), Phaeoacremonium spp. (e.g. P. alvesii, P. amstelodamense, P. griseorubrum, P. minimum, P. rubrigenum, P. tardicrescens, or P. venezuelense) , Phialophora verrucosa, Phoma spp., Phytophtora spp., Pichia spp., Pithomyces chartarum, Pityrosporum ovale, Plasmopara viticola (syn. Peronospora viticola), Pneumocystis (e.g. P. carinii, P. jirovecii), Podosphaera spp., Prototheca spp. (e.g. P. wickerhamii or P. zopfii), Pseudallescheria spp. (e.g. P. boydii, Puccinia arachidis), Pyricularia spp., Pythium spp. (e.g. P. insidiosum, P. aphanidermatum and P. ultimum), Quambalaria spp. (e.g. Q. cyanescens, Q. pitereka, Q. eucalypti, Q. coyrecup or Q. simpsonii), Rhinocladiella spp. (e.g. R. atrovirens or R. mackenziei, Rhizoctonia solani, Rhizomucor spp. (e.g. R. miehei or R. pusillus), Rizopus spp. (e.g. R. micropsorus, R. oryzae, R. pusillus), Rhodotorula spp. (e.g. R. glutinis orR. mucilaginosa), Saccharomyces (e.g. S. cerevisiae), Saksenaea vasiformis, Scedosporium spp. (e.g. S. apiospermum, S. auraticum, S. boydii or S. prolificans), Schizophyllum commune, Sclerotium rolfsii, Scopulariopsis, Sepedonium spp., Septoria spp., Sporothrix schenckii, Syncephalastrum racemosum, Talaromyces marneffei, Torulaspora delbrueckii, Trichoderma spp., Trichophyton spp. (e.g. T. concentricum, T. equinum, T. eritrephon, T. interdigitale, T. mentagrophytes, T. quinckeanum, T. rubrum, T. schoenleinii, T. soudanense, T. tonsurans, T. verrucosum or T. violaceum), Trichosporon spp. (e.g. T. asahii, T. asteroids, T. beigelii, T. cuaneum, T. inkin, T. ovoides, T. roseum or T. terrestre), Uncinula necator (syn. Erysiphe necator), Venturia spp., Veronaea botryose, Verruconis spp. (e.g. V. gallopava), and Wickerhamomyces anomalus.
49. A compound of formula III
Figure imgf000230_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein:
R1, R29 and R2h are as defined in any one of Claims 1 to 22; and wherein the compound of formula III is not a compound selected from the list consisting of:
1 ,2-dihydro-5-methyl-2-[6-(methylamino)-4-pyrimidinyl]-3H-pyrazol-3-one;
N-[3-(1 ,1-dimethylethyl)-1-[6-[3-(1 ,1-dimethylethyl)-5-hydroxy-1 H-pyrazol-1-yl]-4- pyrimidinyl]-1 H-pyrazol-5-yl]acetamide; and
1-[6-[5-amino-3-(1 ,1-dimethylethyl)-1 H-pyrazol-1-yl]-4-pyrimidinyl]-3-(1 ,1-dimethylethyl)- 1 H-pyrazol-5-ol.
50. A compound of formula Ilia
Figure imgf000231_0001
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein: R1 and R2, taken together, form a 5 to 7 membered heterocycloalkyl, optionally substituted by one or more Y1;
R¾ anc| yi are as defjnec| jn any one of Claims 1 to 38.
51. A compound of formula III as claimed in Claim 49 or of formula Ilia as claimed in Claim 50, or a pharmaceutically acceptable salt thereof, for use in medicine.
52. A pharmaceutical formulation comprising a compound of formula III as claimed in Claim 49 or of formula Ilia as claimed in Claim 50, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carrier or excipient.
53. A process for the preparation of a compound of formula III as claimed in Claim 49, or a pharmaceutically acceptable salt thereof, comprising:
(i) reaction of a compound of formula IV
Figure imgf000232_0001
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as defined in Claim 49, with a compound of formula V
Figure imgf000232_0002
or a suitable salt and/or protected derivative thereof, wherein R1 is as as defined in Claim 49 and LG1 represents a suitable leaving group, under conditions known to those skilled in the art;
(ii) reaction of a compound of formula VI
Figure imgf000232_0003
or a suitable salt and/or protected derivative thereof, wherein R1 is as defined in Claim 49 and LG2 represents a suitable leaving group, with a compound of formula VII
Figure imgf000232_0004
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as as defined in Claim 49, under conditions known to those skilled in the art; (iii) for compounds of formula III where R1 represents Ar1 or Het1 wherein Het1 represents heteroaryl, reaction of a compound of formula VIII
Figure imgf000233_0001
or a suitable salt and/or protected derivative thereof, wherein R29 and R2h are as defined in Claim 49 and LG3 represents a suitable leaving group, with a compound of formula IX
Figure imgf000233_0002
or a suitable salt and/or protected derivative thereof, wherein R1 is as as defined in Claim 49 and LG4 represents a suitable leaving group, under conditions known to those skilled in the art;
(iv) for compounds of formula III wherein any substituent represents -OH, reaction of a compound of formula III wherein the corresponding substituent represents -ORzc wherein Rzc represents C1-3 alkyl under conditions known to those skilled in the art; (v) for compounds of formula III wherein any substituent represents a -C(0)0H group, hydrolysis of a compound of formula III wherein the corresponding substituent represents a -C(0)0Rzd group wherein Rzd represents Ci-e alkyl, optionally substituted by one or more fluoro, or an aryl group, optionally substituted by one or more fluoro, under conditions known to those skilled in the art;
(vi) for compounds of formula III wherein any substituent represents a group selected from -C(0)0R1 i to -C(0)0R4i, reaction of a compound of formula III wherein the corresponding substituent represents -C(0)0H with a compound of formula X
Figure imgf000233_0003
wherein Rze represents the required R1 i to R4i group, under conditions known to those skilled in the art; or
(vii) for compounds of formula III that contain only saturated alkyl groups, reduction of a corresponding compound of formula III that contains an unsaturation, such as a double or triple bond, under conditions known to those skilled in the art.
54. A compound, formulation, compound for use, use, method or process substantially as described herein, with reference to the examples.
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